WO2024082872A1 - 一种pak4激酶抑制剂及其制备方法和用途 - Google Patents
一种pak4激酶抑制剂及其制备方法和用途 Download PDFInfo
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- WO2024082872A1 WO2024082872A1 PCT/CN2023/118200 CN2023118200W WO2024082872A1 WO 2024082872 A1 WO2024082872 A1 WO 2024082872A1 CN 2023118200 W CN2023118200 W CN 2023118200W WO 2024082872 A1 WO2024082872 A1 WO 2024082872A1
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- substituted
- unsubstituted
- cancer
- aromatic
- heterocycloalkyl
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- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FQZLNQAUUMSUHT-UHFFFAOYSA-N tert-butyl n,n-bis(2-chloroethyl)carbamate Chemical compound CC(C)(C)OC(=O)N(CCCl)CCCl FQZLNQAUUMSUHT-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 201000009825 uterine corpus cancer Diseases 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- the present invention belongs to the technical field of drug synthesis, and in particular relates to a PAK4 kinase inhibitor and a preparation method and use thereof.
- P21-activated protein kinase (PAK), as a conservative serine/threonine protein kinase, is the effector protein of the small GTPase CDC42 and Rac1 in the Rho family, mediating the transduction of its downstream signaling pathway. According to their sequence homology and activation mode, they can be divided into two categories: class I PAKs (PAK1, 2, 3) and class II PAKs (PAK4, 5, 6). As an important downstream corresponding molecule of Pho family GTPase Rac and Cdc42, PAKs play an important role in cell proliferation, cytoskeleton reorganization, and cell movement.
- PAK P21-activated protein kinase
- PAKs especially its representative members PAK1 and PAK4
- PAK1 and PAK4 have gene amplification, gene mutation, expression level and activity upregulation in a variety of tumor cells and tissues, which is closely related to the occurrence and development of tumors.
- By inhibiting the abnormal activity of PAKs in tumor cells it is expected to inhibit the excessive proliferation, invasion and metastasis of tumor cells, and angiogenesis, and promote the apoptosis of tumor cells.
- PAKs inhibitors have received extensive attention from medicinal chemists in the past decade.
- Wang C et al.'s research showed that the expression level of PAK4 in lung cancer, colon cancer, prostate cancer, pancreatic cancer and breast cancer cells is much higher than that in normal cells, which has an important impact on the occurrence, development, invasion and migration of tumors. Therefore, the development of PAK4 inhibitors is one of the effective strategies for the treatment of various tumors.
- PAK4 is a potential target for drug development, and the development of its inhibitors provides new ideas for the treatment of related cancers. So far, there are very few PAK4 inhibitors, and the activity of most inhibitors is not ideal. In addition, the pharmacokinetic properties are poor, and the drugability problem is a common problem of the reported molecules.
- the small molecule inhibitors that have been reported to enter the clinical stage include ATG-019 (KPT-9274) jointly developed by Antengene and Karyopharm Therapeutics, and PF-3758309 developed by Pfizer. Among them, PF-3758309 is a Class I PAKs inhibitor with a pyrrolopyrazole structure reported by Pfizer in 2009.
- PAK4 IC50 is 19nm, but the compound has a stronger inhibitory ability against PAK1, reaching 14nm, and has serious safety risks.
- ATG-019 is a world-first oral dual-target inhibitor of p21-activated kinase 4 (PAK4) and nicotinic phosphoribosyltransferase (NAMPT), with an unknown mechanism of action.
- PAK4 p21-activated kinase 4
- NAMPT nicotinic phosphoribosyltransferase
- the compounds that can be used as PAK4 kinase inhibitors developed by our company in the early stage are disclosed in patent WO2022033420 A1. These compounds have good PAK4 activity and PAK I/II selectivity, and have greatly improved pharmacokinetic properties compared with reported PAK4 kinase inhibitors. However, in subsequent continued research, the inventors found that these compounds have strong hERG cardiac inhibitory activity, resulting in an increased risk of cardiac toxic side effects. In view of this, the present invention optimizes the structure of the compound on the basis of previous research, and screens out a series of compounds with higher inhibitory activity and PAK I/II selectivity for PAK4 kinase. The compounds not only have excellent liver microsomal stability and rat PK pharmacokinetic properties, but also have greatly reduced hERG cardiac inhibitory activity, and the problem of cardiac toxicity risk is solved.
- the object of the present invention is to provide a compound of general formula I and a preparation method thereof, wherein the compound is a PAK4 kinase inhibitor; another object of the present invention is to provide a use of the compound.
- the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, or solvate thereof:
- a 1 , A 2 , A 3 , A 4 are independently selected from C or N; when any one of A 1 , A 2 , A 3 , A 4 is N, R 2 , R 3 , R 4 , R 5 connected to the N does not exist;
- a 1 , A 2 , A 3 , and A 4 are selected from C.
- R 2 , R 3 , R 4 and R 5 are independently selected from -H, halogen, -OH, -CN, -NH 2 , -NO 2 , -SH, C1-10 straight/branched alkyl, C3-10 cycloalkyl, heterocycloalkyl, alkynyl, alkenyl, aromatic, heterocyclic aromatic, amide, ester, sulfonyl and phosphoryl, wherein the H on the above groups may be substituted by halogen, -OH, -CN, -NH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or unsubstituted aromatic or heterocyclic aromatic.
- the substituent group is selected from halogen, -OH, -CN, -NH2 , -NO2 , -SH, carboxyl, hydroxyamino, alkyl, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic, ester, acyl, carbonyl, amide, sulfonyl, and phosphoryl.
- the cycloalkyl or heterocycloalkyl described in the present invention includes a monocyclic, bridged, spirocyclic or condensed ring cycloalkyl or heterocycloalkyl. Furthermore, the cycloalkyl or heterocycloalkyl includes saturated or unsaturated forms.
- B 1 and B 2 are independently selected from C or N. In a preferred embodiment of the present invention, B 1 and B 2 are N.
- L is selected from -O-, -S-, -NH- or alkylene; preferably, L is -NH-.
- R1 is selected from a substituted or unsubstituted five-membered or six-membered aromatic group or a heterocyclic aromatic group, and a substituted or unsubstituted heterocyclic alkyl group containing at least one N and/or O atom.
- R 1 is selected from substituted or unsubstituted phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, and a five-membered or six-membered heterocycloalkyl group containing at least one N or O atom.
- R 1 has any of the following structures:
- the H on any one or more C atoms in the above structure may be substituted by the following groups: -F, -Cl, -Br, -OH, -CN, -NH 2 , substituted or unsubstituted amide, substituted or unsubstituted C1-3 alkyl or alkoxy, C3-6 cycloalkyl.
- the substituent groups are independently selected from -F, -Cl, -Br, -OH, -CN, -NH2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxymethyl, hydroxyethyl.
- R 6 is selected from -H, -NH 2 , -OH, halogen, amide, sulfonyl, sulfonic acid, C1-6 alkyl or alkoxy, C3-6 cycloalkyl, C3-6 heterocycloalkyl, amine, C6-12 aromatic, C5-12 heterocyclic aromatic; the H on the above-mentioned C1-6 alkyl or alkoxy, C3-6 cycloalkyl, C3-6 heterocycloalkyl, amine, C6-12 aromatic, C5-12 heterocyclic aromatic may be optionally substituted with one or more halogen, -OH, -CN, -NH 2 , -NO 2 , -SH, sulfonic acid.
- Ring Ar is fused to ring Rg, and the fused bond is any bond on ring Ar;
- Ring Ar is selected from an aromatic five-membered heterocyclic group, an aromatic six-membered heterocyclic group or a phenyl group, wherein the aromatic five-membered heterocyclic group is selected from: imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, furanyl or thienyl; the aromatic six-membered heterocyclic group is selected from: pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl; the optional H on the aromatic five-membered heterocyclic group, aromatic six-membered heterocyclic group or phenyl group may be substituted by the following groups: halogen, -OH, -CN, -NH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or unsubsti
- the substituent group is selected from halogen, -OH, -CN, -NH 2 , -NO 2 , -SH, carboxyl, hydroxyamino, alkyl, cycloalkyl, heterocycloalkyl, aromatic, heterocyclic aromatic, ester, acyl, carbonyl, amide, sulfonyl, phosphoryl.
- the ring Rg is selected from C3-8 saturated/unsaturated cycloalkyl or C3-8 saturated/unsaturated heterocycloalkyl containing at least one O, N, S, and the H on the optional C3-8 saturated/unsaturated cycloalkyl or C3-8 saturated/unsaturated heterocycloalkyl containing at least one O, N, S can be substituted by the following groups: halogen, -OH, -CN, -NH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or unsubstituted aromatic or heterocyclic aromatic.
- the substituent group is selected from halogen, -OH, -CN, -NH 2 , -NO 2 , -SH, carboxyl, hydroxyamino, alkyl, cycloalkyl, heterocyclic alkyl, aromatic, heterocyclic aromatic, ester, acyl, carbonyl, amide, sulfonyl, phosphoryl.
- R 7 there is at least one R 7 on the ring Rg, and said R 7 is independently selected from -H, deuterium, tritium, halogen, -OH, -CN, -NH 2 , -NO 2 , -SH, carboxyl, hydroxyamino, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, ester, acyl, carbonyl, amide, sulfonyl, and phosphoryl.
- the compound has a structure shown in Formula II, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, or solvate thereof:
- X is selected from substituted or unsubstituted C1-6 straight chain/branched alkyl, substituted or unsubstituted C3-10 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-6 aromatic or heterocyclic aromatic, alkynyl, alkenyl, amide, ester.
- the substituent group is selected from halogen, -OH, -CN, -NH 2 , -NO 2 , -SH, carboxyl, hydroxyamino, alkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aromatic, heterocyclic aromatic, ester, acyl, carbonyl, amide, sulfonyl, phosphoryl.
- the cycloalkyl or heterocycloalkyl described in the present invention includes a monocyclic, bridged, spirocyclic or condensed ring cycloalkyl or heterocycloalkyl. Furthermore, the cycloalkyl or heterocycloalkyl includes saturated or unsaturated forms.
- R 8 is independently selected from -H, halogen, -OH, -CN, -NH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl or heterocycloalkyl, and the substituent group is selected from halogen, -OH, -CN, -NH 2 , -NO 2 , -SH, -CF 3 , -CHF 2 , -CH 2 F, carboxyl, hydroxyamino, hydroxymethyl, hydroxyethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, phenyl, phenoxy, pyridyl
- the substituted groups are independently selected from -F, -Cl, -Br, -OH, -CN, -NH2 , -CF3 , hydroxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
- R 9 is selected from substituted or unsubstituted phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, and the substituents are independently selected from -F, -Cl, -Br, -OH, -CN, -NH 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and hydroxymethyl.
- R 10 is selected from -NH 2 , -OH, halogen, C1-6 alkyl or alkoxy, C3-6 cycloalkyl, C3-6 heterocycloalkyl; the H on the above C1-6 alkyl or alkoxy, C3-6 cycloalkyl, C3-6 heterocycloalkyl may be optionally substituted by one or more halogen, -OH, -CN, -NH 2 , -NO 2 , -SH.
- the ring Rg is selected from a C3-8 saturated/unsaturated heterocycloalkyl group containing at least one O, N, or S, and the ring Rg has at least one R 11 , R 11 is independently selected from -H, deuterium, tritium, -F, -Cl, -Br, -OH, -CN, -NH 2 , -NO 2 , -SH, hydroxyamino, hydroxymethyl, hydroxyethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, phenyl, phenoxy, sulfonyl, phosphoryl.
- the compound has a structure as shown in Formula III, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, or solvate thereof:
- R 12 is selected from -H, -F, -Cl, -Br, -OH, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxymethyl.
- R 13 and R 14 are independently selected from -H, deuterium, tritium, -F, -Cl, -Br, hydroxymethyl, hydroxyethyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
- R 15 is selected from -H, -F, -Br, -OH, -CN, -NH 2 , substituted or unsubstituted C1-10 straight chain/branched alkyl, substituted or unsubstituted C1-10 straight chain/branched alkoxy, substituted or unsubstituted cycloalkyl or heterocycloalkyl, wherein the H on the above groups may be substituted by the following groups: -F, -Cl, -Br, -OH, -CN, -NH 2 , -CF 3 , hydroxymethyl, methyl, ethyl, propyl, isopropyl, phenyl, methoxy, ethoxy, propoxy, isopropoxy, phenoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
- the C1-10 straight chain/branched chain alkyl group is a C1-6 straight chain/branched chain alkyl group.
- the C1-10 straight chain/branched alkyl group includes but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and 4-methyl-2-pentyl.
- the C1-10 straight chain/branched chain alkoxy group is a C1-6 straight chain/branched chain alkoxy group.
- the C1-10 straight chain/branched alkoxy includes but is not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, and n-hexoxy.
- the cycloalkyl or heterocycloalkyl group includes a monocyclic, bridged, spirocyclic or condensed ring cycloalkyl or heterocycloalkyl group. Furthermore, the cycloalkyl or heterocycloalkyl group includes saturated or unsaturated forms.
- the substituted or unsubstituted cycloalkyl or heterocycloalkyl includes but is not limited to Indicates the position at which the alkynyl group can be attached.
- the compound has a structure as shown in Formula IV, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, or solvate thereof:
- R 16 and R 17 are independently selected from -H, -F, -Cl, -Br, -OH, -CN, -NH 2 , -SH, hydroxyamino, hydroxymethyl, hydroxyethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
- R 18 is selected from -H, -F, -Cl, -Br, -OH, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxymethyl.
- R 19 and R 20 are independently selected from -H, deuterium, tritium, -F, -Cl, -Br, hydroxymethyl, hydroxyethyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
- the compound has a structure as shown in Formula V, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, or solvate thereof:
- R 21 is selected from -H, -F, -Cl, -Br, -OH, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxymethyl.
- R 22 and R 23 are independently selected from -H, deuterium, tritium, -F, -Cl, -Br, hydroxymethyl, hydroxyethyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
- Y is selected from substituted or unsubstituted C1-4 straight chain/branched alkyl, substituted or unsubstituted C3-8 cycloalkyl or heterocycloalkyl, substituted or unsubstituted C5-6 aromatic or heterocyclic aromatic, amide, ester.
- the substituent group is selected from -OH, -CN, -NH 2 , -NO 2 , -SH, carboxyl, hydroxyamino, alkyl, alkoxy, hydroxyalkyl, substituted or unsubstituted C3-8 cycloalkyl or heterocycloalkyl, C5-6 aromatic or heterocyclic aromatic, ester, acyl, carbonyl, amide, sulfonyl, phosphoryl.
- the C5-6 aromatic group or heterocyclic aromatic group includes but is not limited to phenyl and pyrazolyl.
- the alkyl group is preferably a substituted or unsubstituted C1-4 straight chain/branched chain alkyl group.
- the alkoxy group is preferably a substituted or unsubstituted C1-4 straight chain/branched chain alkoxy group, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.
- the C1-4 straight chain/branched chain alkyl group and C1-4 straight chain/branched chain alkoxy group may be further substituted by hydroxyl or hydroxymethyl.
- the hydroxyalkyl group includes but is not limited to hydroxymethyl and hydroxyethyl.
- the R 24 is selected from -H, deuterium, tritium, -F, -Cl, -Br, -OH, -CN, -NH 2 , -NO 2 , -SH, hydroxyamino, hydroxymethyl, hydroxyethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl, phenoxy, substituted or unsubstituted C 3-8 saturated or unsaturated cycloalkyl or heterocycloalkyl.
- the C1-4 straight chain/branched chain alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.
