CN110734428A - small molecule compounds - Google Patents

small molecule compounds Download PDF

Info

Publication number
CN110734428A
CN110734428A CN201911019187.9A CN201911019187A CN110734428A CN 110734428 A CN110734428 A CN 110734428A CN 201911019187 A CN201911019187 A CN 201911019187A CN 110734428 A CN110734428 A CN 110734428A
Authority
CN
China
Prior art keywords
substituted
compound
alkyl
pyrazol
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201911019187.9A
Other languages
Chinese (zh)
Inventor
邢莉
李冠群
王晓磊
蔡雨婷
姜翔
潘翔
朱文浩
汪杨
王增全
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
JIAXING TEKELUO BIOTECHNOLOGY Co Ltd
Original Assignee
JIAXING TEKELUO BIOTECHNOLOGY Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by JIAXING TEKELUO BIOTECHNOLOGY Co Ltd filed Critical JIAXING TEKELUO BIOTECHNOLOGY Co Ltd
Priority to CN201911019187.9A priority Critical patent/CN110734428A/en
Publication of CN110734428A publication Critical patent/CN110734428A/en
Priority to PCT/CN2020/120130 priority patent/WO2021078020A1/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/14—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Abstract

The kinds of small molecule compounds provided by the invention are characterized by having a structure shown by the following molecular general formula:

