CN116375742A - Azaaromatic ring derivative, composition and pharmaceutical application thereof - Google Patents
Azaaromatic ring derivative, composition and pharmaceutical application thereof Download PDFInfo
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- CN116375742A CN116375742A CN202211628220.XA CN202211628220A CN116375742A CN 116375742 A CN116375742 A CN 116375742A CN 202211628220 A CN202211628220 A CN 202211628220A CN 116375742 A CN116375742 A CN 116375742A
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- alkyl
- substituted
- membered
- alkoxy
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- 239000000203 mixture Substances 0.000 title description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 88
- 239000013078 crystal Substances 0.000 claims abstract description 39
- 229940002612 prodrug Drugs 0.000 claims abstract description 37
- 239000000651 prodrug Substances 0.000 claims abstract description 37
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 239000012453 solvate Substances 0.000 claims abstract description 34
- 239000002207 metabolite Substances 0.000 claims abstract description 33
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 102200006539 rs121913529 Human genes 0.000 claims abstract description 12
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 9
- 201000011510 cancer Diseases 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 427
- -1 CF 3 Chemical group 0.000 claims description 321
- 125000003545 alkoxy group Chemical group 0.000 claims description 212
- 125000000623 heterocyclic group Chemical group 0.000 claims description 194
- 229910052739 hydrogen Inorganic materials 0.000 claims description 174
- 229910052731 fluorine Inorganic materials 0.000 claims description 152
- 229910052740 iodine Inorganic materials 0.000 claims description 138
- 229910052760 oxygen Inorganic materials 0.000 claims description 136
- 229910052757 nitrogen Inorganic materials 0.000 claims description 132
- 229910052736 halogen Inorganic materials 0.000 claims description 115
- 125000005842 heteroatom Chemical group 0.000 claims description 113
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 108
- 150000002367 halogens Chemical class 0.000 claims description 106
- 229910052717 sulfur Inorganic materials 0.000 claims description 105
- 125000001072 heteroaryl group Chemical group 0.000 claims description 94
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 90
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 81
- 125000001424 substituent group Chemical group 0.000 claims description 71
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 67
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 65
- 229910052799 carbon Inorganic materials 0.000 claims description 64
- 125000003118 aryl group Chemical group 0.000 claims description 59
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 47
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 38
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- 125000003342 alkenyl group Chemical group 0.000 claims description 30
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- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 26
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
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- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 3
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- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 3
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 3
- 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
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- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 claims description 3
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- RBRNGWFPSSHLOT-UHFFFAOYSA-N 1-cyclobutylazetidine Chemical compound C1CCC1N1CCC1 RBRNGWFPSSHLOT-UHFFFAOYSA-N 0.000 claims description 2
- RHRLGFPTYKGJPR-UHFFFAOYSA-N 1-cyclobutylpiperidine Chemical compound C1CCC1N1CCCCC1 RHRLGFPTYKGJPR-UHFFFAOYSA-N 0.000 claims description 2
- CWUOVZOATVWEKA-UHFFFAOYSA-N 1-cyclohexylazetidine Chemical compound C1CCN1C1CCCCC1 CWUOVZOATVWEKA-UHFFFAOYSA-N 0.000 claims description 2
- CFTHKNVHLLWICQ-UHFFFAOYSA-N 1-cyclopentylazetidine Chemical compound C1CCN1C1CCCC1 CFTHKNVHLLWICQ-UHFFFAOYSA-N 0.000 claims description 2
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- 230000007794 irritation Effects 0.000 description 1
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- HLTNRIWFYBDWKA-UHFFFAOYSA-N methyl 2-bromo-5-fluoropyridine-4-carboxylate Chemical compound COC(=O)C1=CC(Br)=NC=C1F HLTNRIWFYBDWKA-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002808 molecular sieve Substances 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
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 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
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000003585 oxepinyl group Chemical group 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 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
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- VNAUDIIOSMNXBA-UHFFFAOYSA-N pyrazolo[4,3-c]pyrazole Chemical group N1=NC=C2N=NC=C21 VNAUDIIOSMNXBA-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- RQGPLDBZHMVWCH-UHFFFAOYSA-N pyrrolo[3,2-b]pyrrole Chemical group C1=NC2=CC=NC2=C1 RQGPLDBZHMVWCH-UHFFFAOYSA-N 0.000 description 1
- GZTPJDLYPMPRDF-UHFFFAOYSA-N pyrrolo[3,2-c]pyrazole Chemical group N1=NC2=CC=NC2=C1 GZTPJDLYPMPRDF-UHFFFAOYSA-N 0.000 description 1
- 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 102200006531 rs121913529 Human genes 0.000 description 1
- 102200006538 rs121913530 Human genes 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 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
- 230000028327 secretion Effects 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- JVQOZRRUGOADSU-UHFFFAOYSA-N tert-butyl 3-formylazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(C=O)C1 JVQOZRRUGOADSU-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a compound of formula (I) or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and intermediates thereof, and use thereof in KRAS G12D related diseases such as cancer. B-L-K (I).