- the substituted or unsubstituted C3-8 cycloalkyl or heterocycloalkyl includes but is not limited to
- H in the above structure may be substituted by the following groups: -OH, -CN, -NH2 , -NO2 , -SH, hydroxyamino, hydroxymethyl, hydroxyethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl, phenoxy, sulfonyl, phosphoryl.
- the compound has the following structure:
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound described in any one of Formulas I-V or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, or solvate thereof.
- the pharmaceutical composition further comprises pharmaceutically acceptable excipients, including but not limited to: carriers, diluents, adhesives, lubricants, and wetting agents.
- pharmaceutically acceptable excipients including but not limited to: carriers, diluents, adhesives, lubricants, and wetting agents.
- the pharmaceutical composition comprises a therapeutically effective amount of a compound described in any one of Formulas I to V.
- the pharmaceutical composition can be used alone or in combination with other preparations.
- the pharmaceutical composition is suitable for enteral or parenteral administration, such as intravenous, intramuscular, intradermal and subcutaneous administration.
- the pharmaceutical composition also includes an antioxidant, a buffer, an antibacterial agent, and a solute that makes the preparation isotonic with the subject's blood, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents, solubilizers, thickeners, stabilizers and preservatives.
- the compounds described in any one of the general formulas I-V provided by the present invention can be formulated into pharmaceutical preparations in the following forms: injections, syrups, elixirs, suspensions, powders, granules, tablets, capsules, lozenges, creams, ointments, lotions, gels, emulsions, etc.
- the present invention provides a compound of any one of the general formulas I-V or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate thereof, or a pharmaceutical composition comprising a compound of any one of the general formulas I-V or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate thereof for use in the preparation of a drug for treating a disease related to the expression or activity of PAK4 kinase.
- the diseases associated with the expression or activity of PAK4 kinase include cancer, neurodegenerative diseases or immune system diseases.
- the cancers include ovarian cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, hepatocellular carcinoma, glioma, endometrial cancer, melanoma, renal cancer, bladder cancer, biliary tract cancer, lymphoma, hairy cell carcinoma, Nasopharyngeal cancer, pharyngeal cancer, colorectal cancer, rectal cancer, brain and central nervous system cancer, cervical cancer, testicular cancer, genitourinary tract cancer, lung cancer, small cell carcinoma, bone cancer, colon cancer, adenocarcinoma, follicular carcinoma, Hodgkin's leukemia, bronchial cancer, uterine corpus cancer, cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphoid leukemia, myeloid leukemia, primary macroglobulinemia, rhabdom
- the adenocarcinoma includes but is not limited to breast cancer, pancreatic cancer, prostate cancer, lung adenocarcinoma, and thyroid cancer.
- the lymphoma includes, but is not limited to, mantle cell lymphoma and non-Hodgkin's lymphoma.
- the lung cancer includes but is not limited to non-small cell lung cancer.
- the compound described in any one of the general formulas I-V or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates can be used alone or in combination with other types of pharmaceutical preparations and/or treatment methods.
- the other types of pharmaceutical preparations and/or treatment methods include, but are not limited to, immunosuppressants, targeted anti-tumor drugs, glucocorticoids, non-steroidal anti-inflammatory drugs, anti-tumor vaccines, adoptive cellular immunotherapy, chemotherapy or radiotherapy.
- the present invention provides a compound of the general formula VI,
- R 25 and R 26 are independently selected from -H, deuterium, tritium, -F, -Cl, -Br, hydroxymethyl, hydroxyethyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
- the present invention provides a compound of formula VII,
- R 27 is selected from -H, -F, -Cl, -Br, -OH, -CN, methyl, ethyl, propyl, isopropyl, methoxy, Ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxymethyl.
- R 28 and R 29 are independently selected from -H, deuterium, tritium, -F, -Cl, -Br, hydroxymethyl, hydroxyethyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
- the present invention provides a use of a compound of formula VI and/or formula VII in the preparation of any of the following compounds, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, or solvate thereof:
- the technical solution provided by the present invention has the following technical advantages: (1) Compared with the prior art, the compounds of the general formula I-V provided by the present invention or their pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, and solvates as PAK4 inhibitors have higher inhibitory activity and PAK I/II selectivity, and their liver microsome stability and rat PK are also improved; (2) Furthermore, the compounds of the general formula I provided by the present invention or their pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, and solvates as PAK4 inhibitors have greatly reduced hERG cardiac inhibitory activity, thereby solving the risk problem of drug cardiotoxicity.
- DIEA N,N-diisopropylethylamine
- n-BuLi n-butyllithium
- M molar concentration unit mol/L, for example 1M means 1 mol/L;
- N equivalent concentration, for example, 1N HCl means hydrochloric acid with a concentration of 1 mol/L;
- HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
- HBTU benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
- m-CPBA meta-chloroperbenzoic acid
- NMO N-methylmorpholine oxide
- DPPA diphenylphosphoryl azide
- TBDPSCl tert-butyldiphenylchlorosilane
- DIBAL-H diisobutylaluminum hydride
- PE petroleum ether (boiling point 60-90°C);
- DMSO dimethyl sulfoxide
- Pd(PPh 3 ) 2 Cl 2 bis(triphenylphosphine)palladium dichloride
- Pd(dppf)Cl 2 .DCM [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex;
- TBAF.3H 2 O tetrabutylammonium fluoride trihydrate
- 1,4-dioxane 1,4-dioxane.
- Step 1 Preparation of tert-butyl 4-(benzo[d][1,3]dioxol-5-yl)-4-cyanopiperidine-1-carboxylate
- reaction solution was slowly added into a saturated aqueous solution of NH 4 Cl (600 mL) for quenching, and then EA (200 mL*2) was added, extracted twice, the organic phases were combined and washed three times with a saturated aqueous solution of NaCl (100 mL*3), dried over anhydrous sodium sulfate, and concentrated to obtain a brown solid (crude product), which was directly used in the next reaction.
- Step 2 Preparation of tert-butyl 4-(benzo[d][1,3]dioxol-5-yl)-4-carbamoylpiperidine-1-carboxylate
- Step 3 Preparation of tert-butyl 4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidine-1-carboxylate
- Step 1 Preparation of 2-chloro-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-iodoquinazolin-4-amine
- the compound 2,4-dichloro-6-iodoquinazoline (5.00 g, 15.39 mmol) was dissolved in DMF (30 mL), and 5-cyclopropyl-4-fluoro-1H-pyrazole-3-amine (2.20 g, 15.44 mmol) and DIEA (7.90 g, 61.56 mmol) were added thereto in sequence at room temperature. The temperature was raised to 65 ° C and stirred for 2 hours. After the reaction of the raw materials was completed, the reaction solution was cooled to room temperature. The reaction solution was slowly poured into water (300 mL) and extracted with EA twice.
- Step 2 Preparation of 2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-iodoquinazolin-4-amine
- reaction solution was slowly poured into water (300 mL) and extracted twice with EA.
- organic phases were combined and washed once with a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate.
- Step 1 Preparation of 2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-((trimethylsilyl)ethynyl)quinazolin-4-amine
- Step 2 Preparation of 2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-ethynylquinazolin-4-amine
- the liquid was separated, the aqueous phase was extracted once with EA, the organic phases were combined and washed once with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and concentrated to dryness.
- the residue was dissolved in methanol (30 mL), cooled to 0 ° C with an ice-water bath, and sodium borohydride (4.00 g, 105.57 mmol) was added in batches, and stirred at room temperature overnight. After the reaction was completed, water (50 mL) was slowly added to the reaction solution, and then extracted twice with ethyl acetate.
- Step 2 Preparation of 4-(2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-4-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)-1,1,1-trifluorobutyl-3-yn-2-ol
- Step 3 Preparation of 4-(2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-4-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)but-3-yne-1,2-diol
- Step 1 Preparation of methyl 4-(tert-butyldiphenylsilyl)oxy)cyclohexane-1-carboxylate
- Step 3 Preparation of tert-butyl((4-ethynylcyclohexyl)oxy)diphenylsilane
- Step 4 Preparation of 2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-6-(4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)ethynyl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazolin-4-amine
- Step 5 Preparation of 4-((2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)ethynyl)cyclohexane-1-ol
- Step 1 Preparation of 1-((tert-butyldiphenylsilyl)oxy)methyl)-N-methoxy-N-methyl-2-oxacyclo[2.2.2]octane-4-carboxamide
- Step 2 Preparation of 1-((tert-butyldiphenylsilyl)oxy)methyl)-2-oxacyclo[2.2.2]octane-4-carbaldehyde
- Step 3 Preparation of tert-butyl((4-ethynyl-2-oxacyclo[2.2.2]octan-1-yl)methoxy)diphenylsilane
- Step 5 Preparation of (4-((2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-4-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)alkynyl)-2-oxacyclo[2.2.2]octane-1-methyl)methanol
- Step 4 Preparation of 4-((2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-4-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)ethynyl)tetrahydro-2H-pyran-3-ol
- Step 3 Preparation of tert-butyl((5-ethyltetrahydro-2H-pyran-2-ynyl)methoxy)diphenylsilane
- Step 4 Preparation of 2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-6-(6-((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)ethynyl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-methyl)quinazolin-4-amine
- Step 5 Preparation of (5-((2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)ethynyl)tetrahydro-2H-pyran-2-yl)methanol
- Step 1 Preparation of 2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenylboronic acid pinacol ester
- Step 2 Preparation of 2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-6-(4-((2,2-dimethyl-1,3-dioxol-4-yl)methoxy)phenyl)quinazolin-4-amine
- Step 3 Preparation of 3-(4-(2-(4-amino-4-(benzo[d][1,3]diol-5-yl)piperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)phenoxy)propane-1,2-diol
- Step 2 Preparation of 1-(4-(2-(4-amino-4-(benzo[d][1,3]diol-5-yl)piperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)phenyl)ethane-1,2-diol
- Step 1 Preparation of 2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-6-(2-((tert-butyldiphenylsilyl)oxy)methyl)-3,4-dihydro-2H-pyran-5-yl)-N-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)quinazolin-4-amine
- Step 2 Preparation of (5-(2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazolin-6-yl)-3,4-dihydro-2H-pyran-2-yl)methanol
- Step 1 Preparation of 1-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxacyclo[2.2.2]octan-4-amine
- Step 2 Preparation of methyl 2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-4-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-6-carboxylate
- Step 3 Preparation of 2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-4-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-6-carboxylic acid
- Step 4 Preparation of 2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-N-(1-((tert-butyldiphenylsilyl)oxy)methyl)-2-oxacyclo[2.2.2]octan-4-yl)-4-((5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)quinazoline-6-carboxamide
- Step 5 Preparation of 2-(4-amino-4-(benzo[d][1,3]dioxol-5-yl)piperidin-1-yl)-4-(5-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)amino)-N-(1-(hydroxymethyl)-2-oxacyclo[2.2.2]octan-4-yl)quinazoline-6-carboxamide
- PAK4 (Carna, No.07-126), PAK2 (Carna, No.07-124), Kinase substrate 31 (Cisbio, No.61ST2BLE), DMSO (Sigma, No.D0632), 384-well plate (Greiner, No.784075), PF-3758309 (selleckchem, No.S709403)
- the compound was received by the administrator, and the powder was dissolved in 100% DMSO to prepare a 10 mM stock solution and stored in a nitrogen cabinet away from light.
- test compound was tested at a concentration of 1000 nM. It was diluted to a 100% DMSO solution with a 100-fold final concentration in the 384 source plate. The compound was diluted 3-fold with Precision, with 10 concentrations. 250 nL of the compound with a 100-fold final concentration was transferred to the destination 384-well plate using a dispenser Echo 550.
- Conversion%_sample is the conversion rate reading of the sample
- Conversion%_min the mean of the negative control wells, representing the conversion rate reading of the wells without enzyme activity
- Conversion%_max the mean of the positive control well ratio, representing the conversion rate reading of the wells without compound inhibition.
- the log value of the concentration was used as the X-axis and the percentage inhibition rate was used as the Y-axis.
- the log (inhibitor) vs. response–Variable slope of the analysis software GraphPad Prism 5 was used to fit the dose-effect curve to obtain the IC 50 value of each compound on the enzyme activity.
- Test Example 2 hERG test for detecting compound cardiotoxicity
- 1.1 hERG ion channels are stably expressed in HEK293 cells. After the hERG current is stabilized, the magnitude of the hERG current before and after the application of different compound concentrations can be compared to obtain the effect of the compound on the hERG ion channel.
- HEK293 cells expressing hERG ion channel stably HEK293 cells expressing hERG ion channel stably.
- test compound was stored at a concentration of 3 mM in dimethyl sulfoxide (DMSO). On the day of the test, it was redissolved in the extracellular fluid to prepare the required concentration.
- DMSO dimethyl sulfoxide
- the extracellular fluid was: NaCl, 137; KCl, 4; CaCl2, 1.8; MgCl2, 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration).
- test compound and control compound solutions contained 0.3% DMSO.
- Intracellular solution was: K Aspartate, 130; MgCl2, 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2 (KOH titration).
- Compound testing Compounds were perfused using a gravity-based perfusion system. At least one cell was tested for each concentration. After the current stabilized (or 5 minutes), the current changes before and after the compound was used were compared to calculate the blocking effect of the compound.
- Electrophysiology The cells were transferred to a perfusion tank and perfused with extracellular solution.
- the intracellular solution (mM) was: KAspartate, 130; MgCl2, 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2 (KOH titration).
- the intracellular solution was stored in batches in a -80 degree refrigerator and thawed on the day of the experiment.
- the electrodes were pulled with PC-10 (Narishige, Japan). Whole-cell patch clamp recordings were performed, and noise was filtered at one-fifth of the sampling frequency.
- the cells were clamped at -80mV, then depolarized to 40mV with a 4-second square wave, and then hyperpolarized to -40mV with a 2-second square wave to obtain the hERG tail current (see figure). This procedure was repeated every 20 seconds.
- the hERG tail current is a pure hERG current.
- the maximum current induced by the second square wave was detected, and after it stabilized, the test compound was perfused. When the reaction stabilized, the intensity of the blockade was calculated.
- the hERG inhibition rates of the preferred compounds in patent WO2022033420 A1 are higher than the hERG inhibition rates of most of the compounds prepared in Examples 1-25 provided by the present invention, and have a greater risk of cardiotoxicity.
- Test Example 3 Stability test of liver microsomes of test compounds
- liver microsome types are shown in Table 5:
- the first-order elimination kinetic equation is:
- Test Example 4 PK property test of the compound in rats
- SD rats male (purchased from Chengdu Dashuo Experimental Animal Co., Ltd.). Each test compound was administered orally (50 mg/kg, 3 in each group) to SD rats for pharmacokinetic study.
- the test compound was prepared on the day of administration, and the test compound was dissolved with 5% DMSO + 10% solutol + 85% saline, and the administration solution was prepared after vortexing for 2 minutes and ultrasonication for 5 minutes. The animals were fasted for 10-14 hours before oral administration, and the feeding was resumed 4 hours after administration. After oral gavage and intravenous administration of SD rats, pharmacokinetic samples were collected through the jugular vein.
- the collection time points were: before administration, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h after administration.
- Three whole blood samples were collected at each time point, with a collection volume of about 0.2mL, and anticoagulated with sodium heparin. After blood samples were collected, they were immediately placed on ice and centrifuged within 1 hour to separate plasma (centrifugation conditions: 6800 rpm, 6 minutes, 2-8°C). The collected plasma was stored in a –80°C refrigerator before analysis.
