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CN113214230B - 2-substituted pyrazol amino-4-substituted amino-5-pyrimidine formamide compound, composition and application thereof - Google Patents

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

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CN113214230B
CN113214230B CN202110684506.9A CN202110684506A CN113214230B CN 113214230 B CN113214230 B CN 113214230B CN 202110684506 A CN202110684506 A CN 202110684506A CN 113214230 B CN113214230 B CN 113214230B
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amino
pyrazol
carboxamide
pyrimidine
methyl
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CN113214230A (en
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张强
刘彦生
李兴福
胡晨明
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Beijing Scitech MQ Pharmaceuticals Ltd
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    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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Abstract

The invention relates to a novel class of compounds, compositions and uses thereof as JAK inhibitors. Specifically, the invention provides a compound (shown as a formula (1)) with strong JAK inhibitory activity, or a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a metabolite, an isotope derivative and a solvate thereof, and a pharmaceutical composition containing the compound. The invention also discloses the use of a compound or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of an autoimmune disease or cancer.

Description

2-substituted pyrazol amino-4-substituted amino-5-pyrimidine formamide compound, composition and application thereof
The application is a divisional application, the application number of the original application is 201811099717.0, the application date is 09/20/2018, and the invention name is '2-substituted pyrazol amino-4-substituted amino-5-pyrimidine carboxamide compounds, compositions 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 is involved in processes such as cell proliferation, differentiation, apoptosis, angiogenesis, immunoregulation and the like. JAK kinases are key kinases in the JAK-STAT signaling pathway, which was found to be two decades later, the first JAK kinase inhibitor (tofacitinib) was only approved for the treatment of rheumatoid arthritis in 2012 [ Norman p, selective JAK inhibitors in a course for rhematoid arthritis, expert Opin Investig Drugs,2014,23, 1067-1077].
In a mammal, three members in JAK kinase family, namely JAK1, JAK2, JAK3 and TYK2, consist 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 a 'pseudo' kinase region, the pseudo kinase domain is the 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 mutation 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 an SH2 domain (Src homology 2 domain) containing 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 as 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 a class of cytoplasmic proteins that bind to DNA in the regulatory region of target genes and are downstream substrates of JAKs. The STAT family comprises 7 members such as STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT 6. The interaction between JAKs and STATs plays an important role in Cytokine receptor signaling pathways [ O' Sullivan LA et al, cytokine receptor signaling through the JAK-Stat-Socs pathway in disease, mol Immunol,2007, 44. 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 cytokines in cells, such as Interleukins (ILs), interferons (IFNs), erythropoietin (EPO), granulocyte and Macrophage Colony Stimulating Factor (GMCSF), somatotropin (GH), prolactin (PRL), thrombopoietin (TPO), platelet derived factor (PDGF), and Epidermal Growth Factor (EGF), among others, 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,2008,223 132-142].
JAK1 and JAK2 are expressed in each tissue cell of the human body, and JAK3 is mainly expressed in each hematopoietic tissue cell, and mainly exists in bone marrow cells, thymocytes, NK cells, activated B lymphocytes, and T lymphocytes. Deletions of JAK1 and JAK2, etc., cause lethal damage to humans, whereas JAK3 deletion avoids toxic adverse effects that damage other tissue cells [ Yamaoka k., et al, JAK3 connective tissue diagnostic-cell cytokine production and survival, blood,2005, 106. 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 (CP 690550) is a pyrrolopyrimidine selective JAK3 kinase inhibitor developed by Pfizer company, and has JAK3 inhibitory activity (IC) 50 =1 nmol/L) is JAK2 (IC) 50 20 times of =20 nmol/L) and JAK1 (IC) 50 =112 nmol/L). The research 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 hindered, and the synthesis of downstream inflammatory cytokines is inhibited. Tofacitinib shows good clinical curative effect in clinical research, in the clinical trial research of rheumatoid arthritis, a 5mg or 10mg Tofacitinib measuring group and an equivalent placebo group show obvious statistical difference in comparison, but Tofacitinib is found to be related to serious infection risk increase in the clinical trial research, and the long-term safety of Tofacitinib is required to be further researched.
