CN113135896A - Methylpyrazole derivatives as RET inhibitors - Google Patents

Methylpyrazole derivatives as RET inhibitors Download PDF

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CN113135896A
CN113135896A CN202110061785.3A CN202110061785A CN113135896A CN 113135896 A CN113135896 A CN 113135896A CN 202110061785 A CN202110061785 A CN 202110061785A CN 113135896 A CN113135896 A CN 113135896A
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张寅生
陆鹏
秦慧
叶嘉炜
陶亮
陈璞舟
刘戌时
施伟
徐宏江
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Abstract

The application relates to methylpyrazole derivatives serving as RET inhibitors, in particular to a compound shown as a formula (I), a stereoisomer thereof and pharmaceutically acceptable salts thereof, a preparation method thereof and a pharmaceutical composition thereof. The compounds of formula (I) described herein are useful in the prevention or treatment of diseases mediated by aberrant RET activity.

Description

Methylpyrazole derivatives as RET inhibitors
Technical Field
The application relates to methylpyrazole derivatives serving as RET inhibitors, in particular to a compound shown as a formula (I), a stereoisomer and a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition and application thereof in preparing medicines for preventing or treating diseases mediated by abnormal RET activity.
Background
RET (recovered reduced transduction) is a membrane receptor tyrosine kinase encoded by the proto-oncogene RET gene located on chromosome 10 and its ligand is GNDF family proteins (GFLs), such as GDNF, NTRN, ARTN and PSPN. However, unlike other receptor tyrosine kinases, RET does not bind directly to its ligand. GDNF, NTRN, ARTN and PSPN are combined with a co-receptor GFR alpha of RET to form a GFL-GFR alpha complex, the complex mediates dimerization of RET and autophosphorylation of tyrosine residues of an intracellular domain of RET, activates cascade reactions of downstream pathways such as MAPK, PI3K, JAK-STAT, PKA and PKC, and finally regulates the proliferation and differentiation levels of cells. Therefore, abnormal up-regulation of RET activity may cause diseases such as cancer.
RET can be abnormally activated by two pathways: point mutations and gene fusions. The site mutation of the kinase end of RET intracellular domain causes the increase of catalytic phosphorylation activity of RET, such as E768D, L790F, V804M and the like; point mutations in the extracellular domain promote intermolecular disulfide bond formation, leading to ligand-independent dimerization of RET, resulting in autophosphorylation of RET. The gene fusion of RET is easy to cause the fusion of RET kinase end and chaperone protein with dimer end to form hybrid protein with RET catalytic activity, which causes RET non-ligand-dependent dimerization to stimulate RET catalytic activity. The RET fusion genes which have been found so far include RET-CCDC6, RET-PRKAR1A, RET-GOLGA5 and RET-RFG 9. Clinical studies show that various cancers such as thyroid cancer, non-small cell lung cancer, colon cancer and breast cancer are all driven by RET, wherein the RET-driven thyroid papillary carcinoma, medullary thyroid carcinoma and non-small cell lung cancer account for relatively high proportion, and the proportion is respectively 11%, 60% and 2%.
Although the first-generation RET inhibitors such as vandetanib and cabozantinib can inhibit RET activity at low nM concentration, various non-RET kinases can be effectively inhibited, and the inhibitory activity on the non-RET kinases is superior to that on the RET. Therefore, the medicaments show dose-dependent off-target related side effects in clinical experiments, such as hypertension, hand-foot syndrome and urine protein related to VEGFR inhibition; BRAF inhibition-associated skin rash; KIT inhibition-associated hypopigmentation; EGFR inhibition-associated diarrhea, and the like. The incidence rate of the drug administration dosage reduction caused by the dosage tolerance problem of the drug is 23% -79%, and the incidence rate of treatment discontinuation is 6% -21%. In addition, when the first-generation RET inhibitor is used for RET-driven NSCLC treatment, the problems of low overall response rate and short median progression-free survival time still exist, and the patients have far less benefit than NSCLC patients such as EGFR mutation, ALK and ROS1 gene fusion positivity and the like. As with other targeted drugs, the emergence of drug-resistant mutations greatly reduces the potency of first-generation RET inhibitors, leading to rapid progression of cancer conditions. Mutations in RET gatekeeper (e.g., V804L, V804M) are the most major drug resistance mutations. Val is mutated into Leu or Met with larger branched chain volume, so that the steric hindrance of a hydrophobic pocket behind the binding point of a hydrophobic fragment of the RET inhibitor extending into ATP is increased, the affinity with the inhibitor is reduced, and the drug resistance is caused. Another major type of drug resistance mutation is solvent-front mutation (solvent-front mutation) G810R and G810A, which is similar to ALKG1202R, ROS1G2032R, NTRK1G595R and NTRK3G623R, and RET solvent region Gl810 is mutated to a larger amino acid residue, which generates steric hindrance with the solvent region fragment of the drug and reduces the affinity.
Therefore, the clinical use of first generation RET inhibitors is somewhat limited. However, no second-generation RET inhibitors that are highly selective and effective against drug-resistant mutations have been approved for marketing yet, and there is still a need to develop excellent second-generation RET inhibitors that are highly selective and effective against drug-resistant mutations.
Disclosure of Invention
A compound shown in a formula (I), a stereoisomer thereof and pharmaceutically acceptable salts thereof,
Figure BDA0002902944530000021
wherein,
x is selected from NH;
u, V, W are each independently selected from C (R)1) Or N;
q is selected from C (R)2) Or N;
the ring A is a 6-8-membered monocyclic ring, a 6-10-membered bridged heterocyclic ring, a benzene ring, a naphthalene ring, a 7-12-membered fused ring or fused heterocyclic ring, or a 7-12-membered fused heteroaromatic ring, and the monocyclic heterocyclic ring contains at least one N atom;
the ring B is a benzene ring, a naphthalene ring, a 5-6-membered heteroaromatic ring, a 7-12-membered fused heterocyclic ring or a 7-12-membered fused heteroaromatic ring;
-L1-is selected from the group consisting of a single bond, -O-, -S-, -C (O) -, -C (S) -, -S (O)2-or-N (R)A0)-；
-L2-is selected from-O-, -S-, -C (S) -, -S (O)2-、-(CRA2RB2)q-、-N(RA1)-、-C(O)-N(RA1)-、-N(RA1)-C(S)-、-(CRA2RB2)q-C(S)-、-(CRA2RB2)q-S(O)2-、-C(O)-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(O)-(CRA2RB2)q-、-C(S)-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(S)-(CRA2RB2)q-、-S(O)2-N(RA1)-(CRA2RB2)q-、-N(RA1)-S(O)2-(CRA2RB2)q-、-C(O)-N(RA1)-C(O)-、-N(RA1)-C(O)-N(RA1)-、-N(RA1)-C(O)-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(O)-(CRA2RB2)q-N(RA1)-、-N(RA1)-C(O)-(CRA2RB2)q-C(O)-、-N(RA1)-C(O)-N(RA1)-C(O)-、-C(O)-N(RA1)-C(O)-(CRA2RB2)q-、-C(S)-N(RA1)-C(O)-(CRA2RB2)q-、-C(O)-N(RA1)-(CRA2RB2)q-C(O)-、-C(S)-N(RA1)-(CRA2RB2)q-C(O)-、-N(RA1)-C(O)-(CRA2RB2)q-C(O)-N(RA1)-、-C(O)-N(RA1)-(CRA2RB2)q-C(O)-N(RA1) -or-C (O) -N (R)A1)-(CRA2RB2)q-N(RA1)-C(O)-；
RA0Is selected from C1-6Alkyl radical, C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl, said C1-6Alkyl radical, C3-6Cycloalkyl and 3-6 membered heterocycloalkyl may be optionally substituted with one, two or three substituents selected from halo, hydroxy, cyano or amino;
RA1selected from H, C1-6Alkyl radical, C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl, said C1-6Alkyl radical, C3-6Cycloalkyl and 3-6 membered heterocycloalkyl may be optionally substituted with one, two or three substituents selected from halo, hydroxy, cyano or amino;
RA2and RB2Each independently selected from H, halogen, hydroxyl, cyano, amino, COOH, nitro and C1-6Alkyl radical, C1-6alkyl-NH-, C1-6Alkoxy radical, C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl, said C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl and 3-6 membered heterocycloalkyl may be optionally substituted with one, two or three substituents selected from halo, hydroxy, cyano or amino; or RA2、RB2Together with C to which it is attached, form a tri-, tetra-or penta-saturated monocyclic or mono-heterocyclic ring, with no or no substituents, said mono-heterocyclic ring comprising 1 or 2 heteroatoms selected from O or N;
R1、R2and R5Each independently selected from H, halogen, hydroxyl, amino, cyano, COOH, nitro and C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, methoxy, C3-6Alkoxy, 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl; or R1、R2The C atoms connected with the compound form a 3-6-membered monocyclic or 3-6-membered monocyclic heterocycle; said C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, methoxy, C3-6Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered monocyclic ring and 3-6 membered monocyclic ring may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino;
R3selected from halogen, hydroxyl, amino, cyano, COOH, nitro,
Figure BDA0002902944530000031
C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, 3-to 6-membered cycloalkyl, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy and 3-6 membered cycloalkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, cyano or amino;
R4selected from H, halogen, hydroxyl, amino, cyano, COOH, nitro, C2-6Alkenyl radical, C2-6Alkynyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, pyrazolyl, 6-to 10-membered bridged heterocycle, 3-to 6-membered heterocycloalkyl-C1-6An alkylene group; said C is2-6Alkenyl radical, C2-6Alkynyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 6-to 10-membered bridged heterocycle, 3-to 6-membered heterocycloalkyl-C1-6Alkylene groups may optionally be selected from R by one, two or three6Substituted with the substituent(s); the pyrazolyl is substituted by one, two or three substituents selected from halogen, hydroxy, amino, cyano, COOH, nitro;
R6independently halogen, hydroxy, amino, cyano, COOH, nitro, C1-6Alkyl radical, C2-6Alkynyl, C1-6alkyl-NH-, N-di (C)1-6Alkyl) -N-, C1-6alkyl-O-, C1-6alkyl-S-, C1-6alkyl-C (O) -, said C1-6Alkyl radical, C2-6Alkynyl, C1-6alkyl-NH-, N-di (C)1-6Alkyl) -N-, C1-6alkyl-O-, C1-6alkyl-S-and C1-6Alkyl-c (o) -may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino;
n is 0 or 1;
p is 1,2 or 3;
q is 1,2, 3, 4 or 5;
and when ring A is a piperidine ring, L2Is not-C (O) -N (R)A1)-(CRA2RB2)q-and-N (R)A1)-C(O)-(CRA2RB2)q-；
And when only 1 of U, V, W is N, Q is C (CH)3) And n is not 0 when ring A is a piperazine ring;
and the following specific compounds, stereoisomers thereof and pharmaceutically acceptable salts thereof are not encompassed by the present application:
Figure BDA0002902944530000041
in some embodiments, R1Each independently selected from H, halogen, hydroxyl, amino, cyano, COOH, nitro and C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, methoxy, C3-6Alkoxy, 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, methoxy, C3-6The alkoxy group, the 3-to 6-membered cycloalkyl group and the 3-to 6-membered heterocycloalkyl group may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino.
In some embodiments, R1Each independently selected from H, halogen or C1-6Alkyl radical, said C1-6Alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; in some embodiments, R1Each independently selected from H, halogen or C1-4Alkyl radical, said C1-4Alkyl groups may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino.
In some embodiments, R1Each independently selected from H or halogen.
In some embodiments, R1Is H.
In some embodiments, U, V, W are both CH.
In some embodiments, at least one of U, V, W is selected from N.
In some embodiments, U is CH, V is N, and W is N.
In some embodiments, U is CH, V is CH, and W is N.
In some embodiments, U is CH, V is N, and W is CH.
In some embodiments, U is N, V is CH, and W is N.
In some embodiments, Q is C (R)2)。
In some embodiments, R2Selected from H, halogen, hydroxyl, amino, cyano, COOH, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, methoxy, C3-6Alkoxy, 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, methoxy, C3-6The alkoxy group, the 3-to 6-membered cycloalkyl group and the 3-to 6-membered heterocycloalkyl group may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino.
In some embodiments, R2Is selected from H or C1-6Alkyl radical, said C1-6Alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; in some embodiments, R2Is selected from H or C1-4Alkyl radical, said C1-4Alkyl groups may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino.
In some embodiments, R2Selected from H, methyl, ethyl, isopropyl or tert-butyl, which methyl, ethyl, isopropyl or tert-butyl may be optionally substituted with one, two or three substituents selected from halogen.
In some embodiments, R2Selected from H or methyl, which methyl group may be optionally substituted with one, two or three substituents selected from halogen.
In some embodiments, R2Selected from H, methyl, difluoromethyl or trifluoromethyl.
In some embodiments, R2Selected from methyl.
In some embodiments, U is CH, V is N, W is N, Q is C (R)2)。
In some embodimentsU is CH, V is N, W is N, Q is C (CH)3)。
In some embodiments, U is CH, V is CH, W is N, and Q is N.
In some embodiments, R1、R2Together with the C atom to which they are attached form a 5-membered monocyclic ring.
In some embodiments, RA0Independently selected from C1-6Alkyl radical, said C1-6Alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; in some embodiments, RA0Independently selected from C1-4Alkyl radical, said C1-4Alkyl groups may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino.
In some embodiments, RA0Independently selected from methyl, ethyl, isopropyl or tert-butyl.
In some embodiments, RA0Independently selected from methyl.
In some embodiments, L is1Selected from the group consisting of a single bond, -O-, -S-, -C (O) -or-N (R)A0) -; in some embodiments, L is1Selected from a single bond, -C (O) -or-N (R)A0)-。
In some embodiments, L is1Selected from single bond, -C (O) -, -N (CH)3)-、-N(CH2CH3) -or-N (CH)3)2)-。
In some embodiments, L is1Selected from a single bond, -C (O) -or-N (CH)3)-。
In some embodiments, L is1Selected from single bonds.
In some embodiments, ring A is a 6-8 membered mono-heterocyclic ring, a 6-10 membered bridged heterocyclic ring, a benzene ring, an 8-10 membered fused ring, or a fused heterocyclic ring, said mono-heterocyclic ring containing at least one N atom; in some embodiments, ring A is a 6-8 membered saturated mono-heterocyclic ring, a 6-10 membered saturated bridged heterocyclic ring, an 8-10 membered fused or fused ring, a benzene ring, said mono-heterocyclic ring containing at least one N atom.
In some embodiments, ring a is
Figure BDA0002902944530000061
Figure BDA0002902944530000062
Figure BDA0002902944530000063
In some embodiments, ring a is
Figure BDA0002902944530000064
Figure BDA0002902944530000065
In some embodiments, ring a is
Figure BDA0002902944530000066
Figure BDA0002902944530000071
In some embodiments of the present invention, the substrate is,
Figure BDA0002902944530000072
is composed of
Figure BDA0002902944530000073
Figure BDA0002902944530000074
In some embodiments of the present invention, the substrate is,
Figure BDA0002902944530000075
is composed of
Figure BDA0002902944530000076
Figure BDA0002902944530000077
In some embodiments of the present invention, the substrate is,
Figure BDA0002902944530000078
is composed of
Figure BDA0002902944530000079
In some embodiments, R3Independently selected from halogen, hydroxy, amino,
Figure BDA00029029445300000710
Or C1-6Alkyl radical, said C1-6Alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; in some embodiments, R3Independently selected from halogen,
Figure BDA00029029445300000711
Or C1-4Alkyl radical, said C1-4Alkyl groups may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino.
In some embodiments, R3Independently selected from F,
Figure BDA00029029445300000712
Methyl, ethyl, isopropyl or tert-butyl.
In some embodiments, R3Independently selected from F,
Figure BDA0002902944530000081
Or a methyl group.
In some embodiments, n is 0.
In some embodiments, -L2-is selected from-O-, -S-, -C (S) -, -S (O)2-、-(CRA2RB2)q-、-N(RA1)-、-C(O)-N(RA1)-、-N(RA1)-C(S)-、-(CRA2RB2)q-C(S)-、-(CRA2RB2)q-S(O)2-、-C(O)-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(O)-(CRA2RB2)q-、-C(S)-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(S)-(CRA2RB2)q-、-S(O)2-N(RA1)-(CRA2RB2)q-、-N(RA1)-S(O)2-(CRA2RB2)q-、-C(O)-N(RA1)-C(O)-、-N(RA1)-C(O)-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(O)-(CRA2RB2)q-N(RA1)-、-N(RA1)-C(O)-(CRA2RB2)q-C(O)-、-N(RA1)-C(O)-N(RA1)-C(O)-、-C(O)-N(RA1)-C(O)-(CRA2RB2)q-、-C(S)-N(RA1)-C(O)-(CRA2RB2)q-、-C(O)-N(RA1)-(CRA2RB2)q-C(O)-、-C(S)-N(RA1)-(CRA2RB2)q-C(O)-、-N(RA1)-C(O)-(CRA2RB2)q-C(O)-N(RA1)-、-C(O)-N(RA1)-(CRA2RB2)q-C(O)-N(RA1) -or-C (O) -N (R)A1)-(CRA2RB2)q-N(RA1)-C(O)-。
In some embodiments, L is2Selected from-O-, -S-, - (CR)A2RB2)q-、-N(RA1)-、-C(O)-N(RA1)-、-C(S)-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(S)-(CRA2RB2)q-、-C(O)-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(O)-(CRA2RB2)q-、-S(O)2-N(RA1)-(CRA2RB2)q-、-N(RA1)-S(O)2-(CRA2RB2)q-、-N(RA1)-C(O)-N(RA1)-、-N(RA1)-C(O)-N(RA1)-(CRA2RB2)q-or-N (R)A1)-C(O)-(CRA2RB2)q-C(O)-N(RA1)-；
In some embodiments, L is2Selected from-O-, -C (O) -N (R)A1)-、-C(O)-N(RA1)-(CRA2RB2)q-、-S(O)2-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(O)-(CRA2RB2)q-、-C(S)-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(O)-N(RA1)-、-N(RA1)-C(O)-N(RA1)-(CRA2RB2)q-or-N (R)A1)-C(O)-(CRA2RB2)q-C(O)-N(RA1)-；
In some embodiments, L is2Selected from-O-, -C (O) -N (R)A1)-、-C(O)-N(RA1)-(CRA2RB2)-、-S(O)2-N(RA1)-(CRA2RB2)-、-N(RA1)-C(O)-(CRA2RB2)-、-C(S)-N(RA1)-(CRA2RB2)-、-N(RA1)-C(O)-N(RA1)-(CRA2RB2) -or-N (R)A1)-C(O)-(CRA2RB2)-C(O)-N(RA1)-。
In some embodiments, RA1Independently selected from H or C1-6Alkyl radical, said C1-6Alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; in some embodiments, RA1Independently selected from H or C1-4Alkyl radical, said C1-4Alkyl groups may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino.
In some embodiments, RA1Independently selected from H, methyl, ethyl, isopropyl or tert-butyl.
In some embodiments, RA1Independently selected from H or methyl.
In some embodiments, RA1Independently selected from H.
In some embodiments, RA2And RB2Each independently selected from H, halogen, hydroxy, C1-6Alkyl or C1-6alkyl-NH-said C1-6Alkyl and C1-6alkyl-NH-may be optionally substituted by one, two or three substituents selected from halogen, hydroxy, cyano or amino, or RA2、RB2Together with C to which it is attached, form a tri-, tetra-or penta-saturated monocyclic or mono-heterocyclic ring, with no or no substituents, said mono-heterocyclic ring comprising 1 or 2 heteroatoms selected from O or N; in some embodiments, RA2And RB2Each independently selected from H, C1-4Alkyl or C1-4alkyl-NH-said C1-4Alkyl and C1-4alkyl-NH-may be optionally substituted by one, two or three substituents selected from halogen, hydroxy, cyano or amino, or RA2、RB2Together with the C to which it is attached, form a three-membered saturated monocyclic or monocyclic, unsubstituted or substituted, heterocycle comprising 1 or 2 heteroatoms selected from O or N.
In some embodiments, RA2And RB2Each independently selected from H, methyl, ethyl or methyl-NH-.
In some embodiments, RA2And RB2Each independently selected from H or methyl.
In some embodiments, RA2And RB2Are all H.
In some embodiments, RA2Selected from methyl, RB2Selected from methyl, or RA2、RB2Together with the C to which it is attached, form a cyclopropane ring.
In some embodiments, RA2Selected from H, RB2Is selected from methyl; or, RA2Selected from methyl, RB2Is selected from H.
In some embodiments, L is2Selected from-O-, -CH2-、-C(O)-NH-、-C(O)-NH-CH(CH3)-、-C(O)-NH-CH2-、-NH-C(O)-NH-、
Figure BDA0002902944530000091
-S(O)2-NH-CH(CH3)-、-NH-C(O)-CH(CH3)-、-C(S)-NH-CH(CH3)-、-NH-C(O)-NH-CH(CH3)-、-N(CH3)-C(O)-NH-CH(CH3) -or
Figure BDA0002902944530000092
In some embodiments, L is2Selected from-O-, -C (O) -NH-CH (CH)3)-、-C(O)-NH-CH2-、-NH-C(O)-NH-、
Figure BDA0002902944530000093
-S(O)2-NH-CH(CH3)-、-NH-C(O)-CH(CH3)-、-C(S)-NH-CH(CH3)-、-NH-C(O)-NH-CH(CH3)-、-N(CH3)-C(O)-NH-CH(CH3) -or
Figure BDA0002902944530000094
In some embodiments, L is2Selected from-C (O) -NH-or-C (O) -NH-CH (CH)3)-。
In some embodiments, L is2Selected from the group consisting of-C (O) -NH-CH (CH)3)-。
In some embodiments, ring B is a phenyl ring, a 5-6 membered heteroaromatic ring, a 7-10 membered fused heterocyclic ring, or a 7-10 membered fused heteroaromatic ring containing 1,2, or 3 heteroatoms selected from O, N, S; in some embodiments, ring B is a phenyl ring, a 5-6 membered heteroaromatic ring, a 9-10 membered fused heterocyclic ring, or a 9-10 membered fused heteroaromatic ring containing 1,2, or 3 heteroatoms selected from O, N, S.
In some embodiments, ring B is a furan ring, a pyrrole ring, a pyrazole ring, an imidazole ring, an oxazole ring, an isoxazole ring, a thiophene ring, a thiazole ring, an isothiazole ring, a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, an indole ring, a benzimidazole ring, a benzothiazole ring, a benzoxazole ring, a quinoline ring, an isoquinoline ring, a quinazoline ring, a pyridine ring, a pyridazine ring, an indole ring, a benzothiazole ring, a quinoline ring, a quinazoline ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a quinoline ring, a quinazoline ring, a pyridine ring, a pyrimidine ring, a compound,
Figure BDA0002902944530000095
in some embodiments, ring B is a benzene ring, a pyridine ring, a benzimidazole ring, or a benzothiazole ring.
In some embodiments, ring B is
Figure BDA0002902944530000101
Figure BDA0002902944530000102
In some embodiments, ring B is
Figure BDA0002902944530000103
Figure BDA0002902944530000104
In some embodiments, ring B is
Figure BDA0002902944530000105
In some embodiments of the present invention, the substrate is,
Figure BDA0002902944530000106
is composed of
Figure BDA0002902944530000107
Figure BDA0002902944530000108
In some embodiments of the present invention, the substrate is,
Figure BDA0002902944530000109
is composed of
Figure BDA00029029445300001010
Figure BDA00029029445300001011
In some embodiments，
Figure BDA00029029445300001012
Is composed of
Figure BDA00029029445300001013
In some embodiments, R5Independently selected from H, halogen, hydroxy, amino, cyano, C1-6Alkyl, methoxy or C3-6Alkoxy radical, said C1-6Alkyl, methoxy or C3-6Alkoxy groups may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino.
In some embodiments, R5Independently selected from H, halogen, hydroxy, amino, cyano or C1-6Alkyl radical, said C1-6Alkyl groups may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino.
In some embodiments, R5Independently selected from H, halogen, hydroxy, C1-4Alkyl, methoxy or C3-6Alkoxy radical, said C1-4Alkyl, methoxy or C3-6Alkoxy groups may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino.
In some embodiments, R5Independently selected from H, halogen, hydroxy or C1-4Alkyl radical, said C1-4Alkyl groups may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino.
In some embodiments, R5Independently selected from H, halogen, hydroxy, methyl, ethyl, isopropyl, tert-butyl, methoxy, propoxy, isopropoxy, butyl-2-oxy, tert-butyl oxy or pentan-2-yloxy, said methyl, ethyl, isopropyl, tert-butyl, methoxy, propoxy, isopropoxy, butyl-2-oxy, tert-butyl oxy or pentan-2-yloxy may optionally be substituted with one, two or three substituents selected from halogen or cyano.
In some embodimentsIn, R5Independently selected from H, halogen, hydroxy, methyl, ethyl, isopropyl or tert-butyl, which methyl, ethyl, isopropyl or tert-butyl may be substituted with one, two or three substituents selected from halogen.
In some embodiments, R5Independently selected from H, F, hydroxy, trifluoromethyl,
Figure BDA0002902944530000111
Methoxy, trifluoromethyloxy, isopropyloxy, butyl-2-oxy, pentan-2-yloxy.
In some embodiments, R5Independently selected from H, F, hydroxy, trifluoromethyl.
In some embodiments, p is 1 or 2.
In some embodiments, R5Independently selected from H.