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Abstract
涉及一种如通式Ⅰ的化合物,或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物。试验结果表明,所述的化合物对于PAK4激酶具有较高的抑制活性和PAKI/II选择性,具有较好的肝微粒体稳定性及大鼠PK药代动力学性质,尤其hERG心脏毒性风险低,相对于现有技术公开的化合物具有显著进步。
Description
本申请要求于2022年10月19日提交中国专利局、申请号为202211282529.8、发明名称为“一种PAK4激酶抑制剂及其制备方法和用途”的中国专利申请的优先权,其全部内容通过引用结合在本申请中。
本发明属于药物合成技术领域,具体涉及一种PAK4激酶抑制剂及其制备方法和用途。
P21活化蛋白激酶(p21-activated protein kinase,PAK)作为一类保守的丝氨酸/苏氨酸蛋白激酶,是Rho家族中的小GTP酶CDC42及Rac1的效应蛋白,介导其下游信号通路的转导。根据其序列同源性及活化方式的不同,可分为两大类:I类PAKs(PAK1、2、3)和II类PAKs(PAK4、5、6)。作为Pho家族GTP酶Rac和Cdc42的重要下游相应分子,PAKs在细胞增殖、细胞骨架重组、细胞运动过程中发挥着重要的作用。研究表明,PAKs各成员,特别是其代表成员PAK1和PAK4,在多种肿瘤细胞及组织中存在基因扩增、基因突变、表达水平和活性上调的现象,与肿瘤的发生发展密切相关。通过抑制肿瘤细胞内PAKs的异常活性,有望抑制肿瘤细胞的过度增殖、侵袭转移和血管生成,促进肿瘤细胞的凋亡。
有鉴于此,PAKs抑制剂的研究在近十年受到药物化学家的广泛关注。Wang C等研究表明,PAK4在肺癌、结肠癌、前列腺癌、胰腺癌和乳腺癌细胞中的表达含量远远高于正常细胞,对肿瘤的发生、发展、侵袭和迁移产生重要影响。因此,PAK4抑制剂的开发是多种肿瘤治疗行之有效的策略之一。
新近研究发现抑制I类PAKs与心脏急性毒性、hERG副作用等安全性风险具有潜在的相关性,提示PAKs抑制剂的开发应避免对I类PAKs特别是PAK1的抑制作用。因此,发现高选择性的II类PAKs抑制剂将成为未来研究的主流。
PAK4作为一种有潜力的药物开发靶点,其抑制剂的开发为治疗相关的癌症提供了新思路。截至目前,PAK4的抑制剂数量很少,且多数抑制剂的活性不理想。另外,药代动力学性质较差,成药性问题是已报道分子的共同问题。目前已报道进入临床阶段的小分子抑制剂有德琪医药公司和Karyopharm Therapeutics公司共同开发的ATG-019(KPT-9274)和辉瑞研发的PF-3758309。其中,PF-3758309是辉瑞公司于2009年报道的具有吡咯并吡唑结构的I类PAKs抑制剂,是最早进入临床研究的PAKs抑制剂,其PAK4IC50为19nm,但该化合物对PAK1具有更强的抑制能力,达到14nm,具有严重的安全性风险。另外,由
于其口服生物利用度差,仅约为1%,且具有严重的胃肠道不良反应等因素,I期临床研究被迫终止。ATG-019是一款全球首创的p21-活化激酶4(PAK4)和烟碱转磷酸核糖基酶(NAMPT)口服双靶点抑制剂,作用机制不明。目前正在开展包括非霍奇金淋巴瘤、结直肠癌、肺癌、黑色素瘤等领域的多项I期临床研究。
发明内容
本公司前期开发的可作为PAK4激酶抑制剂的化合物公开于专利WO2022033420 A1中,这些化合物均具有较好的PAK4活性和PAK I/II选择性,相较于已报道的PAK4激酶抑制剂在药代动力学性质方面有极大改善。但在后期的继续研究中,发明人发现这些化合物具有较强的hERG心脏抑制活性,导致心脏毒副作用风险增加。有鉴于此,本发明在前期研究基础上对化合物结构进行优化,筛选得到一系列对于PAK4激酶具有更高抑制活性和PAK I/II选择性的化合物,所述化合物不仅具有优良的肝微粒体稳定性和大鼠PK药代动力学性质,而且hERG心脏抑制活性大大降低,心脏毒性风险的问题得到解决。
本发明的目的是提供一种通式为Ⅰ的化合物及其制备方法,所述化合物为PAK4激酶抑制剂;本发明的另一个目的是提供一种所述化合物的用途。
本发明技术方案包括以下内容:
第一方面,本发明提供一种通式为Ⅰ的化合物,或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物:
其中,A1、A2、A3、A4独立的选自C或N,当A1、A2、A3、A4中任意一个为N,与所述N相连的R2、R3、R4、R5不存在;
在本发明的优选实施方式中,所述A1、A2、A3、A4选自C。
R2、R3、R4、R5独立的选自-H、卤素、-OH、-CN、-NH2、-NO2、-SH、C1-10直链/支链烷基、C3-10环烷基、杂环烷基、炔基、烯基、芳香基、杂环芳香基、酰胺基、酯基、磺酰基、磷酰基,其中上述基团上的H可被以下基团取代:卤素、-OH、-CN、-NH2、取代或非取代的烷基、取代或非取代烷氧基、取代或非取代的环烷基或杂环烷基、取代或非取代的芳香基或杂环芳香基。
所述取代基团选自卤素、-OH、-CN、-NH2、-NO2、-SH、羧基、羟氨基、烷基、环烷基、杂环烷基、芳香基、杂环芳香基、酯基、酰基、羰基、酰胺基、磺酰基、磷酰基。
本发明所述的环烷基或杂环烷基包括单环、桥环、螺环或稠环的环烷基或杂环烷基,进一步的,所述环烷基或杂环烷基包括饱和或不饱和两种形式。
B1、B2独立的选自C或N,在本发明的优选实施方式中,所述B1、B2为N。
L选自-O-、-S-、-NH-或亚烷基;优选的,L为-NH-。
R1选自取代或非取代的五元或六元芳香基或杂环芳香基、取代或非取代的含有至少一个N和/或O原子的杂环烷基。
优选的,所述R1选自取代或非取代的苯基、吡唑基、噁唑基、异噁唑基、噻唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、呋喃基、噻吩基、吡咯基、含有至少一个N或O原子的五元或六元杂环烷基。
在本发明的具体实施例中,R1具有以下任意一种结构:
以上结构中的任意一个或多个C原子上的H可被以下基团取代:-F、-Cl、-Br、-OH、-CN、-NH2、取代或非取代的酰胺基、取代或非取代的C1-3的烷基或烷氧基、C3-6环烷基。
优选的,所述的取代基团独立的选自-F、-Cl、-Br、-OH、-CN、-NH2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、羟基甲基、羟基乙基。
R6选自-H、-NH2、-OH、卤素、酰胺基、磺酰基、磺酸基、C1-6的烷基或烷氧基、C3-6环烷基、C3-6杂环烷基、胺基、C6-12芳香基、C5-12杂环芳香基;上述C1-6的烷基或烷氧基、C3-6环烷基、C3-6杂环烷基、胺基、C6-12芳香基、C5-12杂环芳香基上的H可任选的被一个或多个卤素、-OH、-CN、-NH2、-NO2、-SH、磺酸基取代。
环Ar与环Rg稠合,稠合键为环Ar上任一键;
环Ar选自芳香性五元杂环基团、芳香性六元杂环基团或苯基,所述芳香性五元杂环基团选自:咪唑基、噻唑基、噁唑基、吡咯基、吡唑基、呋喃基或噻吩基;所述芳香性六元杂环基团选自:吡啶基、哒嗪基、嘧啶基或吡嗪基;任选的所述芳香性五元杂环基团、芳香性六元杂环基团或苯基上的H可被以下基团取代:卤素、-OH、-CN、-NH2、取代或非取代的烷基、取代或非取代烷氧基、取代或非取代的环烷基或杂环烷基、取代或非取代的芳香基或杂环芳香基。所述取代基团选自卤素、-OH、-CN、-NH2、-NO2、-SH、羧基、羟氨基、烷基、环烷基、杂环烷基、芳香基、杂环芳香基、酯基、酰基、羰基、酰胺基、磺酰基、磷酰基。
环Rg选自C3-8饱和/不饱和环烷基或至少含有一个O、N、S的C3-8饱和/不饱和杂环烷基,任选的所述C3-8饱和/不饱和环烷基或至少含有一个O、N、S的C3-8饱和/不饱和杂环烷基上的H可被以下基团取代:卤素、-OH、-CN、-NH2、取代或非取代的烷基、取代或非取代烷氧基、取代或非取代的环烷基或杂环烷基、取代或非取代的芳香基或杂环芳香基。所述取代基团选自卤素、-OH、-CN、-NH2、-NO2、-SH、羧基、羟氨基、烷基、环烷基、杂环烷基、芳香基、杂环芳香基、酯基、酰基、羰基、酰胺基、磺酰基、磷酰基。
进一步的,环Rg上有至少一个R7,所述R7独立地选自-H、氘、氚、卤素、-OH、-CN、-NH2、-NO2、-SH、羧基、羟氨基、烷基、环烷基、杂烷基、杂环烷基、芳基、杂芳基、酯基、酰基、羰基、酰胺基、磺酰基、磷酰基。
优选的,所述化合物具有式II所示结构,或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物:
X选自取代或非取代的C1-6直链/支链烷基、取代或非取代的C3-10环烷基或杂环烷基、取代或非取代的C5-6芳香基或杂环芳香基、炔基、烯基、酰胺基、酯基。所述取代基团选自卤素、-OH、-CN、-NH2、-NO2、-SH、羧基、羟氨基、烷基、烷氧基、羟基烷基、环烷基、杂环烷基、芳香基、杂环芳香基、酯基、酰基、羰基、酰胺基、磺酰基、磷酰基。
本发明所述的环烷基或杂环烷基包括单环、桥环、螺环或稠环的环烷基或杂环烷基,进一步的,所述环烷基或杂环烷基包括饱和或不饱和两种形式。
X基团上有至少一个R8,所述R8独立地选自-H、卤素、-OH、-CN、-NH2、取代或非取代的烷基、取代或非取代烷氧基、取代或非取代的环烷基或杂环烷基,所述取代基团选自卤素、-OH、-CN、-NH2、-NO2、-SH、-CF3、-CHF2、-CH2F、羧基、羟氨基、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、金刚烷基、苯基、苯氧基、吡啶基、酰胺基、磺酰基、磷酰基。
进一步优选的,所述取代的基团分别独立的选自-F、-Cl、-Br、-OH、-CN、-NH2、-CF3、羟甲基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基。
R9选自取代或非取代的苯基、吡唑基、噁唑基、异噁唑基、噻唑基、咪唑基,所述取代基团独立的选自-F、-Cl、-Br、-OH、-CN、-NH2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、羟基甲基。
R10选自-NH2、-OH、卤素、C1-6的烷基或烷氧基、C3-6环烷基、C3-6杂环烷基;上述C1-6的烷基或烷氧基、C3-6环烷基、C3-6杂环烷基上的H可任选的被一个或多个卤素、-OH、-CN、-NH2、-NO2、-SH取代。
环Rg选自至少含有一个O、N、S的C3-8饱和/不饱和杂环烷基,所述环Rg上有至少
一个R11,R11独立地选自-H、氘、氚、-F、-Cl、-Br、-OH、-CN、-NH2、-NO2、-SH、羟氨基、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、金刚烷基、苯基、苯氧基、磺酰基、磷酰基。
在本发明的优选实施例中,所述化合物具有式Ⅲ所示结构,或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物:
R12选自-H、-F、-Cl、-Br、-OH、-CN、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、羟基甲基。
R13、R14独立的选自-H、氘、氚、-F、-Cl、-Br、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基。
R15选自-H,-F、-Br、-OH、-CN、-NH2、取代或非取代的C1-10直链/支链烷基、取代或非取代的C1-10直链/支链烷氧基、取代或非取代的环烷基或杂环烷基,其中,上述基团上的H可被以下基团取代:-F、-Cl、-Br、-OH、-CN、-NH2、-CF3、羟甲基、甲基、乙基、丙基、异丙基、苯基、甲氧基、乙氧基、丙氧基、异丙氧基、苯氧基、环丙基、环丁基、环戊基、环己基。
进一步优选的,所述C1-10直链/支链烷基为C1-6直链/支链烷基。
在本发明的优选实施例中,所述C1-10直链/支链烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、正己基、4-甲基-2戊基。
进一步优选的,所述C1-10直链/支链烷氧基为C1-6直链/支链烷氧基。
在本发明的优选实施例中,所述C1-10直链/支链烷氧基包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基、正己氧基。
所述的环烷基或杂环烷基包括单环、桥环、螺环或稠环的环烷基或杂环烷基,进一步的,所述环烷基或杂环烷基包括饱和或不饱和两种形式。
在本发明的具体实施例中,所述取代或非取代的环烷基或杂环烷基包括但不限于
表示可与炔基连接的位置。
在本发明的优选实施例中,所述化合物具有式Ⅳ所示结构,或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物:
R16、R17独立的选自-H、-F、-Cl、-Br、-OH、-CN、-NH2、-SH、羟氨基、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、苯基。
R18选自-H、-F、-Cl、-Br、-OH、-CN、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、羟基甲基。
R19、R20独立的选自-H、氘、氚、-F、-Cl、-Br、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基。
在本发明的优选实施例中,所述化合物具有式Ⅴ所示结构,或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物:
R21选自-H、-F、-Cl、-Br、-OH、-CN、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、羟基甲基。
R22、R23独立的选自-H、氘、氚、-F、-Cl、-Br、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基。
Y选自取代或非取代的C1-4直链/支链烷基、取代或非取代的C3-8环烷基或杂环烷基、取代或非取代的C5-6芳香基或杂环芳香基、酰胺基、酯基。所述取代基团选自-OH、-CN、-NH2、-NO2、-SH、羧基、羟氨基、烷基、烷氧基、羟基烷基、取代或非取代的C3-8环烷基或杂环烷基、C5-6芳香基或杂环芳香基、酯基、酰基、羰基、酰胺基、磺酰基、磷酰基。
所述的C5-6芳香基或杂环芳香基包括但不限于苯基、吡唑基。
所述的烷基优选为取代或非取代的C1-4直链/支链烷基。所述的烷氧基优选为取代或非取代的C1-4直链/支链烷氧基,包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基。所述的C1-4直链/支链烷基、C1-4直链/支链烷氧基可进一步被羟基、羟甲基取代。所述的羟基烷基包括但不限于羟甲基、羟乙基。
所述R24选自-H、氘、氚、-F、-Cl、-Br、-OH、-CN、-NH2、-NO2、-SH、羟氨基、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、苯基、苯氧基、取代或非取代的C3-8饱和或不饱和的环烷基或杂环烷基。
所述的C1-4直链/支链烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。
所述的取代或非取代的C3-8环烷基或杂环烷基包括但不限于
表示可与Y连接的位置。上述结构中的H可被以下基团取代:-OH、-CN、-NH2、-NO2、-SH、羟氨基、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、苯基、苯氧基、磺酰基、磷酰基。
在本发明的最优选实施方式中,所述化合物具有如下结构:
第二方面,本发明提供一种药物组合物,所述药物组合物包含通式Ⅰ-Ⅴ任一所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物。
优选的,所述药物组合物还包括药剂学上可接受的辅料,所述辅料包括但不限于:载体、稀释剂、粘合剂、润滑剂、润湿剂。
优选的,所述药物组合物包含治疗有效量的通式Ⅰ-Ⅴ任一所述的化合物。在某些实施方案中,所述药物组合物可单独使用,或与其他制剂联合使用。
所述药物组合物适于胃肠给药或非胃肠给药,如通过静脉内、肌内、皮内和皮下途径给药。优选的,所述药物组合物还包括抗氧化剂,缓冲剂,抑菌剂,和使制剂与受试者血液等渗的溶质,以及含水和非水的无菌悬浮剂,其可包含助悬剂,增溶剂,增稠剂,稳定剂和防腐剂。
本发明提供的通式Ⅰ-Ⅴ任一所述的化合物可以配制为以下形式的药物制剂:针剂、糖浆剂、酏剂、悬浮剂、粉剂、颗粒剂、片剂、胶囊、锭剂、霜剂、膏剂、洗液剂、凝胶剂、乳剂等。
第三方面,本发明提供一种通式Ⅰ-Ⅴ任一所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物,或者包含通式Ⅰ-Ⅴ任一所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物的药物组合物在制备治疗与PAK4激酶的表达或活性有关的疾病的药物中的用途。
所述的与PAK4激酶的表达或活性有关的疾病包括癌症、神经退行性疾病或免疫系统疾病。
其中,所述癌症包括卵巢癌、食道癌、喉癌、成胶质细胞瘤、成神经细胞瘤、胃癌、肝细胞癌、胶质瘤、子宫内膜癌、黑色素瘤、肾癌、膀胱癌、胆道癌、淋巴瘤、毛细胞癌、
