CN114539225A - 2-amino-pyrimidines - Google Patents
2-amino-pyrimidines Download PDFInfo
- Publication number
- CN114539225A CN114539225A CN202111324005.6A CN202111324005A CN114539225A CN 114539225 A CN114539225 A CN 114539225A CN 202111324005 A CN202111324005 A CN 202111324005A CN 114539225 A CN114539225 A CN 114539225A
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- CN
- China
- Prior art keywords
- membered
- cycloalkyl
- alkoxy
- heteroaryl
- aryl
- Prior art date
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- Granted
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 99
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- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- OXXCXDQCAGYFQM-UHFFFAOYSA-N methyl 4-bromo-2-(cyanomethyl)benzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1CC#N OXXCXDQCAGYFQM-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- PHVXTQIROLEEDB-UHFFFAOYSA-N n-[2-(2-chlorophenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-n-pyrrolidin-3-ylbenzamide Chemical compound CC1=CC=CC=C1C1CN(CC=2C=CC(=CC=2)C(=O)N(CCC=2C(=CC=CC=2)Cl)C2CNCC2)CCC1 PHVXTQIROLEEDB-UHFFFAOYSA-N 0.000 description 1
- UZWDCWONPYILKI-UHFFFAOYSA-N n-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine Chemical compound C1CN(CC)CCN1CC(C=N1)=CC=C1NC1=NC=C(F)C(C=2C=C3N(C(C)C)C(C)=NC3=C(F)C=2)=N1 UZWDCWONPYILKI-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 208000008798 osteoma Diseases 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229960004390 palbociclib Drugs 0.000 description 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- BTIHMVBBUGXLCJ-OAHLLOKOSA-N seliciclib Chemical compound C=12N=CN(C(C)C)C2=NC(N[C@@H](CO)CC)=NC=1NCC1=CC=CC=C1 BTIHMVBBUGXLCJ-OAHLLOKOSA-N 0.000 description 1
- 229950000055 seliciclib Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Abstract
The present disclosure relates to 2-amino-pyrimidines. In particular, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the letters are as defined herein. The compounds of formula I can be used as cyclin-dependent kinase inhibitors for prophylaxis and/or therapyTreating diseases related to the disease, such as cell proliferative diseases, cancer or immunological diseases.
Description
Technical Field
The disclosure belongs to the field of medicines, and relates to a 2-amino-pyrimidine compound.
Background
Cyclin-dependent kinases (CDKs) are members of the serine/threonine kinase subfamily, and each CDK/cyclin complex is responsible for a specific phase of turnover or progression within the cell cycle, which plays an important role in regulating eukaryotic cell division and proliferation. The cyclin-dependent kinase catalytic unit is called the regulatory subunit activation of the cyclin. At least 16 mammalian cyclins have been identified (Annu. Rev. Pharmacol. Toxicol. (1999)39: 295-312). Cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6 and possibly other heterodynes are important regulators of cell cycle progression. Other functions of cyclin/CDK heterodynes include transcriptional regulation, DNA repair, differentiation and apoptosis (Annu. Rev. cell. Dev. biol. (1997)13: 261-291).
In recent years, the greatest progress in the field of breast cancer treatment has been undoubtedly that CDK4/6 alone or in combination with endocrine therapy has been approved for the treatment of Hormone Receptor (HR) -positive, human epidermal growth factor receptor 2(HER2) -negative advanced or metastatic breast cancer in hormone receptor-positive advanced breast cancer in postmenopausal women in combination with aromatase inhibitors, and palbociclib and bmiscnib (abemaciclib) have been approved for the treatment of Hormone Receptor (HR) -positive, human epidermal growth factor receptor 2(HER2) -negative advanced or metastatic breast cancer in postmenopausal women after disease progression after endocrine therapy (Nature Reviews (2016)13:417 430, J in oncocol 2017,35,2875 2884). Although CDK4/6 inhibitors show significant clinical efficacy in estrogen receptor ER positive metastatic breast cancers, their action, like other kinases, may be limited over time by the development of primary or acquired resistance.
Overexpression of CDK2 is associated with dysregulation of the cell cycle. The cyclin E/CDK2 complex plays an important role in regulating G1/S switching, histone biosynthesis, and central body replication. The progressive phosphorylation of Rb by cyclin D/Cdk4/6 and cyclin E/Cdk2 releases the G1 transcription factor E2F and promotes S-phase entry. Activation of cyclin a/CDK2 during early S phase promotes phosphorylation of endogenous substrates, which allows DNA replication and inactivation of E2F to complete S phase. (nat. Rev. drug. Discov.2015; 14(2): 130-146).
Studies have shown that inhibition of CDK2 kinase induces apoptosis in tumor cells, but causes only minor damage to normal cells. Monomeric forms of CDK kinase are inactive, whereas cyclin a/E binding to CDK2 and binding that promotes phosphorylation activates CDK 2. CDK2 also binds to cyclin a for the entire progression of S phase and is involved in DNA repair. In recent years, a series of inhibitors for selectively inhibiting CDK2 are respectively identified and found by various companies, and are used for treating diseases such as cancers, such as Seliciclib, Diaciclib and the like, but in order to achieve better cancer treatment effect and better meet market demands, a new generation of selective CDK2 inhibitors with high efficiency and low toxicity still needs to be developed.
Disclosure of Invention
The disclosure provides compounds of formula I or pharmaceutically acceptable salts thereof,
wherein, X1、X2、X3、X4Each independently selected from optionally substituted or unsubstituted C, N, and not both C; optionally substituted C, N includes carbonOr at least one hydrogen on a nitrogen atom is substituted with any permissible substituent(s) to form a stable compound. Exemplary substitutions include, but are not limited to, deuterium, halogen (e.g., fluoro, chloro, bromo), hydroxy, nitro, cyano, alkyl (e.g., C)1-6Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C1-6Alkoxy, including but not limited to methoxy, ethoxy, propoxy, or isopropoxy), cycloalkyl (e.g., C)3-12Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3-to 12-membered heterocycloalkyl, including but not limited to pyrrolyl), aryl (e.g., 5-12-membered aryl, including but not limited to phenyl, naphthyl), heteroaryl (e.g., 5-12-membered heteroaryl, 5-7-membered heterocycloacene, 5-7-membered heterocycloaromatic ring, including but not limited to pyridine, piperidine), SR ', SOR', SO2R'、SO2NR '(R "), COR', COOR 'or CONR' (R"), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO2R'、SO2NR '(R "), COR', COOR 'or CONR' (R"), optional substituents also include spiro or fused ring substitutions.
B is a 3-20 membered ring including monocyclic, fused, bridged, spiro, provided that:
when B is a six membered monocyclic ring, ring A is not optionally substituted or unsubstitutedExemplary rings include, but are not limited to, 3-to 20-membered carbocycles, heterocycles, optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO2R'、SO2NR ' (R "), COR ', COOR ', or CONR ' (R ').