Description
Technical Field
The present invention relates to a compound of general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, as well as intermediates and preparation methods thereof, and uses thereof in KRAS G12D related diseases such as cancer diseases.
Background
RAS proteins are expressed by RAS gene (Rat Sarcoma viral oncogene), are intracellular guanine nucleotide binding proteins, and belong to GTPases (weaker hydrolytic activity). RAS proteins exist in two different states: an inactive GDP-bound state and an active GTP-bound state. The RAS proteins in activated form have an effect on cell growth, differentiation, cytoskeleton, protein transport and secretion, etc. by interacting with different downstream effectors for signaling. Activation of RAS signaling is regulated by guanine nucleotide exchange factors (GEFs, which may cause GDP-GTP exchange) or gtpase-activating proteins (GAPs, which may cause the RAS protein to transition from an activated state to an inactivated state), and resistance to GAPs by mutant RAS proteins may cause the RAS protein to be in a sustained activated state, causing uncontrolled growth of cells, ultimately developing into cancerous tissue (Molecular Cancer,2018, 17:33).
RAS gene mutations are common types of gene mutations in cancer patients (nat. Rev. Drug discovery.2014, 13, 828-851), e.g., 97.7%,52.2%,42.6% and 32.2% of RAS gene mutations in pancreatic cancer, colorectal cancer, multiple myeloma and NSLCL, respectively. The KARS gene (Kristen Rat Sarcoma viral oncogene) mutation is the most affecting mutation among RAS mutations, accounting for 86% of all RAS mutations. The most common way in which the KRAS gene is activated is by point mutation, with 95% of KRAS mutations occurring predominantly at codons 12 and 13 of exon 2, common forms of mutation being KRAS G12C mutation (39%), KRAS G12V (18-21%) and KRAS G12D (17-18%).
KRAS mutein inhibitors have received great attention since the discovery of KRAS muteins in cancer and the observation that inhibiting these muteins can inhibit tumor proliferation. KRAS has long been considered a "non-patentable target": RAS has a very high affinity (picomolar scale) for GTP/GDP and the whole protein lacks additional "ligand binding pockets" (Clin. Cancer Res.2015,21, 1810-1818). KRAS G12D accounts for 36% in pancreatic cancer patients, 12% in colon cancer patients, 4% in NSCLC adenocarcinoma patients, and 6% in endometrial cancer patients. Currently, inhibitors against KRAS G12D mutations are still in an early stage, no compound has entered clinical studies, and only a few companies have relevant patent publications in this field, for example Mirati Therapeutics company filed an inhibitor patent on KRAS-G12D (WO 2021041671).
PROTAC (proteolysis targeting chimera) is a double-function compound capable of simultaneously combining target protein and E3 ubiquitin ligase, and the compound can be recognized by a proteasome of a cell to cause degradation of the target protein, so that the content of the target protein in the cell can be effectively reduced. By introducing ligands capable of binding different targeting proteins into the PROTAC molecule, the application of the PROTAC technology to the treatment of various diseases has become possible, and this technology has received a great deal of attention in recent years.
Accordingly, there is a need to develop a compound capable of degrading KRAS G12D protein for the treatment of related diseases caused by KRAS G12D mutation.
Disclosure of Invention
The invention develops a PROTAC compound which has novel structure, good drug effect, high bioavailability and safer property, can inhibit or degrade KRAS G12 inhibitor and E3 ubiquitin ligase, and is used for treating KRAS-related diseases.
