CN116730978A - Compound containing heteroaromatic ring alkynyl, preparation method and application thereof - Google Patents

Compound containing heteroaromatic ring alkynyl, preparation method and application thereof Download PDF

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CN116730978A
CN116730978A CN202310214944.8A CN202310214944A CN116730978A CN 116730978 A CN116730978 A CN 116730978A CN 202310214944 A CN202310214944 A CN 202310214944A CN 116730978 A CN116730978 A CN 116730978A
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substituted
alkyl
methyl
unsubstituted
membered
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胡有洪
楼丽广
谢志铖
李琳
王蕾
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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Abstract

The invention relates to a compound containing heteroaromatic ring alkynyl, a preparation method and application thereof, wherein the compound containing heteroaromatic ring alkynyl is a compound shown in a formula (I), or deuterated compound, pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof. The compound shown in the formula (I) has a strong killing effect on tumor cells carried by primary KIT mutation and drug-resistant KIT mutation.

Description

Compound containing heteroaromatic ring alkynyl, preparation method and application thereof
Technical Field
The invention relates to a KIT mutation inhibitor, in particular to a heteroaromatic ring-containing alkynyl compound, a preparation method and application thereof. More specifically, the invention relates to a compound capable of inhibiting proliferation of KIT mutant cell strain, a preparation method of the compound and pharmaceutical application of the compound in mutant KIT related diseases.
Background
KIT (also known as CD117 or stem cell factor receptor) is a 145KDa transmembrane receptor tyrosine kinase (Receptor Tyrosine Kinase, RTK). KIT belongs to a third type of RTK and consists of a cytoplasmic domain containing 5 immunoglobulin-like domains (D1-D5), 1 transmembrane domain, and 1 cytoplasmic domain containing a membrane proximal domain (JMD) and a Tyrosine Kinase (TK) domain. Kinases of the same family also include pdgfrα (platelet-derived growth factor receptor α), pdgfrβ (platelet-derived growth factor receptor β), FLT3 (FMS-like tyrosine kinase 3) and CSF-lR (colony stimulating factor 1 receptor). Normally, ligand Stem Cell Factor (SCF) binds to the extracellular domain to dimerize the receptor, resulting in tyrosine autophosphorylation within the TK domain of the cytoplasmic region, further leading to transduction of downstream signaling pathways (such as PI3K, JAK-STAT, ras-Erk, src family kinases, and PLCs, etc.) and to a variety of physiological processes such as cell proliferation, division, and tissue growth, survival.
The KIT function acquired mutation is related to various diseases such as tumor, inflammation, autoimmune diseases and the like. A large number of studies indicate that KIT mutation is closely related to the occurrence and development of gastrointestinal stromal tumor (GIST), systemic mastocytosis, mast cell leukemia, small amount of acute myelogenous leukemia, glioma and lung cancer, wherein the action of mutant KIT in GIST is most widely and deeply studied, and about 85% of GIST is caused by KIT mutation. GIST are the most common m She Yuanxing tumors of the gastrointestinal tract, with a incidence of about 1/10 to 2/10 tens of thousands, accounting for 1 to 3% of all gut tumors, with about 80% of GIST patients having primary KIT mutations located in the membrane proximal domain (exo 11) and the extracellular domain (exo 9). Of these primary mutations, mutations that occur in the JM region (e.g., V560D) are most common and can result in ligand independent constitutive activation of KIT, thereby inducing GIST to occur (Chen, L.L.et al Clin. Cancer Res.2005,11, pg.3668-3677; mol, C.D., et al J.biol. Chem.2004,279, pg.31655-31663). Imatinib is effective as a first-line drug for treating GIST for most primary KIT mutations, but 90% of patients eventually develop resistance due to KIT secondary mutations, resulting in tumor recurrence. These resistance mutations occur predominantly in the ATP binding pocket (exon 13, e.g., K642E, V654A; exon 14, e.g., T670I) and the activating loop (A-loop; exon 17, e.g., D816H, D816V, D820A, N822K, N822H, N822V) of KIT. Sunitinib and Regorafinib are used as the two-and three-wire drug of GIST, and only a few Imatinib resistance mutations (such as V654A and T670I mutations occurring in the ATP binding pocket) can be overcome, and the clinical response rate is low. It has been reported that in Imatinib resistant cases, 50% of patients have secondary mutations in A-loop (Demetri GD, et al Lancet 2006,368:1329-1338;Nishida T,et al.Int.J.Clin.Oncol.2009,14:143-149). Therefore, it is of great clinical importance to develop novel KIT inhibitors that reverse the resistance to a-loop (exon 17) mutations.
At present, development of KIT inhibitors with therapeutic effects on drug resistant GIST is slow, and particularly, development of small molecule KIT inhibitors with potent inhibitory activity on drug resistant mutations occurring in a-loop is more difficult. Ripritinib was approved by the FDA for treatment of GIST in 2020, and can overcome various KIT resistance mutations including exon 17, thereby providing a new treatment means for drug-resistant GIST patients. However, the efficacy of Ripritinib is still to be improved, and the test for GIST two-line treatment fails to achieve optimal efficacy of Sunititinib; in addition, the rilretinib has serious adverse reactions such as hypertension and abdominal pain, is related to poor kinase selectivity, and particularly has strong inhibition activity on VEGFR 2. Therefore, the medicine which has stronger activity, better selectivity to KIT and more effective to drug-resistant mutant KIT is developed, and the effective treatment of GIST has great significance and is urgent.
CN104211639A, CN108456163a and CN111662227a both relate to heteroaralkynyl compounds, in which the linking chain L is-C (O) NH-, -NHC (O) -, ether chain or amino chain. WO2015089210A1 discloses heteroaryl alkynyls, although the linking chain comprises-C (O) NHCH 2 -case, but its pyridine ring meta-position must have sulfonimide as a dominant structure, and the intermediate benzene ring must be unsubstituted; furthermore, their interest was on VEGFR and PDGFR, and not related to the inhibitory activity on KIT mutant cell lines.
Disclosure of Invention
The inventor of the present application found that, based on CN104211639A, CN108456163A and CN111662227A, the inhibition activity of the compound on KIT mutant cell lines can be significantly improved after L is changed to-C (O) NHC (Ra) (Rb) -in the study of the connecting chain L being-C (O) NH-, -NHC (O) -, ether chain or amino chain (as shown in Table 1). The application discovers that the novel parent nucleus structure shows excellent inhibitor activity on KIT mutant cell strains based on the embodiment 1, and has selectivity.
TABLE 1 influence of Structure L on Activity
The application provides a heteroaromatic ring alkynyl small molecule kinase inhibitor with a novel structure, which has very strong proliferation inhibition activity on KIT mutant cell strains (a plurality of mutant forms including KIT D816V). Meanwhile, the compounds have high selectivity, have no obvious cytotoxicity to non-tumor cells (32D cells) and KIT wild type cells (NCI-H526 and Moe 7), and have weak inhibition activity on EGFR and PDGFR dependent cells, thus showing that the compounds have higher selectivity. In addition, the representative compounds have remarkable in vivo tumor inhibiting effect and low toxicity.
The present application provides a compound of formula (I), or a deuterated compound, a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof:
Wherein:
x is selected from- (C (R) a )(R b )) q -；
Wherein R is a 、R b Each independently selected from hydrogen, deuterium, halogen, C1-4 alkyl; or R attached to the same carbon atom a 、R b Together with the carbon atom, form a 3-5 membered carbocyclic ring;
q is selected from 1, 2;
R 1 selected from hydrogen, halogen, C1-6 alkyl;
ring M 1 Selected from the following structures:
wherein:
A 1 、A 2 each independent CR H4 Or an N atom;
A 3 is CR (CR) H2 Or an N atom;
A 4 is CR (CR) H3 、NR H3 Or an N atom;
z is selected from unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted 5-10 membered heterocyclyl; the substitution means that the above groups are each independently substituted with 1 to 5R 2 Group substitution; or Z and the carbon atom to which it is attached and the adjacent A 1 Or A 2 Together form a substituted or unsubstituted ring W 1 The substitution means ring W 1 Is covered by 1-5R 2 Group substitution; in heteroaryl, heterocyclyl, or ring W 1 Optionally substituted by a corresponding number of C (=o) groups, and optionally oxidized to form S-oxide or N-oxide;
w is unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-7 membered heteroaryl, unsubstituted or substituted 5-7 membered heterocyclyl; the substitution means by 1-5R 2 Group substitution; in aryl, heteroaryl or heterocyclyl, one or more ring C atoms are optionally replaced by a corresponding number of C (=o) groups, one or more ring S or N atoms are optionally oxidized to form S-oxide or N-oxide;
The R is 2 Each independently selected from halogen, cyano, C1-6 alkyl, C1-6 heteroalkyl, C1-6 alkoxycarbonyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C4-8 cycloalkenyl, 4-8 membered heterocycloalkenyl, C6-10 aryl, 5-7 membered heteroaryl, 5-7 membered heterocyclyl, -C (=O) (C1-6 alkyl), -C (=O) (C3-6 cycloalkyl), -OR 3 、-N(R 3 ) 2 - (C1-6 alkyl) OR 3 、-C(＝O)N(R 3 ) 2 - (C1-6 alkyl) -C (=O) N (R) 3 ) 2 、-SR 3 、-S(＝O)R 3 、-S(＝O) 2 R 3 、-N(R 3 )C(＝O)R 3 - (C1-6 alkyl) -N (R) 3 )C(＝O)R 3 、-N(R 3 )S(＝O) 2 R 3 、-P(＝O)(R 3 )(R 3 ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein the C1-6 alkyl, C1-6 heteroalkyl, C1-6 alkoxycarbonyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 4-8 membered cycloalkenyl, 4-8 membered heterocycloalkenyl, C6-10 aryl, 5-7 membered heteroaryl, 5-7 membered heterocyclyl are optionally substituted with 1-5R 3 Substitution; or alternatively
Two R 2 And the atoms to which they are attached form a substituted or unsubstituted 3-7 membered carbocyclic or heterocyclic ring, said substitution being by 1-5R 3 Substitution;
the R is 3 Each independently selected from hydroxy, cyano, amino, halogen, C1-6 alkyl, C1-6 alkoxycarbonyl, C3-C6 cycloalkyl, C1-6 heteroalkyl, C1-6 haloalkyl, hydroxy C1-6 alkyl, -NH (C1-6 alkyl), -NH (C3-6 cycloalkyl), -NHC (=O) (C1-6 alkyl), cyano-substituted 5-to 7-membered heterocyclylmethyl comprising one or more selected from O, N, S;
R H1 、R H2 And R is H4 Each independently selected from hydrogen, halogen, amino, cyano, hydroxy, -N (R) 4 )(R 5 )；
The R is 4 、R 5 Each independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C1-6 alkanoyl, C3-6 cycloalkylacyl;
R H3 selected from hydrogen, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C1-6 heteroalkyl, -C (=O) OC1-6 alkyl, -C (=O) OC3-6 cycloalkyl, -C (=O) C1-6 alkyl, -C (=O) C3-6 cycloalkyl, unsubstituted or substituted C2-6 alkenyl, unsubstituted or substituted C4-6 cycloalkenyl, unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-7 membered heteroaryl, unsubstituted or substituted 4-7 membered heterocyclyl; the substitution means that each is independently substituted with 1 to 5R 6 Substituted; in cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, one or more ring C atoms are optionally replaced by a corresponding number of C (=o) groups, one or more ring S or N atoms are optionally oxidized to form S-oxide or N-oxide;
the R is 6 Each independently selected from halogen, cyano, C1-6 alkyl, C1-6 heteroalkylA group, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C4-8 cycloalkenyl, C6-10 aryl, 5-7 membered heteroaryl, 5-7 membered heterocyclyl, -C (=O) R 7 、OR 7 、-N(R 7 ) 2 - (C1-6 alkyl) OR 7 、-C(＝O)N(R 7 ) 2 - (C1-6 alkyl) -C (=O) N (R) 7 ) 2 、-SR 7 、-S(＝O)R 7 、-S(＝O) 2 R 7 、-N(R 7 )C(＝O)R 7 - (C1-6 alkyl) -N (R) 7 )C(＝O)R 7 、-N(R 7 )S(＝O) 2 (R 7 )、-P(＝O)(R 7 )(R 7 ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein the C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C4-8 cycloalkenyl, C6-10 aryl, 5-7 membered heteroaryl, 5-7 membered heterocyclyl are optionally substituted with 1-5R 7 Substitution; or alternatively
Two R 6 Together with the atoms to which they are attached form a substituted or unsubstituted 5-7 membered carbocyclic or 5-7 membered heterocyclic ring, said substitution being by 1-5R 7 Group substitution;
the R is 7 Each independently selected from halogen, hydroxy, cyano, amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 heteroalkyl, C4-6 heterocycloalkyl, C1-6 haloalkyl, hydroxy C1-6 alkyl, NH (C1-6 cycloalkyl), -NHC (=O) (C1-6 alkyl), C (=O) (C3-6 cycloalkyl)
Ring M 2 Selected from unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-7 membered heteroaryl, unsubstituted or substituted 5-7 heterocyclyl; the substitution means that each is independently substituted with 1 to 5R M Substituted;
the R is M Each independently selected from halogen, cyano, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C4-6 cycloalkenyl, C6-10 aryl, 5-7 membered heteroaryl, -C (=O) (C1-6 alkyl), -C (=O) (C3-6 cycloalkyl), -C1-6 alkyl) -R 8 、-OR 8 、-N(R 8 ) 2 -NH (C1-6 alkyl) -R 8 -O (C1-6 alkyl) -R 8 、-C(＝O)N(R 8 ) 2 、-SR 8 、-S(＝O)R 8 、-S(＝O) 2 R 8 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the C1-6 alkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C4-6 cycloalkenyl, 4-6 membered heterocycloalkenyl, C6-10 aryl, 5-7 membered heteroaryl are optionally each independently substituted with 1-5R 8 Substitution; or alternatively
Two R M And the atoms to which they are attached together form a substituted or unsubstituted 3-7 membered carbocyclic or heterocyclic ring, said substitution being by 1-5R 8 Group substitution;
the R is 8 Each independently selected from the group consisting of hydroxy, cyano, amino, halogen, -NH (C1-6 alkyl), C1-6 alkyl, C1-6 heteroalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl.
In a preferred embodiment, the compound has the structure of formula (II) below:
wherein,,
R 1 selected from halogen, C1-3 alkyl; preferably selected from methyl, F, cl;
R a 、R b each independently selected from hydrogen, deuterium, halogen, methyl; or R is a And R is b And together with the carbon atoms to which they are attached form a three-membered carbocyclic ring;
ring M 1 Selected from the following structures:
wherein A is 1 、A 2 、A 3 、A 4 Rings W, Z and R H1 Each as defined above; and
ring M 2 Is defined as above.
In a preferred embodiment, ring M 1 A structure selected from the group consisting of:
wherein "C, N" on the ring atom represents CH or N at this point,
R 2 、R H1 、R H2 And R is H3 Each as defined above.
In a preferred embodiment of the present invention,
ring M 2 Selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted pyridyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted benzothienyl; the substitution means that each is independently substituted with 1 to 5R M Substituted;
the R is M Each independently selected from halogen, hydroxy, amino, cyano, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C4-6 cycloalkenyl, 4-6 membered heterocycloalkenyl, C6-10 aryl, 5-7 membered heteroaryl, -C (=O) (C1-6 alkyl), -C (=O) (C3-6 cycloalkyl), - (C1-6 alkyl) -R 8 、-OR 8 、-N(R 8 ) 2 -NH (C1-6 alkyl) -R 8 -O (C1-6 alkyl) -R 8 、-C(＝O)N(R 8 ) 2 、-SR 8 、-S(＝O)R 8 、-S(＝O) 2 R 8 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the C1-6 alkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C4-6 cycloalkenyl, 4-6 membered heterocycloalkenyl, C6-10 aryl, 5-7 membered heteroaryl are optionally each independently substituted with 1-5R 8 Substitution; or alternatively
Two R M And the atoms to which they are attached form a substituted or unsubstituted 3-7 membered carbocyclic or heterocyclic ring, said substitution being by 1-5R 8 Group substitution;
the R is 8 Each independently selected from the group consisting of hydroxy, cyano, amino, halogen, -NH (C1-6 alkyl), C1-6 alkyl, C1-6 heteroalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl.
In the present invention,
the alkyl is a saturated aliphatic straight-chain or branched-chain alkyl having 1 to 8 carbon atoms; typical alkyl groups include, but are not limited to: methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, and the like.
Each of the halogens is independently selected from F, cl, br, I;
the haloalkyl is an alkyl group in which at least one hydrogen atom is replaced with a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are the same or different from each other;
the heteroalkyl group is an alkyl group in which at least one backbone C atom is replaced with a heteroatom (N, O, S), for example, examples of the heteroalkyl group may include an alkoxy group, an alkylamino group, an alkylthio group, and the like. In certain embodiments, if two or more C atoms are replaced with heteroatoms, the heteroatoms are the same as or different from each other;
the cycloalkyl is a 3-10 membered monocyclic or polycyclic alicyclic ring, saturated or partially unsaturated, and may be a monovalent or divalent group (i.e., cycloalkylene);
The heterocycloalkyl is a saturated 3-10 membered monocyclic or polycyclic alicyclic heterocycle containing one or more heteroatoms selected from N, O, S on the ring, and can be a monovalent group or a divalent group (i.e., an alkylene group);
by aryl is meant that each of the atoms making up the ring in the aromatic ring is a carbon atom, including monocyclic or fused ring polycyclic, and may be a monovalent or divalent group (i.e., arylene). In the present invention, the aryl ring is preferably an aryl group having 5 to 10 carbon atoms, more preferably 5 to 7 carbon atoms.
The heteroaryl is an aromatic group containing one or more heteroatoms selected from N, O, S on the ring. Depending on the structure, the heteroaryl group may be a monovalent group or a divalent group (i.e., heteroarylene).
The heterocyclic group is a single ring or multiple rings, and at least one is a non-aromatic ring group containing one or more heteroatoms selected from N, O, S on the ring. Depending on the structure, the heterocyclic group may be a monovalent group or a divalent group (i.e., a heterocyclylene group).
Preferably, the compound of formula (I) above is selected from the group consisting of compounds of the following formulae:
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the invention also provides a method for preparing the compound of the formula (I), which comprises the following steps: the compound of formula (A) and the compound of formula (B) are subjected to coupling reaction to obtain the compound of formula (I).
Wherein, ring M 1 Ring M 2 X and R 1 Each of which is independently as defined above; TMS is-Si (CH) 3 ) 3 ；
Preferably, the coupling reaction is carried out in the presence of a palladium metal catalyst comprising Pd (PPh 3 ) 2 Cl 2 、Pd(OAc) 2 And Pd (PPh) 3 ) 4 One or more of the following; preferably, the copper metal catalyst comprises CuI and/or CuCl; preferably, the base comprises CsF, cs 2 CO 3 、KF、K 2 CO 3 、NaHCO 3 、Na 2 CO 3 、Et3N、( i Pr) 2 One or more of EtN and DMAP;
preferably, the coupling reaction is carried out in the presence of a solvent comprising one or more of acetonitrile, 1, 4-dioxane, DMF.
Further preferably, the method comprises the steps of: compounds of formula (A) and formula (B) are in cesium fluoride, pd (PPh) 3 ) 2 Cl 2 The coupling reaction is carried out in acetonitrile solvent in the presence of CuI and triethylamine to obtain the compound shown in the formula (I).
Further preferably, the present invention provides a directed synthetic scheme (as shown in scheme I). It will be appreciated that the reagents/reaction conditions shown in the synthetic schemes may be modified or optimized to produce the different compounds of the invention using general knowledge of organic chemistry.
Synthetic route I
The A is 1 、A 2 Ring M 2 、X、Z、R H1 R is R 1 The synthesis route I comprises the following steps independently as described above:
step 1: compounds I-1, I-2 and Et 3 Mixing N, adding a palladium metal catalyst and a copper metal catalyst, and reacting under the protection of argon (for example, under the condition of room temperature) to obtain a compound I-3;
step 2: adding the compounds I-3 and I-4 into a proper solvent, adding a palladium metal catalyst and K 2 CO 3 Heating and reacting under the protection of argon to obtain an important intermediate A; in addition, suitable ligands may also be added;
step 3: compounds I-5 and I-6 undergo a condensation reaction, wherein X is as previously described. After mixing the compound I-5, HATU, DIPEA and DMF (for example, stirring for 30-60 minutes at room temperature), adding the compound I-6, and reacting (for example, reacting for 6-12 hours at room temperature) to obtain an intermediate B;
step 4: mixing intermediate A, B, base and MeCN, adding palladium metal catalyst, copper metal catalyst, reacting under argon protection (e.g. in case of substitution I, at room temperature, and in case of substitution Br, at 80 ℃ for a period of time such as 2-6 hours) to give compound I-7;
preferably, the method comprises the steps of,
the palladium metal catalyst in the steps 1 and 4 is Pd (PPh 3 ) 2 Cl 2 The copper metal catalyst is CuI;
The solvent in the step 2 is one or more of toluene, ethanol, ethylene glycol dimethyl ether, tetrahydrofuran, 1, 4-dioxane and water; the palladium metal catalyst is Pd (PPh) 3 ) 4 ,Pd(OAC) 2 And (dppf) PdCl 2 Any one of them; the alkali is K 2 CO 3 ,Cs 2 CO 3 ,NaHCO 3 And Na (Na) 2 CO 3 Any one of them; the ligands are X-Phos and PPh 3 Any one of them;
the base in the step 4 is cesium fluoride and/or triethylamine;
further preferably, the synthetic route I comprises the steps of:
step 1: into a round bottom flask was added Compound I-1, and Et 3 N, replacing oxygen with argon, adding Pd (PPh 3 ) 2 Cl 2 CuI, repeating the operation of removing oxygen at room temperatureReacting for about 15 minutes, adding I-2, continuing to react for 3 hours at room temperature, and purifying to obtain a compound I-3; wherein, the compounds I-1, I-2 and Pd (PPh) 3 ) 2 Cl 2 And CuI may have an equivalent weight of about 1.0,1.0 to 1.5,0.05 to 0.1,0.1 to 0.2, respectively.
Step 2: adding the compounds I-3, I-4 and K into a round bottom flask 2 CO 3 THF and water, replacing oxygen with argon, and Pd (OAc) was added 2 And X-Phos, repeating the operation of removing oxygen, heating to 80 ℃ for reaction, finishing the reaction for 4-8 hours, and purifying to obtain a compound A; wherein I-3, I-4, K 2 CO 3 、Pd(OAc) 2 And the equivalent weight of X-Phos may be 1.0,1.0-1.5,2.0-3.0,0.05-0.1,0.1-0.2, respectively; THF/H 2 The volume ratio of O is 4/1.