鼻咽癌、咽癌、大肠癌、直肠癌、脑和中枢神经系统癌症、宫颈癌、睾丸癌、泌尿生殖道癌、肺癌、小细胞癌、骨癌、结肠癌、腺癌、滤泡性癌、霍奇金白血病、支气管癌、子宫体癌、子宫颈癌、多发性骨髓瘤、急性髓细胞源性白血病、慢性髓细胞源性白血病、淋巴细胞白血病、慢性淋巴样白血病、骨髓性白血病、原发性巨球蛋白血症、横纹肌肉瘤。
其中,所述腺癌包括但不限于乳腺癌、胰腺癌、前列腺癌、肺腺癌、甲状腺癌。
所述淋巴瘤包括但不限于套细胞淋巴瘤、非霍奇金淋巴瘤。
所述肺癌包括但不限于非小细胞肺癌。
优选的,所述通式Ⅰ-Ⅴ任一所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物可单独使用,或与其它种类的药物制剂和/或治疗方法联合使用。
所述其它种类的药物制剂和/或治疗方法包括但不限于:免疫抑制剂、靶向抗肿瘤药物、糖皮质激素、非甾体抗炎药、抗肿瘤疫苗、过继性细胞免疫治疗、化疗或放射治疗。
第四方面,本发明提供一种通式为Ⅵ的化合物,
其中,R25、R26独立的选自-H、氘、氚、-F、-Cl、-Br、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基。
第五方面,本发明提供一种通式为Ⅶ的化合物,
其中,R27选自-H、-F、-Cl、-Br、-OH、-CN、甲基、乙基、丙基、异丙基、甲氧基、
乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、羟基甲基。
R28、R29独立的选自-H、氘、氚、-F、-Cl、-Br、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基。
第六方面,本发明提供一种式Ⅵ和/或式Ⅶ所述的化合物在制备如下任意一种化合物,或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物中的用途:
(a)式Ⅰ所述的化合物;
(b)式II所述的化合物;
(c)式Ⅲ所述的化合物;
(d)式Ⅳ所述的化合物;
(e)式Ⅴ所述的化合物。
本发明提供的技术方案具有如下技术优势:(1)与现有技术相比,本发明提供的通式Ⅰ-Ⅴ所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物作为PAK4抑制剂具有较高的抑制活性和PAK I/II选择性,同时其肝微粒体稳定性及大鼠PK也得到提升;(2)进一步的,本发明提供的通式Ⅰ的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物作为PAK4抑制剂hERG心脏抑制活性大大降低,解决药物心脏毒性的风险问题。
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明的部分实施例,而不是全部。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
以下实施例中出现的缩写具有如下所示意义:
Et3N:三乙胺;
EA:乙酸乙酯;
THF:四氢呋喃;
MeOH:甲醇;
DIEA:N,N-二异丙基乙胺;
n-BuLi:正丁基锂;
M:摩尔浓度单位mol/L,例如1M是指1mol/L;
N:当量浓度,例如1N HCl是指浓度为1mol/L的盐酸;
HATU:O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸酯;
HBTU:苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐;
m-CPBA:间氯过氧苯甲酸;
NMO:N-甲基吗啉氧化物;
DPPA:叠氮磷酸二苯酯;
DMF:N,N-二甲基甲酰胺;
TBDPSCl:叔丁基二苯基氯硅烷;
DIBAL-H:二异丁基氢化铝;
TLC:薄层色谱;
PE:石油醚(沸点60-90℃);
DCM:二氯甲烷;
H2O:蒸馏水;
DMSO:二甲基亚砜;
Pd(PPh3)2Cl2:双三苯基磷二氯化钯;
Pd(dppf)Cl2.DCM:[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物;
HCl/1,4-dioxane:盐酸/1,4-二氧六环溶液;
TBAF.3H2O:四丁基氟化铵三水合物;
1,4-dioxane:1,4-二氧六环。
中间体的制备
中间体1的制备采用如下合成路线进行:
采用化合物4-(苯并[d][1,3]二氧-5-基)哌啶-4-胺.二盐酸盐的制备方法进行具体描述,如下:
步骤1:4-(苯并[d][1,3]二氧-5-基)-4-氰基哌啶-1-羧酸叔丁酯的制备
称取2-(苯并[d][1,3]二氧醇-5-基)乙腈(10.00g,62.03mmol)和双(2-氯乙基)氨基甲酸叔丁酯(16.52g,68.23mmol)于反应瓶中,加入DMF(120mL),氮气置换两次,冷却至0℃左右。分批加入NaH(9.93g,248.12mmol,60%in oil),保持体系温度在0-10℃之间。加毕,体系升温至60℃,反应2小时。关闭加热,使其在搅拌状态下自然降温至室温,并反应14小时。取样TLC板检测,原料反应完毕,将反应液缓慢加入到饱和NH4Cl的水溶液(600mL)中淬灭,然后加入EA(200mL*2),萃取2次,合并有机相并用饱和NaCl水溶液(100mL*3)洗涤3次,无水硫酸钠干燥,浓缩得到棕色固体(粗品),直接用于下一步反应中。
EM(计算值):330.2;MS(ESI)m/z(M+H)+:331.3
步骤2:4-(苯并[d][1,3]二氧-5-基)-4-氨甲酰哌啶-1-羧酸叔丁酯的制备
将化合物4-(苯并[d][1,3]二氧-5-基)-4-氰基哌啶-1-羧酸叔丁酯(粗品)和NaOH(24.81g,620.30mmol)于反应瓶中,加入DMSO(140mL),升温至60℃后,缓慢滴加H2O2(61mL)。加毕后取样监测反应。反应完毕,冷却至室温。将反应液缓慢倒入水(1120mL)中,产生大量浅黄色固体。搅拌20分钟后,过滤,滤饼用水淋洗3次。将滤饼烘干,得浅黄色固体(粗品),直接用于下一步反应。
EM(计算值):348.2;MS(ESI)m/z(M+H)+:349.3
步骤3:4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-羧酸叔丁酯的制备
称取4-(苯并[d][1,3]二氧-5-基)-4-氨甲酰哌啶-1-羧酸叔丁酯(粗品)于反应瓶中,加入乙腈(250mL)。搅拌下加入KOH(13.89g,248.12mmol)的水溶液(将KOH预先加入到125mL水中分散),于敞口反应瓶中进行。室温下缓慢加入二溴海因(10.64g,37.22mmol),加毕,体系逐步溶清,颜色较浅,室温反应2小时。TLC监测反应完全后,停止搅拌,分液,收集有机相,浓缩掉大部分溶剂。水相采用DCM/MeOH=10/1(100mL*2)萃取2次。将浓缩后的剩余物与萃取液合并,采用饱
和NaCl水溶液洗涤1次,并用无水硫酸钠干燥,浓缩至干,得黑色油状物(粗品),直接用于下一步反应中。
EM(计算值):320.2;MS(ESI)m/z(M+H)+:321.3
步骤4:4-(苯并[d][1,3]二氧-5-基)哌啶-4-胺.二盐酸盐的制备
称取4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-羧酸叔丁酯(粗品)于反应瓶中,加入HCl/1,4-dioxane(127mL,4M)。室温下搅拌10分钟左右有固体析出,继续搅拌1小时,原料反应完全。将反应液直接过滤,滤饼用少量的1,4-dioxane淋洗,得土灰色固体化合物(15.70g,四步反应总收率为86.4%)。
EM(计算值):220.1;MS(ESI)m/z(M+H)+:221.2
中间体2
2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺的制备
步骤1:2-氯-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺的制备
将化合物2,4-二氯-6-碘喹唑啉(5.00g,15.39mmol)溶解于DMF(30mL)中,室温下向其中依次加入5-环丙基-4-氟-1H-吡唑-3-胺(2.20g,15.44mmol)和DIEA(7.90g,61.56mmol)。升温至65℃搅拌2小时。原料反应完毕,将反应液冷却至室温。将反应液缓慢倒入水(300mL)中,EA萃取2次。合并有机相并用饱和NaCl水溶液洗涤1次,无水硫酸钠干燥。浓缩至干,剩余物采用柱层析纯化(DCM/MeOH=50/1),得到目标化合物(6.02g,收率为91.2%),呈黄色固体。
EM(计算值):429.0;MS(ESI)m/z(M+H)+:430.1
步骤2:2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺的制备
将化合物2-氯-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺(6.02g,14.01mmol)溶解于DMF(30mL)中,室温下向其中依次加入4-(苯并[d][1,3]二氧-5-基)哌啶-4-胺.二盐酸盐(4..11g,14.01mmol),KI(4.65g,28.02mmol)和DIEA(7.23g,56.04mmol)。升温至120℃搅拌2小时。原料反应完毕,将反应液冷却至室温。
将反应液缓慢倒入水(300mL)中,EA萃取2次。合并有机相并用饱和NaCl水溶液洗涤1次,无水硫酸钠干燥。浓缩至干,剩余物采用柱层析纯化(DCM/MeOH=50/1),得到目标化合物(5.42g,收率为63.1%),呈黄色固体。
EM(计算值):613.1;MS(ESI)m/z(M+H)+:614.1
实施例化合物的制备
实施例1
4-((2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-4-(5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)乙炔基)四氢-2H-吡喃-4-醇的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺(50mg,0.08mmol)和4-乙基四氢-2H-吡喃-4-醇(30mg,0.24mmol)加入到THF(2mL)中,向其中加入CuI(4mg,0.02mmol),Et3N(24mg,0.24mmol)和Pd(PPh3)2Cl2(15mg,0.02mmol),氮气保护下于50℃搅拌4小时。反应完毕后,向反应液中加入水(20mL),用EA萃取3次。合并有机相并用饱和NaCl水溶液洗涤1次。无水硫酸钠干燥后,浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=25/1),得到目标化合物(13mg,收率为26.6%),呈白色固体。
EM(计算值):611.3;MS(ESI)m/z(M+H)+:612.4
1H NMR(400MHz,DMSO-d6)δ0.75-0.79(2H,m),0.91-0.98(2H,m),1.53-1.56(2H,m),1.69-1.81(4H,m),1.83-1.90(3H,m),1.92-2.11(2H,brs),3.42-3.45(2H,m),3.59-3.63(2H,m),3.75-3.82(2H,m),4.24-4.26(2H,m),5.75(1H,s),5.95(2H,s),6.80(1H,d,J=8.0Hz),6.93(1H,d,J=8.0Hz),7.12(1H,s),7.27(1H,d,J=8.0Hz),7.52(1H,d,J=12.0Hz),8.39(1H,s),9.85(1H,s),12.39(1H,s).
以下表1所示实施例化合物参照实施例1所述方法合成:
表1
实施例10
2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-乙炔基喹唑啉-4-胺的制备
步骤1:2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-((三甲基硅基)乙炔基)喹唑啉-4-胺的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺(90mg,0.15mmol)和三甲基硅乙炔(60mg,0.60mmol)加入到DMF(2mL)中,向其中加入CuI(4mg,0.02mmol),Et3N(45mg,0.45mmol)和Pd(PPh3)2Cl2(22mg,0.03mmol),氮气保护下于45℃搅拌4小时。反应完毕后,向反应液中加入水(20mL),用EA萃取3次。合并有机相并用饱和NaCl水溶液洗涤1次。无水硫酸钠干燥后,浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=40/1),得到目标化合物(65mg,收率为74.3%),呈黄色固体。
EM(计算值):583.3;MS(ESI)m/z(M+H)+:584.4
步骤2:2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-乙炔基喹唑啉-4-胺的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-((三甲基硅基)乙炔基)喹唑啉-4-胺(65mg,0.11mmol)溶于甲醇(5mL)中,向其中加入碳酸钾(30mg,0.22mmol),于室温下搅拌4小时。反应完毕后,将反应液过滤,滤液浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=30/1),得到目标化合物(15mg,收率为26.7%),呈白色固体。
EM(计算值):511.2;MS(ESI)m/z(M+H)+:512.3
1H NMR(400MHz,DMSO-d6)δ0.76-0.79(2H,m),0.93-0.95(2H,m),1.52-1.55(2H,m),1.74-1.77(2H,m),1.84-1.86(1H,m),1.87-1.90(2H,brs),3.39-3.42(2H,m),4.13(1H,s),4.25-4.35(2H,m),5.95(2H,s),6.79(1H,d,J=7.6Hz),6.91(1H,d,J=8.4Hz),7.12(1H,s),
7.26(1H,d,J=8.4Hz),7.55(1H,dd,J=1.6Hz,8.4Hz),8.41(1H,s),9.83(1H,s),12.31(1H,s).
实施例11
4-(2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-4-(5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)-1,1,1-三氟丁基-3-炔-2-醇的制备
步骤1:1,1,1-三氟丁基-3-炔-2-醇的制备
将化合物三甲基硅乙炔(5.19g,52.79mmol)加入到无水THF(30mL)中,冷却到-60℃,向其中缓慢加入n-BuLi(31.67mL,63.35mmol,2M于正己烷中)。搅拌1小时后,向其中缓慢滴加三氟乙酸乙酯(5.00g,35.19mmol),维持该温度继续搅拌5小时。反应完毕后,向反应液中加入饱和NH4Cl水溶液淬灭,加入水(50mL)和EA(50mL)搅拌。分液,将水相采用EA萃取1次,合并有机相并用饱和NaCl水溶液洗涤1次,无水硫酸钠干燥后,浓缩至干。将剩余物溶解于甲醇(30mL)中,采用冰水浴冷却至0℃后,分批次加入硼氢化钠(4.00g,105.57mmol),室温搅拌过夜。反应完毕后,向反应液中缓慢加入水(50mL),再用乙酸乙酯萃取2次。将有机相合并后,用饱和NaCl水溶液洗涤1次,无水硫酸钠干燥后,浓缩至干,得到目标化合物(3.90g,收率为89.4%),呈无色油状物。
EM(计算值):124.0;MS(ESI)m/z(M+H)+:125.0
步骤2:4-(2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-4-(5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)-1,1,1-三氟丁基-3-炔-2-醇的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺(100mg,0.16mmol)和1,1,1-三氟丁基-3-炔-2-醇(40mg,0.32mmol)加入到DMF(5mL)中,向其中加入CuI(4mg,0.02mmol),Et3N(48mg,0.48mmol)和Pd(PPh3)2Cl2(22mg,0.03mmol),氮气保护下于45℃搅拌4小时。反应完毕后,向反应液中加入水(50mL),用EA萃取3次。合并有
机相并用饱和NaCl水溶液洗涤1次。无水硫酸钠干燥后,浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH/NH3.H2O=20/1/0.05),得到目标化合物(46mg,收率为47.2%),呈白色固体。
EM(计算值):609.2;MS(ESI)m/z(M+H)+:610.3
1H NMR(400MHz,DMSO-d6)δ0.76-0.78(2H,m),0.93-0.95(2H,m),1.57-1.63(2H,m),1.84-1.87(3H,m),3.45-3.48(2H,m),4.20-4.29(2H,m),5.23-5.28(1H,m),5.96(2H,s),6.82(1H,d,J=8.0Hz),6.93(1H,d,J=2.0Hz),7.13-7.15(2H,m),7.29(1H,d,J=8.8Hz),7.56(1H,d,J=8.8Hz),8.47(1H,s),9.92(1H,s),12.32(1H,s).