The invention provides a compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, wherein the compound is selected from compounds shown in a general formula (I),
B-L-K(I)；
in certain embodiments, L is selected from a bond or-C 1-50 Hydrocarbyl-, having from 0 to 20 methylene units in said hydrocarbyl optionally further replaced by-Ak-, -Cy-;
in certain embodiments, L is selected from a bond or-C 1-20 Hydrocarbyl-, having from 0 to 20 methylene units in said hydrocarbyl optionally further replaced by-Ak-, -Cy-;
in certain embodiments, L is selected from a bond or-C 1-10 Hydrocarbyl-, having from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) methylene units in the hydrocarbyl group optionally further replaced by-Ak-, -Cy-;
in certain embodiments, each-Ak-is independently selected from Ak1, ak2, ak3, ak4, or Ak5;
in certain embodiments, each-Ak-is independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(＝O)-、-NR L (CH 2 ) q C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-(CH 2 ) q -、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -、-CH＝CH-、-Si(R L ) 2 -、-Si(OH)(R L )-、-Si(OH) 2 -、-P(＝O)(OR L )-、-P(＝O)(R L )-、-S-、-S(＝O)-、-S(＝O) 2 -or a bond, said-CH 2 Optionally further 0 to 2 (e.g. 0, 1 or 2) are selected from H, halogen, OH, CN, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Substituted by alkyl;
in certain embodiments, each-Cy-is independently selected from Cy1, cy2, cy3, cy4, or Cy5;
in certain embodiments, each-Cy-is independently selected from the group consisting of a bond, a 4-8 membered heteromonocyclic ring, a 4-10 membered heteroacene ring, a 5-12 membered heterospiro ring, a 7-10 membered heterobridged ring, a 3-7 membered monocycloalkyl group, a 4-10 membered heterocycloalkyl group, a 5-12 membered spirocycloalkyl group, a 7-10 membered bridged cycloalkyl group, a 5-10 membered heteroaryl group, or a 6-10 membered aryl group, said aryl group, heteroaryl group, cycloalkane Optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) of radicals, heteromonocyclic, heterobicyclic, heterospiro or heterobridged rings are selected from H, F, cl, br, I, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing from 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally further substituted with 0, 1, or 2 = O;
in certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from the group consisting of a bond, a 4-7 membered heteromonocyclic ring, a 4-10 membered heteroacene, a 5-12 membered heterospiro ring, a 7-10 membered heterobridged ring, a 3-7 membered monocycloalkyl, a 4-10 membered cycloalkyl, a 5-12 membered spirocycloalkyl, a 7-10 membered bridged cycloalkyl, a 5-10 membered heteroaryl, or a 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic ring, heteroacene, heterospiro ring, or heterobridged ring optionally further being 0 to 4 (e.g., 0, 1, 2, 3, or 4) selected from H, F, cl, br, I, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing from 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally further substituted with 0, 1, or 2 = O;
In some embodiments of the present invention, in some embodiments, L is selected from the group consisting of-Cy 1-Cy2-Ak2-Cy3-Cy4-Ak 4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak 5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak 1-2-Ak 2-Ak3-Cy3-Cy4-Ak 5-; -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy 1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5- -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak 2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy 3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy 4-Ak4-Ak5-, -1-Cy 2-Cy3-Ak2-Ak 3-Cy4-Ak4-Ak 5-; -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak 4-Ak5-Cy1-Cy2-Cy3-Cy 2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5- -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy 4-; -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy 4-; -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy 3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy 4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4- Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;
In some embodiments of the present invention, in some embodiments, L is selected from the group consisting of-Cy 1-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-Ak2-, cy1-Ak1-Ak2-, cy1-Cy2-, cy1-Ak 2-, cy1-Cy2-, cy2-Cy 2, and Cy 1-Cy-Cy 1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak 4-; -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak 3-, -Cy1-Ak1-Cy2-Ak 3-, -Cy1-Ak 2-Ak3-, -Cy2-Cy3-Ak3-Ak4- -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy 4-, -Cy1-Ak1-Cy2-Ak 3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Ak 3-; -Ak1-Ak2-Cy3-Ak3-Ak4-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy 4-Cy5-, -Ak1-Cy2-Ak2-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak 4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5- -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak 5-; -Ak1-Cy2-Ak 3-Ak4-Ak5-, -Ak1-Cy2-Ak 3-Ak4-, -Ak1-Cy2-Ak 3-;
In certain embodiments, L is selected from the group consisting of-Cy 1-, -Cy1-Ak1-Cy2-, -Ak1-Ak2-Cy3-Ak3-, -Ak1-Ak2-Cy3-Ak 4-, ak1-Cy2-Ak2-, -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;
in certain embodiments, L is selected from the group consisting of-Ak 1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-;
in certain embodiments L is selected from a bond or a group wherein the left side of the group is attached to B;