Step 3: adding the compound I-5, HATU, DIPEA and DMF into a round bottom flask, stirring at room temperature for 30 minutes, adding the compound I-6, and reacting at room temperature; after the reaction is finished for 12 hours, purifying to obtain a compound B; the equivalent weights of the compounds I-5, I-6, HATU and DIPEA may be about 1.0,1.0 to 1.2,1.0 to 1.5,2.0 to 4.0, respectively.
Step 4: compound A, B, et was added to a round bottom flask 3 N, csF and MeCN, replacing oxygen with argon, adding Pd (PPh 3 ) 2 Cl 2 And (3) CuI, repeating the operation of removing oxygen, reacting at room temperature or heating to 80 ℃, finishing the reaction for 3-6 hours, and purifying to obtain a compound I-7; compound A, B, cesium fluoride, pd (PPh) 3 ) 2 Cl 2 CuI and Et 3 The equivalent weights of N may be about 1.0,1.0 to 1.5,2.5 to 3.0,0.05 to 0.1,0.1 to 0.2,2.5 to 3.0, respectively.
The present invention also provides a pharmaceutical composition comprising: one or more selected from the group consisting of the compounds of formula (I) above, deuterated compounds, pharmaceutically acceptable salts, solvates, esters, acids, metabolites and prodrugs thereof, and pharmaceutically acceptable excipients.
The invention also provides the use of a compound of formula (I) as described above or a deuterated compound, a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, or a pharmaceutical composition as described above, in the preparation of a KIT (mutant) inhibitor.
The invention also provides the use of a compound of formula (I) as described above, or a deuterated compound, a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment, prevention or amelioration of one or more diseases or disorders selected from the group consisting of neoplasms, inflammation, autoimmunity, and neurological diseases.
Preferably, the tumor is a gastrointestinal stromal tumor, in particular a gastrointestinal stromal tumor involving KIT mutations, more particularly a gastrointestinal stromal tumor caused by KIT mutations that is resistant to Imatinib and/or Sunitinib.
The compound shown in the formula (I) has a strong killing effect on tumor cells carried by primary KIT mutation and drug-resistant KIT mutation.
According to another embodiment of the invention, the compounds containing a heteroaryinyl structure according to the invention show a strong cell proliferation inhibiting activity against tumor cell lines carrying KIT in the different mutated forms of D816V, V559D, V559D-V654A, V559D/Y823D and V559D/N822K.
According to another embodiment of the invention, the compound containing the heteroaromatic alkynyl structure has low cytotoxicity to normal 32D cells and KIT wild type cell strain NCI-H526 cell strain, and has the advantage of high toxicity selectivity.
According to another embodiment of the invention, the compound containing the heteroaromatic alkynyl structure has lower inhibition activity on cell lines on which BCR-ABL, EGFR, PDGFR depends, and has the advantage of relatively selectivity.
According to another specific embodiment of the invention, the compound containing the heteroaromatic alkynyl structure of the invention shows obvious activity of inhibiting the growth of related tumors on a long-term animal drug effect model, which is obviously superior to a positive drug Ripritinib.
According to another embodiment of the invention, the animal is in a good condition (including no significant weight loss) at the effective dose, and no animal death occurs.
Drawings
FIG. 1 is a graph showing the effect of compounds 77, 85 and Ripretinib on 32D KIT D816V cell KIT and its downstream signaling pathways.
FIG. 2 is a graph showing the effect of compounds 27, 48 and Ripretinib on 32D KIT V559D cell KIT and its downstream signaling pathways.
FIG. 3 is a graph showing the effect of compounds 27, 48 and Ripretinib on KIT of 32D KIT V559D-V654A cells KIT and their downstream signaling pathways.
FIG. 4 is a graph showing the efficacy of compounds 77, 85, ripritinib on subcutaneous transplantation tumor in 32D KIT D816V nude mice.
FIG. 5 is a graph showing the effect of compounds 77, 85, ripritinib on the body weight of tumor-bearing (32D KIT D816V) nude mice.
Detailed Description
The following describes specific embodiments of the present invention in detail. It should be understood that the detailed description and specific examples, while indicating the invention, are intended for purposes of illustration only and are not intended to limit the invention.
Preparation of Compounds example (1)
Example 1 3 preparation of- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N-benzylbenzamide
Step 1: into a round bottom flask was charged 2-amino-5-bromo-3-iodopyridine (1.0 g,3.35 mmol), trimethylsilylacetylene (427.2 mg,4.35 mmol) and Et 3 N (50 mL), replace oxygen with argon, add Pd (PPh 3 ) 2 Cl 2 (117.4 mg,0.17 mmol) and CuI (63.7 mg,0.33 mmol), the oxygen removal operation was repeated, and the reaction was carried out at room temperature for 6 hours; after the reaction, 50mL of ethyl acetate was added to dilute the reaction solution, and the reaction solution was filtered to obtain 900mg (yield: 99.9%) of 2-amino-5-bromo-3-trimethylethynyl pyridine as a product.
Step 2: 2-amino-5-bromo-3-tri-introduced into a round bottom flaskMethyl ethynyl pyridine (300 mg,1.11 mmol), 1-methyl pyrazole-4-boronic acid pinacol ester (348 mg,1.67 mmol), K 2 CO 3 (385 mg,2.79 mmol) and THF/H 2 O (8/2 mL), replace oxygen with argon, add Pd (OAc) 2 (25 mg,0.11 mmol) and X-Phos (106 mg,0.22 mmol), heated to 70℃and reacted for 4 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (15 mL. Times.3) and water (10 mL), and the organic phase was washed with saturated aqueous NaCl solution (10 mL. Times.3), anhydrous Na 2 SO 4 Drying, evaporating the solvent under reduced pressure, and separating by column chromatography to obtain 245.0mg (yield: 81.31%) of 5- (1-methyl-1H-pyrazol-4-yl) -3- ((trimethylsilyl) ethynyl) -2-aminopyridine.
Step 3: to a round bottom flask was added compound 4-methyl-3 iodobenzoic acid (2.0 g,7.63 mmol), HATU (3.8 g,9.92 mmol), DIPEA (2.5 g,19.08 mmol) and DMF (40 mL), and after stirring at room temperature for 30 min, compound benzylamine (812 mg,7.63 mmol) was added and reacted at room temperature for 12 hours; after the completion of the reaction, the reaction mixture was extracted with ethyl acetate (50 mL. Times.3) and water (40 mL), and the organic phase was washed with tap water (30 mL. Times.3), saturated NaCl solution (30 mL. Times.3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, followed by separation by column chromatography to give 2.5g of N-benzyl-3-iodo-4-methylbenzamide (yield: 93%).
Step 4: to a round bottom flask was added the compound N-benzyl-3-iodo-4-methylbenzamide (100 mg,0.28 mmol), 5- (1-methyl-1H-pyrazol-4-yl) -3- ((trimethylsilyl) ethynyl) -2-aminopyridine (100 mg,0.37 mmol), et 3 N (86 mg,0.85 mmol), csF (108 mg,0.71 mmol) and MeCN (20 mL), replace oxygen with argon, add Pd (PPh) 3 ) 2 Cl 2 (10 mg,0.014 mmol) and CuI (5.4 mg,0.028 mmol), the oxygen removal operation was repeated, and the reaction was carried out at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate (30 mL. Times.3) and water (20 mL), and the organic phase was washed with saturated NaCl solution (10 mL. Times.3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, followed by column chromatography to give 78mg (yield: 65%) of the product 3- (2-aminopyridyl-5-bromo-3-ethynyl) -4-methyl-N-benzylbenzamide. 1 H NMR(400MHz,DMSO-d 6 )δ9.08(t,J＝6.0Hz,1H),8.26(d,J＝2.3Hz,1H),8.17(d,J＝1.9Hz,1H),8.08(s,1H),7.84(d,J＝2.4Hz,1H),7.83–7.79(m,2H),7.43(d,J＝8.0Hz,1H),7.35–7.30(m,4H),7.27–7.21(m,1H),6.28(s,2H),4.48(d,J＝5.9Hz,2H),3.84(s,3H),2.53(s,3H).LR-MS 422.1(M+1).
Example 2 3 preparation of- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N-phenylethyl benzamide
The synthesis was as in example 1, except that phenethylamine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ8.60(t,J＝5.8Hz,1H),8.26(d,J＝2.4Hz,1H),8.09(d,J＝4.0Hz,2H),7.85(d,J＝2.3Hz,1H),7.82(s,1H),7.74(dd,J＝1.8,8.0Hz,1H),7.41(d,J＝8.1Hz,1H),7.33–7.23(m,4H),7.20(t,J＝7.2Hz,1H),6.28(s,2H),3.84(s,3H),3.49(q,J＝6.8Hz,2H),2.85(t,J＝7.5Hz,2H),2.53(s,3H).LR-MS 436.1(M+1).
Example 3 3 preparation of- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (1-phenylcyclopropyl) benzamide
The synthesis was as in example 1, except that 1-phenylcyclopropylamine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.21(s,1H),8.26(d,J＝2.4Hz,1H),8.16(d,J＝1.8Hz,1H),8.08(s,1H),7.84(d,J＝2.3Hz,1H),7.82(s,1H),7.79(d,J＝7.5Hz,1H),7.42(d,J＝8.0Hz,1H),7.27(t,J＝7.6Hz,2H),7.22–7.12(m,3H),6.28(s,2H),3.84(s,3H),2.54(s,3H),1.06(br s,4H).LR-MS 448.2(M+1).
Example 4 3 preparation of- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N-benzyl-5-fluorobenzamide
The synthesis was as in example 1, except that 5-fluoro-3-iodobenzoic acid was used instead of 4-methyl-3-iodobenzoic acid.
1 H NMR(400MHz,DMSO-d 6 )δ9.23(t,J＝6.0Hz,1H),8.27(d,J＝2.3Hz,1H),8.06(s,1H),8.01(s,1H),7.82(d,J＝2.3Hz,1H),7.82–7.75(m,3H),7.71(d,J＝9.1Hz,1H),7.34(d,J＝4.5Hz,4H),7.30–7.22(m,1H),6.46(s,2H),4.50(d,J＝5.9Hz,2H),3.84(s,3H).LR-MS 426.2(M+1).
Example 5 3 preparation of- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -5-fluoro-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 5-fluoro-3-iodobenzoic acid was used instead of 4-methyl-3-iodobenzoic acid and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.25(t,J＝5.9Hz,1H),8.18(d,J＝1.3Hz,1H),8.13–8.06(m,1H),8.01(d,J＝1.1Hz,1H),7.96(t,J＝2.0Hz,1H),7.75(d,J＝1.5Hz,1H),7.62–7.53(m,1H),7.36(d,J＝7.5Hz,1H),7.05(dd,J＝1.6,7.5Hz,1H),7.00(d,J＝1.5Hz,1H),6.97(d,J＝1.6Hz,1H),6.29(s,2H),4.55(d,J＝5.7Hz,2H),3.87(s,3H).LR-MS432.1(M+1).
Example 6 3 preparation of- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -5-fluoro-N- (pyridin-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 5-fluoro-3-iodobenzoic acid was used instead of 4-methyl-3-iodobenzoic acid and 3-aminomethylpyridine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.23(t,J＝6.0Hz,1H),8.64(d,J＝1.3Hz,1H),8.47(dd,J＝1.3,5.0Hz,1H),8.13(d,J＝1.3Hz,1H),8.12–8.07(m,2H),7.90–7.83(m,3H),7.61–7.54(m,1H),7.50(dd,J＝5.0,8.0Hz,1H),7.05(d,J＝1.5Hz,1H),6.28(s,2H),4.50(d,J＝5.8Hz,2H),3.85(s,3H).LR-MS 427.2(M+1).
Example 7 3 preparation of- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -5-fluoro-N- ((6-fluoropyridin-3-yl) methyl) benzamide
The synthesis was as in example 1, except that 5-fluoro-3-iodobenzoic acid was used instead of 4-methyl-3-iodobenzoic acid and 6-fluoro-3-aminomethylpyridine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.26(t,J＝5.9Hz,1H),8.38(d,J＝1.4Hz,1H),8.14(d,J＝1.3Hz,1H),8.08(dd,J＝1.6,8.7Hz,2H),8.04–7.99(m,1H),7.95(t,J＝2.0Hz,1H),7.85(d,J＝1.6Hz,1H),7.53(dt,J＝2.0,8.8Hz,1H),7.16(t,J＝8.0Hz,1H),7.06(d,J＝1.6Hz,1H),6.27(s,2H),4.50(d,J＝5.6Hz,2H),3.83(s,3H).LR-MS 445.4(M+1).
Example 8 3 preparation of- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- (4-chlorobenzyl) -4-methylbenzamide
The synthesis was as in example 1, except that 4-chlorobenzylamine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.10(t,J＝6.3Hz,1H),8.26(d,J＝2.2Hz,1H),8.17(s,1H),8.09(s,1H),7.88(d,J＝2.3Hz,1H),7.81(d,J＝9.9Hz,2H),7.44(d,J＝8.0Hz,1H),7.41–7.32(m,4H),6.38(s,2H),4.46(d,J＝6.0Hz,2H),3.84(s,3H),2.54(s,3H).LR-MS 456.7(M+1).
Example 9 3 preparation of- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- (2-trifluoromethylbenzyl) -4-methylbenzamide
The synthesis was as in example 1, except that 2-trifluoromethylbenzylamine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.15(t,J＝5.7Hz,1H),8.26(d,J＝2.2Hz,1H),8.20(s,1H),8.08(s,1H),7.88–7.79(m,3H),7.74(d,J＝7.8Hz,1H),7.66(t,J＝7.6Hz,1H),7.54(d,J＝7.8Hz,1H),7.52–7.43(m,2H),6.27(s,2H),4.67(d,J＝5.6Hz,2H),3.84(s,3H),2.55(s,3H).LR-MS 490.5(M+1).
Example 10 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- (2-methoxybenzyl) -4-methylbenzamide
The synthesis was as in example 1, except that 2-methoxybenzylamine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ8.88(t,J＝5.9Hz,1H),8.26(d,J＝2.3Hz,1H),8.18(s,1H),8.08(s,1H),7.86–7.79(m,3H),7.43(d,J＝8.0Hz,1H),7.24(t,J＝7.8Hz,1H),7.19(d,J＝7.4Hz,1H),7.00(d,J＝8.2Hz,1H),6.91(t,J＝7.4Hz,1H),6.26(s,2H),4.45(d,J＝5.7Hz,2H),3.84(s,3H),3.83(s,3H),2.54(s,3H).LR-MS 452.3(M+1).
Example 11 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- (3-methoxybenzyl) -4-methylbenzamide
The synthesis was as in example 1, except that 3-methoxybenzylamine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.04(d,J＝5.9Hz,1H),8.26(d,J＝2.2Hz,1H),8.16(s,1H),8.08(s,1H),7.86–7.77(m,3H),7.43(d,J＝8.0Hz,1H),7.24(t,J＝8.0Hz,1H),6.93–6.86(m,2H),6.82(d,J＝8.3Hz,1H),6.26(s,2H),4.45(d,J＝5.9Hz,2H),3.84(s,3H),3.73(s,3H),2.53(s,3H).LR-MS 452.3(M+1).
Example 12 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- (3-methoxybenzyl) -4-methylbenzamide
The synthesis was as in example 1, except that 4-methoxybenzylamine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.01(t,J＝6.1Hz,1H),8.27(d,J＝2.3Hz,1H),8.17(s,1H),8.10(s,1H),7.90(s,1H),7.84(s,1H),7.81(d,J＝8.3Hz,1H),7.43(d,J＝8.0Hz,1H),7.26(d,J＝8.3Hz,2H),6.90(d,J＝8.3Hz,2H),6.42(s,2H),4.41(d,J＝5.8Hz,2H),3.85(s,3H),3.73(s,3H),2.54(s,3H).LR-MS 452.3(M+1).
Example 13 preparation of- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- (4-fluorobenzyl) -4-methylbenzamide
The synthesis was as in example 1, except that 4-fluorobenzylamine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.08(t,J＝6.0Hz,1H),8.26(s,1H),8.16(s,1H),8.09(s,1H),7.87(s,1H),7.84–7.78(m,2H),7.43(d,J＝8.0Hz,1H),7.40–7.32(m,2H),7.16(t,J＝8.7Hz,2H),6.36(s,2H),4.46(d,J＝5.9Hz,2H),3.84(s,4H),2.53(s,3H).LR-MS 440.2(M+1).
Example 14 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- (2, 4-difluorobenzyl) -4-methylbenzamide
The synthesis was as in example 1, except that 2, 4-difluorobenzylamine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.05(t,J＝5.8Hz,1H),8.26(d,J＝2.3Hz,1H),8.15(s,1H),8.07(s,1H),7.83(d,J＝2.2Hz,1H),7.80(d,J＝9.5Hz,2H),7.43(q,J＝8.1Hz,2H),7.23(t,J＝10.0Hz,1H),7.07(td,J＝2.4,8.6Hz,1H),6.26(s,2H),4.48(d,J＝5.6Hz,2H),3.84(s,3H),2.53(s,3H).LR-MS 458.1(M+1).
Example 15 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- (2-fluoro-4-chlorobenzyl) -4-methylbenzamide
The synthesis was as in example 1, except that 2-fluoro-4-chlorobenzylamine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.07(t,J＝5.0Hz,1H),8.26(s,1H),8.15(s,1H),8.07(s,1H),7.84–7.77(m,3H),7.46–7.37(m,3H),7.28(d,J＝8.5Hz,1H),6.26(s,2H),4.48(d,J＝5.6Hz,2H),3.84(d,J＝1.4Hz,3H),2.53(s,3H).LR-MS 474.7(M+1).
Example 16 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (pyridin-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 3-aminomethylpyridine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.13(t,J＝5.9Hz,1H),8.57(s,1H),8.47(d,J＝3.9Hz,1H),8.26(d,J＝1.8Hz,1H),8.15(s,1H),8.07(s,1H),7.84(d,J＝2.3Hz,1H),7.82–7.77(m,2H),7.74(d,J＝8.0Hz,1H),7.43(d,J＝8.0Hz,1H),7.37(dd,J＝4.8,7.8Hz,1H),6.27(s,2H),4.50(d,J＝5.8Hz,2H),3.84(s,3H),2.53(s,3H).LR-MS 474.7(M+1).LR-MS 423.5(M+1).
Example 17 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (pyridin-4-ylmethyl) benzamide
The synthesis was as in example 1, except that 4-aminomethylpyridine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.17(t,J＝6.1Hz,1H),8.51(d,J＝4.8Hz,2H),8.26(d,J＝2.3Hz,1H),8.18(s,1H),8.08(s,1H),7.86–7.79(m,3H),7.45(d,J＝8.1Hz,1H),7.32(d,J＝5.3Hz,2H),6.28(s,2H),4.50(d,J＝5.9Hz,2H),3.84(s,3H),2.54(s,3H).LR-MS 423.5(M+1).
Example 18 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (pyrimidin-5-ylmethyl) benzamide
The synthesis was as in example 1, except that 5-aminomethylpyrimidine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.17(t,J＝5.8Hz,1H),9.10(s,1H),8.79(s,2H),8.26(d,J＝2.3Hz,1H),8.15(s,1H),8.07(s,1H),7.95–7.81(m,2H),7.79(d,J＝8.3Hz,1H),7.43(d,J＝8.0Hz,1H),6.28(s,2H),4.50(d,J＝5.7Hz,2H),3.84(s,3H),2.53(s,3H).LR-MS 424.5(M+1).
Example 19 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- ((6-methoxypyridin-3-yl) methyl) -4-methylbenzamide
The synthesis was as in example 1, except that 3-aminomethyl-6-methoxypyridine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.04(t,J＝5.7Hz,1H),8.26(d,J＝2.4Hz,1H),8.14(s,2H),8.08(s,1H),7.87–7.80(m,2H),7.78(dd,J＝1.9,8.0Hz,1H),7.68(dd,J＝2.5,8.5Hz,1H),7.42(d,J＝8.0Hz,1H),6.80(d,J＝8.5Hz,1H),6.27(s,2H),4.40(d,J＝5.8Hz,2H),3.84(s,3H),3.82(s,3H),2.53(s,3H).LR-MS 453.2(M+1).
Example 20 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- ((6-chloropyridin-3-yl) methyl) -4-methylbenzamide
The synthesis was as in example 1, except that 3-aminomethyl-6-chloropyridine was used instead of benzylamine.
1 H NMR(600MHz,DMSO-d 6 )δ9.13(t,J＝5.9Hz,1H),8.40(d,J＝2.5Hz,1H),8.26(d,J＝2.4Hz,1H),8.14(d,J＝1.9Hz,1H),8.07(s,1H),7.83(d,J＝2.4Hz,1H),7.82–7.80(m,2H),7.79(dd,J＝2.0,8.0Hz,1H),7.50(d,J＝8.2Hz,1H),7.43(d,J＝8.0Hz,1H),6.25(s,2H),4.49(d,J＝5.8Hz,2H),3.84(s,3H),2.54(s,3H).LR-MS 457.1(M+1).
Example 21 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- ((6-fluoropyridin-3-yl) methyl) -4-methylbenzamide
The synthesis was as in example 1, except that 3-aminomethyl-6-fluoropyridine was used in place of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.13(t,J＝5.8Hz,1H),8.26(d,J＝2.4Hz,1H),8.21(d,J＝2.5Hz,1H),8.15(d,J＝1.9Hz,1H),8.08(s,1H),7.94(td,J＝2.6,8.2Hz,1H),7.83(d,J＝2.4Hz,1H),7.82(s,1H),7.79(dd,J＝2.0,8.0Hz,1H),7.43(d,J＝8.1Hz,1H),7.16(dd,J＝2.8,8.5Hz,1H),6.27(s,2H),4.49(d,J＝5.8Hz,2H),3.84(s,3H),2.53(s,3H).LR-MS 441.5(M+1).
Example 22 preparation of 3- ((2-amino-5- (1-cyclopropyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- ((6-fluoropyridin-3-yl) methyl) -4-methylbenzamide
The synthesis was as in example 1, except 3-aminomethyl-6-fluoropyridine was used in place of benzylamine and 1-cyclopropyl-1H-pyrazole-4-boronic acid pinacol ester was used in place of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester.