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 histocyte 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, 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 with better drug effect 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 pyrazol-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 TYK 2) 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):
Figure BDA0003124123150000031
wherein,
R 1 is composed of
Figure BDA0003124123150000032
n 1 Is 0 to 1,n 2 Is 0 to 1,n 3 Is a mixture of a water-soluble polymer and a water-soluble polymer, wherein the water-soluble polymer is 0-5%,
L 1 is composed of
Figure BDA0003124123150000033
R 4 And/or R 5 Is H, C 1 -C 3 A linear alkyl group;
R 2 is composed of
Figure BDA0003124123150000034
n 4 Is 0 to 3,n 5 Is 0 to 1,n 6 Is in the range of 0 to 5 percent,
L 2 is composed of
Figure BDA0003124123150000035
R 7 And/or R 8 Is H, C 1 -C 3 A linear alkyl group.
A compound of formula (I) wherein R is a substituent 3 Comprises the following steps:
a) H, a hydroxyl group, a cyano group,
b)C 1 -C 5 a linear or branched alkyl group,
c)C 3 -C 8 cycloalkyl, more preferably C 3 -C 7 A cycloalkyl group,
d)C 1 -C 5 a straight-chain or branched alkoxy group, a linear or branched alkoxy group,
e)C 1 -C 5 a straight-chain or branched alkylthio group having a structure,
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 N is the heteroatom, H or C is attached to N 1 -C 4 Alkyl radical, C 1 -C 3 Acyl, 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 is
Figure BDA0003124123150000041
Wherein: j is a unit of 1 And/or J 2 And/or J 3 And/or J 4 C, N, S, O; r 9 Is C 1 -C 3 A linear or branched alkyl group,
or the structural formula of the substituted or unsubstituted five-membered aryl or heteroaryl is shown as
Figure BDA0003124123150000042
Or
Figure BDA0003124123150000043
Wherein:
J 1 、J 2 、J 3 、J 4 each independently is C, N, S, O,
R 20 、R 21 each independently is C 1 -C 3 A straight-chain 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 formula
Figure BDA0003124123150000044
Wherein:
Q 1 、Q 2 、Q 3 、Q 4 、Q 5 is N or C;
R 10 and/or R 11 And/or R 12 Comprises the following steps:
1)-F、-Cl、-Br、-CF 3 、-OCF 3 a cyano group;
2) -NR 'R ", R', R" being H, C 1 -C 3 Alkyl groups of (a);
3)C 1 -C 3 alkyl radical, C 2 -C 5 Alkynyl, C 3 -C 5 A cycloalkyl group;
4)SO 2 R 13 wherein R is 13 Is H, C 1 -C 3 An alkyl group;
5)
Figure BDA0003124123150000045
wherein q is 0 to 2, M is O, S, R 14 Is H, C 1 -C 5 Straight chain
Or a branched alkyl group;
6)
Figure BDA0003124123150000046
wherein R is 15 、R 16 Is a straight-chain alkyl group,
or the structural formula of the substituted or unsubstituted six-membered aryl or heteroaryl is shown as
Figure BDA0003124123150000047
Wherein:
Q 1 、Q 2 、Q 3 、Q 4 、Q 5 is N or C;
R 17 、R 18 each independently is:
a)-H,
b)-F、-Cl、-Br、-CF 3 、-OCF 3 a cyano group,
c) -NR 'R ", R', R" being H, C 1 -C 3 The alkyl group (b) of (a),
d)C 1 -C 3 alkyl radical, C 2 -C 5 Alkynyl, C 2 -C 5 Alkenyl radical, C 3 -C 5 A cycloalkyl group,
e)SO 2 R 13 wherein R is 13 Is H, C 1 -C 3 An alkyl group, a carboxyl group,
f)
Figure BDA0003124123150000051
wherein q is 0-2, M is O, S, R 14 Is H, C 1 -C 5 A linear or branched alkyl group,
g)
Figure BDA0003124123150000052
wherein R is 15 、R 16 Is C 1 -C 3 The linear alkyl group of (a),
h)-(CH 2 ) t -R 19 t is 1-2, R 19 Is C 3 -C 5 A cycloalkyl group;
i) A five-or six-membered ring containing 0-3 heteroatoms or a five-or six-membered ring containing 1-3 heteroatoms, preferably selected from:
Figure BDA0003124123150000053
the substituent R in the formula (I) 6 Comprises the following steps:
a) H and a hydroxyl group, wherein the hydroxyl group,