in certain embodiments, ak1, ak2, ak3, ak4, ak5 are each independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-(CH 2 ) q -、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -or a bond, said-CH 2 Optionally further 0 to 2 (e.g. 0, 1 or 2) are selected from H, halogen, OH, CN, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Substituted by alkyl;
in certain embodiments, ak1, ak2, ak3, ak4, ak5 are each independently selected from-O-、-OCH 2 -、-CH 2 O-、-OCH 2 CH 2 -、-CH 2 CH 2 O-、-C≡C-、-C(CH 3 ) 2 -、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-N(CH 3 )-、-NH-、-CH 2 N(CH 3 )-、-CH 2 NH-、-NHCH 2 -、-CH 2 CH 2 N(CH 3 )-、-CH 2 CH 2 NH-、-NHCH 2 CH 2 -、-C(＝O)CH 2 -、-C(＝O)-、-C(＝O)CH 2 NH-、-CH 2 C (=o) NH-, -C (=o) NH-or-NHC (=o) -;
in certain embodiments, ak1, ak2, ak3, ak4, ak5 are each independently selected from the group consisting of-O-, -OCH 2 -、-CH 2 O-、-OCH 2 CH 2 -、-CH 2 CH 2 O-、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -, -C (=O) -or-C (=O) CH 2 -；
In certain embodiments, R L Each independently selected from H, C 1-6 Alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl;
In certain embodiments, R L Each independently selected from H or C 1-6 An alkyl group;
in certain embodiments, R L Each independently selected from H or C 1-4 An alkyl group;
in certain embodiments, R L Each independently from H, methyl or ethyl;
in certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexenyl, piperidine, morpholine, piperazine, phenyl, cyclopropyl-and-cyclopropyl, cyclopropyl-and-cyclobutyl, cyclobutyl-and-cyclopentyl, cyclobutyl-and-cyclohexyl, cyclopentyl-and-cyclopentyl, cyclopentyl-and-cyclohexyl, cyclohexyl-and-cyclohexyl, cyclopropyl-and-cyclobutyl, cyclopropyl-and-spirobutyl, cyclopropyl-and-spirocyclopentyl, cyclopropyl-and-spirocyclohexyl, cyclobutyl-and-spirobutyl, cyclobutyl-and-spiropentyl, cyclobutyl-and-spirohexyl, cyclopentyl-and-spirocyclohexyl, cyclohexyl-and-spirocyclohexyl, cyclopropyl-and-azacyclobutyl, cyclopropyl-and-azacyclohexyl, cyclopropyl-and-piperidine, cyclobutyl-and-azacyclobutyl, cyclobutyl-and-azacyclopentyl cyclobutyl azetidine, cyclobutyl piperidine, cyclopentyl azetidine, cyclopentyl piperidine, cyclohexyl azetidine, cyclohexyl-azetidinyl, azetidinyl-hexyl cyclohexyl-azacyclopentyl, cyclohexyl-azacyclohexyl, cyclohexyl-azapiperidine azetidinoazetidines, azetidinoazelohexyl, azetidines, azetidin, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl cyclohexyl spiro-azacyclohexyl, azetidinyl-azacyclopentyl azetidinyl spiro azetidinyl, azacyclopentyl spiroazacyclopentyl, azacyclopentyl spiroazacyclohexyl, azacyclohexyl spiroazacyclobutyl, azacyclohexyl spiroazacyclopentyl, azacyclohexyl spiroazacyclohexyl, cyclobutylspiropiperidine, cyclopentyl spiropiperidine, cyclohexyl spiropiperidine, azacyclobutylspiropiperidine, azacyclopentyl spiropiperidine, azacyclohexyl spiropiperidine, azanyl spiropiperidine,
in certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups:
in certain embodiments, K is selected from
In certain embodiments, K is selected from
in certain embodiments, K is selected from
In certain embodiments, each Q is independently selected from the group consisting of bond, -O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 3-12 membered heterocyclyl, said heterocyclyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, each Q is independently selected from the group consisting of-O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 4-7 membered heterocyclyl group, said heterocyclyl group optionallyFurther from 0 to 4 (e.g. 0, 1,2,3, 4) are selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 (e.g., 1,2,3, 4) heteroatoms selected from O, S, N;
in certain embodiments, R q Selected from H or C 1-6 An alkyl group;
in certain embodiments, R q Selected from H or C 1-4 An alkyl group;
in certain embodiments, R q Selected from H, methyl, ethyl;
in certain embodiments, E is each independently selected from C 3-10 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 (e.g. 1,2,3, 4) heteroatoms selected from O, S, N;
in certain embodiments, E is each independently selected from C 3-8 A carbocycle, a benzene ring, a 4-7 membered heterocycle, an 8-12 membered heterocycle, a 7-12 membered heteroaryl or a 5-6 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 (e.g. 1,2,3, 4) heteroatoms selected from O, S, N;
in certain embodiments, each E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl, oxazolyl, indolinyl, isoindolinyl, 1,2,3, 4-tetrahydroquinolinyl, or 1,2,3, 4-tetrahydroisoquinolinyl;
In certain embodiments, each E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl, or oxazolyl;
in certain embodiments, each E is independently selected from phenyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl;
in certain embodiments, each E is independently selected from a benzene ring or a pyridine ring;
in certain embodiments, A is selected from C 3-10 Carbocyclyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 (e.g. 1, 2, 3 or 4) heteroatoms selected from O, S, N;
in certain embodiments, A, H or H2 are each independently selected from C 3-8 A carbocycle, benzene ring, 4-7 membered heterocycle or 5-6 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 (e.g. 1, 2, 3 or 4) heteroatoms selected from O, S, N;
in certain embodiments, A, H or H2 are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl, or oxazolyl;
in certain embodiments, A, H1 or H2 are each independently selected from phenyl or pyridinyl;
In certain embodiments, F is each independently selected from C 3-20 Carbocyclyl, C 6-20 Aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 (e.g. 1, 2,3, 4) heteroatoms selected from O, S, N;