实施例12
4-(2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-4-(5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)丁-3-炔-1,2-二醇的制备
步骤1:1-((叔丁基二甲基甲硅烷基)氧基)丁-3-炔-2-醇的制备
将化合物2-((叔丁基二甲基甲硅烷基)氧基)乙醛(200mg,1.15mmol)加入到无水THF(10mL)中,采用冰水浴冷却到0℃左右,向其中缓慢加入乙炔基溴化镁(2.76mL,1.38mmol,0.5M于THF中),恢复至室温搅拌2小时。反应完毕后,向反应液中缓慢加入水(50mL),再用乙酸乙酯萃取2次。将有机相合并后,用饱和NaCl水溶液洗涤1次,无水硫酸钠干燥后,浓缩至干,得到目标化合物(189mg,收率为82.2%),呈黄色油状物。
EM(计算值):200.1;MS(ESI)m/z(M+H)+:201.1
步骤2:丁-3-炔-1,2-二醇的制备
将化合物1-((叔丁基二甲基甲硅烷基)氧基)丁-3-炔-2-醇(189mg,0.94mmol)加入到2M HCl/MeOH(5mL)中,升温至45℃后搅拌5小时。反应完毕后,将反应液浓缩至干,得到目标化合物(156mg,粗品),呈黑色油状物。
步骤3:4-(2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-4-(5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)丁-3-炔-1,2-二醇的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺(70mg,0.11mmol)和丁-3-炔-1,2-二醇(156mg,粗品)加入到DMF(5mL)中,向其中加入CuI(4mg,0.02mmol),Et3N(33mg,0.33mmol)和Pd(PPh3)2Cl2(14mg,0.02mmol),氮气保护下于45℃搅拌3小时。反应完毕后,向反应液中加入水(50mL),用EA萃取3次。合并有机相并用饱和NaCl水溶液洗涤1次。无水硫酸钠干燥后,浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=30/1),得到目标化合物(13mg,收率为20.7%),呈淡黄色固体。
EM(计算值):571.2;MS(ESI)m/z(M+H)+:572.3
1H NMR(400MHz,DMSO-d6)δ0.78-0.82(2H,m),0.97-1.01(2H,m),1.56-1.59(2H,m),1.76-1.78(2H,m),1.85-1.90(1H,m),3.41-3.45(2H,m),3.62-3.68(2H,m),4.36-4.40(2H,m),4.49-4.55(1H,m),4.71-4.75(1H,m),5.12(1H,d,J=6.4Hz),5.95(2H,s),6.77(1H,d,J=7.6Hz),6.87(1H,d,J=8.0Hz),7.12(1H,s),7.24(1H,d,J=6.4Hz),7.45(1H,d,J=8.0Hz),8.31(1H,s),9.75(1H,s),12.33(1H,s).
实施例13
4-((2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-4-((5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)乙炔基)环己烷-1-醇的制备
步骤1:4-(叔丁基二苯基甲硅基)氧基)环己烷-1-羧酸甲酯的制备
将化合物4-羟基环己烷羧酸甲酯(2.10g,13.28mmol)加入到DCM(50mL)中,向其中依次加入咪唑(0.90g,13.28mmol),TBDPSCl(3.65g,13.28mmol),于室温下搅拌1小时。反应完毕后,将反应液浓缩至干,剩余物采用柱层析纯化(PE/EA=100/1),得到目标化合物(4.80g,收率为91.3%),呈无色油状物。
EM(计算值):396.2;MS(ESI)m/z(M+H)+:397.2
步骤2:4-((叔丁基二苯基硅烷基)氧)环己烷-1-甲醛的制备
将化合物4-(叔丁基二苯基甲硅基)氧基)环己烷-1-羧酸甲酯(1.00g,2.52mmol)加入到无水DCM(15mL)中,向其中缓慢滴加DIBAL-H(3.0mL,3.03mmol,1.0M于正己烷中),于室温下搅拌1小时。反应完毕后,向反应液中加入水并用EA萃取2次。合并有机相并用饱和NaCl水溶液洗涤1次。无水硫酸钠干燥后,将反应液浓缩至干,得到目标化合物(911mg,收率为98.7%),呈无色油状物。
EM(计算值):366.2;MS(ESI)m/z(M+H)+:367.2
步骤3:叔丁基((4-乙炔基环己基)氧基)二苯基硅烷的制备
将化合物4-((叔丁基二苯基硅烷基)氧)环己烷-1-甲醛(800mg,2.18mmol)加入到MeOH(15mL)中,向其中依次加入碳酸钾(752mg,5.45mmol)和(1-重氮-2-氧丙基)膦酸二甲酯(837mg,4.36mmol),于室温下搅拌过夜。反应完毕后,将反应液浓缩至干,剩余物采用柱层析纯化(PE/EA=80/1),得到目标化合物(431mg,收率为53.9%),呈无色油状物。
EM(计算值):362.2;MS(ESI)m/z(M+H)+:363.2
步骤4:2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-6-(4-((叔丁基二苯基甲硅基)氧基)环己基)乙炔基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)喹唑啉-4-胺的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺(100mg,0.16mmol)和叔丁基((4-乙炔基环己基)氧基)二苯基硅烷(116mg,0.32mmol)加入到DMF(5mL)中,向其中加入CuI(4mg,0.02mmol),Et3N(48mg,0.48mmol)和Pd(PPh3)2Cl2(22mg,0.03mmol),氮气保护下于45℃搅拌4小时。反应完毕后,向反应液中加入水(50mL),用EA萃取3次。合并有机相并用饱和NaCl水溶液洗涤1次。无水硫酸钠干燥后,浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=30/1),得到目标化合物(67mg,收率为49.4%),呈黄色油状物。
EM(计算值):847.4;MS(ESI)m/z(M+H)+:848.5
步骤5:4-((2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-4-((5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)乙炔基)环己烷-1-醇的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-6-(4-((叔丁基二苯基甲硅基)氧基)环己基)乙炔基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)喹唑啉-4-胺(67mg,0.08mmol)溶解于THF(5mL)中,向其中加入TBAF.3H2O(76mg,0.24mmol),于室温下搅拌过夜。反应完毕后,向反应液中加入水(20mL),用EA萃取3次。合并有机相并用饱和NaCl水溶液洗涤1次。无水硫酸钠干燥后,浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=30/1),得到目标化合物(13mg,收率为26.7%),呈淡黄色固体。
EM(计算值):609.3;MS(ESI)m/z(M+H)+:610.4
1H NMR(400MHz,DMSO-d6)δ0.76-0.80(2H,m),0.93-0.97(2H,m),1.39-1.47(2H,m),1.52-1.58(2H,m),1.59-1.65(1H,m),1.74-1.81(1H,m),1.83-1.87(4H,m),1.94-2.01(4H,m),3.40-3.47(4H,m),4.28-4.39(1H,m),4.57(1H,d,J=4.0Hz),5.96(2H,s),6.881(1H,d,J=8.0Hz),6.94(1H,d,J=8.0Hz),7.13(1H,s),7.24(1H,d,J=8.0Hz),7.46(1H,d,J=8.0Hz),8.32(1H,s),9.76(1H,s),12.28(1H,s).
实施例14
(4-((2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-4-(5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)炔基)-2-氧杂环[2.2.2]辛烷-1-甲基)甲醇的制备
步骤1:1-((叔丁基二苯基甲硅烷基)氧基)甲基)-N-甲氧基-N-甲基-2-氧杂环[2.2.2]辛烷-4-甲酰胺的制备
将化合物1-((叔丁基二苯基甲硅烷基)氧基)甲基)-2-氧双环[2.2.2]辛烷-4-羧酸(1.00g,2.36mmol)加入到DCM(30mL)中,向其中依次加入二甲羟胺盐酸盐(276mg,2.83mmol),HBTU(1.34g,3.54mmol)和DIEA(760mg,5.90mmol),于室温下搅拌过夜。反应完毕后,将反应液浓缩至干,剩余物采用柱层析纯化(PE/EA=50/1),得到目标化合物(708mg,收率为64.2%),呈无色油状物。
EM(计算值):467.2;MS(ESI)m/z(M+H)+:468.2
步骤2:1-((叔丁基二苯基甲硅基)氧基)甲基)-2-氧杂环[2.2.2]辛烷-4-甲醛的制备
将化合物1-((叔丁基二苯基甲硅烷基)氧基)甲基)-N-甲氧基-N-甲基-2-氧杂环[2.2.2]辛烷-4-甲酰胺(700mg,1.50mmol)加入到无水THF(10mL)中,冰水浴冷却后向其中缓慢滴加DIBAL-H(2.3mL,2.3mmol,1.0M于正己烷中),后于室温下搅拌3小时。反应完毕后,向反应液中加入水并用EA萃取2次。合并有机相并用饱和NaCl水溶液洗涤1次。无水硫酸钠干燥后,将反应液浓缩至干,得到目标化合物(435mg,收率为71.0%),呈无色油状物。
EM(计算值):408.2;MS(ESI)m/z(M+H)+:409.2
步骤3:叔丁基((4-乙炔基-2-氧杂环[2.2.2]辛烷-1-基)甲氧基)二苯基硅烷的制备
将化合物1-((叔丁基二苯基甲硅基)氧基)甲基)-2-氧杂环[2.2.2]辛烷-4-甲醛(435mg,1.07mmol)加入到MeOH(10mL)中,向其中依次加入碳酸钾(443mg,3.21mmol)和(1-重氮-2-氧丙基)膦酸二甲酯(411mg,2.14mmol),于室温下搅拌过夜。反应完毕后,将反应液浓缩至干,剩余物采用柱层析纯化(PE/EA=50/1),得到目标化合物(386mg,收率为89.4%),呈无色油状物。
EM(计算值):404.2;MS(ESI)m/z(M+H)+:405.2
步骤4:(4-乙炔基-2-氧杂环[2.2.2]辛烷-1-基)甲醇的制备
将化合物叔丁基((4-乙炔基-2-氧杂环[2.2.2]辛烷-1-基)甲氧基)二苯基硅烷(386mg,0.95mmol)溶解于THF(10mL)中,向其中加入TBAF.3H2O(899mg,2.85mmol),于室温下搅拌过夜。反应完毕后,向反应液中加入水(30mL),用EA萃取2次。
合并有机相并用饱和NaCl水溶液洗涤1次。无水硫酸钠干燥后,浓缩至干,得到目标化合物(359mg,粗品),呈无色油状物。
EM(计算值):166.1;MS(ESI)m/z(M+H)+:167.1;
步骤5:(4-((2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-4-(5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)炔基)-2-氧杂环[2.2.2]辛烷-1-甲基)甲醇的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺(100mg,0.16mmol)和(4-乙炔基-2-氧杂环[2.2.2]辛烷-1-基)甲醇(359mg,粗品)加入到DMF(10mL)中,向其中加入CuI(4mg,0.02mmol),Et3N(48mg,0.48mmol)和Pd(PPh3)2Cl2(22mg,0.03mmol),氮气保护下于45℃搅拌3小时。反应完毕后,向反应液中加入水(100mL),用EA萃取3次。合并有机相并用饱和NaCl水溶液洗涤1次。无水硫酸钠干燥后,浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=30/1),得到目标化合物(62mg,收率为59.6%),呈淡黄色固体。
EM(计算值):651.3;MS(ESI)m/z(M+H)+:652.4;
1H NMR(400MHz,DMSO-d6)δ0.76-0.80(2H,m),0.93-0.97(2H,m),1.39-1.47(2H,m),1.52-1.58(2H,m),1.59-1.65(1H,m),1.74-1.81(1H,m),1.83-1.87(4H,m),1.94-2.01(4H,m),3.40-3.47(4H,m),4.28-4.39(1H,m),4.57(1H,d,J=4.0Hz),5.96(2H,s),6.881(1H,d,J=8.0Hz),6.94(1H,d,J=8.0Hz),7.13(1H,s),7.24(1H,d,J=8.0Hz),7.46(1H,d,J=8.0Hz),8.32(1H,s),9.76(1H,s),12.28(1H,s).
实施例15
4-((2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-4-(5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)乙炔基)四氢-2H-吡喃-3-醇的制备
步骤1:3,7-二氧杂环[4.1.0]庚烷的制备
将化合物3,6二氢-2H-吡喃(1.00g,11.89mmol)加入到DCM(20mL)中,采用冰水浴冷却到0℃后,向其中分批次加入m-CPBA(4.10g,23.78mmol),于室温下搅拌过夜。反应完毕后,将反应液用水洗涤,收集有机相并用饱和NaCl水溶液洗涤1次,无水硫酸钠干燥后再浓缩至干,剩余物采用柱层析纯化(PE/EA=20/1),得到目标化合物(600mg,收率为50.4%),呈无色油状物。
EM(计算值):100.1;MS(ESI)m/z(M+H)+:101.1
步骤2:4-((三甲基硅烷基)乙炔基)四氢-2H-吡喃-3-醇的制备
将化合物三甲基硅乙炔(1.18g,11.98mmol)加入到无水THF(10mL)中,冷却到-78℃,向其中缓慢加入n-BuLi(7.20mL,14.38mmol,2M于正己烷中)。搅拌1小时后,向其中缓慢滴加3,7-二氧杂环[4.1.0]庚烷(600mg,5.99mmol),维持该温度继续搅拌0.5小时。再加入三氟化硼乙醚溶液,继续搅拌0.5小时。反应完毕后,向反应液中缓慢加入饱和NH4Cl水溶液淬灭,加入水(20mL)和EA(20mL)搅拌。分液,将水相采用EA萃取1次,合并有机相并用饱和NaCl水溶液洗涤1次,无水硫酸钠干燥后,浓缩至干,得到目标化合物(465mg,收率为39.2%),呈黄色油状物。
EM(计算值):198.1;MS(ESI)m/z(M+H)+:199.1
步骤3:4-乙基四氢-2H-吡喃-3-醇的制备
将化合物4-((三甲基硅烷基)乙炔基)四氢-2H-吡喃-3-醇(465mg,2.35mmol)加入到MeOH(15mL)中,向其中加入碳酸钾(649mg,4.70mmol),于室温下搅拌0.5小时。反应完毕后,将反应液浓缩至干,剩余物采用柱层析纯化(PE/EA=15/1),得到目标化合物(236mg,收率为79.7%),呈黄色油状物。
EM(计算值):126.1;MS(ESI)m/z(M+H)+:127.2
步骤4:4-((2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-4-(5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)乙炔基)四氢-2H-吡喃-3-醇的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺(100mg,0.16mmol)和4-乙基四氢-2H-吡喃-3-醇(40mg,0.32mmol)加入到DMF(3mL)中,向其中加入CuI(4mg,0.02mmol),Et3N(48mg,0.48mmol)和Pd(PPh3)2Cl2(22mg,0.03mmol),氮气保护下于45℃搅拌4小时。反应完毕后,向反应液中加入水(100mL),用EA萃取3次。合并有机相并用饱和NaCl水溶液洗涤1次。无水硫酸钠干燥后,浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=30/1),得到目标化合物(16mg,收率为16.4%),呈黄色固体。
EM(计算值):611.3;MS(ESI)m/z(M+H)+:612.4
1H NMR(400MHz,DMSO-d6)δ0.77-0.79(2H,m),0.95-1.00(2H,m),1.22-1.25(2H,m),1.60-1.63(2H,m),1.86-1.89(2H,m),2.01-2.04(1H,m),2.65-2.70(1H,m),3.07-3.12(1H,m),3.49-3.55(4H,m),3.77-3.84(2H,m),4.18-4.25(2H,m),5.26(1H,d,J=8.0Hz),5.98(2H,s),6.84(1H,d,J=8.0Hz),6.97(1H,d,J=8.0Hz),7.15(1H,s),7.27(1H,d,J=8.0Hz),7.53(1H,d,J=12.0Hz),8.37(1H,s),9.82(1H,s),12.30(1H,s).