b) -NR 'R ", R' and R" being H, C 1 -C 3 The alkyl group of (a) is,
c)C 1 -C 5 a linear or branched alkyl group,
d)C 3 -C 8 a cycloalkyl group,
e)C 1 -C 5 a straight-chain or branched alkoxy group, or a linear or branched alkoxy group,
f)C 1 -C 5 a straight-chain or branched alkylthio group having a structure,
g) A heterocyclic group, preferably a five-or six-membered oxygen-and/or nitrogen-containing heterocyclic group, such as
Figure BDA0003124123150000054
The present invention provides a compound, or an isomer, solvate or pharmaceutically acceptable salt thereof, having the structural formula (I):
Figure BDA0003124123150000055
wherein,
R 1 is composed of
Figure BDA0003124123150000056
n 1 Is 0 to 2,n 2 Is 0 to 1,n 3 Is a mixture of a water-soluble polymer and a water-soluble polymer, wherein the water-soluble polymer is 0-5%,
L 1 is composed of
Figure BDA0003124123150000061
R 4 And/or R 5 Is H, C 1 -C 3 Linear alkyl;
R 2 is composed of
Figure BDA0003124123150000062
n 4 Is 0 to 3,n 5 Is 0 to 1,n 6 Is in the range of 0 to 5 percent,
L 2 is composed of
Figure BDA0003124123150000063
R 7 And/or R 8 Is H, C 1 -C 3 A linear alkyl group;
R 3 is R 22 Substituted C 1 -C 3 Alkoxy or R 22 Substituted C 1 -C 3 Alkylthio radical, R 22 Is hydroxy, C 1 -C 3 Alkoxy radical, C 1 -C 3 Alkylthio, -NR' R ", hydroxy-substituted C 1 -C 3 Alkoxy, amino substituted C 1 -C 3 Alkoxy, hydroxy-substituted C 1 -C 3 Alkylthio, amino substituted C 1 -C 3 Alkylthio, wherein R ', R' are H, C 1 -C 3 Alkyl groups of (a);
R 6 is a) H, a hydroxyl group,
b) -NR 'R ", R' and R" being H, C 1 -C 3 The alkyl group (b) of (a),
c)C 1 -C 5 straight chainOr a branched alkyl group,
d)C 3 -C 8 a cycloalkyl group,
e)C 1 -C 5 a straight-chain or branched alkoxy group, or a linear or branched alkoxy group,
f)C 1 -C 5 a straight or branched alkylthio group, or
g)
Figure BDA0003124123150000064
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:
Figure BDA0003124123150000071
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 1- (2-methoxyethyl) -1H-pyrazol-4-amine:
Figure BDA0003124123150000072
66%。 1 H NMR(400MHz,DMSO-d 6 )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) + .
Figure BDA0003124123150000073
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 2- [2- (methylthio) ethyl ] -1H-pyrazol-4-amine:
Figure BDA0003124123150000081
column chromatography (petroleum ether: ethyl acetate = 4) gave 180mg of a yellow oil in 54% yield. LCMS M/z =188.0 (M + H) + .
Figure BDA0003124123150000082
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)
Figure BDA0003124123150000083
Figure BDA0003124123150000084
Figure BDA0003124123150000091
Preparation of intermediate 23-cyclopropyl-1H-pyrazol-4-amine:
Figure BDA0003124123150000101
cyclopropyl boronic acid (320mg, 3.72mmol), copper acetate (326mg, 1.79mmol), pyridine (144mg, 1.82mmol) and sodium carbonate (432mg, 4.08mmol) were added, and the mixture was reacted at 70 ℃ under an argon atmosphere for 4 hours. The reaction solution was concentrated by column chromatography (petroleum ether: ethyl acetate =4 = 1) to obtain 110mg of a yellow oil in 41% yield. LCMS M/z =154.1 (M + H) + .
Figure BDA0003124123150000102
To a mixed solution of ethyl acetate (2 mL), raney nickel (15 mg) was added and the reaction was carried out under 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%. 1 H NMR(400MHz,DMSO-d 6 )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 24- (6-methoxyhexyl) -1H-pyrazol-4-amine:
Figure BDA0003124123150000103
hexane (864mg, 3.54mmol) was reacted at 80 ℃ for 3 hours. The reaction solution 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). LCMS M/z =276.0 (M + H) + .