In some embodiments, R4Selected from H, halogen, hydroxy, amino, cyano, C2-6Alkynyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, pyrazolyl, 6-to 8-membered bridged heterocycle or 3-to 6-membered heterocycloalkyl-C1-6Alkylene radical of the formula C2-6Alkynyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 6-to 8-membered bridged heterocycle or 3-to 6-membered heterocycloalkyl-C1-6Alkylene groups may optionally be selected from R by one, two or three6Substituted with the substituent(s); the pyrazolyl group is substituted with one, two or three substituents selected from halogen, hydroxy, amino, cyano, COOH, nitro.
In some embodiments, R4Selected from H, halogen, cyano, C2-4Alkynyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, pyrazolyl, 6-to 7-membered bridged heterocycle or 5-to 6-membered heterocycloalkyl-C1-4Alkylene radical of the formula C2-4Alkynyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 6-to 7-membered bridged heterocycle or 5-to 6-membered heterocycloalkyl-C1-4Alkylene groups may optionally be selected from R by one, two or three6Substituted with the substituent(s); the pyrazolyl group is substituted with one, two or three substituents selected from halogen, hydroxy, amino, cyano, COOH, nitro.
In some embodiments, R4Selected from H, halogen, cyano, ethynyl, 1-propynyl, 2-propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, pyrazolyl, and mixtures thereof,
Figure BDA0002902944530000121
Tetrahydropyrrolyl-1-methylene, tetrahydropyrrolyl-2-methylene, tetrahydropyrrolyl-3-methylene, piperidyl-1-methylene, piperidyl-2-methylene, piperidyl-3-methylene, piperidyl-4-methylene, piperazinyl-1-methylene or piperazinyl-2-methylene, with ethynyl, 1-propynyl, 2-propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, piperidyl, piperazinyl, o-methyl-ethyl-methyl-ethyl-propyl, cyclopropyl-butyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, piperidinyl, piperazinyl,
Figure BDA0002902944530000122
Tetrahydropyrrolyl-1-methylene, tetrahydropyrrolyl-2-methylene, tetrahydropyrrolyl-3-methylene, piperidinyl-1-methylene, piperidinyl-2-methylene, piperidinyl-3-methylene, piperidinyl-4-methylene, piperazinyl-1-methylene or piperazinyl-2-methylene groups may optionally be substituted with one, two or three groups selected from R6Substituted with the substituent(s); the pyrazolyl group is substituted with one, two or three substituents selected from halogen, hydroxy, amino, cyano, COOH, nitro.
In some embodiments, R4Selected from H, F, cyano, ethynyl, cyclopropyl, cyclopentyl, azetidinyl, tetrahydropyrrolyl, pyrazolyl, and mixtures thereof,
Figure BDA0002902944530000123
Tetrahydropyrrolyl-1-methylene or piperazinyl-1-methylene, said ethynyl, cyclopropyl, cyclopentyl, azetidinyl, tetrahydropyrrolyl,
Figure BDA0002902944530000124
Tetrahydropyrrolyl-1-methylene or piperazinyl-1-methylene optionally substituted with one,Two or three are selected from R6Substituted with the substituent(s); the pyrazolyl group is substituted with one, two or three substituents selected from halogen.
In some embodiments, R6Independently selected from halogen, hydroxy, amino, cyano, C1-6Alkyl radical, C2-6Alkynyl, C1-6alkyl-NH-, N-di (C)1-6Alkyl) -N-, said C1-6Alkyl radical, C2-6Alkynyl, C1-6alkyl-NH-and N, N-di (C)1-6Alkyl) -N-may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; in some embodiments, R6Independently selected from halogen, cyano, C1-4Alkyl radical, C2-4Alkynyl or N, N-di (C)1-4Alkyl) -N-, said C1-4Alkyl radical, C2-4Alkynyl and N, N-di (C)1-4Alkyl) -N-may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino.
In some embodiments, R6Independently selected from halogen, cyano, methyl, ethynyl or N, N-dimethylamino.
In some embodiments, R6Independently selected from F.
In some embodiments, R4Selected from H, F, cyano, ethynyl,
Figure BDA0002902944530000125
Figure BDA0002902944530000131
In some embodiments, R4Is selected from
Figure BDA0002902944530000132
In some embodiments, the aforementioned compound of formula (I) has the structure shown in formula (II),
Figure BDA0002902944530000133
wherein R is2、R3、R4、R5Ring A, ring B, L2N, p are as defined above for the compounds of formula (I).
In some embodiments, the aforementioned compound of formula (I) has the structure shown in formula (III),
Figure BDA0002902944530000134
wherein R is3、R4、R5Ring A, ring B, L2N, p are as defined above for the compounds of formula (I).
In some embodiments, the aforementioned compound of formula (I) has the structure shown in formula (IV),
Figure BDA0002902944530000135
wherein R is3、R4、R5Ring a, ring B, n, p are as defined above for compounds of formula (I), and ring a is not a piperidine ring.
In some embodiments, the aforementioned compound of formula (I) has the structure shown in formula (IV-a),
Figure BDA0002902944530000141
wherein R is3、R4、R5Ring a, ring B, n, p are as defined above for compounds of formula (I), and ring a is not a piperidine ring.
In some embodiments, the aforementioned compound of formula (I) has the structure shown in formula (V),
Figure BDA0002902944530000142
wherein R is3、R4、R5Ring A、L2N, p are as defined above for the compounds of formula (I).
In some embodiments, the aforementioned compound of formula (I) has the structure shown in formula (VII),
Figure BDA0002902944530000143
wherein R is3、R5Ring A, L2N, p are as defined above for the compounds of formula (I).
In some embodiments, the aforementioned compound of formula (I) has the structure shown in formula (VIII),
Figure BDA0002902944530000151
wherein R is3、R5Ring A, n, p are as defined above for compounds of formula (I) and ring A is not a piperidine ring.
In some embodiments, the aforementioned compound of formula (I) has the structure shown in formula (VIII-a),
Figure BDA0002902944530000152
wherein R is3、R5Ring A, n, p are as defined above for compounds of formula (I) and ring A is not a piperidine ring.
In some embodiments, the present application is selected from the following compounds, stereoisomers thereof, and pharmaceutically acceptable salts thereof:
Figure BDA0002902944530000153
Figure BDA0002902944530000161
Figure BDA0002902944530000171
Figure BDA0002902944530000181
Figure BDA0002902944530000191
Figure BDA0002902944530000201
Figure BDA0002902944530000211
Figure BDA0002902944530000221
Figure BDA0002902944530000231
Figure BDA0002902944530000241
Figure BDA0002902944530000251
Figure BDA0002902944530000261
Figure BDA0002902944530000271
Figure BDA0002902944530000281
Figure BDA0002902944530000291
in another aspect, the present application relates to pharmaceutical compositions comprising a compound of formula (I) of the present application, stereoisomers thereof and pharmaceutically acceptable salts thereof.
In some embodiments, the pharmaceutical compositions of the present application comprise a therapeutically effective amount of a compound of formula (I) of the present application, stereoisomers thereof, and pharmaceutically acceptable salts thereof.
In some embodiments, the pharmaceutical compositions of the present application further comprise a pharmaceutically acceptable excipient.
The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These adjuvants enable the compounds of the present application to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.
Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid adjuvants, optionally the mixture obtained is milled, if desired with further suitable adjuvants, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
In another aspect, the present application relates to a method of treating a disease mediated by aberrant RET activity in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, as described herein.
In all methods of administration of the compounds of formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, the dosage administered per day is from 0.01 to 100mg/kg body weight, preferably from 0.05 to 50mg/kg body weight, more preferably from 0.1 to 5mg/kg body weight, in single or divided doses.
In another aspect, the present application relates to the use of a compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of a disease mediated by abnormal RET activity.
In another aspect, the present application relates to the use of compounds of formula (I), stereoisomers thereof and pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of diseases mediated by abnormal RET activity.
In another aspect, the present application relates to compounds of formula (I), stereoisomers thereof and pharmaceutically acceptable salts thereof, for the prevention or treatment of diseases mediated by abnormal RET activity.
Diseases mediated by aberrant RET activity as described herein include cancer.
In some embodiments, the cancer described herein is selected from Papillary Thyroid Carcinoma (PTC), Medullary Thyroid Carcinoma (MTC), Pheochromocytoma (PC), pancreatic cancer, multiple endocrine tumors (MEN2A and MEN2B), breast cancer, testicular cancer, small cell lung cancer, non-small cell lung cancer, hematological tumors, colorectal cancer, ovarian cancer, cervical cancer, gastric cancer, prostate cancer, salivary gland cancer.
Definition of
The following terms used in the present application have the following meanings, unless otherwise specified. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present application prepared from the compounds found herein to have particular substituents with relatively nontoxic acids or bases. When compounds of the present application contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a suitable base. When compounds of the present application contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a suitable acid. Certain specific compounds of the present application contain both basic and acidic functionalities and thus can be converted to any base or acid addition salt.
Certain compounds of the present application may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present application.
When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E, Z geometric isomer unless otherwise specified. Similarly, whatAll tautomeric forms are included within the scope of the application, for example,
Figure BDA0002902944530000301
and
Figure BDA0002902944530000302
in tautomeric form.
The compounds of the present application may exist in specific geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present application. For example, contained in the structure of the compound
Figure BDA0002902944530000311
As a diastereoisomer; e.g. as comprised in the structure of a compound
Figure BDA0002902944530000312
As the (R) -and (S) -enantiomers.
Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).
The compounds of the present application may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioisotopes, such as deuterium (g) ((R))2H) Tritium (A)3H) Iodine-125 (125I) Or C-14(14C) In that respect All isotopic variations of the compounds of the present application, whether radioactive or not, are intended to be encompassed within the scope of the present application.
The term "pharmaceutically acceptable adjuvants" refers to those adjuvants which do not have a significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
The term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or pharmaceutical agent to achieve the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
The words "comprise" or "comprise" and variations thereof such as "comprises" or "comprising," are to be understood in an open, non-exclusive sense, i.e., "including but not limited to.
The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl is "optionally" substituted with halo, meaning that ethyl may be unsubstituted (CH)2CH3) Monosubstituted (e.g. CH)2CH2F) Polysubstituted (e.g. CHFCH)2F、CH2CHF2Etc.) or completely substituted (CF)2CF3). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.
C as used hereinm-nMeaning that the moiety has m-n carbon atoms. For example, "C3-10Cycloalkyl "means that the cycloalkyl group has 3 to 10 carbon atoms. "C0-6Alkylene "means that the alkylene group has 0 to 6 carbon atoms, and when alkylene has 0 carbon atom, the group is a bond.
Numerical ranges herein refer to each integer in the given range. E.g. "C1-10By "is meant that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is keto (i.e., ═ O) (also known as oxo), meaning that two hydrogen atoms are substituted, the keto substitution does not occur on the aromatic group.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
When one of the variables is selected from a bond, it means that the two groups to which it is attached are directly linked, for example, L in A-L-Z represents a bond, it means that the structure is actually A-Z.
When one substituent is absent, tableThe substituent is absent, e.g., X is absent in A-X, indicating that the structure is actually A. When a substituent's bond can cross-link two atoms on a ring, such substituent can be bonded to any atom on the ring. When it is not specified in the listed substituents through which atom it is attached to a compound included in the chemical structural formula but not specifically mentioned, such substituent may be bonded through any atom thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit
Figure BDA0002902944530000321
Meaning that it may be substituted at any position on the cyclohexyl or cyclohexadiene. For example a structural unit
Figure BDA0002902944530000322
To represent
Figure BDA0002902944530000323
The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.
The term "hydroxy" refers to-OH.
The term "cyano" refers to — CN.
The term "amino" refers to the group-NH2。
The term "nitro" means-NO2。
The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. The particular alkyl group includes all isomeric forms thereof, e.g., propyl includes-CH2CH2CH3、-CH(CH3)2For example, butyl includes-CH2CH2CH2CH3、-CH(CH3)(CH2CH3)、-C(CH3)3、-CH2CH(CH3)2. The term "C1-6Alkyl "refers to an alkyl group having 1 to 6 carbon atoms. The term "C1-4Alkyl "refers to an alkyl group having 1 to 4 carbon atoms. The term "C1-3Alkyl "refers to an alkyl group having 1 to 3 carbon atoms. The "alkyl group", "C1-8Alkyl group "," C1-6Alkyl "or" C1-3Alkyl "may be unsubstituted or substituted with one or more substituents selected from hydroxy, halogen or amino.
The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH2-, "ethylene" means-CH2-CH2-, "propylene" means-CH2-CH2-CH2-, "butylene" means-CH2-CH2-CH2-CH2-and the like.
The term "alkoxy" refers to an alkyl group as described above having the specified number of carbon atoms attached through an oxygen bridge. C1-6Alkoxy radicals comprising C1、C2、C3、C4、C5And C6Alkoxy group of (2). Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and S-pentoxy.
The term "alkyleneoxy" means that one hydrogen atom of an alkoxy group is further substituted.
The term "alkenyl" refers to a straight or branched hydrocarbon chain containing 2 to 12 carbon atoms and having one or more double bonds. Examples of alkenyl groups include, but are not limited to, allyl, propenyl, 2-butenyl, and 3-hexenyl. One of the double bond carbons may optionally be the point of attachment of an alkenyl substituent.
The term "alkynyl" refers to a straight or branched hydrocarbon chain containing 2 to 12 carbon atoms and characterized by having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of an alkynyl substituent.
Unless otherwise specified, the term "hetero" means a heteroatom or a heteroatom group (i.e., a heteroatom-containing radical) including carbon (C)) And atoms other than hydrogen (H) and atomic groups containing these hetero atoms include, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), — O-, -S-, ═ O, ═ S, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O), — S (═ O), -S (═ O)2-, and-C (═ O) N (H) -, -C (═ NH) -, -S (═ O)2N (h) -or-S (═ O) n (h) -.
Unless otherwise specified, the term "monocyclic" denotes a saturated or partially saturated monocyclic cyclic hydrocarbon, said monocyclic ring comprising 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic rings include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, cyclooctane, and the like.
The term "cycloalkyl" refers to a saturated monocyclic ring.
The term "monocyclic heterocycle" refers to a monocyclic ring having 3 to 12 ring atoms, wherein 1 or 2 ring atoms are selected from N, O, S (O)n(wherein n is 0, 1 or 2) and the remaining ring atoms are C. Such rings may be saturated or unsaturated (e.g. with one or more double bonds), but do not have a fully conjugated pi-electron system. Examples of 3-membered saturated monoheterocycles include, but are not limited to
Figure BDA0002902944530000331
Examples of 4-membered saturated monoheterocycles include, but are not limited to
Figure BDA0002902944530000332
Examples of 5-membered saturated monoheterocycles include, but are not limited to
Figure BDA0002902944530000333
Figure BDA0002902944530000341
Examples of 6-membered saturated monoheterocycles include, but are not limited to
Figure BDA0002902944530000342
Figure BDA0002902944530000343
Examples of 7-membered saturated monoheterocycles include, but are not limited to
Figure BDA0002902944530000344
Examples of 5-membered unsaturated mono-heterocycles include, but are not limited to
Figure BDA0002902944530000345
Examples of 6-membered unsaturated mono-heterocycles include, but are not limited to
Figure BDA0002902944530000346
The term "heterocycloalkyl" refers to a saturated mono-heterocyclic ring.
The term "bridged heterocyclic ring" refers to a 5-to 14-membered polycyclic ring in which two or more rings share two or more atoms, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system, wherein one or more ring atoms are selected from N, O, S (O)n(wherein n is 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 6 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycles depending on the number of constituent rings, preferably bicyclic or tricyclic, more preferably bicyclic. Non-limiting examples of bridged heterocycles include:
Figure BDA0002902944530000347
Figure BDA0002902944530000348
the term "fused ring" refers to a 7-20 membered all-carbon polycyclic ring in which two rings share two adjacent carbon atoms, wherein at least one ring has a fully conjugated pi-electron system. Preferably 6 to 14, more preferably 6 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycles according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably, 5-or 6-membered bicyclic rings. Non-limiting examples of fused rings include:
Figure BDA0002902944530000349
the term "fused heterocycle" refers to a5 to 20 membered polycyclic ring in which two rings share two adjacent ring atoms, wherein at least one ring has a fully conjugated pi-electron system, wherein one or more ring atoms are selected from N, O, S (O)n(wherein n is 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 6 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycles according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably, 5-or 6-membered bicyclic rings. Non-limiting examples of fused heterocycles include:
Figure BDA0002902944530000351
Figure BDA0002902944530000352
the term "fused heteroaromatic ring" refers to a fused heterocyclic ring in which the ring system has a completely conjugated pi-electron system, non-limiting examples of fused heteroaromatic rings include:
Figure BDA0002902944530000353
the term "heteroaryl ring" or "heteroaryl" refers to a monocyclic ring having a conjugated pi-electron system comprising 1 to 4 heteroatoms, 5 to 8 ring atoms, wherein the heteroatoms are selected from O, N, S and the remaining ring atoms are C. Heteroaryl is preferably 5 to 6 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferred examples thereof include imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl and the like, and preferred examples thereof are imidazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl or pyrazinyl.
In this application, L1、L2The connection with the ring a and the ring B means sequential connection from left to right. For example, -L2-is selected from-N (R)A1)-C(O)-(CRA2RB2)qWhen-is-only denotes the ring A-N (R)A1)-C(O)-(CRA2RB2)q-ring B.
"EA" refers to ethyl acetate.
"TFA" refers to trifluoroacetic acid.
"DCM" means dichloromethane.
"DMF" refers to N, N-dimethylformamide.
"HATU" refers to 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.
"DMSO" refers to dimethyl sulfoxide.
"EDTA" refers to ethylenediaminetetraacetic acid.
"BINAP" refers to 1,1 '-binaphthyl-2, 2' -diphenylphosphine.
"Dioxane" refers to Dioxane.
“Pd2dba3"refers to tris (dibenzylideneacetone) dipalladium.
"DavePhos" refers to 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl.
"LiHMDS" refers to lithium hexamethyldisilazide.
"THF" refers to tetrahydrofuran.
"DIPEA" refers to N, N' -diisopropylethylamine.
"Triphosgene" refers to Triphosgene.
"CDI" refers to N' N-carbonyldiimidazole.
The room temperature is 20-30 ℃.
Detailed description of the preferred embodiments
The present application is described in detail below by way of examples, but is not meant to be limited to any of the disadvantages of the present application. Having described the disclosure in detail and having disclosed specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Example 1: preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide)
The reaction process comprises the following steps:
Figure BDA0002902944530000361
step A: preparation of 1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethanone
10g (71.88mmol) of 2-fluoro-5-acetylpyridine, 100mL of DMF, 6.18g (71.88mmol) of 4-fluoro-1H-pyrazole and 9.93g (71.88mmol) of potassium carbonate were added to a 250mL sealed tube, and the mixture was heated to 100 ℃ and stirred for reaction for 10 hours. The heating was turned off, and the reaction was cooled to room temperature, poured into 400mL of water, and stirred for 30 min. Filtration, washing of the filter cake with water, collection of the filter cake and drying gave 13.7g of beige target product. The crude product was used in the next reaction without purification.
And B: preparation of (R) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide
A500 mL three-necked round-bottomed flask was charged with 150mL of anhydrous tetrahydrofuran, 13.7g (66.7mmol) of 1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethanone, 8.09g (66.7mmol) of R-t-butylsulfinamide, 17.92g (133.4mmol) of diethylene glycol dimethyl ether, and 30.46g (133.4mmol) of tetraethyltitanate, and the reaction mixture was heated under reflux for 5 hours. Cooling the reaction liquid to-78 ℃, slowly dropwise adding 200.3mL of 1M tetrahydrofuran solution of lithium tri-sec-butylborohydride under the protection of nitrogen, and continuously stirring and reacting for 40min at-78 ℃ after dropwise adding. 20mL of methanol is added dropwise to quench the reaction, the reaction solution is naturally heated to 0 ℃, and the reaction solution is poured into 500mL of water and stirred. Filter and wash the filter cake with ethyl acetate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give a crude yellow oil. 150mL of petroleum ether was added to the crude product, stirred at room temperature for 2h, filtered, and the filter cake was washed with petroleum ether to give 12.1g of an off-white target. The product was used directly in the next reaction without purification.
And C: preparation of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylamine dihydrochloride
A250 mL round bottom flask was charged with (R) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide 12.1g and 50mL methanol. After the mixture was dissolved by stirring, 100mL of a1, 4-dioxane solution of 1M hydrogen chloride was added thereto under stirring, and the mixture was stirred at room temperature overnight. After the reaction, the reaction solution was concentrated to give a pale yellow oily crude product, to which was added 30mL of ethyl acetate and stirred at room temperature for 1.5 hours. Filtration, washing of the filter cake with a small amount of ethyl acetate, collection of the filter cake and drying gave 9.4g of the pale yellow target product.
MS(ESI,[M+H]+)m/z:207.1.
Step D: preparation of 2-chloro-6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine
A100 mL round-bottomed flask was charged with 12g (73.6mmol) of 2, 4-dichloro-6-methylpyridine, 50mL of DMSO, 7.86g (73.6mmol) of 5-methyl-1H-pyrazol-3-amine, and 14.2g (110 mmol) of diisopropylethylamine, and the reaction mixture was heated to 60 ℃ and reacted overnight. The reaction solution was cooled to room temperature, poured into 400mL of water, extracted with methyl tert-butyl ether, and the combined organic phases were washed with a saturated aqueous NaCl solution and dried. The organic phase is concentrated and the crude product obtained is taken up in 50mL of dichloromethane and slurried with stirring overnight. Filtration and washing of the filter cake with a small amount of dichloromethane, the filter cake was collected and dried to give 9.9g of white target.
MS(ESI,[M+H]+)m/z:224.1.
Step E: preparation of tert-butyl 4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxylate
In a 100mL round-bottomed flask, 0.5g (2.235mmol) of 2-chloro-6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine, 5mL of DMF and 0.833g (4.47mmol) of piperazine-1-carboxylic acid tert-butyl ester, N2The mixture was heated to 100 ℃ for 7h under protection. The reaction solution was poured directly into 50mL of ice-water, and extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave 1.5g of a colorless oil. Purification by column chromatography gave 0.8g of an off-white powdery solid.
MS(ESI,[M+H]+)m/z:374.4。
Step F: preparation of 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate
To a 50mL round-bottomed flask, 0.78g (1.938mmol) of tert-butyl 4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxylate, 10mL of DCM and 1.105g (9.69mmol) of trifluoroacetic acid were added in this order, and the mixture was stirred at room temperature overnight, after the completion of the reaction, the reaction mixture was concentrated to obtain 0.8g of a white solid product which was used in the next reaction without purification.
1H-NMR(500MHz,DMSO-d6):δ10.85(s,1H),9.31(s,2H),6.38(s,1H),6.24(s,1H),3.99(s,4H),3.29(s,4H),2.33(s,3H),2.35(s,3H)；
MS(ESI,[M+H]+)m/z:274.4。
Step G: preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide)
Triphosgene 0.011g (0.037mmol) was dissolved in 3mL of dichloromethane, N2Under the protection, the temperature is reduced to 0 ℃ under the ice salt bath condition, and 2mL of dichloromethane solution containing 0.030g (0.107mmol) of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridine-3-yl) ethyl-1-amine dihydrochloride and 0.086g (0.852mmol) of triethylamine is added dropwise. After the reaction mixture was stirred at 0 ℃ for 5min, 0.05g (0.107mmol) of 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate and triethylamine were added and the mixture was stirred at room temperature for 20 min. After completion of the reaction, the reaction mixture was diluted with 50mL of methylene chloride and washed with 10mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography to give 32mg of a white powdery solid as a target.
1H NMR(500MHz,DMSO-d6):δ11.82(s,1H),9.25(s,1H),8.66(d,J＝4.5Hz,1H),8.42(s,1H),7.96(d,J＝8.5Hz,1H),7.89(m,2H),6.97(d,J＝7.5Hz,1H),6.22(br,1H),6.14(br,1H),4.94(m,1H),3.68(s,4H),3.40(s,4H),2.21(s,3H),2.13(s,3H),1.45(d,J＝7.0Hz,3H)；
MS(ESI,[M+H]+)m/z:506.5。
Example 2: preparation of (1S, 4S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -5- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000381
the synthesis method is referred to example 1.
1H NMR(500MHz,DMSO-d6):δ11.88(s,1H),9.30(br,1H),8.63(s,1H),8.39(s,1H),7.89(m,3H),6.74(s,1H),6.23(br,2H),4.86(m,1H),3.65(m,3H),3.07(m,3H),2.21(s,3H),2.12(s,3H),1.40(d,J＝7.0Hz,3H),1.26(t,J＝7.0Hz,2H)；
MS(ESI,[M+H]+)m/z:518.34。
Example 3: preparation of (1R, 4R) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -5- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000391
the synthesis method is referred to example 1.
1H-NMR(500MHz,DMSO-d6):δ11.88(s,1H),9.97(s,1H),8.64(d,J＝5.0Hz,1H),8.37(d,J＝5.0Hz,1H),7.85(m,3H),6.73(s,1H),6.23(br,2H),4.89(m,1H),3.43(m,2H),3.07(m,4H),2.19(s,3H),2.13(s,3H),1.42(d,J＝10.0Hz,3H),1.24(s,2H)；
MS(ESI,[M+H]+)m/z:518.29。
Example 4: preparation of N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -6- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-3-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000392
the synthesis method is referred to example 1.