Wherein Y is selected from CR5-NR6R7、*NR7;
Each R1、R2、R3、R4、R5、R6Each independently selected from hydrogen, deuterium, halogen (e.g., fluorine, chlorine, bromine), hydroxy, nitro, cyano, amino, alkyl (e.g., C)1-6Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C1-6Alkoxy, including but not limited to methoxy, ethoxy, propoxy, or isopropoxy), cycloalkyl (e.g., C)3-12Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3 to 12 membered heterocycloalkyl, including but not limited to pyrrolyl), aryl (e.g., 5-12 membered aryl, including but not limited to phenyl, naphthyl), heteroaryl (e.g., 5-12 membered heteroaryl, 5-7 membered heterocycloacene, 5-6 membered heteroaryl, including but not limited to pyridine, piperidine), SR ', SOR', SO2R'、SO2NR ' (R "), COOR ' or CONR ' (R"), the amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with one or more groups selected from halo, hydroxy, oxo, nitro, cyano, alkyl optionally substituted with Z, cycloalkyl optionally substituted with Z, heterocyclyl optionally substituted with Z, alkoxy optionally substituted with Z, alkenyl optionally substituted with Z, alkynyl optionally substituted with Z, aryl optionally substituted with Z, heteroaryl optionally substituted with Z, SR ', SOR ', SO2R'、SO2NR ' (R "), COR ', COOR ', or CONR ' (R ');
R1、R2not hydrogen at the same time;
each R7Are respectively and independently selected from-SR ', -SOR', -SO2R'、-SO2NR'(R”);
Each R 'and R' is independently selected from hydrogen, deuterium, hydroxy, alkyl (e.g. C)1-6Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C1-6Alkoxy, including but not limited to methoxy, ethoxy, propoxy, or isopropoxy), amino, imino, cycloalkyl (e.g., C)3-12Cycloalkyl groups, including but not limited to cyclopropyl, cyclopentyl,cyclohexyl), heterocyclyl (such as 3 to 12 membered heterocycloalkyl including but not limited to pyrrolyl), aryl (such as 5-12 membered aryl including but not limited to phenyl, naphthyl) or heteroaryl (such as 5-12 membered heteroaryl, 5-7 membered heterocycloacene, 5-7 membered heterocycloaromatic ring, 5-6 membered heteroaryl including but not limited to pyridine, piperidine), said amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, oxo, nitro, cyano, alkyl optionally substituted with Z, alkoxy optionally substituted with Z, cycloalkyl optionally substituted with Z, heterocyclyl optionally substituted with Z, aryl optionally substituted with Z, heteroaryl optionally substituted with Z;
z is selected from halogen (such as fluorine, chlorine, bromine), hydroxyl, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR8、SOR8、SO2R8、SO2NR8(R9)、NR8(R9)、COR8、COOR8Or CONR8(R9) Said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR8、SOR8、SO2R8、SO2NR8(R9)、NR8(R9)、COR8、COOR8Or CONR8(R9);
Each R8Or R9Independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl.
m and n are respectively and independently selected from 0, 1,2 and 3;
wherein x represents a site of attachment and the dotted line is selected from a single bond, a double bond.
In some embodiments, a heterocyclyl in the present disclosure can be, 3-12 membered heterocyclyl, 3-5 membered heterocyclyl, 5-7 membered heterocyclyl, 9-12 membered heterocyclyl, 6-10 membered heterocyclyl, and the heterocyclyl contains 1-4 heteroatoms independently selected from N, O or S, or 2-3 heteroatoms independently selected from N, O or S.
In some embodiments, the cycloalkyl group in the present disclosure may be C3-7Cycloalkyl radical, C5-7Cycloalkyl radical, C6-7A cycloalkyl group.
In some embodiments, an aryl group in the present disclosure can be a 5-12 membered aryl group, a 5-7 membered aryl group, a 6-10 membered aryl group, a 9-12 membered aryl group, a 6-8 membered aryl group.
In some embodiments, the heteroaryl in the present disclosure can be a 3-12 membered heteroaryl, a 3-5 membered heteroaryl, a 5-7 membered heteroaryl, a 9-12 membered heteroaryl, a 6-10 membered heteroaryl, and the heteroaryl contains 1-4 heteroatoms independently selected from N, O or S, or contains 2-3 heteroatoms independently selected from N, O or S.
In some embodiments, the compound of formula I is a compound of formula Ia,
wherein, ring B, R1、R2、R3、R4、Y、X1、X2、X3M and n are as defined in the compounds of formula I.
In some embodiments, X1、X2、X3Each independently selected from C-O, CR10R11、NR12;
Said R is10Or R11Each independently selected from hydrogen, deuterium, halogen (e.g., fluorine, chlorine, bromine), hydroxy, nitro, cyano, alkyl (e.g., C)1-6Alkyl including but not limited to methyl, ethyl, propyl or isopropylAlkyl), alkoxy (e.g. C)1-6Alkoxy, including but not limited to methoxy, ethoxy, propoxy, or isopropoxy), cycloalkyl (e.g., C)3-12Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3-to 12-membered heterocycloalkyl, including but not limited to pyrrolyl), aryl (e.g., 5-12-membered aryl, including but not limited to phenyl, naphthyl), heteroaryl (e.g., 5-12-membered heteroaryl, 5-7-membered heterocycloacene, 5-7-membered heterocycloaromatic ring, including but not limited to pyridine, piperidine), SR ', SOR', SO2R'、SO2NR '(R "), COR', COOR 'or CONR' (R"), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO2R'、SO2NR ' (R "), COR ', COOR ', or CONR ' (R ').
Or, R10Or R11Together with the adjacent carbon atoms to form a 3-to 12-membered spirocyclic ring, or CR10R11Form a 3-to 12-membered ring with its adjacent atoms and are linked to ring a.
The carbocyclic or heterocyclic ring may be an aromatic or non-aromatic carbocyclic or heterocyclic ring, which may include one or more heteroatoms selected from O, N or S (e.g., furan, thiophene, pyrrole, thiazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine). Preferably 3-to 12-membered carbocycle, heterocycle, optionally substituted by a group selected from halogen, hydroxy, oxo, nitro, cyano, C1-6 alkyl, C1-6 alkoxy, C3-7 cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO2R'、SO2NR ' (R "), COR ', COOR ' or CONR ' (R ');
R12selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, alkyl (e.g. C)1-6Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C1-6Alkoxy, including but not limited to methoxy, ethoxyOxy, propoxy or isopropoxy), cycloalkyl such as C3-12Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3-to 12-membered heterocycloalkyl, including but not limited to pyrrolyl), aryl (e.g., 5-12-membered aryl, including but not limited to phenyl, naphthyl), heteroaryl, such as 5-12-membered heteroaryl, 5-7-membered heterocycloacene, 5-7-membered heterocycloaromatic ring, including but not limited to pyridine, piperidine), SR ', SOR', SO2R'、SO2NR '(R "), COR', COOR 'or CONR' (R"), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO2R'、SO2NR ' (R "), COR ', COOR ', or CONR ' (R ').
R ', R' are as defined above for the compounds of formula I.
In some embodiments, formula Ia is
In some embodiments, R10Selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, amino, C1-6Alkyl (e.g. methyl, ethyl, propyl or isopropyl), C1-6Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), C3-7Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl), 5-12 membered aryl (e.g., phenyl, naphthyl), or 5-12 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl being optionally substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano.
In some embodiments, R10Selected from hydrogen, fluoro, chloro, methyl, ethyl, propyl or isopropyl.
In some embodiments, R12Selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, C1-6Alkyl (e.g. methyl, ethyl, propyl or isopropyl), C1-6Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), C3-7Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl), 5-12 membered aryl (e.g., phenyl, naphthyl), or 5-12 membered heteroaryl.
In some embodiments, R12Selected from hydrogen, fluorine, chlorine, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7A cycloalkyl group.
In some embodiments, R12Selected from methyl, ethyl, propyl or isopropyl.
Ring B, R1、R2、R3、R4、Y、X1、X2、X3、X4M and n are as defined in the compounds of formula I.
In some embodiments, X1、X2、X3、X4Each independently selected from C-O, CR10R11、NR12;
The R is10Or R11Each independently selected from hydrogen, deuterium, halogen (e.g., fluorine, chlorine, bromine), hydroxy, nitro, cyano, alkyl (e.g., C)1-6Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C1-6Alkoxy, including but not limited to methoxy, ethoxy, propoxy, or isopropoxy), cycloalkyl (e.g., C)3-12Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3-to 12-membered heterocycloalkyl, including but not limited to pyrrolyl), aryl (e.g., 5-12-membered aryl, including but not limited to phenyl, naphthyl), heteroaryl (e.g., 5-12-membered heteroaryl, 5-7-membered heterocycloacene, 5-7-membered heterocycloaromatic ring, including but not limited to pyridine, piperidine), SR ', SOR', SO2R'、SO2NR '(R "), COR', COOR 'or CONR' (R"), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO2R'、SO2NR ' (R "), COR ', COOR ', or CONR ' (R ').