1 H NMR(400MHz,DMSO-d 6 )δ9.15(t,J＝5.7Hz,1H),8.49(d,J＝1.4Hz,1H),8.31–8.22(m,1H),8.12(d,J＝2.2Hz,1H),7.98(d,J＝1.3Hz,2H),7.82(d,J＝1.3Hz,1H),7.80(dd,J＝2.0,7.5Hz,1H),7.30(dd,J＝1.2,7.4Hz,1H),7.08(d,J＝1.5Hz,1H),6.92(t,J＝8.1Hz,1H),6.39(s,2H),4.50(t,J＝5.7Hz,2H),2.52(s,3H),2.44–2.37(m,1H),0.85–0.74(m,2H),0.61–0.49(m,2H).LR-MS 467.2(M+1).
Example 23 preparation of 3- ((2-amino-5- (1-isopropyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- ((6-fluoropyridin-3-yl) methyl) -4-methylbenzamide
The synthesis was as in example 1, except 3-aminomethyl-6-fluoropyridine was used in place of benzylamine and 1-methyl-1H-pyrazole-4-boronic acid pinacol ester was used in place of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester.
1 H NMR(400MHz,DMSO-d 6 )δ9.13(t,J＝5.7Hz,1H),8.45(d,J＝1.3Hz,1H),8.23(d,J＝1.3Hz,1H),8.12–8.04(m,3H),7.86(d,J＝1.6Hz,1H),7.75(dd,J＝2.0,7.5Hz,1H),7.37(dd,J＝1.2,7.5Hz,1H),7.14(t,J＝8.0Hz,1H),7.06(d,J＝1.5Hz,1H),5.05(s,2H),4.62–4.52(m,1H),4.52(t,J＝5.6Hz,2H),2.54(s,3H),1.30(d,J＝6.8Hz,6H).LR-MS 469.5(M+1).
Example 24 preparation of 3- ((2-amino-5- (1-isopropyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- ((6-fluoropyridin-3-yl) methyl) -4-methylbenzamide
The synthesis was as in example 1, except that 3-aminomethyl-6-methylaminopyridine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ8.90(t,J＝5.8Hz,1H),8.26(d,J＝2.4Hz,1H),8.12(d,J＝1.9Hz,1H),8.08(s,1H),7.95(d,J＝2.4Hz,1H),7.83(d,J＝2.4Hz,1H),7.82(s,1H),7.77(dd,J＝1.9,7.9Hz,1H),7.41(d,J＝8.1Hz,1H),7.37(dd,J＝2.4,8.5Hz,1H),6.43–6.37(m,2H),6.26(s,2H),4.28(d,J＝5.7Hz,2H),3.84(s,3H),2.73(d,J＝4.8Hz,3H),2.52(s,3H).LR-MS 452.2(M+1).
Example 25 preparation of N- ((6- (1H-pyrazol-1-yl) pyrazol-3-yl) methyl) -3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methylbenzamide
The synthesis was as in example 1, except that (6- (1H-pyrazol-1-yl) pyridin-3-yl) methylamine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.16(t,J＝5.9Hz,1H),8.60(d,J＝2.5Hz,1H),8.45(d,J＝1.4Hz,1H),8.26(d,J＝2.4Hz,1H),8.16(d,J＝1.9Hz,1H),8.07(s,1H),7.95(dd,J＝2.2,8.5Hz,1H),7.91(dd,J＝0.8,8.5Hz,1H),7.83(d,J＝2.4Hz,1H),7.82–7.79(m,3H),7.44(d,J＝8.1Hz,1H),6.57(dd,J＝1.7,2.6Hz,1H),6.27(s,2H),4.53(d,J＝5.8Hz,2H),3.84(s,3H),2.54(s,3H).LR-MS 489.6(M+1).
EXAMPLE 26 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- (3-fluorobenzyl) -4-methylbenzamide
The synthesis was as in example 1, except that 3-fluorobenzylamine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.10(t,J＝6.0Hz,1H),8.26(d,J＝2.4Hz,1H),8.17(d,J＝1.9Hz,1H),8.07(s,1H),7.83(d,J＝2.4Hz,1H),7.83–7.79(m,2H),7.44(d,J＝8.1Hz,1H),7.38(td,J＝6.1,7.9Hz,1H),7.17(d,J＝7.8Hz,1H),7.16–7.11(m,1H),7.08(td,J＝2.7,8.9Hz,1H),6.25(s,2H),4.49(d,J＝5.9Hz,2H),3.84(s,3H),2.54(s,3H).LR-MS 440.5(M+1).
Example 27 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.01(t,J＝5.9Hz,1H),8.26(d,J＝2.4Hz,1H),8.15(d,J＝1.9Hz,1H),8.08(s,1H),7.84(d,J＝2.4Hz,1H),7.82(s,1H),7.80(dd,J＝2.0,8.0Hz,1H),7.49(dd,J＝3.0,4.9Hz,1H),7.42(d,J＝8.1Hz,1H),7.34(dd,J＝1.2,3.0Hz,1H),7.09(dd,J＝1.2,4.9Hz,1H),6.27(s,2H),4.47(d,J＝5.8Hz,2H),3.84(s,3H),2.53(s,3H).LR-MS 427.1(M+1).
Example 28 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-2-ylmethyl) benzamide
The synthesis was as in example 1, except that 2-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ8.97(t,J＝5.8Hz,1H),8.30(d,J＝1.3Hz,1H),8.17(d,J＝2.0Hz,1H),8.05(d,J＝1.3Hz,1H),7.75(d,J＝1.6Hz,1H),7.73(dd,J＝2.1,7.6Hz,1H),7.44(dd,J＝1.6,7.5Hz,1H),7.29(dd,J＝1.1,7.7Hz,1H),7.12(dd,J＝1.7,7.6Hz,1H),7.06–6.97(m,2H),6.29(s,2H),4.42(d,J＝5.8Hz,2H),3.92(s,3H),2.53(s,3H).LR-MS 428.3(M+1).
Example 29 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiazol-4-ylmethyl) benzamide
The synthesis was as in example 1, except that 4-aminomethylthiazole was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.10(t,J＝5.9Hz,1H),9.07(d,J＝2.0Hz,1H),8.26(d,J＝2.4Hz,1H),8.18(d,J＝1.9Hz,1H),8.08(s,1H),7.84(d,J＝2.5Hz,1H),7.83–7.80(m,2H),7.50–7.46(m,1H),7.43(d,J＝8.1Hz,1H),6.27(s,2H),4.62(d,J＝5.7Hz,2H),3.84(s,3H),2.54(s,3H).LR-MS 429.5(M+1).
Example 30 preparation of 4-methyl-3- ((5- (1-methyl-1H-pyrazol-4-yl) -2- (methylamino) pyridin-3-yl) ethynyl) -N- (pyridin-3-ylmethyl) benzamide
Step 1: adding 2-chloro-5-Bromo-3-iodopyridine (1.0 g,3.14 mmol) and MeNH2 (2.0M, 5 mL) were reacted overnight with heating to 80 ℃. After the reaction, the solvent was evaporated under reduced pressure, and then separated by column chromatography to give 650mg (yield: 66%) of 2-methylamino-5-bromo-3-iodopyridine. 1 H NMR(400MHz,DMSO-d 6 )δ8.10(d,J＝2.2Hz,1H),8.07(d,J＝2.2Hz,1H),6.32–6.24(m,1H),2.78(d,J＝4.6Hz,3H).LR-MS 313.1(M+1).
Step 2: into a round bottom flask was charged 2-methylamino-5-bromo-3-iodopyridine (300 mg,0.96 mmol), trimethylsilylacetylene (122.4 mg,1.25 mmol) and Et 3 N (20 mL), replacing oxygen with argon, and adding Pd (PPh) 3 ) 2 Cl 2 (34 mg,0.048 mmol) and CuI (18 mg,0.096 mmol), the oxygen removal operation was repeated, and the reaction was carried out at room temperature for 4 hours; after the reaction, 20mL of ethyl acetate was added to dilute the reaction solution, and the reaction solution was filtered to obtain 260mg (yield: 96%) of 2-methylamino-5-bromo-3-trimethylethynyl pyridine as a product. 1 H NMR(400MHz,DMSO-d 6 )δ8.11(d,J＝2.5Hz,1H),7.67(d,J＝2.4Hz,1H),6.34(q,J＝4.3Hz,1H),2.85(d,J＝4.7Hz,3H),0.25(s,9H).LR-MS 284.2(M+1).
Step 3: to a round bottom flask was added 2-amino-5-bromo-3-trimethylethynyl pyridine (200 mg,0.71 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (254 mg,1.41 mmol), K 2 CO 3 (244 mg,1.77 mmol) and THF/H 2 O (8/2 mL), replace oxygen with argon, add Pd (OAc) 2 (16 mg,0.071 mmol) and X-Phos (50 mg,0.11 mmol) were heated to 70℃and reacted for 3 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (15 mL. Times.3) and water (10 mL), and the organic phase was washed with saturated aqueous NaCl solution (10 mL. Times.3), anhydrous Na 2 SO 4 Dried, the solvent was evaporated under reduced pressure, and separated by column chromatography to give 150mg (yield: 74.7%) of 5- (1-methyl-1H-pyrazol-4-yl) -3- ((trimethylsilyl) ethynyl) -2-methylaminopyridine. LR-MS 285.4 (M+1).
Step 4: to a round bottom flask was added 4-methyl-3 iodobenzoic acid (2.0 g,7.63 mmol), HATU (3.8 g,9.92 mmol), DIPEA (2.5 g,19.08 mmol) and DMF (40 mL), and after stirring at room temperature for 30 min, 3-aminomethylpyridine (8235 mg,7.63 mmol) was added and reacted at room temperature for 12 hours; after the completion of the reaction, the reaction mixture was extracted with ethyl acetate (50 mL. Times.3) and water (40 mL), and the organic phase was washed with water (30 mL. Times.3), saturated NaCl solution (30 mL. Times.3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, followed by separation by column chromatography to give 2.5g of 3-iodo-4-methyl-N- (pyridin-3-ylmethyl) benzamide (yield: 93%). LR-MS 353.1 (M+1).
Step 5: to a round bottom flask was added 3-iodo-4-methyl-N- (pyridin-3-ylmethyl) benzamide (100 mg,0.28 mmol), 5- (1-methyl-1H-pyrazol-4-yl) -3- ((trimethylsilyl) ethynyl) -2-methylaminopyridine (101 mg,0.35 mmol), et 3 N (86 mg,0.85 mmol), csF (108 mg,0.71 mmol) and MeCN (15 mL), replace oxygen with argon, add Pd (PPh) 3 ) 2 Cl 2 (10 mg,0.014 mmol) and CuI (5.4 mg,0.028 mmol), the oxygen removal operation was repeated, and the reaction was carried out at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate (20 mL. Times.3) and water (20 mL), the organic phase was washed with saturated NaCl solution (10 mL. Times.3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, followed by column chromatography to obtain 90mg (yield: 72.6%) of the product 4-methyl-3- ((5- (1-methyl-1H-pyrazol-4-yl) -2- (methylamino) pyridin-3-yl) ethynyl) -N- (pyridin-3-ylmethyl) benzamide. 1 H NMR(400MHz,DMSO-d 6 )δ9.15(t,J＝5.9Hz,1H),8.56(d,J＝2.2Hz,1H),8.47(dd,J＝1.6,4.8Hz,1H),8.33(d,J＝2.4Hz,1H),8.17(d,J＝1.9Hz,1H),8.06(s,1H),7.83(d,J＝2.3Hz,1H),7.82–7.78(m,2H),7.74(dt,J＝2.0,8.0Hz,1H),7.44(d,J＝8.1Hz,1H),7.37(dd,J＝4.7,7.8Hz,1H),6.45(q,J＝4.3Hz,1H),4.50(d,J＝5.8Hz,2H),3.84(s,3H),2.91(d,J＝4.6Hz,3H),2.53(s,3H).LR-MS 437.5(M+1).
Example 31 preparation of 4-methyl-3- ((5- (1-methyl-1H-pyrazol-4-yl) -2- (ethylamino) pyridin-3-yl) ethynyl) -N- (pyridin-3-ylmethyl) benzamide
The synthesis was as in example 30, except that ethylamine was used instead of methylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.16(t,J＝6.0Hz,1H),8.57(s,1H),8.47(s,1H),8.32(d,J＝2.4Hz,1H),8.15(d,J＝1.9Hz,1H),8.06(s,1H),7.83(d,J＝2.4Hz,1H),7.83–7.78(m,2H),7.74(d,J＝8.0Hz,1H),7.44(d,J＝8.0Hz,1H),7.37(dd,J＝4.7,7.9Hz,1H),6.34(t,J＝5.8Hz,1H),4.50(d,J＝5.8Hz,2H),3.84(s,3H),3.50–3.39(m,3H),2.54(s,3H),1.17(t,J＝7.0Hz,3H).LR-MS 451.2(M+1).
Example 32 preparation of 3- ((2-ethylamino) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- ((6-fluoropyridin-3-yl) methyl) -4-methylbenzamide
The synthesis was as in example 37, except that ethylamine was used in place of methylamine and 3-aminomethyl-6-fluoropyridine was used in place of 3-aminomethylpyridine.
1 H NMR(400MHz,DMSO-d 6 )δ9.20(t,J＝6.0Hz,1H),8.39(d,J＝1.3Hz,1H),8.17(dd,J＝1.6,3.2Hz,2H),8.08(d,J＝1.3Hz,1H),8.04–7.98(m,1H),7.93(s,1H),7.84(d,J＝1.6Hz,1H),7.66(dd,J＝2.0,7.5Hz,1H),7.36(dd,J＝1.2,7.6Hz,1H),7.15(t,J＝7.9Hz,1H),7.06(d,J＝1.6Hz,1H),4.50(d,J＝5.8Hz,2H),3.85(s,3H),3.47(q,J＝8.0Hz,2H),2.54(s,3H),1.09(t,J＝8.0Hz,3H).LR-MS 469.3(M+1).
Example 33 preparation of 3- ((2-ethylamino) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 30, except that ethylamine was used in place of methylamine and 3-aminomethylthiophene was used in place of 3-aminomethylpyridine.
1 H NMR(400MHz,DMSO-d 6 )δ9.14(t,J＝6.0Hz,1H),8.22(d,J＝1.0Hz,1H),8.16(d,J＝2.1Hz,1H),8.00(d,J＝1.3Hz,1H),7.93(s,1H),7.75(d,J＝1.5Hz,1H),7.70(dd,J＝2.0,7.5Hz,1H),7.36(d,J＝8.1Hz,1H),7.28(dd,J＝1.2,7.6Hz,1H),7.06–6.99(m,2H),6.96(d,J＝1.6Hz,1H),4.55(t,J＝6.0Hz,2H),3.90(s,3H),3.47(q,J＝8.0Hz,2H),2.51(s,3H),1.07(t,J＝8.0Hz,3H).LR-MS 456.7(M+1).
Example 34 preparation of 3- ((2-cyclopropylamino) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 30, except that cyclopropylamine was used instead of methylamine and 3-aminomethylthiophene was used instead of 3-aminomethylpyridine.
1 H NMR(400MHz,DMSO-d 6 )δ9.07(t,J＝5.8Hz,1H),8.25(d,J＝1.3Hz,1H),8.17(d,J＝2.0Hz,1H),8.16(d,J＝1.3Hz,1H),7.88(s,1H),7.85(d,J＝1.5Hz,1H),7.68(dd,J＝2.0,7.5Hz,1H),7.43–7.32(m,2H),7.09(d,J＝1.6Hz,1H),7.03(dd,J＝1.6,7.5Hz,1H),7.00(d,J＝1.5Hz,1H),6.28(s,2H),3.93(s,3H),2.57(s,3H),2.29(m,1H),0.75–0.47(m,4H).LR-MS 468.4(M+1).
Example 35- ((2- (N-acetamido) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
To a round bottom flask was added compound 27 (80 mg,0.187 mmol), et3N (57 mg,0.561 mmol) and THF (3 mL), acetyl chloride (26. Mu.L, 0.374 mmol) was added dropwise over an ice bath and stirred at room temperature for 3h. The reaction was quenched with methanol, followed by evaporation of the solvent under reduced pressure, and separation and purification by column chromatography gave 70mg (pale yellow solid; yield: 73%) of the product 3- ((2- (N-acetamido) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide. 1 H NMR(400MHz,DMSO-d 6 )δ9.24(t,J＝5.9Hz,1H),8.87(d,J＝2.3Hz,1H),8.48–8.38(m,2H),8.14(s,1H),8.01(d,J＝1.9Hz,1H),7.85(dd,J＝8.0,2.0Hz,1H),7.46(d,J＝8.1Hz,1H),7.40(dd,J＝5.1,1.3Hz,1H),7.03(d,J＝3.5Hz,1H),6.97(dd,J＝5.1,3.4Hz,1H),4.63(d,J＝5.8Hz,2H),3.91(s,3H),2.44(s,3H),2.25(s,6H).LR-MS 512.2(M+1).
Example 36 preparation of 3- ((2-amino-5- (3, 5-dimethylisoxazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except 3, 5-dimethylisoxazole-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.01(t,J＝5.9Hz,1H),8.15(d,J＝1.9Hz,1H),7.99(d,J＝2.3Hz,1H),7.80(dd,J＝8.0,1.9Hz,1H),7.66(d,J＝2.3Hz,1H),7.49(dd,J＝4.9,3.0Hz,1H),7.42(d,J＝8.1Hz,1H),7.35–7.31(m,1H),7.09(dd,J＝4.9,1.3Hz,1H),6.50(s,2H),4.46(d,J＝5.8Hz,2H),2.51(s,3H),2.37(s,3H),2.20(s,3H).LR-MS 443.1(M+1).
Example 37 preparation of- ((2-amino-5- (1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 1H-pyrazole-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ11.42(s,1H),9.07(t,J＝5.8Hz,1H),8.20(d,J＝1.3Hz,1H),8.17(d,J＝2.0Hz,1H),8.02(d,J＝1.3Hz,1H),7.70(dd,J＝2.0,7.5Hz,1H),7.37(d,J＝7.3Hz,1H),7.28(dd,J＝1.1,7.4Hz,1H),7.23(s,2H),7.02(dd,J＝1.6,7.3Hz,1H),7.01(s,1H),6.26(s,2H),4.55(d,J＝5.8Hz,2H),2.52(s,3H).LR-MS 414.5(M+1).
Example 38 preparation of- ((2-amino-5- (3, 5-dimethyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 3, 5-dimethyl-1H-pyrazole-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ11.95(s,1H),8.96(t,J＝5.8Hz,1H),8.18(d,J＝1.3Hz,1H),8.16(d,J＝2.0Hz,1H),7.95(d,J＝1.1Hz,1H),7.70(dd,J＝2.1,7.6Hz,1H),7.37(d,J＝7.4Hz,1H),7.28(dd,J＝1.2,7.2Hz,1H),7.07–6.97(m,2H),6.29(s,2H),4.42(d,J＝5.7Hz,2H),2.53(s,3H),2.39(s,3H),2.36(s,3H).LR-MS 442.3(M+1).
Example 39 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-5-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 1-methyl-1H-pyrazole-5-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.14(t,J＝5.7Hz,1H),8.79(d,J＝1.3Hz,1H),8.08(d,J＝2.0Hz,1H),7.98(d,J＝1.1Hz,1H),7.78(dd,J＝2.0,7.5Hz,1H),7.64(d,J＝7.5Hz,1H),7.37(d,J＝7.4Hz,1H),7.28(dd,J＝1.1,7.4Hz,1H),7.07–6.97(m,2H),6.35(d,J＝7.5Hz,1H),6.29(s,2H),4.43(d,J＝5.7Hz,2H),3.88(s,3H),2.54(s,3H).LR-MS428.1(M+1).
Example 40 preparation of 3- ((2-amino-5- (1-methyl-1H-imidazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 1-methyl-1H-imidazole-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ8.76(t,J＝5.8Hz,1H),8.88(d,J＝1.3Hz,1H),8.17(d,J＝2.0Hz,1H),8.05(d,J＝1.3Hz,1H),7.83(s,1H),7.70(dd,J＝2.0,7.5Hz,1H),7.36(d,J＝7.6Hz,1H),7.33(s,1H),7.28(dd,J＝1.1,7.4Hz,1H),7.05(dd,J＝1.3,7.5Hz,1H),7.00(d,J＝1.5Hz,1H),6.31(s,2H),4.41(d,J＝5.7Hz,2H),3.69(s,3H),2.53(s,3H).LR-MS 428.1(M+1).
Example 41 preparation of 3- ((2-amino-5- (1, 3, 5-trimethyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 1,3, 5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.12(t,J＝5.7Hz,1H),8.18(d,J＝1.3Hz,1H),8.09(d,J＝2.0Hz,1H),7.95(d,J＝1.1Hz,1H),7.77(dd,J＝2.1,7.6Hz,1H),7.37(d,J＝7.4Hz,1H),7.28(dd,J＝1.1,7.6Hz,1H),7.06–6.99(m,2H),6.28(s,2H),4.42(d,J＝5.8Hz,2H),3.84(s,3H),2.54(s,3H),2.52(s,3H),2.38(s,3H).LR-MS 456.6(M+1).
Example 42 preparation of 3- ((2-amino-5- (1-cyclopropyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The procedure was followed as in example 1, except that 1-cyclopropyl-1H-pyrazole-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.04(t,J＝6.0Hz,1H),8.12(d,J＝2.0Hz,1H),7.98(s,1H),7.97(s,1H),7.82(d,J＝1.3Hz,1H),7.80(dd,J＝2.0,7.5Hz,1H),7.30(dd,J＝1.2,7.5Hz,1H),7.19(d,J＝8.5Hz,1H),7.08(d,J＝1.5Hz,1H),6.88(d,J＝11.9Hz,4H),4.46(d,J＝5.8Hz,2H),2.45(s,3H),2.41(q,J＝7.0Hz,1H),0.79(ddd,J＝4.2,6.0,7.2Hz,2H),0.59–0.49(m,2H).LR-MS 454.2(M+1).
Example 43 preparation of 3- ((2-amino-5- (1-isopropyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The procedure was followed as in example 1, except that 1-isopropyl-1H-pyrazole-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.01(t,J＝5.8Hz,1H),8.29(d,J＝2.4Hz,1H),8.19(s,1H),8.15(d,J＝1.9Hz,1H),7.86(d,J＝2.4Hz,1H),7.82(d,J＝0.8Hz,1H),7.80(dd,J＝8.0,1.9Hz,1H),7.49(dd,J＝4.9,2.9Hz,1H),7.42(d,J＝8.0Hz,1H),7.34(dd,J＝3.0,1.3Hz,1H),7.09(dd,J＝5.0,1.3Hz,1H),6.24(s,2H),4.51–4.43(m,3H),2.54(s,3H),1.43(d,J＝6.6Hz,6H).LR-MS 456.2(M+1).