1H NMR(500MHz,DMSO-d6):δ12.30(s,1H),10.51(s,1H),8.64(d,J＝3.5Hz,1H),8.35(s,1H),7.90(d,J＝4.5Hz,2H),7.81(d,J＝8.5Hz,1H),6.76(s,1H),6.31(m,2H),4.88(m,1H),3.90(m,2H),3.46(m,2H),3.05(m,2H),2.37(s,3H),2.29(s,3H),1.59(s,2H),1.40(m,3H)；
MS(ESI,[M+H]+)m/z:518.5。
Example 5: preparation of N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000401
the synthesis method is referred to example 1.
1H NMR(500MHz,DMSO-d6):δ11.92(s,1H),10.45(s,1H),8.55(m,1H),8.29(s,1H),7.88(m,1H),7.79(d,J＝8Hz,1H),7.66(d,J＝9Hz,1H),7.22(m,1H),6.31(s,1H),6.18(s,1H),4.82(m,1H),4.31(m,2H),4.10(m,2H),3.48(m,2H),2.21(s,3H),2.15(s,3H),1.43(m,3H),1.36(m,2H)；
MS(ESI,[M+H]+)m/z:518.5。
Example 6: preparation of N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -8- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-3-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000402
the synthesis method is referred to example 1.
1H-NMR(500MHz,DMSO-d6):δ11.87(s,1H),9.32(s,1H),8.67(d,J＝5.0Hz,1H),8.39(s,1H),7.90(m,3H),6.77(d,J＝5.0Hz,1H),6.15(m,2H),4.91(m,1H),4.66(s,2H),3.74(d,J＝10.0Hz,2H),3.00(d,J＝10.0Hz,2H),2.21(s,3H),2.14(s,3H),1.84(s,2H),1.69(d,J＝5.0Hz,2H),1.42(d,J＝10.0Hz,3H)；
MS(ESI,[M+H]+)m/z:532.30。
Example 7: preparation of N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000411
the synthesis method is referred to example 1.
1H-NMR(500MHz,DMSO-d6):δ11.88(s,1H),9.90(s,1H),8.67(d,J＝5.0Hz,1H),8.42(s,1H),7.92(m,3H),7.13(d,J＝5.0Hz,1H),6.15(m,2H),4.96(m,1H),4.42(d,J＝5.0Hz,2H),4.29(d,J＝5.0Hz,2H),3.08(d,J＝5.0Hz,2H),2.21(s,3H),2.13(s,3H),1.75(s,2H),1.59(d,J＝10.0Hz,2H),1.46(d,J＝5.0Hz,3H)；
MS(ESI,[M+H]+)m/z:532.30。
Example 8: preparation of (R) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000412
the synthesis method is referred to example 1.
1H NMR(500MHz,CDCl3)δ8.37–8.38(m,2H),7.89(d,J＝8.5Hz,1H),7.77(d,J＝7.7Hz,1H),7.56(d,J＝4.0Hz,1H),7.19(s,1H),6.06(d,J＝21.0Hz,2H),5.06–5.11(m,1H),4.75(d,J＝6.0Hz,1H),4.54(d,J＝12.5Hz,1H),4.45(d,J＝13.0Hz,1H),4.15(s,1H),3.76(d,J＝12.5Hz,1H),3.20–3.27(m,2H),3.05–3.11(m,1H),2.29(s,3H),2.23(s,3H),1.54(d,J＝7.0Hz,3H),1.19(d,J＝6.5Hz,3H)；
MS(ESI,[M+H]+)m/z:520.27。
Example 9: preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000421
the synthesis method is referred to example 1.
1H NMR(500MHz,CDCl3)δ8.38–8.40(m,2H),7.90(d,J＝8.5Hz,1H),7.79(dd,J＝8.5,2.5Hz,1H),7.58(d,J＝4.0Hz,1H),7.31(s,1H),6.07(d,J＝17.0Hz,2H),5.08–5.18(m,1H),4.81(d,J＝7.0Hz,1H),4.55(d,J＝12.5Hz,1H),4.47(d,J＝13.0Hz,1H),4.13–4.18(m,1H),3.80(d,J＝13.0Hz,1H),3.21–3.27(m,2H),3.07–3.13(m,1H),2.30(s,3H),2.24(s,3H),1.56(d,J＝7.0Hz,3H),1.21(d,J＝7.0Hz,3H)；
MS(ESI,[M+H]+)m/z:520.25。
Example 10: (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -7- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -4, 7-diazaspiro [2.5] octane-4-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000422
the synthesis method is referred to example 1.
1H NMR(500MHz,CDCl3)δ8.36–8.37(m,2H),7.88(d,J＝8.5Hz,1H),7.75(d,J＝8.5Hz,1H),7.56(d,J＝4.5Hz,2H),6.03(s,2H),5.66(d,J＝7.0Hz,1H),5.07–5.20(m,1H),3.67(s,6H),2.26(s,3H),2.19(s,3H),1.56(d,J＝7.0Hz,3H),1.01(d,J＝15.5Hz,4H)；
MS(ESI,[M+H]+)m/z:532.28。
Example 11: preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000431
the synthesis method is referred to example 1.
1H NMR(500MHz,CDCl3)δ8.39–8.40(m,2H),7.90(d,J＝8.5Hz,1H),7.79(d,J＝8.5Hz,1H),7.58(d,J＝4.5Hz,1H),7.18(s,1H),6.07(d,J＝18.0Hz,2H),5.07–5.14(m,1H),4.87(s,1H),4.77(d,J＝6.5Hz,1H),4.46(d,J＝13.5Hz,1H),3.90(d,J＝12.0Hz,1H),3.69(d,J＝13.0Hz,1H),3.29–3.35(m,2H),3.05–3.11(m,1H),2.30(s,3H),2.25(s,3H),1.57(d,J＝7.0Hz,3H),1.23(d,J＝6.5Hz,3H)；
MS(ESI,[M+H]+)m/z:520.5。
Example 12: preparation of (R) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000432
the synthesis method is referred to example 1.
1H NMR(500MHz,CDCl3)δ8.40–8.41(m,2H),7.92(d,J＝8.5Hz,1H),7.81(d,J＝8.5Hz,1H),7.59(d,J＝4.0Hz,1H),6.97(s,1H),6.09(d,J＝25.0Hz,2H),5.10–5.15(m,1H),4.88(s,1H),4.68(d,J＝6.6Hz,1H),4.50(d,J＝13.3Hz,1H),3.89(d,J＝12.0Hz,1H),3.69(d,J＝13.0Hz,1H),3.30–3.38(m,2H),3.07–3.13(m,1H),2.33(s,3H),2.27(s,3H),1.57(d,J＝7.0Hz,3H),1.25(s,3H).
MS(ESI,[M+H]+)m/z:520.5。
Example 13: 4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N-phenylpiperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000441
the synthesis method is referred to example 1.
1H NMR(500MHz,CDCl3)δ7.39(d,J＝8.0Hz,2H),7.29(t,J＝8.0Hz,2H),7.04(t,J＝7.5Hz,1H),6.96(s,1H),6.50(s,1H),6.14(s,1H),6.02(s,1H),3.87(s,4H),3.58(s,4H),2.31(s,3H),2.25(s,3H).
MS(ESI,[M+H]+)m/z:393.3。
Example 14: (S) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (1- (pyridin-3-yl) ethyl) -1-carboxamide
Figure BDA0002902944530000442
The synthesis method is referred to example 1.
1H NMR(500MHz,CDCl3)δ8.63(s,1H),8.50(s,1H),7.66(d,J＝10.0Hz,1H),6.84(s,1H),6.15(s,1H),6.01(s,1H),5.34(s,1H),5.08(m,1H),4.72(d,J＝7.0Hz,1H),3.82(s,4H),3.57(s,4H),2.31(s,3H),2.26(s,3H),1.54(d,J＝7.0Hz,3H).
MS(ESI,[M+H]+)m/z:422.4。
Example 15: preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -2-aza-spiro [3.3] heptane-6-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000443
step A: preparation of (S) -6- ((1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) carbamoyl) -2-azaspiro [3.3] heptane-2-tert-butyl carboxylate
In a 50mL round-bottomed flask, 0.4g (1.658mmol) of 2- (tert-butoxycarbonyl) -2-azaspiro [3.3] heptane-6-carboxylic acid, 5mL of tetrahydrofuran, 0.463g (1.658mmol) of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylamine dihydrochloride, 0.693g (1.824mmol) of HATU, and 0.857g (6.63mmol) of N, N-diisopropylethylamine were sequentially added, and the reaction was stirred at room temperature, and when the reaction was completed, the stirring was stopped, and 100mL of ethyl acetate and 20mL of water were added to the reaction system. The organic phase was collected, washed with saturated brine and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate, and purifying the obtained crude product by column chromatography to obtain 0.7g of white powdery solid product.
MS(ESI,[M+Na]+)m/z:452.4。
And B: preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-aza-spiro [3.3] heptane-6-carboxamide
A50 mL round-bottomed flask was charged with (S) -6- ((1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) carbamoyl) -2-azaspiro [3.3] heptane-2-tert-butylcarboxylate 0.27g (0.624mmol), acetonitrile 5mL, and trimethylbromosilane 0.764g (4.99mmol) in this order, and stirred at room temperature for 3 hours. After completion of the reaction, 20mL of water was added to the reaction system, followed by extraction with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave 0.13g of a gray-like oil. The product was used in the next reaction without further purification.
MS(ESI,[M+H]+)m/z:330.2。
And C: preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -2-aza-spiro [3.3] heptane-6-carboxamide
To a 35mL microwave tube were added in this order (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-aza-spiro [3.3] heptane-6-carboxamide 0.12g (0.364mmol), isopropanol 10mL, triethylamine 0.147g (1.457mmol), and 2-chloro-6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine 0.081g (0.364mmol), and the mixture was reacted by heating at 120 ℃ for 2 hours in a microwave reactor. After the reaction, the reaction solution was poured into 50mL of water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed three times with saturated brine and then dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate, and performing column chromatography on the obtained crude product to obtain 82mg of a white powdery solid target.
1H NMR(500MHz,DMSO-d6):δ12.04(s,1H),8.67(d,J＝4.5Hz,1H),8.36(m,2H),7.95(m,3H),6.25(m,2H),4.99(t,J＝7.5Hz,1H),4.11(s,2H),3.99(s,2H),2.98(t,J＝8.0Hz,1H),2.36(d,J＝8.0Hz,3H),2.19(m,7H),1.40(d,J＝7.0Hz,3H)；
MS(ESI,[M+H]+)m/z:517.5。
Example 16: preparation of (1R, 5S, 6R) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3-azabicyclo [3.1.0] hexane-6-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000451
the synthesis method is referred to example 15.
1H NMR(500MHz,DMSO-d6):δ12.00(s,1H),8.67(s,1H),8.59(d,J＝6.5Hz,1H),8.40(s,1H),7.90(m,4H),6.25(m,2H),5.00(d,J＝6.0Hz,1H),3.91(s,2H),3.56(s,2H),3.10(s,1H),2.21(m,3H),2.03(m,3H),1.42(s,2H),1.24(s,3H)；
MS(ESI,[M+H]+)m/z:503.4。
Example 17: preparation of (1R, 3R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -8- (4-methyl-6- (5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -8-azabicyclo [3.2.1] octane-3-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000461
the synthesis method is referred to example 15.
1H-NMR(500MHz,DMSO-d6)：δ11.83(s,1H),9.22(br,1H),8.65(d,J＝4.5Hz,1H),8.33(m,2H),7.91-7.85(m.3H),6.15(br,2H),4.90(t,J＝7.5Hz,1H),4.60(m,2H),2.88(m,1H),2.18(s,3H),2.11(s,3H),1.37(d,J＝7Hz,3H),1.97(m,2H),1.78(m,2H),1.51(m,3H)；
MS(ESI,[M+H]+)m/z:531.4。
Example 18: preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperidine-4-sulfonamide
The reaction process comprises the following steps:
Figure BDA0002902944530000462
step A: preparation of (S) -4- (N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) sulfonamido) piperidine-1-carboxylic acid tert-butyl ester
A25 mL round-bottomed flask was charged with 0.17g (0.71mmol) of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylamine dihydrochloride, 5mL of dichloromethane, 0.14g (1.41mmol) of triethylamine, and 0.2g (0.71mmol) of N-tert-butoxycarbonyl-4-chlorosulfonylpiperidine in this order, and the reaction was stirred at room temperature overnight. After completion of the reaction, 50mL of methylene chloride was added to dilute the reaction solution, and the reaction solution was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was collected and concentrated, and the crude product was purified by column chromatography to give 0.36g of an off-white solid.
1H-NMR(500MHz,DMSO-d6)：δ8.68(d,J＝4.5Hz,1H),8.46(d,J＝1Hz,1H),8.02(dd,J＝1.5Hz,8.5Hz,1H),7.93-7.88(m,3H),4.62(m,1H),4.00(m,2H),3.07(m,1H),2.03-1.94(m,2H),1.46(m,4H),1.36(m,12H)；
MS(ESI,[M+Na]+)m/z:476.5。
And B: preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylpiperidine-4-sulfonamide hydrochloride
(S) -4- (N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) sulfanyl) piperidine-1-carboxylic acid tert-butyl ester 0.36g (0.81mmol) was dissolved in 10mL of a 1mol/L HCl solution in methanol, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain 0.27g of crude product. The product was used in the next reaction without purification.
And C: preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperidine-4-sulfonamide
To a 35mL microwave tube were added in this order (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylpiperidine-4-sulfonylamine hydrochloride 0.13g (0.33mmol), isopropyl alcohol 10mL, triethylamine 0.14g (1.33mmol), and 2-chloro-6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine 0.075g (0.33mmol), and the mixture was reacted by heating at 120 ℃ in a microwave reactor for 5 hours, pouring the reaction solution into 50mL of water, extracting twice by using ethyl acetate, combining organic phases, washing the organic phase for three times by using saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, and subjecting the crude product to column chromatography to obtain 43mg of a white powdery solid target product.
1H-NMR(500MHz,DMSO-d6)：δ11.85(s,1H),9.20(s,1H),8.67(d,J＝4.5Hz,1H),8.47(s,1H),8.01(d,J＝8.5Hz,1H),7.92-7.85(m,3H),6.22(br,1H),6.09(br,1H),4.71(t,J＝8.5Hz,1H),4.63(t,J＝7Hz,1H),3.14(t,J＝8.5Hz,1H),2.81(t,1H),2.81(t,J＝12Hz,1H),2.71(t,J＝12Hz,1H),2.20(s,3H),2.10(s,3H),2.00(d,J＝12.5Hz,1H),1.90(d,J＝12.5Hz,1H),1.46(m,4H)；
MS(ESI,[M+H]+)m/z：541.4。
Example 19: preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000471
step A: preparation of tert-butyl (S) -4- (6-chloro-4-methylpyridin-2-yl) -2-methylpiperazine-1-carboxylate
2, 6-dichloro-4-methylpyridine (1g,6.17mmol), tert-butyl (S) -2-methylpiperazine-1-carboxylate (1.236g,6.17mmol), palladium acetate (0.069g,0.309mmol), BINAP (0.384g,0.617mmol), cesium carbonate (3.02g,9.26mmol) and Dioxane were sequentially added to a 30mL sealed tube, and the mixture was placed in a microwave reactor, heated to 120 ℃ at 100W, and reacted for 2 hours after purging air with nitrogen. Filtration, collection of the filtrate and concentration, and column chromatography of the crude product yielded 0.44g of the target product as a brown solid.
MS(ESI,[M+H]+)m/z:326.1.
And B: preparation of tert-butyl (S) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxylate
To a 20mL sealed tube was added tert-butyl (S) -4- (6-chloro-4-methylpyridin-2-yl) -2-methylpiperazine-1-carboxylate (439mg,1.349mmol), 5-methyl-1H-pyrazol-3-amine (131mg,1.349mmol), Pd in that order2dba3(61.8mg,0.067mmol), DavePhos (53.1mg,0.135mmol), LiHMDS (564mg,3.37mmol) and THF (3ml), purged with nitrogen, placed in a microwave reactor and heated to 130 ℃ at 100W for 30 min. The reaction was quenched by the addition of 2mL of 1M saturated ammonium chloride solution dropwise under ice-bath conditions and diluted with 20mL of ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase is concentrated and the crude product is purified by column chromatography to yield 0.320g of the target yellow solid.
MS(ESI,[M+H]+)m/z:387.2.
And C: preparation of (S) -4-methyl-N- (5-methyl-1H-pyrazol-3-yl) -6- (3-methylpiperazin-1-yl) pyridin-2-amine trifluoroacetate
In a 50mL round bottom flask, 0.320g (0.83mmol) of t-butyl (S) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxylate, 10mL of DCM, and 0.473g (4.15mmol) of trifluoroacetic acid were sequentially added, and the mixture was stirred at room temperature overnight, after completion of the reaction, the reaction solution was concentrated to obtain 0.31g of a white solid product, which was used in the next reaction without purification.
MS(ESI,[M+H]+)m/z:287.1.
Step D: preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
0.011g (0.037mmol) of triphosgene is dissolved in 5mL of dichloromethane, and under the protection of nitrogen, the temperature is reduced to 0 ℃ under the condition of ice salt bath, and 2mL of dichloromethane solution containing 0.226g (0.807mmol) of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylamine dihydrochloride and 0.716g (6.456mmol) of triethylamine is added dropwise. After the reaction mixture was stirred at 0 ℃ for 5min, 0.31g (0.807mmol) of (S) -4-methyl-N- (5-methyl-1H-pyrazol-3-yl) -6- (3-methylpiperazin-1-yl) pyridin-2-amine trifluoroacetate and triethylamine were added and the mixture was stirred at room temperature for 20 min. After completion of the reaction, the reaction mixture was diluted with 50mL of methylene chloride and washed with 20mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography to give 131mg of a white powdery solid as the target.
1H-NMR(500MHz,DMSO-d6):8.39(d,J＝12.5Hz,2H),7.84(d,J＝30.1Hz,2H),7.57(s,1H),7.38(s,1H),6.92(s,2H),6.07(s,1H),5.88(d,J＝17.4Hz,2H),5.17(s,1H),4.18(s,1H),3.97-3.99(m,1H),3.78-3.89(m,2H),3.19–3.29(m,2H),2.99–3.03(m,1H),2.26(s,3H),2.18(s,3H),1.56(s,3H),1.23(s,3H)；
MS(ESI,[M+H]+)m/z:519.3.
Example 20: preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000491
step A: preparation of tert-butyl (S) -4- (4-chloro-6-methylpyridin-2-yl) -2-methylpiperazine-1-carboxylate
A25 mL single-necked flask was charged with 2, 4-dichloro-6-methylpyridine (2g,12.34mmol), tert-butyl (S) -2-methylpiperazine-1-carboxylate (2.72g,13.58mmol), Et in that order3N (1.499g,2.065mL,14.81mmol) and DMSO (20mL), the mixture was heated to 100 ℃ under nitrogen protection for 16 h. 10mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, and filteredFiltration and concentration gave a brown oil which was purified by column chromatography to give 1.24g of the title product as a brown solid.
MS(ESI,[M+H]+)m/z:326.3.
And B: preparation of tert-butyl (S) -2-methyl-4- (6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxylate
To a 20mL sealed tube was added tert-butyl (S) -4- (6-chloro-4-methylpyridin-2-yl) -2-methylpiperazine-1-carboxylate (439mg,1.349mmol), 5-methyl-1H-pyrazol-3-amine (131mg,1.349mmol), Pd in that order2dba3(61.8mg,0.067mmol), DavePhos (53.1mg,0.135mmol), LiHMDS (564mg,3.37mmol) and THF (3mL), purged with nitrogen, placed in a microwave reactor and heated to 130 ℃ at 100W for 30 min. The reaction was quenched by the addition of 2mL of 1M saturated ammonium chloride solution dropwise under ice-bath conditions and diluted with 20mL of ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase is concentrated and the crude product is purified by column chromatography to yield 0.309g of the target product as a yellow solid.
MS(ESI,[M+H]+)m/z:387.4.
And C: preparation of (S) -2-methyl-N- (5-methyl-1H-pyrazol-3-yl) -6- (3-methylpiperazin-1-yl) pyridin-4-amine
In a 50mL round bottom flask, tert-butyl (S) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxylate 0.309g (0.801mmol), DCM 10mL and trifluoroacetic acid 0.456g (4.01mmol) were added in this order, stirred at room temperature overnight, and after completion of the reaction, the reaction was concentrated to give 0.30g of a white solid product which was used in the next reaction without purification.
MS(ESI,[M+H]+)m/z:287.1.
Step D: preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
0.011g (0.037mmol) of triphosgene is dissolved in 5mL of dichloromethane, and under the protection of nitrogen, the temperature is reduced to 0 ℃ under the condition of ice salt bath, and 2mL of dichloromethane solution containing 0.218g (0.807mmol) of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethan-1-amine dihydrochloride and 0.717g (6.456mmol) of triethylamine is added dropwise. After the reaction mixture was stirred at 0 ℃ for 5min, 0.30g (0.780mmol) of (S) -4-methyl-N- (5-methyl-1H-pyrazol-3-yl) -6- (3-methylpiperazin-1-yl) pyridin-2-amine trifluoroacetate and triethylamine were added and the mixture was stirred at room temperature for 20 min. After completion of the reaction, the reaction mixture was diluted with 50mL of methylene chloride and washed with 20mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography to give 120mg of a white powdery solid as a target.
1H-NMR(500MHz,CDCl3)δ12.05(s,1H),8.35(d,J＝20.2Hz,2H),7.80(s,2H),7.54(s,1H),6.88(s,1H),5.89(s,1H),5.84(s,1H),5.80(s,1H),5.05(s,1H),4.28(s,1H),3.83–3.85(m,1H),3.62–3.64(m,1H),3.51–3.53(m,1H),3.25–3.33(m,2H),3.13–3.15(m,1H),2.32(s,3H),2.17(s,3H),1.53(s,3H),1.13(s,3H)；
MS(ESI,[M+H]+)m/z:519.6.
Example 21: preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carbothioamide
The reaction process comprises the following steps:
Figure BDA0002902944530000501
step A: preparation of tert-butyl (1R, 5S) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
In a 100mL single-necked flask were charged 0.3g (1.341mmol) of 2-chloro-6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine and 0.43g (2.012mmol) of tert-butyl DMF5mL, 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate. Reacting for 10 hours at 100 ℃ under the protection of nitrogen. After the reaction, the reaction mixture was diluted with 50ml of water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 380mg of a clear granular solid.
MS(ESI,[M+H]+)m/z:400.5.
And B: preparation of 2- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine trifluoroacetate
To a 100mL single-necked flask were added 0.38g (0.951mmol) of tert-butyl (1R, 5S) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, 10mL of dichloromethane, and 0.868g (7.61mmol) of trifluoroacetic acid. The reaction was carried out at room temperature for 12 h. After the reaction, the reaction solution was directly concentrated to obtain a white oily substance, which was added with ethyl acetate and then slurried and filtered to obtain 0.52g of a white powdery solid.
MS(ESI,[M+H]+)m/z:300.4.
And C: preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carbothioamide
In a 50mL single-necked flask, 0.16g (0.573mmol) of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethan-1-amine dihydrochloride, 5mL of chloroform, 0.23g (2.293mmol) of triethylamine, and 0.079g (0.688mmol) of thiophosgene were added. Then 2mL of water was added to cover the reaction surface. The reaction was carried out at room temperature for 20 min. The aqueous layer was removed and a solution of 0.302g (0.573mmol) of 2- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine trifluoroacetate, 0.23g (2.293mmol) of triethylamine in 4mL of chloroform was then added. The reaction was carried out at room temperature for 2 h. After the reaction, 50mL of dichloromethane was added to the reaction solution, and the organic phase was collected after washing with saturated brine. Dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 140mg of a yellow solid.
1H-NMR(500MHz,CDCl3):δ12.10(s,1H),8.45(s,1H),8.36(d,J＝4.5Hz,1H),7.87(s,2H),7.56(d,J＝4.2Hz,1H),6.45(s,1H),6.11(s,1H),6.04(s,1H),5.89(p,J＝7.2Hz,1H),3.14(q,J＝7.3Hz,4H),2.27(m,6H),1.65(d,J＝7.0Hz,3H),1.34(t,J＝7.3Hz,6H),0.89(dd,J＝12.7,9.5Hz,1H)；
MS(ESI,[M+H]+)m/z:548.2.
Example 22: preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carbothioamide
The reaction process comprises the following steps:
Figure BDA0002902944530000511
synthesis method reference is made to example 21
1H NMR(500MHz,CDCl3):δ8.44(s,1H),8.39(d,J＝4.5Hz,1H),7.91(d,J＝8.5Hz,1H),7.84(d,J＝8.0Hz,1H),7.58(d,J＝8.5Hz,1H),7.22(s,1H),6.10(s,1H),6.04(s,1H),5.93(m,1H),5.86(s,1H),4.79(s,1H),4.38(m,3H),3.49(m,4H),2.32(s,3H),2.25(s,3H),1.67(d,J＝8.0Hz,3H),1.29(m,3H)；
MS(ESI,[M+H]+)m/z:536.2.
EXAMPLE 23 preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-amide
The reaction process comprises the following steps:
Figure BDA0002902944530000512
step A: preparation of tert-butyl (1R, 5S) -3- (4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
In a 100mL single-necked flask were charged 0.3g (1.431mmol) of 2-chloro-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine and 0.456g (2.147mmol) of tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate in 5mL of DMF. Reacting for 10 hours at 100 ℃ under the protection of nitrogen. After completion of the reaction, the reaction mixture was diluted with 50mL of water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 0.52g of a brown solid.