Figure BDA0003124123150000104
The reaction mixture was quenched with saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered to dryness, and subjected to reverse phase column chromatography (petroleum ether: ethyl acetate = 5. LCMS M/z =228.1 (M + H) + .
Figure BDA0003124123150000105
Raney nickel (25 mg) was reacted under 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 25-methyl-1-pentylamine:
3-Methylpentanenitrile (400mg, 4.11mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) at 0 deg.C with argon
Figure BDA0003124123150000111
–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)
Figure BDA0003124123150000112
Preparation of intermediate 29 2- (methoxymethyl) phenyl ] methylamine:
step 1): preparation of 2- (methoxymethyl) benzonitrile:
Figure BDA0003124123150000113
=148.1(M+H) + .
step 2): preparation of [2- (methoxymethyl) phenyl ] methylamine:
Figure BDA0003124123150000114
the crude yield was 78%. 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 (5 mL) and argon was applied at 0 deg.C
Figure BDA0003124123150000121
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
Figure BDA0003124123150000122
The reaction solution was obtained in 263mg as a white solid with a yield of 77%. LCMS M/z =179.1 (M + H) + .
Examples
Example 1 preparation of 4-benzylamino-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:
step 1): preparation of 2-chloro-4- (benzylamino) pyrimidine-5-carboxamide:
Figure BDA0003124123150000123
(M+H) + .
step 2): preparation of 4-benzylamino-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:
Figure BDA0003124123150000124
(s,1H),7.42–7.36(m,5H),4.79(s,2H),3.79(s,3H).LCMS:m/z=324.1(M+H) + .
example 2 preparation of 4- [ (5-hydroxypentyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:
Figure BDA0003124123150000131
Figure BDA0003124123150000132
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 3 preparation of 4- [ (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
Figure BDA0003124123150000133
Solid 70mg, yield 95%. LCMS: M/z =382.1 (M + H) + .
Figure BDA0003124123150000134
MHz,DMSO-d 6 +DCl/D 2 O)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 4 preparation of 4- [ (3-hydroxy-3-methylbutyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:
Figure BDA0003124123150000141
Figure BDA0003124123150000142
the yield was 72%. LCMS M/z =320.1 (M + H) + .
Figure BDA0003124123150000143
Extraction with ethyl ester, washing with saturated brine, drying over anhydrous sodium sulfate, filtration to dryness, thin layer chromatography (dichloromethane: methanol = 10). 1 H NMR(400MHz,DMSO-d 6 +DCl/D 2 O)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 5 preparation of 4- [ [ (1-acetylpiperidin-4-yl) methyl ] amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:
Figure BDA0003124123150000151
saturated brine (40 mL), stirred for 15 min, filtered and the filter cake washed with petroleum ether to give 150mg of a white solid in 79% yield. LCMS M/z =370.2 (M + H) + .
Figure BDA0003124123150000152
The yield was 66%. LCMS m/z =431.2(M+H) + .
Figure BDA0003124123150000153
Triethylamine (160mg, 1.58mmol) was added thereto, 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 obtain 30mg of a white solid in a two-step yield of 30%. 1 H NMR(400MHz,DMSO-d 6 +DCl/D 2 O)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 6 preparation of 4- [ [2- (1-acetylpiperidin-4-yl) ethyl ] amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide:
Figure BDA0003124123150000154
after stirring for 15 min, filtration was carried out 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) + .
Figure BDA0003124123150000161
Acid (0.1 mL) was added and the reaction was stopped 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) + .
Figure BDA0003124123150000162
(176mg, 1.36mmol), and after stirring for 2 minutes, acetyl chloride (69mg, 0.88mmol) 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 obtain 10mg of a pale yellow solid in a two-step yield of 7%. 1 H NMR(400MHz,DMSO-d 6 +DCl/D 2 O)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) + .
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.
Figure BDA0003124123150000163
Reaction conditions are as follows: 1) R is 1 CH 2 NH 2 ,DIEA,THF,25℃,2~16h;2)
Figure BDA0003124123150000171
TFA,s-BuOH,60~100℃,2~16h.