Description

small molecule compounds
Technical Field
The invention relates to the field of small molecule compounds, in particular to small molecule compounds which can be used for treating, preventing and regulating systemic autoimmune diseases and inflammatory skin diseases.
Background
There are approximately over 500 protein kinases in mammals, protein kinases catalyze phosphorylation of amino acids at specific sites of proteins, and are classified into Tyrosine kinases, serine and arginine kinases according to the phosphorylation of amino acids, among which there are nearly 100 of Tyrosine kinases, JAK (janus Kinase) is families of intracellular non-receptor Tyrosine protein kinases (Tyrosine Kinase), including JAK1, JAK2, JAK3 and Tyk2, JAK is mainly expressed in hematopoietic cells, leukocytes and intestinal epithelial cells, and is responsible for mediating the signaling of various cytokines involved in inflammatory reactions, JAK is activated by autophosphorylation when cytokines are bound to cell surface receptors, activated JAK then activates and recruits STAT protein family members by the intracellular portion of phosphorylated receptor, STAT is then activated by JAK to form dimers, departs from receptor to enter phosphorylation, and performs gene Transcription regulation, thereby affecting the biological function of cells, and thus there are many important drugs for JAK Kinase and inflammatory diseases, especially for intracellular signaling of JAK receptor, and intracellular signaling mechanisms of JAK receptor to stimulate JAK receptor, thus many important drugs for treating JAK diseases, especially for autoimmune diseases, especially for treating autoimmune diseases, JAK Kinase has been developed in the clinical research and development of many of drugs for treating autoimmune diseases.
The pathogenesis of Psoriasis (Psoriasisis) is related to two aspects of skin and immune Cells, , epidermal hyperplasia in psoriatic lesions is accompanied by parakeratosis, the epidermal renewal speed is reduced from 28-30 days to 3-5 days, , immune Cells including Dendritic Cells (DC), Macrophages (Macrophages) and T Cells (T Cells) are activated and enter the epidermis and secrete various inflammatory cytokines such as Tumor Necrosis Factor alpha (Tumor Necrosis Factor α - α), interleukin 1beta (interleukin 8651 β -1 β), interleukin 6(interleukin 6, IL-6), interleukin 22(interleukin-22, IL-22) and the like, and the cytokines induce epidermal prion (Keinocyte CSF), the proliferation of epidermal Cells is also induced by the pathological cytokine secretion such as TNF-Granulocyte macrophage-1-5- β), the proliferation of epidermal leukocyte secretion-2 (interleukin-22, IL-22) and the like, so that the inflammatory cytokines such as TNF-Granulocyte macrophage-5-1-interleukin-1- β, the epidermal leukocyte secretion-6 and the inflammatory cytokines are induced by the pathological cytokine secretion such as TNF-leukocyte secretion, TNF-2, TNF-interleukin-2, interleukin-CSF, interleukin-6, interleukin-IL-6, interleukin-secreting and inflammatory cytokines such as TNF-leukocyte secretion, TNF-IL-activating polypeptide, and inflammatory cytokines such as TNF-leukocyte secretion, and inflammatory cytokine-leukocyte secretion, TNF-activating polypeptide, and inflammatory cytokines, thereby inducing the pathological cytokine-leukocyte secretion in the pathological leukocyte secretion in the stratum corneum, epidermal leukocyte secretion of epidermal leukocyte secretion, epidermal leukocyte secretion, epidermal leukocyte secretion, epidermal leukocyte.
Studies have shown that the above cytokine-mediated signal transduction system finally leads to intracellular gene expression affecting the cellular biological function by activating the JAK family members JAK1, JAK2, JAK3 and TYK2 tyrosine kinases, phosphorylating cytokine receptors, recruiting STAT (signal transduction receptor) receptors, and finally causing intracellular gene expression, the pairing between JAK members is directly related to upstream cytokines, different pairing combinations of JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/TYK2, JAK 2/2 may occur depending on different cytokine stimuli, among which JAK1 pairing is most common, TYK2 is important for the signal transduction of JAK type interferons (IFN-alpha, IFN-beta), IL-6 and IL-23, the signal transduction of inflammatory diseases and autoimmune diseases is very important for the signal transduction of the JAK family members TYK2, and the autoimmune diseases is usually associated with the efficient inhibition of the JAK family members TYK2 tyrosine kinase, and the activation of the JAK2 tyrosine kinase, especially the inhibitory activity of the JAK2 receptor, the JAK2 receptor signaling of the autoimmune diseases.
There is currently no curative treatment for psoriasis, mild psoriasis, , can be better controlled by topical drugs such as glucocorticoids, retinoic acid and vitamin D derivatives, moderate psoriasis, by topical drugs combined with Phototherapy (PUVA), severe psoriasis, considering systemic drugs such as oral methotrexate (methotrexate), retinoids (retinoids), or injected biologicals, however, 90% of psoriasis patients choose topical drugs, but topical drugs with high efficacy and few side effects are still lacking and cannot meet the needs of patients, many pharmaceutical companies have now made new drug development for JAK family members, but mostly focus on inhibition of JAK1, TYK2 and k3. for example, based on the role of JAK3 in immune cell differentiation and development, the JAK3 inhibitor developed by fevere (xeljanz) was approved by the FDA for treating rheumatoid arthritis in the year, the study of TYK2 inhibitors is not very common, only the development of TYK 3 inhibitor is only a tyeljanb (xeljanz) for JAK 3526, especially for the development of a new drug for inhibiting autoimmune diseases, especially for a slight psoriasis, especially for 493 23.
The present invention provides a good opportunity for developing new drugs for external use against inflammatory skin diseases, Jakafi is Th JAK inhibitor entering the market, JAK1/JAK2 inhibitor, used for treating polycystic blood disease or myelofibrosis, Tofacitinib of pfeiri is Th JAK inhibitor for treating autoimmune diseases, selectivity for of JAK1, JAK2 and JAK3, with knowledge of functions of JAK and its involved cytokine receptors, many pharmaceutical companies have been striving for more selective compounds in the past to regulate specific cytokine signaling pathways, JAK1 inhibitors such as gobitinib, upitatinib, PF04965842 or TYK2 inhibitor BMS-986165, and currently, clinical auto-development of autoimmune diseases such as RA, psoriasis, or Crohn, Ty7, Ty-Tyk inhibitors, Tyk inhibitors and Tyk-2 inhibitors are expected to have a great effect in treating autoimmune diseases, especially psoriasis, and multiple kinds of autoimmune diseases such as autoimmune diseases, Tyk-2, Tyk receptor differentiation, and Tyk-induced apoptosis, and Tyk receptor differentiation of autoimmune diseases, and Tyk-induced by using multiple clinical autoimmune diseases such as anticancer drugs for treating autoimmune diseases, and anti-inflammatory cell proliferation of autoimmune diseases such as a series of autoimmune diseases.
Disclosure of Invention
The invention aims to develop a high-efficiency and specific JAK kinase inhibitor, a Tyk2 inhibitor, and/or a JAK1 inhibitor, and/or a JAK1/Tyk2 dual inhibitor, and/or a Tyk2/Jak2 dual inhibitor which is suitable for systemic administration or external smearing administration, and can be used as a small molecular drug for treating the first-choice indications of psoriasis and/or eczema.
The micromolecular compounds provided by the invention are characterized by being compounds shown by the following structural formula or stereoisomers, geometric isomers, tautomers, racemates, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs thereof:
Figure BDA0002246639810000021
wherein, X is1、X2Selected from carbon or nitrogen;
in the present invention, the small molecule compound is preferably a compound of three types as shown in the following structure:
Figure BDA0002246639810000022
a above1、A2、A3、A4、A5Wherein or more than carbons are replaced by nitrogen, sulfur or oxygen;
from the above A1、A2、A3、A4、A5The five-membered ring formed has aromaticity;
namely, A1、A2、A3、A4、A5The five-membered ring formed may be a similar compound as shown in the following structure:
Figure BDA0002246639810000031
any or any number of hydrogen atoms on the five-membered ring are replaced by R, and the five-membered ring is a similar compound shown in the following structure;
when R is polysubstituted, each R is the same or different;
r is selected from hydrogen, halogen, alkyl, substituted alkyl, amino, substituted amino, carboxyl, amido-CONH2Substituted amido, ester (-C (O) O-R)z，RzIs alkyl, aryl, etc.), substituted carbonyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl.
The alkyl group is typically a branched alkyl group or a branched alkyl group having not more than 6 carbon atoms;
the substituted alkyl refers to the substitution of or or more of the hydrogen atoms on the alkyl carbon chain by other groups, and the other groups referred to herein can be cycloalkyl (in a manner similar to that of
Figure BDA0002246639810000033
Etc., any hydrogen atom on the cycloalkyl ring may also be substituted with a halogen, cyano, alkyl, hydroxy, carboxy, etc., heterocycloalkyl (i.e., at least carbon atoms on the alkyl ring are replaced with oxygen, sulfur, nitrogen, etc., in addition to the cycloalkyl described above), halogen (F, Cl, Br, I), carboxy, cyano (-CN), sulfonic acid (-SO), etc4-, -) sulfonyl (-SO)2Ra，RaHydrogen, alkyl, aryl, etc.), alkynyl (-C.ident.CH, -C.ident.CR)b，RbIs alkyl, aryl, etc.), an amide group (-C (O) NR)xRy，RxRyAlkyl, aryl, etc.), ester group (-C (O) O-R)z，RzAlkyl, aryl, etc.), aryl, heteroaryl, etc.;
preferably, when R is substituted alkyl, it can be a compound of the following structure:
that is, the above R may be
Figure BDA0002246639810000041
That is, the terminal of the alkyl chain is attached with a substituent.
Wherein n is a natural number 1,2, 3.. times; preferably within 6.
R is as defined above1Is an alkyl group, such as: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and the like branched or straight chain alkyl groups;
the or more hydrogen atoms in the alkyl group may also be substituted with cycloalkyl, cyano, halogen, alkyl halide (groups of alkyl halide such as chloromethane, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, bromomethyl, dibromomethyl, tribromomethyl, bromoethyl, bromopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, and the like), in which case the substituted methyl group forms the structure shown in the following formula:
R11、R12identical or different, are respectively selected from cyano, halogen and alkyl halide;
or R1Is cycloalkyl such as cyclopropane, cyclobutane, cyclopentane, cyclohexane and so on, or more hydrogen atoms on the cycloalkyl alkyl ring can be replaced by alkyl, cyano, halogen and alkyl halide, and the specific structure can be the compound shown in the following structural formula:
Figure BDA0002246639810000043
n1 is 0,1,2,3,4, 5;
R13 or more hydrogen atoms on the alkyl ring are substituted or not substituted by halogen and cyano;
or R1The heterocyclic alkyl group is a four-membered heterocyclic ring, a five-membered heterocyclic ring or a six-membered heterocyclic ring of aza, oxa or thia, or more hydrogen atoms on the ring of the heterocyclic alkyl group can be substituted by alkyl, cyano, halogen or alkyl halide, and the specific structure can be a compound shown in the following structural formula:
Figure BDA0002246639810000044
B1、B2、B3、B4、B5、B6carbon, oxygen, sulfur, nitrogen;
R14 or more hydrogen atoms on the alkyl ring are substituted or not substituted by halogen or cyano.
In addition, the above R may be
Figure BDA0002246639810000045
I.e. the methyl group is three substituents, R2、R3and-C (O) -R1Substituted;
wherein R is as defined above2、R3The same or different alkyl groups (for example, means an alkyl group having not more than 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.).
In addition, the above R may be
Figure BDA0002246639810000046
That is, two hydrogens on the methyl group form an alkyl ring through a bridge, and another hydrogens are-C (O) -R1Substituted;
wherein m is 0,1,2,3,4,5, i.e. cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc., and or more hydrogen atoms on the cycloalkyl alkyl ring can be R4Alkyl, cyano, halogen, alkyl halide, or unsubstituted.
The substituted amino refers to that or more than of hydrogen atoms on the amino are substituted by other groups, and the other groups referred to herein can be alkyl, cycloalkyl, carboxyl, cyano, sulfonic acid group, amido, ester group and the like;
preferably, when R is a substituted amide group, it may be a compound of the following structure:
r is a nitrogen-containing group.
Such as: is composed ofAnd a product which reacts with the amide group;
or is NH2And with NH2The product of the reaction of the groups;
preferably, when R is a substituted amine group, it can be a compound of the following structure:
r may be
Figure BDA0002246639810000052
Wherein R is as defined above1Hydrogen and alkyl (such as refers to alkyl with carbon number not more than 6 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.);
r is as defined above2Is alkyl (same as above), substituted alkyl (same as above), cycloalkyl (cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc.), substituted cycloalkyl (i.e., or more of the hydrogen atoms on the cycloalkyl ring are substituted by halogen, cyano, alkynyl, e.g.: the
Figure BDA0002246639810000053
Form shown by structure, R15Is halogen, cyano, alkynyl, etc.), heterocycloalkyl (at least carbon atoms on the 3-to 7-membered ring are substituted with nitrogen, sulfur or oxygen), substituted heterocycloalkyl ( or more of the hydrogen atoms on the heterocycloalkyl ring are substituted with halogen, cyano, alkynyl), sulfone group(s) (
Figure BDA0002246639810000054
R16Is alkyl, halogen, aryl, etc.), sulfoxide group(s) ((R)
Figure BDA0002246639810000055
R17Is alkyl, halogen, aryl, etc.), substituted carbonyl group: (
Figure BDA0002246639810000056
R17Alkyl, substituted alkyl, aryl, etc.).
In addition, the above R may be
Wherein R is as defined above3Hydrogen, alkyl;
r is as defined above4Same as R2。
Preferably, when R is a substituted amide group, it may be a compound of the following structure:
in addition, the above R may be
Figure BDA0002246639810000058
Wherein n is 0 or a natural number;
r is as defined above5Hydrogen, alkyl;
r is as defined above6Same as R2。
Preferably, when R is a substituted carbonyl group, it can be a compound of the following structure:
r is as defined above
Figure BDA0002246639810000059
Wherein R is as defined above7Same as R2。
Preferably, when R is a substituted amide group, it may be a compound of the following structure:
in addition, the above R may be
Figure BDA0002246639810000061
Wherein R is as defined above17Selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, hydroxyl, ether, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
r is as defined above18Selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, hydroxyl, ether, aryl, substituted aryl, heteroaryl, substitutedA heteroaryl group.
the small molecular compounds provided by the invention also have the characteristics of,
R is as defined above
Figure BDA0002246639810000062
Wherein R is as defined above8、R9Are alkyl groups which may be the same or different.
the small molecular compounds provided by the invention also have the characteristics of,
R is as defined above
Figure BDA0002246639810000063
Wherein m is 0,1,2,3,4, 5.
the small molecule compounds of the present invention also have the feature that A is1、A2、A3、A4、A5The five-membered ring formed is replaced with another polyvalent aromatic ring. Such as: six-membered, seven-membered or benzo rings, and the like.
The substituted cycloalkyl groups referred to in this invention refer to ring rings wherein or more hydrogen atoms are replaced by other groups, such as alkyl, substituted alkyl (as above), halogen (F, Cl, Br, I), carboxyl, cyano (-CN), sulfonic (-SO), and the like4-, -) sulfonyl (-SO)2Ra，RaHydrogen, alkyl, aryl, etc.), alkynyl (-C.ident.CH, -C.ident.CR)b，RbIs alkyl, aryl, etc.), an amide group (-C (O) NR)xRy，RxRyAlkyl, aryl, etc.), ester group (-C (O) O-R)z，RzAlkyl, aryl, etc.), aryl, heteroaryl, etc.
The substituted heterocycloalkyl group referred to in the present invention means that or more carbon atoms in the ring are replaced by oxygen, sulfur, nitrogen, on the basis of the above-mentioned substituted cycloalkyl group.
The aryl group in the present invention means a six-membered or more aromatic ring such as benzene and naphthalene, or a benzo aromatic ring.
The substituted aryl group mentioned in the present invention refers to five or more aromatic rings such as benzene, naphthalene, fluorene, etc. or benzo aromatic ring, wherein or more hydrogen atoms on the ring are substituted by other groups, and the other groups referred to herein may be alkyl, substituted alkyl (same as above), halogen (F, Cl, Br, I), carboxyl, cyano (-CN), sulfonic (-SO), etc4-, -) sulfonyl (-SO)2Ra，RaHydrogen, alkyl, aryl, etc.), alkynyl (-C.ident.CH, -C.ident.CR)b，RbIs alkyl, aryl, etc.), an amide group (-C (O) NR)xRy，RxRyAlkyl, aryl, etc.), ester group (-C (O) O-R)z，RzAlkyl, aryl, etc.), aryl, heteroaryl, etc.
The heteroaryl group in the invention refers to five-membered or more aromatic heterocyclic rings such as thiophene, pyrrole, pyridine, furan, imidazole, benzimidazole, quinoline, and the like, or benzo aromatic heterocyclic rings.
The substituted heteroaryl mentioned in the invention refers to five-membered or more aromatic heterocyclic rings or benzo aromatic heterocyclic rings such as thiophene, pyrrole, pyridine, furan, imidazole, benzimidazole and quinoline, wherein or more hydrogen atoms on the rings are substituted by other groups, and the other groups referred to herein can be alkyl, substituted alkyl (same as above), halogen (F, Cl, Br, I), carboxyl, cyano (-CN), sulfonic (-SO)4-, -) sulfonyl (-SO)2Ra，RaHydrogen, alkyl, aryl, etc.), alkynyl (-C.ident.CH, -C.ident.CR)b，RbIs alkyl, aryl, etc.), an amide group (-C (O) NR)xRy，RxRyAlkyl, aryl, etc.), ester group (-C (O) O-R)z，RzAlkyl, aryl, etc.), aryl, heteroaryl, etc.
the small molecule compounds provided by the invention also have the characteristics of treating, preventing and relieving the inflammatory dermatosis related to autoimmunity, and can be prepared into various dosage forms such as oral administration, external application, injection and the like.
The invention has the following functions and effects:
the invention is reasonably designed according to the protein structure of JAK kinase, in particular to the protein structures of JAK1 and Tyk2, the synthesized compound is firstly subjected to the kinase biochemical activity detection of JAK, then SAR (structure-activity correlation) is established according to IC50, and the cytological test is carried out on a potent inhibitor of IC50 below 200nM, and the selectivity of the compound is determined. Referring to specific activity experimental data, the compounds related to the invention have good inhibition capacity of cell activity.
The inhibitor provided by the invention can also be used for other autoimmune related skin diseases such as alopecia areata, leucoderma, lupus erythematosus mainly manifested by skin, lichen planus, lichen glossus, lichen sclerosis atrophicus, panniculitis, atopic dermatitis and the like.
The JAK inhibitors, Tyk2 inhibitors, and/or JAK1 inhibitors, and/or JAK1/Tyk2 dual inhibitors obtained in the present invention, suitable for oral or intravenous administration, may still be useful for the treatment of psoriasis and other autoimmune diseases such as RA, IBD, MS, etc.
Detailed Description
EXAMPLE general procedure for for the Synthesis of Compound (TDM-180607)
Figure BDA0002246639810000071
Step 1: example 7c
The original compound 7a, i.e., 4, 6-dichloropyrimidine (10.0g, 0.067mol) and acetonitrile (100mL) were added to a three-necked flask, and then compound 7b, i.e., 4-nitro-1H-pyrazole (7.59g, 0.067mol) and N, N-diisopropylethylamine (12.5mL, 0.073mol) were added to the three-necked flask, and after refluxing at 50 ℃ for 16 hours, the reaction solution was concentrated under reduced pressure and column-purified (petroleum ether/ethyl acetate ═ 3/1) to give compound 7c, i.e., 4-chloro-6- (4-nitro-1H-pyrazol-1-yl) pyrimidine (5.7g, yield 38%), as a white solid.
1H NMR(400MHz,DMSO-d6)δ9.63(d,J＝0.6Hz,1H),9.11(d,J＝1.0Hz,1H),8.77(d,J＝0.6Hz,1H),8.17(d,J＝1.0Hz,1H).
Step 2, Example 7e
The compound 7c (2.8g,12.4mmol), N, N-diisopropylethylamine (2.3mL,13.7mmol) and N, N-dimethylformamide (20mL) were added to a single-neck flask, stirred for 5 minutes, the compound 7d, 1-methyl-1H-pyrazol-4-amine (1.21g,12.4mmol) was added to a single-neck flask at 20 deg.C, heated to 90 deg.C, and stirred for reaction for 16H. Then the reaction solution was poured into methanol to precipitate a large amount of yellow solid, which was filtered and dried to obtain compound 7e, i.e., N- (1-methyl-1H-pyrazol-4-yl) -6- (4-nitro-1H-pyrazol-1-yl) pyrimidin-4-amine (3.1g, yield 87%). LCMS (liquid Crystal Module) (M + 1)]+＝287.2
Step 3, Example 7f
Compound 7e (2.0g,6.98mmol), iron powder (1.96g,34.96mmol), ammonium chloride (1.88g,34.96mmol), ethanol and water (80mL, ethanol: water ═ 2:1) were added to a single-neck bottle. The mixture was then heated at 90 ℃ for 3H, cooled to room temperature, the reaction was washed with water and extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried, filtered and concentrated to give 7f, 6- (4-amino-1H-pyrazol-1-yl) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-4-amine, as a yellow solid (1.0g, 56% yield). LCMS (liquid Crystal Module) (M + 1)]+＝257.1
Step 4. Example 7(TDM-180607)
The compound 7f (50mg,0.194mmol), triethylamine (19.7mg,0.292mmol) and anhydrous dichloromethane (10mL) were charged into a single-necked flask, and after stirring for 5min, compound 7g, i.e., 2-difluorocyclopropanecarboxylic acid (26mg,0.214mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (56mg,0.292mmol) were added, and the mixture was stirred at room temperature for 16H, and the reaction mixture was concentrated and purified by a spatula (petroleum ether/ethyl acetate ═ 0/100) to give 2, 2-difluoro-N- (1- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) cyclopropylamide (17.8 mg) as a white solid, yield 25%). LCMS (liquid Crystal Module) (M + 1)]+＝361.0
1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),9.75(s,1H),8.69(d,J＝0.5Hz,1H),8.49(s,1H),7.97(s,1H),7.88(s,1H),7.49(s,1H),7.03(s,1H),3.83(s,3H),2.77(ddd,J＝13.5,10.9,7.9Hz,1H),2.17–1.89(m,2H).
The compound traits and yields in the above table are as follows:
white solid TDM-180608, i.e. 3,3, 3-trifluoro-N- (1- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) propionamide (5mg, yield: 12%)
TDM-180613 as an off-white solid, N- (1- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) cyclopropane-methyl (5mg, yield: 4%)
Yellow solid TDM-180614, 2-cyano-N- (1- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) acetamide (25.2mg, yield: 4%)
EXAMPLE two general procedure for the Synthesis of Compound TDM-180611
Figure BDA0002246639810000082
Step 1. Example11
The compound 7f (100mg,0.388mmol), ethylsulfonyl chloride (16mg,0.128mmol), triethylamine (39.4mg,0.584mmol) and anhydrous dichloromethane were added to a single vial, and after stirring at room temperature for 16H, the reaction was concentrated and purified with a spatula to obtain compound 11, N- (1- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) ethanesulfonamide (16.2mg, 12% yield) as a white solid. LCMS (liquid Crystal Module) (M + 1)]+＝349.0。
1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),8.48(s,1H),7.99(s,1H),7.72(s,1H),7.52(s,1H),7.10(s,1H),3.83(s,3H),3.06(q,J＝7.3Hz,2H),1.22(d,J＝7.4Hz,3H).
The off-white solid compound TDM-180612, N- (1- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) propane-1-sulfonamide (16.2mg, yield: 16%)
EXAMPLE III general procedure for the Synthesis of Compound TDM-180627
Figure BDA0002246639810000091
Step 1: example 27c
The compound 7f (50mg,0.194mmol), triethylamine (19.7mg,0.292mmol) and anhydrous dichloromethane were added to a single-necked flask, and after stirring for 5min, compound 27b, i.e., 2-acetoxyacetic acid (25mg,0.214mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (56mg,0.292mmol) were added, stirred at room temperature for 2H, the reaction was concentrated and purified by scraper to give compound 27c, i.e., 2- ((1- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) amino) -2-oxoethyl acetate as a white solid (40mg, 58% yield). LCMS (liquid Crystal Module) (M + 1)]+＝357.0
Step 2: example 27(TDM-180627)
The compound 27c (40mg,0.112mmol), lithium hydroxide (27mg,1.12mmol), tetrahydrofuran (5mL) and water (3mL) were added to a single-neck flask, stirred at room temperature for 2H, the reaction solution was washed with water and extracted with ethyl acetate, the organic phases were combined, dried, filtered and concentrated to obtain compound 27, i.e., 2-hydroxy-N- (1- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) acetamide (6mg, yield 17%) as a white solid by scraping and high pressure liquid chromatography. LCMS (liquid Crystal Module) (M + 1)]+＝315.1
1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),9.75(s,1H),8.79(s,1H),8.49(s,1H),8.00(d,J＝16.6Hz,2H),7.49(s,1H),7.02(s,1H),4.01(d,J＝5.7Hz,2H),3.83(s,3H).
EXAMPLE four general procedure for the Synthesis of Compound TDM-180615
Figure BDA0002246639810000092
Step 1: example 15c
The original compound 15a, i.e., 4, 6-dichloropyrimidine (5.96g,40mmol) and acetonitrile (50mL) were added to a three-necked flask, and then compound 15b, i.e., ethyl 1H-pyrazole-4-carboxylate (5.6g,40mmol) and potassium carbonate (16.58g,120mmol) was added to a three-necked flask. The reaction solution was heated to 50 ℃ for reaction for 16H, cooled to room temperature, washed with water, extracted with ethyl acetate, the organic phases were combined, the organic phase was dried and concentrated, and purified by column chromatography to give a white solid compound 15c, i.e., ethyl 1- (6-chloropyrimidin-4-yl) -1H-pyrazole-4-carboxylate (5.92g, 58.7% yield). LCMS (liquid Crystal Module) (M + 1)]+＝253.0
Step 2: example 15e
The compound 15c (2.0g,7.92mmol), potassium carbonate (3.28g,23.8mmol) and N, N-dimethylformamide (25mL) were added to a single-neck flask, stirred for 5min, compound 15d, i.e., 1-methyl-1H-pyrazol-4-amine (1.21g,12.4mmol), was added to the single-neck flask at 20 deg.C, heated to 70 deg.C, and stirred for reaction for 16H. The reaction was then filtered, the filtrate was concentrated to give a white solid, which was washed with methanol (20mL), filtered and dried to give compound 15e, i.e., ethyl 1- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazole-4-carboxylate (1.42g, 57% yield). LCMS (liquid Crystal Module) (M + 1)]+＝314.1
And step 3: example 15f
The compound 15e (500mg,1.59mmol), sodium hydroxide (191mg,4.79mmol), tetrahydrofuran (20mL) and water (10mL) were added to a single-neck flask, stirred at room temperature for 16H, the reaction solution was washed with water and extracted with ethyl acetate, the aqueous phase was separated, the pH of the aqueous phase was adjusted with 1M hydrochloric acid to precipitate a white solid, which was filtered and dried to give the compound 15f, i.e., 1- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazole-4-carboxylic acid (300mg, yield 66%). LCMS (liquid Crystal Module) (M + 1)]+＝286.0。
And 4, step 4: example 15(TDM-180615)
The compound 15f (50mg,0.175mmol), N, N-diisopropylethylamine (52mg,0.40mmol) and N, N-dimethylformamide (5mL) were added to a single-necked flask and stirred for 5 min. 15g of compound, 2,2, 2-trifluoroethylamine (20mg,0.20mmol) and HATU (77mg,0.20mmol) were added to a single-necked flask at 20 ℃ and reacted at room temperature for 16 hours. Pouring the reaction solution into water to separate out white solid, filtering and drying the white solid, and preparing a white solid compound 15, namely 1- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidine-4-yl) -N- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) by using high pressure liquid chromatographyFormamide (13.2mg, 24% yield). LCMS (liquid Crystal Module) (M + 1)]+＝367.0
1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),9.22(s,1H),9.01(s,1H),8.56(s,1H),8.24(s,1H),8.00(s,1H),7.52(s,1H),7.11(s,1H),4.14–4.01(m,3H),3.84(s,3H).
Figure BDA0002246639810000101
The compound TDM-180616 white solid, N- (cyanomethyl) -1- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazole-4-carboxamide (41.2mg, yield: 64%)
EXAMPLE four general procedure for the Synthesis of Compound TDM-180628
Figure BDA0002246639810000102
Step 1: example 28c
The original compound 28b, i.e., 1-propylamine (5.96g,40mmol), triethylamine (552mg,5.45mmol), 1H-pyrazole-4-sulfonyl chloride (300mg,1.818mmol) and dichloromethane (10mL) were added to a single-necked flask, and the mixture was stirred at room temperature for 2 hours, followed by concentration and column chromatography (petroleum ether/ethyl acetate: 1/1) using a sand-core funnel to give the compound 28c, i.e., N-propyl-1H-pyrazole-4-sulfonamide (360mg, crop) as a yellow oil. LCMS (liquid Crystal Module) (M + 1)]+＝190。
Step 2: example 28e
The compound 28c (180mg,0.95mmo), the compound 28d i.e. 4, 6-dichloropyrimidine (709mg,4.76mmol), potassium carbonate (393mg,2.85mmol) and acetonitrile (10mL) were added to a single vial and heated to 60 ℃ for 4 h. The reaction solution was filtered, the filtrate was concentrated, and purified by a spatula (petroleum ether/ethyl acetate: 1/1) to obtain compound 28e, i.e., 1- (6-chloropyrimidin-4-yl) -N-propyl-1H-pyrazole-4-sulfonamide, as a white solid (150mg, 52.4% yield). LCMS (liquid Crystal Module) (M + 1)]+＝302。
And step 3: example 28(TDM-180628)
The compound 28e (60mg,0.198mmol), the compound 28f i.e. 1-methyl-1H-pyrazol-4-amine (38.8mg,0.297mmol), potassium carbonate (82.9mg, 0.297mmol) were added0.594mmol) and N, N-dimethylformamide (5mL) were added to a single-necked flask, the mixture was heated to 70 ℃ for reaction for 4 hours, the reaction solution was filtered, the filtrate was concentrated, and after purification with a spatula (petroleum ether/ethyl acetate: 0/100), compound 28, i.e., 1- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -N-propyl-1H-pyrazole-4-sulfonamide was obtained as a white solid by high pressure liquid chromatography (25mg, yield 34.9%). LCMS (liquid Crystal Module) (M + 1)]+＝363.0
1H NMR(400MHz,MeOD)δ8.91(d,J＝0.5Hz,1H),8.51(s,1H),8.01(s,2H),7.56(s,1H),7.14(s,1H),3.90(s,3H),2.90(t,J＝7.0Hz,2H),1.60–1.47(m,2H),0.92(t,J＝7.4Hz,3H).
EXAMPLE five general procedure for the Synthesis of Compound TDM-180629
Figure BDA0002246639810000111
Step 1: example 29c
The original compound 29b, i.e., 1-ethylamine (9.09mL,18.18mmol), triethylamine (552mg,5.45mmol), 1H-pyrazole-4-sulfonyl chloride (300mg,1.818mmol) and dichloromethane (20mL) were added to a single vial, and the mixture was stirred at room temperature for reaction for 2 hours, and then the reaction solution was concentrated and purified by column chromatography using a sand-core funnel (petroleum ether/ethyl acetate ═ 1/1) to obtain compound 29c, i.e., N-ethyl-1H-pyrazole-4-sulfonamide (310mg, crede), as a yellow oil. LCMS [ M +1] + ═ 176
Step 2: example 29e
The compound 29c (160mg,0.914mmol), the compound 29d, i.e. 4, 6-dichloropyrimidine (408mg,2.74mmol), potassium carbonate (379mg,2.74mmol) and acetonitrile (10mL) were added to a single vial and heated to 60 ℃ for reaction for 3 h. After cooling to room temperature, the reaction mixture was filtered, the filtrate was concentrated, and purified by a spatula (petroleum ether/ethyl acetate: 1/1) to give compound 29e, i.e., 1- (6-chloropyrimidin-4-yl) -N-ethyl-1H-pyrazole-4-sulfonamide, as a white solid (130mg, 49.6% yield). LCMS (liquid Crystal Module) (M + 1)]+＝288
And step 3: example 29(TDM-180629)
The compound 29e (30mg,0.1045mmol), the compound 29f, i.e., 1-methyl-1H-pyrazol-4-amine (16.22mg,0.1672mmol), and potassium carbonate (43.26mg, 3526 mmol) were added0.3135mmol) and N, N-dimethylformamide (5mL) were added to a single-necked flask and heated to 70 ℃ for 4 h. The reaction solution was filtered, the filtrate was concentrated, and after purification with a spatula (petroleum ether/ethyl acetate: 1/100), compound 29, i.e., 1- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -N-ethyl-1H-pyrazole-4-sulfonamide (15mg, yield 41.2%) was obtained as a yellow solid by high pressure liquid chromatography. LCMS (liquid Crystal Module) (M + 1)]+＝349.4
1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.84(d,J＝0.7Hz,1H),8.56(s,1H),8.15(s,1H),8.02(s,1H),7.56(dd,J＝14.6,9.0Hz,2H),7.13(s,1H),3.84(s,3H),2.92-2.83(m,2H),1.04(t,J＝7.2Hz,3H).
EXAMPLE sixty, general procedure for the Synthesis of Compound TDM-180619
Figure BDA0002246639810000112
Step 1: example 19c
The original compound 19a, i.e., 2, 4-dichloropyridine (5.00g,33.8mmol) and N, N-dimethylformamide (50mL) were added to a three-necked flask, and then compound 19b, i.e., 4-nitro-1H-pyrazole (3.44g,30.4mmol) and cesium carbonate (16.5g,50.7mmol) were added to the three-necked flask, and refluxed at 100 ℃ for 16 hours. Then, the reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried, concentrated and purified by column chromatography (petroleum ether/ethyl acetate 3/1) to obtain compound 19c, i.e., 2-chloro-4- (4-nitro-1H-pyrazol-1-yl) (1.33g, yield 17.5%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ9.93(d,J＝4.4Hz,1H),8.70(s,1H),8.59(s,1H),8.20(d,J＝4.2Hz,1H),8.05(s,1H).
Step 2 sample 19e
The compound 19c (1.19g,5.3mmol), sodium carbonate (786mg,7.4mmol)), the compound 19d, i.e., 1-methyl-1H-pyrazol-4-amine (514mg,5.3mmol) and N, N-dimethylformamide (30mL) were added to a single-neck flask, stirred for 5min, and Pd was added at 20 ℃2(dba)3(485mg,0.53mmol) and Xantphos (613mg,1.06mmol) were added to a single-necked flask and the N replaced2Heating the mixture to 130 ℃,and in N2The reaction was stirred for 22h with protection. After cooling to room temperature, the reaction mixture was washed with water and extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried, concentrated and purified by column chromatography (petroleum ether/ethyl acetate: 1/1) to give compound 19e, i.e., N- (1-methyl-1H-pyrazol-4-yl) -4- (4-nitro-1H-pyrazol-1-yl) pyridin-2-amine, as a yellow solid (400mg, yield 26.5%). LCMS (liquid Crystal Module) (M + 1)]+＝286.0
Step 3 Example 19f
Compound 19e (360mg,1.263mmol), iron powder (353.7mg,6.316mmol), ammonium chloride (337.9mg,6.316mmol), ethanol and water (80mL, ethanol: water ═ 4:1) were added to a single-neck flask, and the mixture was heated at 90 ℃ for 3 h. After cooling to room temperature, the reaction mixture was washed with water and extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried, filtered and concentrated to give a yellow solid compound 19f, i.e., 4- (4-amino-1H-pyrazol-1-yl) -N- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine (260mg, yield 80.7%). LCMS (liquid Crystal Module) (M + 1)]+＝256.1
Step 4. Example 19(TDM-180619)
The compound 19f (20mg,0.078mmol), triethylamine (12mg,0.118mmol) and anhydrous dichloromethane (6mL) were added to a single vial and after stirring for 5min, compound 19g, i.e., 3,3, 3-trifluoropropionic acid (11mg,0.0858mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (22.6mg,0.118mmol) were added and stirred at room temperature for 3 h. The reaction solution was then concentrated and purified with a spatula (petroleum ether/ethyl acetate: 0/100) to give 3,3, 3-trifluoro-N- (1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -1H-pyrazol-4-yl) propionamide (8mg, yield 28.1%) as a white solid. LCMS (liquid Crystal Module) (M + 1)]+＝366.0
1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.91(s,1H),8.57(s,1H),8.13(d,J＝5.7Hz,1H),7.94(s,1H),7.84(s,1H),7.41(d,J＝0.6Hz,1H),7.13-6.93(m,2H),3.81(s,3H),3.51(q,J＝11.1Hz,2H).
Figure BDA0002246639810000121
The off-white solid compound TDM-180620, 2-difluoro-N- (1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -1H-pyrazol-4-yl) cyclopropane-methyl (7mg, yield: 25%)
The off-white solid compound TDM-180621, N- (1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -1H-pyrazol-4-yl) cyclopropane-methyl (15mg, yield: 39.4%)
The off-white solid compound TDM-180622, 2-cyano-N- (1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -1H-pyrazol-4-yl) acetamide (8mg, yield: 31.9%)
EXAMPLE seventhly, general procedure for the Synthesis of Compound TDM-180623
Figure BDA0002246639810000132
Step 1: example 23(TDM-180623)
The compound 19f (50mg,0.196mmol), triethylamine (29.7mg,0.294mmol), tetrahydrofuran (15mL) and anhydrous dichloromethane (15mL) were added to a single vial, and after stirring for 5 minutes, the compound 23b, i.e., ethylsulfonyl chloride (25.2mg,0.196mmol) was added and the reaction stirred at room temperature for 3 h. The reaction was then concentrated and purified by scraper (petroleum ether/ethyl acetate: 0/100) to give compound 23, N- (1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -1H-pyrazol-4-yl) ethanesulfonamide (8.0mg, 11.7% yield) as a yellow solid. LCMS (liquid Crystal Module) (M + 1)]+＝348.1
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),9.40(s,1H),8.39(s,1H),8.08(d,J＝6.2Hz,1H),7.95(s,1H),7.74(s,1H),7.49(s,1H),7.31-7.22(m,1H),7.22-7.16(s,1H),3.84(s,3H),3.12(q,J＝7.3Hz,2H),1.24(t,J＝8.2Hz,3H).
Figure BDA0002246639810000133
The yellow solid compound TDM-180624, N- (1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -1H-pyrazol-4-yl) propane-1-sulfonamide (14mg, yield: 19.8%)
EXAMPLE eight general procedure for the synthesis of compound TDM-180626
Figure BDA0002246639810000134
Step 1: example 26c