MS(ESI,[M+H]+)m/z:386.5.
And B: preparation of 2- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine trifluoroacetate
To a 100ml single-neck flask were added 0.52g (1.341mmol) of tert-butyl (1R, 5S) -3- (4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, 10ml of dichloromethane, and 1.223g (10.73mmol) of trifluoroacetic acid. The reaction was carried out at room temperature for 12 h. After the reaction, the reaction solution was directly concentrated to obtain a white oily substance, and 20ml of ethyl acetate was added to the white oily substance, and the mixture was pulped and filtered to obtain 0.76g of a yellowish white powdery solid.
MS(ESI,[M+H]+)m/z:286.4.
And C: preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-amide
In a 50mL three-necked flask, 0.064g (0.217mol) of triphosgene was dissolved in 3mL of dichloromethane and the ice salt bath was cooled to 0 ℃ under nitrogen. 3mL of a dichloromethane solution containing 0.055g (0.197mmol) of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethan-1-amine dihydrochloride and 0.160g (1.576mmol) of triethylamine was added dropwise. The reaction solution was stirred at 0 ℃ for 5 min. 3mL of a solution of 0.100g (0.197mmol) of 2- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine trifluoroacetate and 0.160g (1.576mmol) of triethylamine in methylene chloride was added. The reaction was carried out at room temperature for 30 min. After the reaction, 50mL of dichloromethane was added to the reaction solution to dilute the reaction solution, and the organic phase was collected after washing with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 54mg of a yellow solid.
1H-NMR(500MHz,CDCl3):δ12.05(s,1H),11.21(s,4H),8.43(s,1H),8.36(d,J＝4.7Hz,1H),7.88(m,3H),7.55(d,J＝4.4Hz,1H),3.67(m,7H),3.37–3.17(m,3H),2.32(s,3H),1.92(s,2H),1.72(s,2H)；
MS(ESI,[M+H]+)m/z:518.3.
Example 24: preparation of N- (4-fluorophenyl) -N- (1- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperidin-4-yl) cyclopropane-1, 1-dicarboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000531
step A: preparation of methyl 1- ((4-fluorophenyl) amidomethyl) cyclopropyl-1-carboxylate
In a 100mL three-necked flask, 20mL of toluene, 2.22g (19.98mmol) of 4-fluoroaniline and 4.32g (19.98mmol) of sodium methoxide were sequentially added. Reacting for 30min at 100 ℃ under the protection of nitrogen, cooling to 66 ℃, and distilling off methanol in the reaction system under nitrogen flow. After methanol was completely distilled off, 3.79g (23.97mmol) of dimethyl 1, 1-cyclopropanedicarboxylate was added. The reaction is carried out under the protection of nitrogen at 66 ℃, and the operation of distilling off the methanol by nitrogen flow is carried out every 1h until the reaction is completed. The reaction solution was concentrated to give an oil, 100mL of water was added, and the pH of the system was adjusted to weak acidity with 1.2M dilute hydrochloric acid. And (4) extracting with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 2.07g of a yellow-green solid.
MS(ESI,[M-H]-)m/z:236.2.
And B: preparation of 1- ((4-fluorophenyl) amidomethyl) cyclopropyl-1-carboxylic acid.
A50 mL single-necked flask was charged with 5mL of methanol, 0.13g (0.548mmol) of methyl 1- ((4-fluorophenyl) amidomethyl) cyclopropyl-1-carboxylate, and 1.1mL of a 1N aqueous solution of sodium hydroxide. The reaction was carried out at room temperature overnight. 50mL of ice water is poured into the phase reaction liquid, 1M dilute hydrochloric acid is dripped into the ice water to adjust the pH value of the system to be subacidity, dichloromethane is used for extraction, organic phases are combined, anhydrous sodium sulfate is dried, and then filtration and concentration are carried out to obtain 0.12g of white powdery solid.
MS(ESI,[M-H]-)m/z:222.2.
And C: preparation of tert-butyl (1- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperidin-4-yl) aminocarboxylate
In a 100mL single-necked flask were sequentially added 1g (4.47mmol) of 2-chloro-6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine, DMF10mL and 0.985g (4.92mmol) of 4-tert-butoxycarbonylaminopiperidine. Reacting for 8 hours at 100 ℃ under the protection of nitrogen. After diluting the reaction mixture with 80mL of water, it was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 1.54g of a white powdery solid.
MS(ESI,[M+H]+)m/z:388.5.
Step D: preparation of 2- (4-aminopiperidin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-aminotrifluoroacetate
In a 100mL single-necked flask were charged 1.54g (3.97mmol) of t-butyl (1- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperidin-4-yl) carbamate, 20mL of methylene chloride, and 4.53g (39.7mmol) of trifluoroacetic acid. The reaction was carried out at room temperature for 12 h. After the reaction, the reaction solution was directly concentrated, 20mL of ethyl acetate was added, and after pulping, 2.1g of a white powdery solid was obtained by filtration.
MS(ESI,[M+H]+)m/z:288.3.
Step E: preparation of N- (4-fluorophenyl) -N- (1- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperidin-4-yl) cyclopropane-1, 1-dicarboxamide
A100 mL single-necked flask was charged with 0.12g (0.538mmol) of 1- ((4-fluorophenyl) amidomethyl) cyclopropyl-1-carboxylic acid, 5mL of DMF, and 0.307g (0.645mmol) of HATU. 0.33g (0.645mmol) of 2- (4-aminopiperidin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-aminotrifluoroacetate and 0.556g (4.3mmol) of DIPEA were dissolved in 5mL of DMF and added to the reaction system. The reaction was carried out at room temperature for 4 h. After the reaction is completed. 80ml of purified water was poured into the reaction solution, followed by extraction with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 0.15g of a white solid.
1H-NMR(500MHz,CDCl3):δ10.43(s,1H),7.52(dd,J＝8.8,4.8Hz,2H),7.12(s,1H),7.02(t,J＝8.5Hz,2H),6.10(s,1H),6.03(d,J＝8.2Hz,2H),4.66(dd,J＝13.8,3.9Hz,2H),4.05(m,1H),3.11–2.99(m,2H),2.31(s,3H),2.24(s,3H),1.98(d,J＝15Hz,2H),1.70(q,J＝4.7Hz,2H),1.46–1.39(m,3H),1.32(q,J＝4.6Hz,2H)；
MS(ESI,[M+H]+)m/z:493.2.
Example 25: preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) oxy) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000541
step A: preparation of 2-chloro-4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) oxy) pyrimidine
In a 100mL round-bottom flask, 1.309g (8.03mmol) of 2, 4-dichloro-6-methylpyrimidine, 20mL of DMF, 0.876g (8.93mmol) of 5-methyl-1H-pyrazol-3-ol and 1.315g (10.17mmol) of DIPEA were sequentially added, the mixture was uniformly stirred, heated to 85 ℃, and stirred for reaction for 20 hours. The heating was stopped, the temperature was reduced to room temperature, 50mL of water was added to the reaction solution to dilute it, and it was extracted with ethyl acetate, and the combined organic phases were washed with a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give 0.718g of a white solid.
MS(ESI,[M+Na]+)m/z:247.1.
And B: preparation of tert-butyl (1R, 5S) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) oxy) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
A100 mL single-neck flask was charged with 0.2g (0.890mmol) of 2-chloro-4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) oxy) pyrimidine, 0.78 mL of DMF10mL of (1R, 5S) -3, 8-diazabicyclo [ 3.2.1%]Octane-8-carboxylic acid tert-butyl ester 0.227g (1.068mmol) and potassium carbonate 0.246g (1.781mmol), N2The mixture was heated to 100 ℃ for 7h under protection. The reaction solution was poured directly into 50mL of ice-water, and extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. Filtering, concentrating, and purifying by column chromatography to obtain white powder solid 0.26 g.
MS(ESI,[M+H]+)m/z:401.4.
And C: preparation of trifluoroacetate salt of (1R, 5S) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) oxy) -6-pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane
To a 100mL single-necked flask were added tert-butyl (1R, 5S) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) oxy) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 0.39g (0.974mmol), 10mL of DCM and trifluoroacetic acid 1.105g (0.746mL,9.69mmol) in this order, and the mixture was stirred at room temperature overnight. The reaction was concentrated to give a colorless oil, and 10mL of ethyl acetate was added and stirred at room temperature for 30 min. Filtration gave 0.32g of a white powdery solid.
MS(ESI,[M+H]+)m/z:301.3.
Step D: preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) oxy) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide
179mg (0.602mmol) of triphosgene, 5mL of methylene chloride, and N were sequentially added to a 50mL three-necked flask2Under the protection, the temperature is reduced to 0 ℃ under the ice salt bath condition, and 5mL of dichloromethane solution containing 210mg (0.753mmol) of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridine-3-yl) ethane-1-amine dihydrochloride and 0.4mL of triethylamine is added dropwise. After the reaction mixture was stirred at 0 ℃ for 5 minutes, the mixture was added with a solution containing (1R, 5S) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) oxy) -6-pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]300mg (0.753mmol) of trifluoroacetate salt of octane and 0.8mL of triethylamine in 10mL of DCM. Stirring the reaction solution at low temperature for 5-10 min, and transferring to room temperature for stirring for 20 min. The reaction mixture was diluted with 50mL of dichloromethane and washed with a saturated aqueous solution of sodium chloride. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography to give 250mg of a white powdery solid.
1H-NMR(500MHz,DMSO-d6):δ12.17(s,1H),8.66(d,J＝5Hz,1H),8.41(s,1H),7.91(m,3H),7.08(d,J＝10.0Hz,1H),6.01(s,1H),5.83(s,1H),4.95(m,1H),4.30(m,4H),2.97(d,J＝10.0Hz,2H),2.23(d,J＝5Hz,6H),1.75(s,2H),1.54(d,J＝10.0Hz,2H),1.45(d,J＝5.0Hz,3H).
MS(ESI,[M+H]+)m/z：533.4.
Example 26: preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (6-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000551
step A: preparation of tert-butyl (1R, 5S) -3- (2-chloro-6-methylpyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
In a 50mL single-necked flask, 90mg (0.552mmol) of 2, 4-dichloro-6-methylpyrimidine, 10mL of n-butanol, 129mg (0.607mmol) of tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate and 107mg (0.145mL,0.828mmol) of diisopropylethylamine were sequentially added, and the mixture was heated to 100 ℃ and reacted for 15 hours. When the reaction was completed, 50mL of ethyl acetate was added to the reaction system, and the reaction system was washed twice with 20mL of water. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain 154mg of a beige solid target.
MS(ESI,[M+H]+)m/z:339.4.
And B: preparation of tert-butyl (1R, 5S) -3- (6-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
In a 50mL single-neck flask, 122mg (0.360mmol) of tert-butyl (1R, 5S) -3- (2-chloro-6-methylpyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, 5mL of isopropanol, and 175mg (1.800mmol) of 5-methyl-1H-pyrazol-3-amine were added in this order, and the mixture was heated to 100 ℃ under nitrogen protection and reacted for 36 hours. The solvent was concentrated and removed, and 5mL of a mixed solution of ethanol and water (ethanol: water: 1:3) was added to the reaction system. To the reaction system was added 59.7mg (0.432mmol) of potassium carbonate, and the mixture was stirred at room temperature for 1.5 hours. To the reaction system were added 50mL of ethyl acetate and 20mL of water. The organic phase was separated, collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow oil. Purifying by column chromatography to obtain colorless oily substance 0.2 g.
MS(ESI,[M+H]+)m/z:400.4.
And C: preparation of 4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-2-amine trifluoroacetate
To a 100mL single-necked flask were added (1R, 5S) -3- (6-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 0.2g (0.5mmol), dichloromethane 5mL, and trifluoroacetic acid 0.868g (2.50 mmol). The reaction was carried out at room temperature for 12 h. After the reaction, the reaction solution was directly concentrated to obtain a white oily substance, which was added with ethyl acetate and then filtered to obtain 0.218g of a white powdery solid.
MS(ESI,[M+H]+)m/z:300.4.
Step D: preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (6-methyl-2- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide
In a 50mL three-necked flask, 0.043g (0.145mmol) of triphosgene is dissolved in 3mL of dichloromethane, the temperature is reduced to about 0 ℃ under the ice salt bath condition under the protection of nitrogen, 0.090g (0.440mmol) of (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethan-1-amine dihydrochloride is dissolved in 2mL of dichloromethane by taking another 35mL microwave tube, and 0.137g (1.23mmol) of triethylamine is added. The neutralized material was slowly added dropwise to a solution of triphosgene in methylene chloride, and after about 2 minutes, the addition was complete. The reaction solution was stirred at 0 ℃ for 5 min. A solution of 0.09g (0.44mmol) of 4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-2-amine trifluoroacetate and 0.08g (0.72mmol) of triethylamine in 3mL of dichloromethane was added. The reaction solution was stirred at 0 ℃ for 5min, then warmed to room temperature and stirred for 20 min. The reaction mixture was diluted with 50mL of dichloromethane and washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to give 49mg of a white powdery solid.
1H-NMR(500MHz,DMSO-d6):δ12.23(s,1H),10.34(s,1H),8.66(d,J＝3.5Hz,1H),8.43(s,1H),7.91(m,3H),7.31(d,J＝7.5Hz,1H),6.35(s,1H),6.09(s,1H),4.95(d,J＝7.0Hz,1H),4.49(m,2H),4.43(m,2H),3.01(m,2H),2.28(s,3H),2.22(s,3H),1.80(s,2H),1.57(d,J＝3.0Hz,2H),1.46(d,J＝6.5Hz,3H)；
MS(ESI,[M+H]+)m/z:532.5.
Example 27: preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000571
the synthesis method is referred to example 19.
1H NMR(500MHz,CDCl3):δ11.64(s,1H),8.61(m,2H),8.42(s,1H),7.88(m,3H),7.13(d,J＝7.5Hz,1H),6.33(s,1H),6.23(s,1H),5.86(s,1H),4.95(m,1H),4.44(m,2H),3.84(m,2H),2.89(m,2H),2.18(s,3H),2.11(s,3H),1.77(d,J＝3.5Hz,2H),1.67(d,J＝7.5Hz,2H),1.45(d,J＝7Hz,3H).
MS(ESI,[M+H]+)m/z:531.3.
Example 28: preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -4- (3-methyl-5- ((5-methyl-1H-pyrazol-3-yl) amino) phenyl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000572
the synthesis method is referred to example 19.
1H NMR(500MHz,DMSO-d6):δ11.60(s,1H),10.27(s,1H),8.66(d,J＝4.5Hz,1H),8.41(m,1H),7.93(m,4H),7.04(d,J＝7.5Hz,1H),6.78(s,1H),6.16(s,1H),5.58(s,1H),4.93(m,1H),3.47(d,J＝4.5Hz,4H),3.33(s,4H),2.17(s,6H),1.44(d,J＝7.0Hz,3H).
MS(ESI,[M+H]+)m/z:504.3.
Example 29: preparation of N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) cyclopropyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000573
step A: preparation of 1- (6-bromopyridin-3-yl) cyclopropane-1-amine
A25 mL three-necked flask was charged with tetraisopropyl titanate 6.99g (24.59mmol) and THF (3mL), N2The mixture was heated to 50 ℃ with protection. Subsequently, 3g (16.39mmol) of 2-bromo-5-cyanopyridine was added, and 5.46g (41.0mmol) of ethylmagnesium bromide was slowly added dropwise at 50 ℃. The reaction was heated at 50 ℃ for 4 h. After the reaction, the reaction solution was concentrated and purified by column chromatography to obtain 0.8g of a yellow solid product.
MS(ESI,[M+H]+)m/z:213.0,215.0.
And B: preparation of N- (1- (6-bromopyridin-3-yl) cyclopropyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The synthesis was as in step G of example 1.
MS(ESI,[M+H]+)m/z:512.1,514.1.
And C: preparation of N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) cyclopropyl) - (S) -4- (4-methyl-6- ((methyl-1H-pyrazol-3-yl) -2-yl) -N- (1- (6- ((trimethylsilyl) ethynyl) pyrimidin-3-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester-1-carboxamide
To a 30mL microwave tube were added N- (1- (6-bromopyridin-3-yl) cyclopropyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide 300mg (0.585mmol), 4-fluoro-1H-pyrazole 252mg (2.93mmol), cesium carbonate 572mg (1.756mmol), trans- (1R,2R) -N, N' -dimethyl-1, 2-cyclohexanediamine 112mg (0.585mmol), cuprous iodide 83mg (0.585mmol), and N, N-dimethylformamide (10mL) in that order, N2 was purged of air, placed in a microwave reactor, and heated to 120 ℃ at 200W for 60 minutes. The reaction solution was poured directly into 50mL of ice-water, and extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate, and purifying by column chromatography to obtain 36mg of target product.
1H NMR(500MHz,Chloroform-d)δ8.38(s,2H),7.87(d,J＝8.5Hz,1H),7.78(d,J＝10.4Hz,1H),7.58(d,J＝4.0Hz,1H),6.85(s,1H),6.16(s,1H),6.04(s,1H),5.35(s,1H),3.85(s,4H),3.48(s,4H),2.33(s,3H),2.28(s,3H),1.32(d,J＝14.6Hz,4H).
MS(ESI,[M+H]+)m/z:518.5.
Example 30: preparation of (S) -N- (1- (6- (4-methyl-1H-imidazol-1-yl) pyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000581
step A: preparation of (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide
The synthesis method refers to example 1, step B.
MS(ESI,[M+H]+)m/z:306.3.
And B: preparation of (R) -2-methyl-N- ((S) -1- (6- (4-methyl-1H-imidazol-1-yl) pyridin-3-yl) ethyl) propane-2-sulfinamide under nitrogen protection in a 30mL sealed tube were added (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide (350mg,1.147mmol), DMF (10mL), 4-methylimidazole (284mg,3.46mmol), cesium carbonate (1120mg,3.44mmol), trans- (1R,2R) -N, N' -dimethyl 1, 2-cyclohexanediamine (163mg,1.147mmol), cuprous iodide (219mg,1.147mmol), blowing air by nitrogen, placing in a microwave reactor, and heating to 120 ℃ under 100W for reaction for 60 min.
Filtration, collection of the filtrate and concentration, addition of 40mL EA and 60mL H2And O, shaking up, separating liquid, drying by using anhydrous sodium sulfate, filtering and concentrating. The crude product was purified by column chromatography to give 140mg of a white solid.
MS(ESI,[M+H]+)m/z:307.1.
And C: preparation of (S) -1- (6- (4- (4-methyl-1H-imidazol-1-yl) pyridin-3-yl) ethan-1-amine hydrochloride
Synthesis method reference was made to example 1, step C.
MS(ESI,[M+H]+)m/z:203.2.
Step D: preparation of (S) -N- (1- (6- (4-methyl-1H-imidazol-1-yl) pyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The synthesis was as in step G of example 1.
1H NMR(500MHz,DMSO-d6)δ11.86(s,1H),9.25(s,1H),8.41(d,J＝2.3Hz,1H),8.36(d,J＝1.3Hz,1H),7.91(dd,J＝8.5,2.3Hz,1H),7.67(d,J＝8.4Hz,1H),7.61(s,1H),6.95(d,J＝7.6Hz,1H),6.54–5.98(m,2H),4.92(p,J＝7.1Hz,1H),3.74–3.59(m,4H),3.44–3.37(m,4H),2.22–2.10(m,9H),1.43(d,J＝7.1Hz,3H).
MS(ESI,[M+H]+)m/z:502.3.
Example 31: preparation of (S) -N- (1- (6-cyanopyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000591
step A: preparation of (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide
The synthesis method refers to example 1, step B.
MS(ESI,[M+H]+)m/z:306.3.
And B: preparation of (R) -N- ((S) -1- (6-cyanopyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide
Under the protection of nitrogen, 30mL of sealed tube is sequentially added with (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide (1000mg,3.28mmol), DMA (10mL), dppf (150mg,0.271mmol), zinc powder (80mg,1.224mmol), zinc cyanide (300mg,2.56mmol), Pd2(dba)3(150mg,0.164mmol), purged with nitrogen and placed in a microwave reactor and heated to 100 ℃ at 100W for 120 min. Filtration, collection of the filtrate and concentration, addition of 30mL EA and 50mL H2And O, shaking up, separating liquid, drying by using anhydrous sodium sulfate, filtering and concentrating.The crude product was purified by column chromatography to give 700mg of a yellow solid.
MS(ESI,[M+H]+)m/z:252.1.
And C: preparation of (S) -5- (1-aminoethyl) pyridinoline hydrochloride
Synthesis method reference was made to example 1, step C.
MS(ESI,[M+H]+)m/z:148.0.
Step D: preparation of (S) -N- (1- (6-cyanopyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The synthesis was as in step G of example 1.
1H NMR(500MHz,DMSO-d6)δ11.86(s,1H),9.26(s,1H),8.76–8.70(m,1H),7.98(qd,J＝8.1,1.4Hz,2H),7.04(d,J＝7.3Hz,1H),6.18(d,J＝41.0Hz,2H),4.95(p,J＝7.1Hz,1H),3.73–3.63(m,4H),3.44–3.36(m,4H),2.21(s,3H),2.13(s,3H),1.43(d,J＝7.1Hz,3H).
MS(ESI,[M+H]+)m/z:447.3.
Example 32: preparation of (S) -N- (1- (6-ethynylpyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) pyridin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000601
step A: preparation of (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide
The synthesis method refers to example 1, step B.
MS(ESI,[M+H]+)m/z:305.0
And B: preparation of (R) -2-methyl-N- ((S) -1- (6- ((trimethylsilyl) ethynyl) pyrimidin-3-yl) ethyl) propane-2-sulfinamide
To a 30mL microwave tube were added (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide 404mg (1.324mmol), trimethylethynyl silicon 260mg (2.65mmol), and bis (triphenylphosphine) palladium dichloride 46.5mg (0.066 m)mol), cuprous iodide 25mg (0.132mmol) and triethylamine 670mg (6.62mmol) were added acetonitrile (10ml), N2The mixture was heated to 120 ℃ for 10min under protection. After the reaction, the reaction solution was concentrated and purified by column chromatography to obtain 0.38g of a yellow solid product.
MS(ESI,[M+H]+)m/z:323.1.
And C: preparation of (S) -1- (6- ((trimethylsilyl) ethynyl) pyrimidin-3-yl) ethan-1-amine
Synthesis method reference was made to example 1, step C.
MS(ESI,[M+H]+)m/z:219.2.
Step D: preparation of (S) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (1- (6- ((trimethylsilyl) ethynyl) pyridin-3-yl) ethyl) piperazine-1-carboxamide
The synthesis was as in step G of example 1.
MS(ESI,[M+H]+)m/z:518.4.
Step E: preparation of (S) -N- (1- (6-ethynylpyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
To a 50mL eggplant-shaped bottle were added (S) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (1- (6- ((trimethylsilyl) ethynyl) pyridin-3-yl) ethyl) piperazine-1-carboxamide 660mg (1.275mmol), dichloromethane (2mL), and methanol (3mL) in this order, followed by potassium carbonate 881mg (6.37mmol), N2And reacting at room temperature for 3 hours under protection. After the reaction, the reaction solution was concentrated and purified by column chromatography to obtain 58mg of the target product.
1H NMR(500MHz,Chloroform-d)δ8.61(s,1H),7.66(d,J＝7.8Hz,1H),7.46(d,J＝7.7Hz,1H),7.29(s,1H),7.12(s,1H),6.09(d,J＝55.0Hz,2H),5.07-5.10(m,1H),4.88(d,J＝6.2Hz,1H),3.83(s,4H),3.48(s,4H),2.29(d,J＝27.2Hz,6H),1.55(s,3H).
MS(ESI,[M+H]+)m/z:446.2.
Example 33: preparation of (S) -N- (1- (2-cyanopropan-2-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000621
step A: preparation of 2- (5-bromopyridin-2-yl) -2-methylpropanenitrile
A25 mL three-necked flask was charged with 2g (10.15mmol) of 2- (5-bromopyridin-2-yl) acetonitrile, 2.285g (25.4mmol) of potassium tert-butoxide, 6402 mg (1.523mmol) of 18-crown ether, tetrahydrofuran (10mL), and N2Stirring at room temperature under protection. Subsequently, 11.53g (81mmol) of methyl iodide was added thereto, and the reaction was allowed to proceed overnight at room temperature. The reaction solution was subjected to reduced pressure evaporation by a rotary evaporator to remove the solvent, and purified by column chromatography to obtain 1.66g of a white solid product.
MS(ESI,[M+H]+)m/z:225.0
And B: preparation of 2- (5-acetylpyridin-2-yl) -2-methylpropanenitrile
A25 ml three-necked flask was taken, and 1.2g (5.33mmol) of 2- (5-bromopyridin-2-yl) -2-methylpropanenitrile and 10ml of tetrahydrofuran were added thereto, and the mixture was cooled to-78 ℃ under nitrogen. 0.41g (6.4mmol) of n-butyllithium was added dropwise to the reaction system using a syringe, maintaining the internal temperature below-65 ℃. Stirring at low temperature for 15min after the addition. 0.715g (6.93mmol) of N, N-dimethylacetamide was dissolved in 5ml of THF, and added dropwise to the reaction system with a syringe while maintaining the internal temperature below-65 ℃. Stirring at low temperature for reaction for 2h after the addition is finished. The reaction solution was subjected to reduced pressure evaporation by a rotary evaporator to remove the solvent, and purified by column chromatography to obtain 1.66g of a white solid product.