TABLE 3 structures and characterizations of intermediate Compound A and target Compound B of examples 7-28
Figure BDA0003124123150000172
Figure BDA0003124123150000181
Figure BDA0003124123150000191
Figure BDA0003124123150000201
Figure BDA0003124123150000211
TABLE 4 structures and characterizations of intermediate Compound A and target Compound B of examples 29-35
Figure BDA0003124123150000212
Figure BDA0003124123150000221
Figure BDA0003124123150000231
EXAMPLE 1 assay for inhibition of JAK1, JAK2, JAK3, TYK2 kinase Activity by Compounds of the 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
Figure BDA0003124123150000232
Second, testing method
The following experimental conditions are described in the appendix, taking JAK3 as an example, and JAK1, JAK2, JAK3 and TYK2 as specific examples.
1. Preparing a reagent:
preparation of EDTA (0.5M pH8.0) solution by accurately weighing 14.612g of EDTA powder, adding ultrapure water, and diluting 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), 190.175mg of EGTA, and 5mL of MgCl 2 The 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 XDeprotection Buffer 1mL 10 XDeprotection Buffer was added to 9mL water and mixed.
4 × stop solution: 0.8mL of the above EDTA (0.5M, pH 8.0) solution, 1mL of 10 × Detection Buffer, and 8.2mL of ultrapure water were mixed together.
4 XJAK 3 Kinase solution the 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 (Tyr 1023) 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 Europian-anti-phosphorus-tyrosine antibody (PT 66) was diluted to a concentration of 8nM with 1 XDedetection Buffer 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(s) is carried out,
in a 96-well plate, compounds were diluted 3-fold in DMSO solution 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 the 384-well plate according to a standard 2-well rotary plate.
3) Add 4 × kinase solution: mu.l of the above 4 Xkinase solution was added to the corresponding reaction well of 384-well plate by using a discharge 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 to which 2.5. Mu.l/well 4 Xsubstrate, 2.5. Mu.l 4 Xenzyme solution, 2.5. Mu.l 1 XKinase Assay Buffer and 2.5. Mu.l ultrapure water containing 4% DMSO were added.
6) And (4) centrifuging, mixing uniformly, and reacting for 60min at room temperature in the dark.
7) Termination of the enzymatic reaction:
mu.l of the 4 Xstop buffer 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 60min.
9) The 384-well plate is placed in a plate reader, and the corresponding program detection signal is called.
10 Inhibition ratio and IC 50 And (3) calculating:
well readings =10000 × EU665 value/EU 615 value
Inhibition = [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 to calculate the corresponding IC 50 The 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 (Tyr 1023) 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 0.042nM. 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 (Tyr 1023) 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 total concentration was 11 concentrations, and the minimum final concentration was 0.042nM. 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 (Tyr 1023) 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 0.042nM. 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 (Tyr 1023) 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 total concentration was 11 concentrations, and the minimum final concentration was 0.042nM. 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 table 50 The values represent the concentration of compound at which the enzyme inhibits 50% of its maximum, and NT indicates that the corresponding enzyme was not tested.
TABLE 6 results of measurement of JAK1, JAK2, JAK3 and TYK2 tyrosine kinase inhibitory Activity of some of the compounds of the present invention
Figure BDA0003124123150000251
Figure BDA0003124123150000261
Experimental example 2 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 by 3-fold gradient dilution starting from the highest concentration of 5000nM (the maximum final concentration of drug used in this experiment was 5000nM and the minimum final concentration was 0.76 nM).
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) Centrifuge 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 in another 15ml centrifuge tube, adding 10ml RPMI1640 complete medium, 300g,4 ℃, and centrifuging for 4 minutes;
10 The supernatant was discarded, the cells were resuspended by adding complete medium, and then cell counting was performed. The cell suspension is washed repeatedly according to the ninth step;
11 Cells were transferred to a petri dish (containing 2.5 μ g/mL of concanavalin a) at a cell density of 200 to 500 million/mL for overnight culture;
12 The next day, the cells were transferred to a 15mL centrifuge tube and centrifuged at 300g for 5min;
13 Discarding 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 ) the cell suspension was seeded in 96-well plates, with 80. Mu.l of cell suspension per well, at a density of 100000 cells/well;
15 20. Mu.L of the above 5X compound solution diluted with the culture solution was added to each well and mixed well;
16 Add 10. Mu.L CCK-8 reagent per well after 72 hours of incubation, incubate for 2 hours (reaction time can be adjusted according to shade of color);
17 Read its OD value at 450nm on a multifunction plate reader.
18 Data processing:
cell viability (%) = [ (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 imported into Graphpad Prism5 software for curve fitting and IC50 was calculated.