The compound 26a (30mg,0.118mmol), triethylamine (17.9mg,0.177mmol), tetrahydrofuran (8mL) and anhydrous dichloromethane (8mL) were added to a single-necked flask, and after stirring for 5min, the compound 26b, i.e., 2-acetoxyacetic acid (11.1mg,0.129mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (33.9mg,0.177mmol) were added, and the mixed solution was stirred at room temperature for 3 h. The reaction was then concentrated and purified by scraper (petroleum ether/ethyl acetate: 0/100) to give compound 26c, 2- ((1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -1H-pyrazol-4-yl) amino) -2-oxoethyl acetate as a white solid (30mg, 71.6% yield). LCMS (liquid Crystal Module) (M + 1)]+＝356.1
Step 2: example 26(TDM-180626)
The compound 26c (30mg,0.0845mmol), lithium hydroxide (20.3mg,0.845mmol), tetrahydrofuran (6mL) and water (0.6mL) were added to a single-necked flask and stirred at room temperature for 3 h. The reaction solution was then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by spatula to give compound 26 as a brown solid, 2-hydroxy-N- (1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -1H-pyrazol-4-yl) acetamide (16mg, 60.5% yield). LCMS (liquid Crystal Module) (M + 1)]+＝314.1
1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.91(s,1H),8.57(s,1H),8.12(d,J＝5.6Hz,1H),7.94(d,J＝6.3Hz,2H),7.41(s,1H),7.06-6.98(m,1H),5.79(t,J＝5.9Hz,1H),4.01(d,J＝5.9Hz,2H),3.81(s,3H)。
EXAMPLE nine A general procedure for the synthesis of compound TDM-180632
Figure BDA0002246639810000141
Step 1: example 32b
The compound 29c (193mg,1.1029mmol), the compound 32a, i.e., 2, 4-dichloropyridine (486.4mg,3.3087mmol), cesium carbonate (1078mg,3.3087mmol) and N, N-dimethylformamide (3mL) were added to a single vial and heated to 50 ℃ for reaction for 3 h. The reaction mixture was washed with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried, filtered, concentrated, and purified with a spatula (petroleum ether/ethyl acetate: 3/1) to give 1- (2-chloropyridin-4-yl) -N-ethyl-1H-pyrazole-4-sulfonamide (113mg, yield 35.9%) as a white solid compound 32 b. LCMS (liquid Crystal Module) (M + 1)]+＝287
Step 2: example 32(TDM-180632)
The compound 32b (30mg,0.1053mmol), the compound 32c, i.e., 1-methyl-1H-pyrazol-4-amine (30.6mg,0.316mmol), potassium carbonate (102.9mg,0.3mmol) and N, N-dimethylformamide (5mL) were added to a single-neck flask, stirred for 5min, and Pd was added at 20 ℃2(dba)3(9.6mg,0.01mmol) and Xantphos (12.2mg,0.02mmol) were added to a single-necked flask and N was replaced2Heating to 130 ℃ and under N2The reaction was stirred for 4h with protection. After cooling to room temperature, the reaction mixture was filtered, the filtrate was concentrated, and purified by scraper (petroleum ether/ethyl acetate ═ 1/100) to give compound 32, i.e., N-ethyl-1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -1H-pyrazole-4-sulfonamide (17.3mg, yield 47.3%) as a yellow solid. LCMS (liquid Crystal Module) (M + 1)]+＝348.0
1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),9.02(s,1H),8.19(d,J＝5.7Hz,1H),8.08(s,1H),7.94(s,1H),7.52(t,J＝5.7Hz,1H),7.43(s,1H),7.22(dd,J＝5.7,1.9Hz,1H),7.15(d,J＝1.7Hz,1H),3.81(s,3H),2.98–2.81(m,2H),1.04(t,J＝7.2Hz,3H).
EXAMPLE ten general procedure for the synthesis of compound TDM-180633
Step 1: example 33b
The compound 28c (120mg,0.634mmol), the compound 33a, i.e., 2, 4-dichloropyridine (282mg,1.9mmol), cesium carbonate (620mg,1.9mmol) and N, N-dimethylformamide (5mL) were added toIn a single-mouth bottle, the mixture is heated to 60 ℃ and reacted for 2 h. After washing the reaction mixture with water, ethyl acetate was added for extraction, and the organic phases were combined and washed with saturated brine, followed by drying, filtration, concentration and purification with a spatula (petroleum ether/ethyl acetate: 3/1) to give compound 33b, i.e., 1- (2-chloropyridin-4-yl) -N-propyl-1H-pyrazole-4-sulfonamide, as a white solid (100mg, 52.6% yield). LCMS (liquid Crystal Module) (M + 1)]+＝301
Step 2: example 33(TDM-180633)
The compound 33b (30mg,0.1mmol), the compound 32c, i.e., 1-methyl-1H-pyrazol-4-amine (30.6mg,0.3mmol), potassium carbonate (102.9mg,0.3mmol) and N, N-dimethylformamide (5mL) were added to a single-neck flask, stirred for 5min, and Pd was added at 20 ℃2(dba)3(9.6mg,0.01mmol) and Xantphos (12.2mg,0.02mmol) were added to a single-necked flask and N was replaced2Heating to 130 ℃ and under N2The reaction was stirred for 4h with protection. The reaction mixture was filtered, and the filtrate was concentrated and purified with a spatula (petroleum ether/ethyl acetate: 1/100), followed by high performance liquid chromatography to give compound 33, i.e., N-propyl-1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -1H-pyrazole-4-sulfonamide (20mg, yield 49.6%) as a yellow solid. LCMS (liquid Crystal Module) (M + 1)]+＝362.1
1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),9.15(s,1H),8.16(d,J＝6.1Hz,1H),8.12(s,1H),7.96(s,1H),7.59(t,J＝5.8Hz,1H),7.48(s,1H),7.25(s,1H),3.83(s,3H),2.82(dd,J＝13.0,7.0Hz,2H),1.49-1.39(m,2H),0.84(t,J＝7.4Hz,3H).
EXAMPLE ten A -like procedure for the synthesis of compound TDM-180634
Figure BDA0002246639810000151
Step 1: example 34c
The original compound 34a, i.e., 2, 4-dichloropyridine (3.0g,20.3mmol) and N, N-dimethylformamide (30mL) were added to a three-necked flask, and then compound 34b, i.e., ethyl 1H-pyrazole-4-carboxylate (2.56g,18.24mmol) and cesium carbonate (9.9g,30.45mmol) were added to the three-necked flask and reacted at 60 ℃ for 4H. Then cooling the reaction solution to room temperature, adding water to wash the reaction solution, and adding ethyl acetateThe ester was extracted, the organic phases were combined, washed with brine, dried, concentrated and purified by column chromatography (petroleum ether/ethyl acetate 5/1) to give compound 34c, ethyl 1- (2-chloropyridin-4-yl) -1H-pyrazole-4-carboxylate, as a white solid (2.9g, 56.8% yield). LCMS (liquid Crystal Module) (M + 1)]+＝253.0
Step 2: example 34e
The compound 34c (1.006g,4.0mmol), sodium carbonate (594mg,5.6mmol), compound 34d, i.e. 1-methyl-1H-pyrazol-4-amine (388mg,4.0mmol) and N, N-dimethylformamide (32mL) were added to a single-neck flask, stirred for 5min, and Pd was added at 20 ℃2(dba)3(36.6mg,0.04mmol) and Xantphos (46.3mg,0.08mmol) were added to a single-necked flask and N was replaced2Heating to 130 ℃ and under N2The reaction was stirred for 3h with protection. The reaction mixture was cooled to room temperature, washed with water and then extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried and concentrated, and purified by column chromatography (petroleum ether/ethyl acetate: 1/1) to give compound 34e, i.e., ethyl 1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -1H-pyrazole-4-carboxylate, as a yellow solid (910mg, yield 72.9%). LCMS (liquid Crystal Module) (M + 1)]+＝313.0
And step 3: example 34f
Compound 34e (810mg,2.6mmol), sodium hydroxide (1.04g,26.0mmol), tetrahydrofuran (30mL) and water (10mL) were added to a single-neck flask, stirred at room temperature for 24H, the reaction mixture was washed with water and extracted with ethyl acetate, the aqueous phase was separated, the pH of the aqueous phase was adjusted to 5 with 1M hydrochloric acid to precipitate a white solid, and dried compound 34f, i.e., 1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -1H-pyrazole-4-carboxylic acid (510mg, 69.1% yield) was filtered. LCMS (liquid Crystal Module) (M + 1)]+＝285.0
And 4, step 4: example 34(TDM-180634)
The compound 34f (64mg,0.225mmol), N, N-diisopropylethylamine (70mg,0.54mmol) and N, N-dimethylformamide (6mL) were added to a single-necked flask and stirred for 5 min. 34g of compound, 2, 2-trifluoroethylamine (26.8mg,0.270mmol) and HATU (128.5mg,0.338mmol) were added to a single vial at 20 ℃ and reacted at room temperature for 2 h. Then pouring the reaction liquid into water to separate out white solid, filtering and dryingPrepared by hplc to give compound 34 as a white solid, i.e., 1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -N- (2,2, 2-trifluoroethyl) -1H-pyrazole-4-carboxamide (48mg, 58.4% yield). LCMS (liquid Crystal Module) (M + 1)]+＝366.0
1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),9.13(s,1H),8.94(s,1H),8.30(s,1H),8.16(d,J＝6.5Hz,1H),7.96(s,1H),7.48(s,1H),7.22(d,J＝4.7Hz,2H),4.10(dd,J＝9.8,6.3Hz,2H),3.84(s,3H).
Figure BDA0002246639810000161
The gray solid compound TDM-180635, N- (cyanomethyl) -1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyridin-4-yl) -1H-pyrazole-4-carboxamide (24.5mg, yield: 33.8%)
EXAMPLE twelve, general procedure for the Synthesis of Compound TDM-180601
Figure BDA0002246639810000162
Step 1. Example 1c
A slurry of compound 1a, i.e., 2, 4-dichloropyrimidine (10.0g, 0.067mol), and acetonitrile (120mL) was added to a three-necked flask, and compound 1b, i.e., 4-nitro-1H-pyrazole (7.23g, 0.064mol) and N, N-diisopropylethylamine (12.5mL, 0.073mol) were added in that order, with stirring at 20 ℃. After stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 3/1) to give the compound 1c, i.e. 2-chloro-4- (4-nitro-1H-pyrazolyl-1-yl) pyrimidine, as a white solid (5.6g, 37% yield).
1H NMR(400MHz,CDCl3)δ9.31(d,J＝5.0Hz,1H),8.79(s,1H),8.32(s,1H),7.94(d,J＝5.4Hz,1H).
Step 2, Example 1e
A mixture of compound 1c (5.0g, 22.16mmol) and N, N-diisopropylethylamine (3.44g, 26.6mmol) in N, N-dimethylformamide (50mL) was stirred at room temperature for 5 minutes. To this mixture was added compound 1d, i.e. 1-methyl-1H-pyrazol-4-amine (2.37g, 24.4 mmol). After refluxing at 60 ℃ for 16 hours, the reaction solution was poured into water (100mL), and the mixture was extracted with ethyl acetate (100 mL. times.4). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was stirred with dichloromethane (10mL) for 30 minutes and then filtered to give compound 1e, i.e. N- (1-methyl-1H-pyrazol-4-yl) -4- (4-nitro-1H-pyrazol-1-yl) pyrimidin-2-amine, as a yellow solid (6.2g, 97% yield).
1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),9.37(s,1H),8.72-8.56(m,2H),7.96(s,1H),7.25(t,J＝7.0Hz,1H),3.85(s,3H).
Step 3 Example1
To a mixture of compound 1e (5.0g, 17.5mmol) in acetic acid (100mL) was added iron powder (29.4g, 525 mmol). The resulting mixture was heated at 60 ℃ for 4 hours, then cooled, then tetrahydrofuran (200mL) was added, filtered, the filtrate was adjusted to pH9 with aqueous ammonia solution, filtered, dried over anhydrous sodium sulfate, and concentrated. This gave compound 1f, 4 (4-amino-1H-pyrazol-1-yl) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine, as a yellow solid (1.85g, yield 41.3%). LCMS (liquid Crystal Module) (M + 1)]+＝257.0
Step 4. Example 1(TDM-180601)
Compound 1f (100mg,0.39 mmol) and triethylamine (59.1mg, 0.585mmol) were added to dichloromethane (30mL) and stirred at room temperature for 5 minutes. To the mixture was added compound 1g, i.e., cyclopropylcarboxylic acid (36.9mg, 0.429mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (112.1mg, 0.585 mmol). The resulting mixture was stirred at room temperature for 4 hours, and then concentrated under reduced pressure. Purification by spatula (petroleum ether/ethyl acetate 0/100) gave compound 1, N- (1(2(- (1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) cyclopropaneamide (28mg, 22.2% yield), as an off-white solid. LCMS (liquid Crystal Module) (M + 1)]+＝325.0
1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.66(s,1H),8.77(s,1H),8.45(d,J＝5.3Hz,1H),8.06-7.73(m,2H),7.55(s),7.10(d,J＝6.4Hz,1H),3.82(s,3H),1.78-1.67(m,1H),1.25(d,J＝10.2Hz,2H),0.81(d,J＝6.1,2H).
The gray solid compound TDM-180602, i.e. 3,3, 3-trifluoro-N- (1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) propionamide (55mg, yield: 41.6%)
The gray solid compound TDM-180603, 2-difluoro-N- (1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) cyclopropane-1-carboxamide (61mg, yield: 43.4%)
The yellow solid compound TDM-180604, 2-cyano-N- (1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) acetamide (60mg, yield: 47.5%)
A yellow solid compound TDM-180605, N- (1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) ethanesulfonamide (38mg, yield: 28.1%)
The yellow solid compound TDM-180606, N- (1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) propane-1-sulfonamide (30mg, yield: 21.2%)
EXAMPLE thirteen, general procedure for the Synthesis of Compound TDM-180625
Step 1 Example 25c
Compound 25a (100mg,0.39 mmol) and triethylamine (59.1mg, 0.585mmol) were added to dichloromethane (30mL) and stirred at room temperature for 5 minutes. To the mixture was added compound 25b, i.e., 2-acetoxyacetic acid (50.7mg, 0.429mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (112.1mg, 0.585 mmol). The resulting mixture was stirred at room temperature for 4 hours, and then concentrated under reduced pressure. Purification by scraper (petroleum ether/ethyl acetate ═ 0/100) gave compound 25c, 2- ((1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) amino) -2-oxoethyl acetate, as an off-white solid (103mg, 74.0% yield). LCMS (liquid Crystal Module) (M + 1)]+＝357.0
Step 2 Example sample 25(TDM-180625)
Compound 25c (70mg, 0.196mmol) was dissolved in a mixed solution of tetrahydrofuran (20mL) and water (2mL), followed by addition of lithium hydroxide (47mg, 1.96 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by scraping a silica gel plate gave compound 25 as an off-white solid, 2-hydroxy-N- (1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) acetamide (21mg, 34.1% yield). LCMS (liquid Crystal Module) (M + 1)]+＝315.1
1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.70(s,1H),8.91(s,1H),8.46(d,J＝5.3Hz,1H),8.05(s,1H),7.87(s,1H),7.55(s,1H),7.12(d,J＝5.3Hz,1H),5.82(t,J＝5.3Hz,1H),4.03(d,J＝5.3Hz,2H),3.83(s,3H).
EXAMPLE fourteen, general procedure for the synthesis of Compound TDM-180609
Figure BDA0002246639810000182
Step 1 Example 9c
Compound 9a (5.0g, 0.0335mol) and acetonitrile (80mL) were added to a three-necked flask, followed by the addition of compound 9b (4.7g, 0.0335mol), i.e., ethyl 1H-pyrazole-4-carboxylate, and potassium carbonate (13.9g, 0.1mol) in that order, and stirred at 50 ℃ overnight. The reaction solution was poured into ice water. After extraction with ethyl acetate (50 mL. times.2), the combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by column chromatography (petroleum ether/EtOAc ═ 8/1) gave compound 9c, ethyl 1- (2-chloropyrimidin-4-yl) -1H-pyrazole-4-carboxylate, as a yellow solid (3.2g, 38% yield). LCMS (liquid Crystal Module) (M + 1)]+＝253.6
Step 2 Example 9e
To 1, 4-dioxane (40mL) was added compound 9c (500mg,1.98mmol), compound 9d (250mg,2.58mmol), i.e., 1-methyl-1H-pyrazol-4-amine, palladium acetate (44mg,0.20mmol), potassium carbonate (820mg,5.95mmol), and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (229mg,0.40mmol), and the mixture was stirred at 100 ℃ overnight. Then, it was cooled and extracted with ethyl acetate (20 mL. times.2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate ═ 1/1) to give compound 9e, i.e., ethyl 1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazole-4-carboxylate (153mg, 25% yield), as a yellow solid.
Step 3 Example 9f
Compound 9e (153mg, 0.48mmol), tetrahydrofuran (5mL) and lithium hydroxide (35.1mg, 1.465mmol) were added sequentially in a three-necked flask and stirred at room temperature overnight. The reaction solution was diluted with water and adjusted to pH 2 with dilute hydrochloric acid. After extraction with ethyl acetate (50mL × 3), the combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give compound 9f, i.e., 1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazole-4-carboxylic acid, as a white solid (90mg, 64.7% yield). LCMS (liquid Crystal Module) (M + 1)]+＝286.0
Step 4. Example 9
Compound 9f (45mg, 0.157mmol) and N, N-dimethylformamide (5mL) were added to a three-necked flask, then compound 9g (16.78mg, 0.181mmol), N, N-diisopropylethylamine (70.2mg,0.544mmol) and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (68.9mg, 0.181mmol) were added sequentially with stirring at , stirred overnight at room temperature, the reaction solution was poured into ice water (20mL), then filtered and dried to give compound 9 as a yellow solid, N- (cyanomethyl) -1 (2- (1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazole-4-carboxamide (30.3mg, yield 59.4%). LCMS [ M +1], []+＝324.0
1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),9.17-9.4(m,2H),8.55(d,J＝4.0Hz,1H),8.29(s,1H),7.92(s,1H),7.61(s,1H),7.19(s,J＝4.0Hz,1H),4.15-4.07(m,2H),3.85(s,3H)
Figure BDA0002246639810000191
The white solid compound TDM-180610, 1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -N- (2,2, 2-trifluoroethyl) -1H-pyrazole-4-carboxamide (21mg, yield: 36.3%)
EXAMPLE fifteen general procedure for the Synthesis of Compound TDM-180630
Step 1 Example 30c
Compound 30b, i.e., 1-propylamine (1.07g,18.18mmol), triethylamine (552mg,5.45mmol), 1H-pyrazole-4-sulfonyl chloride (300mg,1.818mmol) and dichloromethane (10mL) were added to a single-necked flask, and the mixture was stirred at room temperature for reaction for 2 hours, concentrated and purified by column chromatography using a sand-core funnel (petroleum ether/ethyl acetate ═ 1/1) to give compound 30c, i.e., N-propyl-1H-pyrazole-4-sulfonamide (390mg, crude product), as a yellow solid. LCMS (liquid Crystal Module) (M + 1)]+＝190
Step 2 sample 30e
Compound 30c (190mg,1mmol), compound 30d i.e. 2, 4-dichloropyrimidine (447mg,3mmol), potassium carbonate (414mg,3mmol) and acetonitrile (10mL) were added to a single vial, heated to 60 ℃ for reaction for 4H, filtered, the filtrate was washed with water and extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried and concentrated, and purified by scraper purification (petroleum ether/ethyl acetate-1/1) to give compound 30e i.e. 1 (2-chloropyrimidin-4-yl) -N-propyl-1H-pyrazole-4-sulfonamide as a white solid (132mg, 43.9% yield). LCMS (liquid Crystal Module) (M + 1)]+＝302
Step 3 Example sample 30(TDM-180630)
Compound 30e (60mg,0.198mmol), compound 30f i.e. 1-methyl-1H-pyrazol-4-amine (38.8mg,0.297mmol), potassium carbonate (82.9mg,0.594mmol) and N, N-dimethylformamide (5mL) were added to a single vial, heated to 70 ℃ for reaction for 4H, the reaction solution was filtered, the filtrate was concentrated, and after purification with a spatula (petroleum ether/ethyl acetate ═ 1/100), compound 30 i.e. 1(2- (1-methyl-1H-pyrazol-4-yl) aminopyrimidin-4-yl) -N-propyl-1H-pyrazole-4-sulfonamide (25mg, yield 34.9%) was prepared as a white solid by HPLC. LCMS (liquid Crystal Module) (M + 1)]+＝363
1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.84(s,1H),8.58(d,J＝4.8Hz,1H),8.18(s,1H),7.88(s,1H),7.68(t,J＝5.8Hz,1H),7.20(d,J＝5.3Hz,1H),3.83(s,3H),2.82(dd,J＝13.1,6.8Hz,2H),1.49-1.37(m,2H),0.84(t,J＝7.4Hz,3H).
EXAMPLE sixteen general procedure for the synthesis of compound TDM-180631
Figure BDA0002246639810000201
Step 1. Example 31c
Compound 31b, i.e., 1-ethylamine (9.09mL,18.18mmol), triethylamine (552mg,5.45mmol), 1H-pyrazole-4-sulfonyl chloride (300mg,1.818mmol) and dichloromethane (20mL) were added to a single-necked flask, and the mixture was stirred at room temperature for reaction for 2H, concentrated and purified by column chromatography using a sand-core funnel (petroleum ether/ethyl acetate ═ 1/1) to give compound 31c (310mg, crude) as a yellow oil, i.e., N-ethyl-1H-pyrazole-4-sulfonamide. LCMS (liquid Crystal Module) (M + 1)]+＝176