MS(ESI,[M+H]+)m/z:189.3.
And C: preparation of (R) -N- ((S) -2- (5- (1-aminoethyl) pyridin-2-yl) -2-methylpropanone-2-sulfinamide
The synthesis method refers to example 1, step B.
MS(ESI,[M+H]+)m/z:294.3.
Step D: preparation of (S) -2- (5- (1-aminoethyl) pyridin-2-yl) -2-methylpropanenitrile
Synthesis method reference was made to example 1, step C.
MS(ESI,[M+H]+)m/z:190.2.
Step E: preparation of (S) -N- (1- (2-cyanopropan-2-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The synthesis was as in step G of example 1.
1H NMR(500MHz,Chloroform-d)δ10.98(s,1H),8.60(s,1H),8.27(s,1H),7.70(s,1H),7.51(s,1H),6.10(d,J＝26.0Hz,2H),5.21(s,1H),5.04-5.06(m,1H),3.81(s,4H),3.50(s,4H),2.27(d,J＝19.5Hz,6H),1.75(s,6H),1.52(d,J＝6.8Hz,3H).
MS(ESI,[M+H]+)m/z:489.3.
Example 34: preparation of (S) -N- (1- (6-cyclopropylpyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000631
step A: preparation of (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide
The synthesis method refers to example 1, step B.
MS(ESI,[M-H]-) 303.0 is the ratio of m/z. And B: preparation of (R) -N- ((S) -1- (6-cyclopropylpyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide
A50 mL round bottom flask was charged with 405mg (1.327mmol) of (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide, 228mg (2.65mmol) of cyclopropylboronic acid, 74mg (0.265mmol) of tricyclohexylphosphine, 925mg (5.31mmol) of potassium phosphate, and 30mg (0.133mmol) of palladium acetate in this order, with water (1mL) and toluene (5mL), and N2The mixture was heated to 110 ℃ for 6h under protection. The stirring was stopped, the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure by a rotary evaporator, and purified by column chromatography to obtain 220mg of a brown oil.
MS(ESI,[M+H]+)m/z:267.1
And C: preparation of (S) -1- (6-cyclopropylpyridin-3-yl) ethan-1-amine
Synthesis method reference was made to example 1, step C.
MS(ESI,[M+H]+)m/z:163.1.
Step D: preparation of (S) -N- (1- (6-cyclopropylpyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The synthesis was as in step G of example 1.
1H NMR(500MHz,Chloroform-d)δ8.46(s,1H),7.53(d,J＝10.1Hz,1H),7.10(d,J＝8.1Hz,1H),7.05(s,1H),6.13(s,1H),6.04(s,1H),5.01-5.06(m,1H),4.73(d,J＝6.8Hz,1H),3.81-3.83(m,4H),3.45-3.50(m,4H),2.32(s,3H),2.26(s,3H),2.01-2.06(m,1H),1.52(d,J＝6.9Hz,3H),0.98-1.01(m,4H).
MS(ESI,[M+H]+)m/z:462.3.
Example 35: preparation of (S) -N- (1- (6- (methoxypyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
Figure BDA0002902944530000641
The synthesis method is referred to example 1.
1H NMR(500MHz,DMSO-d6)δ11.84(s,1H),9.24(s,1H),8.09(d,J＝2.4Hz,1H),7.68(dd,J＝8.6,2.5Hz,1H),6.83(d,J＝7.8Hz,1H),6.76(d,J＝8.5Hz,1H),4.83(p,J＝7.2Hz,1H),3.81(s,3H),3.69–3.61(m,4H),3.41–3.35(m,4H),2.20(s,3H),2.12(s,3H),1.38(d,J＝7.1Hz,3H).
MS(ESI,[M+H]+)m/z:452.3.
Example 36: preparation of (S) -N- (1- (6-isopropoxypyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-amide
The reaction process comprises the following steps:
Figure BDA0002902944530000642
step A: preparation of 1- (6-isopropoxypyridin-3-yl) ethanone
A50 mL three-necked flask was charged with 2.0g (9.26mmol) of 2-isopropoxy-5-bromopyridine and 20mL of THF. Cooling to-78 ℃ under the protection of nitrogen. Subsequently, 0.72g (2.5mol/L,11.24mmol) of n-butyllithium was slowly added dropwise. Stirring at low temperature for a while after the dropwise addition. 1.241g (12.03mmol) of N-methoxy-N-methylacetamide was dissolved in 5ml of THF and slowly added to the reaction system. After the reaction was completed, 20mL of a saturated ammonium chloride solution was added to the reaction solution to quench the reaction. The reaction solution was then poured into 100mL of purified water. EA extraction, and the combined organic phase is dried by adding anhydrous sodium sulfate. Filtration and concentration gave 1.59g of a yellow oil.
MS(ESI,[M+H]+)m/z:180.1.
And B: preparation of (S, Z) -N- (1- (6-isopropoxypyridin-3-yl) ethylene) -2-methylpropane-2-sulfinamide
1.59g (8.87mmol) of 1- (6-isopropoxypyridin-3-yl) ethanone, 25mL of THF, 2.98g (22.18mmol) of diethylene glycol dimethyl ether, 5.06g (22.18mmol) of tetraethyltitanate, 2.69g (22.28mmol) of (R) - (+) -tert-butylsulfinamide were successively charged in a 50mL single-neck flask. Reacting at 80 ℃ under the protection of nitrogen. After the reaction was completed, the reaction solution was poured into 100mL of purified water, at which time a large amount of white solid was precipitated. After suction filtration, the filter cake is washed with EA, and the organic phases are combined and dried by adding anhydrous sodium sulfate. Followed by filtration, concentration and purification by column chromatography gave 1.8g of a yellow liquid.
MS(ESI,[M+H]+)m/z:283.3.
And C: preparation of (S) -N- ((S) -1- (6-isopropoxypyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide
A100 mL three-necked flask was charged with 1.8g (6.39mmol) of (S, Z) -N- (1- (6-isopropoxypyridin-3-yl) ethylene) -2-methylpropane-2-sulfinamide and 20mL of THF. Cooling to-80 ℃. Subsequently, 2.43g (1mol/L,12.78mmol) of lithium tri-sec-butylborohydride was slowly added dropwise to the reaction system. After the dropwise addition, the reaction is carried out at the low temperature of minus 80 ℃. After the reaction was completed, 10mL of methanol was added to the reaction system to quench the reaction. The reaction solution was then poured into 100mL of ice-water, at which time a large amount of solid precipitated. The filter cake was washed with EA after suction filtration. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give 0.6g of a white solid.
MS(ESI,[M+H]+)m/z:285.2.
Step D: preparation of (S) -1- (6-isopropoxypyridin-3-yl) ethylamine hydrochloride
In a 100mL single-necked flask were added in succession 0.672g (2.363mmol) of (S) -N- ((S) -1- (6-isopropoxypyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide, 20mL of methanol, and 5.9mL (4mol/L,23.62mmol) of a hydrogen chloride dioxane solution. And reacting at room temperature under the nitrogen atmosphere. After the reaction is completed, the reaction solvent is evaporated to dryness. After 20mLEA was added, a white solid precipitated, which was filtered after pulping, the filter cake was collected and dried in vacuo to give 470mg of a white solid.
MS(ESI,[M+H]+)m/z:181.1.
Step E: preparation of (S) -N- (1- (6-isopropoxypyridin-3-yl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
A50 mL three-necked flask was charged with 0.142g (0.878mmol) of CDI and 10mL of DCM. And cooling the ice salt bath to 0 ℃ under the protection of nitrogen. A10 mL test tube was charged with 0.202g (0.798mmol) of (S) -1- (6-isopropoxypyridin-3-yl) ethylamine hydrochloride, 0.485g (4.79mmol) of triethylamine, and 5mL of DCM, and the solution was slowly added to the reaction system. After reacting at low temperature for about 30min, 5mL of a DCM solution containing 0.4g (0.798mmol) of 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate and 0.485g (4.79mmol) of triethylamine was added to the reaction system. After the reaction, the reaction solution was poured into 100mL of purified water and extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate. Followed by filtration, concentration and purification by column chromatography gave 120mg of a white solid.
1H NMR(500MHz,DMSO-d6)δ11.86(s,1H),9.25(s,1H),8.07(d,J＝2.1Hz,1H),7.65(s,2H),7.02(s,1H),6.82(d,J＝7.7Hz,1H),6.68(d,J＝8.5Hz,1H),5.21(hept,J＝6.2Hz,1H),4.83(p,J＝7.0Hz,1H),3.66(t,J＝5.0Hz,4H),3.38(t,J＝5.0Hz,4H),2.21(s,3H),2.13(s,3H),1.38(d,J＝7.0Hz,3H),1.27(d,J＝6.2Hz,6H).
MS(ESI,[M+H]+)m/z:480.3.
Example 37: preparation of (S) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (1- (6- (pyrrolidin-1-yl) pyridin-3-yl) ethyl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000661
step A: preparation of (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide
A250 mL three-necked flask was charged with 1- (6-bromopyridin-3-yl) ethan-1-one (5.26g,26.3mmol), THF (100mL), tetraethyltitanate (12.00g,52.6mmol), (R) - (+) -t-butylsulfinamide (6.37g,52.6mmol), diethylene glycol dimethyl ether (3.53g,26.3mmol) in that order, replaced with nitrogen three times, warmed to 75 ℃ and heated at a controlled temperature for 7 hours. Cooling the reaction system to-78 ℃, blowing air by nitrogen, measuring lithium tri-sec-butylborohydride (15.00g,79mmol) under the protection of the nitrogen, and dropwise adding the lithium tri-sec-butylborohydride into a bottle at the temperature of not higher than-70 ℃. Controlling the temperature to be not higher than-40 ℃ for reaction for 4 hours. Adding 30mL of MeOH into the reaction solution for quenching, pouring the quenched mixture into 300mL of ice water for pulping for 30min, performing suction filtration, collecting the filtrate, concentrating, adding 100mL of EA, and shaking the liquid uniformly. The combined organic phases were dried over anhydrous sodium sulfate, filtered and spun to give 6.86g of a yellow oily liquid.
MS(ESI,[M+H]+)m/z:305.3.
And B: preparation of (R) -2-methyl-N- ((S) -1- (6- (pyrrolidinyl-1-yl) pyridin-3-yl) ethyl) propane-2-sulfinamide
Under the protection of nitrogen, 30mL of sealed tube is sequentially added with (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide (1000mg,3.28mmol), THF (8mL), tetrahydropyrrole (500mg,7.03mmol), Davephos (260mg,0.661mmol) and Pd2(dba)3(300mg,0.328mmol), LiHMDS (1372mg,8.20mL,8.20mmol), nitrogen is blown off air, and the mixture is placed in a microwave reactor and heated to 130 ℃ at 100W for 30 min. The reaction was quenched by the addition of 2mL of 1M saturated ammonium chloride solution dropwise under ice-bath conditions, and diluted with 20mL of ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase was concentrated and the crude product purified by column chromatography to yield 135mg of the target yellow solid.
MS(ESI,[M+H]+)m/z:296.1.
And C: preparation of (S) -1- (6- (pyrrolidin-1-yl) pyridin-3-yl) ethan-1-amine hydrochloride
In a 50mL round bottom flask were added sequentially (R) -2-methyl-N- ((S) -1- (6- (pyrrolidinyl-1-yl) pyridin-3-yl) ethyl) propane-2-sulfinamide (280mg,0.948mmol), MeOH (50mL), HCl in Dioxane (346mg,0.288mL,9.48mmol), stirred overnight at room temperature, and after completion of the reaction was concentrated to give 0.26g of a white solid product which was used in the next reaction without purification.
MS(ESI,[M+H]+)m/z:192.2.
Step D: preparation of (S) -4- (4-methyl-6- (((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (1- (6- (pyrrolidin-1-yl) pyridin-3-yl) ethyl) piperazine-1-carboxamide
To a 50mL eggplant-shaped bottle were added (S) -1- (6- (pyrrolidin-1-yl) pyridin-3-yl) ethan-1-amine hydrochloride (225mg,0.988mmol), DCM (10mL), TEA (1000mg,9.88mmol), and CDI (160mg,0.988mmol) in that order. The reaction was carried out at room temperature for 1 hour. Another 25mL single-necked flask was charged with 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate (367mg,0.988mmol), DCM (10mL), and TEA (1000mg,9.88mmol) in that order. After stirring until the solid was completely dissolved, the mixture was added to a 50mL bottle and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with 50mL of dichloromethane and washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to give 290mg of a white powdery solid.
1H NMR(500MHz,DMSO-d6)δ9.32(s,1H),7.97(d,J＝2.4Hz,1H),7.54(dd,J＝8.8,2.4Hz,2H),6.75(d,J＝7.9Hz,1H),6.47(d,J＝8.8Hz,1H),4.75(p,J＝7.2Hz,1H),3.76–3.58(m,4H),3.06(q,J＝7.3Hz,6H),2.20(s,3H),2.13(s,3H),1.95–1.88(m,4H),1.35(d,J＝7.0Hz,3H).
MS(ESI,[M+H]+)m/z:491.4.
Example 38: preparation of 4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (3- ((4-methylpiperazin-1-yl) methyl) phenyl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000671
step A: preparation of 1-methyl-4- (3-nitrobenzyl) piperazine
In a 100mL single-necked flask, 2g (9.26mmol) of 3-nitrobenzyl bromide, 0.928g (9.26mmol) of N-methylpiperazine, 1.28g (9.26mmol) of potassium carbonate and 15mL of DMF were added in this order. The reaction was stirred at room temperature. After the reaction, 100mL of purified water was added to the reaction system, followed by EA extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 2.08g of a yellow oil.
MS(ESI,[M+H]+)m/z:236.1.
And B: preparation of 3- ((4-methylpiperazin-1-yl) methyl) aniline
In a 100mL single-necked flask, 1g of 1-methyl-4- (3-nitrobenzyl) piperazine and 0.1g of palladium on carbon (10% m/c) were charged. Stirring for about 1h at room temperature under hydrogen atmosphere. After the reaction is finished, filtering and separating palladium carbon, washing a filter cake by EA
. The combined organic phases were concentrated to give 0.75g of a yellow oil.
MS(ESI,[M+H]+)m/z:206.2.
And C: preparation of 4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (3- ((4-methylpiperazin-1-yl) methyl) phenyl) piperazine-1-carboxamide
In a 50mL three-necked flask 0.118g (0.399mol) of triphosgene was dissolved in 3mL of methylene chloride, N2Cooling the ice salt bath to 0 ℃ under protection. 3mL of a dichloromethane solution containing 0.082g (0.399mmol) of 3- ((4-methylpiperazin-1-yl) methyl) aniline and 0.242g (2.4mmol) of triethylamine was added dropwise. The reaction solution was stirred at 0 ℃ for 5 min. A solution of 0.200g (0.399mmol) of 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate and 0.242g (2.4mmol) of triethylamine in 3ml of methylene chloride was added. The reaction was carried out at room temperature for 30 min. After the reaction is finished, adding into the reaction solutionAfter diluting with 50mL of dichloromethane, the mixture was washed with saturated brine and the organic phase was collected. Dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 57mg of a white solid.
1H NMR(500MHz,DMSO-d6)δ11.88(s,1H),9.27(s,1H),8.58(s,1H),7.42(d,J＝9.6Hz,2H),7.17(t,J＝7.7Hz,1H),6.86(d,J＝7.5Hz,1H),6.19(d,J＝49.0Hz,2H),3.74(t,J＝5.1Hz,4H),3.52(t,J＝5.1Hz,4H),3.41(s,2H),2.43(s,8H),2.23(d,J＝11.9Hz,6H),2.14(s,3H).
MS(ESI,[M+H]+)m/z:505.3.
Example 39: preparation of 4- (4-methyl-6- (((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000681
the synthesis was as in step G of example 1.
1H NMR(500MHz,DMSO-d6):δ11.72(s,1H),9.26(s,1H),8.86(s,1H),7.90(s,1H),7.75(d,J＝8.0Hz,1H),7.57(d,J＝8.5Hz,1H),6.20(m,2H),3.75(d,J＝5.0Hz,4H),3.53(m,6H),2.38(s,8H),2.21(s,3H),2.17(s,3H),2.14(s,3H).
MS(ESI,[M+H]+)m/z:573.3.
Example 40: preparation of (S) -4- (4-methyl-6- (((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) ethyl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000682
step A: preparation of benzyl (S) - (1- ((2-amino-5- (trifluoromethyl) phenyl) amino) -1-oxopropan-2-yl) carbamate
In a 50mL single-necked flask, ((benzyloxy) carbonyl) -L-alanine (1g, 4.48mmol), dichloromethane (20mL), 4- (trifluoromethyl) benzene-1, 2-diamine (0.789g, 4.48mmol), triethylamine (1.36g, 13.44mmol) and EDCI (0.859g, 4.48mmol) were added in this order, and the mixture was stirred at room temperature for 1.5 h. The reaction system was diluted with 20mL of dichloromethane and washed once with 20mL of saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 1.4g of a brown oil. The reaction was continued without further purification.
MS(ESI,[M+H]+)m/z:382.1.
And B: preparation of benzyl (S) - (1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) ethyl) carbamate
In a 50mL single-necked flask, benzyl (S) - (1- ((2-amino-5- (trifluoromethyl) phenyl) amino) -1-oxopropan-2-yl) carbamate (1.4g, 3.67mmol) and glacial acetic acid (15mL) were added sequentially and the mixture was heated to 70 ℃ and stirred for 1.5 h. And after the reaction is completed, concentrating half of the glacial acetic acid under reduced pressure to obtain a brown glacial acetic acid solution. The subsequent reaction was continued without further purification.
MS(ESI,[M+H]+)m/z:364.1.
And C: preparation of (S) -1- (5- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) ethan-1-amine hydrobromide
To the brown glacial acetic acid solution obtained in step B, 20mL of 48% aqueous HBr were added and the mixture was stirred at room temperature for 24 h. And (3) after the reaction is completed, concentrating the reaction solution under reduced pressure to remove the solvent to obtain a brown oily crude product. To the crude product was added 5mL of water, the pH was adjusted to about 8 with saturated aqueous sodium carbonate, and the mixture was extracted with ethyl acetate (30 mL. times.3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 780mg of white crystals.
MS(ESI,[M+H]+)m/z:230.1.
Step D: preparation of (S) -4- (4-methyl-6- (((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- (1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) ethyl) piperazine-1-carboxamide
Synthetic methods reference example 1, step G.
1H NMR(500MHz,CDCl3):δ12.52(s,1H),11.87(s,1H),9.26(s,1H),7.84(m,2H),7.47(s,1H),7.10(d,J＝5.0Hz,1H),6.20(m,2H),5.15(m,1H),3.71(s,4H),3.46(s,4H),2.21(s,3H),2.14(s,3H),1.58(d,J＝5.0Hz,3H).
MS(ESI,[M+H]+)m/z:529.3。
Example 41: preparation of 2- (4- ((6- (dimethylamino) pyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine
The reaction process comprises the following steps:
Figure BDA0002902944530000691
step A: preparation of 2- (4- ((6-chloropyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine
A100 mL single-necked flask was charged with 1g (1.994mmol) of 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate, dichloromethane (25mL), and 807mg (7.98mmol) of triethylamine. Stirring until the solid is completely dissolved, and clarifying the solution. Subsequently, 282mg (1.994mmol) of 6-chloronicotinaldehyde and 1.268g (5.98mmol) of sodium triacetoxyborohydride were added. The reaction was stirred at room temperature overnight. The reaction solution was subjected to reduced pressure evaporation by a rotary evaporator to remove the solvent, and purified by column chromatography to obtain 1.8g of a white solid product.
MS(ESI,[M+H]+)m/z:399.2。
And B: preparation of 2- (4- ((6- (dimethylamino) pyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine
To a 30mL sealed tube were added in sequence 500mg (1.253mmol) of 2- (4- ((6-chloropyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine, 565mg (12.53mmol) of dimethylamine and N-methylpyrrolidone (10mL), placed in a microwave reactor and heated to 180 ℃ at 200 Watts for 2H. The reaction solution was poured directly into 50mL of ice-water, and extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, and purification by column chromatography gave 60mg of an off-white powdery solid.
1H NMR(500MHz,Chloroform-d)δ8.06(s,1H),7.49(d,J＝8.6Hz,1H),6.97(s,1H),6.52(d,J＝8.7Hz,1H),6.03(d,J＝15.4Hz,2H),3.79(s,4H),3.43(s,2H),3.09(s,6H),2.48(s,4H),2.26(d,J＝27.7Hz,6H).
MS(ESI,[M+H]+)m/z:408.4。
Example 42: preparation of (S) -N- (benzo [ d ] [1,3] dioxin-5-ylmethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000701
the synthesis method is referred to example 19.
1H NMR(500MHz,Chloroform-d)δ6.83(s,1H),6.75-6.79(m,2H),6.68(s,1H),6.14(s,1H),5.94(s,2H),5.92(s,1H),5.83(s,1H),4.76-4.78(m,1H),4.32-4.40(m,2H),4.17(s,1H),4.02(d,J＝12.2Hz,1H),3.92(d,J＝12.7Hz,1H),3.79-3.81(m,1H),3.28-3.33(m,1H),3.21-3.24(m,1H),3.00-3.05(m,1H),2.27(s,3H),2.20(s,3H),1.24(d,J＝6.8Hz,3H).
MS(ESI,[M+H]+)m/z:464.3.
Example 43: preparation of (S) -N- ((2, 2-difluorobenzo [ d ] [1,3] dioxin-5-yl) methyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000711
step A: preparation of 2, 2-difluorobenzo [ d ] [1,3] dioxine-5-carbaldehyde oxime
A50 mL eggplant-shaped bottle was charged with 1g (5.37mmol) of 2, 2-difluoro-1, 3-benzodioxole-5-carbaldehyde, 373mg (5.37mmol) of hydroxylamine hydrochloride and 10mL of methanol in this order, followed by 1.06g (13.43mmol) of pyridine and N2And reacting at room temperature for 2 hours under protection. Reaction solution is passed throughThe solvent was evaporated under reduced pressure using a rotary evaporator and purified by column chromatography to obtain 0.6g of a white solid product.
And B: preparation of (2, 2-difluorobenzo [ d ] [1,3] dioxin-5-yl) methylamine
Into a 25mL three-necked flask, 189mg (4.97mmol) of lithium aluminum hydride and N were added2Tetrahydrofuran (5mL) was added under protection, the system was cooled to 0 ℃ and then a solution of 1g (4.97mmol) of 2, 2-difluoro-1, 3-benzodioxolane-5-carbaldehyde oxime in tetrahydrofuran (5mL) was added dropwise and the mixture was transferred to room temperature for 2 h. Adding 5mL of saturated ammonium chloride aqueous solution into the reaction system, adding 30mL of ethyl acetate, extracting, separating an organic phase, drying with anhydrous sodium sulfate, filtering, evaporating the filtrate under reduced pressure by using a rotary evaporator to remove the solvent, and purifying by using column chromatography to obtain 0.25g of a white solid product.
MS(ESI,[M+H]+)m/z:188.3.
And C: preparation of (S) -N- ((2, 2-difluoro-1, 3-benzodioxolan-5-yl) methyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxamide
Synthesis method reference was made to example 19, step D.
1H NMR(500MHz,Chloroform-d)δ8.61(s,1H),7.34(d,J＝8.3Hz,1H),7.28(s,1H),7.16(t,J＝5.7Hz,1H),7.10(d,J＝8.3Hz,1H),6.33(s,1H),6.01(s,1H),5.96(s,1H),4.21-4.30(m,3H),4.10(d,J＝12.1Hz,1H),4.01(s,1H),3.82(d,J＝12.9Hz,1H),3.06-3.11(m,1H),2.96-2.99(m,1H),2.74-2.78(m,1H),2.18(s,3H),2.12(s,3H),1.10(d,J＝6.5Hz,3H).
MS(ESI,[M+H]+)m/z:500.3.
Example 44: preparation of (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) (4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazin-1-yl) methanone
The reaction process comprises the following steps:
Figure BDA0002902944530000721
step A: preparation of methyl 6- (4-fluoro-1H-pyrazol-1-yl) nicotinate
Synthesis method reference was made to example 1A.
MS(ESI,[M+H]+)m/z:222.1.
And B: preparation of 6- (4-fluoro-1H-pyrazol-1-yl) nicotinic acid
A50 mL reaction flask was charged with 300mg (1.356mmol) of methyl 6- (4-fluoro-1H-pyrazol-1-yl) nicotinate and ethanol (25 mL). The reaction system was suspended in white, and 2mL of 20% aqueous sodium hydroxide solution was added to the reaction system, followed by stirring at room temperature for 1 hour. And distilling the reaction system under reduced pressure to remove the solvent, dropwise adding concentrated hydrochloric acid to adjust the pH value to 2, extracting for multiple times by using dichloromethane 20mL by 5, separating an organic phase, drying by using anhydrous sodium sulfate, filtering, and distilling the filtrate under reduced pressure to remove the solvent to obtain a white solid of 250 mg.
MS(ESI,[M-H]-)m/z:206.1.