Or, R10Or R11Together with the adjacent carbon atoms to form a 3-to 12-membered spirocyclic ring, or CR10R11Form a 3-to 12-membered ring with its adjacent atoms and the ring is attached to ring A, said 3-to 12-membered ring is preferably a 3-to 12-membered carbocyclic or heterocyclic ring which may include one or more heteroatoms selected from O, N or S (e.g. furan, thiophene, pyrrole, thiazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine), said carbocyclic or heterocyclic ring being optionally selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO2R'、SO2NR ' (R "), COR ', COOR ', or CONR ' (R ');
R12selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, alkyl (e.g. C)1-6Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C1-6Alkoxy, including but not limited to methoxy, ethoxy, propoxy, or isopropoxy), cycloalkyl (e.g., C)3-12Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3-to 12-membered heterocycloalkyl, including but not limited to pyrrolyl), aryl (e.g., 5-12-membered aryl, including but not limited to phenyl, naphthyl), heteroaryl (e.g., 5-12-membered heteroaryl, 5-7-membered heterocycloacene, 5-7-membered heterocycloaromatic ring, including but not limited to pyridine, piperidine), SR ', SOR', SO2R'、SO2NR '(R "), COR', COOR ', or CONR' (R"), the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl groupOptionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO2R'、SO2NR ' (R "), COR ', COOR ', or CONR ' (R ');
r ', R' are as defined above for the compounds of formula I.
In some embodiments, R10、R11Each independently selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, amino, C1-6Alkyl (e.g. methyl, ethyl, propyl or isopropyl), C1-6Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), C3-7Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl), 5-12 membered aryl (e.g., phenyl, naphthyl), or 5-12 membered heteroaryl (e.g., pyridine, piperidine), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl being optionally substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano.
In some embodiments, R10、R11Each independently selected from hydrogen, fluoro, chloro, methyl, ethyl, propyl or isopropyl.
In some embodiments, R12Selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, C1-6Alkyl (e.g. methyl, ethyl, propyl or isopropyl), C1-6Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), C3-7Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl), 5-12 membered aryl (e.g., phenyl, naphthyl)) Or 5-12 membered heteroaryl (e.g., pyridine, piperidine).
In some embodiments, R12Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl and cyclohexyl.
ring C is selected from C3-7Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl);
R13selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, C1-6Alkyl (e.g. methyl, ethyl, propyl or isopropyl), C1-6Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), C3-7Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl), 5-12 membered aryl (e.g., phenyl, naphthyl), or 5-12 membered heteroaryl (e.g., pyridine, piperidine).
o is selected from 0, 1, 2;
in some embodiments, R13Selected from the group consisting of preferably hydrogen, fluorine, chlorine, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl.
In some embodiments, R12Selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, C1-6Alkyl (e.g. methyl, ethyl, propyl or isopropyl), C1-6Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), C3-7Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl), 5-12 membered aryl (e.g., phenyl, naphthyl), or 5-12 membered heteroaryl (e.g., pyridine, piperidine).
In some embodiments, R12Selected from hydrogen, fluorine, chlorine, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl and cyclohexyl.
In some embodiments, formula Ib is
(ii) a Wherein,
ring D is selected from C3-7Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl).
R13Each independently selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, C1-6Alkyl (e.g. methyl, ethyl, propyl or isopropyl), C1-6Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), C3-7Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl), 5-12 membered aryl (e.g., phenyl, naphthyl), or 5-12 membered heteroaryl (e.g., pyridine, piperidine).
o is selected from 0, 1, 2.
In some embodiments, R13Each independently selected from hydrogen, fluorine, chlorine, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl and cyclohexyl.
In some embodiments, R12Selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, C1-6Alkyl (e.g. methyl, ethyl, propyl or isopropyl), C1-6Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), C3-7Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl), 5-12 membered aryl (e.g., phenyl, naphthyl), or 5-12 membered heteroaryl (e.g., pyridine, piperidine).
In some embodiments, R12Selected from hydrogen, fluorine, chlorine, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl and cyclohexyl.
In some embodiments of the present invention, the substrate is,is selected fromWherein p and q are respectively and independently selected from 0, 1,2 and 3, and p and q are not 0 at the same time.
In some embodiments, when Y is selected from CR5-NR6R7When R is5、R6Each independently selected from hydrogen.
In some embodiments, R in Y7Is selected from-SO2R'、-SO2NR'(R”)。
In some embodiments, the-SO2R'、-SO2NR ' (R '), R ' is selected from C1-6Alkyl (e.g. methyl, ethyl, propyl or isopropyl), C1-6Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), C3-7Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl), 5-12 membered aryl (e.g., phenyl, naphthyl), or 5-12 membered heteroaryl (e.g., pyridine, piperidine), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl being optionally substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano.
In some embodiments, the-SO2R'、-SO2NR ' (R ') wherein R ' is selected from methyl, ethyl, propyl, 5-12 membered heteroaryl (e.g. pyridine, piperidine),C1-6Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy),
In some embodiments, the-SO2R ' in NR ' (R ') is selected from hydrogen, C1-6Alkyl radical(e.g., methyl, ethyl, propyl, or isopropyl).
In some embodiments, the-SO2NR ' (R ') wherein R ' is selected from hydrogen, methyl, ethyl, propyl.
In some embodiments, R1Selected from halogens (such as fluorine, chlorine, bromine), preferably fluorine, chlorine.
In some embodiments, R2Selected from hydrogen and deuterium.
In some embodiments, R3Selected from hydrogen, deuterium, halogen, preferably hydrogen, fluorine, chlorine.
In some embodiments, n is selected from 1.
In some embodiments, R4Selected from hydrogen, deuterium, halogen, preferably hydrogen.
In some embodiments, m is selected from 0, 1, preferably 0.
In some embodiments, the compound isPreference is given toRing C is selected from C3-7Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl).
R13Selected from hydrogen, fluorine, chlorine, hydroxyl, methyl, ethyl and propyl.
R14Selected from methyl, ethyl, propyl, 5-12 membered heteroaryl,C1-6Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy),
o is selected from 0, 1, 2.
ring D is selected from C3-7Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl);
R13selected from hydrogen, fluorine, chlorine, hydroxyl, methyl, ethyl, propyl;
R14selected from methyl, ethyl, propyl, 5-12 membered heteroaryl (e.g. pyridine, piperidine),C1-6Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy),
o is selected from 0, 1, 2.
In some casesIn embodiments, ring B is selected fromWherein p and q are respectively and independently selected from 0, 1,2 and 3, and p and q are not 0 at the same time.
In some embodiments, R1Selected from halogens (such as fluorine, chlorine, bromine), preferably fluorine, chlorine.
R14Selected from methyl, ethyl, propyl, 5-12 membered heteroaryl (e.g. pyridine, piperidine),C1-6Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy),
In some embodiments, R1Selected from halogens (such as fluorine, chlorine, bromine), preferably fluorine, chlorine.
In some embodiments, a compound is selected from:
or a pharmaceutically acceptable salt thereof.
The disclosure also provides a process for preparing a compound of formula I,
when Y is selected from CR5-NR6R7When is composed of
When Y is selected from NR7When is composed of
Wherein LG1Or LG2Selected from leaving groups and Ra is selected from protecting groups.
In some embodiments, the leaving group comprises a halogen, a sulfonate, a boronic acid, a boronic ester.
In some embodiments, the protecting group comprises a tert-butoxycarbonyl group, a benzyloxycarbonyl group.
Also provided in the present disclosure is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound described in the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In some embodiments, the unit dose of the pharmaceutical composition is 0.001mg to 1000 mg.
In certain embodiments, the pharmaceutical composition comprises from 0.01 to 99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.
In certain embodiments, the pharmaceutical composition comprises from 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2% to 98% of a pharmaceutically acceptable excipient. The present disclosure also provides a method for preventing and/or treating a patient having a protein-dependent kinase associated disease by administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition.
In some embodiments, the protein dependent kinase associated disease is selected from a cell proliferative disease, cancer, or an immunological disease.
In some embodiments, the protein-dependent kinase associated disease is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer (including HCC), pancreatic cancer, colorectal cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma, or adenocarcinoma), kidney cancer (including RCC), skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, chorioepithelial cancer, or pediatric tumor.