Step 2, Example 31e
Compound 31c (160mg,0.914mmol), compound 31d i.e. 2, 4-dichloropyrimidine (408mg,2.74mmol), potassium carbonate (379mg,2.74mmol) and acetonitrile (10mL) were added to a single vial, heated to 60 ℃ for 3H, filtered, the filtrate was concentrated and purified with a spatula (petroleum ether/ethyl acetate: 1/1) to give compound 31e i.e. 1- (2-chloropyrimidin-4-yl) -N-ethyl-1H-pyrazole-4-sulfonamide as a white solid (130mg, 49.6% yield). LCMS (liquid Crystal Module) (M + 1)]+＝288
Step 3 Example 31(TDM-180631)
Example 31(TDM-180631) was prepared as described in preparation TDM-180629 to yield N-ethyl-1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazole-4-sulfonamide (130mg, 49.6% yield) as a white solid. LCMS (liquid Crystal Module) (M + 1)]+＝349.4
1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.85(s,1H),8.58(d,J＝4.6Hz,1H),8.18(d,J＝0.4Hz,1H),7.88(s,1H),7.66(t,J＝5.6Hz,2H),7.20(d,J＝5.3Hz,1H),3.83(s,3H),2.98-2.79(m,2H),1.05(t,J＝7.2Hz,3H).
EXAMPLE seventeen A general procedure for the synthesis of compound TDM-180710
Figure BDA0002246639810000202
Step 1 sample 110c
To a mixture of compound 110a (200mg, 0.95mmol), i.e. 4-chloro-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine, and compound 110b (130.8mg, 1.045mmol), i.e. methyl 1H-pyrazole-3-carboxylate, cesium carbonate (928.6mg, 2.85mmol) and N, N-dimethylformamide (15mL) were added at room temperature. The mixture was then heated to 100 ℃ and stirred for 2.5 hours. After the reaction was completed, the mixture was extracted with ethyl acetate (50 mL. times.3). The organic layer was washed with saturated brine (60mL × 6), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. To the residue was added EtOAc and PE, and the precipitate was collected by filtration to give compound 110c, methyl 1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazole-3-carboxylate (181.4mg, yield 64%) as a white solid. LCMS (liquid Crystal Module) (M + 1)]+＝300.
Step 2. Example 110d
To a mixed solution of compound 110c (181.4mg, 0.61mmol) in methanol (5mL) and tetrahydrofuran (5mL) was added an aqueous solution of lithium hydroxide (240mg) at room temperature. The mixture was then stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to remove excess methanol and tetrahydrofuran, and then the solution was neutralized with hydrochloric acid (2M), and the precipitate was collected by filtration. Ethanol was added to the precipitate, and water was removed by concentration under reduced pressure to give 110d (151.5mg, yield 87%) as a white solid, i.e., 1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazole-3-carboxylic acid. LCMS (liquid Crystal Module) (M + 1)]+＝286.
Step 3 Example sample 110(TDM-180710)
To a mixture of compound 110e (34mg, 0.368mmol), i.e., 2-aminoacetonitrile in N, N-dimethylformamide (10mL) was added N, N-diisopropylethylamine (126.6mg, 0.98mmol) at room temperature. The mixture was stirred for 5 minutes, then 2- (7-benzotriazol-oxide) -N, N' -tetramethyluronium hexafluorophosphate (139.65mg, 0.368mmol) and compound 110d (70mg, 0.245mmol) were added to the mixture, and stirred at room temperature for 3 hours. After completion of the reaction, water (40mL) was added to the mixture, and the precipitate was collected by filtration. Ethyl acetate and petroleum ether were added to the precipitate, and then the white solid compound 110, TDM-180710, i.e. N- (cyanomethyl) -1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-3-ylmethane, was collected by filtrationAmide (56.6mg, 71.5% yield). LCMS (liquid Crystal Module) (M + 1)]+＝324.
1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),9.22(t,J＝5.6Hz,1H),8.78(s,1H),8.60(d,J＝4.8Hz,1H),7.97(s,1H),7.52(s,1H),7.28(d,J＝5.3Hz,1H),7.03(d,J＝2.4Hz,1H),4.33(d,J＝5.7Hz,2H),3.85(s,3H).
EXAMPLE eighteen general procedure for the synthesis of compound TDM-180711
Figure BDA0002246639810000211
Step 1. Example 111c
To a mixture of compound 111a (200mg, 0.95mmol), i.e. 4-chloro-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine, and compound 111b (130.8mg, 1.045mmol), i.e. methyl 1H-pyrrole-3-carboxylate, cesium carbonate (928.6mg, 2.85mmol) and N, N-dimethylformamide (15mL) were added at room temperature. The mixture was then heated to 100 ℃ and stirred for 2.5 hours. At the end of the reaction, the mixture was extracted with ethyl acetate (50 mL. times.3). The organic layer was washed with saturated brine (60mL × 6) and dried over anhydrous sodium sulfate, and then the filtrate was concentrated under reduced pressure. To the residue were added ethyl acetate and petroleum ether, and the precipitate was collected by filtration to give 111c (238.5mg, yield 84%) as a white solid, i.e., methyl 1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrrole-3-carboxylate. LCMS (liquid Crystal Module) (M + 1)]+＝299.
Step 2, Example 111d
To a mixed solution of compound 111c (238.5mg, 0.8mmol) in methanol (5mL) and tetrahydrofuran (5mL) was added a solution of lithium hydroxide (400mg) in water (10mL) at room temperature. The mixture was then stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to remove excess methanol and tetrahydrofuran, and then the solution was neutralized with hydrochloric acid (2M), and the precipitate was collected by filtration. Ethanol was added to the precipitate, and the mixture was concentrated under reduced pressure with residual water to give 111d (219mg, yield 96.5%) as a pale yellow solid, i.e., 1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrrole-3-carboxylic acid. LCMS (liquid Crystal Module) (M + 1)]+＝285.
Step 3 Example 111(TDM-180711)
Compound 111d (100mg, 0.35mmol) was dissolved in N, N-dimethylformamide (10mL) at room temperature, then N, N-diisopropylethylamine (181mg, 1.4mmol) was added, the mixture was stirred for 5 minutes, then 2- (7-oxybenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate (139.65mg), 0.368mmol) and compound 111e (48.6mg, 0.525mmol), i.e., 2-aminoacetonitrile, were added to the mixture, and stirred at room temperature for 3 hours. Water (40mL) was added to the mixture and the precipitate was collected by filtration. To the precipitate was added ethyl acetate and petroleum ether, and then the compound 111, TDM-180711(73.1mg, 64.8% yield) was collected by filtration as a white solid, i.e., N- (cyanomethyl) -1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrrole-3-carboxamide. LCMS (liquid Crystal Module) (M + 1)]+＝323
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),8.87(s,1H),8.48(d,J＝5.3Hz,1H),8.29(t,J＝1.9Hz,1H),7.88(s,1H),7.76(s,1H),7.54(s,1H),7.09(d,J＝5.5Hz,1H),6.77(dd,J＝3.2,1.6Hz,1H),4.29(d,J＝5.6Hz,2H),3.84(s,3H).
EXAMPLE nineteen, general procedure for the Synthesis of Compound TDM-180738
Figure BDA0002246639810000221
Step 1: example 138b
Mixing compound B0(627mg,3.0mmol), compound 138a (508mg,3.3mmol) and Cs2CO3A mixture of (1.93g,6.0mmol) of DMF (20mL) was heated to 100 ℃ and stirred for 2 hours. The mixture was poured (. about.50 mL) and the precipitated solid was collected by filtration. The crude solid was slurried with EtOAc/PE (. about.1: 2), filtered and the solid dried to give compound 138b as a pale green solid (620mg, 58% yield), ethyl 5-methyl-1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazole-4-carboxylate.
LCMS[M+1]+＝328.2
Step 2: example 138c
To a mixture of compound 138b (570mg,1.74mmol) in THF (15mL) and MeOH (15mL) was added LiOH (15mL, saturated). The mixture was stirred at room temperature for 2 hoursThen (c) is performed. For mixtures H2Diluted O (30mL) and extracted with EtOAc (50 mL). The aqueous layer was separated and the pH adjusted to 2 with HCl (1N), and the precipitated solid was collected by filtration and dried in vacuo. Compound 138c (440mg, 78% yield) was obtained as a white solid, 5-methyl-1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazole-4-carboxylic acid.
LCMS[M+1]+＝300.1
And step 3: example 138(TDM-180738)
To a solution of compound 138c (80mg, 0.27mmol), i.e. 3-methyl-1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazole-4-carboxylic acid in N, N-dimethylformamide (10mL), was added N, N-diisopropylethylamine (139mg, 1.08mmol), the mixture was stirred for 5 minutes, then compound 138d (37.5mg, 0.405mmol), i.e. aminoacetonitrile hydrochloride and 2- (7-oxabenzotriazol) -N, N' -tetramethylurea hexafluorophosphate (153.9mg, 0.405mmol) were added and stirred at room temperature for 16 hours. Water was added to the mixture, and the precipitate was collected by filtration, ethanol was added to the precipitate, and the residue was concentrated under reduced pressure to remove residual water, ethyl acetate and petroleum ether were added to the residue, and the precipitate was collected by filtration to give compound 138, TDM-180738, (71.6mg, yield 78.7%) as a white solid, i.e., 3-methyl-1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -N- (2,2, 2-trifluoroethyl) -1H-pyrazole-4-carboxamide. LCMS (liquid Crystal Module) (M + 1)]+＝3381H NMR(400MHz,DMSO-d6)δ9.76(s,1H),9.32(s,1H),9.14(s,1H),8.51(d,J＝5.3Hz,1H),7.97(s,1H),7.59(s,1H),7.14(d,J＝5.3Hz,1H),4.31(d,J＝5.4Hz,2H),3.87(s,3H),2.47(s,3H).
A similar procedure prepared the following compounds:
Figure BDA0002246639810000222
TDM-180739 white solid compound 139, i.e., 3-methyl-1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -N- (2,2, 2-trifluoroethyl) -1H-pyrazole-4-carboxamide (82.7mg, yield: 80.5%).
EXAMPLE twenty A general procedure for the synthesis of compound TDM-180741
Figure BDA0002246639810000231
Step 1: example 141b
1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazole-4-carboxylic acid ethyl ester
A mixture of compound B0(326mg, 1.56mmol), compound 141a (240mg, 1.72mmol) and Cs2CO3(1.27g, 3.9mmol) in DMF (12mL) was reacted at 110 ℃ for 2 h. The reaction mixture was poured into H2O (20mL), and the precipitated solid was collected by filtration. The solid was slurried with ethyl acetate/petroleum ether (1: 2), filtered, and dried under vacuum. Compound 141b was obtained as a pale yellow solid (400mg, yield: 82%). LCMS (liquid Crystal Module) (M + 1)]+＝314.0.
Step 2: example 141c
1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazole-4-carboxylic acid
To a mixture of compound 141b (400mg, 1.28mmol) in MeOH (8mL) was added a solution of LiOH (8mL, saturated) and the reaction was stirred at 30 deg.C for 4 h. The mixture was concentrated under reduced pressure, neutralized to pH about 5 with HCl (2N), precipitate precipitated, collected by filtration, the solid was added ethanol, concentrated and dried. Compound 141c was obtained as a pale green solid (300mg, 82% yield).
LCMS[M+1]+＝286
And step 3: example 141(TDM-180741)
N- (2-cyanoethyl) -1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazole-4-carboxamide
To compound 141c (150mg, 0.52mmol) in DIPEA (335mg, 2.6mmol) and DMF (10mL) was added HATU (297mg, 0.78mmol) and compound 141d (110mg, 1.56 mmol). The resulting mixture was stirred at room temperature for 6 hours, the mixture was concentrated under reduced pressure to remove DMF, then H2O (15mL) was added, the solid was washed with H2O, then slurried with ethyl acetate/petroleum ether (ca. 5: 1), the solid was collected by filtration and dried. Compound 141 was obtained as an off-white solid (136.4 mg; yield 78%).
LCMS[M+1]+＝338.
1H NMR(400MHz,DMSO-d6)δ9.78(brs,1H),9.06(s,1H),8.88-8.98(m,1H),8.55(d,J＝5.2Hz,1H),8.24(s,1H),7.92(s,1H),7.59(brs,1H),7.19(d,J＝5.2Hz,1H),3.85(s,3H),3.45-3.55(m,2H),2.75-2.83(m,2H).
A similar procedure prepared the following compounds:
Figure BDA0002246639810000232
TDM-180742 off-white solid compound 142, 1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -N- (3,3, 3-trifluoropropyl) -1H-pyrazole-4-carboxamide (128.4 mg; yield 64%).
EXAMPLE twenty A -like procedure for the synthesis of compound TDM-180743
Figure BDA0002246639810000233
Step 1: example 143b
N- (1-methyl-1H-pyrazol-4-yl) -4- (4-nitro-1H-pyrazol-1-yl) pyrimidin-2-amine
A mixture of compound B0(326mg, 1.56mmol), compound 143a (264mg, 2.34mmol) and Cs2CO3(1.27g, 3.9mmol) in DMF (12mL) was heated to 110 ℃ and reacted for 5 h. The mixture was poured into H2O (20mL) and the precipitated solid was collected by filtration. The solid obtained is slurried with ethyl acetate/petroleum ether (1: 2), filtered and dried. Compound 143b was obtained as a yellow solid (240mg, 54% yield).
LCMS[M+1]+＝287.
Step 2: example 143c
4- (4-amino-1H-pyrazol-1-yl) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine
To a solution of compound 143b (220mg, 0.77mmol) in MeOH (30mL) was added Pd/C (100mg, 10% w.t.). The resulting mixture was heated to 35 ℃ for 3 hours. The mixture was diluted with DCM (50mL), filtered through a pad of celite, washed with DCM/MeOH, the filtrate and washings concentrated and dried under vacuum. Compound 143c was obtained as a pale yellow solid (170mg, yield 86%).
LCMS[M+1]+＝257.1.
And step 3: example 143(TDM-180743)
3-cyano-N- (1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) propionamide
To a solution of compound 143c (80mg, 0.31mmol) in DIPEA (120mg, 0.93mmol) and DMF (10mL) were added HATU (171mg, 0.45mmol) and compound 143d (62mg, 0.62 mmol). The reaction solution was stirred at room temperature for 6 hours. After completion of the reaction, the mixture was poured into H2O, extracted with EtOAc (30mL × 3), the combined organic layers were washed with H2O and brine, dried over Na2 SO4, filtered, concentrated, and purified by column chromatography (DCM/MeOH ═ 10/1) to give the crude product. The crude product was slurried with ethyl acetate/petroleum ether (4: 1) to give compound 143 as a white solid (35.5 mg; yield 44%).
LCMS[M+1]+＝338.
1H NMR(400MHz,DMSO-d6) δ 10.5(s,1H),9.71(s,1H),8.85(brs,1H),8.47(d, J ═ 5.2Hz,1H),7.88(s,2H),7.55(brs,1H),7.13(d, J ═ 5.2Hz,1H),3.83(s,3H),2.65-2.82(m,4H). similarly prepared compounds are as follows:
Figure BDA0002246639810000241
TDM-180744 white solid compound 144, namely 4,4, 4-trifluoro-N- (1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) butanamide (22.2 mg; 22% yield).
EXAMPLE twenty-two, a -like procedure for the synthesis of compound TDM-180746
Figure BDA0002246639810000242
Step 1. Example 146c
To a solution of compound 146a (500mg, 2.4mmol), i.e. 4-chloro-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine, in N, N-dimethylformamide (25mL), compound 146b (304mg, 2.4mmol), i.e. 5-methyl-4-nitro-1H-pyrazole and cesium carbonate (1.95g, 6mmol) were added at room temperature. The mixture was then heated to 115 ℃ and stirred for 4 hoursThen (c) is performed. After the reaction was completed, water was added to the mixture, and the precipitate was collected by filtration, and petroleum ether and ethyl acetate were added to the precipitate, and the precipitate was collected to give 146c (250mg, yield 34.7%) as a yellow solid, i.e., N- (1-methyl-1H-pyrazol-4-yl) -4- (3-methyl-4-nitro-1H-pyrazol-1-yl) pyrimidin-2-amine. LCMS (liquid Crystal Module) (M + 1)]+＝301.
Step 2. Example 146d
To a solution of compound 146C (250mg, 0.83mmol) in methanol (30mL) at room temperature was added the appropriate amount of Pd/C, then the mixture was degassed under vacuum, heated to 35 ℃ under hydrogen atmosphere and stirred for 3 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 146d (140mg, yield 62.5%) as a grey solid, i.e. 4- (4-amino-3-methyl-1H-pyrazol-1-yl) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine. LCMS (liquid Crystal Module) (M + 1)]+＝271.
Step 3 Example 146f (TDM-180746)
To a solution of compound 146d (40mg, 0.15mmol) in N, N-dimethylformamide (10mL) was added N, N-diisopropylethylamine (57.4mg, 0.444mmol) at room temperature, the mixture was stirred for 5 minutes, then to the mixture was added 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (84mg, 0.222mmol) and compound 146e (18.8mg, 0.222mmol), i.e., cyanoacetic acid, and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to remove N, N-dimethylformamide, and water was added to the residue and extracted with ethyl acetate (60mL × 3). The organic layer was washed with saturated brine (30mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and purified through a silica gel column (ethyl acetate: methanol ═ 20: 1) to give compound 146, TDM-180746(19.7mg, yield 39.5%) as a white solid, i.e., 2-cyano-N- (3-methyl-1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) acetamide. LCMS (liquid Crystal Module) (M + 1)]+＝338
1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.65(s,1H),8.87(s,1H),8.43(d,J＝5.4Hz,1H),7.86(s,1H),7.53(s,1H),7.06(d,J＝5.4Hz,1H),3.97(s,2H),3.83(s,3H),2.32(d,J＝10.0Hz,3H).
A similar procedure prepared the following compounds:
Figure BDA0002246639810000251
TDM-180747 white solid compound 147, i.e. 3,3, 3-trifluoro-N- (3-methyl-1- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) propionamide (29.9mg, yield: 26.6%).
EXAMPLE twenty-three, a general procedure for the synthesis of compound TDM-180704
Figure BDA0002246639810000252
Step 1: example 104b
The compound 104a (30mg,0.117mmol), methyl iodide (20mg,0.141mmol), potassium hydroxide (19.7mg, 0.351mmol) and tetrahydrofuran (5mL) were added to a single-necked flask. After stirring and reacting at 66 ℃ for 4 hours, the reaction solution was filtered, and the filtrate was concentrated to give a white-like solid compound 104b, i.e., N- (1-methyl-1H-pyrazol-4-yl) -4- (4- (methylamino) -1H-pyrazol-1-yl) pyrimidin-2-amine (30.5mg, crude product). LCMS (liquid Crystal Module) (M + 1)]+＝271.1
Step 2 Example sample 104(TDM-180704)
The compound 104b (30mg, 0.106mmol), triethylamine (16mg, 0.159mmol), the compound 104c (16.3mg, 0.133mmol), HATU, i.e., 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (63.4mg,0.167mmol), and dichloromethane (5mL) were added to a 50mL single vial and stirred at room temperature for 1.5 hours. The reaction mixture was then washed with water (10 mL. times.2), and the organic layer was separated and washed with Mg2SO4Drying, and concentrating under reduced pressure. Purification by preparative silica gel plates (100% ethyl acetate) gave compound 104, 2-difluoro-N-methyl-N- (1- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) cyclopropanecarboxamide as an off-white solid (22.5mg, 51.4% yield). LCMS (liquid Crystal Module) (M + 1)]+＝375.1。
1H NMR(400MHz,CDCl3)δ8.78(s,1H),8.45–8.30(m,2H),7.95(s,1H),7.82(s,1H),7.68(s,1H),7.25–7.23(m,1H),3.98(s,3H),3.58(s,3H),2.57–2.38(m,1H),2.23(td,J＝14.0,7.7Hz,1H),1.81(tdd,J＝12.3,7.9,4.8Hz,1H).
EXAMPLE twenty-four, a general procedure for the synthesis of compound TDM-180698
Figure BDA0002246639810000261
Step 1: example 98c
The compound 98a (100mg,0.391mmol), the compound 98b (73mg,0.469mmol), potassium hydroxide (66mg, 1.173mmol) and tetrahydrofuran (20mL) were added to a single-necked flask. After stirring and reacting at 66 ℃ for 16 hours, the reaction mixture was filtered, the filtrate was concentrated, and the concentrate was purified by preparative silica gel plate (100% ethyl acetate) to give an off-white solid compound 98c, i.e., 4- (4- (ethylamino) -1H-pyrazol-1-yl) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (90.5mg, yield 81.5%). LCMS (liquid Crystal Module) (M + 1)]+＝285.1
Step 2 sample 98(TDM-180698)