实施例16
(5-((2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-4-((5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)乙炔基)四氢-2H-吡喃-2-基)甲醇的制备
步骤1:6-(((叔丁基二苯基甲硅烷基)氧基)甲基)-N-甲氧基-N-甲基四氢-2H-吡喃-3-甲酰胺的制备
将化合物6-((叔丁基二苯基甲硅烷基)氧基)甲基)四氢-2H-吡喃-3-羧酸(556mg,1.40mmol)加入到DCM(20mL)中,向其中依次加入二甲羟胺盐酸盐(205mg,2.10mmol),HBTU(637mg,1.68mmol)和DIEA(452mg,3.50mmol),于室温下搅拌5小时。反应完毕后,将反应液浓缩至干,剩余物采用柱层析纯化(PE/EA=10/1),得到目标化合物(524mg,收率为84.8%),呈无色油状物。
EM(计算值):441.2;MS(ESI)m/z(M+H)+:442.2
步骤2:6-(((叔丁基二苯基甲硅基)氧)甲基)四氢-2H-吡喃-3-甲醛的制备
将化合物6-(((叔丁基二苯基甲硅烷基)氧基)甲基)-N-甲氧基-N-甲基四氢-2H-吡喃-3-甲酰胺(524mg,1.19mmol)加入到无水THF(10mL)中,冰水浴冷却后向其中缓慢滴加DIBAL-H(2.4mL,2.38mmol,1.0M于正己烷中),维持该温度继续搅拌0.5小时。反应完毕后,向反应液中加入水并用EA萃取2次。合并有机相并用饱和NaCl水溶液洗涤1次。无水硫酸钠干燥后,将反应液浓缩至干,得到目标化合物(1.20g,粗品),呈无色油状物。
EM(计算值):382.2;MS(ESI)m/z(M+H)+:383.3
步骤3:叔丁基((5-乙基四氢-2H-吡喃-2-炔基)甲氧基)二苯基硅烷的制备
将化合物6-(((叔丁基二苯基甲硅基)氧)甲基)四氢-2H-吡喃-3-甲醛(1.20g,粗品)加入到MeOH(10mL)中,向其中依次加入碳酸钾(493mg,3.57mmol)和(1-重氮-2-氧丙基)膦酸二甲酯(419mg,2.38mmol),于室温下搅拌过夜。反应完毕后,将反应液浓缩至干,剩余物采用柱层析纯化(PE/EA=20/1),得到目标化合物(285mg,两步反应总收率为63.3%),呈无色油状物。
EM(计算值):378.2;MS(ESI)m/z(M+H)+:379.3
步骤4:2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-6-(6-((叔丁基二苯基甲硅烷基)氧基)甲基)四氢-2H-吡喃-3-基)乙炔基)-N-(5-环丙基-4-氟-1H-吡唑-3-甲基)喹唑啉-4-胺的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺(227mg,0.37mmol)和叔丁基((5-乙基四氢-2H-吡喃-2-炔基)甲氧基)二苯基硅烷(285mg,0.75mmol)加入到DMF(10mL)中,向其中加入CuI(8mg,0.04mmol),Et3N(112mg,1.11mmol)和Pd(PPh3)2Cl2(28mg,0.04mmol),氮气保护下于45℃搅拌4小时。反应完毕后,向反应液中加入水(100mL),用EA萃取3次。合并有机相并用饱和NaCl水溶液洗涤1次。
无水硫酸钠干燥后,浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=20/1),得到目标化合物(200mg,收率为62.7%),呈棕黄色油状物。
EM(计算值):863.4;MS(ESI)m/z(M+H)+:864.5
步骤5:(5-((2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-4-((5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)乙炔基)四氢-2H-吡喃-2-基)甲醇的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-6-(6-((叔丁基二苯基甲硅烷基)氧基)甲基)四氢-2H-吡喃-3-基)乙炔基)-N-(5-环丙基-4-氟-1H-吡唑-3-甲基)喹唑啉-4-胺(200mg,0.23mmol)溶解于THF(10mL)中,向其中加入TBAF.3H2O(218mg,0.69mmol),于40℃下搅拌2小时。反应完毕后,向反应液中加入水(30mL),用EA萃取2次。合并有机相并用饱和NaCl水溶液洗涤1次。无水硫酸钠干燥后,浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=20/1),得到目标化合物(97mg,收率为67.5%),呈深黄色固体。
EM(计算值):625.3;MS(ESI)m/z(M+H)+:626.4
1H NMR(400MHz,DMSO-d6)δ0.77-0.80(2H,m),0.94-0.96(2H,m),1.28-1.34(1H,m),1.57-1.67(4H,m),1.84-1.89(3H,m),2.11-2.20(1H,m),3.48-3.63(6H,m),4.02-4.07(1H,m),4.13-4.37(2H,m),4.67(1H,t,J=4.0Hz),5.97(2H,s),6.82(1H,d,J=8.0Hz),6.95(1H,d,J=12.0Hz),7.14(1H,s),7.25(1H,d,J=8.0Hz),7.48(1H,d,J=8.0Hz),8.34(1H,s),9.80(1H,s),12.30(1H,s).
实施例17
2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-(1H-吡唑-4-基)喹唑啉-4-胺的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺(30mg,0.05mmol)和4-吡唑硼酸频哪醇酯(19mg,0.10mmol)加入到1,4-dioxane/H2O(2mL,5/1)中,向其中加入碳酸钠(21mg,0.20
mmol)和Pd(dppf)Cl2.DCM(7mg,0.01mmol),氮气保护下于80℃搅拌4小时。反应完毕后,将反应液浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH/NH3.H2O=20/1/0.05),得到目标化合物(5mg,收率为18.1%),呈白色固体。
EM(计算值):553.2;MS(ESI)m/z(M+H)+:554.3
1H NMR(400MHz,DMSO-d6)δ0.77-0.80(2H,m),0.95-0.96(2H,m),1.54-1.57(2H,m),1.82-1.91(4H,m),1.96-2.01(1H,m),3.41-3.50(2H,m),4.30-4.34(2H,m),5.96(2H,s),6.80(1H,d,J=7.6Hz),6.94(1H,d,J=9.6Hz),7.13(1H,s),7.32(1H,d,J=8.4Hz),7.85(1H,d,J=8.8Hz),8.01-8.15(2H,m),8.48(1H,s),9.72(1H,s),12.32(1H,s),12.94(1H,brs).
实施例18
2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-(1-甲基-1H-吡唑-4-基)喹唑啉-4-胺的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺(30mg,0.05mmol)和1-甲基-4-吡唑硼酸频哪醇酯(21mg,0.10mmol)加入到1,4-dioxane/H2O(2mL,5/1)中,向其中加入碳酸钠(21mg,0.20mmol)和Pd(dppf)Cl2.DCM(7mg,0.01mmol),氮气保护下于80℃搅拌4小时。反应完毕后,将反应液浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH/NH3.H2O=20/1/0.05),得到目标化合物(4mg,收率为14.1%),呈白色固体。
EM(计算值):567.3;MS(ESI)m/z(M+H)+:568.3
1H NMR(400MHz,DMSO-d6)δ0.74-0.77(2H,m),0.93-0.95(2H,m),1.44(3H,s),1.50-1.55(2H,m),1.78-1.86(2H,m),1.87-1.89(2H,brs),1.91-1.96(1H,m),3.45-3.52(2H,m),4.33-4.37(2H,m),5.95(2H,s),6.77(1H,d,J=6.4Hz),6.91(1H,d,J=8.0Hz),7.12(1H,s),7.30(1H,d,J=7.2Hz),7.80(1H,d,J=8.0Hz),8.00-8.11(2H,m),8.44(1H,s),9.72(1H,s),12.32(1H,s).
实施例19
3-(4-(2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-4-((5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)苯氧基)丙烷-1,2-二醇的制备
步骤1:2-(4-((2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)苯硼酸频哪醇酯的制备
将化合物4-羟基苯硼酸频哪醇酯(2.20g,10.00mmol)加入到DMSO(40mL)中,向其中依次加入碳酸钾(2.07g,15.00mmol),4-(氯甲基)-2,2-二甲基-1,3-二氧戊环(1.80g,12.00mmol),升温至120℃搅拌10小时。反应完毕后,将反应液冷却至室温,向其中加入水(400mL),用EA萃取2次。合并有机相并用饱和NaCl水溶液洗涤1次,无水硫酸钠干燥后,浓缩至干,剩余物采用柱层析纯化(PE/EA=10/1),得到目标化合物(1.7g,收率为50.9%),呈棕色油状物。
EM(计算值):334.2;MS(ESI)m/z(M+H)+:335.2
步骤2:2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-(4-((2,2-二甲基-1,3-二氧环-4-基)甲氧基)苯基)喹唑啉-4-胺的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺(100mg,0.16mmol)和2-(4-((2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)苯硼酸频哪醇酯(107mg,0.32mmol)加入到1,4-dioxane/H2O(10mL,5/1)中,向其中加入碳酸钠(34mg,0.32mmol)和Pd(dppf)Cl2.DCM(14mg,0.02mmol),氮气保护下于80℃搅拌5小时。反应完毕后,将反应液浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=30/1),得到目标化合物(50mg,收率为45.1%),呈棕色固体。
EM(计算值):693.3;MS(ESI)m/z(M+H)+:694.4
步骤3:3-(4-(2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-4-((5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)苯氧基)丙烷-1,2-二醇的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-(4-((2,2-二甲基-1,3-二氧环-4-基)甲氧基)苯基)喹唑啉-4-胺(50mg,0.07mmol)加入到THF(5mL)中,向其中加入浓盐酸(0.5mL),于室温下搅拌1小时。反应完毕后,将反应液浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=15/1),得到目标化合物(20mg,收率为42.5%),呈淡黄色固体。
EM(计算值):653.3;MS(ESI)m/z(M+H)+:654.4
1H NMR(400MHz,DMSO-d6)δ0.76-0.79(2H,m),0.83-0.85(2H,m),1.53-1.56(2H,m),1.79-1.84(2H,m),1.87-1.89(1H,m),1.92-2.01(2H,brs),3.45-3.48(2H,m),3.81-3.82(1H,m),3.89-3.93(1H,m),4.03-4.07(1H,m),4.31-4.39(2H,m),4.70-4.73(1H,m),4.99-5.00(1H,m),5.95(2H,s),6.80(1H,d,J=8.0Hz),6.92(1H,d,J=7.6Hz),7.04(2H,d,J=8.8Hz),7.13(1H,s),7.37(1H,d,J=8.8Hz),7.75(2H,d,J=8.8Hz),7.90(1H,d,J=8.8Hz),8.54(1H,s),9.91(1H,s),12.30(1H,s).
实施例20
1-(4-(2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-4-((5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)苯基)乙烷-1,2-二醇的制备
步骤1:1-(4-溴苯基)乙烷-1,2-二醇的制备
将化合物1-溴-4-乙烯基苯(200mg,1.10mmol)加入到DCM/H2O(10mL,4/1)中,向其中加入NMO(258mg,2.20mmol)和KOsO4.2H2O(810mg,2.20mmol),于室温下搅拌3小时。反应完毕后,将反应液浓缩至干,将得到的粗品采用柱层析纯化(PE/EA=5/1),得到目标化合物(120mg,收率为50.5%),呈白色固体。
EM(计算值):216.0;MS(ESI)m/z(M+H)+:217.0
步骤2:1-(4-(2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-4-((5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)苯基)乙烷-1,2-二醇的制备
将化合物1-(4-溴苯基)乙烷-1,2-二醇(100mg,0.46mmol)溶解于1,4-dioxane(5mL)中,依次向其中加入醋酸钾(90mg,0.92mmol)和Pd(dppf)Cl2.DCM(28mg,0.04mmol),氮气保护下于90℃搅拌5小时。反应完毕后,将反应液冷却至室温,向其中依次加入2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺(140mg,0.23mmol),碳酸钠(49mg,0.46mmol)和Pd(dppf)Cl2.DCM(14mg,0.02mmol),氮气保护下于90℃搅拌6小时。反应完毕后,将反应液冷却至室温,过滤后将滤液浓缩至干,将得到的粗品依次采用柱层析和制备HPLC纯化,得到目标化合物(5mg,收率为3.5%),呈黄色固体。
EM(计算值):623.3;MS(ESI)m/z(M+H)+:624.4
1H NMR(400MHz,DMSO-d6)δ0.78-0.81(2H,m),0.93-0.98(2H,m),1.51-1.54(2H,m),1.76-1.80(2H,m),1.81-1.84(1H,m),1.89-1.95(2H,brs),3.41-3.47(2H,m),4.13-4.18(2H,m),4.25-4.32(2H,m),5.00-5.06(1H,m),5.18-5.27(1H,m),5.55-5.60(1H,m),5.96(2H,s),6.81-6.86(2H,m),6.92-6.98(2H,m),7.13(1H,s),7.33(2H,d,J=6.4Hz),7.52-7.58(2H,m),8.41(1H,s),9.87(1H,s),12.33(1H,s).
实施例21
2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-乙烯基喹唑啉-4-胺的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺(60mg,0.10mmol)和乙烯三氟硼酸钾(27mg,0.20mmol)加入到1,4-dioxane/H2O(10mL,5/1)中,向其中加入Et3N(30mg,0.30mmol)和Pd(dppf)Cl2.DCM(14mg,0.02mmol),氮气保护下于80℃搅拌4小时。反应完毕后,将反应液浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=30/1),得到目标化合物(46mg,收率为89.6%),呈黄色固体。
EM(计算值):513.2;MS(ESI)m/z(M+H)+:514.3
1H NMR(400MHz,DMSO-d6)δ0.78-0.81(2H,m),0.94-0.97(2H,m),1.51-1.54(2H,m),1.72-1.77(2H,m),1.85-1.88(1H,m),1.90-1.95(2H,brs),3.37-3.43(2H,m),4.25-4.35(2H,m),5.25-5.351(2H,m),5.95(2H,s),6.02-6.05(1H,m),6.83(1H,d,J=6.4Hz),6.90(1H,d,J=8.0Hz),7.13(1H,s),7.29(1H,d,J=8.0Hz),7.51(1H,d,J=8.4Hz),8.37(1H,s),9.81(1H,s),12.30(1H,s).