The present disclosure also provides a method for preventing and/or treating a patient having a cancer selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer (including HCC), pancreatic cancer, colorectal cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), kidney cancer (including RCC), skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, chorioepithelioma or pediatric tumors.
The present disclosure provides the use of a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing, in the manufacture of a medicament for the prevention and/or treatment of a protein-dependent kinase-associated disease, preferably CDK2, preferably a cell proliferative disorder, cancer or an immune disorder.
In some embodiments, the present disclosure provides the use of a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing, in the manufacture of a medicament for the treatment of cancer, preferably, the cancer is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer (including HCC), pancreatic cancer, colorectal cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), kidney cancer (including RCC), skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureter tumor, bladder tumor, gall bladder cancer, bile duct cancer, chorioepithelial cancer or pediatric tumor.
In another aspect, the pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic or organic salts.
In another aspect, the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present disclosure.
In addition, the compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactam isomerizations. An example of a lactam-lactam equilibrium is between A and B as shown below.
All compounds of the present invention can be drawn as form a or form B. All tautomeric forms are within the scope of the invention. The naming of the compounds does not exclude any tautomers.
The disclosed compounds may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.
Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).
The disclosure also includes some isotopically-labeled compounds of the present disclosure that are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as respectively2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I and36cl, and the like.
Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The compound of examples can have a natural abundance of deuterium greater than that of deuterium of at least 1000 times the abundance of deuterium, deuterium of at least 2000 times the abundance of deuterium, deuterium of at least 3000 times the abundance of deuterium, deuterium of at least 4000 times the abundance of deuterium, deuterium of at least 5000 times the abundance of deuterium, deuterium of at least 6000 times the abundance of deuterium, or deuterium of greater abundance. The disclosure also includes various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds of the formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane tetrahydrofuran solutions, deuterated lithium aluminum hydrides, deuterated iodoethanes, deuterated iodomethanes, and the like.
"optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "C1-6 alkyl optionally substituted with halogen or cyano" means that halogen or cyano may, but need not, be present, and that the description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.
In the chemical structure of the compound of the present invention, a bondDenotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structureCan be thatOrOr at the same time containAndtwo configurations. Although all of the above structural formulae are drawn as certain isomeric forms for the sake of simplicity, the present invention may include all isomers, such as tautomers, rotamers, geometric isomers, diastereomers, racemates and enantiomers.
Interpretation of terms:
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifier that has been approved by the U.S. food and drug administration for use in humans or livestock animals.
An "effective amount" or "therapeutically effective amount" as referred to in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the method and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.
"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 6 carbon atoms. Non-limiting examples includeMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, and various branched isomers thereof, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
"alkenyl" includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups. E.g. "C2-6Alkenyl "denotes alkenyl having 2,3,4, 5 or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl, and 4-hexenyl. Alkenyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroarylOptionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro and cyano.
"alkynyl" includes branched and straight chain alkynyl groups having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups, or if the specified number of carbon atoms is specified, that particular number is intended. For example, ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl groups. Alkynyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The term "cycloalkyl" or "carbocyclic ring" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The cycloalkyl ring may be fused to an aryl or heteroaryl ring, where the ring to which the parent structure is attached is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl. Cycloalkenyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocyclic alkoxyBase, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The term "heterocycloalkyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocycloalkyl groups include spiro, fused and bridged heterocycloalkyl groups. Non-limiting examples of "heterocycloalkyl" include:
The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring joined together with the parent structure is heterocycloalkyl, non-limiting examples of which include:
The heterocycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12-membered, more preferably 5-or 6-membered. For example. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl,Pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine,and so on.
The heteroaryl ring may be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, where the ring joined to the parent structure is a heteroaryl ring, non-limiting examples of which include:
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5 to6-membered aryl or heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano. Similarly, "alkynyloxy", "alkenyloxy", "cycloalkoxy", "heterocycloalkoxy", "cycloalkenyloxy" are as defined above for "alkoxy".
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "cyano" refers to — CN.
The term "nitro" means-NO2。
The term "oxo" refers to the ═ O substituent.
"monovalent group" means a compound that "formally" eliminates a monovalent atom or group. "subunit" refers to a compound that "formally" eliminates two monovalent or one divalent formed atoms or groups of atoms. Examples "alkyl" refers to the moiety remaining after removal of 1 hydrogen atom from an alkane molecule, and includes straight and branched chain monovalent groups of 1 to 20 carbon atoms. "alkylene (-CH)2- "then denotes the remaining part of the alkane molecule after removal of 2 hydrogen atoms, including straight and branched chain subgroups of 1 to 20 carbon atoms. Alkylene having 1 to 6 carbon atoms, non-limiting examples of which include methylene (-CH)2-), ethylene (e.g. -CH)2CH2-or-CH (CH)3) -), propylene (e.g. -CH)2CH2CH2-or-CH (CH)2CH3) -) butylene (e.g., -CH2CH2CH2CH2-). Alkylene groups may be substituted or unsubstituted and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, alkynyloxy,C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C3-8Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
Similarly, "alkyleneoxy", "alkenylene", "alkyleneoxy", "cycloalkylene", "heterocycloalkylene" are as defined for "alkylene".
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds. Optional substituents also include spiro or fused ring substitutions.
Detailed Description
The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.
Experimental procedures, in which specific conditions are not noted in the examples of the present disclosure, are generally performed under conventional conditions, or under conditions recommended by manufacturers of raw materials or commercial products. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
MS was measured using a Shimadzu 2010Mass Spectrometer or Agilent 6110A MSD Mass Spectrometer.
HPLC measurements were performed using Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200LC HPLC (Ultimate XB-C183.0X 150mm column or XTmate C182.1X 30mm column).
Chiral HPLC analysis and determination using Chiralpak IC-3100 × 4.6mm I.D.,3um, Chiralpak AD-3150 × 4.6mm I.D.,3um, Chiralpak AD-350 × 4.6mm I.D.,3um, Chiralpak AS-3150 × 4.6mm I.D.,3um, Chiralpak AS-4.6 mm I.D.,3 μm, Chiralcel OD-3150 × 4.6mm I.D.,3um, Chiralcel OD- × 4.6mm I.D.,3 μm, Chiralcel OJ-H150 × 4.6mm I.D.,5um, Chiralcel OJ-3150 × 4.6mm I.D.,3um chromatographic column;
the thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel of Tibet Huanghai silica gel as a carrier.
The chiral preparative column used DAICEL CHIRALPAK IC (250 mm. about.30 mm,10um) or Phenomenex-Amylose-1(250 mm. about.30 mm,5 um).
The CombiFlash rapid preparation instrument uses CombiFlash Rf150(TELEDYNE ISCO).
Average inhibition rate of kinase and IC50The values were determined with a NovoStar microplate reader (BMG, Germany).
Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, Acros Organics, Aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: the volume ratio of petroleum ether/ethyl acetate/methanol and solvent is regulated according to the different polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for regulation.
Example 1
N- (3- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) cyclobutyl) methanesulfonamide
First step of
Tert-butyl (3- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) cyclobutyl) carbamate 1c
Compound 1a (170mg,0.53mmol, prepared by the method disclosed in patent application "WO 201075074") and compound 1b (98mg,0.53mmol) were dissolved in 4mL of N, N-dimethylformamide, and cesium carbonate (430mg,1.32mmol) was added and reacted at 100 ℃ for 12 hours. After completion of the reaction, 10mL of water was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL. times.3). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography eluting with petroleum ether, ethyl acetate to give the title compound 1b (190mg, yield: 76%) to give the title compound 1b (105mg, yield: 95%).
1H NMR(400MHz,CDCl3):δppm 8.25-8.17(m,1H),8.07(s,1H),7.73(d,J=11.6Hz,1H),5.40-5.24(m,1H),4.71(td,J=7.2,13.6Hz,2H),4.16-4.08(m,2H),2.67(s,3H),2.38(br t,J=6.4Hz,2H),1.68(d,J=7.2Hz,6H),1.45(s,9H).(ESI).