And C: preparation of (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) (4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazin-1-yl) methanone
A50 mL reaction flask was charged with 746mg (0.965mmol) of 6- (4-fluoro-1H-pyrazol-1-yl) nicotinic acid, N, N-dimethylformamide (10mL), and methylene chloride (10mL), followed by 441mg (1.159mmol) of 2- (1H-benzotriazol L-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate, stirred at room temperature for 5 minutes, followed by 196mg (1.93mmol) of N-methylmorpholine. N is a radical of2And stirring for 1h at room temperature under protection. The above reaction system was slowly added dropwise to a solution of 746mg (1.931mmol) of 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate and 196mg (1.93mmol) of N, N-methylmorpholine in N, N-dimethylformamide. N is a radical of2Protected and stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure by a rotary evaporator to remove the solvent, 50mL of dichloromethane and 20mL of saturated brine were added and washed several times, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography to obtain 150mg of a yellow solid product.
1H NMR(500MHz,Chloroform-d)δ8.50(s,1H),8.43(d,J＝4.4Hz,1H),8.02(d,J＝8.4Hz,1H),7.92(d,J＝6.3Hz,1H),7.63(d,J＝4.2Hz,1H),7.06(s,1H),6.16(s,1H),6.04(s,1H),3.85(s,6H),3.56(s,2H),2.30(s,3H),2.25(s,3H).
MS(ESI,[M+H]+)m/z:463.3.
Example 45: preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000731
step A: preparation of 6, 7-dihydro-5H-cyclopenta [ d ] pyrimidine-2, 4-diol
A50 mL three-necked flask was charged with 5g (35.2mmol) of 2-methoxycarbonylcyclopentanone, 4.22g (70.3mmol) of urea and 5mL of N, N-dimethylformamide (N)2The temperature was reduced to 0 ℃ under protection, and 4.59g (42.2mmol) of trimethylchlorosilane was injected from a syringe, and then the reaction system was warmed to room temperature to react overnight. 10ml of water was added to the reaction system to produce a large amount of white solid, which was filtered, the filter cake was washed with 5ml of water and 5ml of petroleum ether, and the filter cake was transferred to an eggplant-shaped bottle to remove the solvent by distillation under reduced pressure. To the above white solid was added 10mL of water, the solid was insoluble, then 4.22g (106mmol) of sodium hydroxide was added, and the system was heated to 70 ℃ with the open air and stirred for 1 h. And cooling the reaction system to 0 ℃, dropwise adding concentrated hydrochloric acid, adjusting the pH of the system to 2, separating out a large amount of white solid, filtering, washing a filter cake with 10mL of water, and distilling the filter cake under reduced pressure to remove water to obtain 4.6g of white solid.
MS(ESI,[M-H]-)m/z:151.0.
And B: preparation of 2, 4-dichloro-6, 7-dihydro-5H-cyclopenta [ d ] pyrimidine
In a 50mL three-necked flask, 6, 7-dihydro-5H-cyclopenta [ d ] is added in sequence]Pyrimidine-2, 4-diol 3g (19.72mmol) and phosphorus oxychloride (15mL), N2Heating to 110 ℃ under protection, and refluxing for 5 h. And distilling the reaction system under reduced pressure to remove the solvent, cooling to 0 ℃, adding 50mL of water, stirring vigorously to separate out a large amount of yellow solid, filtering, washing the filter cake with 10mL of water, and drying the filter cake under reduced pressure to remove water to obtain 2.5g of yellow solid.
MS(ESI,[M+Na]+)m/z:212.0.
And C-F: preparation of (S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-2-yl) piperazine-1-carboxamide
The synthesis method is referred to example 1.
1H NMR(500MHz,DMSO-d6)δ11.91(s,1H),8.74(s,1H),8.66(d,J＝4.3Hz,1H),8.40(s,1H),7.95(d,J＝8.4Hz,1H),7.90(d,J＝4.0Hz,1H),7.86(d,J＝8.4Hz,1H),6.88(d,J＝7.5Hz,1H),6.36(s,1H),4.92-4.98(m,1H),4.46(d,J＝12.2Hz,1H),4.39(d,J＝12.6Hz,1H),4.31(s,1H),3.83(d,J＝12.9Hz,1H),2.99-3.04(m,2H),2.81-2.84(m,1H),2.61-2.67(m,4H),2.22(s,3H),1.91-1.94(m,2H),1.44(d,J＝7.0Hz,3H),1.03(d,J＝6.4Hz,3H).
MS(ESI,[M+H]+)m/z:546.4.
Example 46: preparation of N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -9- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3-oxa-7, 9-diazabicyclo [3.3.1] nonane-7-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000741
step A: preparation of tert-butyl 9- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3-oxa-7, 9-diazabicyclo [3.3.1] nonane-7-carboxylate
To a 30mL microwave tube were added, in order, 70mg (0.313mmol) of 2-chloro-6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine, N, N-dimethylformamide (5mL), 3-oxa-7, 9-diazabicyclo [ 3.3.1%]79mg (0.344mmol) of tert-butyl nonane-7-carboxylate and 121mg (0.939mmol) of N, N-diisopropylethylamine. N is a radical of2Heating to 140 ℃ under protection and reacting for 40 h. The reaction solution was evaporated under reduced pressure by a rotary evaporator to remove the solvent, 50mL of dichloromethane and 20mL of saturated brine were added to wash the reaction solution for several times, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography to obtain 100mg of a yellow oily product.
MS(ESI,[M+H]+)m/z:416.3.
And B: preparation of 2- (3-oxo-7, 9-diazabicyclo [3.3.1] non-9-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine trifluoroacetate
Synthesis method reference was made to example 1, step F.
And C: preparation of N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -9- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3-oxa-7, 9-diazabicyclo [3.3.1] nonane-7-carboxamide
The synthesis was as in step G of example 1.
MS(ESI,[M+H]+)m/z:548.3.
Example 47: preparation of 2- (4- ((6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine
The reaction process comprises the following steps:
Figure BDA0002902944530000751
step A: preparation of 2- (4- ((6-bromopyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine
In a 100mL single-necked flask were charged 0.5g (0.997mmol) of 6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate, 25mL of methylene chloride, 0.404g (3.99mmol) of triethylamine and 0.185g (0.997mmol) of 2-bromo-5-formylpyridine. The reaction was carried out at room temperature. After the reaction is finished, the solid and the liquid are separated by suction filtration, filter cakes are washed by dichloromethane, organic phases are combined, concentrated and purified by column chromatography to obtain 535mg of white semisolid.
MS(ESI,[M+H]+)m/z:443.1.
And B: preparation of 2- (4- ((6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine
To a 30mL microwave tube were added, in order, 0.661g (2.030mmol) of cesium carbonate, 0.193g (1.015mmol) of cuprous iodide, 10mL of DMF, 0.175g (2.030mmol) of 4-fluoro-1H-pyrazole, 0.3g (0.677mmol) of 2- (4- ((6-bromopyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine, and 0.144g (1.015mmol) of trans- (1R,2R) -N, N' -dimethyl-1, 2-cyclohexanediamine. And covering and sealing the reactor after nitrogen protection, and reacting under the microwave condition of 150 ℃/200W. After completion of the reaction, the reaction mixture was poured into 150mL of purified water, extracted with DCM, and washed with saturated brine. The combined organic phases were dried over anhydrous sodium sulfate. Followed by filtration, concentration and purification by column chromatography gave 130mg of a yellow solid.
1H NMR(500MHz,DMSO-d6)δ11.83(s,1H),9.20(s,1H),8.69(d,J＝4.5Hz,1H),8.40(s,1H),8.02–7.84(m,3H),6.21(s,1H),6.10(s,1H),3.70(t,4H),3.58(s,2H),3.33(s,3H),2.44(t,J＝5.0Hz,4H),2.18(s,3H).
MS(ESI,[M+H]+)m/z:449.2.
Example 48: preparation of 2- (4- ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine
The reaction process comprises the following steps:
Figure BDA0002902944530000761
the synthesis was as in example 47.
1H NMR(500MHz,DMSO-d6)δ11.88(s,1H),9.29(s,1H),8.12(s,1H),7.70(d,J＝7.7Hz,1H),6.83(d,J＝8.4Hz,1H),6.24(s,1H),6.11(s,1H),3.85(s,3H),3.43–3.32(m,4H),3.14–3.04(m,2H),2.54(s,2H),2.19(s,3H),2.12(s,3H),1.18(t,J＝7.3Hz,2H).
MS(ESI,[M+H]+)m/z:395.3.
Example 49: preparation of 2- ((1R, 5S) -8- ((6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) methyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine
The reaction process comprises the following steps:
Figure BDA0002902944530000762
the synthesis was as in example 47.
1H NMR(500MHz,DMSO-d6)δ11.83(s,1H),9.19(s,1H),8.68(d,J＝4.2Hz,1H),8.45(s,1H),8.03(d,J＝8.4Hz,1H),7.91(s,2H),6.17(s,2H),4.21(d,J＝11.7Hz,2H),3.60(s,2H),3.23(s,2H),3.00(d,J＝11.9Hz,2H),2.18(s,3H),2.10(s,3H),1.99–1.94(m,2H),1.54(d,J＝7.5Hz,2H).
MS(ESI,[M+H]+)m/z:475.3.
Example 50: preparation of 2- (6- ((6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine
The reaction process comprises the following steps:
Figure BDA0002902944530000771
the synthesis was as in example 47.
1H NMR(500MHz,DMSO-d6)δ11.88(s,1H),9.33(s,1H),8.66(s,1H),8.41(s,1H),7.97(d,J＝7.4Hz,1H),7.91(s,1H),7.88(s,1H),6.38(s,1H),6.23(s,1H),3.77(s,2H),3.73(s,2H),3.51(s,2H),2.27(s,3H),2.18(s,2H),2.16(s,3H),1.23(s,2H).
MS(ESI,[M+H]+)m/z:461.3.
Example 51: preparation of 4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- ((S) -1- (6- (((S) -pentan-2-yl) oxy) pyridin-3-yl) ethyl) piperazine-1-amide
The reaction process comprises the following steps:
Figure BDA0002902944530000772
the synthesis method is referred to example 36.
1H NMR(500MHz,DMSO-d6)δ11.87(s,1H),9.26(s,1H),8.06(d,J＝2.4Hz,1H),7.65(s,1H),6.82(d,J＝7.8Hz,1H),6.69(d,J＝8.5Hz,1H),6.14(s,2H),5.18–5.10(m,1H),4.83(p,J＝7.0Hz,1H),3.67(t,J＝5.0Hz,4H),3.39(t,J＝5.0Hz,4H),2.21(s,3H),2.13(s,3H),1.68–1.47(m,2H),1.38(d,J＝7.1Hz,3H),1.37–1.28(m,2H),1.23(d,J＝6.1Hz,3H),0.88(t,J＝7.4Hz,3H).
MS(ESI,[M+H]+)m/z:508.3.
Example 52: preparation of (S) -N- (chroman-6-ylmethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-amide
The reaction process comprises the following steps:
Figure BDA0002902944530000781
the synthesis method is referred to example 19.
1H NMR(500MHz,DMSO-d6)δ11.62(s,1H),8.55(s,1H),6.94(s,3H),6.65(s,1H),6.35(s,1H),6.01(s,1H),5.95(s,1H),4.26(s,2H),4.08(s,4H),3.81(s,1H),3.02(d,J＝46.5Hz,2H),2.69(s,2H),2.17(s,3H),2.11(s,3H),1.89(s,2H),1.29(d,J＝59.9Hz,2H),1.09(s,3H).
MS(ESI,[M+H]+)m/z:476.3.
Example 53: preparation of (1R, 5S) -N- ((R) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-amide
The reaction process comprises the following steps:
Figure BDA0002902944530000782
step A: preparation of 6- (4-fluoro-1H-pyrazol-1-yl) pyridine-3-ethanone
In a 250mL single-neck flask were added 3g (15mmol) of 5-acetyl-2-bromopyridine, 1.549g (18mmol) of 4-fluoro-1H-pyrazole, 4.15g (30mmol) of potassium carbonate, and 25mL of DMF. The reaction was heated at 100 ℃ for about 5h under nitrogen. After the reaction was completed, 100mL of purified water was added to the reaction solution, and a large amount of solid precipitated. The purified water washes the filter cake several times before collecting the solid and drying and then adding a suitable amount of PE for pulping. After filtration and drying, 2.45g of a brown solid product was obtained.
MS(ESI,[M+H]+)m/z:206.1.
And B: preparation of (S, E) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylene) -2-methylpropane-2-sulfinamide
A250 mL single-neck flask was charged with 2.45g (11.94mmol) of 6- (4-fluoro-1H-pyrazol-1-yl) pyridine-3-ethanone, 50mL of THF, 3.20g (23.88mmol) of diethylene glycol dimethyl ether, 5.45g (23.88mmol) of ethyl titanate, and 2.89g (23.88mmol) of S-t-butylsulfinamide. The reaction was heated at 80 ℃ for about 3h under nitrogen. After the reaction is finished, the reaction solution is not treated, and the next reaction is directly carried out.
And C: preparation of (S) -N- ((R) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide
And (3) placing the reaction system in the last step in a nitrogen atmosphere, and cooling to-80 ℃. 5.45g (1 mol/L; 28.7 mL; 28.7mmol) of lithium tri-sec-butylborohydride was slowly added dropwise to the system with a syringe. After the dropwise addition, the reaction is kept at-80 ℃. After the reaction was completed, the reaction solution was poured into 150mL of purified water, at which time a large amount of solid precipitated. After suction filtration the filter cake was washed with EA, the organic phases were combined and concentrated under reduced pressure to give 9.7g of crude product as a yellow oil. The crude product was directly subjected to the next reaction without further purification.
Step D: preparation of (R) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylamine hydrochloride
In a 250mL single neck flask was added (S) -N- ((R) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide 3.54g (11.40mmol), methanol 50mL, and hydrochloric acid 4.2g (4 mol/L; 28.8 mL; 115 mmol). The reaction was carried out at room temperature under a nitrogen atmosphere. After the reaction, the solvent was removed under reduced pressure, and 50mL of EA was added and slurried. Filtration was followed by EA washing. The filter cake was dried under vacuum to give 3.19g of a product as an off-white solid.
MS(ESI,[M+H]+)m/z:207.14.
Step E: preparation of tert-butyl (1R, 5S) -3- (6-chloro-4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
A50 mL single-neck flask was charged with 0.6g (2.78mmol) of 2, 6-dichloro-4-trifluoromethylpyridine, 5mL of DMF, 0.637g (3.00mmol) of 8-BOC-3, 8-diazabicyclo [3.2.1] octane, and 0.718g (0.970 mL; 5.56mmol) of DIPEA. The mixture was heated to 110 ℃ for about 5 h. After the reaction, the reaction mixture was diluted with 50ml of LEA, and the organic phase was washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 0.4g of a white solid product.
Step F: preparation of tert-butyl (1R, 5S) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a 35mL microwave tube were added 660mg (1.684mmol) of tert-butyl (1R, 5S) -3- (6-chloro-4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, 15mL of THF, 180mg (1.853mmol) of 3-amino-5-methylpyrazole, 154mg (0.168mmol) of tris (dibenzylideneacetone) dipalladium, 133mg (0.337mmol) of 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl, and 730mg (4.36mmol) of bistrimethylsilylamidolithium. Placing into a CEM microwave reaction instrument under nitrogen atmosphere, heating and reacting at 130 deg.C and 100W power for 30 min. After the reaction was completed, 50mL of EA was added to the reaction mixture to dilute the mixture, and the organic phase was washed with saturated brine. The collected organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 480mg of a brown solid product.
MS(ESI,[M+H]+)m/z:453.2.
Step G: preparation of 6- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -N- (5-methyl-1H-pyrazol-3-yl) -4- (trifluoromethyl) pyridin-2-amine trifluoroacetate
A250 mL single-necked flask was charged with 0.48g (1.061mmol) of tert-butyl (1R, 5S) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, 20mL of DCM, and 0.605g (5.30mmol) of trifluoroacetic acid. The reaction was carried out at room temperature for about 5 h. After the reaction is finished, the reaction solvent and excessive trifluoroacetic acid are directly removed under reduced pressure, and after the mixture is pulped by DCM, the mixture is filtered and dried to obtain 0.4g of off-white solid.
MS(ESI,[M+H]+)m/z:353.2.
Step H: preparation of (1R, 5S) -N- ((R) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-amide
A25 mL three-necked flask was charged with 0.073g (0.246mmol) of triphosgene as a solid and 5mL of DCM. And cooling the ice salt bath to 0 ℃ under the protection of nitrogen. A15 mL test tube was charged with 0.063g (0.224mmol) of (R) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylamine hydrochloride, 0.136g (1.344mmol) of triethylamine, and 5mL of DCM, and this solution was slowly added to the reaction system. After reacting at low temperature for about 30min, 5mL of a DCM solution containing 0.13g (0.224mmol) of 6- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -N- (5-methyl-1H-pyrazol-3-yl) -4- (trifluoromethyl) pyridin-2-amine trifluoroacetate and 0.136g (1.344mmol) of triethylamine was added to the reaction system. After the addition, the reaction was carried out at 0 ℃ for about 30 min. After the reaction, the reaction solution was poured into 100mL of purified water and extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate. Followed by filtration, concentration and purification by column chromatography gave 67mg of a product as an off-white solid.
1H NMR(500MHz,DMSO-d6)δ11.81(s,1H),9.18(s,1H),8.66(d,J＝4.3Hz,1H),8.41(s,1H),7.95(d,J＝8.3Hz,1H),7.90(s,1H),7.86(s,1H),7.14(d,J＝7.6Hz,1H),6.82(s,1H),6.21(s,1H),6.03(s,1H),4.95(p,J＝6.7Hz,1H),4.45(d,J＝13.9Hz,2H),3.95(d,J＝6.1Hz,2H),3.51(s,1H),2.98(d,J＝11.6Hz,2H),2.20(s,3H),1.79(s,1H),1.66(d,J＝7.8Hz,2H),1.45(d,J＝6.9Hz,3H).
MS(ESI,[M+H]+)m/z:585.3.
Example 54: preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -8- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-3-amide
The reaction process comprises the following steps:
Figure BDA0002902944530000801
the synthesis was as in example 53.
1H NMR(500MHz,DMSO-d6)δ11.85(s,1H),9.28(s,1H),8.68(s,1H),8.39(s,1H),7.93(d,J＝9.1Hz,1H),7.91(s,1H),7.86(d,J＝8.2Hz,1H),6.90–6.69(m,2H),6.34(s,1H),6.05(s,1H),4.90(p,J＝7.7Hz,1H),4.62(s,2H),3.72(s,1H),3.70(s,1H),3.03(d,J＝11.9Hz,2H),2.21(s,3H),1.90(s,2H),1.72(s,2H),1.41(d,J＝6.1Hz,3H).
MS(ESI,[M+H]+)m/z:585.3.
Example 55: preparation of (R) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) piperazine-1-amide
The reaction process comprises the following steps:
Figure BDA0002902944530000811
the synthesis was as in example 53.
1H NMR(500MHz,DMSO-d6)δ11.83(s,1H),9.21(s,1H),8.68(d,J＝4.4Hz,1H),8.42(s,1H),8.00–7.84(m,3H),6.96(d,J＝7.4Hz,1H),6.85(s,1H),6.32(s,1H),6.03(s,1H),4.95(p,J＝6.9Hz,1H),4.31(s,1H),4.21(d,J＝12.2Hz,1H),4.13(d,J＝12.7Hz,1H),3.88(d,J＝13.0Hz,1H),3.17–3.01(m,2H),2.97–2.85(m,1H),2.21(s,3H),1.45(d,J＝7.1Hz,3H),1.09(d,J＝6.5Hz,3H).
MS(ESI,[M+H]+)m/z:573.3.
Example 56: preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -4- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) piperazine-1-amide
The reaction process comprises the following steps:
Figure BDA0002902944530000812
the synthesis was as in example 53.
1H NMR(500MHz,DMSO-d6)δ11.83(s,1H),9.22(s,1H),8.67(d,J＝4.5Hz,1H),8.42(d,J＝1.8Hz,1H),7.99–7.94(m,1H),7.93–7.85(m,2H),7.03(d,J＝7.5Hz,1H),6.88(s,1H),6.33(s,1H),6.03(s,1H),4.94(p,J＝7.0Hz,1H),3.54(d,J＝5.2Hz,4H),3.47(d,J＝5.1Hz,4H),2.21(s,3H),1.45(d,J＝7.1Hz,3H).
MS(ESI,[M+H]+)m/z:559.4.
Example 57: preparation of (S) -N- (1- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000821
step A: preparation of (S) -N- (1- (4-bromophenyl) ethyl) -2,2, 2-trifluoroacetamide
In a 50mL three-necked flask, (R) -1- (4-bromophenyl) ethan-1-amine (1g, 5.00mmol) was dissolved in 10mL of dichloromethane, the reaction system was cooled to 0 ℃ in a cold salt bath, and trifluoroacetic anhydride (1.260g, 0.847mL, 6.00mmol) was slowly added dropwise to the reaction system via a syringe over 3 min. The mixture was stirred at 0 ℃ for 1h, warmed up naturally and stirred at room temperature overnight. After the reaction was completed, 40mL of methylene chloride and 10mL of water were added to the reaction system, followed by extraction, and the organic phase was collected and washed with 1M aqueous sodium hydrogen sulfate (20mL) followed by saturated sodium bicarbonate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 1.45g of a white powdery solid.
MS(ESI,[M-H]-)m/z:294.1.
And B: preparation of (S) -2,2, 2-trifluoro-N- (1- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) ethyl) acetamide
To a 35mL microwave tube were added in this order (R) -N- (1- (4-bromophenyl) ethyl) -2,2, 2-trifluoroacetamide (1.2g, 4.05mmol), N, N-dimethylacetamide (15mL), 4-fluoro-1H-pyrazole (0.419g, 4.86mmol), copper iodide (0.154g, 0.811mmol), 1, 10-phenanthroline (0.292g, 1.621mmol), and Cs2CO3(2.64g, 8.11mmol), the reaction was transferred to a microwave reactor under microwave conditions: 160 ℃ for 3 h. After the reaction is finished, 40mL of ethyl acetate and kieselguhr are added into the reaction systemThe filtrate was filtered, and the filtrate was washed three times with 30mL of saturated brine. Dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 200mg of a brown oil.
MS(ESI,[M+H]+)m/z:302.1.
And C: preparation of (S) -1- (4- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) ethan-1-amine
In a 25mL single-necked flask, (R) -2,2, 2-trifluoro-N- (1- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) ethyl) acetamide (0.03g, 0.100mmol), methanol (5mL), and a 1M aqueous solution of LiOH (5mL) were sequentially added, and the mixture was stirred at room temperature overnight. To complete the reaction, 40mL of ethyl acetate and 10mL of water were added to the reaction system. The organic phase was washed twice with 10mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give 10mg of a pale yellow oil.
Step D: preparation of (S) -N- (1- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) ethyl) -4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperazine-1-carboxamide
Step D reference was made to step D of example 19.
1H NMR(500MHz,CDCl3):δ12.37(s,1H),12.35(s,1H),8.64(d,J＝4.5Hz,1H),7.80(d,J＝4.0Hz,1H),7.71(d,J＝8.5Hz,2H),7.46(d,J＝8.5Hz,2H),7.01(d,J＝7.5Hz,1H),6.30(m,2H),4.90(m,1H),3.82(s,4H),3.53(s,4H),2.36(s,3H),2.25(s,3H),1.42(d,J＝7.0Hz,3H)。MS(ESI,[M+H]+)m/z:505.2。
Example 58: preparation of 1- (6- (2-cyanopropan-2-yl) pyridin-3-yl) -3- (1- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperidin-4-ylurea
The reaction process comprises the following steps:
Figure BDA0002902944530000831
the synthesis method is referred to example 1.
1H NMR(500MHz,DMSO-d6):δ11.85(s,1H),9.19(s,1H),8.65(s,1H),8.55(d,J＝2.5Hz,1H),7.61(m,1H),7.56(d,J＝9.0Hz,1H),6.78(d,J＝8Hz,1H),6.22(s,1H),6.10(s,1H),3.76(m,1H),3.07(m,2H),2.51(m,2H),2.20(s,3H),2.12(s,3H),1.89(m,2H),1.67(s,6H),1.37(m,2H).
MS(ESI,[M+H]+)m/z:475.3。
Example 59: preparation of (1R, 5S) -3- (5-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -N- ((S) -1- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) ethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000832
the synthesis method is referred to example 1.
1H NMR(500MHz,DMSO-d6):δ12.07(s,1H),8.62(d,J＝4.5Hz,2H),8.00(s,1H),7.79(d,J＝4.0Hz,1H),7.71(d,J＝8.5Hz,2H),7.44(d,J＝8.5Hz,2H),7.01(d,J＝8.0Hz,1H),6.29(s,1H),4.91(t,J＝7.0Hz,1H),4.42(m,2H),4.18(s,2H),3.02(d,J＝12Hz,2H),2.24(s,3H),1.76(t,J＝4.5Hz,2H),1.57(d,J＝8.5Hz,2H),1.41(d,J＝7.0Hz,3H).
MS(ESI,[M+H]+)m/z:551.3。
Example 60: preparation of (1R, 5S) -N- ((S) -1- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) ethyl) -3- (5-fluoro-4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000833
the synthesis method is referred to example 1.
1H NMR(500MHz,DMSO-d6):δ12.03(s,1H),9.44(s,1H),8.62(d,J＝4.5Hz,1H),7.92(d,J＝3.5Hz,1H),7.79(d,J＝4.0Hz,1H),7.71(d,J＝8.5Hz,2H),7.44(d,J＝8.5Hz,2H),7.02(d,J＝8.0Hz,1H),6.33(s,1H),4.91(t,J＝7.0Hz,1H),4.42(m,2H),4.14(m,2H),3.01(d,J＝12.5Hz,2H),2.24(s,3H),1.76(t,J＝4.0Hz,2H),1.59(d,J＝8.0Hz,2H),1.41(d,J＝7.0Hz,3H).