Example 44 preparation of- ((2-amino-5- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 1- (oxetanyl-3-yl) -1H-pyrazole-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.07(t,J＝5.8Hz,1H),8.12(d,J＝2.0Hz,1H),7.98(s,1H),7.96(s,1H),7.82(d,J＝1.3Hz,1H),7.80(dd,J＝2.0,7.5Hz,1H),7.30(dd,J＝1.1,7.4Hz,1H),7.22–7.16(m,1H),7.08(d,J＝1.5Hz,1H),6.88–6.82(m,2H),6.39(s,2H),5.33–5.26(m,2H),5.08–5.01(m,2H),4.97–4.87(m,1H),4.55(d,J＝5.7Hz,2H),2.54(s,3H).LR-MS 470.2(M+1).
Example 45 preparation of 3- ((2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 1- (piperidin-4-yl) -1H-pyrazole-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.10(t,J＝5.7Hz,1H),8.24(d,J＝1.3Hz,1H),8.17(d,J＝2.1Hz,1H),8.13(d,J＝1.3Hz,1H),7.86(d,J＝1.5Hz,1H),7.70(dd,J＝2.0,7.5Hz,1H),7.42–7.32(m,2H),7.13(d,J＝1.3Hz,1H),7.06–6.99(m,2H),6.28(s,2H),4.46(d,J＝5.8Hz,2H),4.30–4.18(m,1H),3.17–3.02(m,2H),2.78–2.62(m,2H),2.53(s,2H),2.44(s,1H),1.87–1.72(m,2H),1.70–1.51(m,2H).LR-MS 497.3(M+1).
Example 46 preparation of 3- ((2-amino-5- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 1- (1-methylpiperidin-4-yl) -1H-pyrazole-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.06(t,J＝5.7Hz,1H),8.24(d,J＝1.3Hz,1H),8.17(d,J＝2.0Hz,1H),8.13(d,J＝1.3Hz,1H),7.86(d,J＝1.6Hz,1H),7.70(dd,J＝2.1,7.6Hz,1H),7.41–7.34(m,2H),7.13(d,J＝1.3Hz,1H),7.03(dd,J＝1.6,7.5Hz,1H),7.00(d,J＝1.5Hz,1H),6.27(s,2H),4.45(d,J＝5.8Hz,2H),4.33–4.15(m,1H),3.02–2.83(m,2H),2.53(s,3H),2.25(s,3H),2.22–1.87(m,4H),1.76–1.54(m,2H).LR-MS 511.3(M+1).
Example 47 preparation of- ((2-amino-5- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝6.0Hz,1H),8.24(d,J＝1.3Hz,1H),8.18(d,J＝2.0Hz,1H),8.13(d,J＝1.1Hz,1H),7.87(d,J＝1.5Hz,1H),7.70(dd,J＝2.0,7.5Hz,1H),7.43–7.33(m,2H),7.13(d,J＝1.6Hz,1H),7.03(dd,J＝1.5,7.5Hz,1H),7.00(d,J＝1.5Hz,1H),6.29(s,2H),4.45(d,J＝5.8Hz,2H),4.12–3.95(m,1H),3.95–3.79(m,2H),3.63–3.37(m,2H),2.53(s,3H),2.19–1.91(m,2H),1.89–1.66(m,2H).LR-MS498.6(M+1).
Example 48 preparation of- ((2-amino-5- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 1- (2-hydroxyethyl) -1H-pyrazole-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.00(t,J＝5.8Hz,1H),8.27(d,J＝2.4Hz,1H),8.15(d,J＝1.9Hz,1H),8.10(s,1H),7.85(d,J＝2.4Hz,1H),7.84(s,1H),7.80(dd,J＝1.9,8.1Hz,1H),7.49(dd,J＝3.0,5.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.34(s,1H),7.09(d,J＝4.4Hz,1H),6.24(s,2H),4.92(t,J＝5.4Hz,1H),4.47(d,J＝5.8Hz,2H),4.13(t,J＝5.7Hz,2H),3.75(q,J＝5.5Hz,2H),2.53(s,3H).LR-MS 458.1(M+1).
Example 49 preparation of- ((2-amino-5- (1- (2-hydroxypropyl) -1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 1- (2-hydroxypropyl) -1H-pyrazole-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.04(t,J＝5.9Hz,1H),8.26(d,J＝1.3Hz,1H),8.17(d,J＝2.0Hz,1H),8.03(d,J＝1.3Hz,1H),7.76(d,J＝1.5Hz,1H),7.70(dd,J＝2.0,7.5Hz,1H),7.37(d,J＝7.4Hz,1H),7.28(d,J＝8.0Hz,1H),7.06–6.98(m,3H),6.28(s,2H),4.50(d,J＝4.8Hz,1H),4.42(d,J＝5.8Hz,1H),4.21(dd,J＝6.9,12.4Hz,1H),4.07(dd,J＝6.9,12.3Hz,1H),4.01–3.90(m,1H),2.53(s,3H),1.16(d,J＝6.8Hz,3H).LR-MS 472.6(M+1).
Example 50 preparation of- ((2-amino-5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 1- (2- (dimethylamino) ethyl) -1H-pyrazole-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.04(t,J＝5.8Hz,1H),8.26(d,J＝1.3Hz,1H),8.17(d,J＝2.1Hz,1H),8.04(d,J＝1.3Hz,1H),7.77(d,J＝1.6Hz,1H),7.70(dd,J＝2.0,7.5Hz,1H),7.37(d,J＝7.6Hz,1H),7.28(dd,J＝1.2,7.3Hz,1H),7.09–6.96(m,3H),4.66(t,J＝7.5Hz,2H),6.26(s,2H),4.44(d,J＝5.8Hz,2H),3.00(t,J＝7.5Hz,2H),2.52(s,3H),2.37(s,6H).LR-MS 485.5(M+1).
Example 51 preparation of- ((2-amino-5- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 1- (2-fluoroethyl) -1H-pyrazole-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.06(t,J＝5.7Hz,1H),8.25(d,J＝1.3Hz,1H),8.17(d,J＝2.0Hz,1H),8.05(d,J＝1.1Hz,1H),7.78(d,J＝1.5Hz,1H),7.70(dd,J＝2.0,7.5Hz,1H),7.37(d,J＝7.5Hz,1H),7.28(dd,J＝1.2,7.4Hz,1H),7.08(d,J＝1.6Hz,1H),7.05–6.97(m,2H),4.63(m,2H),4.55(s,2H),4.42(d,J＝5.6Hz,2H),3.96(t,J＝3.0Hz,2H),2.54(s,3H).LR-MS 460.5(M+1).
Example 52 preparation of ethyl 2- (4- (6-amino-5- ((2-methyl-5- ((thiophen-3-ylmethyl) carbamoyl) phenyl) ethynyl) pyridin-3-yl) -1H-pyrazol-1-yl) acetate
The synthesis was as in example 1, except that ethyl 2- (4-boronic acid pinacol ester-1H-pyrazol-1-yl) acetate was used instead of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.01(t,J＝5.8Hz,1H),8.28(d,J＝2.4Hz,1H),8.14(d,J＝1.9Hz,1H),8.12(s,1H),7.90(s,1H),7.86(d,J＝2.4Hz,1H),7.79(dd,J＝2.0,7.9Hz,1H),7.48(dd,J＝3.0,4.9Hz,1H),7.42(d,J＝8.1Hz,1H),7.36–7.31(m,1H),7.09(dd,J＝1.3,4.9Hz,1H),6.27(s,2H),5.05(s,2H),4.46(d,J＝5.8Hz,2H),4.16(q,J＝7.1Hz,2H),2.53(s,3H),1.21(t,J＝7.1Hz,3H).LR-MS 500.2(M+1).
Example 53 preparation of- ((2-amino-5- (1- (2-dimethylamino) -2-oxoethyl) -1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
Into a round bottom flask was charged compound 52 (100 mg,0.20 mmol) and THF/MeOH/H 2 O (2/0.5/0.5 mL), liOH.H was added 2 O (21 mg,0.50 mmol), after 2 hours at room temperature, was directly added to the reaction mixture under reduced pressure. The solid was redissolved in DMF (2 mL), HATU (99 mg,0.26 mmol) and DIPEA (77 mg,0.60 mmol) were added, after stirring at room temperature for 20 min, a solution of dimethylamine in tetrahydrofuran (1.0 m,0.4 mL) was added, after continuing the reaction for 3 hours, extracted with ethyl acetate (10 ml×3) and water (10 mL), the organic phases were combined, washed with water (10 ml×3) and saturated NaCl solution (10 ml×2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the column chromatography separated to give 3- ((2-amino-5- (1- (2-dimethylamino) -2-oxoethyl) -1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide 55mg (yield: 55.3%). 1 H NMR (600 MHz, chloroform-d) delta 8.17 (d, j=2.3 hz, 1H), 7.91 (d, j=1.9 hz, 1H), 7.71-7.68 (M, 3H), 7.66 (d, j=2.3 hz, 1H), 7.32-7.28 (M, 2H), 7.23-7.21 (M, 1H), 7.10 (dd, j=1.3, 5.0hz, 1H), 6.67 (t, j=5.6 hz, 1H), 5.09 (s, 2H), 4.99 (s, 2H), 4.64 (d, j=5.6 hz, 2H), 3.09 (s, 3H), 2.99 (s, 3H), 2.53 (s, 3H) LR-MS 499.5 (m+1).
Example 54 preparation of 3- ((2-amino-5- (1-trifluoromethyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 1-trifluoromethyl-1H-pyrazolyl-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazolyl-4-boronic acid pinacol ester.
1 H NMR(400MHz,DMSO-d 6 )δ9.06(t,J＝5.7Hz,1H),8.26(d,J＝1.3Hz,1H),8.16(d,J＝2.0Hz,1H),8.05(d,J＝1.3Hz,1H),7.82(d,J＝1.5Hz,1H),7.71(dd,J＝2.0,7.5Hz,1H),7.37(d,J＝7.4Hz,1H),7.28(dd,J＝1.2,7.4Hz,1H),7.22(d,J＝1.5Hz,1H),7.03(dd,J＝1.5,7.5Hz,1H),7.00(d,J＝1.5Hz,1H),6.25(s,2H),4.42(d,J＝5.8Hz,2H),2.52(s,3H).LR-MS 482.1(M+1).
Example 55 preparation of- ((2-amino-5- (1-trifluoromethyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- ((6-fluoropyridin-3-yl) methyl) -4-methylbenzamide
The procedure was followed except that 1-trifluoromethyl-1H-pyrazolyl-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazolyl-4-boronic acid pinacol ester and 3-aminomethyl-6-fluoropyridine was used instead of benzylamine, as in example 1.
1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝6.1Hz,1H),8.38(d,J＝1.3Hz,1H),8.16(d,J＝2.0Hz,1H),8.13(d,J＝1.3Hz,1H),8.10(d,J＝1.4Hz,1H),8.07–8.00(m,1H),7.92(d,J＝1.5Hz,1H),7.64(dd,J＝2.0,7.5Hz,1H),7.37(dd,J＝1.2,7.6Hz,1H),7.28(d,J＝1.5Hz,1H),7.15(t,J＝8.0Hz,1H),6.27(s,2H),4.50(d,J＝5.9Hz,2H),2.55(s,3H).LR-MS 495.3(M+1).
Example 56 preparation of 3- ((2-amino-5- (1-difluoromethyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 1-difluoromethyl-1H-pyrazolyl-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazolyl-4-boronic acid pinacol ester.
1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝6.0Hz,1H),8.20(d,J＝1.3Hz,1H),8.16(d,J＝2.0Hz,1H),8.03(d,J＝1.1Hz,1H),7.81(t,J＝51.4Hz,1H),7.79(d,J＝1.5Hz,1H),7.73–7.67(m,1H),7.37(d,J＝7.4Hz,1H),7.28(dd,J＝1.2,7.5Hz,1H),7.13(d,J＝1.6Hz,1H),7.06–6.97(m,2H),6.29(s,2H),4.55(d,J＝5.9Hz,2H),2.54(s,3H).LR-MS464.4(M+1).
Example 57 preparation of- ((2-amino-5- (1- (methyl-d 3) -1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 1- (methyl-d 3) -1H-pyrazolyl-4-boronic acid pinacol ester was used instead of 1-methyl-1H-pyrazolyl-4-boronic acid pinacol ester.
1 H NMR(400MHz,DMSO-d 6 )δ8.98(t,J＝5.9Hz,1H),8.12(d,J＝2.0Hz,1H),7.98(d,J＝1.3Hz,1H),7.97(d,J＝1.6Hz,1H),7.82(d,J＝1.3Hz,1H),7.80(dd,J＝2.0,7.5Hz,1H),7.30(dd,J＝1.1,7.5Hz,1H),7.23–7.15(m,1H),7.05(d,J＝1.3Hz,1H),6.91–6.84(m,4H),4.55(d,J＝5.7Hz,2H),2.45(s,3H).LR-MS 431.5(M+1).
Wherein the synthesis of 1- (methyl-d 3) -1H-pyrazolyl-4-boronic acid pinacol ester is as follows:
to a round bottom flask was added 1H-pyrazolyl-4-boronic acid pinacol ester (0.5 g,2.58 mmol), cesium carbonate (2.5 g,7.73 mmol) and DMF (10 mL), ice-bath, deuterated iodomethane (411 mg,2.83 mmol) was added dropwise, reacted overnight at room temperature, water (20 mL) was poured in, ethyl acetate (25 mL. Times.3) was extracted, the organic phases were combined, washed with water (20 mL. Times.3) and saturated NaCl solution (20 mL. Times.2) respectively, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and column chromatography was performed to obtain 467mg (yield: 85.9%) of 1- (methyl-d 3) -1H-pyrazolyl-4-boronic acid pinacol ester. LR-MS (ESI) M/z 212.3 (M+1).
Example 58 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethylene-d 2) benzamide
The synthesis was as in example 1, except that thiophen-3-ylmethylene-d 2-amine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.03(s,1H),,8.12(d,J＝2.0Hz,1H),7.97(dd,J＝1.4,4.1Hz,2H),7.82(d,J＝1.3Hz,1H),7.80(dd,J＝2.0,7.5Hz,1H),7.30(d,J＝7.5Hz,1H),7.19(d,J＝8.5Hz,1H),7.05(d,J＝1.3Hz,1H),6.88(m,2H),6.28(s,2H),3.94(s,3H),2.48(s,3H).LR-MS(ESI)m/z 430.3(M+1).
Wherein the preparation method of the thiophen-3-ylmethylene-d 2-amine is as follows:
LiAlD4 (962mg, 22.91 mmol) was added to the round-bottomed flask, argon was fully substituted for the gas, anhydrous diethyl ether (60 mL), an ice bath was added, a solution of 3-cyanothiophene (1.0 g,9.16 mmol) in anhydrous diethyl ether (10 mL) was added dropwise under argon protection, and after completion, the temperature was raised to room temperature and the reaction was heated under reflux overnight. After cooling to room temperature, diethyl ether (60 mL) was added for dilution, 10% aqueous NaOH (2 mL) and water (5 mL) were added dropwise under ice-bath, celite was filtered, the cake was washed with diethyl ether (25 mL. Times.3), the solvent was evaporated under reduced pressure, and 750mg of thiophen-3-ylmethylene-d 2-amine was isolated by column chromatography (yield: 71.06%). LR-MS (ESI) M/z 116.2 (M+1).
Example 59 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- ((6-fluoropyridin-3-yl) methylene-d 2) -4-methyl-benzamide
The synthesis was as in example 1, except that 6-fluoropyridin-3-ylmethylene-d 2-amine was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ8.49(d,J＝1.4Hz,1H),8.30–8.23(m,1H),8.20(s,1H),8.12(d,J＝2.0Hz,1H),7.97(dd,J＝1.4,4.1Hz,2H),7.82(d,J＝1.3Hz,1H),7.80(dd,J＝2.0,7.5Hz,1H),7.30(dd,J＝1.1,7.5Hz,1H),7.05(d,J＝1.3Hz,1H),6.94–6.87(m,3H),3.94(s,3H),2.45(s,3H).LR-MS(ESI)m/z 443.2(M+1).
Example 60 preparation of methyl-4- (6-amino-5- ((2-methyl-5- ((thiophen-3-ylmethyl) formyl) phenyl) ethynyl) pyridin-3-yl) -1H-pyrazole-1-carboxylic acid ester
The procedure was followed except that 1- (methoxyformyl) -1H-pyrazole-4-boronic acid pinacol ester was used in place of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used in place of benzylamine, as in example 1.
1 H NMR(400MHz,DMSO-d 6 )δ9.02(t,J＝5.9Hz,1H),8.81(s,1H),8.46(d,J＝2.4Hz,1H),8.37(s,1H),8.17(d,J＝1.9Hz,1H),8.09(d,J＝2.4Hz,1H),7.80(dd,J＝8.0,2.0Hz,1H),7.49(dd,J＝5.0,2.9Hz,1H),7.43(d,J＝8.1Hz,1H),7.34(dd,J＝3.0,1.2Hz,1H),7.09(dd,J＝4.9,1.3Hz,1H),6.48(s,2H),4.47(d,J＝5.8Hz,2H),4.00(s,3H),2.54(s,3H).LR-MS(ESI)m/z 472.2(M+1).
The preparation method of the 1- (methoxyformyl) -1H-pyrazole-4-boric acid pinacol ester is as follows:
to a round bottom flask was added 1H-pyrazole-4-boronic acid pinacol ester (2.0 g,10.31 mmol) and DMF (30 mL), naH (60% wt,618mg,15.46 mmol) was added in portions on ice, and after stirring for 15 min methyl chloroformate (1.95 g,20.61 mmol) was added and the reaction stirred at room temperature for 5H. After the reaction is finished, slowly dropwise adding saturated NH in an ice bath 4 The reaction was quenched with aqueous Cl, poured into water (20 mL), extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with water (20 mL. Times.3) and saturated NaCl solution (20 mL. Times.2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, followed by column chromatography to give 640mg (yield: 24.6%) of 1- (methoxyformyl) -1H-pyrazole-4-boronic acid pinacol ester. 1 H NMR (400 MHz, chloroform-d) δ8.44 (s, 1H), 7.93 (s, 1H), 4.06 (s, 3H), 1.31 (s, 12H) LR-MS (ESI) M/z 253.1 (M+1).
Example 61 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- ((5-cyclopropylthiophene-2-yl) methyl) -4-methyl-benzamide
The synthesis was as in example 1, except that (5-cyclopropyl-thiophen-2-yl) methylamine was used instead of (5-methyl-thiophen-2-yl) methylamine.
1 H NMR(600MHz,DMSO-d 6 )δ9.08(t,J＝5.9Hz,1H),8.26(d,J＝2.4Hz,1H),8.13(d,J＝1.9Hz,1H),8.07(s,1H),7.83(d,J＝2.4Hz,1H),7.81(d,J＝0.8Hz,1H),7.78(dd,J＝7.9,1.9Hz,1H),7.42(d,J＝8.1Hz,1H),6.78(d,J＝3.5Hz,1H),6.63(dd,J＝3.5,0.8Hz,1H),6.25(s,2H),4.52(d,J＝5.8Hz,2H),3.84(s,3H),2.53(s,3H),2.09–2.00(m,1H),0.96–0.90(m,2H),0.63–0.56(m,2H).LR-MS(ESI)m/z 468.3(M+1).
Wherein the preparation method of the (5-cyclopropyl thiophene-2-yl) methyl amine is as follows:
Into a round bottom flask5-Cyclopropylthiophene-2-carbaldehyde (1.0 g,6.57 mmol), NH was added 4 OAc (2.53 g,32.85 mmol) and MeOH (20 mL), naBH was added 3 CN (1.24 g,19.71 mmol), was stirred at 50℃for 12h. After the reaction is finished, the saturated NaHCO is poured in 3 In the aqueous solution, most of methanol was evaporated under reduced pressure, the ethyl acetate (30 mL. Times.3) was extracted, the organic phases were combined, washed with saturated NaCl solution (20 mL. Times.2), dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure, followed by column chromatography to obtain 300mg (yield: 29.8%) of (5-cyclopropylthiophene-2-yl) methylamine. 1 H NMR(400MHz,DMSO-d 6 )δ7.05(d,J＝6.2Hz,1H),6.82(d,J＝6.1Hz,1H),5.03(br s,2H),4.30(s,2H),2.29–2.15(m,1H),1.03–0.85(m,4H).LR-MS(ESI)m/z 128.1(M+1).
Example 62 preparation of 3- ((2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) ethynyl) -N- ((5-chlorothien-2-yl) methyl) -4-methyl-benzamide
The synthesis was as in example 61, except that 5-chlorothiophene-2-aldehyde was used instead of 5-cyclopropylthiophene-2-aldehyde.
1 H NMR(400MHz,DMSO-d 6 )δ8.83(t,J＝8.0Hz,1H),8.18(s,1H),8.12(d,J＝2.1Hz,1H),7.98(d,J＝2.0Hz,1H),7.82(d,J＝2.0Hz,1H),7.77(dd,J＝7.6,1.9Hz,1H),7.33(dq,J＝7.6,1.0Hz,1H),7.30(s,1H),7.09(s,2H),6.92(d,J＝6.4Hz,1H),6.60(d,J＝6.4Hz,1H),4.75(d,J＝8.0Hz,2H),3.94(s,3H),2.45(s,3H).LR-MS(ESI)m/z 463.0(M+1).
Example 63 preparation of 3- ((2-amino-5- (4-cyclopropyl-1H-imidazol-1-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
Step 1: to a round bottom flask was added 4-methyl-3 iodobenzoic acid (2.0 g,7.63 mmol), HATU (3.8 g,9.92 mmol), DIPEA (2.5 g,19.08 mmol) and DMF (40 mL), and after stirring at room temperature for 30 min, 3-aminomethylthiophene (864 mg,7.63 mmol) was added and reacted at room temperature for 12 hours. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate (50 mL. Times.3) and water (40 mL), and the organic phase was washed with water (30 mL. Times.3), saturated aqueous NaCl solution (30 mL. Times.3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, followed by separation by column chromatography to give 2.4g of 3-iodo-4-methyl-N- (thiophen-3-ylmethyl) benzamide (pale yellow solid; yield: 88%).