The compound 98c (30mg, 0.106mmol), triethylamine (16mg, 0.159mmol), compound 98d (16.2mg, 0.127mmol), EDCI, i.e., 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (30.5mg, 0.159mmol) and dichloromethane (10mL) were added to a 50mL one-necked flask and stirred at room temperature for 16 hours. The reaction mixture was then washed with water (10 mL. times.2), and the organic layer was separated and washed with Mg2SO4Drying, and concentrating under reduced pressure. Purification by preparative silica gel plates (100% ethyl acetate) gave compound 98 as an off-white solid, N-ethyl-2, 2-difluoro-N- (1- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) cyclopropanecarboxamide (9.6mg, 23.3% yield). LCMS (liquid Crystal Module) (M + 1)]+＝389.1。
1H NMR(400MHz,CDCl3)δ8.76(s,1H),8.40(d,J＝5.4Hz,1H),7.91(s,1H),7.84(s,1H),7.73(s,1H),7.58(s,1H),7.17(d,J＝5.4Hz,1H),4.05(q,J＝7.0Hz,2H),3.94(s,3H),2.52–2.41(m,1H),2.23(td,J＝14.0,7.6Hz,1H),1.86–1.75(m,2H),1.30(t,J＝6.1Hz,4H).
A similar procedure prepared the following compounds:
Figure BDA0002246639810000262
TDM-180705 white-like solid compound 105, N-ethyl-3, 3, 3-trifluoro-N- (1- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-4-yl) propionamide (17.4mg, yield: 41.7%)
EXAMPLE twenty five, general procedure for the Synthesis of Compound TDM-180713
Figure BDA0002246639810000263
Step 1: example113c
The compound 113a (50.0mg, 0.195mmol) was dissolved in dichloromethane (10mL), and the compound 113b (24.5mg, 0.215mmol) and acetic acid (0.2mL) were added and stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (49.6mg, 0.234mmol) was then added, and the reaction solution was stirred at room temperature for 18 hours. The reaction solution was poured into water (20mL), the pH was adjusted to near neutrality with sodium bicarbonate, the organic layer was separated, the aqueous layer was extracted with dichloromethane (15mL × 2), the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the concentrate was purified by preparative TLC (methanol/dichloromethane ═ 1/20) to give compound 113c, i.e., N- (1-methyl-1H-pyrazol-4-yl) -4- (4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) -1H-pyrazol-1-yl) pyrimidin-2-amine, as a white solid (52mg, yield 75.3%). LCMS (liquid Crystal Module) (M + 1)]+＝355.1。
Step 2. Example113 (TDM-180713)
To a solution of the compound 113c (30mg, 0.085mmol) in tetrahydrofuran (10mL) were added potassium hydroxide (14.5mg, 0.255mmol) and methyl iodide (14.5mg, 0.102mmol), and the reaction was stirred at 66 ℃ for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was purified by preparative TLC (100% EtOAc) to give compound 113, 4- (4- (methyl ((tetrahydro-2H-pyran-4-yl) methyl) amino) -1H-pyrazol-1-yl) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (20.3mg, 64.8%) as an off-white solid. LCMS (liquid Crystal Module) (M + 1)]+＝369.2。
1H NMR(400MHz,CDCl3)δ8.37(d,J＝5.5Hz,1H),7.83(s,1H),7.75(s,1H),7.67(s,1H),7.43(s,1H),7.14(d,J＝5.5Hz,1H),4.01(dd,J＝11.1,3.7Hz,2H),3.93(s,3H),3.57(s,3H),3.41(td,J＝11.9,1.8Hz,2H),2.97(d,J＝6.7Hz,2H),1.85(s,1H),1.72(d,J＝12.9Hz,2H),1.39(ddd,J＝25.0,12.2,4.5Hz,4H),0.88(t,J＝6.7Hz,2H).
EXAMPLE twenty-six, general procedure for the Synthesis of Compound TDM-180717
Figure BDA0002246639810000271
Step 1: example117c
The compound 117a (50.0mg, 0.195mmol) was dissolved in dichloromethane (10mL), and the compound 117b (21.5mg, 0.215mmol) and acetic acid (0.2mL) were added and stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (49.6mg, 0.234mmol) was then added. The reaction solution was stirred at room temperature for 3 hours. The reaction mixture was poured into water (20mL), the pH was adjusted to near neutrality with sodium bicarbonate, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (15 mL. times.2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 117c, which is N- (1-methyl-1H-pyrazol-4-yl) -4- (4- (((3-methylpyridin-3-yl) methyl) amino) -1H-pyrazol-1-yl) pyrimidin-2-amine as a white solid (61mg, yield 91.9%, crude). LCMS (liquid Crystal Module) (M + 1)]+＝341.2。
Step 2 Example sample 117(TDM-180717)
To a solution of the compound 117c (53mg, 0.156mmol) in tetrahydrofuran (10mL) were added potassium hydroxide (26.2mg, 0.468mmol) and methyl iodide (26.5mg, 0.187mmol), and the reaction solution was stirred at 66 ℃ for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrate was purified by preparative TLC (100% ethyl acetate) and preparative HPLC to give compound 117 as an off-white solid, i.e., 4- (4- (methyl ((3-methylpyridin-3-yl) methyl) amino) -1H-pyrazol-1-yl) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-ylamine (8.2mg, 14.8%). LCMS (liquid Crystal Module) (M + 1)]+＝355.2。
1H NMR(400MHz,CDCl3)δ8.38(d,J＝5.5Hz,1H),7.88(s,1H),7.75(s,1H),7.67(s,1H),7.49(d,J＝13.7Hz,1H),7.15(d,J＝5.5Hz,1H),5.32(d,J＝14.8Hz,1H),4.55(d,J＝5.9Hz,2H),4.46(d,J＝6.0Hz,2H),3.94(s,3H),3.58(s,3H),3.26(s,2H),1.40(s,4H).
EXAMPLE twenty-seven, general procedure for the Synthesis of Compound TDM-180718
Figure BDA0002246639810000272
Step 1: example118c
The compound 118a (50.0mg, 0.195mmol) was dissolved in dichloromethane (10mL), and the compound 118b (21.5mg, 0.215mmol) and acetic acid (0.2mL) were added and stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (49.6mg, 0.234mmol) was then added. The reaction solution was stirred at room temperature for 4 hours. The reaction mixture was poured into water (20mL), the pH was adjusted to near neutrality with sodium bicarbonate, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (15 mL. times.2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give compound 118c, i.e., 4- (4- (((4, 4-difluoroethoxy) methyl) amino) -1H-pyrazol-1-yl) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine, as a white solid (51mg, yield 67.4%, crude). LCMS (liquid Crystal Module) (M + 1)]+＝389.2。
Step 2. Example118 (TDM-180718)
To a solution of the compound 118c (51mg, 0.131mmol) in tetrahydrofuran (10mL) were added potassium hydroxide (22.1mg, 0.394mmol) and methyl iodide (22.4mg, 0.158mmol), and the reaction solution was stirred at 66 ℃ for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrate was purified by preparative HPLC to give compound 118, i.e., 4- (4- (((4, 4-difluorocyclohexyl) methyl) (methyl) amino) -1H-pyrazol-1-yl) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (11.2mg, 21.3%) as an off-white solid. LCMS (liquid Crystal Module) (M + 1)]+＝403.2。
1H NMR(400MHz,CDCl3)δ8.37(d,J＝5.3Hz,1H),7.82(s,1H),7.74(s,1H),7.68(s,1H),7.42(s,1H),7.13(d,J＝5.4Hz,1H),3.93(s,3H),3.57(s,3H),2.98(d,J＝6.5Hz,2H),2.13(s,2H),1.90(d,J＝13.5Hz,3H),1.63(d,J＝23.3Hz,3H),1.38(dd,J＝23.3,11.2Hz,3H).
EXAMPLE twenty eight A general procedure for the synthesis of compound TDM-180699
Figure BDA0002246639810000281
Step 1 Example 99c
Compound 99a, i.e. 4-chloro-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (824mg,4.0mmol), compound 99b, i.e. tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate (2.35g,8.0mmol), Pd (dppf) Cl2(292mg,0.4mol), sodium carbonate (292mg,0.4mmol), 1, 4-dioxane (42mL) and water (7mL) were added to a three-necked flask. The nitrogen is pumped and replaced for three times under the condition of a system water pump. The reaction mixture was reacted at 95 ℃ for 24 hours and then cooled. After completion of the reaction, the crude product was concentrated under reduced pressure and purified by column chromatography (eluent: ethyl acetate/methanol 1/20) to give compound 99c, i.e., N- (1-methyl-1H-pyrazol-4-yl) -4- (1H-pyrazol-4-yl) pyrimidin-2-amine (0.8g, yield 83%) as an off-white solid. LCMS (liquid Crystal Module) (M + 1)]+＝242.1
Step 2 Example 99e
Compound 99c (600mg,2.48mmol), cesium carbonate (3.23g,9.92mmol) and compound 99d, methyl 2, 4-dibromobutyrate (710mg,2.73mmol) were added to dimethylformamide (15mL), and the mixture was stirred at 45 ℃ for 2 hours. After completion of the reaction, it was poured into water (30mL) and extracted with ethyl acetate (40mL × 4). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the crude product was subjected to column chromatography (eluent: ethyl acetate) to separate and purify the crude product to obtain an off-white solid compound of methyl 1- (4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) cyclopropanecarboxylate (420mg, yield 50%) as 99 e.
LCMS[M+1]+＝340.1
1H NMR(400MHz,DMSO-d6))δ9.36(s,1H),8.59(s,1H),8.35(d,J＝5.2Hz,1H),8.15(s,1H),7.94(s,1H),7.51(s,1H),7.00(d,J＝5.2Hz,1H),4.23-4.47(m,2H),3.83(s,3H),3.64(s,3H),1.72-1.81(m,4H).
Step 3 Example 99f
To a solution of compound 99e (400mg,1.18mmol) in methanol (5mL) was added an aqueous solution of lithium hydroxide (1M,5 mL). The reaction solution was allowed to react at room temperature for 2 hours. After the reaction was completed, spin-dried under reduced pressure, acidified with hydrochloric acid (2M) to pH 4 to precipitate a solid precipitate, filtered, and the filter cake was dried to obtain a green solid compound 99f, i.e., 1- (4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) cyclopropanecarboxylic acid (320mg, yield 84%).
LCMS[M+1]+＝326.1
1H NMR(400MHz,DMSO-d6)δ13.14(br s,1H),9.35(s,1H),8.56(s,1H),8.34(d,J＝5.2Hz,1H),8.11(s,1H),7.94(s,1H),7.51(s,1H),7.00(d,J＝5.2Hz,1H),3.83(s,3H),1.61-1.76(m,4H).
Step 4 sample 99(TDM-180699)
Compound 74h 99f (80mg,0.25mmol) and N, N' -diisopropylethylamine (57mg,0.44mmol) were added to dimethylformamide (5mL) and stirred for 5 minutes. Subsequently, 99g of compound, i.e., 3-difluoroazetidine hydrochloride (43mg,0.34mmol) and HATU (100mg,0.26mmol) were added. The resulting mixture was stirred at room temperature for 4 hours, poured into water (30mL), and extracted with ethyl acetate (30mL × 3). The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and purified by column chromatography of the crude product (ethyl acetate/petroleum ether ═ 0-100%) to give compound 99, i.e., (3, 3-difluoropyrrolidin-1-yl) (1- (4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) cyclopropyl) methanone as a white solid (97.2mg, 84% yield).
LCMS[M+1]+＝401.1
1H NMR(400MHz,Chloroform-d)δ8.39(d,J＝5.2Hz,1H),8.18(s,1H),8.09(s,1H),7.81(s,1H),7.59(s,1H),6.94(s,1H),6.83(d,J＝5.2Hz,1H),4.23-4.47(m,2H),3.95(s,3H),3.69-3.86(m,2H),1.94-1.99(m,2H),1.57-1.65(m,2H).
A similar procedure prepared the following compounds:
Figure BDA0002246639810000291
TDM-180700 off-white solid Compound 100, namely (3, 3-difluoropyrrolidin-1-yl) (1- (4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) cyclopropyl) methanone (85mg, yield 79%)
EXAMPLE twenty-nine A general procedure for the synthesis of compound TDM-180714
Figure BDA0002246639810000292
Step 1: example114b
To a solution of the compound 114a (80.0mg, 0.588mmol) in dichloromethane (10mL) were added DMF (0.5mL) and thionyl chloride (209.8mg, 1.763mmol), and the mixture was stirred at 40 ℃ for 3 hours. After removal of the solvent under reduced pressure, compound 114b, i.e., 3-difluorocyclobutanecarbonyl chloride (90.9mg, crop) was obtained as a colorless oily liquid.
Step 2 sample 114(TDM-180714)
To a solution of the compound 114c (70.8mg, 0.294mmol) in DMF (5mL) were added triethylamine (89.1mg, 0.882mmol) and compound 114b (90.9mg, 0.588mmol), and the solution was stirred at room temperature for 1.5 h. The reaction was concentrated under reduced pressure and the concentrate was purified by preparative HPLC to give compound 114 (3, 3-difluorocyclobutyl) (3- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) methanone as a yellow solid (6.9mg, 6.5%). LCMS (liquid Crystal Module) (M + 1)]+＝360.1。
1H NMR(400MHz,CDCl3)δ8.76(s,1H),8.39(d,J＝5.1Hz,1H),8.22(s,1H),7.83(s,1H),7.55(s,1H),7.10(s,1H),6.87(d,J＝5.1Hz,1H),4.25–4.04(m,1H),3.93(s,3H),3.01(dt,J＝14.5,8.7Hz,4H).
EXAMPLE thirty, general procedure for the Synthesis of Compound TDM-180737
Figure BDA0002246639810000301
Step 1 Example 137c
To a solution of compound 137a (150mg, 0.62mmol), i.e., N- (1-methyl-1H-pyrazol-4-yl) -4- (1H-pyrazol-4-yl) pyrimidin-2-amine, in N, N-dimethylformamide (10mL), compound 137b (241mg, 1.24mmol), i.e., ethyl 2-bromo-2-methylpropionate and cesium carbonate (505mg, 1.55mmol) were added at room temperature. The mixture was then heated to 60 ℃ and stirred for 2 hours. After the reaction was completed, the mixture was extracted with ethyl acetate (40 mL. times.3) andthe organic layer was washed with saturated brine (30 mL. times.6), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. This was purified by silica gel column (petroleum ether: ethyl acetate ═ 13:87) to give compound 137c (213mg, yield 85%) as a white solid, i.e., ethyl 2-methyl-2- (4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionate. LCMS (liquid Crystal Module) (M + 1)]+＝356.
Step 2 Example 137d
To a mixed solution of compound 137c (189mg, 0.53mmol) in methanol (4mL) and tetrahydrofuran (4mL) was added a solution of sodium hydroxide (212mg) in water (8mL) at room temperature. The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to remove excess methanol and tetrahydrofuran, and then the solution was neutralized with hydrochloric acid (2M). The solution was extracted with ethyl acetate (50mL × 3), the organic layer was washed with saturated brine (30mL), and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give compound 137d (127mg, yield 73.4%) as a yellow solid, i.e., 2-methyl-2- (4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propionic acid. LCMS (liquid Crystal Module) (M + 1)]+＝328.
Step 3 Example 137(TDM-180737)
To a solution of compound 137d (60mg, 0.183mmol) and compound 137e (39.4mg, 0.275mmol), i.e., 3-difluoropyrrolidine, in N, N-dimethylformamide (10mL), triethylamine (74mg, 0.732mmol) was added at room temperature. The mixture was stirred for 5 minutes, then 2- (7-benzotriazol-oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (104mg, 0.275mmol) was added to the mixture and stirred at room temperature for 16 hours. To the mixture was added water (40mL) and extracted with ethyl acetate (40 mL. times.3), the organic layer was washed with saturated brine (30 mL. times.6) and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. This was purified by silica gel column (petroleum ether: ethyl acetate ═ 0: 100) to give compound 137, TDM-180737(61mg, yield 80%) as a white solid, i.e., 1- (3, 3-difluoropyrrolidin-1-yl) -2-methyl-2- (4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1H-pyrazol-1-yl) propan-1-one. LCMS (liquid Crystal Module) (M + 1)]+＝417
1H NMR(400MHz,CDCl3)δ8.29(d,J＝5.2Hz,1H),8.03(d,J＝12.9Hz,2H),7.75(s,1H),7.46(s,1H),6.81(s,1H),6.76(d,J＝5.2Hz,1H),3.84(s,3H),3.71(s,2H),2.80(d,J＝13.3Hz,2H),2.13(s,2H),1.58(s,3H),1.18(s,3H).
Experiments for identifying inhibitory effects of compounds on JAK kinase Activity
Janus kinases (JAKs) include JAK1, JAK2, JAK3 and Tyk2, transduce cytokine-mediated signals through the JAK-STAT pathway. The size of the kinase is 120-140kDa, and 7 defined homologous regions are JH1-JH 7. JH1 is an important region of enzymatic activity and contains the typical tyrosine kinase signature, and phosphorylation of tyrosine results in a conformational change in the JAK protein, thereby facilitating substrate binding. The JAK-STAT system comprises three major components: receptors that cross cell membranes, Janus kinases linked to receptors, and Signaling and Transcriptional Activators (STATs) that transport signals into the nucleus and DNA. When cytokines bind to receptors, JAKs phosphorylate the receptors, attracting STAT proteins, which are also phosphorylated and then bind to each other to form dimers, which enter the nucleus and bind to DNA, resulting in gene transcription.
The EZ Reader of PerkinElmer company can be used for detecting phosphorylation of a polypeptide substrate catalyzed by kinase, the device can directly detect a fluorescence-labeled substrate and a product based on a micro-control fluid separation technology, the separation step is realized in a micro-fluid chip by controlling pressure and electric field intensity, a kinase experiment generally controls the product conversion rate to be 20-30%, and the biological test method is used for identifying the inhibition effect of a compound on JAK kinase activity.
1. Experimental Material
S1.1 test Compounds
The compound powder was dissolved in DMSO and stored in a refrigerator at-20 ℃ under sealed conditions. Internalization compound Ref1 was used for positive controls for JAK1, JAK2 and Tyk2 tests, and Ref2 was used for positive control for JAK3 tests.
2. Reagent
S2.1, 1M HEPES buffer
S2.2, 40mM ATP solution
S2.3, 0.5% Tween 20
S2.4, 35% bovine serum albumin
S2.5, 1M dithiothreitol solution
S2.6, 0.5mM Jaktide Peptide substrate solution
S2.7, 0.5mM IRStide Peptide substrate solution
S2.8, Assay Buffer: 20mM HEPES buffer, pH 7.4, 10mM magnesium chloride, 0.01% bovine serum albumin BSA, 0.0005% Tween-20, 1mM dithiothreitol solution.
S2.9, Stop Buffer of reaction termination solution: 180mM HEPES Buffer, 20mM ethylenediaminetetraacetic acid, 0.2% Coating Reagent 3.S2.10, Separation Buffer: 100mM HEPES buffer, 10mM EDTA, 0.0005% Tween 20, 0.1% Coating Reagent 3, 1% dimethyl sulfoxide.
3. Experimental methods
S3.1 preparation of Compound plate
The compound was dissolved in 10mM DMSO, diluted to 0.6mM in volumes, and 10. mu.l of 0.6mM dilution was added to 384 microwell plates, followed by 3-fold gradient dilution, for a total of 8 concentration points.
S3.2 arrangement of Compounds
Figure BDA0002246639810000311
Positive control (HPE 1): ref1, final concentration: 10 μ M
Positive control (HPE 1): ref2, final concentration: 10 μ M
Negative control (ZPE): DMSO to a final concentration of 1.6%
A compound: the highest final concentration was 10 μ M, 3-fold dilution, 8 concentration points, 2 replicates.
4. Experimental procedure
S4.1, adding 250nl of compound into each hole of an ECHO to an experimental plate, and centrifuging for 1 minute at 1000 revolutions;
s4.2, adding 5 mul of experiment buffer solution, and shaking for several seconds to fully dissolve the compound;
s4.3, adding 5 mul of 3 multiplied substrate solution, adding 5 mul of 3 multiplied kinase solution, and centrifuging for 1 minute at 800 revolutions;
s4.4. the final concentrations of JAK1, JAK2, JAK3 and Tyk2 kinase in the reaction system were 20, 1, 1, and 1nM, respectively.
S4.5, incubation at room temperature, wherein each kinase needs different time, and the kinases in different batches have time difference
S4.6, reacting to 20% -30%, adding 15 mul of stop solution to stop, and centrifuging for 2 minutes at 1000 rpm.
And S4.7, placing the plate on an EZ Reader to read the plate.
S4.8.ez Reader reading is calculated from peak height,% product turnover ═ product/(product + substrate) × 100
5. Data processing: IC50 calculation
Test compound concentration curves were generated using the mapping software Xlfit and IC50 values were calculated.
The IC50 values for the compounds shown in the above examples obtained using this experimental procedure are listed in the table below:
the following table lists the IC50 values for the compounds shown in the various examples above. "A" means ≧ 10 μ M; "B" means ≧ 1 μ M and <10 μ M; "C" means ≥ 0.1. mu.M and < 1. mu.M; "D" means < 0.1. mu.M.
Figure BDA0002246639810000321
Figure BDA0002246639810000331
Figure BDA0002246639810000341