MS(ESI,[M+H]+)m/z:535.3.
Example 61: preparation of (1R, 5S) -N- ((S) -1- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) ethyl) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000841
the synthesis method is referred to example 27.
1H NMR(500MHz,DMSO-d6):δ11.80(s,1H),9.16(s,1H),8.62(d,J＝4.5Hz,1H),7.79(d,J＝4.0Hz,1H),7.71(d,J＝8.5Hz,2H),7.45(d,J＝8.5Hz,2H),7.06(d,J＝8.0Hz,1H),6.83(s,1H),6.21(s,1H),6.03(s,1H),4.92(m,1H),4.46(m,2H),3.94(m,2H),3.00(m,2H),2.21(s,3H),1.79(d,J＝4.5Hz,2H),1.67(d,J＝8.0Hz,2H),1.41(d,J＝7.0Hz,3H).
MS(ESI,[M+H]+)m/z:584.4。
Example 62: preparation of 2- (1- (4-methyl-6- (((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) piperidin-4-yl) -N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) acetamide
The reaction process comprises the following steps:
Figure BDA0002902944530000842
the synthesis method is referred to example 15.
1H NMR(500MHz,DMSO-d6):δ11.85(d,J＝5.0Hz,1H),9.88(s,1H),9.21(s,1H),7.54(d,J＝5.0Hz,2H),7.19(d,J＝8.5Hz,2H),6.11(s,2H),4.64(m,2H),2.80(m,2H),2.31(m,5H),2.24(d,J＝7.5Hz,3H),2.18(s,3H),2.15(s,3H),2.10(s,3H),2.02(m,2H),1.70(d,J＝11.0Hz,2H),1.35(s,1H),1.14(m,4H).
MS(ESI,[M+H]+)m/z:518.5.
Example 63: preparation of N- (6- (2-cyanopropan-2-yl) pyridin-3-yl) -2- (1- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-ylpiperidin-4-yl acetamide
The reaction process comprises the following steps:
Figure BDA0002902944530000851
the synthesis method is referred to example 15.
1H NMR(500MHz,DMSO-d6):δ11.85(s,1H),10.25(s,1H),9.21(s,1H),8.72(d,J＝2.0Hz,1H),8.14(m,1H),7.55(d,J＝8.5Hz,1H),6.11(m,2H),4.65(m,2H),2.80(m,2H),2.30(d,J＝7.0Hz,2H),2.19(s,3H),2.11(s,3H),1.99(s,1H),1.72(m,2H),1.68(s,6H),1.17(m,2H).
MS(ESI,[M+H]+)m/z:474.4。
Example 64: preparation of (S) -N- ((S) -1- (6- ((R) -3-fluoropyrrolidin-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-ylpiperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000852
step A: preparation of (S) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide
80mL of anhydrous tetrahydrofuran, 1- (6-bromopyridin-3-yl) ethane-1-one (6g, 66.7mmol), R-tert-butylsulfinamide (7.27g,60.0mmol), diethylene glycol dimethyl ether (4.02g,30.0mmol) and tetraethyltitanate (13.68g,60.0mmol) are sequentially added into a 250mL three-neck round-bottom flask, nitrogen is protected in a reaction system, and the reaction solution is heated and refluxed for 5 hours. Cooling the reaction liquid to-78 ℃, slowly dropwise adding 1M tetrahydrofuran solution (90mL,90mmol) of lithium tri-sec-butylborohydride under the protection of nitrogen, controlling the temperature to be not higher than-70 ℃, and continuously stirring and reacting for 40min at-78 ℃ after dropwise adding. 40mL of methanol is added dropwise to quench the reaction, the reaction solution is naturally heated to 0 ℃, and the reaction solution is poured into 500mL of water and stirred. Filter and wash the filter cake with ethyl acetate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and concentrated to a yellow solid. To the crude product was added 50mL of petroleum ether: the mixture was stirred at room temperature for 2 hours with ethyl acetate at a ratio of 5:1, filtered, and the filter cake was washed with petroleum ether to give 5.6g of a white powdery solid.
And B: preparation of (S) -N- ((S) -1- (6- ((R) -3-fluoropyrrolidin-1-yl) pyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide
In a 35mL microwave tube, (R) -N- ((S) -1- (6-bromopyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide (300mg,0.983mmol), THF (10mL), (R) -3-fluoropyrrolidine hydrochloride (123mg,0.983mmol), davephos (26mg,0.066mmol), Pd2(dba)3(30mg,0.033mmol), 1M LiHMDS (0.825mL,0.825mmol), nitrogen blanket was added sequentially into a microwave reactor under microwave conditions: 130 ℃ for 30 min. When the reaction was completed, 50mL of a diluted dichloromethane solution was added to the reaction system, and the reaction mixture was washed three times with 20mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography gave 0.14g of a brown oil.
MS(ESI,[M+H]+)m/z:314.2。
And C: preparation of (S) -1- (6- ((R) -3-fluoropyrrolidin-1-yl) pyridin-3-yl) ethan-1-amine dihydrochloride
In a 50mL single-necked flask, (S) -N- ((S) -1- (6- ((R) -3-fluoropyrrolidin-1-yl) pyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide (0.14g,0.447mmol), methanol (10mL), 1M dilute hydrochloric acid (4mL, 4.02mmol) were added sequentially, and the mixture was stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure to give a brown solid, 20mL of ethyl acetate was added and slurried for 2h, and the filter cake was collected to give 0.07g of a gray solid.
Step D: preparation of (S) -N- ((S) -1- (6- ((R) -3-fluoropyrrolidin-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-ylpiperazine-1-carboxamide
The synthesis was as in step G of example 1.
1H NMR(500MHz,DMSO-d6):δ11.77(s,1H),8.67(s,1H),8.01(d,J＝2.0Hz,1H),7.55(d,J＝7.5Hz,1H),6.71(d,J＝8.0Hz,1H),6.50(d,J＝9.0Hz,1H),6.32(s,1H),6.01(m,2H),4.79(m,1H),4.28(t,J＝3.0Hz,1H),4.05(m,2H),3.82(m,1H),3.60(m,3H),3.03(m,2H),2.72(m,1H),2.24(m,2H),2.18(s,3H),2.12(s,3H),1.36(m,3H),1.22(m,2H),1.07(d,J＝6.0Hz,3H).
MS(ESI,[M+H]+)m/z:522.3.
Example 65: preparation of (2S) -N- (((1S) -1- (6- (3-azabicyclo [3.1.0] ] hex-3-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-ylpiperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000861
the synthesis method is referred to example 64.
1H NMR(500MHz,DMSO-d6):δ11.71(s,1H),8.62(s,1H),7.97(d,J＝2.0Hz,1H),7.46(m,1H),6.66(d,J＝8.0Hz,1H),6.40(m,2H),6.01(m,2H),4.76(m,1H),4.27(t,J＝3.0Hz,1H),4.06(m,2H),3.81(m,1H),3.61(m,2H),3.28(d,J＝9.0Hz,2H),3.01(m,2H),2.71(m,1H),2.18(s,3H),2.11(s,3H),1.65(m,2H),1.34(d,J＝7.5Hz,3H),1.06(d,J＝8.0Hz,3H),0.85(m,1H),0.70(m,1H).
MS(ESI,[M+H]+)m/z:516.4.
Example 66: preparation of (S) -N- ((S) -1- (6- (azetidin-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000862
the synthesis method is referred to example 64.
1H NMR(500MHz,DMSO-d6):δ11.77(d,J＝5.0Hz,1H),8.66(s,1H),7.97(d,J＝3.0Hz,1H),7.55(d,J＝3.5Hz,1H),6.71(d,J＝7.5Hz,1H),6.36(m,2H),6.01(m,2H),4.76(m,1H),4.28(d,J＝3.0Hz,1H),4.05(m,2H),3.91(m,4H),3.81(m,1H),2.96(m,2H),2.72(m,1H),2.30(d,J＝7.5Hz,2H),2.17(s,3H),2.11(s,3H),1.34(m,3H),1.06(d,J＝6.5Hz,3H).
MS(ESI,[M+H]+)m/z:490.4.
Example 67: preparation of (S) -N- ((S) -1- (6- ((S) -3-fluoropyrrolidin-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-ylpiperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000871
the synthesis method is referred to example 64.
1H NMR(500MHz,DMSO-d6):δ11.73(s,1H),8.65(s,1H),8.01(s,1H),7.53(d,J＝7.5Hz,1H),6.70(d,J＝8.0Hz,1H),6.48(d,J＝8.5Hz,1H),6.32(s,1H),6.00(m,2H),4.78(m,1H),4.29(s,1H),4.06(m,2H),3.81(m,1H),3.61(m,3H),3.03(m,2H),2.93(d,J＝9.5Hz,1H),2.72(m,2H),2.18(s,3H),2.12(s,3H),1.36(d,J＝7.0Hz,3H),1.23(s,2H),1.07(d,J＝6.0Hz,3H).
MS(ESI,[M+H]+)m/z:522.4.
Example 68: preparation of (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -4- (6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrazin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000872
the synthesis method is referred to example 27.
1H NMR(500MHz,DMSO-d6):δ11.83(s,1H),9.19(s,1H),8.66(d,J＝4.0Hz,1H),8.41(s,1H),7.89(m,3H),7.78(s,1H),7.55(s,1H),7.01(d,J＝7.5Hz,1H),6.11(s,1H),4.93(m,1H),3.48(m,8H),2.51(s,3H),2.20(s,3H).
MS(ESI,[M+H]+)m/z:492.3.
Example 69: preparation of (S) -N- ((S) -1- (6- (3-fluoroazetidin-1-yl) pyridin-3-yl) ethyl) -2-methyl-4- (4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000881
the synthesis method is referred to example 64.
1H NMR(500MHz,CDCl3):δ11.66(s,1H),8.63(s,1H),8.04(s,1H),7.54(d,J＝8.0Hz,1H),6.72(d,J＝7.5Hz,1H),6.43(d,J＝8.5Hz,1H),6.32(s,1H),6.02(s,1H),5.95(s,1H),5.48(m,1H),4.79(m,1H),4.23(m,3H),3.75(m,4H),3.81(m,1H),3.08(t,J＝11Hz,1H),2.92(d,J＝10.5Hz,1H),2.71(t,J＝11Hz,1H),2.18(s,3H),2.12(s,3H),1.36(d,J＝6.0Hz,3H),1.07(m,3H).
MS(ESI,[M+H]+)m/z:508.3.
Example 70: preparation of (S) -4- (4- (difluoromethyl) -6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylpiperazine-1-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000882
step A: preparation of 2, 6-dichloro-4- (difluoromethyl) pyridine
Cuprous chloride (1.301g,13.14mmol) and potassium tert-butoxide (2.95g, 26.3mmol) were added to a 50mL three-necked flask under nitrogen, 20mL of anhydrous DMF was added to the reaction, the reaction was stirred at room temperature for 15min, (difluoromethyl) trimethylsilane (2.041g, 16.43mmol) was slowly added to the reaction, and after 5min addition, the reaction was stirred at room temperature for 5 min. 1, 10-phenanthroline (2.369g, 13.14mmol) is dissolved in 5mL of anhydrous DMF and added to the reaction system in one portion, the reaction system is stirred for 20min at room temperature, 2, 6-dichloro-4-iodopyridine (3g, 10.95mmol) is dissolved in 15mL of anhydrous DMF and added to the system in one portion, and the mixture is stirred at room temperature overnight. When the reaction was completed, 20mL of water and 50mL of ethyl acetate were added to the reaction system, and the organic phase was collected. The organic phase was washed three times with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 1.0g of a colorless oil.
And B: synthesis of tert-butyl 4- (6-chloro-4- (difluoromethyl) pyridin-2-yl) piperazine-1-carboxylate
In a 50mL single neck flask was added 2, 6-dichloro-4- (difluoromethyl) pyridine (0.4mg, 2.02mmol), N, N-dimethylformamide (10mL), N-Boc-piperazine (0.75g, 4.04mmol), diisopropylethylamine (0.78g,6.06mmol) in that order, and the mixture was heated to 120 ℃ for 4 h. To the reaction solution, 30mL of ethyl acetate and 10mL of water were added, and the organic phase was collected by extraction. The organic phase was washed three times with 10mL of saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated in filtrate, and purified by column chromatography to give 0.4g of pale yellow oil.
MS(ESI,[M-Boc+H]+)m/z:248.1.
And C: synthesis of tert-butyl 4- (4- (difluoromethyl) -6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxylate
To a 35mL microwave tube, tert-butyl 4- (6-chloro-4- (difluoromethyl) pyridin-2-yl) piperazine-1-carboxylate (0.4g, 1.150mmol), tetrahydrofuran (10mL), 5-methyl-1H-pyrazol-3-amine (0.117g, 1.208mmol), 2'- (dicyclohexylphosphino) -N, N-dimethyl- [1,1' -biphenyl, were added]2-amine (0.045g, 0.115mmol), 1M lithium bis (trimethylsilyl) amide (5.2mL, 5.18mmol), Pd2(dba)3(0.053g, 0.058 mmol). The nitrogen gas is used for blowing off air, and the mixture is placed into a microwave reactor and heated to 130 ℃ by 400W for reaction for 30 minutes. The reaction was quenched by the addition of 5mL of 1M saturated ammonium chloride solution dropwise under ice-bath conditions and diluted with 20mL of ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase is concentrated and the crude product is purified by column chromatography to give 0.18g of a pale yellow oil.
MS(ESI,[M+H]+)m/z:409.2.
Step D: synthesis of trifluoroacetate salt of 4- (difluoromethyl) -N- (5-methyl-1H-pyrazol-3-yl) -6- (piperazin-1-yl) pyridin-2-amine (1: 2)
To a 50mL round bottom flask, tert-butyl 4- (4- (difluoromethyl) -6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) piperazine-1-carboxylate (0.18g, 0.441mmol), dichloromethane (10mL), and trifluoroacetic acid (0.251g, 2.203mmol) were added in this order, and the mixture was stirred at room temperature overnight, after completion of the reaction, the reaction mixture was concentrated to obtain 0.18g of a brown solid product, and the next reaction was continued without purification.
MS(ESI,[M+H]+)m/z:309.1.
Step E: synthesis of (S) -4- (4- (difluoromethyl) -6- (((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylpiperazine-1-carboxamide
Triphosgene (0.053g, 0.178mmol) was dissolved in 5mL of dichloromethane, cooled to 0 ℃ in an ice salt bath under nitrogen protection, and 5mL of a dichloromethane solution containing (S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylamine dihydrochloride (0.056g, 0.198mmol) and triethylamine (0.17g, 1.584mmol) was added dropwise. After the reaction mixture was stirred at 0 ℃ for 5min, 4- (difluoromethyl) -N- (5-methyl-1H-pyrazol-3-yl) -6- (piperazin-1-yl) pyridin-2-amine trifluoroacetate (0.1g, 0.198mmol) and triethylamine (0.09g, 0.792mmol) were added, and the mixture was stirred at room temperature for 20 min. After completion of the reaction, the reaction mixture was diluted with 50mL of methylene chloride and washed with 20mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography to give 47mg of a white powdery solid as the target.
1H NMR(500MHz,DMSO-d6):δ11.76(s,1H),9.02(s,1H),8.67(d,J＝3.5Hz,1H),8.42(s,1H),7.88(m,3H),7.02(d,J＝6.5Hz,1H),6.88(m,1H),6.15(d,J＝6.5Hz,1H),6.23(s,1H),6.02(s,1H),4.94(m,1H),3.47(m,8H),2.20(s,3H),1.44(d,J＝6.5Hz,3H).
MS(ESI,[M+H]+)m/z:541.2。
Example 71: preparation of (1R, 5S) -8- (4- (difluoromethyl) -6- ((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3, 8-diazabicyclo [3.2.1] octane-3-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000891
the synthesis method is referred to example 70.
1H NMR(500MHz,DMSO-d6):δ11.75(s,1H),9.04(s,1H),8.67(d,J＝5.0Hz,1H),8.38(s,1H),7.90(m,3H),6.85(m,3H),6.21(s,1H),6.04(s,1H),4.89(t,J＝5.0Hz,1H),4.54(s,2H),3.69(m,2H),3.03(m,2H),2.20(s,3H),1.8 9(s,2H),1.73(m,2H),1.41(d,J＝7.0Hz,3H).
Example 72: preparation of 2- (4- ((6-isopropoxypyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine
The reaction process comprises the following steps:
Figure BDA0002902944530000901
6-methyl-N- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) pyrimidin-4-amine trifluoroacetate (500mg,1.065mmol), DCM (20mL), TEA (431mg,0.594mL,4.26mmol), 6- (1-methylethoxy) -3-pyridinecarbaldehyde (194mg,1.172mmol), sodium triacetoxyborohydride (677mg,3.20mmol) were added in this order to a 100mL single-neck flask, and stirred at room temperature overnight. Filtration, collection of filtrate and concentration, addition of 20mL DCM and 60mL H2And O, shaking up, separating liquid, drying by using anhydrous sodium sulfate, filtering and concentrating. The crude product was purified by column chromatography to give 427mg of a white solid.
1H NMR(500MHz,DMSO-d6)δ9.57(s,1H),8.22(s,1H),7.84–7.70(m,1H),6.80(d,J＝8.5Hz,1H),6.21(d,J＝96.4Hz,2H),5.26(p,J＝6.2Hz,1H),4.18(s,2H),3.09(q,J＝7.0Hz,4H),2.18(d,J＝18.5Hz,6H),1.29(d,J＝6.2Hz,6H),1.19(s,1H),1.18(s,2H),1.16(s,1H).
MS(ESI,[M+H]+)m/z:423.3.
Example 73: preparation of (1R, 5S) -N- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -3- (6- ((5-methyl-1H-pyrazol-3-yl) amino) -4- (trifluoromethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide
The reaction process comprises the following steps:
Figure BDA0002902944530000902
the synthesis was as in example 53.
1H NMR(500MHz,DMSO-d6)δ11.80(s,1H),9.16(s,1H),8.69–8.61(m,1H),8.40(d,J＝2.2Hz,1H),7.97–7.84(m,3H),7.13(d,J＝7.7Hz,1H),6.82(s,1H),6.20(s,1H),6.02(s,1H),4.94(p,J＝7.1Hz,1H),4.44(d,J＝15.3Hz,2H),3.94(d,J＝5.9Hz,2H),2.97(d,J＝12.2Hz,2H),2.19(s,3H),1.44(d,J＝7.1Hz,3H),1.23(s,4H).
MS(ESI,[M+H]+)m/z:585.3.
Experimental example 1: inhibition of the Activity of in vitro kinases RET, RET (M918T), RET (Y791F), RET (V804L), RET (V804M), KDR
1.1 RET inhibitory Activity screening
With kinase buffer (50mM HEPES, 10mM MgCl)22mM DTT, 1mM EGTA, 0.01% Tween 20) 50 ng/. mu.L of RET stock solution was diluted, 6. mu.L of 1.67X 0.000334 ng/. mu.L working solution (final concentration of 0.0002 ng/. mu.L) was added to each well, and DMSO-dissolved different compounds were added to the wells using a nanoliter applicator to give a final concentration of 1000nM-0.24nM, 4-fold gradient, 7 concentrations, blank control wells (no enzyme) and negative control wells (enzyme-containing, vehicle DMSO), and 2 duplicate wells were set. After the enzyme reacts with the compound or the solvent for 30min, 5 × 50 μ M ATP (final concentration of 10 μ M) prepared by using a kinase buffer solution and 5 × 0.5 μ M substrate (final concentration of 0.1 μ M, ULight-poly GT) are mixed according to a ratio of 1:1 and added into the wells according to 4 μ L per well; after the plate is sealed and the plate is covered with a membrane, after reacting for 2h at room temperature, 5 μ L of 4 × 40mM EDTA (final concentration is 10mM) is added into each hole, 5min at room temperature is carried out, 5 μ L of 4 × 8nM detection reagent (final concentration is 2nM, Eu-anti-phosphorus-tyrosine antibody) is added into each hole, and incubation is carried out for 1h at room temperature; reading the plate (excitation 320nm and emission 665nm) by using a PE Envision multifunctional microplate reader, and fitting by adopting four parametersComputing IC50。
1.2 RET (M918T) inhibitory Activity screening
With kinase buffer (50mM HEPES, 10mM MgCl)22mM DTT, 1mM EGTA, 0.01% Tween 20) 50 ng/. mu.L of RET (M918T) stock solution was diluted, 6. mu.l of 1.67X 0.000835 ng/. mu.L working solution (final concentration of 0.0005 ng/. mu.L) was added to each well, DMSO-dissolved different compounds were added to the wells using a nanoliter loader to give a final concentration of 1000nM-0.24nM, 4-fold gradient for 7 concentrations, and blank (no enzyme-containing) and negative control (enzyme-containing, DMSO-containing) wells were set for 2 duplicate wells. After the enzyme reacts with the compound or the solvent for 30min, 5 × 50 μ M ATP (final concentration of 10 μ M) prepared by using a kinase buffer solution and 5 × 0.5 μ M substrate (final concentration of 0.1 μ M, ULight-poly GT) are mixed according to a ratio of 1:1 and added into the wells according to 4 μ L per well; after the plate is sealed and the plate is covered with a membrane, after reacting for 2h at room temperature, 5 μ L of 4 × 40mM EDTA (final concentration is 10mM) is added into each hole, 5min at room temperature is carried out, 5 μ L of 4 × 8nM detection reagent (final concentration is 2nM, Eu-anti-phosphorus-tyrosine antibody) is added into each hole, and incubation is carried out for 1h at room temperature; reading the plate (excitation 320nm and emission 665nm) by using a PE Envision multifunctional microplate reader, adopting four-parameter fitting, and calculating IC50。
1.3 RET (Y791F) inhibitory Activity screening
With kinase buffer (50mM HEPES, 10mM MgCl)22mM DTT, 1mM EGTA, 0.01% Tween 20) 50 ng/. mu.L of RET (Y791F) stock solution was diluted, 6. mu.L of 1.67X 0.000835 ng/. mu.L working solution (final concentration of 0.0005 ng/. mu.L) was added to each well, DMSO-dissolved different compounds were added to the wells using a nanoliter loader to give a final concentration of 1000nM-0.24nM, 4-fold gradient for 7 concentrations, blank control wells (no enzyme) and negative control wells (enzyme-containing, vehicle DMSO) were set, and 2 duplicate wells were set. After the enzyme reacts with the compound or the solvent for 30min, 5 × 50 μ M ATP (final concentration of 10 μ M) prepared by using a kinase buffer solution and 5 × 0.5 μ M substrate (final concentration of 0.1 μ M, ULight-poly GT) are mixed according to a ratio of 1:1 and added into the wells according to 4 μ L per well; after the plate was covered with a membrane, the reaction was carried out at room temperature for 2 hours, and 5. mu.L of 4X 40mM EDTA (final concentration: 10mM) was added to each well for 5 minutes at room temperature, and 5. mu.L of 4X 8nM detection reagent (final concentration is 2nM, Eu-anti-phosphorus-tyrosine antibody), and room temperature incubation is performed for 1 h; reading the plate (excitation 320nm and emission 665nm) by using a PE Envision multifunctional microplate reader, adopting four-parameter fitting, and calculating IC50。
1.4 RET (V804L) inhibitory Activity screening
With kinase buffer (50mM HEPES, 10mM MgCl)22mM DTT, 1mM EGTA, 0.01% Tween 20) 50 ng/. mu.L of RET (V804L) stock solution was diluted, 6. mu.L of 1.67X 0.000334 ng/. mu.L working solution (final concentration of 0.0002 ng/. mu.L) was added to each well, DMSO-dissolved different compounds were added to the wells using a nanoliter loader to give a final concentration of 1000nM-0.24nM, 4-fold gradient for 7 concentrations, blank control wells (no enzyme) and negative control wells (enzyme-containing, vehicle DMSO) were set, and 2 duplicate wells were set. After the enzyme reacts with the compound or the solvent for 30min, 5 × 50 μ M ATP (final concentration of 10 μ M) prepared by using a kinase buffer solution and 5 × 0.5 μ M substrate (final concentration of 0.1 μ M, ULight-poly GT) are mixed according to a ratio of 1:1 and added into the wells according to 4 μ L per well; after the plate is sealed and the plate is covered with a membrane, after reacting for 2h at room temperature, 5 μ L of 4 × 40mM EDTA (final concentration is 10mM) is added into each hole, 5min at room temperature is carried out, 5 μ L of 4 × 8nM detection reagent (final concentration is 2nM, Eu-anti-phosphorus-tyrosine antibody) is added into each hole, and incubation is carried out for 1h at room temperature; reading the plate (excitation 320nm and emission 665nm) by using a PE Envision multifunctional microplate reader, adopting four-parameter fitting, and calculating IC50。
1.5 RET (V804M) inhibitory Activity screening
With kinase buffer (50mM HEPES, 10mM MgCl)22mM DTT, 1mM EGTA, 0.01% Tween 20) 50 ng/. mu.L of RET (V804M) stock solution was diluted, 6. mu.L of 1.67X 0.0835 ng/. mu.L working solution (final concentration of 0.05 ng/. mu.L) was added to each well, DMSO-dissolved different compounds were added to the wells using a nanoliter loader to give a final concentration of 1000nM-0.24nM, 4-fold gradient for 7 concentrations, blank control wells (no enzyme-containing) and negative control wells (enzyme-containing, DMSO-containing) were set, and 2 duplicate wells were set. After the enzyme has reacted with the compound or vehicle for 30min, 5X 50. mu.M ATP (final concentration of 10. mu.M) prepared in kinase buffer and 5X 0.5. mu.M substrate (final concentration of 0.1. mu.M, ULight-poly GT) are mixed in a 1:1 ratioAdding the mixture into the holes according to 4 mu L per hole after combination; after the plate is sealed and the plate is covered with a membrane, after reacting for 2h at room temperature, 5 μ L of 4 × 40mM EDTA (final concentration is 10mM) is added into each hole, 5min at room temperature is carried out, 5 μ L of 4 × 8nM detection reagent (final concentration is 2nM, Eu-anti-phosphorus-tyrosine antibody) is added into each hole, and incubation is carried out for 1h at room temperature; reading the plate (excitation 320nm and emission 665nm) by using a PE Envision multifunctional microplate reader, adopting four-parameter fitting, and calculating IC50。
1.5 KDR inhibitory Activity screening
With kinase buffer (50mM HEPES, 10mM MgCl)22mM DTT, 1mM EGTA, 0.01% Tween 20), 50 ng/. mu.L of KDR stock solution was diluted, 6. mu.L of 1.67X 0.1336 ng/. mu.L working solution (final concentration of 0.08 ng/. mu.L) was added to each well, DMSO-dissolved different compounds were added to the wells using a nanoliter loading apparatus to give a final concentration of 1000nM-0.24nM, 4-fold gradient, 7 concentrations, blank control wells (no enzyme) and negative control wells (enzyme-containing, vehicle DMSO-loaded) were set, and 2 duplicate wells were set. After the enzyme reacts with the compound or the solvent for 30min, 5 × 25 μ M ATP (final concentration of 5 μ M) prepared by using a kinase buffer solution and 5 × 0.5 μ M substrate (final concentration of 0.1 μ M, ULight-poly GT) are mixed according to a ratio of 1:1 and added into the wells according to 4 μ L per well; after the plate is sealed and the plate is covered with a membrane, after reacting for 2h at room temperature, 5 μ L of 4 × 40mM EDTA (final concentration is 10mM) is added into each hole, 5min at room temperature is carried out, 5 μ L of 4 × 8nM detection reagent (final concentration is 2nM, Eu-anti-phosphorus-tyrosine antibody) is added into each hole, and incubation is carried out for 1h at room temperature; reading the plate (excitation 320nm and emission 665nm) by using a PE Envision multifunctional microplate reader, adopting four-parameter fitting, and calculating IC50。
1.6 in vitro kinase RET, RET (M918T), RET (Y791F), RET (V804L), RET (V804M), KDR activity results, see Table 1.