Step 2: to a round bottom flask was added 3-iodo-4-methyl-N- (thiophen-3-ylmethyl) benzamide (100 mg,0.28 mmol), 5-bromo-3- ((trimethylsilyl) ethynyl) -2-aminopyridine (90 mg,0.34 mmol), et 3 N (85 mg,0.84 mmol), csF (128 mg,0.84 mmol) and MeCN (20 mL), replace oxygen with argon, add Pd (PPh) 3 ) 2 Cl 2 (10 mg,0.014 mmol) and CuI (5.3 mg,0.028 mmol), the oxygen removal operation was repeated, and the reaction was carried out at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate (30 mL. Times.3) and water (20 mL), the organic phase was washed with saturated NaCl solution (10 mL. Times.3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, followed by column chromatography to obtain 85mg (yellow solid; yield: 71%) of the product 3- ((2-amino-5-bromopyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide.
Step 3: to a round bottom flask was added 3- ((2-amino-5-bromopyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide (80 mg,0.19 mmol), 4-cyclopropylimidazole (30 mg,0.28 mmol), cuI (7 mg,0.038 mmol), cs2CO3 (122 mg,0.38 mmol) and DMF (2 mL) and reacted at 120℃for 30h under argon. Cooled to room temperature, the reaction mixture was diluted with 10mL of ethyl acetate, filtered, and the filter cake was washed with ethyl acetate, the solvent was evaporated under reduced pressure, and the product was isolated by column chromatography as 50mg (yellow solid; yield: 59%) of 3- ((2-amino-5- (4-cyclopropyl-1H-imidazol-1-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide. 1 H NMR(400MHz,DMSO-d 6 )δ8.82(t,J＝6.0Hz,1H),8.52(d,J＝2.0Hz,1H),8.12(d,J＝2.0Hz,1H),7.80(d,J＝1.5Hz,1H),7.77(dd,J＝7.6,1.9Hz,1H),7.60(d,J＝2.0Hz,1H),7.33(dq,J＝7.6,1.1Hz,1H),7.22(dd,J＝4.8,1.8Hz,1H),7.16(d,J＝2.2Hz,1H),7.07–7.02(m,2H),6.25(s,2H),4.55(d,J＝5.9Hz,2H),2.45(d,J＝0.9Hz,3H),2.14(pd,J＝7.9,0.7Hz,1H),1.33–1.11(m,4H).
Example 64 preparation of 3- ((3-aminoisoquinolin-4-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 4-iodo-isoquinolin-3-amine was used instead of 5-bromo-3-iodopyridin-2-amine and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝6.1Hz,1H),8.91(s,1H),8.26(d,J＝1.9Hz,1H),7.93(t,J＝8.3Hz,2H),7.80(dd,J＝8.0,2.0Hz,1H),7.71–7.66(m,1H),7.50(dd,J＝5.0,2.9Hz,1H),7.45(d,J＝8.1Hz,1H),7.35(d,J＝1.4Hz,1H),7.30(dd,J＝8.3,7.1Hz,1H),7.11(dd,J＝5.0,1.3Hz,1H),6.54(s,2H),4.49(d,J＝5.9Hz,2H),2.61(s,3H).LR-MS(ESI)m/z 398.1(M+1).
Example 65 preparation of 3- ((2-aminopyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 5-iodo-pyrimidin-2-amine was used instead of 5-bromo-3-iodopyridin-2-amine and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.9Hz,1H),8.45(s,2H),7.99(d,J＝1.9Hz,1H),7.78(dd,J＝8.0,1.9Hz,1H),7.48(dd,J＝4.9,2.9Hz,1H),7.41(d,J＝8.1Hz,1H),7.36–7.31(m,1H),7.19(s,2H),7.08(dd,J＝4.9,1.3Hz,1H),4.45(d,J＝5.8Hz,2H),2.48(s,3H).LR-MS(ESI)m/z 349.1(M+1).
Example 66 preparation of 3- ((2-amino-5- (5, 5-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-3-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 5, 5-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole-3-boronic acid pinacol ester (synthesis methods referenced J.Med. Chem.2020,63,24,15564-15590) was used instead of N-methylpyrazole-4-boronic acid pinacol ester and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR (400 MHz, chloroform-d) delta 8.11 (d, j=2.3 hz, 1H), 7.94 (d, j=2.0 hz, 1H), 7.71-7.66 (M, 2H), 7.61 (d, j=2.3 hz, 1H), 7.32-7.27 (M, 2H), 7.22-7.19 (M, 1H), 7.08 (dd, j=5.0, 1.3hz, 1H), 6.80 (t, j=5.7 hz, 1H), 5.07 (s, 2H), 4.63 (d, j=5.6 hz, 2H), 3.87 (s, 2H), 2.83 (s, 2H), 2.53 (s, 3H), 1.32 (s, 6H) LR-MS (ESI) M/z.2 (m+1).
Example 67 preparation of 3- ((2-amino-5- (2- (((4-cyanotetrahydro-2H-pyran-4-yl) methyl) amino) thiazol-4-yl) pyridin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
Step 1: the synthetic method of reference example 1 can prepare intermediate 67-IM, except that pinacol ester of (2- ((tert-butoxyformyl) ((4-cyanotetrahydro-2H-pyran-4-yl) methyl) amino) thiazole-4-boronic acid (synthetic method reference eur. J. Med. Chem.,158 (2018): 896-916.) is used instead of pinacol ester of N-methylpyrazole-4-boronic acid and 3-aminomethylthiophene is used instead of benzylamine. 1 H NMR (400 MHz, chloroform-d) delta 8.54 (s, 1H), 8.02-7.99 (M, 1H), 7.93 (d, j=2.0 hz, 1H), 7.70 (dd, j=8.0, 1.9hz, 1H), 7.34-7.29 (M, 2H), 7.22 (s, 1H), 7.12-7.07 (M, 1H), 7.01 (s, 1H), 6.54 (s, 1H), 5.27 (s, 2H), 4.65 (d, j=5.5 hz, 2H), 4.51 (s, 2H), 3.98-3.89 (M, 2H), 3.70 (td, j=11.8, 3.3hz, 2H), 2.55 (s, 3H), 1.93-1.83 (M, 4H), 1.64 (s, 9H) LR-MS (ESI) M/z (66 i) m+1.9.
Step 2: to a round bottom flask was added intermediate 67-IM (50 mg,0.075 mmol) and DCM (2 mL), TFA (0.5 mL) was added and the reaction was allowed to proceed overnight at room temperature. Pouring the reaction solution into NaHCO 3 In aqueous solution and extracted with DCM, the organic phases are combined, washed with aqueous NaCl, dried over anhydrous Na 2 SO 4 Drying, evaporating the solvent under reduced pressure, and separating by column chromatography to obtain 40mg (pale yellow solid; yield: 94%). 1 H NMR(400MHz,DMSO-d 6 )δ9.01(t,J＝5.9Hz,1H),8.52(d,J＝2.3Hz,1H),8.16(d,J＝2.0Hz,1H),8.09–8.01(m,2H),7.80(dd,J＝8.0,2.0Hz,1H),7.49(dd,J＝5.0,3.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.34(dd,J＝2.9,1.2Hz,1H),7.09(dd,J＝5.0,1.3Hz,1H),6.99(s,1H),6.44(s,2H),4.47(d,J＝5.8Hz,2H),3.92(d,J＝11.2Hz,2H),3.66(d,J＝6.3Hz,2H),3.55–3.41(m,2H),2.53(s,3H),1.89(d,J＝13.5Hz,2H),1.71(td,J＝13.1,12.7,4.4Hz,2H).LR-MS(ESI)m/z 569.2(M+1).
Example 68 preparation of 4-methyl-3- ((6- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-b ] pyrazin-3-yl) ethynyl) -N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 6-chloro-3-iodoimidazo [1,2-b ] pyrazine was used in place of 5-bromo-3-iodopyridin-2-amine and 3-aminomethylthiophene was used in place of benzylamine.
1 H NMR(400MHz,DMSO-d 6 )δ9.11(t,J＝6.6Hz,1H),8.47(s,1H),8.24(d,J＝9.5Hz,1H),8.18–8.05(m,3H),7.86(d,J＝8.0Hz,1H),7.72(d,J＝9.4Hz,1H),7.50(d,J＝7.0Hz,2H),7.35(s,1H),7.11(d,J＝5.0Hz,1H),4.48(d,J＝5.7Hz,2H),3.94(s,3H),2.67(s,3H).LR-MS(ESI)m/z 453.1(M+1).
Example 69 preparation of tert-butyl-5- ((2-methyl-5- ((thiophen-3-ylmethyl) carbamoyl) phenyl) ethynyl) -1H-pyrazolo [3,4-b ] pyridine-1-carbonate
The procedure was followed except for using tert-butyl-5-bromo-1H-pyrazolo [3,4-b ] pyridine-1-carbonate in place of 5-bromo-3-iodopyridin-2-amine and 3-aminomethylthiophene in place of benzylamine.
1 H NMR (400 MHz, chloroform-d) δ8.88 (d, j=2.0 hz, 1H), 8.23 (d, j=2.0 hz, 1H), 8.19 (s, 1H), 7.94 (d, j=2.0 hz, 1H), 7.71 (dd, j=8.0, 2.0hz, 1H), 7.37-7.31 (M, 3H), 7.27-7.21 (M, 15H), 7.11 (dd, j=4.9, 1.3hz, 1H), 6.34 (s, 1H), 4.67 (d, j=5.5 hz, 2H), 2.58 (s, 3H), 1.74 (s, 9H). LR-MS (ESI) M/z 473.2 (m+1).
Example 70 preparation of- ((1H-pyrazolo [3,4-b ] pyridin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 80, except that compound 83 was used instead of compound 79.
1 H NMR(400MHz,DMSO-d 6 )δ13.94(s,1H),9.07(t,J＝5.9Hz,1H),8.72(d,J＝2.0Hz,1H),8.51(d,J＝2.0Hz,1H),8.21(d,J＝1.4Hz,1H),8.08(d,J＝1.9Hz,1H),7.83(dd,J＝8.0,1.9Hz,1H),7.49(dd,J＝5.0,3.0Hz,1H),7.45(d,J＝8.1Hz,1H),7.34(dd,J＝2.9,1.3Hz,1H),7.09(dd,J＝4.9,1.3Hz,1H),4.47(d,J＝5.8Hz,2H),2.55(s,3H).LR-MS(ESI)m/z 373.1(M+1).
Example 71 preparation of 3- (imidazo [1,2-a ] pyrimidin-3-ylethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 1, except that 3-bromoimidazo [1,2-a ] pyrimidine was used instead of 5-bromo-3-iodopyridin-2-amine and 3-aminomethylthiophene was used instead of benzylamine.
1 H NMR (400 MHz, chloroform-d) delta 8.81 (dd, j=4.6, 1.6hz, 1H), 8.21 (dd, j=8.0, 1.7hz, 1H), 8.01 (d, j=2.0 hz, 1H), 7.76 (dd, j=8.1, 2.0hz, 1H), 7.40 (dd, j=8.0, 4.6hz, 1H), 7.38-7.33 (M, 2H), 7.25 (s, 2H), 7.12 (dd, j=4.9, 1.3hz, 1H), 6.36 (t, j=6.5 hz, 1H), 4.67 (d, j=5.5 hz, 2H), 2.63 (s, 3H) LR-MS (ESI) M/z 373.2 (m+1).
Example 72 preparation of 3- ((4-amino-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
Step 1: 5-iodo-7H-pyrrolo [2,3-d ] was added to a round bottom flask]And pyrimidine-4 amine (1.0 g,3.85 mmol), K 2 CO 3 (1.59 g,11.54 mmol) and anhydrous DMF (10 mL), methyl iodide (0.29 mL,4.61 mmol) was added dropwise and reacted at room temperature for 8 hours. After the reaction was completed, 2mL of an aqueous sodium thiosulfate solution was added, stirred at room temperature for 15min, then poured into water, extracted with DCM, and the organic phases were combined and washed with water, an aqueous NaCl solution, respectively, over anhydrous Na 2 SO 4 Drying, evaporating solvent under reduced pressure, and separating by column chromatography to obtain 5-iodine-7-methyl-7H-pyrrole [2,3-d ]]Pyrimidine-4-amine 600mg (yield: 60%). Different N-substitutes can be obtained by changing different halides and adjusting reaction conditions (such as alkali, temperature, etc.).
Step 2: 5-iodo-7-methyl-7H-pyrrole [2,3-d ] was added to a round bottom flask]Pyrimidin-4-amine (0.5 g,1.82 mmol), trimethylsilylacetylene (233 mg,2.37 mmol), et 3 N (5 mL) and MeCN (20 mL), oxygen was replaced with argon, and Pd (PPh) was added 3 ) 2 Cl 2 (64 mg,0.091 mmol), cuI (17.4 mg,0.091 mmol), repeated oxygen removal operation, and reaction at room temperature overnight; after the reaction is finished, 50mL of ethyl acetate is added to dilute the reaction solution, the solution is filtered, the solvent is evaporated to dryness under reduced pressure, and the product 7-methyl-5- ((trimethylsilyl) ethynyl) -7H-pyrrole [2,3-d ] is obtained by column chromatography separation]And 420mg (yield: 94.2%).
Step 3: round bottomInto a flask was charged 3-iodo-4-methyl-N- (thiophen-3-ylmethyl) benzamide (90 mg,0.25 mmol), 7-methyl-5- ((trimethylsilyl) ethynyl) -7H-pyrrole [2,3-d]Pyrimidin-4-amine (62 mg,0.25 mmol), et 3 N (76 mg,0.76 mmol), csF (115 mg,0.76 mmol) and MeCN (10 mL), replace oxygen with argon, add Pd (PPh) 3 ) 2 Cl 2 (9 mg,0.013 mmol) and CuI (5 mg,0.025 mmol), the oxygen removal operation was repeated, and the reaction was carried out at room temperature for 3 hours. After the reaction, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was washed with saturated NaCl solution (10 mL. Times.3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, followed by column chromatography to give the product 3- ((4-amino-7-methyl-7H-pyrrole [2, 3-d) ]Pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide 60mg (light yellow solid; yield: 59%). 1 H NMR(400MHz,DMSO-d 6 )δ9.04(t,J＝5.7Hz,1H),8.17(s,1H),8.06(s,1H),7.79(d,J＝8.0Hz,1H),7.70(s,1H),7.49(s,1H),7.42(d,J＝8.0Hz,1H),7.34(s,1H),7.09(d,J＝5.0Hz,1H),6.71(s,2H),4.47(d,J＝5.8Hz,2H),3.73(s,3H),2.52(s,3H).LR-MS(ESI)m/z 402.1(M+1).
Example 73 preparation of 3- ((4-amino-7- (methyl-d 3) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that deuterated iodomethane was used instead of iodomethane.
1 H NMR(400MHz,DMSO-d 6 )δ9.02(t,J＝6.0Hz,1H),8.20(s,1H),8.08(s,1H),7.79(d,J＝7.8Hz,1H),7.70(s,1H),7.50(s,1H),7.42(d,J＝8.0Hz,1H),7.26-7.19(m,2H),6.63(s,2H),4.45(d,J＝5.9Hz,2H),2.53(s,3H).LR-MS(ESI)m/z 405.1(M+1).
Example 74 preparation of tert-butyl 4-amino-5- ((2-methyl-5- (thiophen-3-ylmethyl) carbamoyl) phenyl) ethynyl) -7H-pyrrolo [2,3-d ] pyrimidine-7-carbonate
The procedure was followed except for using tert-butyl 4-amino-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine-7-carbonate in place of 5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine.
1 H NMR(400MHz,DMSO-d 6 )δ8.96(t,J＝5.9Hz,1H),8.13(s,1H),8.12(d,J＝2.0Hz,1H),7.77(dd,J＝7.6,1.9Hz,1H),7.33(d,J＝7.6Hz,1H),7.22(dd,J＝4.8,1.8Hz,1H),7.13(s,1H),7.07–7.02(m,2H),6.63(s,2H),4.55(d,J＝5.7Hz,2H),2.52(s,3H),1.52(s,9H).LR-MS(ESI)m/z 488.2(M+1).
Example 75 preparation of 3- ((4-amino-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 67, except that compound 74 was used instead of 67-IM.
1 H NMR(400MHz,DMSO-d 6 )δ13.15(s,1H),9.06(t,J＝6.0Hz,1H),8.41(s,1H),8.14(d,J＝1.9Hz,1H),7.94(d,J＝2.4Hz,1H),7.82(dd,J＝8.0,2.0Hz,1H),7.49(dd,J＝5.0,3.0Hz,1H),7.43(d,J＝8.1Hz,1H),7.33(d,J＝2.9Hz,1H),7.11–7.06(m,1H),6.70(s,2H),4.46(d,J＝5.8Hz,2H),2.51(s,3H).LR-MS(ESI)m/z 388.1(M+1).
Example 76 preparation of 3- ((4-amino-7-ethyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that iodoethane was used instead of iodomethane in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.8Hz,1H),8.19(s,1H),8.05(s,1H),7.84–7.71(m,2H),7.49(dd,J＝5.0,2.9Hz,1H),7.42(d,J＝8.0Hz,1H),7.33(s,1H),7.09(d,J＝5.4Hz,1H),6.68(s,2H),4.46(d,J＝5.8Hz,2H),4.18(q,J＝7.2Hz,2H),2.52(s,3H),1.36(t,J＝7.2Hz,3H).LR-MS(ESI)m/z 416.1(M+1).
Example 77 preparation of 3- ((4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that 2-iodopropane was used instead of iodomethane in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.9Hz,1H),8.15(s,1H),8.05(s,1H),7.86(s,1H),7.78(dd,J＝8.0,1.9Hz,1H),7.48(dd,J＝5.0,3.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.33(d,J＝2.8Hz,1H),7.09(d,J＝4.9Hz,1H),6.66(s,2H),4.92(hept,J＝7.7Hz,1H),4.46(d,J＝5.8Hz,2H),2.52(s,3H),1.45(d,J＝6.7Hz,6H).LR-MS(ESI)m/z 430.2(M+1).
Example 78- ((4-amino-7-isopropyl-6-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The procedure was followed as in example 72, except that 5-iodo-7-isopropyl-6-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (synthesis method reference WO 2014184069) was used instead of 5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine.
1 H NMR(400MHz,DMSO-d 6 )δ8.96(t,J＝5.7Hz,1H),8.12(d,J＝2.0Hz,1H),8.10(s,1H),7.77(dd,J＝7.6,1.9Hz,1H),7.36–7.30(m,1H),7.22(dd,J＝4.8,1.8Hz,1H),7.09–7.01(m,2H),6.62(s,2H),4.85(hept,J＝4.5Hz,1H),4.55(d,J＝5.6Hz,2H),2.51(s,3H),2.27(s,3H),1.32(d,J＝4.4Hz,6H).LR-MS(ESI)m/z 444.2(M+1).
Example 79 preparation of 3- ((4-acetamido-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
Into a round bottom flask was charged compound 72 (80 mg,0.2 mmol) and AcOH/Ac 2 O (1 mL/1 mL), reacting for 8H at 80 ℃, evaporating the solvent under reduced pressure after the reaction is finished, and separating by column chromatography to obtain 3- ((4-acetamido-7-methyl-7H-pyrrole [2, 3-d)]And pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide 40mg (yield: 45%).
1 H NMR(400MHz,DMSO-d 6 )δ10.22(s,1H),9.02(t,J＝6.0Hz,1H),8.65(s,1H),7.99(s,2H),7.78(d,J＝9.0Hz,1H),7.49(dd,J＝5.4,2.9Hz,1H),7.41(d,J＝8.1Hz,1H),7.33(s,1H),7.09(d,J＝5.4Hz,1H),4.46(d,J＝5.7Hz,2H),3.84(s,3H),2.51(s,3H),2.16(s,3H).LR-MS(ESI)m/z 444.1(M+1).
Example 80 preparation of 4-methyl-3- ((7-methyl-4- (methylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -N- (thiophen-3-ylmethyl) benzamide
The procedure was followed except for using 5-iodo-N, 7-dimethyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine in place of 5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine.
1 H NMR(400MHz,DMSO-d 6 )δ9.01(t,J＝5.9Hz,1H),8.15(s,1H),8.05(s,1H),7.86(s,1H),7.78(dd,J＝8.0,1.9Hz,1H),7.48(dd,J＝5.0,3.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.33(d,J＝2.8Hz,1H),7.09(d,J＝4.9Hz,1H),5.66(br s,1H),4.46(d,J＝5.7Hz,2H),3.95(s,3H),2.73(d,J＝2.6Hz,3H),2.52(s,3H).LR-MS(ESI)m/z 416.1(M+1).
Example 81 preparation of 4-methyl-3- ((7-methyl-4- (isopropylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -N- (thiophen-3-ylmethyl) benzamide
The procedure was followed except for using 5-iodo-N-isopropyl-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine in place of 5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine.
1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝6.0Hz,1H),8.16(s,1H),8.05(s,1H),7.86(s,1H),7.78(dd,J＝8.0,1.9Hz,1H),7.48(dd,J＝5.0,3.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.33(d,J＝2.8Hz,1H),7.09(d,J＝4.9Hz,1H),5.46(br s,1H),4.45(d,J＝5.9Hz,2H),3.15–2.98(m,1H),2.73(d,J＝2.6Hz,3H),2.52(s,3H),1.17(d,J＝5.9Hz,6H).LR-MS(ESI)m/z 444.2(M+1).
Example 82 preparation of 3- ((4-amino-1-methyl-1H-pyrazolopyrimidin-3-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The procedure was followed except that 3-iodo-1-methyl-1H-pyrazolo [3,4-d ] pyrimidin-4-amine was used instead of 5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine.
1 H NMR(400MHz,DMSO-d 6 )δ9.06(t,J＝5.7Hz,1H),8.85(s,2H),8.27(s,1H),8.20(s,1H),7.86(d,J＝8.0Hz,1H),7.52–7.41(m,2H),7.34(s,1H),7.09(d,J＝5.0Hz,1H),4.47(d,J＝5.8Hz,2H),3.94(s,3H),2.53(s,3H).LR-MS(ESI)m/z 403.1(M+1).