Claims (10)

  1. The kinds of small molecule compounds are characterized in that the compounds are shown by the following structural formula or stereoisomers, geometric isomers, tautomers, racemates, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs thereof:
    Figure FDA0002246639800000011
    wherein, X is1、X2Selected from carbon or nitrogen;
    a is described1、A2、A3、A4、A5Wherein or more than carbons are replaced by nitrogen, sulfur or oxygen;
    from said A1、A2、A3、A4、A5The five-membered ring formed has aromaticity;
    any or any number of hydrogen atoms on the five-membered ring are replaced by R;
    and R is selected from hydrogen, halogen, alkyl, substituted alkyl, amino, substituted amino, carboxyl, amido, substituted amido, ester, substituted carbonyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl.
  2. 2. The small molecule compounds of claim 1, wherein:
    and R is a nitrogen-containing group.
  3. 3. The small molecule compounds of claim 1, wherein:
    r is
    Figure FDA0002246639800000012
    Wherein, R is1Hydrogen, alkyl;
    the R is2Is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, sulfone, sulfoxide, substituted carbonyl.
  4. 4. The small molecule compounds of claim 1, wherein:
    r is
    Figure FDA0002246639800000013
    Wherein, R is3Hydrogen, alkyl;
    the R is4Is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, sulfone, sulfoxide, substituted carbonyl.
  5. 5. The small molecule compounds of claim 1, wherein:
    r is
    Figure FDA0002246639800000014
    Wherein n is 0 or a natural number;
    the R is5Hydrogen, alkyl;
    the R is6Is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, sulfone, sulfoxide, substituted carbonyl.
  6. 6. The small molecule compounds of claim 1, wherein:
    r is
    Wherein n is 0,1, 2;
    the R is7Is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl.
  7. 7. The small molecule compounds of claim 5, wherein:
    r is
    Figure FDA0002246639800000022
    Wherein, R is8、R9Are alkyl groups which may be the same or different.
  8. 8. The small molecule compounds of claim 5, wherein:
    r is
    Figure FDA0002246639800000023
    Wherein m is 0,1,2,3,4, 5.
  9. 9. The small molecule compounds of claim 1, wherein:
    the R is1Is composed of
    Figure FDA0002246639800000024
    Wherein, R is17Selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, hydroxyl, ether, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
    the R is18Selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, hydroxyl, ether, aryl, substituted aryl, heteroaryl, substituted heteroaryl.
  10. 10. The small molecule compound of any one of claims 1-9 to , wherein:
    can be used for treating, preventing and relieving autoimmune diseases such as rheumatic arthritis and inflammatory dermatoses related to autoimmunity.
CN201911019187.9A 2019-10-24 2019-10-24 small molecule compounds Pending CN110734428A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201911019187.9A CN110734428A (en) 2019-10-24 2019-10-24 small molecule compounds
PCT/CN2020/120130 WO2021078020A1 (en) 2019-10-24 2020-10-10 Small molecule compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201911019187.9A CN110734428A (en) 2019-10-24 2019-10-24 small molecule compounds