Second step of
N1- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) cyclobutane-1, 3-diamine 1d
Compound 1c (190mg, 0.40mmol) was dissolved in 4mL of methanol, and 4mL of methanolic hydrogen chloride solution (4M) was added to the solution, followed by reaction at 25 ℃ for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the title compound 1d (150mg, crude product).
1H NMR(400MHz,CDCl3):δppm 8.62-8.47(m,2H),8.16(br d,J=11.2Hz,1H),5.16(br d,J=7.2Hz,1H),4.08-3.80(m,1H),3.71-3.56(m,1H),2.94(br s,1H),2.72(s,3H),2.67(br s,2H),2.50-2.22(m,1H),1.82(d,J=6.8Hz,6H).
The third step
N- (3- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) cyclobutyl) methanesulfonamide 1
Compound 1d (150mg,0.40mmol) and triethylamine (0.14mL,1.0mmol) were dissolved in 4mL of dichloromethane, and housekeeping chloride (0.040mL,0.52mmol) was added at 0 ℃ to react for 2 hours at 20 ℃. After completion of the reaction, 10mL of water was added, and the mixture was extracted with ethyl acetate (15 mL. times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography eluting with 0.225% aqueous formic acid, acetonitrile to give the title compound 1(23mg, yield: 13%).
MS(ESI)m/z 451.2[M+H]+
1H NMR(400MHz,CDCl3):δppm 8.30(d,J=2.4Hz,1H),8.29(d,J=2.4Hz,1H),8.27(s,1H),8.24(s,1H),7.77(s,1H),7.76-7.73(m,1H),4.97-4.91(m,2H),4.41(quin,J=6.0Hz,1H),4.15(quin,J=7.2Hz,2H),3.77-3.66(m,1H),2.94(s,3H),2.93(s,3H),2.93-2.88(m,2H),2.70(s,6H),2.50(t,J=6.8Hz,4H),2.07-1.93(m,2H),1.72(d,J=1.6Hz,6H),1.71(d,J=1.2Hz,6H).
Example 2
Trans-N- (3- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) cyclopentyl) methanesulfonamide
The synthetic procedure of example 2 is as in example 1, wherein compound 1b is replaced by the compound trans-tert-butyl- (3-aminocyclopentyl) carbamate.
MS(ESI)m/z 465.2[M+H]+
1H NMR(400MHz,CDCl3):δ8.23(d,J=3.6Hz,1H),8.07(s,1H),7.73(d,J=12.0Hz,1H),5.08(br d,J=6.4Hz,1H),4.72(td,J=6.8,14.0Hz,1H),4.48-4.38(m,1H),4.27(br d,J=6.4Hz,1H),4.09-3.95(m,1H),3.00(s,3H),2.68(s,3H),2.40-2.26(m,2H),2.09(t,J=7.2Hz,2H),1.69(d,J=6.8Hz,6H),1.64-1.59(m,2H).
Example 3
5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) -N- ((1- (methylsulfonyl) azetidin-3-yl) methyl) pyrimidin-2-amine
The synthetic procedure of example 3 is as in example 1, wherein compound 1b is replaced by the compound tert-butyl-3- (aminomethyl) azetidinyl-1-carboxylate.
MS(ESI)m/z 451.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ=8.44(d,J=3.8Hz,1H),8.10(br s,1H),7.60(br d,J=11.9Hz,1H),7.53(br t,J=5.6Hz,1H),4.90-4.76(m,1H),3.92(t,J=8.3Hz,2H),3.71-3.63(m,2H),3.55(br s,2H),2.97(s,3H),2.87(br s,1H),2.63(s,3H),1.59(d,J=6.8Hz,6H).
Example 4
6- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -4, 4-dimethyl-3, 4-dihydroisoquinolin-1 (2H) -one
First step of
4c
Compound 4a (30mg, 0.12mmol), pinacol diboron (45mg, 0.18mmol), potassium acetate (23mg,0.24mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (18mg,0.02mmol) were dissolved in 2mL of 1, 4-dioxane, in that order, under a nitrogen atmosphere. The reaction was carried out at 100 ℃ for 1 hour. The reaction mixture was cooled to room temperature, and 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphoadamantane (14mg, 0.05mmol), potassium carbonate (33mg, 0.24mmol), 4b (30mg,0.18mmol), tris (dibenzylideneacetone) dipalladium (22mg,0.02mmol) and 0.5mL of water were added thereto and reacted at 80 ℃ for 1 hour. The reaction solution was cooled to room temperature, filtered, the filtrate was collected, concentrated under reduced pressure, and the residue was purified by C-18 reverse phase chromatography to give the title compound 4C (25mg, yield: 69%).
MS(ESI)m/z 306.4[M+H]+.
Second step of
6- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -4, 4-dimethyl-3, 4-dihydroisoquinolin-1 (2H) -one 4
Compound 4c (25mg, 0.08mmol), 4d (16mg, 0.09mmol), cesium carbonate (53mg,0.16mmol), tris (dibenzylideneacetone) dipalladium (15mg,0.02mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (19mg,0.03mmol) were dissolved in 2mL of N, N-dimethylformamide in that order under a nitrogen atmosphere. The reaction was carried out at 100 ℃ for 1 hour. The reaction solution was cooled to room temperature, filtered, the filtrate was collected, concentrated under reduced pressure, and the residue was purified by C-18 reverse phase chromatography to give the title compound 2(0.3mg, yield: 1%).
MS(ESI)m/z 448.5[M+H]+.
Example 5
6- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -2,4, 4-trimethyl-3, 4-dihydroisoquinolin-1 (2H) -one
First step of
7-bromo-2, 4, 4-trimethyl-3, 4-dihydroisoquinolin-1 (2H) -one 5a
4a (100mg,0.393mmol) was dissolved in 2mL of N, N-dimethylformamide at 0 deg.C, sodium hydride (100mg,0.393mmol) was added, and the reaction was stirred at 25 deg.C under argon for 0.5 h. Methyl iodide (112mg,0.787mmol) was then added to the reaction mixture at 0 ℃ and the reaction mixture was heated to 25 ℃ and stirred under argon for 0.5 hour. After completion of the reaction, the reaction mixture was poured into 20mL of an ice-water mixture, extracted with ethyl acetate (10 mL. times.3), the organic phases were combined, washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and the filtrate was concentrated under reduced pressure to give the title compound 5a (105mg, yield: 95%).
MS(ESI)m/z 268.3,270.3[M+H]+.
Second step of
2,4, 4-trimethyl-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydroisoquinoline-1 (2H) -one 5b
Compound 5a (105mg, 0.392mmol), pinacol diboron ester (129mg, 0.509mmol), and potassium acetate (77mg,0.783mmol) were dissolved in 2mL dioxane, and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (29mg,0.039mmol) was added, and the reaction was stirred under argon at elevated temperature to 95 ℃ for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, water was added, extraction was performed with ethyl acetate (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain the title compound 5b (120mg, yield: 97%).
MS(ESI)m/z 316.5[M+H]+.
The third step
6- (2-chloro-5-fluoropyrimidin-4-yl) -2,4, 4-trimethyl-3, 4-dihydroisoquinolin-1 (2H) -one 5c
Compound 5b (120mg,0.381mmol), compound 4b (64mg,0.381mmol) and potassium carbonate (105mg,0.761mmol) were dissolved in 2mL dioxane and 0.5mL water, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (28mg,0.038mmol) was added, and the reaction was stirred under argon at 95 ℃ for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, water was added, extraction was performed with ethyl acetate (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with petroleum ether and ethyl acetate to give the title compound 5c (80mg, yield: 65%).
MS(ESI)m/z 320.4[M+H]+.
The fourth step
6- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -2,4, 4-trimethyl-3, 4-dihydroisoquinolin-1 (2H) -one 5
Compound 5c (80mg,0.250mmol), compound 4d (67mg,0.375mmol), 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine (23mg,0.038mmol) and cesium carbonate (244mg,0.751mmol) were dissolved in 2mL of tetrahydrofuran, palladium acetate (8mg,0.038mmol) was added, and the reaction was stirred with a microwave under argon at 80 ℃ for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography eluting with water and acetonitrile to give the title compound 5(45.5mg, yield: 39%).