Example 83 preparation of- ((4-amino-7- (2, 2-trifluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
Except that the corresponding halide (BrCH 2 CF 3 ) The synthesis was as in example 72, instead of methyl iodide. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.8Hz,1H),8.23(s,1H),8.09(d,J＝1.9Hz,1H),7.81(dd,J＝7.9,2.0Hz,1H),7.76(s,1H),7.49(dd,J＝5.0,3.0Hz,1H),7.43(d,J＝8.1Hz,1H),7.33(dd,J＝2.9,1.2Hz,1H),7.09(dd,J＝4.9,1.3Hz,1H),6.82(s,2H),5.10(q,J＝9.1Hz,2H),4.47(d,J＝5.8Hz,2H),2.51(s,3H).LR-MS(ESI)m/z 470.1(M+1).
Example 84 preparation of- ((4-amino-7- (1, 1-trifluoropropan-2-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
Except that in step 1 the corresponding halide (CH 3 CHBrCF 3 ) The synthesis was as in example 72, instead of methyl iodide. 1 H NMR(400MHz,DMSO-d 6 )δ9.02(t,J＝5.9Hz,1H),8.23(s,1H),8.11(d,J＝1.9Hz,1H),7.82(dd,J＝7.9,2.0Hz,1H),7.76(s,1H),7.49(dd,J＝5.0,3.0Hz,1H),7.43(d,J＝8.1Hz,1H),7.33(dd,J＝2.8,1.3Hz,1H),7.09(dd,J＝4.9,1.3Hz,1H),6.66(s,2H),5.02–4.89(m,1H),4.47(d,J＝5.8Hz,2H),2.52(s,3H),1.39(d,J＝6.4Hz,3H).LR-MS(ESI)m/z 484.1(M+1).
Example 85 preparation of 3- ((4-amino-7- (2-methoxyethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
Except that in step 1 the corresponding halide (CH 3 OCH 2 CH 2 Br) instead of methyl iodide, the synthesis was as in example 72. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.8Hz,1H),8.24(s,1H),8.06(d,J＝1.9Hz,1H),7.79(dd,J＝8.0,1.9Hz,1H),7.70(s,1H),7.49(dd,J＝4.9,2.9Hz,1H),7.42(d,J＝8.1Hz,1H),7.33(dd,J＝3.0,1.2Hz,1H),7.09(dd,J＝5.0,1.3Hz,1H),6.69(s,2H),4.46(d,J＝5.8Hz,2H),4.31(t,J＝5.3Hz,2H),3.69(t,J＝5.3Hz,2H),3.24(s,3H),2.51(s,3H).LR-MS(ESI)m/z 446.2(M+1).
Example 86 preparation of- ((4-amino-7- (1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
Except that in step 1 the corresponding halide (CH 3 OCH 2 CH(CH 3 ) Br) instead of methyl iodide, the synthesis was as in example 72. 1 H NMR(400MHz,DMSO-d 6 )δ8.96(t,J＝5.9Hz,1H),8.12(d,J＝2.0Hz,1H),8.10(s,1H),7.77(dd,J＝7.6,1.9Hz,1H),7.54(s,1H),7.33(dd,J＝7.5,1.0Hz,1H),7.22(dd,J＝4.8,1.8Hz,1H),7.08–7.02(m,2H),6.66(s,2H),4.55(d,J＝5.7Hz,2H),4.27–4.12(m,1H),4.10–3.95(m,1H),3.27(s,3H),3.19–3.04(m,1H),2.51(s,3H),1.34(d,J＝6.2Hz,3H).LR-MS(ESI)m/z 460.2(M+1).
Example 87 preparation of- ((4-amino-7- (2- (dimethylamino) ethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
Except that the corresponding halide ((CH) was used in step 1 3 ) 2 NCH 2 CH 2 Br) instead of methyl iodide, the synthesis was as in example 72. 1 H NMR(400MHz,DMSO-d 6 )δ9.04(t,J＝5.9Hz,1H),8.21(s,1H),8.06(d,J＝2.1Hz,1H),7.85–7.72(m,2H),7.49(dd,J＝4.9,2.9Hz,1H),7.43(d,J＝8.0Hz,1H),7.33(s,1H),7.09(d,J＝5.0Hz,1H),6.78(s,2H),4.56–4.48(m,2H),4.47(d,J＝5.8Hz,2H),3.61–3.42(m,2H),2.77(s,6H),2.51(s,3H).LR-MS(ESI)m/z 459.2(M+1).
Example 88 preparation of 3- ((4-amino-7- (1- (dimethylamino) propan-2-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
Except that the corresponding halide ((CH) was used in step 1 3 ) 2 NCH 2 CH(CH 3 ) Br) instead of methyl iodide, the synthesis was as in example 72. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.9Hz,1H),8.15(s,1H),8.06(d,J＝1.9Hz,1H),7.79(dd,J＝8.0,1.9Hz,1H),7.70(s,1H),7.48(dd,J＝5.0,3.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.36–7.30(m,1H),7.09(dd,J＝5.0,1.3Hz,1H),6.66(s,2H),4.46(d,J＝5.8Hz,2H),4.27–4.12(m,1H),4.10–3.95(m,1H),3.19–3.04(m,1H),2.18(s,6H),0.87(s,3H).LR-MS(ESI)m/z 473.2(M+1).
Example 89 preparation of 3- ((4-amino-7-cyclobutyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.9Hz,1H),8.15(s,1H),8.06(d,J＝1.9Hz,1H),8.00(s,1H),7.79(dd,J＝8.0,1.9Hz,1H),7.49(dd,J＝5.0,3.0Hz,1H),7.42(d,J＝8.1Hz,1H),7.33(dd,J＝3.0,1.3Hz,1H),7.09(dd,J＝4.9,1.3Hz,1H),6.68(s,2H),5.15(p,J＝8.6Hz,1H),4.47(d,J＝5.8Hz,2H),2.61–2.52(m,2H),2.51(s,3H),2.44–2.35(m,2H),1.88–1.78(m,2H).LR-MS(ESI)m/z 442.2(M+1).
Example 90 preparation of tert-butyl-3- (4-amino-5- ((2-methyl-5- ((thiophen-3-ylmethyl) carbamoyl) phenyl) ethynyl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) azetidine-1-carbonate
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR (400 MHz, chloroform-d) delta 8.29 (s, 1H), 7.90 (d, j=2.0 hz, 1H), 7.66 (dd, j=8.0, 2.0hz, 1H), 7.55 (s, 1H), 7.36-7.29 (M, 2H), 7.24 (dd, j=3.0, 1.2hz, 4H), 7.10 (dd, j=4.9, 1.3hz, 1H), 6.39 (t, j=5.5 hz, 1H), 5.70 (s, 2H), 5.60-5.49 (M, 1H), 4.66 (d, j=5.5 hz, 2H), 4.49 (dd, j=9.6, 5.0hz, 2H), 2.55 (s, 3H), 1.48 (s, 5.5hz, 1.48 (LR) M-1H).
Example 91 preparation of 3- ((4-amino-7- (1-ethylazetidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
Step 1: to a round bottom flask was added compound 90 (0.3 g,0.55 mmol) and DCM (5 mL), HCl. Dioxane solution (0.5 mL,2 mmol) was added and stirred overnight at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure to give 91-IM as a yellow solid (0.26 g, yield: 98.2%) which was used in the next step without further purification.
Step 2: 106-IM (80 mg,0.17 mmol) obtained in the previous step, K, was added to a round bottom flask 2 CO 3 (115 mg,0.84 mmol) and anhydrous DMF (2 mL), IEt (16. Mu.L, 0.2 mmol) was added dropwise and reacted overnight at room temperature. After the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, and the organic phases were combined and separated with H 2 O, naCl washing with an aqueous solution of anhydrous Na 2 SO 4 DryingEvaporating the solvent under reduced pressure, and separating by column chromatography to obtain 3- ((4-amino-7- (1-ethylazetidin-3-yl) -7H-pyrrole [2, 3-d)]And pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide 25mg (white solid; yield: 32%). 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.9Hz,1H),8.16(s,1H),8.07(d,J＝1.9Hz,1H),8.03(s,1H),7.80(dd,J＝8.0,2.0Hz,1H),7.49(dd,J＝4.9,2.9Hz,1H),7.42(d,J＝8.0Hz,1H),7.33(dd,J＝2.9,1.2Hz,1H),7.09(dd,J＝5.0,1.3Hz,1H),6.73(s,2H),5.29–5.18(m,1H),4.47(d,J＝5.8Hz,2H),3.83–3.67(m,2H),3.56–3.37(m,2H),2.66–2.54(m,2H),2.52(s,3H),0.95(t,J＝7.1Hz,3H).LR-MS(ESI)m/z 471.2(M+1).
Example 92 preparation of 3- ((4-amino-7- (1-isopropylazetidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 91. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝6.0Hz,1H),8.17(s,1H),8.05(d,J＝2.0Hz,1H),8.03(s,1H),7.81(d,J＝8.0Hz,1H),7.51(dd,J＝4.9,2.9Hz,1H),7.42(d,J＝8.0Hz,1H),7.33(dd,J＝2.9,1.2Hz,1H),7.09(dd,J＝5.0,1.3Hz,1H),6.67(s,2H),5.27–5.18(m,1H),4.45(d,J＝5.9Hz,2H),3.83–3.67(m,2H),3.52–3.34(m,2H),2.88–2.65(m,1H),2.52(s,3H),1.05(d,J＝5.1Hz,6H).LR-MS(ESI)m/z485.2(M+1).
Example 93 preparation of- ((4-amino-7- (1-cyclopropylazetidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 91. 1 H NMR(400MHz,DMSO-d 6 )δ9.01(t,J＝6.0Hz,1H),8.14(s,1H),8.09(s,1H),8.03(s,1H),7.80(dd,J＝8.0,2.0Hz,1H),7.51(dd,J＝5.1,2.5Hz,1H),7.42(d,J＝8.0Hz,1H),7.33(d,J＝2.9Hz,1H),7.11(d,J＝5.0Hz,1H),6.68(s,2H),5.27–5.16(m,1H),4.45(d,J＝5.9Hz,2H),3.83–3.67(m,2H),3.56–3.37(m,2H),2.52(s,3H),2.46–2.34(m,1H),0.90–0.76(m,2H),0.64–0.52(m,2H).LR-MS(ESI)m/z483.2(M+1).
Example 94 preparation of 3- ((4-amino-7- (1-acetylazetidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
Into a round bottom flask was added compound 91-IM (80 mg,0.17 mmol), et 3 N (70. Mu.L, 0.5 mmol) and anhydrous DCM (3 mL), acetyl chloride (13. Mu.L, 0.18 mmol) was added dropwise in ice-bath and reacted at room temperature for 1h. After 0.2mL of methanol is added for quenching reaction, the solvent is evaporated under reduced pressure, and 3- ((4-amino-7- (1-acetyl azetidin-3-yl) -7H-pyrrole [2, 3-d) is separated by column chromatography]And pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide 15mg (light yellow solid; yield: 18.5%). 1 H NMR(400MHz,DMSO-d 6 )δ9.04(t,J＝5.7Hz,1H),8.17(s,1H),8.06(s,1H),7.79(d,J＝8.0Hz,1H),7.70(s,1H),7.49(s,1H),7.42(d,J＝8.0Hz,1H),7.34(s,1H),7.09(d,J＝5.0Hz,1H),6.71(s,2H),4.96–4.80(m,1H),4.47(d,J＝5.8Hz,2H),4.12–3.96(m,2H),3.93–3.76(m,2H),2.52(s,3H),2.01(s,3H).LR-MS(ESI)m/z484.2(M+1).
Example 95 preparation of 3- ((4-amino-7- (1-methanesulfonylazetidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 94, except that methanesulfonyl chloride was used instead of acetyl chloride. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.9Hz,1H),8.15(s,1H),8.05(s,1H),7.86(s,1H),7.78(dd,J＝8.0,1.9Hz,1H),7.48(dd,J＝5.0,3.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.33(d,J＝2.8Hz,1H),7.09(d,J＝4.9Hz,1H),6.66(s,2H),4.92–4.79(m,1H),4.46(d,J＝5.8Hz,2H),4.15–3.99(m,2H),3.94–3.78(m,2H),2.89(s,3H),2.52(s,3H).LR-MS(ESI)m/z 521.1(M+1).
Example 96 preparation of 3- ((4-amino-7- (3-oxocyclobutyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR (400 MHz, chloroform-d) delta 8.31 (s, 1H), 7.91 (d, j=2.0 hz, 1H), 7.65 (dd, j=8.0, 2.0hz, 1H), 7.37-7.30 (m, 3H), 7.24 (dd, j=2.9, 1.2hz, 1H), 7.10 (dd, j=4.9, 1.3hz, 1H), 6.35 (t, j=5.7 hz, 1H), 5.66 (s, 2H), 5.39-5.32 (m, 1H), 4.66 (d, j=5.5 hz, 2H), 3.87-3.63 (m, 4H), 2.54 (s, 3H) LR-MS (ESI) m/z 456.1(M+1).
Example 97 preparation of 3- ((4-amino-7- (3-hydroxycyclobutyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
Into a round bottom flask was added compound 96 (50 mg,0.11 mmol) and anhydrous THF (2 mL), naBH was added 4 (12 mg,0.33 mmol) was reacted at room temperature for 2h. Adding NH 4 The Cl aqueous solution is decompressed and evaporated to dryness, and the solvent is separated by column chromatography to obtain 3- ((4-amino-7- (3-hydroxycyclobutyl) -7H-pyrrole [2, 3-d)]And pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide 20mg (white solid; yield: 40%). 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.9Hz,1H),8.14(s,1H),8.06(d,J＝1.9Hz,1H),7.93(s,1H),7.79(d,J＝8.1Hz,1H),7.49(dd,J＝4.9,2.9Hz,1H),7.42(d,J＝8.1Hz,1H),7.33(s,1H),7.09(d,J＝4.9Hz,1H),6.69(s,2H),5.28(d,J＝7.0Hz,1H),4.73–4.63(m,1H),4.47(d,J＝5.8Hz,2H),4.08–3.92(m,1H),2.84–2.73(m,2H),2.52(s,3H),2.38–2.27(m,2H).LR-MS(ESI)m/z 458.2(M+1).
Example 98 preparation of 3- ((4-amino-7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ8.96(t,J＝6.0Hz,1H),8.12(d,J＝2.0Hz,1H),8.10(s,1H),7.77(dd,J＝7.6,1.9Hz,1H),7.54(s,1H),7.33(dd,J＝7.5,1.0Hz,1H),7.22(dd,J＝4.8,1.8Hz,1H),7.06(t,J＝1.6Hz,1H),7.04(dd,J＝4.9,1.6Hz,1H),6.69(s,2H),5.13–5.04(m,2H),4.96–4.88(m,1H),4.88–4.81(m,2H),4.55(d,J＝5.9Hz,2H),2.52(s,3H).LR-MS(ESI)m/z444.1(M+1).
Example 99 preparation of 3- ((4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.04(t,J＝5.9Hz,1H),8.17(s,1H),8.05(d,J＝1.9Hz,1H),7.83(s,1H),7.79(dd,J＝8.0,1.9Hz,1H),7.49(dd,J＝4.9,2.9Hz,1H),7.42(d,J＝8.0Hz,1H),7.36–7.31(m,1H),7.09(dd,J＝5.0,1.3Hz,1H),6.68(s,2H),5.04(m,1H),4.47(d,J＝5.8Hz,2H),2.52(s,3H),2.11(m,2H),1.95–1.82(m,4H),1.69(m,2H).LR-MS(ESI)m/z456.2(M+1).
Example 100 preparation of 3- ((4-amino-7- (tetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ8.96(t,J＝6.0Hz,1H),8.12(d,J＝2.0Hz,1H),8.10(s,1H),7.77(dd,J＝7.6,1.9Hz,1H),7.54(s,1H),7.33(dd,J＝7.5,1.0Hz,1H),7.22(dd,J＝4.8,1.8Hz,1H),7.07–7.01(m,2H),6.68(s,2H),4.55(d,J＝5.9Hz,2H),4.18–4.00(m,2H),3.98–3.76(m,3H),2.52(s,3H),2.26–2.14(m,1H),2.02–1.88(m,1H).LR-MS(ESI)m/z 458.2(M+1).
Example 101 preparation of tert-butyl-4- (4-amino-5- ((2-methyl-5 ((thiophen-3-yl) carbamoyl) phenyl) ethynyl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) piperidine-1-carbonate
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR (400 MHz, chloroform-d) delta 8.29 (s, 1H), 7.90 (d, j=2.0 hz, 1H), 7.65 (dd, j=8.0, 2.0hz, 1H), 7.32-7.27 (M, 2H), 7.27 (s, 1H), 7.22-7.20 (M, 1H), 7.08 (dd, j=5.0, 1.3hz, 1H), 6.61 (t, j=5.6 hz, 1H), 5.79 (s, 2H), 4.79 (tt, j=12.1, 4.0hz, 1H), 4.64 (d, j=5.6 hz, 2H), 4.41-4.19 (M, 2H), 2.98-2.81 (M, 2H), 2.52 (s, 3H), 2.08-2.01 (M, 2H), 1.89-1.80 (M, 2H), 4.79 (s, 2H), 4.79 (MS, 2H), 4.38M (48H).
Example 102 preparation of 3- ((4-amino-7- (1-methylpiperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.9Hz,1H),8.15(s,1H),8.05(d,J＝1.9Hz,1H),7.85(s,1H),7.79(dd,J＝8.0,1.9Hz,1H),7.48(dd,J＝5.0,3.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.33(d,J＝2.9Hz,1H),7.09(d,J＝4.9Hz,1H),6.67(s,2H),4.56–4.48(m,1H),4.46(d,J＝5.8Hz,2H),2.90(d,J＝7.1Hz,2H),2.51(s,3H),2.22(s,3H),2.12–1.96(m,4H),1.91–1.80(m,2H).LR-MS(ESI)m/z 485.2(M+1).
Example 103 preparation of 3- ((4-amino-7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ8.96(t,J＝6.0Hz,1H),8.10(s,1H),8.02(d,J＝2.0Hz,1H),7.77(dd,J＝7.6,1.9Hz,1H),7.54(s,1H),7.33(dd,J＝7.5,1.0Hz,1H),7.26–7.18(m,1H),7.09–7.01(m,2H),6.64(s,2H),4.48(d,J＝5.9Hz,2H),3.90–3.73(m,3H),3.52–3.34(m,2H),2.53(s,3H),2.04–1.88(m,2H),1.79–1.64(m,2H).LR-MS(ESI)m/z 472.2(M+1).
Example 104 preparation of 3- ((4-amino-7-cyclopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.9Hz,1H),8.15(s,1H),8.05(s,1H),7.86(s,1H),7.78(dd,J＝8.0,1.9Hz,1H),7.48(dd,J＝5.0,3.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.33(d,J＝2.8Hz,1H),7.09(d,J＝4.9Hz,1H),6.62(s,2H),5.01-4.92(m,1H),4.46(d,J＝5.8Hz,2H),2.52(s,3H),0.64–0.51(m,2H),0.41–0.26(m,2H).LR-MS(ESI)m/z 428.1(M+1).
Example 105 preparation of 3- ((4-amino-7- (pentan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.9Hz,1H),8.15(s,1H),8.05(d,J＝1.9Hz,1H),7.85(s,1H),7.79(dd,J＝8.0,1.9Hz,1H),7.48(dd,J＝5.0,3.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.33(d,J＝2.9Hz,1H),7.09(d,J＝4.9Hz,1H),6.67(s,2H),4.56–4.47(m,1H),2.52(s,3H),1.47–1.36(m,4H),0.83(t,J＝4.5Hz,6H).LR-MS(ESI)m/z 458.2(M+1).
Example 106 preparation of 3- ((4-amino-7-isobutyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.02(t,J＝5.8Hz,1H),8.19(s,1H),8.05(s,1H),7.84–7.71(m,2H),7.49(dd,J＝5.0,2.9Hz,1H),7.42(d,J＝8.0Hz,1H),7.33(s,1H),7.09(d,J＝5.4Hz,1H),6.68(s,2H),4.44(d,J＝5.8Hz,2H),4.02(d,J＝6.9Hz,2H),2.51(s,3H),2.05–1.89(m,1H),0.91(d,J＝4.6Hz,6H).LR-MS(ESI)m/z 444.2(M+1).
Example 107 preparation of 3- ((4-amino-7- ((3-methyloxetan-3-yl) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.9Hz,1H),8.12(s,1H),8.05(s,1H),7.86(s,1H),7.77(dd,J＝8.0,1.9Hz,1H),7.48(dd,J＝5.0,3.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.33(d,J＝2.8Hz,1H),7.09(d,J＝4.9Hz,1H),6.64(s,2H),4.46(d,J＝5.8Hz,2H),4.29(d,J＝9.3Hz,2H),4.14(d,J＝9.4Hz,2H),3.91(s,2H),2.52(s,3H),0.97(s,3H).LR-MS(ESI)m/z472.2(M+1).
Example 108 preparation of 3- ((7- (2-acetamidoethyl) -4-amino-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.04(t,J＝5.9Hz,1H),8.21(s,1H),8.06(d,J＝2.1Hz,1H),7.97(t,J＝5.6Hz,1H),7.85–7.72(m,2H),7.49(dd,J＝4.9,2.9Hz,1H),7.43(d,J＝8.0Hz,1H),7.33(s,1H),7.09(d,J＝5.0Hz,1H),6.78(s,2H),4.69(t,J＝6.5Hz,2H),4.45(d,J＝5.8Hz,2H),3.35–3.23(m,2H),2.51(s,3H),1.89(s,3H).LR-MS(ESI)m/z 473.2(M+1).
Example 109 preparation of 3- ((4-amino-7- (3-dimethylamino) -3-oxopropyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.01(t,J＝6.0Hz,1H),8.17(s,1H),8.06(d,J＝2.1Hz,1H),7.85–7.72(m,2H),7.49(dd,J＝4.9,2.9Hz,1H),7.43(d,J＝8.0Hz,1H),7.31(s,1H),7.09(d,J＝5.0Hz,1H),6.68(s,2H),4.83(t,J＝10.2Hz,2H),4.47(d,J＝6.0Hz,2H),2.76(s,6H),2.52(s,6H),2.41(t,J＝10.0Hz,2H).LR-MS(ESI)m/z 487.2(M+1).
Example 110 preparation of 3- ((4-amino-7- (2-fluoroethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.8Hz,1H),8.24(s,1H),8.06(d,J＝1.9Hz,1H),7.79(dd,J＝8.0,1.9Hz,1H),7.70(s,1H),7.49(dd,J＝4.9,2.9Hz,1H),7.42(d,J＝8.1Hz,1H),7.33(dd,J＝3.0,1.2Hz,1H),7.09(dd,J＝5.0,1.3Hz,1H),6.69(s,2H),4.46–4.26(m,2H),4.31(t,J＝5.5Hz,2H),4.12–3.98(m,2H),2.51(s,3H).LR-MS(ESI)m/z 434.1(M+1).