实施例22
1-(2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-4-((5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)乙烷-1,2-二醇的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-乙烯基喹唑啉-4-胺(40mg,0.08mmol)加入到DCM/THF/H2O(10mL,4/1/1)中,向其中加入NMO(19mg,0.16mmol)和KOsO4.2H2O(60mg,0.16mmol),于室温下搅拌2小时。反应完毕后,将反应液浓缩至干,将得到的粗品采用制备HPLC纯化,得到目标化合物(10mg,收率为22.9%),呈黄色固体。
EM(计算值):547.2;MS(ESI)m/z(M+H)+:548.3
1H NMR(400MHz,DMSO-d6)δ0.75-0.79(2H,m),0.91-0.94(2H,m),1.49-1.52(2H,m),1.75-1.79(2H,m),1.89-1.96(3H,m),3.39-3.44(2H,m),4.11-4.17(2H,m),4.27-4.34(2H,m),5.02-5.09(1H,m),5.20-5.29(1H,m),5.59-5.63(1H,m),5.97(2H,s),6.87(1H,d,J=5.2Hz),6.94(1H,d,J=7.6Hz),7.12(1H,s),7.33(1H,d,J=7.6Hz),7.55(1H,d,J=8.0Hz),8.39(1H,s),9.84(1H,s),12.31(1H,s).
实施例23
(5-(2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-4-((5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)-3,4-二氢-2H-吡喃-2-基)甲醇的制备
步骤1:2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-6-(2-((叔丁基二苯基甲硅烷基)氧基)甲基)-3,4-二氢-2H-吡喃-5-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)喹唑啉-4-胺的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺(120mg,0.20mmol)和叔丁基二苯基((5-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)-3,4-二氢-2H-吡喃-2-基)甲氧基)硅烷(120mg,0.25mmol)加入到1,4-dioxane/H2O(10mL,5/1)中,向其中加入碳酸钠(42mg,0.40mmol)和Pd(dppf)Cl2.DCM(21mg,0.03mmol),氮气保护下于80℃搅拌过夜。反应完毕后,将反应液浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=30/1),得到目标化合物(80mg,收率为47.8%),呈黄色固体。
EM(计算值):837.4;MS(ESI)m/z(M+H)+:838.5
步骤2:(5-(2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-4-((5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)-3,4-二氢-2H-吡喃-2-基)甲醇的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-6-(2-((叔丁基二苯基甲硅烷基)氧基)甲基)-3,4-二氢-2H-吡喃-5-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)喹唑啉-4-胺(80mg,0.10mmol)溶解于THF(10mL)中,向其中加入TBAF.3H2O(95mg,0.30mmol),于40℃下搅拌3小时。反应完毕后,向反应液中加入水(30mL),用EA萃取2次。合并有机相并用饱和NaCl水溶液洗涤1次。无水硫酸钠干燥后,浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=20/1),得到目标化合物(50mg,收率为83.3%),呈白色固体。
EM(计算值):599.3;MS(ESI)m/z(M+H)+:600.4
1H NMR(400MHz,DMSO-d6)δ0.81-0.85(2H,m),0.96-1.00(2H,m),1.43-1.47(2H,m),1.74-1.78(2H,m),1.88-1.92(1H,m),1.99-2.04(2H,m),2.13-2.17(2H,m),3.45-3.52(2H,m),3.79-3.86(2H,m),4.46-4.50(1H,m),4.68-4.77(2H,m),5.33(1H,t,J=4.0Hz),6.02(2H,s),6.38(1H,s),6.92(1H,d,J=8.0Hz),7.04(1H,d,J=8.0Hz),7.21(1H,s),7.32(1H,d,J=8.0Hz),7.72(1H,d,J=12.0Hz),8.12(1H,s),9.87(1H,s),12.34(1H,s).
实施例24
(5-(2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-4-((5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)四氢-2H-吡喃-2-基)甲醇的制备
将化合物(5-(2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-4-((5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-基)-3,4-二氢-2H-吡喃-2-基)甲醇(40mg,0.07mmol)溶解于甲醇(10mL)中,向其中加入Pd/C(10mg,10%含量),氢气置换后于室温下搅拌过夜。反应完毕后,将反应液过滤,滤液浓缩至干,得到的粗品采用柱层析纯化(DCM/MeOH=20/1),得到目标化合物(20mg,收率为47.6%),呈白色固体。
EM(计算值):601.3;MS(ESI)m/z(M+H)+:602.4
1H NMR(400MHz,DMSO-d6)δ0.79-0.82(2H,m),0.93-0.95(2H,m),1.37-1.42(2H,m),1.70-1.784(2H,m),1.85-1.90(1H,m),1.79-2.03(2H,m),2.11-2.16(2H,m),2.35-2.39(1H,m),3.47-3.53(2H,m),3.81-3.87(2H,m),4.49-4.53(1H,m),4.56-4.60(2H,m),4.69-4.76(2H,m),5.34(1H,t,J=4.0Hz),5.96(2H,s),6.88(1H,d,J=7.6Hz),7.05(1H,d,J=8.4Hz),7.15(1H,s),7.28(1H,d,J=6.4Hz),7.68(1H,d,J=8.0Hz),8.21(1H,s),9.69(1H,s),12.28(1H,s).
实施例25
2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-4-(5-环丙基-4-氟-1H-吡唑-3-基)氨基)-N-(1-(羟甲基)-2-氧杂环[2.2.2]辛烷-4-基)喹唑啉-6-甲酰胺的制备
步骤1:1-(((叔丁基二苯基甲硅基)氧基)甲基)-2-氧杂环[2.2.2]辛烷-4-胺的制备
将化合物1-((叔丁基二苯基甲硅烷基)氧基)甲基)-2-氧双环[2.2.2]辛烷-4-羧酸(1.00g,2.36mmol)加入到甲苯(15mL)中,向其中加入Et3N(715mg,7.08mmol),分子筛和DPPA(1.30g,4.72mmol),升温至100℃搅拌4小时。反应完毕后,将反应液浓缩至干,将剩余物溶解在THF(20mL)中,向其中加入叔丁醇钾(530mg,4.72mmol),于室温下搅拌过夜。反应完毕后,将反应液浓缩至干,将得到的粗品采用柱层析纯化(PE/EA=5/1),得到目标化合物(437mg,收率为46.9%),呈黄色油状物。
EM(计算值):395.2;MS(ESI)m/z(M+H)+:396.2
步骤2:甲基2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-4-(5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-羧酸酯的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-N-(5-环丙基-4-氟-1H-吡唑-3-基)-6-碘喹唑啉-4-胺(75mg,0.12mmol)加入到甲醇(10mL)中,向其中加入Et3N(36mg,0.36mmol)和Pd(dppf)Cl2.DCM(14mg,0.02mmol),一氧化碳气氛下于70℃搅拌过夜。反应完毕后,将反应液浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=30/1),得到目标化合物(63mg,收率为96.3%),呈黄色固体。
EM(计算值):545.2;MS(ESI)m/z(M+H)+:546.3
步骤3:2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-4-(5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-羧酸的制备
将化合物甲基2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-4-(5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-羧酸酯(63mg,0.12mmol)加入到甲醇/H2O(10mL,4/1)中,向其中加入LiOH.H2O(15mg,0.36mmol),升温至50℃搅拌2小时。反应完毕后,将反应液浓缩至干,得到目标化合物(粗品),呈黄色固体。
EM(计算值):531.2;MS(ESI)m/z(M-H)-:530.2
步骤4:2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-N-(1-((叔丁基二苯基甲硅基)氧基)甲基)-2-氧杂环[2.2.2]辛烷-4-基)-4-((5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-甲酰胺的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧-5-基)哌啶-1-基)-4-(5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-羧酸(粗品)加入到THF(10mL)中,向其中依次加入1-(((叔丁基二苯基甲硅基)氧基)甲基)-2-氧杂环[2.2.2]辛烷-4-胺(71mg,0.18mmol),HATU(68mg,0.18mmol)和DIEA(31mg,0.24mmol),于室温下搅拌4小时。反应完毕后,将反应液浓缩至干,剩余物采用柱层析纯化(DCM/MeOH=20/1),得到目标化合物(61mg,两步反应总收率为56.0%),呈黄色固体。
EM(计算值):908.4;MS(ESI)m/z(M+H)+:909.5
步骤5:2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-4-(5-环丙基-4-氟-1H-吡唑-3-基)氨基)-N-(1-(羟甲基)-2-氧杂环[2.2.2]辛烷-4-基)喹唑啉-6-甲酰胺的制备
将化合物2-(4-氨基-4-(苯并[d][1,3]二氧醇-5-基)哌啶-1-基)-N-(1-((叔丁基二苯基甲硅基)氧基)甲基)-2-氧杂环[2.2.2]辛烷-4-基)-4-((5-环丙基-4-氟-1H-吡唑-3-基)氨基)喹唑啉-6-甲酰胺(61mg,0.07mmol)溶解于THF(10mL)中,向其中加入TBAF.3H2O(66mg,0.21mmol),于50℃下搅拌2小时。反应完毕后,向反应液中加入水(30mL),用EA萃取2次。合并有机相并用饱和NaCl水溶液洗涤1次。无水硫酸钠干燥后,浓缩至干,将得到的粗品采用柱层析纯化(DCM/MeOH=20/1),得到目标化合物(15mg,收率为34.1%),呈黄色固体。
EM(计算值):670.3;MS(ESI)m/z(M+H)+:671.4
1H NMR(400MHz,DMSO-d6)δ0.79-0.81(2H,m),0.95-0.97(2H,m),1.62-1.83(6H,m),1.87-1.91(1H,m),1.94-2.04(4H,m),2.12-2.31(2H,m),3.18(2H,d,J=4.0Hz),3.44-3.48(4H,m),3.59-3.63(2H,m),4.01(2H,s),4.57(1H,t,J=4.0Hz),6.00(2H,s),6.88(1H,d,J=8.0Hz),7.01(1H,d,J=8.0Hz),7.17(1H,s),7.31(1H,d,J=8.0Hz),7.53-7.57(1H,m),7.92(1H,d,J=12.0Hz),8.65(1H,s),9.84(1H,s),12.33(1H,s).
试验例1化合物对激酶的活性抑制效应
1:试验材料
PAK4(Carna,No.07-126),PAK2(Carna,No.07-124),Kinase substrate31(Cisbio,No.61ST2BLE),DMSO(Sigma,No.D0632),384-well plate(Greiner,No.784075),PF-3758309(selleckchem,No.S709403)
2:实验方法
2.1化合物配制
化合物由管理员接收,并将粉末溶解在100%DMSO中,配制成10mM储存液于氮气柜避光储存。
2.2激酶反应过程
(1)配制1×Kinase buffer。
(2)化合物浓度梯度的配制:受试化合物测试浓度为1000nM,在384source板中稀释成100倍终浓度的100%DMSO溶液,用Precision 3倍稀释化合物,10个浓度。使用分液器Echo 550向目的板384-well plate转移250nL 100倍终浓度的化合物。
(3)用1×Kinase buffer配制2.5倍终浓度的激酶溶液。
(4)在化合物孔和阳性对照孔分别加10μL的2.5倍终浓度的激酶溶液;在阴性对照孔中加10μL的1×Kinase buffer。
(5)1000rpm离心30秒,反应板振荡混匀后室温孵育10分钟。
(6)用1×Kinase buffer配制5/3倍终浓度的ATP和Kinase substrate22的混合溶液。
(7)加入15μL的5/3倍终浓度的ATP和底物的混合溶液,起始反应。
(8)将384孔板1000rpm离心30秒,振荡混匀后室温孵60min。
(9)加入30μL终止检测液停止激酶反应,1000rpm离心30秒,振荡混匀。
(10)用Caliper EZ Reader读取转化率。
2.3数据分析
其中:Conversion%_sample是样品的转化率读数;Conversion%_min:阴性对照孔均值,代表没有酶活孔的转化率读数;Conversion%_max:阳性对照孔比值均值,代表没有化合物抑制孔的转化率读数。
拟合量效曲线:
以浓度的log值作为X轴,百分比抑制率为Y轴,采用分析软件GraphPad Prism 5的log(inhibitor)vs.response–Variable slope拟合量效曲线,从而得出各个化合物对酶活性的IC50值。计算公式是:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
测试结果见表2:
表2化合物对PAK4和PAK2激酶的抑制活性(IC50)
试验例2检测化合物心脏毒性hERG测试
1、试验原理
1.1 hERG离子通道稳定地表达在HEK293细胞上。在hERG电流稳定后,比较不同化合物浓度应用前后hERG电流的大小,可以得到化合物对hERG离子通道的影响。
1.2遵循的规章
本次实验并没有遵循GLP的规定但按奥丽芙的标准操作规章(SOP)以及在SCI上发表的相关的文献进行实验。
2、试验动物(细胞/试剂)
hERG离子通道稳态表达的HEK293细胞。
3、试验仪器
膜片钳仪器:PC-505B
微操控仪器:MP-225
拉制电极仪器:PC-10(Narishige,Japan)
4、药物配制
测试化合物的保存浓度为3mM,溶于二甲基亚砜(DMSO)。测试当天再溶于细胞外液,配制成要求浓度。
化合物除用于酸碱滴定的NaOH和KOH外,均从Sigma(St.Louis,MO)公司购买。测试化合物的最终浓度均在当天配制,再溶于细胞外液。细胞外液(mM)为:NaCl,137;KCl,4;CaCl2,1.8;MgCl2,1;HEPES,10;glucose 10;pH 7.4(NaOH滴定)。
所有测试化合物和对照化合物溶液均含0.3%DMSO。细胞内液(mM)为:K Aspartate,130;MgCl2,5;EGTA 5;HEPES,10;Tris-ATP 4;pH 7.2(KOH滴定)。
5、试验方法
细胞:所有实验都在室温下进行。每个细胞都以自身为对照。
化合物的测试:化合物均采用利用自身重力的灌流系统进行灌流。每个浓度至少测试1个细胞。在电流稳定(或5分钟)后,再比较化合物使用前后的电流大小变化来计算化合物的阻断作用。
阳性对照:无
电生理:将细胞转移到灌流槽中,用细胞外液进行灌流。细胞内液(mM)为:KAspartate,130;MgCl2,5;EGTA 5;HEPES,10;Tris-ATP 4;pH 7.2(KOH滴定)。细胞内液分批少量储存于-80度冰箱,实验当天融化。电极用PC-10(Narishige,Japan)拉制。全细胞膜片钳记录,噪音用采样频率的五分之一进行过滤。