MS(ESI)m/z 462.5[M+H]+.
Example 6
2-cyclopropyl-6- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -4, 4-dimethyl-3, 4-dihydroisoquinolin-1 (2H) -one
The synthetic procedure of example 6 is as in example 5, wherein the compound iodomethane is replaced by the compound iodocyclopropane.
MS(ESI)m/z 488.5[M+H]+.
Examples 7 and 8
Trans N- (3- ((4- (4, 4-dimethyl-1-carbonyl-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -5-fluoropyrimidin-2-yl) amino) cyclopentyl) methanesulfonamide isomer 1 and isomer 2
First step of
Trans-tert-butyl (3- ((4- (4, 4-dimethyl-1-carbonyl-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -5-fluoropyrimidin-2-yl) amino) cyclopentyl) carbamate 7b
Compound 4c (520mg, 1.7mmol), 7a (409mg, 2.0mmol), and N, N-diisopropylethylamine (440mg,3.4mmol) were dissolved in 12mL of N, N-dimethylacetamide in this order under a nitrogen atmosphere. The reaction was carried out at 125 ℃ for 5 hours. The reaction solution was cooled to room temperature, 100mL of water was added, extraction was performed with ethyl acetate (100 mL. times.3), the organic phases were combined, washed with a saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, concentrated under reduced pressure, and the residue was purified by C-18 reverse phase chromatography to give the title compound 7b (680mg, yield: 85%).
MS(ESI)m/z 470.5[M+H]+。
Second step of
Trans-6- (2- ((3-aminocyclopentyl) amino) -5-fluoropyrimidin-4-yl) -4, 4-dimethyl-3, 4-dihydroisoquinolin-1 (2H) -one 7c
Compound 7a (400mg, 0.85mmol) was dissolved in 16mL of methanol at room temperature. 2mL of trifluoroacetic acid was added and the reaction was carried out at room temperature for 3 hours. Concentrated under reduced pressure, 100mL of a saturated sodium bicarbonate solution was added, extracted with ethyl acetate (100 mL. times.3), the organic phases were combined, washed with a saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and concentrated under reduced pressure to give the title compound 7c (310mg, yield: 99%).
MS(ESI)m/z 370.5[M+H]+
The third step
Trans N- (3- ((4- (4, 4-dimethyl-1-carbonyl-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -5-fluoropyrimidin-2-yl) amino) cyclopentyl) methanesulfonamide isomer 1 and isomer 2
Compound 7c (100mg, 0.27mmol) was dissolved in 10mL of dichloromethane at room temperature. The temperature was reduced to 0 ℃ and methanesulfonyl chloride (34mg, 0.3mmol) was added and reacted at 0 ℃ for 1 hour. Concentration under reduced pressure, and purification of the residue by C-18 reverse phase chromatography gave a crude product which was resolved by chiral column supercritical fluid chromatography to give compounds 7(39.6mg, yield: 33%) and 8(38.4mg, yield: 32%). The chiral analysis method is Chiralpak IG-3, mobile phase A-supercritical carbon dioxide, B-methanol + 0.05% diethylamine, the flow rate is 4ml/min, and the isocratic degree is 40% B. The resulting isomers were isolated and, depending on the isomer retention time:
compound 7:
MS(ESI)m/z 448.5[M+H]+
chiral assay Retention Time (RT)2.576min
Compound 8:
MS(ESI)m/z 448.5[M+H]+
chiral assay Retention Time (RT)3.385 min.
Example 9
6'- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -2',3 '-dihydro-1' H-spiro [ cyclobutane ] o
-1,4 '-isoquinoline ] -1' -one
First step of
4-bromo-2- (cyanomethyl) benzoic acid methyl ester 9b
Compound 9a (2.6g,8.4mmol) was dissolved in 20mL acetonitrile, potassium carbonate (2.3g,16.9mmol) and trimethylsilonitrile (1.0g,10.1mmol) were added, and the mixture was stirred at room temperature for 14 hours. The reaction was quenched by the addition of 100mL of saturated sodium hydroxide solution. Extraction with ethyl acetate (100 mL. times.3), combining the organic phases and chlorination with saturated waterThe sodium solution was washed (100mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether, ethyl acetate to give the title compound 9b (1.15g, yield: 54%). MS (ESI) M/z 254.3,256.3[ M + H ]]+
Second step of
4-bromo-2- (1-cyanocyclobutyl) benzoic acid methyl ester 9d
Compound 9b (300mg, 1.2mmol) was dissolved in 8mL of N, N-dimethylformamide under nitrogen. The temperature was reduced to 0 ℃ and sodium hydride (132mg, 3.3mmol) was added portionwise and stirred at 0 ℃ for half an hour. 9c (286mg, 1.4mmol) was added and stirred at 0 ℃ for half an hour. The temperature is raised to 10 ℃ and stirred for half an hour. The reaction was quenched with 80mL of saturated ammonium chloride solution, extracted with ethyl acetate (80 mL. times.3), the organic phases were combined, washed with saturated sodium chloride solution (80mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether, ethyl acetate to give the title compound 9d (60mg, yield: 17%).
MS(ESI)m/z 294.3,296.3[M+H]+
The third step
6 '-bromo-2', 3 '-dihydro-1' H-spiro [ cyclobutane-1, 4 '-isoquinoline ] -1' -one 9e
Compound 9d (60mg, 0.2mmol) was dissolved in 4mL of methanol under nitrogen. The temperature was reduced to 0 deg.C, cobalt chloride hexahydrate (145mg, 0.6mmol) was added, sodium borohydride (41mg, 1.2mmol) was added in portions and stirred at 0 deg.C for 1 hour. The reaction was quenched with 30mL of a saturated ammonium chloride solution, extracted with ethyl acetate (30 mL. times.3), the organic phases were combined, washed with a saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether, ethyl acetate to give the title compound 9e (20mg, yield: 37%).
MS(ESI)m/z 266.3,268.3[M+H]+
The fourth step
6'- (2-chloro-5-fluoropyrimidin-4-yl) -2',3 '-dihydro-1' H-spiro [ cyclobutane-1, 4 '-isoquinoline ] -1' -one 9f
Compound 9e (120mg, 0.45mmol), pinacol diboron (172mg, 0.68mmol), potassium acetate (89mg,0.9mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (67mg,0.1mmol) were dissolved in 2mL of 1, 4-dioxane, in that order, under a nitrogen atmosphere. The reaction was carried out at 100 ℃ for 1 hour. The reaction mixture was cooled to room temperature, and 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphoadamantane (40mg, 0.14mmol), potassium carbonate (125mg, 0.9mmol), 4b (113mg,0.68mmol), tris (dibenzylideneacetone) dipalladium (83mg,0.09mmol) and 0.5mL of water were added thereto and reacted at 80 ℃ for 1 hour. The reaction solution was cooled to room temperature, filtered, the filtrate was collected, concentrated under reduced pressure, and the residue was purified by C-18 reverse phase chromatography to give the title compound 9f (75mg, yield: 52%).
MS(ESI)m/z 318.4[M+H]+
The fifth step
6'- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -2',3 '-dihydro-1' H-spiro [ cyclobutane-1, 4 '-isoquinolin ] -1' -one 9
Under nitrogen, compound 9f (35mg, 0.11mmol), 4d (29mg, 0.17mmol), cesium carbonate (72mg,0.2mmol), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (20mg,0.02mmol) were dissolved in 2mL of N, N-dimethylformamide in that order. The reaction was carried out at 100 ℃ for 1 hour. The reaction solution was cooled to room temperature, filtered, the filtrate was collected, concentrated under reduced pressure, and the residue was purified by C-18 reverse phase chromatography to give the title compound 9(0.6mg, yield: 1%).