in certain embodiments, each F is independently selected from 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 5-10 membered bridged cycloalkyl, 4-7 membered heteromonocyclic, 4-10 membered heterobicyclic, 5-12 membered heterospirocyclic, 5-10 membered heterobridged ring, C 6-14 Aryl or 5-10 membered heteroaryl, said heteromonocyclic, heterobicyclic, heterospiro, heterobridged, or heteroaryl containing 1 to 4 (e.g., 1, 2,3, 4) heteroatoms selected from O, S, N;
in some embodiments of the present invention, in some embodiments, F is each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridinyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, azacyclopentyl, piperidinyl, morpholinyl, pyridonyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl or pyrazinopyrazinyl;
In certain embodiments, R k2 Each independently selected from the group consisting of bond, -CO-, -SO 2 -, -SO-or-C (R) k3 ) 2 -；
In certain embodiments, R k2 Each independently selected from-CO-, -SO 2 -or-C (R) k3 ) 2 -；
In certain embodiments, R k1 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally further being 0 to 4 (e.g. 0, 1, 2, 3, 4) selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R k3 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, R k1 、R k3 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CF 3 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further selected from H, F, cl, br, I, OH, NH by 0 to 4 (e.g. 0, 1, 2, 3 or 4) 2 Is substituted by a substituent of (2);
in certain embodiments, R k1 、R k3 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CF 3 、CN、COOH、CONH 2 Methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, optionally further from 0 to 4 (e.g. 0, 1, 2, 3 or 4) being selected from H, F, cl, br, I, OH, NH 2 Is substituted by a substituent of (2);
in certain embodiments, two R' s k3 And the carbon atoms or ring skeletons directly linked to each other form together a 3-8 membered carbocycle or 3-8 membered heterocycle, said carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocycle containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, two R' s k3 And the carbon atoms or ring skeletons directly linked to each other together form a 3-6 membered carbocycle or 3-7 membered heterocycle, said carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocycle containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;
In certain embodiments, R k4 Each independently selected from H, OH, NH 2 、CN、CONH 2 、C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclylOptionally further selected from H, F, cl, br, I, OH, = O, NH by 0 to 4 (e.g. 0, 1, 2, 3, 4) 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, R k4 Each independently selected from H, OH, NH 2 、CF 3 、CN、C 1-4 An alkyl group;
in certain embodiments, R k5 Each independently selected from CO, CH 2 、SO 2 、
In certain embodiments, R k6 Each independently selected from CO, CH, SO, SO 2 、CH 2 Or N;
in certain embodiments, R k7 Each independently selected from CO, CH, N, CH 2 、O、S、N(CH 3 ) Or NH;
in certain embodiments, R k7 Each independently selected from CH 2 、O、N(CH 3 ) Or NH;
in certain embodiments, R k8 Each independently selected from C, N or CH;
in certain embodiments, R k9 Each independently selected from CO, SO 2 Or CH (CH) 2 ；
In certain embodiments, M 1 Selected from the group consisting of bond, -C (=O) NH-, -NHC (=O) -, -CH 2 -C(＝O)NH-、-C(＝O)CH 2 NH-, 5-6 membered heteroaryl, said heteroaryl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) selected from H, F, cl, br, I, OH, = O, CF 3 、NH 2 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Substituted with an alkoxy substituent, said heteroaryl containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, M1 is selected from the group consisting of a bond, -C (=o) NH-, -CH 2 -C(＝O)NH-、-C(＝O)CH 2 NH-, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl; in certain embodiments, M 2 Selected from-NHC (=o) -C 1-6 Alkyl, -NHC (=o) -C 3-6 Cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, M 2 Selected from-NHC (=o) -C 1-4 Alkyl, -NHC (=o) -C 3-6 Cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
In certain embodiments, M 2 Selected from-NHC (=O) -CH 3 -NHC (=o) -cyclopropyl, -NHC (=o) -cyclobutyl, azetidinyl, benzazetidinyl, optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, M 3 Selected from-NH-or-O-;
in certain embodiments, R k10 Selected from C 1-6 Alkyl optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) alkyl groups selected from H, F, cl, br, I, =o, OH, C 1-6 Alkyl or C 3-6 Substituted cycloalkyl;
in certain embodiments, R k10 Selected from C 1-4 Alkyl optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, C 1-4 Alkyl or C 3-6 Substituted cycloalkyl;
in certain embodiments, R k10 Selected from methyl, ethyl, isopropyl, propyl, tert-butyl, said methyl, ethyl, isopropyl, propyl, tert-butyl optionally further being 0 to 4 selected from H, F, cl, br, I, =o, OH, C 1-4 Alkyl or C 3-6 Substituted cycloalkyl;
in certain embodiments, G is selected from 6-10 membered aryl or 5-10 membered heteroaryl, optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) selected from H, F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl group substituted with a substituent, the heteroaryl group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, S;