Table 7 shows the results of the test for the inhibitory activity of the compounds of the present invention on the proliferation of mouse splenocytes, wherein A represents IC 50 Less than or equal to 100nM, B representing IC 50 Greater than 100nM but less than or equal to 500nM, C represents IC 50 Greater than 500nM but less than or equal to 1000nM, D representing IC 50 Greater than 1000nM.
TABLE 7 test results of the inhibitory Activity of the Compounds of the present invention on mouse splenocyte proliferation
Figure BDA0003124123150000281
Use, formulation, administration
Medical application and indications
The biological data provided by the present invention indicate that the compounds of the present invention are useful for the treatment or prevention of diseases caused by tyrosine kinase (JAK 1, JAK2, JAK3, TYK 2) abnormalities. 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 tumors, 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, cholangiocarcinoma. 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 a monotherapy or in a combination therapy, in combination with a plurality of the compounds of the present invention or in combination with other drugs outside the present invention.
Pharmaceutical process
The pharmaceutical methods of the invention comprise determining a therapeutically effective amount of a compound of the invention in 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. An effective dose of the compounds of the invention is generally measured as the amount administered per kg of body weight of the patient, preferably from 0.1 to 125 mg/kg body weight, typically from 0.01 to 500 mg/kg 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 will be achieved when the preferred compounds of the invention are administered at a daily dosage of about 0.01 to 500 mg/kg. The preferred dosage is 0.1 to 125 mg/kg, and the more preferred dosage is 1 to 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 a pharmaceutically acceptable salt or other derivative. 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, cyclopentane, 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, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valeric acid salts, 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 that a compound can be converted in vivo to a compound of the present invention represented by formula (I). 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 vehicles, dispersing or suspending aids, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as appropriate to 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. 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 500 mg, 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 doses are in the range of from 0.01 to 500 mg/kg body weight, preferably from 0.1 to 125 mg/kg body weight, more preferably from 1 to 25 mg/kg body weight.
The active compounds of the invention are generally combined with one or more adjuvants, excipients or carriers to form 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 to 150mg, 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 emulsions 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. Creams should preferably be non-greasy, non-staining and washable products with a suitable consistency to avoid leakage from tubes or other containers. 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, and 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 arts.
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 solubilisation (i.e. propylene glycol) or micelle solubilisation (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 that can be administered to a patient with a compound of the invention, and which does not destroy pharmaceutical activity and is non-toxic at doses sufficient to deliver a therapeutic amount of 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-atopHenol 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, surfactants used in partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool fat. Cyclodextrins, such as α -, β -, and γ -cyclodextrins, or chemically modified derivatives such as hydroxyalkyl, including 2 and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives may also be advantageously employed to enhance delivery of the compounds of the formulae described herein. The pharmaceutical compositions may be administered orally in any acceptable dosage form, including but not limited to capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, for example, are also commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When administered orally using aqueous suspensions and/or emulsions, the active ingredient may be suspended or dissolved in an oily phase with emulsifying and/or suspending agents. If desired, certain sweetening, flavoring and/or coloring agents may be added. The pharmaceutical composition may comprise the use of liposomes or microencapsulation techniques, various examples of which are found in the literature. The pharmaceutical composition may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents, examples of which are also well known in the art.
Combination drug
The compounds of the present invention may be used as such, 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 together 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 efficacy 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 cytostatics, 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.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made in the embodiment of the invention without departing from the spirit and scope of the invention.