MS(ESI)m/z 460.5[M+H]+
Example 10
6'- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -2',3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinolin ] -1' -one
The synthetic procedure of example 10 is as in example 9, wherein compound 9c is replaced by compound 1, 2-dibromoethane.
MS(ESI)m/z 446.5[M+H]+
Example 11
6- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -2,2',3,3',5',6' -hexahydro-1H-spiro [ isoquinoline-4, 4' -pyran ] -1-one
The synthetic procedure of example 11 is as in example 9, wherein compound 9c is replaced by the compound 1-bromo-2- (2-bromoethoxy) ethane.
MS(ESI)m/z 490.5[M+H]+
Example 12
6'- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -2',3 '-dihydro-1' H-spiro [ cyclopenta-1, 4 '-isoquinolin ] -1' -one
The synthetic procedure of example 12 is as in example 9, wherein compound 9c is replaced by compound 1, 4-dibromobutane.
MS(ESI)m/z 474.5[M+H]+
Example 13
6'- (5-fluoro-2- (((1- (methylsulfonyl) azetidin-3-yl) methyl) amino) pyrimidin-4-yl) -2',3 '-dihydro-1' H-spiro [ cyclobutane-1, 4 '-isoquinolin-1' -one
The synthetic procedure of example 13 is as in example 9, wherein compound 4d is replaced with the compound (1- (methylsulfonyl) azetidin-3-yl) methylamine.
MS(ESI)m/z 446.4[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.50(d,J=3.5Hz,1H),8.16(s,2H),7.99(d,J=8.1Hz,1H),7.93(d,J=8.0Hz,1H),7.62(s,1H),3.93(t,J=8.3Hz,2H),3.67(dd,J=8.2,5.7Hz,2H),3.55(t,J=6.6Hz,2H),3.47(d,J=2.9Hz,2H),2.97(s,3H),2.87(s,1H),2.26(d,J=6.0Hz,2H),2.12(d,J=10.1Hz,4H).
Example 14
6'- (5-chloro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -2',3 '-dihydro-1' H-spiro [ cyclobutane and cyclo-b
-1,4 '-isoquinoline ] -1' -one
The synthetic procedure of example 14 is as in example 9, wherein compound 2,4, 5-trichloropyrimidine is substituted for compound 4 b.
MS(ESI)m/z 446.4[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.13(br s,1H),7.99-7.85(m,2H),7.69(br s,2H),3.86(br s,1H),3.53(br d,J=11.8Hz,2H),3.46(br d,J=2.4Hz,2H),2.92-2.80(m,5H),2.30-2.18(m,2H),2.16-2.05(m,3H),1.98(br s,2H),2.03-1.92(m,1H),1.64-1.49(m,2H).
Example 15
6'- (2- ((1- (methylsulfonyl) piperidin-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -2',3 '-dihydro-1' H-spiro [ cyclobutane-1, 4 '-isoquinolin ] -1' -one
The synthetic procedure for example 15 is as in example 9, wherein compound 4b is replaced by compound 2, 4-dichloro-5- (trifluoromethyl) pyrimidine.
MS(ESI)m/z 510.5[M+H]+
Example 16
6- (5-fluoro-2- (((1- (methylsulfonyl) azetidin-3-yl) methyl) amino) pyrimidin-4-yl) -4, 4-dimethyl-3, 4-
Dihydroisoquinolin-1 (2H) -ones
The synthetic procedure of example 16 is as in example 4, wherein compound 4d is replaced with the compound (1- (methylsulfonyl) azetidin-3-yl) methylamine.
MS(ESI)m/z 434.4[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.12(s,1H),8.03–7.94(m,2H),7.91(d,J=8.1Hz,1H),7.60(s,1H),3.92(t,J=8.2Hz,2H),3.67(dd,J=8.1,5.7Hz,2H),3.53(d,J=6.6Hz,2H),3.23(d,J=3.1Hz,2H),2.97(s,3H),2.86(s,1H),1.32(s,6H).
Example 17
6'- (5-chloro-2- (((1- (methylsulfonyl) azetidinyl-3-yl) methyl) amino) pyrimidin-4-yl) -2',3 '-dihydro-1' H-
Spiro [ cyclobutane-1, 4 '-isoquinoline ] -1' -one
The synthetic procedure for example 17 is as in example 9, replacing compound 4b with the compound 2,4, 5-trichloropyrimidine and replacing compound 4d with the compound (1- (methylsulfonyl) azetidin-3-yl) methylamine.
MS(ESI)m/z 462.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.07(s,1H),7.89(d,J=7.9Hz,1H),7.81(s,1H),7.62(s,1H),3.84(t,J=8.3Hz,2H),3.59(dd,J=8.2,5.7Hz,2H),3.46(t,J=6.5Hz,2H),3.40(d,J=2.9Hz,2H),2.90(s,3H),2.25–2.15(m,3H),2.11–1.88(m,4H).
Biological evaluation
The present disclosure is further described and explained below in conjunction with test examples, but these examples are not meant to limit the scope of the present disclosure.
Test example 1 detection of cyclin-dependent kinase Activity by Compounds of the disclosure
1. Experimental materials and instruments
2. Experimental procedure
Compound dilutions were transferred to each well of the assay plate using Echo 550 (784075, Greiner). Seal assay plate, centrifuge assay plate at 1000g for 1 minute; prepare 2 Xenzyme in 1 Xkinase buffer (prepared from 1 volume of 5 Xkinase buffer and 4 volumes of distilled water and 50uM DTT), add 2.5. mu.l of 2 Xenzyme to 384 well assay plates, centrifuge the plates at 1000g for 30s, and allow to stand at room temperature for 10 minutes. A2 Xsubstrate and ATP mixture was prepared in 1 Xkinase buffer and the reaction was started by adding 2.5. mu.l of the 2 Xsubstrate and ATP mixture. The plate was centrifuged at 1000g for 30 seconds, the assay plate was sealed and the reaction was carried out at room temperature for 1 hour. Mu.l ADP-Glo reagent was added and incubated at room temperature for 40 minutes, and 8. mu.l kinase detection reagent was added and incubated at room temperature for 40 minutes.
Each well illumination signal was read on an Envision 2104 reader plate.
Percent inhibition was calculated as follows:
the suppression percentage is 100- (cmpd signal-Ave _ PC signal)/(Ave _ VC signal-Ave _ PC signal) × 100.
IC50 was calculated using GraphPad 8.0 by fitting the percent inhibition values and the log of compound concentration to a non-linear regression (dose response-variable slope).
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X: logarithm of inhibitor concentration; y: % inhibition.
Measured IC50The values are shown in Table 1.
TABLE 1 Compound of the present disclosure vs CDK2/Cyclin E IC50
Example numbering | CDK2(nM) |
PHA-793887 | 8.1 |
1 | 44.7 |
2 | 12.0 |
3 | 16.4 |
4 | 2.4 |
5 | 3.5 |
6 | 9.0 |
7 | 17.7 |
8 | 1.8 |
9 | 0.9 |
10 | 1.1 |
11 | 0.9 |
12 | 0.5 |
13 | 37.9 |
14 | 4.2 |
15 | 63.1 |
16 | 11.4 |
17 | 123 |
Claims (31)
1. A compound of formula I or a pharmaceutically acceptable salt thereof,
wherein, X1、X2、X3、X4Each independently selected from optionally substituted or unsubstituted C, N, and not both C;
b is 3-20 membered ring including monocyclic ring, fused ring, bridged ring, spiro ring,
the conditions are as follows:
Wherein Y is selected from CR5-NR6R7、*NR7;
Each R1、R2、R3、R4、R5、R6Each independently selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, SR ', SOR', SO2R'、SO2NR ' (R "), COOR ' or CONR ' (R"), the amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with one or more groups selected from halo, hydroxy, oxo, nitro, cyano, alkyl optionally substituted with Z, cycloalkyl optionally substituted with Z, heterocyclyl optionally substituted with Z, alkoxy optionally substituted with Z, alkenyl optionally substituted with Z, alkynyl optionally substituted with Z, aryl optionally substituted with Z, heteroaryl optionally substituted with Z, SR ', SOR ', SO2R'、SO2NR ' (R "), COR ', COOR ', or CONR ' (R ');
and R is1、R2Not hydrogen at the same time;
each R7Are respectively and independently selected from-SR ', -SOR' and-SO2R'、-SO2NR'(R”);
Each R', R "is independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, amino, imino, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, cyano, alkyl optionally substituted with Z, alkoxy optionally substituted with Z, cycloalkyl optionally substituted with Z, heterocyclyl optionally substituted with Z, aryl optionally substituted with Z, heteroaryl optionally substituted with Z;
z is selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR8、SOR8、SO2R8、SO2NR8(R9)、NR8(R9)、COR8、COOR8Or CONR8(R9) The alkyl, alkoxy, or the like,Cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR8、SOR8、SO2R8、SO2NR8(R9)、NR8(R9)、COR8、COOR8Or CONR8(R9);
Each R8Or R9Independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl;
m and n are respectively and independently selected from 0, 1,2 and 3;
wherein, indicates the connecting site, and the dotted line is selected from single bond and double bond.