in certain embodiments, R k11 Each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylthio or-O-C (=o) -C 1-6 Alkyl, said alkyl, alkoxy or alkylthio optionally further being selected from H, F, cl, br, I, OH, C by 0 to 4 (e.g. 0, 1, 2, 3, 4) 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R k11 Each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-4 Alkyl, C 1-4 Alkoxy or C 1-4 Alkylthio or-O-C (=o) -C 1-4 Alkyl, said alkyl, alkoxy or alkylthio being optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
In some casesIn embodiments, R k11 Each independently selected from H, F, cl, br, I, =o, OH, SH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio or-O-C (=o) -CH 3 Said methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio optionally further being 0 to 4 groups selected from H, F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R k12 、R k13 Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R k12 、R k13 Each independently selected from H, C 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R k12 、R k13 Each independently selected from H, methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl, optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R k14 Selected from 5-6 membered heteroaryl, optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) selected from H, F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl radicalsSubstituted with substituents of (a) said heteroaryl containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, S;
in certain embodiments, R k14 Selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl, pyridyl, pyridazinyl, pyrazinyl, or pyrimidinyl, said pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl, pyridyl, pyridazinyl, pyrazinyl, or pyrimidinyl optionally further being 0 to 4 selected from H, F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
in certain embodiments, K is selected from the group in table a, the left side of the group being attached to L;
In certain embodiments, K is selected from one of the following structural fragments:
in certain embodiments, K is selected from one of the following structural fragments:
in certain embodiments, B is selected from
In certain embodiments, B is selected from
In certain embodiments, a is selected from 0, 1, 2, 3, or 4;
in certain embodiments, B is selected from
In certain embodiments, b is selected from 0, 1, 2, 3, or 4;
in certain embodiments, B is selected from
In certain embodiments, ring W is selected from 7 to 12 membered heterocycles or C 7-10 A carbocycle, said heterocycle or carbocycle being selected from one of the following groups, saturated or partially saturated: a monocyclic, parallel, bridged or spiro ring, said heterocyclic or carbocyclic ring optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) R a A substitution, said heterocycle containing from 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;
in some embodiments of the present invention, in some embodiments,
selected from one of the following unsubstituted or substituted: />
in some embodiments of the present invention, in some embodiments,
selected from->
In certain embodiments, Z 1 、Z 2 Each independently selected from C or N;
in certain embodiments, Z 1 When selected from N, X 2 Selected from the group consisting of a bond;
in certain embodiments, Z 1 When selected from C, X 2 Selected from bonds or NR x ；
In certain embodiments, Z 1 When selected from C, X 2 Selected from the group consisting of a bond;
in certain embodiments, Z 1 When selected from C, X 2 Selected from NR x ；
In certain embodiments, X 1 Each independently selected from bond, O, -OCH 2 -、-CH 2 O-or NR x ；
In certain embodiments, X 1 Selected from bonds, O or NR x ；
In certain embodiments, B is selected from
In certain embodiments, R x Selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
in certain embodiments, R x Selected from H or C 1-4 An alkyl group;
in certain embodiments, R x Selected from H, methyl or ethyl;
in certain embodiments, R 1 Selected from H, halogen, OH, cyano, CF 3 、NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy optionallyFurther from 0 to 4 (e.g. 0, 1, 2, 3, 4) are selected from halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
in certain embodiments, R 1 Selected from H, F, cl, br, I, OH, NH 2 、-NHCH 3 、-N(CH 3 ) 2 Cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy optionally further being 0 to 4 (e.g. 0, 1, 2, 3, 4) selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R 1 Selected from H, F, cl, br, I, OH, cyano, methyl, ethyl, propyl, isopropyl;
in certain embodiments, R 1 Selected from H, F, cl, br, methyl, ethyl, propyl, isopropyl;
in certain embodiments, R a Each independently selected from H, halogen, OH, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 (v), =o, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
in certain embodiments, any two R' s a Directly connected to form C 3-6 Carbocycles or 3-to 8-membered heterocycles, said carbocycles or heterocycles optionally being further substituted with 1 to 4 groups selected from halogen, OH, cyano, CF 3 、COOH、NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
in certain embodiments, R a Each independently selected from H, F, cl, br, I, OH, NH 2 、-NHCH 3 、-N(CH 3 ) 2 (c) =o, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy optionally further being 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、-NHCH 3 、-N(CH 3 ) 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, any two R' s a Directly connecting to form cyclopropyl and cyclobutyl;
in certain embodiments, Y 1 Each independently selected from N, CH or C (C) 1-4 Alkyl) optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