Publications (1)

Publication Number Publication Date
CN110734428A true CN110734428A (en) 2020-01-31

Family

ID=69271268

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201911019187.9A Pending CN110734428A (en) 2019-10-24 2019-10-24 small molecule compounds

Country Status (2)

Country Link
CN (1) CN110734428A (en)
WO (1) WO2021078020A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112159394A (en) * 2020-10-09 2021-01-01 嘉兴特科罗生物科技有限公司 Small molecule compound as JAK kinase inhibitor and application thereof
WO2021078020A1 (en) * 2019-10-24 2021-04-29 嘉兴特科罗生物科技有限公司 Small molecule compound
WO2022171140A1 (en) * 2021-02-09 2022-08-18 明慧医药（杭州）有限公司 Prodrug compound, preparation method therefor and use thereof
WO2023001045A1 (en) * 2021-07-20 2023-01-26 上海椿安生物医药科技有限公司 External anti-inflammatory coupling compound drug, and preparation method therefor and use thereof
WO2023011301A1 (en) * 2021-08-06 2023-02-09 嘉兴特科罗生物科技有限公司 Jak inhibitor with high oral bioavailability

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113264919B (en) * 2021-05-26 2022-09-13 无锡捷化医药科技有限公司 Preparation method of 1- (2-methoxypyridine-4-yl) -1H-pyrazole-4-amine
CA3234554A1 (en) * 2021-10-06 2023-04-13 Aerie Pharmaceuticals, Inc. Janus kinase inhibiting pyrazole compounds and uses thereof
WO2023076161A1 (en) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007053776A1 (en) * 2005-11-03 2007-05-10 Sgx Pharmaceuticals, Inc. Pyrimidinyl-thiophene kinase modulators
CN103298794A (en) * 2010-11-09 2013-09-11 塞尔卓姆有限公司 Pyridine compounds and aza analogues thereof as TYK2 inhibitors
EP2832734A1 (en) * 2012-03-28 2015-02-04 Takeda Pharmaceutical Company Limited Heterocyclic compound
WO2015016206A1 (en) * 2013-07-30 2015-02-05 武田薬品工業株式会社 Heterocyclic compound
WO2016014542A1 (en) * 2014-07-21 2016-01-28 Dana-Farber Cancer Institute, Inc. Imidazolyl kinase inhibitors and uses thereof
WO2016023014A2 (en) * 2014-08-08 2016-02-11 Dana-Farber Cancer Institute, Inc. Uses of salt-inducible kinase (sik) inhibitors
WO2018053373A1 (en) * 2016-09-16 2018-03-22 The General Hospital Corporation Uses of satl-inducible kinase (sik) inhibitors for treating osteoporosis

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JOP20190080A1 (en) * 2016-10-14 2019-04-11 Bayer Pharma AG Substituted 6-(1h-pyrazol-1-yl)pyrimidin-4-amine derivatives and uses thereof
CN110734428A (en) * 2019-10-24 2020-01-31 嘉兴特科罗生物科技有限公司 small molecule compounds
CN110627775A (en) * 2019-10-24 2019-12-31 嘉兴特科罗生物科技有限公司 Small molecule compound
CN110862380A (en) * 2019-10-24 2020-03-06 嘉兴特科罗生物科技有限公司 Small molecule compound

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007053776A1 (en) * 2005-11-03 2007-05-10 Sgx Pharmaceuticals, Inc. Pyrimidinyl-thiophene kinase modulators
CN103298794A (en) * 2010-11-09 2013-09-11 塞尔卓姆有限公司 Pyridine compounds and aza analogues thereof as TYK2 inhibitors
EP2832734A1 (en) * 2012-03-28 2015-02-04 Takeda Pharmaceutical Company Limited Heterocyclic compound
WO2015016206A1 (en) * 2013-07-30 2015-02-05 武田薬品工業株式会社 Heterocyclic compound
EP3029031A1 (en) * 2013-07-30 2016-06-08 Takeda Pharmaceutical Company Limited Heterocyclic compound
WO2016014542A1 (en) * 2014-07-21 2016-01-28 Dana-Farber Cancer Institute, Inc. Imidazolyl kinase inhibitors and uses thereof
WO2016023014A2 (en) * 2014-08-08 2016-02-11 Dana-Farber Cancer Institute, Inc. Uses of salt-inducible kinase (sik) inhibitors
WO2018053373A1 (en) * 2016-09-16 2018-03-22 The General Hospital Corporation Uses of satl-inducible kinase (sik) inhibitors for treating osteoporosis

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021078020A1 (en) * 2019-10-24 2021-04-29 嘉兴特科罗生物科技有限公司 Small molecule compound
CN112159394A (en) * 2020-10-09 2021-01-01 嘉兴特科罗生物科技有限公司 Small molecule compound as JAK kinase inhibitor and application thereof
WO2022073425A1 (en) * 2020-10-09 2022-04-14 嘉兴特科罗生物科技有限公司 Small molecule compound serving as jak kinase inhibitor, and use thereof
WO2022171140A1 (en) * 2021-02-09 2022-08-18 明慧医药（杭州）有限公司 Prodrug compound, preparation method therefor and use thereof
WO2023001045A1 (en) * 2021-07-20 2023-01-26 上海椿安生物医药科技有限公司 External anti-inflammatory coupling compound drug, and preparation method therefor and use thereof
CN117355527A (en) * 2021-07-20 2024-01-05 上海椿安生物医药科技有限公司 External anti-inflammatory coupling compound medicine and preparation method and application thereof
WO2023011301A1 (en) * 2021-08-06 2023-02-09 嘉兴特科罗生物科技有限公司 Jak inhibitor with high oral bioavailability

Also Published As

Publication number Publication date
WO2021078020A1 (en) 2021-04-29

Similar Documents

Publication Publication Date Title
CN110734428A (en) small molecule compounds
CN105073733B (en) Kinases inhibitor
CN111635408B (en) Triazolo-pyrimidine compounds and uses thereof
KR20170140370A (en) JAK inhibitor
KR20160003035A (en) Quinazolinone derivatives useful as fgfr kinase modulators
JP7397187B2 (en) small molecule compound
AU2012228090A1 (en) Pyrrolopyridineamino derivatives as Mps1 inhibitors
TW201400486A (en) Imidazo[1,2-b]pyridazine analogues as kinase inhibitors
JP6338665B2 (en) New 6-alkynylpyridine
CN110862380A (en) Small molecule compound
CN112055709A (en) Pyrazine compounds and uses thereof
CN110862376A (en) Small molecule compound
JP2024505732A (en) Pyridopyrimidinone derivatives and their production methods and uses
JP2021517555A (en) Phenyl-2-hydroxy-acetylamino-2-methyl-phenyl compound
WO2018010514A1 (en) Heterocyclic compound used as fgfr inhibitor
CN112457326B (en) Aromatic heterocyclic lactam compound, preparation method and application
WO2014100540A1 (en) Pyrazole substituted imidazopyrazines as casein kinase 1 d/e inhibitors
CN114685487A (en) Pyrimidine heterocyclic compound, preparation method and application
TW202204351A (en) Compounds having a macrocyclic structure and uses thereof
JP2020516672A (en) Therapeutic compound
CN111655689B (en) Pyrazolopyridinone compounds
CN112313207A (en) Cyano-substituted pyridine and cyano-substituted pyrimidine compounds, and preparation methods and applications thereof
CN113292561A (en) Compound with dipyrrolopyridine structure, preparation method and medical application
WO2021104441A1 (en) Polyaromatic compound as egfr kinase inhibitor
CN111747954B (en) Pyrazine compounds and uses thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20200131