Example 111 preparation of 3- ((4-amino-7-hydroxyethyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.9Hz,1H),8.21(s,1H),8.06(d,J＝1.9Hz,1H),7.77(dd,J＝8.0,2.0Hz,1H),7.70(s,1H),7.49(dd,J＝4.9,2.9Hz,1H),7.42(d,J＝8.1Hz,1H),7.33(dd,J＝3.0,1.2Hz,1H),7.09(dd,J＝5.0,1.3Hz,1H),6.69(s,2H),4.96(t,J＝6.5Hz,1H),4.46(d,J＝5.8Hz,2H),4.32(t,J＝7.1Hz,2H),3.52–3.43(m,2H),2.53(s,3H).LR-MS(ESI)m/z 432.1(M+1).
Example 112 preparation of 3- ((4-amino-7- (2-hydroxy-2-methylpropyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.9Hz,1H),8.15(s,1H),8.06(d,J＝1.9Hz,1H),8.00(s,1H),7.79(dd,J＝8.0,1.9Hz,1H),7.49(dd,J＝5.0,3.0Hz,1H),7.42(d,J＝8.1Hz,1H),7.33(dd,J＝3.0,1.3Hz,1H),7.09(dd,J＝4.9,1.3Hz,1H),6.68(s,2H),4.67(s,1H),4.47(d,J＝5.8Hz,2H),3.92(s,2H),2.51(s,3H),1.23(s,6H).LR-MS(ESI)m/z 460.2(M+1).
Example 113 preparation of 3- ((4-amino-7- ((2R, 5S) -5- (hydroxymethyl) tetrahydrofuran-2-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ8.96(t,J＝6.0Hz,1H),8.12(d,J＝2.0Hz,1H),8.10(s,1H),7.77(dd,J＝7.6,1.9Hz,1H),7.54(s,1H),7.33(dd,J＝7.5,1.0Hz,1H),7.22(dd,J＝4.8,1.8Hz,1H),7.07–7.01(m,2H),6.62(s,2H),4.92–4.83(m,1H),4.55(d,J＝5.9Hz,2H),4.50(t,J＝7.4Hz,1H),4.42–4.31(m,1H),3.79(ddd,J＝11.8,7.4,6.3Hz,1H),3.54(ddd,J＝11.9,7.3,6.2Hz,1H),2.52(s,3H),2.22–2.06(m,2H),1.98–1.85(m,2H).LR-MS(ESI)m/z488.2(M+1).
Example 114 preparation of 3- ((4-amino-7- (3, 3-difluorocyclobutyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.9Hz,1H),8.14(s,1H),8.06(d,J＝1.9Hz,1H),7.93(s,1H),7.79(d,J＝8.1Hz,1H),7.49(dd,J＝4.9,2.9Hz,1H),7.42(d,J＝8.1Hz,1H),7.33(s,1H),7.09(d,J＝4.9Hz,1H),6.69(s,2H),4.73–4.63(m,1H),4.47(d,J＝5.8Hz,2H),2.73–2.54(m,2H),2.51(s,3H),2.47–2.25(m,2H).LR-MS(ESI)m/z 478.1(M+1).
Example 115 preparation of 3- ((4-amino-7- (3, 6-dihydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
Except for 7- (3, 6-dihydro-2H-pyran-4-yl) -5-iodo-7H-pyrrole [2,3-d ]]Substituted 5-iodo-7-methyl-7H-pyrrole [2,3-d ] with pyrimidyl-4-amine]And pyrimidine-4-amine was synthesized as in example 72. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.9Hz,1H),8.14(s,1H),8.06(d,J＝1.9Hz,1H),7.93(s,1H),7.79(d,J＝8.1Hz,1H),7.49(dd,J＝4.9,2.9Hz,1H),7.42(d,J＝8.1Hz,1H),7.33(s,1H),7.09(d,J＝4.9Hz,1H),6.69(s,2H),5.67–5.52(m,1H),4.47(d,J＝5.8Hz,2H),4.17(d,J＝4.6Hz,2H),3.92–3.71(m,2H),2.51(s,3H),2.01–1.84(m,2H).LR-MS(ESI)m/z 470.2(M+1).
Wherein the synthetic route of the intermediate 7- (3, 6-dihydro-2H-pyran-4-yl) -5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-4-amine is shown below.
Step 1: 7H-pyrrole [2,3-d ] was added to a round bottom flask ]And pyrimidin-4-amine (1.0 g,7.45 mmol), DMF-DMA (1.07 g,8.95 mmol) and DMF (20 mL) were reacted overnight at room temperature. Evaporating the solvent under reduced pressure to obtain crude product, adding DCM for redissolving, and respectively using H 2 Washing with aqueous solution of O and NaCl, passing through anhydrous Na 2 SO 4 After drying, the compound 115-2 950mg (yield: 67.4%) was isolated by column chromatography. 1 H NMR(400MHz,DMSO-d 6 )δ12.06(s,1H),8.73(s,1H),8.20(s,1H),7.19(d,J＝2.7Hz,1H),6.62(dd,J＝3.4,1.9Hz,1H),2.87(s,3H),2.83(s,3H).LR-MS(ESI)m/z 190.1(M+1).
Step 2: to a round bottom flask was added compound 115-2 (250 mg,1.32 mmol), 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (333 mg,1.59 mmol), copper acetate (29 mg,1.59 mmol), 2' -bipyridine (248 mg,1.59 mmol), anhydrous Na 2 CO 3 (420 mg,3.96 mmol) and DMAC (10 mL). Stirred for 4h at 90 ℃, DCM was added and washed three times with water. The organic phase was treated with anhydrous Na 2 SO 4 After drying, intermediate 115-3 was obtained by evaporation under reduced pressure without further purification.
Step 3: etOH (10 mL) and ethylenediamine (0.2 mL) were added to the previous step intermediate 115-3 and the reaction was refluxed for 16h. After the reaction, the mixture was distilled under reduced pressureThe solvent was dried and redissolved with DCM, washed with aqueous NaCl, dried over anhydrous Na 2 SO 4 After drying, the solvent was evaporated under reduced pressure, and the compound 115-4 160mg (total yield in two steps: 56%) was obtained by column chromatography. 1 H NMR(400MHz,DMSO-d 6 )δ8.71(s,1H),7.70(d,J＝5.7Hz,1H),7.52(d,J＝6.0Hz,1H),6.72(s,2H),5.20–4.97(m,1H),4.20–4.10(m,2H),3.88–3.82(m,2H),2.17–2.05(m,2H).LR-MS(ESI)m/z 217.1(M+1).
Step 4: to a round bottom flask was added compound 115-4 (160 mg,0.74 mmol), NIS (183 mg,0.81 mmol) and DMF (3 mL) and reacted at room temperature for 4h. After the reaction is finished, the solvent is evaporated to dryness under reduced pressure, and 7- (3, 6-dihydro-2H-pyran-4-yl) -5-iodo-7H-pyrrole [2,3-d ] is obtained by column chromatography separation ]And 180mg of pyrimidyl-4-amine (yield: 71%). 1 H NMR(400MHz,DMSO-d 6 )δ8.73(s,1H),7.68(s,1H),6.68(s,2H),5.13–4.96(m,1H),4.21–3.88(m,4H),2.13–2.01(m,2H).LR-MS(ESI)m/z 343.1(M+1).
Example 116 preparation of 3- ((4-amino-7- ((1-methyl-1H-pyrazol-4-yl) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding halide was used instead of methyl iodide in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.02(t,J＝5.9Hz,1H),8.15(s,1H),8.05(s,1H),7.86(s,1H),7.78(dd,J＝8.0,1.9Hz,1H),7.48(dd,J＝5.0,3.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.36(s,2H),7.33(d,J＝2.8Hz,1H),7.09(d,J＝4.9Hz,1H),6.64(s,2H),5.57(s,2H),4.46(d,J＝6.0Hz,2H),3.94(s,3H),2.52(s,3H).LR-MS(ESI)m/z 482.2(M+1).
Example 117 preparation of- ((4-amino-7- (1-methyl-1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 115, except that the corresponding diazole derivative was used in place of 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester in step 2. 1 H NMR(400MHz,DMSO-d 6 )δ9.02(t,J＝6.0Hz,1H),8.14(s,1H),8.05(d,J＝1.9Hz,1H),7.93(s,1H),7.79(d,J＝8.1Hz,1H),7.52(d,J＝1.8Hz,1H),7.49(dd,J＝4.9,2.9Hz,1H),7.42(d,J＝8.1Hz,1H),7.33(s,1H),7.30(d,J＝1.6Hz,1H),7.09(d,J＝4.9Hz,1H),6.69(s,2H),4.47(d,J＝5.8Hz,2H),2.51(s,3H),3.89(s,3H).LR-MS(ESI)m/z 468.2(M+1).
Example 118 preparation of 3- ((4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (1- (thiophen-3-yl) cyclopropyl) benzamide
The synthesis was as in example 72, except that the corresponding 2-iodopropane was used instead of iodomethane in step 1, and the corresponding intermediate was obtained by referring to the procedure of step 3 of example 1. 1 H NMR(400MHz,DMSO-d 6 )δ8.86(s,1H),8.12(d,J＝2.0Hz,1H),8.10(s,1H),7.77(dd,J＝7.6,1.9Hz,1H),7.54(s,1H),7.33(d,J＝7.6,1H),7.25(dd,J＝5.2,1.9Hz,1H),7.10–7.05(m,2H),6.64(s,2H),4.94–4.75(m,1H),2.45(d,J＝0.9Hz,3H),1.32(d,J＝6.5Hz,6H),0.95–0.79(m,2H),0.71–0.54(m,2H).LR-MS(ESI)m/z 456.2(M+1).
Example 119 preparation of 3- ((4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl-d 2) benzamide
The synthesis was as in example 72, except that the corresponding 2-iodopropane was used instead of iodomethane in step 1, and the corresponding intermediate was obtained by referring to the procedure of step 3 of example 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(s,1H),8.17(s,1H),8.05(s,1H),7.86(s,1H),7.78(dd,J＝8.0,1.9Hz,1H),7.48(dd,J＝5.0,3.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.33(d,J＝2.8Hz,1H),7.09(d,J＝4.9Hz,1H),6.65(s,2H),4.92(hept,J＝7.7Hz,1H),2.52(s,3H),1.45(d,J＝6.7Hz,6H).LR-MS(ESI)m/z432.2(M+1).
Example 120 preparation of 3- ((4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-2-ylmethyl) benzamide
The synthesis was as in example 72, except that the corresponding 2-iodopropane was used instead of iodomethane in step 1, and the corresponding intermediate was obtained by referring to the procedure of step 3 of example 1. 1 H NMR(400MHz,DMSO-d 6 )δ8.98(t,J＝6.0Hz,1H),8.12(d,J＝2.0Hz,1H),8.10(s,1H),7.77(dd,J＝7.6,1.9Hz,1H),7.54(s,1H),7.44(dd,J＝5.1,1.8Hz,1H),7.33(dd,J＝7.5,1.0Hz,1H),7.12(dd,J＝6.4,1.8Hz,1H),7.02(dd,J＝6.4,5.1Hz,1H),6.64(s,2H),4.89–4.81(m,1H),4.45(d,J＝5.9Hz,2H),2.53(s,3H),1.34(d,J＝4.6Hz,6H).LR-MS(ESI)m/z 430.2(M+1).
Example 121 preparation of 3- ((4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -N- ((5-chlorothien-2-yl) methyl) -4-methylbenzamide
The synthesis was as in example 72, except that the corresponding 2-iodopropane was used instead of iodomethane in step 1, and the corresponding intermediate was obtained by referring to the procedure of step 3 of example 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.04(t,J＝8.0Hz,1H),8.36–8.29(m,2H),7.98(dd,J＝7.6,1.9Hz,1H),7.75(s,1H),7.54(d,J＝7.5Hz,1H),7.33(d,J＝6.4Hz,1H),7.27(d,J＝6.4Hz,1H),6.67(s,2H),5.12–5.03(m,1H),4.56(d,J＝8.0Hz,2H),2.54(s,3H),1.43(d,J＝4.6Hz,6H).LR-MS(ESI)m/z 464.1(M+1).
Example 122 preparation of 3- ((4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -N- ((5-cyclopropylthiophene-2-yl) methyl) -4-methylbenzamide
The synthesis was as in example 72, except that the corresponding 2-iodopropane was used instead of iodomethane in step 1, and the corresponding intermediate was obtained by referring to the procedure of step 3 of example 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.02(t,J＝5.8Hz,1H),8.31(d,J＝2.0Hz,1H),8.29(s,1H),7.96(dd,J＝7.6,1.9Hz,1H),7.73(s,1H),7.52(dd,J＝7.5,1.0Hz,1H),7.15–7.07(m,2H),6.62(s,2H),5.10–4.98(m,1H),4.54(d,J＝6.0Hz,2H),2.64(s,3H),2.05–1.93(m,1H),1.51(d,J＝4.6Hz,6H),0.91–0.70(m,4H).LR-MS(ESI)m/z 470.2(M+1).
Example 123 preparation of 3- ((4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -N- ((6-fluoropyridin-3-yl) methyl) -4-methylbenzamide
The synthesis was as in example 72, except that the corresponding 2-iodopropane was used instead of iodomethane in step 1, and the corresponding intermediate was obtained by referring to the procedure of step 3 of example 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.03(t,J＝5.8Hz,1H),8.42–8.37(m,2H),8.19(d,J＝2.0Hz,1H),8.17(s,1H),7.84(dd,J＝7.6,1.9Hz,1H),7.61(s,1H),7.40(dd,J＝7.5,1.0Hz,1H),7.23–7.08(m,1H),6.72(s,2H),4.97–4.85(m,1H),4.47(d,J＝5.7Hz,2H),2.52(s,3H),1.39(d,J＝4.7Hz,6H).LR-MS(ESI)m/z 443.2(M+1).
Example 124 preparation of 3- ((4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- ((6-methylpyridin-3-yl) methyl) benzamide
The synthesis was as in example 72, except that the corresponding 2-iodopropane was used instead of iodomethane in step 1, and the corresponding intermediate was obtained by referring to the procedure of step 3 of example 1. 1 H NMR(400MHz,DMSO-d 6 )δ8.96(t,J＝6.0Hz,1H),8.55(d,J＝2.3Hz,1H),8.12(d,J＝2.0Hz,1H),8.10(s,1H),7.92(dd,J＝7.5,2.2Hz,1H),7.77(dd,J＝7.6,1.9Hz,1H),7.54(s,1H),7.33(dd,J＝7.5,1.1Hz,1H),7.29(d,J＝7.5Hz,1H),6.64(s,2H),4.89–4.82(m,1H),4.50(d,J＝5.7Hz,2H),2.58(s,3H),2.52(s,3H),1.34(d,J＝4.9Hz,6H).LR-MS(ESI)m/z 439.2(M+1).
Example 125 preparation of 3- ((4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -N- ((6-cyclopropylpyridin-3-yl) methyl) -4-methylbenzamide
The synthesis was as in example 72, except that the corresponding 2-iodopropane was used instead of iodomethane in step 1, and the corresponding intermediate was obtained by referring to the procedure of step 3 of example 1. 1 H NMR(400MHz,DMSO-d 6 )δ9.02(t,J＝6.0Hz,1H),8.52(d,J＝2.1Hz,1H),8.09(d,J＝2.0Hz,1H),8.04(s,1H),7.92(dd,J＝7.5,1.9Hz,1H),7.77(dd,J＝7.6,1.9Hz,1H),7.54(s,1H),7.33(d,J＝7.5Hz,1H),7.29(d,J＝7.5Hz,1H),6.64(s,2H),4.89–4.82(m,1H),4.45(d,J＝5.7Hz,2H),3.31–2.89(m,1H),2.53(s,3H),1.34(d,J＝4.9Hz,6H),0.98–0.73(m,4H).LR-MS(ESI)m/z 465.2(M+1).
Example 126 preparation of ethyl-4-amino-5- ((2-methyl-5- ((thiophen-3-ylmethyl) carbamoyl) phenyl) ethynyl) -7H-pyrrolo [2,3-d ] pyrimidine-7-carboxylate
Except ethyl-4-amino-5-iodo-7H-pyrrole [2,3-d ]]Substituted 5-iodo-7-methyl-7H-pyrrole [2,3-d ] with pyrimidine-7-carbonate (126-3)]And pyrimidine-4-amine was synthesized as in example 72. 1 H NMR(400MHz,DMSO-d 6 )δ8.96(t,J＝5.8Hz,1H),8.13(s,1H),8.12(d,J＝2.0Hz,1H),7.77(dd,J＝7.6,1.9Hz,1H),7.72(s,1H),7.33(dd,J＝7.5,1.0Hz,1H),7.22(dd,J＝4.8,1.8Hz,1H),7.07–7.02(m,2H),6.70(s,2H),4.55(d,J＝5.9Hz,2H),4.36(q,J＝6.2Hz,2H),2.45(d,J＝0.9Hz,3H),1.26(t,J＝5.9Hz,3H).LR-MS(ESI)m/z 460.1(M+1).
The synthesis method of the intermediate 126-3 is as follows:
step 1: to a round bottom flask was added 115-2 (0.5 g,2.64 mmol) and anhydrous THF (30 mL), naH (60%, 211 mg) was added under ice-bath, and after stirring for 30 minutes, chloroformylethyl (430 mg,3.96 mmol) was added and reacted at room temperature for 2 hours. After the completion of the reaction, the reaction was quenched by dropwise addition of saturated aqueous ammonium chloride solution in an ice bath, extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to give 142-1 (400 mg, yellow oil, yield 57.9%). 1 H NMR(400MHz,DMSO-d 6 )δ9.03(s,1H),8.20(s,1H),7.23(d,J＝2.7Hz,1H),6.62(dd,J＝3.4,1.9Hz,1H),4.36(q,J＝4.2Hz,2H),2.83(s,6H),1.26(t,J＝4.3Hz,3H).LR-MS(ESI)m/z 388.1(M+1).
Step 2 and step 3 126-3 was obtained as a brown solid by step 3 and step 4, respectively, of reference example 115. 1 H NMR(400MHz,DMSO-d 6 )δ8.63(s,1H),7.16(s,1H),6.65(s,2H),4.36(q,J＝4.2Hz,2H),1.26(t,J＝4.3Hz,3H).LR-MS(ESI)m/z 333.1(M+1).
Example 127 preparation of 3- ((4-amino-7- (cyclopropcarbamoyl) -7-H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- (thiophen-3-ylmethyl) benzamide
The synthesis was as in example 126, except that chloroformyl cyclopropane was used in place of chloroformylethyl ester in step 1. 1 H NMR(400MHz,DMSO-d 6 )δ8.96(t,J＝6.0Hz,1H),8.13(s,1H),8.12(d,J＝2.0Hz,1H),7.77(dd,J＝7.6,1.9Hz,1H),7.37–7.29(m,1H),7.30(s,1H),7.22(dd,J＝4.8,1.8Hz,1H),7.06(t,J＝1.6Hz,1H),7.04(dd,J＝4.9,1.6Hz,1H),6.62(s,2H),4.55(d,J＝5.9Hz,2H),2.53(s,3H),1.92–1.80(m,1H),1.20–0.99(m,4H).LR-MS(ESI)m/z 456.1(M+1).
Example 128 preparation of 3- ((4-amino-7-isopropyl-7-H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- ((5-methylthiophene-3-yl) methyl) benzamide
The synthesis method was as described in example 72, except that 2-iodopropane was used instead of iodomethane in step 1, and 3-iodo-4-methyl-N- (3-methylthiophene-3-ylmethyl) benzamide was used instead of 3-iodo-4-methyl-N- (3-methylthiomethyl) benzamide in step 3. 1 H NMR (500 MHz, chloroform-d) δ8.84 (t, j=5.8 hz, 1H), 8.18 (s, 1H), 7.87 (d, j=1.9 hz, 1H), 7.77 (dd, j=8.1, 2.0hz, 1H), 7.55 (s, 1H), 7.32 (dd, j=8.1, 1.0hz, 1H), 6.90 (d, j=1.6 hz, 1H), 6.68 (dd, j=1.6, 0.7hz, 1H), 5.96 (s, 2H), 4.74-4.69 (M, 1H), 4.51 (d, j=5.7 hz, 2H), 2.52 (s, 3H), 2.36 (s, 3H), 1.53 (d, j=4.9 hz, 6H) LR-MS (ESI) M/z 444.2 (m+1).
Example 129 preparation of 3- ((4-amino-7-isopropyl-7-H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -N- ((5-chlorothien-3-yl) methyl) -4-methylbenzamide
The synthesis method was as described in example 72, except that 2-iodopropane was used instead of iodomethane in step 1, and 3-iodo-4-methyl-N- (3-thiofuran-3-ylmethyl) benzamide was used instead of 3-iodo-4-methyl-N- (3-ylmethyl) benzamide in step 3. 1 H NMR(500MHz,DMSO-d 6 )δ8.92(t,J＝5.9Hz,1H),8.19(s,1H),7.87(d,J＝1.9Hz,1H),7.80(dd,J＝8.1,1.9Hz,1H),7.55(s,1H),7.33(dd,J＝8.1,1.0Hz,1H),7.03(d,J＝1.8Hz,1H),6.87(d,J＝1.6Hz,1H),6.58(s,2H),4.77–4.68(m,1H),4.54(d,J＝6.0Hz,2H),253(s,3H),1.50(d,J＝4.9Hz,6H).LR-MS(ESI)m/z 464.1(M+1).
Example 130 preparation of 3- ((4-amino-7-isopropyl-7-H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -N- ((5-methoxythiophen-2-yl) methyl) -4-methylbenzamide
The synthesis method was as described in example 72, except that 2-iodopropane was used instead of iodomethane in step 1, and 3-iodo-4-methyl-N- (3-thiofuran-3-ylmethyl) benzamide was used instead of 3-iodo-4-methyl-N- (5-methoxythiofuran-2-ylmethyl) benzamide in step 3. 1 H NMR(500MHz,DMSO-d 6 )δ9.02(t,J＝6.0Hz,1H),8.25(s,1H),7.94(d,J＝1.9Hz,1H),7.87(dd,J＝8.2,1.9Hz,1H),7.62(s,1H),7.41–7.37(m,1H),6.97(d,J＝7.0Hz,1H),6.87(d,J＝7.0Hz,1H),6.61(s,2H),4.85–4.77(m,1H),4.58(d,J＝5.6Hz,2H),3.93(s,3H),2.52(s,3H),1.56(d,J＝4.9Hz,6H).LR-MS(ESI)m/z 460.2(M+1).