in certain embodiments, Y 1 Each independently selected from N, CH or C (C) 1-4 An alkyl group);
in certain embodiments, Y 1 Each independently selected from N or CH;
in certain embodiments, Y 2 Each independently selected from N, CH or CR Y ；
In certain embodiments, Y 2 Each independently selected from N, CH, C (Cl) or C (F);
in certain embodiments, R Y Selected from H, halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
in certain embodiments, R Y Selected from H, halogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
In certain embodiments, R Y Selected from H, F, cl, br, I, methyl, ethyl, cyclopropyl;
in certain embodiments, R 2 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, - (CH) 2 ) q -3 to 12 membered heterocycle or- (CH) 2 ) q -C 3-10 Carbocycles, said CH 2 Optionally further substituted with 0 to 4R 2a A substitution, said heterocycle containing from 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, R 2 Selected from C 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) q -4-7 membered heteromonocyclic, - (CH) 2 ) q -4-10 membered hybrid ring, - (CH) 2 ) q -5-12 membered heterospiro, - (CH) 2 ) q -7-10 membered heterobridged ring, - (CH) 2 ) q -3-7 membered monocycloalkyl- (CH) 2 ) q -, 4-10 membered cycloalkyl, - (CH) 2 ) q -5-12 membered spirocycloalkyl or- (CH) 2 ) q -7-10 membered bridged cycloalkyl, said CH 2 Optionally further substituted with 0 to 4R 2a A substitution, said heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, R 2a Each independently selected from H, halogen, = O, OH, cyano, COOH, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocycle or 3-to 12-membered heterocycle, said alkyl, alkoxy, carbocycle, heterocycle optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl;
in certain embodiments, R 2a Each independently selected from H, halogen, = O, OH, cyano, CF 3 、C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycle or 3-to 6-membered heterocycle, said alkyl, alkoxy, carbocycle, heterocycle optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R 2a Each independently selected from H, F, cl, br, I, = O, OH, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further being 0 to 4 selected from H, F, cl, br, I, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R 2a Each independently selected from H, F, cl, br, I, = O, OH, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy;
in certain embodiments, R 4 Selected from C 1-6 Alkyl, C 3-10 Carbocyclyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl or 5 to 10 membered heteroaryl, said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl optionally being further substituted with 0 to 5R 4a A substitution, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, R 4 Selected from C 6-10 Carbocyclyl, 6-to 10-membered heterocyclyl, C 6-10 Aryl or 5-to 10-membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroaryl optionally being further substituted with 0 to 5R 4a A substitution, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, R 4 Selected from one of the following substituted or unsubstituted: phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolylIndazole, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, pyridinyl, when substituted, are optionally further substituted with 0 to 5R 4a Substitution;
in certain embodiments, R 4 Selected from one of the following substituted or unsubstituted: phenyl, naphthyl, benzimidazolyl, benzothiazolyl, benzopyrazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, pyridinyl, when substituted, are optionally further substituted with 0 to 5 (e.g. 0, 1, 2, 3, 4 or 5) selected from H, F, cl, br, I, OH, NH 2 Cyano, CF 3 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkylthio, C 2-4 Alkynyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, said heterocycloalkyl containing 1 to 2 heteroatoms selected from O, S, N;
in certain embodiments, R 4 Selected from one of the following substituted or unsubstituted: phenyl, naphthyl, benzothiazolyl, pyridinyl, benzopyrazolyl, optionally further substituted with 0 to 5 (e.g. 0, 1, 2, 3, 4 or 5) selected from H, F, cl, br, I, OH, NH 2 Cyano, CF 3 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkylthio, C 2-4 Alkynyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, said heterocycloalkyl containing 1 to 2 heteroatoms selected from O, S, N;
in certain embodiments, R 4 Selected from one of the following substituted or unsubstituted: phenyl, naphthyl, benzimidazolyl, benzothiazolyl, benzopyrazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, pyridinyl, when substituted, are optionally further substituted with 0 to 5 (e.g. 0, 1, 2, 3, 4 or 5) selected from H, F, cl, br, I, OH, NH 2 Cyano, CF 3 Methyl, ethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxyDifluoromethoxy, monofluoromethoxy, -SCH 3 、-SCH 2 CH 3 Acetylene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, morpholine, piperazine, oxetanyl, oxepinyl;