Claims (10)

1. A compound, or a pharmaceutically acceptable salt thereof, having the structural formula (I):
Figure FDA0003779902760000011
wherein,
R 1 is composed of
Figure FDA0003779902760000012
n 1 Is 0 to 2,n 2 Is 0 to 1,n 3 Is a group of a number of 0 s,
L 1 is composed of
Figure FDA0003779902760000013
R 4 And/or R 5 Is H, C 1 -C 3 A linear alkyl group;
R 2 is composed of
Figure FDA0003779902760000014
n 4 Is 0,n 5 Is 0,n 6 Is a group of a number of 0 s,
L 2 is composed of
Figure FDA0003779902760000015
R 7 And/or R 8 Is H, C 1 -C 3 A linear alkyl group;
R 3 is a) a hydrogen, hydroxy, cyano,
b)C 1 -C 5 a straight-chain or branched alkyl group,
c)C 3 -C 7 a cycloalkyl group, which is a cyclic alkyl group,
d)C 1 -C 5 a straight-chain or branched alkoxy group, or a linear or branched alkoxy group,
e)C 1 -C 5 a straight-chain or branched alkylthio group,
f) A 5-7 membered heterocyclic ring, said 5-7 membered heterocyclic ring containing 1-2 heteroatoms selected from O and/or N and/or S, when the heteroatom is N, the N is attached acetyl or propionyl;
R 6 is composed of
c)C 1 -C 5 A straight-chain or branched alkyl group,
g)
Figure FDA0003779902760000016
2. a compound, or a pharmaceutically acceptable salt thereof, having the structural formula (I):
Figure FDA0003779902760000021
wherein,
R 1 is composed of
Figure FDA0003779902760000022
n 1 Is 0 to 2,n 2 Is 0 to 1,n 3 Is a group of a number of 0 s,
L 1 is composed of
Figure FDA0003779902760000023
R 4 And/or R 5 Is H, C 1 -C 3 A linear alkyl group;
R 2 is composed of
Figure FDA0003779902760000024
n 4 Is 0,n 5 Is 0,n 6 Is a non-volatile organic compound (I) with a value of 0,
L 2 is composed of
Figure FDA0003779902760000025
R 7 And/or R 8 Is H, C 1 -C 3 Linear alkyl;
R 3 is R 22 Substituted C 1 -C 3 Alkoxy radical, R 22 Is hydroxy, C 1 -C 3 Alkoxy, hydroxy-substituted C 1 -C 3 An alkoxy group;
R 6 is C) C 1 -C 5 A linear or branched alkyl group, or
g)
Figure FDA0003779902760000026
3. A compound, or a pharmaceutically acceptable salt thereof, selected from:
4- [ (5-hydroxypentyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;
4- [ (5-methoxypentyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;
4- [ (3-hydroxy-3-methylbutyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;
4- [ [ (1-acetylpiperidin-4-yl) methyl ] amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;
4- [ [2- (1-acetylpiperidin-4-yl) ethyl ] 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;
2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- (heptylamino) pyrimidine-5-carboxamide;
4- [ (cyanomethyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;
4- [ (2-cyanoethyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;
4- [ (2-hydroxyethyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;
4- [ (2-methoxyethyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;
4- [ (3-methoxypropyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) 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;
2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- [ [ (tetrahydro-2H-pyran-4-yl) methyl ] 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- [ (2-cyclohexylethyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidine-5-carboxamide;
2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -4- [ [2- (tetrahydro-2H-pyran-4-yl) ethyl ] amino ] pyrimidine-5-carboxamide.
4. A compound, or a pharmaceutically acceptable salt thereof, selected from:
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-tert-butyl-1H-pyrazol-4-yl) amino) -4- ((2- (2-methoxyethoxy) ethyl) amino) pyrimidine-5-carboxamide;
4- ((2- (2-methoxyethoxy) ethyl) amino) -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- (2-hydroxyethoxy) ethoxy) ethyl) amino) pyrimidine-5-carboxamide.
5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the salt is selected from: malate, hydrochloride, sulfate, methanesulfonate, formate, acetate, citrate, tartrate, fumarate, gluconate, oxalate.
6. A pharmaceutical composition consisting of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4 and a pharmaceutically acceptable carrier or excipient.
7. A pharmaceutical composition comprising: comprising as active ingredient a compound of formula (I) as defined in any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, one or more further therapeutic agents, and one or more pharmaceutically acceptable carriers or excipients.
8. Use of a compound of formula (I) according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of autoimmune diseases associated with the tyrosine kinases JAK1, JAK2, JAK3, TYK2 and cancer, wherein the diseases comprise: 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, nasopharyngeal cancer, esophageal cancer, brain tumor, lymphoma, multiple myeloma, biliary tract cancer sarcoma, bile duct cancer.
9. The use of claim 8, wherein the leukemia comprises chronic myelogenous leukemia or acute myelogenous leukemia.
10. The use of claim 8, wherein the lymphoma comprises non-Hodgkin's lymphoma, B-cell or T-cell lymphoma.
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