TABLE 1
Figure BDA0002902944530000931
Figure BDA0002902944530000941
"- -" represents no detection.

Claims (23)

1. A compound shown in a formula (I), a stereoisomer thereof and pharmaceutically acceptable salts thereof,
Figure FDA0002902944520000011
wherein,
x is selected from NH;
u, V, W are each independently selected from C (R)1) Or N;
q is selected from C (R)2) Or N;
the ring A is a 6-8-membered monocyclic ring, a 6-10-membered bridged heterocyclic ring, a benzene ring, a naphthalene ring, a 7-12-membered fused ring or fused heterocyclic ring, or a 7-12-membered fused heteroaromatic ring, and the monocyclic heterocyclic ring contains at least one N atom;
the ring B is a benzene ring, a naphthalene ring, a 5-6-membered heteroaromatic ring, a 7-12-membered fused heterocyclic ring or a 7-12-membered fused heteroaromatic ring;
-L1-is selected from the group consisting of a single bond, -O-, -S-, -C (O) -, -C (S) -, -S (O)2-or-N (R)A0)-；
-L2-is selected from-O-, -S-, -C (S) -, -S (O)2-、-(CRA2RB2)q-、-N(RA1)-、-C(O)-N(RA1)-、-N(RA1)-C(S)-、-(CRA2RB2)q-C(S)-、-(CRA2RB2)q-S(O)2-、-C(O)-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(O)-(CRA2RB2)q-、-C(S)-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(S)-(CRA2RB2)q-、-S(O)2-N(RA1)-(CRA2RB2)q-、-N(RA1)-S(O)2-(CRA2RB2)q-、-C(O)-N(RA1)-C(O)-、-N(RA1)-C(O)-N(RA1)-、-N(RA1)-C(O)-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(O)-(CRA2RB2)q-N(RA1)-、-N(RA1)-C(O)-(CRA2RB2)q-C(O)-、-N(RA1)-C(O)-N(RA1)-C(O)-、-C(O)-N(RA1)-C(O)-(CRA2RB2)q-、-C(S)-N(RA1)-C(O)-(CRA2RB2)q-、-C(O)-N(RA1)-(CRA2RB2)q-C(O)-、-C(S)-N(RA1)-(CRA2RB2)q-C(O)-、-N(RA1)-C(O)-(CRA2RB2)q-C(O)-N(RA1)-、-C(O)-N(RA1)-(CRA2RB2)q-C(O)-N(RA1) -or-C (O) -N (R)A1)-(CRA2RB2)q-N(RA1)-C(O)-；
RA0Is selected from C1-6Alkyl radical, C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl, said C1-6Alkyl radical, C3-6Cycloalkyl and 3-6 membered heterocycloalkyl may be optionally substituted with one, two or three substituents selected from halo, hydroxy, cyano or amino;
RA1selected from H, C1-6Alkyl radical, C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl, said C1-6Alkyl radical, C3-6Cycloalkyl and 3-6 membered heterocycloalkyl may be optionally substituted with one, two or three substituents selected from halo, hydroxy, cyano or amino;
RA2and RB2Each independently selected from H, halogen, hydroxyl, cyano, amino, COOH, nitro and C1-6Alkyl radical, C1-6alkyl-NH-, C1-6Alkoxy radical, C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl, said C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl and 3-6 membered heterocycloalkyl may be optionally substituted with one, two or three substituents selected from halo, hydroxy, cyano or amino; or RA2、RB2Together with the C to which they are attached form a saturated monocyclic ring, without or with substituents, of three, four or five membersOr a mono-heterocyclic ring comprising 1 or 2 heteroatoms selected from O or N;
R1、R2and R5Each independently selected from H, halogen, hydroxyl, amino, cyano, COOH, nitro and C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, methoxy, C3-6Alkoxy, 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl; or R1、R2The C atoms connected with the compound form a 3-6-membered monocyclic or 3-6-membered monocyclic heterocycle; said C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, methoxy, C3-6Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered monocyclic ring and 3-6 membered monocyclic ring may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino;
R3selected from halogen, hydroxyl, amino, cyano, COOH, nitro,
Figure FDA0002902944520000021
C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, 3-to 6-membered cycloalkyl, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy and 3-6 membered cycloalkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, cyano or amino;
R4selected from H, halogen, hydroxyl, amino, cyano, COOH, nitro, C2-6Alkenyl radical, C2-6Alkynyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, pyrazolyl, 6-to 10-membered bridged heterocycle, 3-to 6-membered heterocycloalkyl-C1-6An alkylene group; said C is2-6Alkenyl radical, C2-6Alkynyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 6-to 10-membered bridged heterocycle, 3-to 6-membered heterocycloalkyl-C1-6Alkylene groups may optionally be selected from R by one, two or three6Substituted with the substituent(s); the pyrazolyl is substituted by one, two or three substituents selected from halogen, hydroxy, amino, cyano, COOH, nitro;
R6independently halogen, hydroxy, amino, cyano, COOH, nitro, C1-6Alkyl radical, C2-6Alkynyl, C1-6alkyl-NH-, N-di (C)1-6Alkyl) -N-, C1-6alkyl-O-, C1-6alkyl-S-, C1-6alkyl-C (O) -, said C1-6Alkyl radical, C2-6Alkynyl, C1-6alkyl-NH-, N-di (C)1-6Alkyl) -N-, C1-6alkyl-O-, C1-6alkyl-S-and C1-6Alkyl-c (o) -may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino;
n is 0 or 1;
p is 1,2 or 3;
q is 1,2, 3, 4 or 5;
and when ring A is a piperidine ring, L2Is not-C (O) -N (R)A1)-(CRA2RB2)q-and-N (R)A1)-C(O)-(CRA2RB2)q-；
And when only 1 of U, V, W is N, Q is C (CH)3) And n is not 0 when ring A is a piperazine ring;
and the following specific compounds, stereoisomers thereof and pharmaceutically acceptable salts thereof are not encompassed by the present application:
Figure FDA0002902944520000031
2. a compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein R1Each independently selected from H, halogen or C1-6Alkyl radical, said C1-6Alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; preferably, R1Each independently selected from H, halogen or C1-4Alkyl radical, said C1-4Alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; more preferably, R1Each independently of the otherIs selected from H or halogen; most preferably, R1Each independently selected from H.
3. A compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof according to claim 1, wherein, U, V, W are all CH; or, U is CH, V is N, W is N; or, U is CH, V is CH, W is N; or U is CH, V is N, W is CH; or U is N, V is CH, and W is N.
4. A compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein R2Is selected from H or C1-6Alkyl radical, said C1-6Alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; preferably, R2Is selected from H or C1-4Alkyl radical, said C1-4Alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; more preferably, R2Selected from H, methyl, ethyl, isopropyl or tert-butyl, which methyl, ethyl, isopropyl or tert-butyl may be optionally substituted with one, two or three substituents selected from halogen; more preferably, R2Selected from H, methyl, difluoromethyl or trifluoromethyl; most preferably, R2Selected from methyl.
5. A compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein R is1、R2Together with the C atom to which they are attached form a 5-membered monocyclic ring.
6. A compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein RA0Independently selected from C1-6Alkyl radical, said C1-6Alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; preferably, RA0Independently selected from C1-4Alkyl radical, said C1-4The alkyl group may optionally be selected from halogen by one, two or threeHydroxy, cyano or amino; more preferably, RA0Independently selected from methyl, ethyl, isopropyl or tert-butyl; most preferably, RA0Independently selected from methyl.
7. A compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein L1Selected from the group consisting of a single bond, -O-, -S-, -C (O) -or-N (R)A0) -; preferably, L1Selected from a single bond, -C (O) -or-N (R)A0) -; more preferably, L1Selected from single bond, -C (O) -, -N (CH)3)-、-N(CH2CH3) -or-N (CH)3)2) -; more preferably, L1Selected from a single bond, -C (O) -or-N (CH)3) -; most preferably, L1Selected from single bonds.
8. The compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof as claimed in claim 1, wherein ring a is 6-8 membered mono-heterocyclic ring, 6-10 membered bridged heterocyclic ring, benzene ring, 8-10 membered fused ring or fused heterocyclic ring, said mono-heterocyclic ring containing at least one N atom; preferably, the ring A is a 6-8-membered saturated mono-heterocyclic ring, a 6-10-membered saturated bridged heterocyclic ring, an 8-10-membered fused ring or fused heterocyclic ring and a benzene ring, and the mono-heterocyclic ring contains at least one N atom; more preferably, ring A is ring A
Figure FDA0002902944520000041
Figure FDA0002902944520000042
Figure FDA0002902944520000043
Further preferably, ring A is
Figure FDA0002902944520000044
Figure FDA0002902944520000045
Figure FDA0002902944520000051
Figure FDA0002902944520000052
Even more preferably, ring A is
Figure FDA0002902944520000053
Figure FDA0002902944520000054
9. A compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, according to claim 1, wherein,
Figure FDA0002902944520000055
is composed of
Figure FDA0002902944520000056
Figure FDA0002902944520000057
Figure FDA0002902944520000058
Preferably, the first and second liquid crystal materials are,
Figure FDA0002902944520000059
Figure FDA0002902944520000061
more preferably, it is a mixture of more preferably,
Figure FDA0002902944520000062
is composed of
Figure FDA0002902944520000063
10. A compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein R3Independently selected from halogen, hydroxy, amino,
Figure FDA0002902944520000064
Or C1-6Alkyl radical, said C1-6Alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; preferably, R3Independently selected from halogen,
Figure FDA0002902944520000065
Or C1-4Alkyl radical, said C1-4Alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; more preferably, R3Independently selected from F,
Figure FDA0002902944520000066
Methyl, ethyl, isopropyl or tert-butyl; most preferably, R3Independently selected from F,
Figure FDA0002902944520000067
Or a methyl group.
11. A compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein L2Selected from-O-, -S-, - (CR)A2RB2)q-、-N(RA1)-、-C(O)-N(RA1)-、-C(S)-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(S)-(CRA2RB2)q-、-C(O)-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(O)-(CRA2RB2)q-、-S(O)2-N(RA1)-(CRA2RB2)q-、-N(RA1)-S(O)2-(CRA2RB2)q-、-N(RA1)-C(O)-N(RA1)-、-N(RA1)-C(O)-N(RA1)-(CRA2RB2)q-or-N (R)A1)-C(O)-(CRA2RB2)q-C(O)-N(RA1) -; preferably, L2Selected from-O-, -C (O) -N (R)A1)-、-C(O)-N(RA1)-(CRA2RB2)-、-S(O)2-N(RA1)-(CRA2RB2)-、-N(RA1)-C(O)-(CRA2RB2)-、-C(S)-N(RA1)-(CRA2RB2)-、-N(RA1)-C(O)-N(RA1)-、-N(RA1)-C(O)-N(RA1)-(CRA2RB2) -or-N (R)A1)-C(O)-(CRA2RB2)-C(O)-N(RA1) -; more preferably, L2Selected from-O-, -C (O) -N (R)A1)-、-C(O)-N(RA1)-(CRA2RB2)q-、-S(O)2-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(O)-(CRA2RB2)q-、-C(S)-N(RA1)-(CRA2RB2)q-、-N(RA1)-C(O)-N(RA1)-(CRA2RB2)q-or-N (R)A1)-C(O)-(CRA2RB2)q-C(O)-N(RA1)-。
12. A compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein RA1Independently selected from H or C1-6Alkyl radical, said C1-6Alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; preferably, RA1Independently selected from H or C1-4Alkyl radical, said C1-4Alkyl may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; more preferably, RA1Independently selected from H, methyl, ethyl, isopropyl or tert-butyl; more preferably, RA1Independently selected from H or methyl; most preferably, RA1Independently selected from H.
13. A compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein RA2And RB2Each independently selected from H, halogen, hydroxy, C1-6Alkyl or C1-6alkyl-NH-said C1-6Alkyl and C1-6alkyl-NH-may be optionally substituted by one, two or three substituents selected from halogen, hydroxy, cyano or amino, or RA2、RB2Together with C to which it is attached, form a tri-, tetra-or penta-saturated monocyclic or mono-heterocyclic ring, with no or no substituents, said mono-heterocyclic ring comprising 1 or 2 heteroatoms selected from O or N; preferably, RA2And RB2Each independently selected from H, C1-4Alkyl or C1-4alkyl-NH-said C1-4Alkyl and C1-4alkyl-NH-may be optionally substituted by one, two or three substituents selected from halogen, hydroxy, cyano or amino, or RA2、RB2Together with the C to which it is attached, form a three-membered saturated monocyclic or monocyclic, unsubstituted or substituted, heterocycle comprising 1 or 2 heteroatoms selected from O or N; more preferably, RA2And RB2Each independently selected from H, methyl, ethyl or methyl-NH-; more preferably, RA2And RB2Each independently selected from H or methyl; more preferably, RA2Selected from methyl, RB2Selected from methyl, or RA2、RB2Together with C to which it is attached, form a cyclopropane ring; most preferably, RA2Selected from H, RB2Is selected from methyl; or, RA2Selected from methyl, RB2Is selected from H.
14. A compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein L2Selected from-O-, -CH2-、-C(O)-NH-、-C(O)-NH-CH(CH3)-、-C(O)-NH-CH2-、-NH-C(O)-NH-、
Figure FDA0002902944520000071
-S(O)2-NH-CH(CH3)-、-NH-C(O)-CH(CH3)-、-C(S)-NH-CH(CH3)-、-NH-C(O)-NH-CH(CH3)-、-N(CH3)-C(O)-NH-CH(CH3) -or
Figure FDA0002902944520000072
Preferably, L2Selected from-C (O) -NH-or-C (O) -NH-CH (CH)3) -; more preferably, L2Selected from the group consisting of-C (O) -NH-CH (CH)3)-。
15. A compound of formula (I), stereoisomers thereof and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein ring B is a phenyl ring, a 5-6 membered heteroaromatic ring, a 7-10 membered fused heterocyclic ring or a 7-10 membered fused heteroaromatic ring containing 1,2 or 3 heteroatoms selected from O, N, S; preferably, ring B is a benzene ring, a 5-to 6-membered heteroaromatic ring, a 9-to 10-membered fused heterocyclic ring or a 9-to 10-membered fused heteroaromatic ring containing 1,2 or 3 heteroatoms selected from O, N, S; preferably, ring B is a furan ring, a pyrrole ring, a pyrazole ring, an imidazole ring, an oxazole ring, an isoxazole ring, a thiophene ring, a thiazole ring, an isothiazole ring, a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, an indole ring, a benzimidazole ring, a benzothiazole ring, a benzoxazole ring, a quinoline ring, an isoquinoline ring, a quinazoline ring, a pyridine ring, a pyridazine ring, an indole ring, a thiazole ring, a quinoline ring, a thiazole ring, a quinoline ring, a thiazole ring, a quinoline ring, a thiazole ring, a quinoline ring, a thiazole ring, a quinoline ring, a thiazole ring, a quinoline ring, a quinazoline ring, a,
Figure FDA0002902944520000073
Preferably, ring B is a benzene ring, a pyridine ring, a benzimidazole ring or a benzothiazole ring; more preferably, ring B is
Figure FDA0002902944520000074
Figure FDA0002902944520000075
More preferably, ring B is
Figure FDA0002902944520000076
Figure FDA0002902944520000077
Most preferably, ring B is
Figure FDA0002902944520000078
16. A compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, according to claim 1, wherein,
Figure FDA0002902944520000081
is composed of
Figure FDA0002902944520000082
Figure FDA0002902944520000083
Preferably, the first and second liquid crystal materials are,
Figure FDA0002902944520000084
is composed of
Figure FDA0002902944520000085
Figure FDA0002902944520000086
More preferably, it is a mixture of more preferably,
Figure FDA0002902944520000087
is composed of
Figure FDA0002902944520000088
17. A compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein R5Independently selected from H, halogen, hydroxy, amino, cyano, C1-6Alkyl, methoxy or C3-6Alkoxy radical, said C1-6Alkyl, methoxy or C3-6Alkoxy may be optionally substituted with one, two or three substituents selected from halo, hydroxy, cyano or amino; preferably, R5Independently selected from H, halogen, hydroxy, C1-4Alkyl, methoxy or C3-6Alkoxy radical, said C1-4Alkyl, methoxy or C3-6Alkoxy may be optionally substituted with one, two or three substituents selected from halo, hydroxy, cyano or amino; further preferably, R5Independently selected from H, halogen, hydroxy, methyl, ethyl, isopropyl, tert-butyl, methoxy, propoxy, isopropoxy, butyl-2-oxy, tert-butyl oxy or pentan-2-yloxy, said methyl, ethyl, isopropyl, tert-butyl, methoxy, propoxy, isopropoxy, butyl-2-oxy, tert-butyl oxy or pentan-2-yloxy being optionally substituted with one, two or three substituents selected from halogen or cyano; even more preferably, R5Independently selected from H, F, hydroxy, trifluoromethyl,
Figure FDA0002902944520000089
Methoxy, trifluoromethyloxy, isopropyloxy, butyl-2-oxy, pentan-2-yloxy; even more preferably, R5Independently selected from H, F, hydroxy, trifluoromethyl.
18. A compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein R4Selected from H, halogen, hydroxy, amino, cyano, C2-6Alkynyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, pyrazolyl, 6-to 8-membered bridged heterocycle or 3-to 6-membered heterocycloalkyl-C1-6Alkylene radical of the formula C2-6Alkynyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 6-to 8-membered bridged heterocycle or 3-to 6-membered heterocycloalkyl-C1-6Alkylene groups may optionally be selected from R by one, two or three6Substituted with the substituent(s); the pyrazolyl is substituted by one, two or three substituents selected from halogen, hydroxy, amino, cyano, COOH, nitro; preferably, R4Selected from H, halogen, cyano, C2-4Alkynyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, pyrazolyl, 6-to 7-membered bridged heterocycle or 5-to 6-membered heterocycloalkyl-C1-4Alkylene radical of the formula C2-4Alkynyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 6-to 7-membered bridged heterocycle or 5-to 6-membered heterocycloalkyl-C1-4Alkylene groups may optionally be selected from R by one, two or three6Substituted with the substituent(s); the pyrazolyl is substituted by one, two or three substituents selected from halogen, hydroxy, amino, cyano, COOH, nitro; further preferably, R4Selected from H, halogen, cyano, ethynyl, 1-propynyl, 2-propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, pyrazolyl, and mixtures thereof,
Figure FDA0002902944520000091
Tetrahydropyrrolyl-1-methylene, tetrahydropyrrolyl-2-methylene, tetrahydropyrrolyl-3-methylene, piperidyl-1-methylene, piperidyl-2-methylene, piperidyl-3-methylene, piperidyl-4-methylene, piperazinyl-1-methylene or piperazinyl-2-methylene, with ethynyl, 1-propynyl, 2-propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, piperidyl, piperazinyl, o-methyl-ethyl-methyl-ethyl-propyl, cyclopropyl-butyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, piperidinyl, piperazinyl,
Figure FDA0002902944520000092
Tetrahydropyrrolyl-1-methylene, tetrahydropyrrolyl-2-methylene, tetrahydropyrrolyl-3-methylene, piperidinyl-1-methylene, piperidinyl-2-methylene, piperidinyl-3-methylene, piperidinyl-4-methylene, piperazinyl-1-methylene or piperazinyl-2-methylene groups may optionally be substituted with one, two or three groups selected from R6Substituted with the substituent(s); the pyrazolyl is substituted by one, two or three substituents selected from halogen, hydroxy, amino, cyano, COOH, nitro; even more preferably, R4Selected from H, F, cyano, ethynyl, cyclopropyl, cyclopentyl, azetidinyl, tetrahydropyrrolyl, pyrazolyl, and mixtures thereof,
Figure FDA0002902944520000093
Tetrahydropyrrolyl-1-methylene or piperazinyl-1-methylene, said ethynyl, cyclopropyl, cyclopentyl, azetidinyl, tetrahydropyrrolyl,
Figure FDA0002902944520000094
Tetrahydropyrrolyl-1-methylene or piperazinyl-1-methylene may optionally be substituted with one, two or three R6Substituted with the substituent(s); the pyrazolyl group is substituted with one, two or three substituents selected from halogen; even more preferably, R4Selected from H, F, cyano, ethynyl,
Figure FDA0002902944520000095
Figure FDA0002902944520000096
Figure FDA0002902944520000097
Even more preferably, R4Is selected from
Figure FDA0002902944520000098
19. A compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein R6Independently selected from halogen, hydroxy, amino, cyano, C1-6Alkyl radical, C2-6Alkynyl, C1-6alkyl-NH-, N-di (C)1-6Alkyl) -N-, said C1-6Alkyl radical, C2-6Alkynyl, C1-6alkyl-NH-and N, N-di (C)1-6Alkyl) -N-may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; preferably, R6Independently selected from halogen, cyano, C1-4Alkyl radical, C2-4Alkynyl or N, N-di (C)1-4Alkyl) -N-, said C1-4Alkyl radical, C2-4Alkynyl and N, N-di (C)1-4Alkyl) -N-may be optionally substituted with one, two or three substituents selected from halogen, hydroxy, cyano or amino; more preferably, R6Independently selected from halogen, cyano, methyl, ethynyl or N, N-dimethylamino; most preferably, R6Independently selected from F.
20. The compound of formula (I) according to claim 1 having the structure of formula (IV-a),
Figure FDA0002902944520000101
wherein R is3、R4、R5Ring a, ring B, n, p are as defined above for compounds of formula (I), and ring a is not a piperidine ring.
21. The following compounds, stereoisomers thereof and pharmaceutically acceptable salts thereof:
Figure FDA0002902944520000102
Figure FDA0002902944520000111
Figure FDA0002902944520000121
Figure FDA0002902944520000131
Figure FDA0002902944520000141
Figure FDA0002902944520000151
Figure FDA0002902944520000161
Figure FDA0002902944520000171
Figure FDA0002902944520000181
22. a pharmaceutical composition comprising a compound of any one of claims 1-21, stereoisomers thereof, and pharmaceutically acceptable salts thereof.
23. Use of a compound of any one of claims 1 to 21, stereoisomers thereof and pharmaceutically acceptable salts thereof, or a pharmaceutical composition of claim 22, for the manufacture of a medicament for the prevention or treatment of a disease mediated by aberrant RET activity.
CN202110061785.3A 2020-01-18 2021-01-18 Methylpyrazole derivatives as RET inhibitors Pending CN113135896A (en)

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US12018016B2 (en) 2021-08-18 2024-06-25 Amgen Inc. Aryl sulfonyl (hydroxy) piperidines as CCR6 inhibitors

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US12012403B2 (en) 2021-08-18 2024-06-18 Chemocentryx, Inc. Aryl sulfonyl compounds as CCR6 inhibitors
US12018016B2 (en) 2021-08-18 2024-06-25 Amgen Inc. Aryl sulfonyl (hydroxy) piperidines as CCR6 inhibitors

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