2. A compound according to claim 1, which is a compound of formula II-a, II-b, II-c or II-d,
the R is10Selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, SR ', SOR', SO2R'、SO2NR '(R "), COR', COOR 'or CONR' (R"), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO2R'、SO2NR ' (R "), COR ', COOR ', or CONR ' (R '),
R12selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, SR ', SOR', SO2R'、SO2NR '(R "), COR', COOR 'or CONR' (R"), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO2R'、SO2NR ' (R "), COR ', COOR ', or CONR ' (R ');
ring B, R1、R2、R3、R4Y, m, n, R' are each as defined in claim 1.
3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof,
R10selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, amino, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-7 membered heterocyclyl, 5-12 membered aryl or 5-12 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano; hydrogen, fluorine, chlorine, methyl, ethyl, propyl or isopropyl are preferred.
4. A compound according to any one of claims 2 to 3, or a pharmaceutically acceptable salt thereof,
R12selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-7 membered heterocyclyl, 5-12 membered aryl or 5-12 membered heteroaryl, preferably hydrogen, fluoro, chloro, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl groups, more preferably methyl, ethyl, propyl, isobutyl, ethyl, pentyl, hexyl, heptyl, octyl, decyl, octyl, and octyl,Propyl or isopropyl.
5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is
Wherein, X1、X2、X3、X4Each independently selected from C-O, CR10R11、NR12;
The R is10Or R11Each independently selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, SR ', SOR', SO2R'、SO2NR '(R "), COR', COOR 'or CONR' (R"), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO2R'、SO2NR ' (R "), COR ', COOR ', or CONR ' (R '),
or, R10Or R11Together with the adjacent carbon atoms to form a 3-to 12-membered spirocyclic ring, or CR10R11Form a 3-to 12-membered ring with its adjacent atoms and the ring is connected to ring A, said 3-to 12-membered ring, preferably a 3-to 12-membered carbocycle, heterocycle, said carbocycle or heterocycle being optionally selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO2R'、SO2NR ' (R "), COR ', COOR ', or CONR ' (R ');
R12selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, SR ', SOR', SO2R'、SO2NR '(R "), COR', COOR 'or CONR' (R"), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO2R'、SO2NR ' (R "), COR ', COOR ', or CONR ' (R ');
ring B, R1、R2、R3、R4Y, m, n, R' are each as defined in claim 1.
7. A compound or pharmaceutically acceptable salt according to claim 5 or 6, wherein R10、R11Are respectively and independently selected from hydrogen, deuterium, halogen, hydroxyl, nitro, cyano, amino and C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-7 membered heterocyclyl, 5-12 membered aryl or 5-12 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano; hydrogen, fluorine, chlorine, methyl, ethyl, propyl or isopropyl are preferred.
8. A compound according to any one of claims 5 to 7, or a pharmaceutically acceptable salt thereof,
R12selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-7 membered heterocyclyl, 5-12 membered aryl or 5-12 membered heteroaryl, preferably hydrogen, fluoro, chloro, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl.
9. A compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein formula Ib is a compound of formula III-d or III-e,
wherein ring D is selected from C3-7Cycloalkyl, 3-7 membered heterocyclyl;
R13are respectively and independently selected from hydrogen, deuterium, halogen, hydroxyl, nitro, cyano and C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-7 membered heterocyclyl, 5-12 membered aryl or 5-12 membered heteroaryl, preferably hydrogen, fluoro, chloro, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl;
o is selected from 0, 1, 2;
ring B, R1、R2、R3、R4Y, m, n are as defined in claim 5;
R12selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-7 membered heterocyclyl, 5-12 membered aryl or 5-12 membered heteroaryl, preferably hydrogen, fluoro, chloro, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl.
12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, when Y is selected from
*CR5-NR6R7When R is5、R6Each independently selected from hydrogen.
14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein Y is R7Is selected from-SO2R'、-SO2NR' (R "); wherein R' is selected from C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl, 3-7 membered heterocyclyl, 5-12 membered aryl or 5-12 membered heteroaryl, said alkyl, alkoxy, cyclicAlkyl, heterocyclyl, aryl or heteroaryl optionally substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano; preferably methyl, ethyl, propyl, 5-12 membered heteroaryl, C1-6An alkoxy group; 5-12 membered heteroaryl is preferredC1-6Alkoxy is preferredThe R' is selected from hydrogen and C1-6Alkyl, preferably hydrogen, methyl, ethyl, propyl.
15. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R1Selected from halogens, preferably fluorine and chlorine.
16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R2Selected from hydrogen and deuterium.
17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R3Selected from hydrogen, deuterium, halogen, preferably hydrogen, fluorine, chlorine.
18. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein n is selected from 1.
19. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R4Selected from hydrogen, deuterium, halogen, preferably hydrogen.
20. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein m is selected from 0 or 1, preferably 0.
21. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which isWherein,
ring D is selected from C3-7Cycloalkyl, 3-7 membered heterocyclyl;
R13selected from hydrogen, fluorine, chlorine, hydroxyl, methyl, ethyl, propyl;
R14selected from methyl, ethyl, propyl, 5-12 membered heteroaryl, C1-6An alkoxy group; 5-12 membered heteroaryl is preferredC1-6Alkoxy is preferred
R1As defined in claim 1;
o is selected from 0, 1, 2.
24. A compound or pharmaceutically acceptable salt according to any one of claims 21 to 23, wherein R1Selected from halogens, preferably fluorine and chlorine.
R14Selected from methyl, ethyl, propyl, 5-12 membered heteroaryl, C1-6An alkoxy group; 5-12 membered heteroaryl is preferredC1-6Alkoxy is preferred
R1Selected from halogens, preferably fluorine and chlorine.
27. An isotopic substitution of the compound of any one of claims 1 to 26, preferably wherein said isotopic substitution is with a deuterium atom.
28. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
29. Use of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 28, in the manufacture of a medicament for the prevention and/or treatment of a protein-dependent kinase-associated disease, preferably CDK2, preferably a cell proliferative disorder, cancer or an immunological disorder.
30. Use of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 28, for the manufacture of a medicament for the prevention and/or treatment of cancer, the cancer is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, stomach cancer, liver cancer (including HCC), pancreatic cancer, colorectal cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), kidney cancer (including RCC), skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureter tumor, bladder tumor, gallbladder cancer, bile duct cancer, chorioepithelial cancer, or pediatric tumor.
31. A process for the preparation of a compound of formula I as claimed in claim 1,
when Y is selected from CR5-NR6R7When is composed of
When Y is selected from NR7When is composed of
Wherein, B, R1、R2、R3、R4、R5、R6、R7、X1、X2、X3、X4M, n are as defined in claim 1;
LG1or LG2Selected from a leaving group, preferably halogen, phenylsulfonyl, methylsulfonyl or p-toluenesulfonyl;
ra is selected from protecting groups, preferably tert-butoxycarbonyl and benzyloxycarbonyl.
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