测试过程和结果:将细胞钳制在-80mV,然后用持续4秒方波去极化到40mV,再用持续2秒方波超极化到-40mV,以得到hERG尾电流(见图)。这一程序每20秒重复一次。hERG尾电流是纯hERG电流。检测第二个方波引发的最大电流,待其稳定后,灌流测试化合物,当反应稳定后,计算阻断的强度。
测试结果见表3:
表3化合物hERG通道电流的抑制率(%)
(1um浓度下)
采用同样的实验条件和方法,将专利WO2022033420 A1中的部分优选化合物进行hERG抑制率的测试,结果见下表4:
表4专利WO2022033420 A1中部分化合物hERG通道电流的抑制率(%)(1um浓度下)
抑制率越高,说明药物的hERG心脏毒性的风险越大。从表4可以看出,专利WO2022033420 A1中的优选化合物的hERG抑制率均比本发明提供的实施例1-25制备的绝大部分化合物的hERG抑制率更高,具有更大的心脏毒性风险。对比可以发现,经过结构优化,本发明制备得到的大部分化合物的hERG抑制率低,心脏毒性风险较小。
试验例3检测化合物肝微粒体稳定性测试
1:材料和方法
缓冲液:
(1)100mM的磷酸钾缓冲液,pH 7.4;(2)10mM MgCl2。
化合物溶液的配制:
(1)100μM工作溶液的配制:取5μL测试组或对照组的储备液(10mM),用495μL甲醇稀释,所得化合物浓度为100μM(99%MeOH)。
(2)10μM工作溶液的配制:取50μL 100μM工作溶液,用450μL 100mM的磷酸钾缓冲液稀释,所得化合物浓度为10μM(9.9%MeOH)。
NADPH(原型辅酶Ⅱ)再生体系的组成成分(异柠檬酸脱氢酶在培养液中的终浓度为1.0unit/mL):
β-烟酰胺腺嘌呤二核苷酸磷酸,供应商:Chem-impex international货号:N00616
肝微粒体溶液的制备(最终浓度为0.5mg蛋白/mL),肝微粒体种类见表5:
表5
终止液:
含有100ng/mL甲苯磺丁脲和100ng/mL拉贝洛尔为内标物的乙腈冰冷溶液。
操作步骤:
(1)除空白基质板位孔外,其他各板孔(T0、T5、T10、T20、T30、T60以及NCF60)中均加入10μL测试或对照药物的工作液。
(2)用Apricot将80μL/孔微粒体溶液分配到每个平板上,在37℃下孵育微粒体溶液和化合物的混合物约10分钟。
(3)向NCF60中加入10μL 100mM磷酸钾缓冲液/孔,37℃孵育,启动定时器1,时间见表6。
表6
(4)预热后,用Apricot将10μL/孔的NADPH再生系统分配到每个平板上以开始反应。
表7孵育培养基中每种成分的最终浓度
(5)37℃孵育,启动计时器2,数据见表8。
表8
(6)每孔加入4℃预冷的终止液(含内标物甲苯磺丁脲100ng/mL和柳胺苄心定100ng/mL)终止反应。
(7)然后样品板在摇扳机上摇动约10分钟。
(8)将样品在4℃以4000rpm的速度离心20min。
(9)另取96孔板,每孔均加入300μL HPLC级别的水,取100μL离心所得的上清液加入相应孔位,两者混匀后用于LC/MS/MS检测。
数据分析:
根据一级消除动力学计算t1/2和CLint(mic)值
一级消除动力学方程式为:
部分化合物肝微粒体稳定性试验结果见表9:
表9部分化合物肝微粒体稳定性数据
试验例4检测化合物大鼠PK性质测试
SD大鼠,雄性(购于成都达硕实验动物有限公司)。各受试化合物分别以口服(50mg/kg,每组3只)给药方式单次给予SD大鼠进行药代动力学研究。受试化合物给药当天配制,采用5%DMSO+10%solutol+85%saline对受试化合物进行溶解,并经涡旋2min,超声5min之后配制成给药溶液。口服给药前动物需禁食10-14小时,并于给药4小时后恢复给食。SD大鼠经灌胃口服与静脉给药后,经颈静脉采集药代动力学样本,采集时间点为:给药前、给药后5min、15min、30min、1h、2h、4h、6h、8h和24h,每个时间点采集3个全血样本,采集量约0.2mL,并经肝素钠抗凝。血液样本采集后立即置于冰上,于1小时之内离心分离血浆(离心条件:6800转/分钟,6分钟,2-8℃)。收集的血浆分析前存放于–80℃冰箱内。
本发明部分化合物的药代动力学测试结果如下表10所示:
表10本发明部分化合物的药代动力学测试结果
最后应说明的是:以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (19)
- 一种通式为Ⅰ的化合物,或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物:
其中,A1、A2、A3、A4独立的选自C或N,当A1、A2、A3、A4中任意一个为N,与所述N相连的R2、R3、R4、R5不存在;R2、R3、R4、R5独立的选自-H、卤素、-OH、-CN、-NH2、-NO2、-SH、C1-10直链/支链烷基、C3-10环烷基、杂环烷基、炔基、烯基、芳香基、杂环芳香基、酰胺基、酯基、磺酰基、磷酰基,其中上述基团上的H可被以下基团取代:卤素、-OH、-CN、-NH2、取代或非取代的烷基、取代或非取代烷氧基、取代或非取代的环烷基或杂环烷基、取代或非取代的芳香基或杂环芳香基;所述取代基团选自卤素、-OH、-CN、-NH2、-NO2、-SH、羧基、羟氨基、烷基、环烷基、杂环烷基、芳香基、杂环芳香基、酯基、酰基、羰基、酰胺基、磺酰基、磷酰基;B1、B2独立的选自C或N;L选自-O-、-S-、-NH-或亚烷基;R1选自取代或非取代的五元或六元芳香基或杂环芳香基、取代或非取代的含有至少一个N和/或O原子的杂环烷基;R6选自-H、-NH2、-OH、卤素、酰胺基、磺酰基、磺酸基、C1-6的烷基或烷氧基、C3-6环烷基、C3-6杂环烷基、胺基、C6-12芳香基、C5-12杂环芳香基;上述C1-6的烷基或烷氧基、C3-6环烷基、C3-6杂环烷基、胺基、C6-12芳香基、C5-12杂环芳香基上的H可任选的被一个或多个卤素、-OH、-CN、-NH2、-NO2、-SH、磺酸基取代;环Ar与环Rg稠合,稠合键为环Ar上任一键;环Ar选自芳香性五元杂环基团、芳香性六元杂环基团或苯基,所述芳香性五元杂环 基团选自:咪唑基、噻唑基、噁唑基、吡咯基、吡唑基、呋喃基或噻吩基;所述芳香性六元杂环基团选自:吡啶基、哒嗪基、嘧啶基或吡嗪基;任选的所述芳香性五元杂环基团、芳香性六元杂环基团或苯基上的H可被以下基团取代:卤素、-OH、-CN、-NH2、取代或非取代的烷基、取代或非取代烷氧基、取代或非取代的环烷基或杂环烷基、取代或非取代的芳香基或杂环芳香基;所述取代基团选自卤素、-OH、-CN、-NH2、-NO2、-SH、羧基、羟氨基、烷基、环烷基、杂环烷基、芳香基、杂环芳香基、酯基、酰基、羰基、酰胺基、磺酰基、磷酰基;环Rg选自C3-8饱和/不饱和环烷基或至少含有一个O、N、S的C3-8饱和/不饱和杂环烷基,任选的所述C3-8饱和/不饱和环烷基或至少含有一个O、N、S的C3-8饱和/不饱和杂环烷基上的H可被以下基团取代:卤素、-OH、-CN、-NH2、取代或非取代的烷基、取代或非取代烷氧基、取代或非取代的环烷基或杂环烷基、取代或非取代的芳香基或杂环芳香基;所述取代基团选自卤素、-OH、-CN、-NH2、-NO2、-SH、羧基、羟氨基、烷基、环烷基、杂环烷基、芳香基、杂环芳香基、酯基、酰基、羰基、酰胺基、磺酰基、磷酰基;环Rg上有至少一个R7,所述R7独立地选自-H、氘、氚、卤素、-OH、-CN、-NH2、-NO2、-SH、羧基、羟氨基、烷基、环烷基、杂烷基、杂环烷基、芳基、杂芳基、酯基、酰基、羰基、酰胺基、磺酰基、磷酰基。 - 根据权利要求1所述的化合物,其特征在于,所述R1选自取代或非取代的苯基、吡唑基、噁唑基、异噁唑基、噻唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、呋喃基、噻吩基、吡咯基、含有至少一个N或O原子的五元或六元杂环烷基;所述的取代基团独立的选自-F、-Cl、-Br、-OH、-CN、-NH2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、羟基甲基、羟基乙基。
- 根据权利要求2所述的化合物,其特征在于,所述R1具有以下任意一种结构:
以上结构中的任意一个或多个C原子上的H可被以下基团取代:-F、-Cl、-Br、-OH、-CN、-NH2、取代或非取代的酰胺基、取代或非取代的C1-3的烷基或烷氧基、C3-6环烷基;所述的取代基团独立的选自-F、-Cl、-Br、-OH、-CN、-NH2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、羟基甲基、羟基乙基。 - 根据权利要求1所述的化合物,其特征在于,所述化合物具有式II所示结构,或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物:
X选自取代或非取代的C1-6直链/支链烷基、取代或非取代的C3-10环烷基或杂环烷基、取代或非取代的C5-6芳香基或杂环芳香基、炔基、烯基、酰胺基、酯基;所述取代基团选自卤素、-OH、-CN、-NH2、-NO2、-SH、羧基、羟氨基、烷基、烷氧基、羟基烷基、环烷基、杂环烷基、芳香基、杂环芳香基、酯基、酰基、羰基、酰胺基、磺酰基、磷酰基;X基团上有至少一个R8,R8独立地选自-H、卤素、-OH、-CN、-NH2、取代或非取代的烷基、取代或非取代烷氧基、取代或非取代的环烷基或杂环烷基,所述取代基团选自卤素、-OH、-CN、-NH2、-NO2、-SH、-CF3、-CHF2、-CH2F、羧基、羟氨基、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、金刚烷基、苯基、苯氧基、吡啶基、酰胺基、磺酰基、磷酰基;R9选自取代或非取代的苯基、吡唑基、噁唑基、异噁唑基、噻唑基、咪唑基,所述取代基团独立的选自-F、-Cl、-Br、-OH、-CN、-NH2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、羟基甲基;R10选自-NH2、-OH、卤素、C1-6的烷基或烷氧基、C3-6环烷基、C3-6杂环烷基;上述C1-6的烷基或烷氧基、C3-6环烷基、C3-6杂环烷基上的H可任选的被一个或多个卤素、-OH、-CN、-NH2、-NO2、-SH取代;环Rg选自至少含有一个O、N、S的C3-8饱和/不饱和杂环烷基,环Rg上有至少一个R11,R11独立地选自-H、氘、氚、-F、-Cl、-Br、-OH、-CN、-NH2、-NO2、-SH、羟氨基、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、金刚烷基、苯基、苯氧基、磺酰基、磷酰基。 - 根据权利要求4所述的化合物,其特征在于,所述化合物具有式Ⅲ所示结构,或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物:
R12选自-H、-F、-Cl、-Br、-OH、-CN、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、羟基甲基;R13、R14独立的选自-H、氘、氚、-F、-Cl、-Br、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基;R15选自-H,-F、-Br、-OH、-CN、-NH2、取代或非取代的C1-10直链/支链烷基、取代或非取代的C1-10直链/支链烷氧基、取代或非取代的环烷基或杂环烷基,其中,上述基团上的H可被以下基团取代:-F、-Cl、-Br、-OH、-CN、-NH2、-CF3、羟甲基、甲基、乙基、丙基、异丙基、苯基、甲氧基、乙氧基、丙氧基、异丙氧基、苯氧基、环丙基、环丁基、环戊基、环己基。 - 根据权利要求5所述的化合物,其特征在于,所述的取代或非取代的环烷基或杂环烷基包括单环、桥环、螺环或稠环的环烷基或杂环烷基,还包括饱和或不饱和两种形式。
- 根据权利要求6所述的化合物,其特征在于,所述取代或非取代的环烷基或杂环烷基包括 表示可与炔基连接的位置。
- 根据权利要求4所述的化合物,其特征在于,所述化合物具有式Ⅳ所示结构,或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物:
R16、R17独立的选自-H、-F、-Cl、-Br、-OH、-CN、-NH2、-SH、羟氨基、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、苯基;R18选自-H、-F、-Cl、-Br、-OH、-CN、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、羟基甲基;R19、R20独立的选自-H、氘、氚、-F、-Cl、-Br、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基。 - 根据权利要求4所述的化合物,其特征在于,所述化合物具有式Ⅴ所示结构,或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物:
R21选自-H、-F、-Cl、-Br、-OH、-CN、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、羟基甲基;R22、R23独立的选自H、氘、氚、-F、-Cl、-Br、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基;Y选自取代或非取代的C1-4直链/支链烷基、取代或非取代的C3-8环烷基或杂环烷基、取代或非取代的C5-6芳香基或杂环芳香基、酰胺基、酯基;所述取代基团选自-OH、-CN、-NH2、-NO2、-SH、羧基、羟氨基、烷基、烷氧基、羟基烷基、取代或非取代的C3-8环烷基或杂环烷基、C5-6芳香基或杂环芳香基、酯基、酰基、羰基、酰胺基、磺酰基、磷酰基;所述R24选自-H、氘、氚、-F、-Cl、-Br、-OH、-CN、-NH2、-NO2、-SH、羟氨基、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、苯基、苯氧基、取代或非取代的C3-8饱和或不饱和的环烷基或杂环烷基。 - 根据权利要求9所述的化合物,其特征在于,所述的取代或非取代的C3-8环烷基或杂环烷基包括 表示可与Y连接的位置;上述结构中的H可被以下基团取代:-OH、-CN、-NH2、-NO2、-SH、羟氨基、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、苯基、苯氧基、磺酰基、磷酰基。
- 根据权利要求1-10所述的化合物,其特征在于,所述化合物具有如下结构:
- 一种药物组合物,所述药物组合物包含权利要求1-11任一项所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物。
- 一种权利要求1-11任一项所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物,或者权利要求12所述的药物组合物在制备治疗与PAK4激酶的表达或活性有关的疾病的药物中的用途。
- 根据权利要求13所述的用途,其特征在于,所述的与PAK4激酶的表达或活性有关的疾病包括癌症、神经退行性疾病或免疫系统疾病。
- 根据权利要求14所述的用途,其特征在于,所述癌症包括卵巢癌、食道癌、喉癌、成胶质细胞瘤、成神经细胞瘤、胃癌、肝细胞癌、胶质瘤、子宫内膜癌、黑色素瘤、肾癌、膀胱癌、胆道癌、淋巴瘤、毛细胞癌、鼻咽癌、咽癌、大肠癌、直肠癌、脑和中枢神经系统癌症、宫颈癌、睾丸癌、泌尿生殖道癌、肺癌、小细胞癌、骨癌、结肠癌、腺癌、滤泡性癌、霍奇金白血病、支气管癌、子宫体癌、子宫颈癌、多发性骨髓瘤、急性髓细胞源性白血病、慢性髓细胞源性白血病、淋巴细胞白血病、慢性淋巴样白血病、骨髓性白血病、原发性巨球蛋白血症、横纹肌肉瘤。
- 根据权利要求15所述的用途,其特征在于,所述腺癌包括乳腺癌、胰腺癌、前列腺癌、肺腺癌、甲状腺癌;所述淋巴瘤包括套细胞淋巴瘤、非霍奇金淋巴瘤;所述肺癌包括非小细胞肺癌。
- 一种通式为Ⅵ的化合物,
其中,R25、R26独立的选自-H、氘、氚、-F、-Cl、-Br、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基。 - 一种通式为Ⅶ的化合物,
其中,R27选自-H、-F、-Cl、-Br、-OH、-CN、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、羟基甲基;R28、R29独立的选自H、氘、氚、-F、-Cl、-Br、羟甲基、羟乙基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基。 - 一种式Ⅵ和/或式Ⅶ所述的化合物在制备权利要求1-11任一项所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物中的用途。
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US5232931A (en) * | 1990-05-29 | 1993-08-03 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Oxazolidinones |
WO2003059913A1 (en) * | 2002-01-10 | 2003-07-24 | Bayer Healthcare Ag | Roh-kinase inhibitors |
CN114075175A (zh) * | 2020-08-14 | 2022-02-22 | 成都海博为药业有限公司 | 一种作为pak4激酶抑制剂的化合物及其制备方法和应用 |
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