Example 131 preparation of 3- ((4-amino-7-isopropyl-7-H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethynyl) -4-methyl-N- ((5-methylthiophene-2-yl) methyl) benzamide
The synthesis method was as described in example 72, except that 2-iodopropane was used instead of iodomethane in step 1, and 3-iodo-4-methyl-N- (3-thiofuran-3-ylmethyl) benzamide was used instead of 3-iodo-4-methyl-N- (5-methylthiophene-2-ylmethyl) benzamide in step 3. 1 H NMR(400MHz,DMSO-d 6 )δ8.90(t,J＝5.8Hz,1H),8.19(s,1H),7.87(d,J＝1.9Hz,1H),7.80(dd,J＝8.1,1.9Hz,1H),7.55(d,J＝0.7Hz,1H),7.33(dd,J＝8.1,1.0Hz,1H),6.99(d,J＝6.3Hz,1H),6.89(d,J＝6.3Hz,1H),6.61(s,2H),4.79–4.69(m,1H),4.54(d,J＝5.7Hz,2H),2.52(s,3H),2.35(s,3H),1.50(d,J＝4.9Hz,6H).LR-MS(ESI)m/z 444.2(M+1).
Example 132 preparation of ethyl (7-isopropyl-5- ((2-methyl-5- ((thiophen-3-ylmethyl) carbamoyl) phenyl) ethynyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) carbamate
To a round bottom flask was added compound 77 (80 mg,0.186 mmol), DIPEA (72 mg,0.559 mmol) and anhydrous DMF (2 mL), ethyl chloroformate (30 mg,0.279 mmol) was added dropwise under ice, and after stirring for 1 hour, the reaction was quenched by dropwise methanol. The solvent was evaporated under reduced pressure, and compound 132 (30 mg, yellow solid, yield: 32%) was obtained by column chromatography. 1 H NMR (400 MHz, chloroform-d) delta 8.71 (s, 1H), 8.42 (s, 1H), 8.02 (s, 1H), 7.74 (d, j=8.1 hz, 1H), 7.47 (s, 1H), 7.37-7.29 (M, 2H), 7.26-7.22 (M, 1H), 7.11 (d, j=5.0 hz, 1H), 6.63 (br s, 1H), 5.12 (p, j=6.6 hz, 1H), 4.67 (d, j=5.5 hz, 2H), 4.29 (q, j=7.0 hz, 2H), 2.58 (s, 3H), 1.55 (d, j=6.8 hz, 6H), 1.30 (t, j=7.3 hz, 3H) LR-MS (ESI) M/z 502.2 (m+1).
Example 133 preparation of isopropyl (7-isopropyl-5- ((2-methyl-5- ((thiophen-3-ylmethyl) carbamoyl) phenyl) ethynyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) carbamate
The synthesis was as in example 132, except that isopropyl chloroformate was used instead of ethyl chloroformate. 1 H NMR(400MHz,DMSO-d 6 )δ9.92(s,1H),8.90(t,J＝6.0Hz,1H),8.29(s,1H),7.87(d,J＝1.9Hz,1H),7.80(dd,J＝8.1,1.9Hz,1H),7.57(s,1H),7.36–7.29(m,2H),7.24(t,J＝1.7Hz,1H),6.98(dd,J＝5.0,1.7Hz,1H),5.03–4.92(m,1H),4.78–4.69(m,1H),4.55(d,J＝5.9Hz,2H),2.52(s,3H),1.50(d,J＝4.9Hz,6H),1.29(d,J＝5.7Hz,6H).LR-MS(ESI)m/z 516.2(M+1).
(II) biological Activity detection examples
Experimental example one: proliferation inhibitory Activity of Compounds against KIT cells harboring different drug resistant mutations
The experimental method comprises the following steps:
the effect of the compounds on cell proliferation was examined using the MTT method. Collecting cells in good condition, inoculating the cells to a 96-well plate, and adding compounds with different concentrations; at 37deg.C with 5% CO 2 Culturing in a saturated humidity incubator for 72 hours (h). After the drug action is finished, MTT is added into each hole, and the temperature is continued to 37 ℃ and 5% CO is added 2 Culturing in a saturated humidity incubator for 4 hours. Adding triple solution (10% SDS,5% isobutanol, 0.01mol/L HCl), and placing in a 37 ℃ incubator for 12 hours to ensure that the blue-violet formazan is completely dissolved; OD values were measured on a microplate reader at 570nm and 690nm wavelengths. The inhibition of cells by the compounds was calculated according to the following formula:
inhibition (%) = (control well OD value-dosing well OD value)/control well OD value x 100%
Calculation of Compound IC with Graphpad Prism 8.0 software 50 And a concentration (log) -inhibition plot was generated.
Experimental results:
the inhibitory activity of the compounds and positive drugs Ripretinib of the embodiment of the invention on 32D KIT D816V cell proliferation is shown in Table 2:
inhibition of 32D KIT D816V cell proliferation by the compounds of Table 2
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Conclusion of experiment: as can be seen from Table 2, the heteroaromatic alkynyl compounds of the examples of the present invention have significant inhibitory activity on 32D KIT D816V cell proliferation, with 33 compounds being superior to Ripretinib. Examples 76, 77, 99 and 120 have IC inhibitory Activity against 32D KIT D816V cell proliferation 50 The value is less than 1nM, which is obviously better than the positive drug Ripretinib, and shows that the compounds have the advantage of strong inhibition of proliferation of cells carrying KIT D816V drug-resistant mutation.
Representative compounds and positive drug Ripretinib were selected for further evaluation of their proliferation inhibitory activity against other KIT mutant cells (32D KIT V559D, 32D KIT V559D-V654A, 32D KIT V559D-Y823D and 32D KIT V559D-N822K), KIT wild-type cells (NCI-H526, mo7e, HMC-1) and 32D cells, and the results are shown in Table 3.
Table 3 comparison of representative Compounds for inhibition of proliferation of wild-type and normal cells carrying different mutant KIT
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NT:not test.
The result shows that the representative compound has strong inhibition activity on cell proliferation carrying different mutation KIT of V559D, V559D-V654A, V D-Y823D and V559D-N822K, and shows that the compound has broad-spectrum inhibition mutation Advantages of KIT; at the same time, representative compounds have weaker activity against wild-type KIT-dependent cell lines and have a higher therapeutic index than mutant KIT, e.g., against KIT D861V The selection index of (2) is higher than 490 times and is superior to the positive drug, ripriretinib. In addition, the compound has no cytotoxicity to 32D normal cells, shows that the compound has good selectivity and can avoid potential off-target toxic and side effects.
Representative compounds were further tested for proliferation inhibitory activity against other wild-type target-dependent cell lines, including pdgfrα (U118 MG), EGFR (a 431), and the results are shown in table 4.
The result shows that the representative compound has no cytotoxicity to wild PDGFR and EGFR dependent cell lines, and initially shows good target selectivity; the positive drug ripratinib has obvious inhibition activity on PDGFR-dependent U118MG cells, and has low therapeutic index.
Table 4 proliferation inhibitory Activity of representative Compounds against PDGFR alpha and EGFR-dependent cell lines
Experimental example two: representative Compounds 27, 48, 77 and 85 affect KIT and downstream signaling mediated thereby
Western Blot (Western Blot) detection of effect of compounds on KIT and downstream signaling pathways in 32D KIT D816V,32D KIT V559D and 32D KIT V559D-V654A cells
The experimental method comprises the following steps:
inoculating cells into six-hole plate, adding medicines with different concentrations, and heating at 37deg.C and 5% CO 2 The mixture was treated in a saturated humidity incubator for 4 hours. Cells were lysed on ice with 1 XSDS gel loading buffer (50 mM Tris-HCl (pH 6.8), 100mM DTT,2% SDS,10% glycerol, 0.1% bromophenol blue). Heating cell lysate in boiling water bath for 10min for denaturation, performing SDS-PAGE electrophoresis, transferring protein to PVDF membrane after electrophoresis, sealing in sealing solution (5% skimmed milk powder diluted in TBST) at room temperature for 1 hr, washing, adding corresponding I antibody and II antibody, and applying ECL reagentAnd developing, and finally observing and photographing in an ECL chemiluminescent imaging system.
Conclusion of experiment:
representative compounds and positive agent Ripretinib inhibited KIT and downstream signaling pathway results in tumor cells harboring different mutant KIT are shown in FIGS. 1-3. From FIGS. 1-3, it can be seen that the heteroaryl ring alkynyl-containing compounds of the examples of the present invention significantly inhibit activation of various mutant forms of KIT and its downstream signaling pathways at the cellular level.
Experimental example three: in vivo efficacy evaluation test of mice
The experimental method comprises the following steps:
BALB/c-nu nude mice, 5-6 weeks, male. Each nude mouse is inoculated with 32D KIT D816V cells subcutaneously until the average tumor volume reaches 100mm 3 Animals were then grouped according to tumor volume (D0). Mice were given intragastrically (i.g.), 2 times daily, at a volume of 10mL/kg; the solvent group gives the same volume of "solvent"; tumor volumes were measured 2 times per week, mice weights were weighed, and data were recorded.
Compounds 77, 85, and Repritinib all use "solvent" (5% DMSO/5% EtOH/40% PEG 400/50% H) 2 And (3) preparing O.
Experimental results:
compound 85 (30, 100mg/kg, i.g., BID x 12) dose-dependently inhibited growth of 32d KIT d816v nude mice with tumor inhibition rates of 20% and 50%, respectively; compound 77 (20, 40mg/kg, i.g., BID x 12) also dose-dependently inhibited growth of subcutaneous engraftment tumors in 32d KIT d816v nude mice at tumor inhibition rates of 45% and 71%, respectively; the tumor inhibition rates of Ripritinib (30, 100mg/kg, i.g., BID×12) on 32D KIT D816V nude mice were 13% and 21%, respectively; the tumor-bearing mice can better tolerate the drugs, and no obvious symptoms such as weight reduction and the like occur. In comparison, compounds 77, 85 all had significantly greater efficacy against 32d KIT d816v nude mice with subcutaneous transplants than riretinib (P <0.05, high dose group comparison).
In conclusion, the compound containing the heteroaromatic alkynyl has strong inhibitory activity on 32D KIT D816V cells; meanwhile, representative compounds 27, 48, 77 and 85 have strong inhibitory activity on KIT in different mutation forms of V559D, V D-V654A, V D/Y823D and V559D/N822K, and the compounds have the advantages of strong and broad-spectrum inhibition on different types of mutation KIT. The representative compounds 27, 48, 77 and 85 have weak inhibition effect on 32D normal cells and cells carrying wild KIT, PDGRF alpha and EGFR, which shows that the compounds have high selectivity and can avoid the toxic and side effects of related off-target; importantly, the representative compounds 77 and 85 have obvious drug effects on a 32D KIT D816V nude mice subcutaneous transplantation tumor model; the drug effect of the compound is obviously stronger than that of a reference compound Riprestinib (P is less than 0.05), which shows that the compound containing the heteroaromatic alkynyl has the advantage of stronger in vivo drug effect.
The preferred embodiments of the present invention have been described in detail above with reference to the accompanying drawings, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all such simple modifications belong to the protection scope of the present invention.

Claims (10)

1. A compound of formula (I), or a deuterated compound, pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof:
wherein:
x is selected from- (C (R) a )(R b )) q -；
Wherein R is a 、R b Each independently selected from hydrogen, deuterium, halogen, C1-4 alkyl; or R attached to the same carbon atom a 、R b Together with the carbon atom, form a 3-5 membered carbocyclic ring;
q is selected from 1, 2;
R 1 selected from hydrogen, halogen, C1-6 alkyl;
ring M 1 Selected from the following structures:
wherein:
A 1 、A 2 each independently CR H4 Or an N atom;
A 3 is CR (CR) H2 Or an N atom;
A 4 is CR (CR) H3 、NR H3 Or an N atom;
z is selected from unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted 5-10 membered heterocyclyl; the substitution means that the above groups are each independently substituted with 1 to 5R 2 Group substitution; or Z and the carbon atom to which it is attached and the adjacent A 1 Or A 2 Together form a substituted or unsubstituted ring W 1 The substitution means ring W 1 Is covered by 1-5R 2 Group substitution; in heteroaryl, heterocyclyl, or ring W 1 Optionally substituted by a corresponding number of C (=o) groups, and optionally oxidized to form S-oxide or N-oxide;
w is unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-7 membered heteroaryl or unsubstituted or substituted 5-7 membered heterocyclyl; the substitution means by 1-5R 2 Group substitution; in aryl, heteroaryl or heterocyclyl, one or more ring C atoms are optionally replaced by a corresponding number of C (=o) groups, one or more ring S or N atoms are optionally oxidized to form S-oxide or N-oxide;
the R is 2 Each independently selected from halogen, cyano, C1-6 alkyl, C1-6 heteroalkyl, C1-6 alkoxycarbonyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C4-8 cycloalkenyl, 4-8 membered heterocycloalkenyl, C6-10 aryl, 5-7 membered heteroaryl, 5-7 membered heterocyclyl, -C (=O) (C1-6 alkyl), -C (=O) (C3-6 cycloalkyl), -OR 3 、-N(R 3 ) 2 - (C1-6 alkyl) OR 3 、-C(＝O)N(R 3 ) 2 - (C1-6 alkyl) -C (=O) N (R) 3 ) 2 、-SR 3 、-S(＝O)R 3 、-S(＝O) 2 R 3 、-N(R 3 )C(＝O)R 3 - (C1-6 alkyl) -N(R 3 )C(＝O)R 3 、-N(R 3 )S(＝O) 2 R 3 、-P(＝O)(R 3 )(R 3 ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein the C1-6 alkyl, C1-6 heteroalkyl, C1-6 alkoxycarbonyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 4-8 membered cycloalkenyl, 4-8 membered heterocycloalkenyl, C6-10 aryl, 5-7 membered heteroaryl, 5-7 membered heterocyclyl are optionally substituted with 1-5R 3 Substitution; or alternatively
Two R 2 And the atoms to which they are attached together form a substituted or unsubstituted 3-7 membered carbocyclic or heterocyclic ring, said substitution being by 1-5R 3 Substitution;
the R is 3 Each independently selected from hydroxy, cyano, amino, halogen, C1-6 alkyl, C1-6 alkoxycarbonyl, C3-C6 cycloalkyl, C1-6 haloalkyl, hydroxyc 1-6 alkyl, -NH (C3-6 cycloalkyl), -NHC (=o) (C1-6 alkyl), cyano-substituted 5-7 membered heterocyclylmethyl comprising one or more selected from O, N, S;
R H1 、R H2 and R is H4 Each independently selected from hydrogen, halogen, amino, cyano, hydroxy, -N (R) 4 )(R 5 )；
The R is 4 、R 5 Each independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C1-6 alkanoyl, C3-6 cycloalkylacyl;
R H3 selected from hydrogen, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C1-6 heteroalkyl, -C (=O) OC1-6 alkyl, -C (=O) OC3-6 cycloalkyl, -C (=O) C1-6 alkyl, -C (=O) C3-6 cycloalkyl, unsubstituted or substituted C2-6 alkenyl, unsubstituted or substituted C4-6 cycloalkenyl, unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-7 membered heteroaryl, unsubstituted or substituted 4-7 membered heterocyclyl; the substitution means that each is independently substituted with 1 to 5R 6 Substituted; in cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, one or more ring C atoms are optionally replaced by a corresponding number of C (=o) groups, one or more ring S or N atoms are optionally oxidized to form S-oxide or N-oxide;
the R is 6 Each independently selected from halogen, cyano, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C4-8 cycloalkenyl, C6-10 aryl, 5-7 membered heteroaryl, 5-7 membered heterocyclyl, -C (=O) R 7 、OR 7 、-N(R 7 ) 2 - (C1-6 alkyl) OR 7 、-C(＝O)N(R 7 ) 2 - (C1-6 alkyl) -C (=O) N (R) 7 ) 2 、-SR 7 、-S(＝O)R 7 、-S(＝O) 2 R 7 、-N(R 7 )C(＝O)R 7 - (C1-6 alkyl) -N (R) 7 )C(＝O)R 7 、-N(R 7 )S(＝O) 2 (R 7 )、-P(＝O)(R 7 )(R 7 ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein the C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C4-8 cycloalkenyl, C6-10 aryl, 5-7 membered heteroaryl, 5-7 membered heterocyclyl are optionally substituted with 1-5R 7 Substitution; or alternatively
Two R 6 And the atoms to which they are attached together form a substituted or unsubstituted 5-7 membered carbocyclic or 5-7 membered heterocyclic ring, said substitution being by 1-5R 7 Group substitution;
the R is 7 Each independently selected from halogen, hydroxy, cyano, amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 heteroalkyl, C4-6 heterocycloalkyl, C1-6 haloalkyl, hydroxy C1-6 alkyl, NH (C1-6 cycloalkyl), -NHC (=O) (C1-6 alkyl), C (=O) (C3-6 cycloalkyl);
Ring M 2 Selected from unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-7 membered heteroaryl, unsubstituted or substituted 5-7 heterocyclyl; the substitution means that each is independently substituted with 1 to 5R M Substituted;
the R is M Each independently selected from halogen, cyano, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C4-6 cycloalkenyl, C6-10 aryl, 5-7 membered heteroaryl, -C (=O) (C1-6 alkyl), -C (=O) (C3-6 cycloalkyl), -C1-6 alkyl) -R 8 、-OR 8 、-N(R 8 ) 2 -NH (C1-6 alkyl) -R 8 -O (C1-6 alkyl) -R 8 、-C(＝O)N(R 8 ) 2 、-SR 8 、-S(＝O)R 8 、-S(＝O) 2 R 8 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the C1-6 alkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C4-6 cycloalkenyl, 4-6 membered heterocycloalkenyl, C6-10 aryl, 5-7 membered heteroaryl are optionally each independently substituted with 1-5R 8 Substitution; or alternatively
Two R M And the atoms to which they are attached together form a substituted or unsubstituted 3-7 membered carbocyclic or heterocyclic ring, said substitution being by 1-5R 8 Group substitution;
the R is 8 Each independently selected from the group consisting of hydroxy, cyano, amino, halogen, -NH (C1-6 alkyl), C1-6 alkyl, C1-6 heteroalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl.
2. The compound of claim 1, or a deuterated compound, pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof: wherein the compound has the structure of formula (II):
Wherein,,
R 1 selected from halogen, C1-3 alkyl; preferably selected from methyl, F, cl;
R a 、R b each independently selected from hydrogen, deuterium, halogen, methyl; or R is a And R is b And together with the carbon atoms to which they are attached form a three-membered carbocyclic ring;
ring M 1 Selected from the following structures:
wherein A is 1 、A 2 、A 3 、A 4 Rings W, Z and R H1 Is as defined in claim 1; and
ring M 2 Is defined as in claim 1.
3. The compound of claim 1, or a deuterated compound, a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof,
wherein, ring M 1 A structure selected from the group consisting of:
wherein "C, N" on a ring atom represents a group where CH or N,
R 2 、R H1 、R H2 and R is H3 Is defined as in claim 1.
4. The compound of any one of claims 1-3, or a deuterated compound, a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof, wherein
Ring M 2 Selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted thienyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted pyridyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted benzothienyl; the substitution means that each is independently substituted with 1 to 5R M Substituted;
the R is M Each independently selected from halogen, cyano, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C4-6 cycloalkenyl, 4-6 membered heterocycloalkenyl, C6-10 aryl, 5-7 membered heteroaryl, -C (=O) (C1-6 alkyl), -C (=O) (C3-6 cycloalkyl), - (C1-6 alkyl) -R 8 、-C(＝O)N(R 8 ) 2 、-SR 8 、-S(＝O)R 8 、-S(＝O) 2 R 8 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the C1-6 alkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C4-6 cycloalkenyl, 4-6 membered heterocycloalkenyl, C6-10 aryl, 5-7 membered heteroaryl are optionally each independently substituted with 1-5R 8 Substitution; or alternatively
Two R M And the atoms to which they are attached form a substituted or unsubstituted 3-7 membered carbocyclic or heterocyclic ring, said substitution being by 1-5R 8 Group substitution;
the R is 8 Each independently selected from the group consisting of hydroxy, cyano, amino, halogen, -NH (C1-6 alkyl), C1-6 alkyl, C1-6 heteroalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl.
5. A compound according to any one of claims 1-3, or a deuterated compound, a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof, wherein the compound is selected from the group consisting of:
/>
6. a process for preparing a compound according to any one of claims 1 to 5, comprising the steps of:
Coupling reaction of the compound of formula (A) with the compound of formula (B) to obtain the compound of formula (I):
wherein, ring M 1 Ring M 2 X and R 1 Is defined as set forth in the corresponding claims; TMS is-Si (CH) 3 ) 3 。
7. The method of claim 6, wherein
The coupling reaction is carried out in the presence of a palladium metal catalyst and a copper metal catalyst in the presence of a base in a solvent;
the palladium metal catalyst comprises Pd (PPh) 3 ) 2 Cl 2 、Pd(OAc) 2 And Pd (PPh) 3 ) 4 One or more of the following;
the copper metal catalyst comprises CuI and/or CuCl;
the alkali comprises CsF, cs 2 CO 3 、KF、K 2 CO 3 、NaHCO 3 、Na 2 CO 3 、Et3N、( i Pr) 2 One or more of EtN and DMAP;
the solvent comprises one or more of acetonitrile, 1, 4-dioxane and DMF.
8. A pharmaceutical composition comprising one or more selected from the group consisting of a compound according to any one of claims 1-5, deuterated compounds, pharmaceutically acceptable salts, solvates, esters, acids, metabolites, and prodrugs thereof, and pharmaceutically acceptable excipients.
9. Use of a compound according to any one of claims 1-5, or a deuterated compound, a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof, or a pharmaceutical composition according to claim 8, in the preparation of a KIT inhibitor.
10. Use of a compound according to any one of claims 1-5, or a deuterated compound thereof, a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof, or a pharmaceutical composition according to claim 8 in the manufacture of a medicament for the treatment, prevention, or amelioration of one or more diseases or disorders selected from the group consisting of tumors, inflammatory disorders, autoimmune and neurological disorders.
CN202310214944.8A 2022-03-11 2023-03-08 Compound containing heteroaromatic ring alkynyl, preparation method and application thereof Pending CN116730978A (en)

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