in certain embodiments, R 4a Each independently selected from H, halogen, = O, OH, cyano, CF 3 、COOH、NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 6-10 Aryl or 5-to 10-membered heteroaryl, said alkyl, alkoxy, alkylthio, alkynyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, said heterocycloalkyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, R 4a Each independently selected from H, halogen, = O, OH, cyano, CF 3 、NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 Alkynyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, phenyl or 5-to 6-membered heteroaryl, said alkyl, alkoxy, alkylthio, alkynyl, alkenyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl, C 1-4 Substituted with an alkoxy substituent, said heterocycloalkyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, R 4a Each independently selected from H, halogen,OH、NH 2 Cyano, CF 3 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 2-4 Alkynyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl or 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, alkylthio, alkynyl, alkenyl, cycloalkyl, heterocycloalkyl optionally being further substituted by 0 to 4 members selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl, C 1-4 Substituted with an alkoxy substituent, said heterocycloalkyl containing 1 to 2 heteroatoms selected from O, S, N;
in certain embodiments, R 4a Each independently selected from H, F, cl, br, I, OH, NH 2 Cyano, CF 3 Methyl, ethyl, isopropyl, methoxy, ethoxy, -OCF 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl;
In certain embodiments, R 4a Each independently selected from H, F, cl, OH, cyano, CF 3 Ethynyl;
in certain embodiments, R 3 、R 5 Each independently selected from H, halogen, OH, cyano, COOH, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkynyl, C 2-6 Alkenyl, C 4-7 Heterocyclyl, C 3-6 Cycloalkyloxy or C 3-6 Cycloalkyl, said alkyl, alkoxy, alkylthio, alkynyl, alkenyl, heterocyclyl, cycloalkyloxy or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 4-7 Heterocyclyl or C 3-6 Substituted cycloalkyl;
in certain embodiments, R 3 、R 5 Each independently selected from H, halogen, OH, cyano, COOH, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 2-4 Alkynyl, C 2-4 Alkenyl, C 4-7 Heterocyclyl, C 3-6 Cycloalkyl oxyOr C 3-6 Cycloalkyl, said alkyl, alkoxy, alkylthio, alkynyl, alkenyl, heterocyclyl, cycloalkyloxy or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R 3 、R 5 Each independently selected from H, F, cl, br, I, OH, cyano, CF 3 Methyl, ethyl, cyclopropyl, cyclopropyloxy or methoxy;
In certain embodiments, R 3 、R 5 Each independently selected from H, methyl, ethyl, cyclopropyl, methoxy, or F;
in certain embodiments, R 3 Selected from H or F;
in certain embodiments, R 5 Selected from methyl, ethyl, cyclopropyl, methoxy;
in certain embodiments, B is selected from
In certain embodiments, q is each independently selected from 0, 1, 2, 3, 4, 5, or 6;
in certain embodiments, q is each independently selected from 0, 1, 2, 3, or 4;
in certain embodiments, q is each independently selected from 0, 1, or 2;
in certain embodiments, n1, n2, n3 are each independently selected from 0, 1, 2, or 3;
in certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, 3, 4, or 5;
in certain embodiments, p1 or p2 are each independently selected from 0, 1, or 2.
As a first embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
B-L-K(I)；
l is selected from a bond or-C 1-50 Hydrocarbyl-, having from 0 to 20 methylene units in said hydrocarbyl optionally further replaced by-Ak-, -Cy-;
each-Ak-is independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(＝O)-、-NR L (CH 2 ) q C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-(CH 2 ) q -、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -、-CH＝CH-、-Si(R L ) 2 -、-Si(OH)(R L )-、-Si(OH) 2 -、-P(＝O)(OR L )-、-P(＝O)(R L )-、-S-、-S(＝O)-、-S(＝O) 2 -or a bond, said-CH 2 Optionally further 0 to 2 are selected from H, halogen, OH, CN, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Substituted by alkyl;
q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;
R L each independently selected from H, C 1-6 Alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl;
each-Cy-is independently selected from the group consisting of a bond, 4-8 membered heteromonocyclic ring, 4-10 membered heterobicyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered heterocycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl, or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic ring, heterofused ring, heterospiro ring, or heterobridged ring optionally further being 0 to 4 selected from H, F, cl, br, I, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing from 1 to 4 heteroatoms selected from O, S, N, optionally further substituted with 0, 1, or 2 = O when the heteroatom is selected from S;
b is selected from
R 1 Selected from H, halogen, OH, cyano, CF 3 、NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
ring W is selected from 7-to 12-membered heterocyclic ring or C 7-10 A carbocycle, said heterocycle or carbocycle being selected from one of the following groups, saturated or partially saturated: a monocyclic, parallel, bridged or spiro ring, said heterocyclic or carbocyclic ring optionally being further substituted with 0 to 4R a A substitution, said heterocycle containing from 1 to 4 heteroatoms selected from O, S, N;
R a each independently selected from H, halogen, OH, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 (v), =o, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
alternatively, any two R a Directly connected to form C 3-6 Carbocycles or 3-to 8-membered heterocycles, said carbocycles or heterocycles optionally being further substituted with 1 to 4 groups selected from halogen, OH, cyano, CF 3 、COOH、NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
Z 1 、Z 2 each independently selected from C or N;
when Z is 1 When selected from N, X 2 Selected from the group consisting of a bond;
when Z is 1 When selected from C, X 2 Selected from bonds or NR x ；
X 1 Each independently selected from bond, O, -OCH 2 -、-CH 2 O-or NR x ；
Y 1 Each independently selected from N, CH or C (C) 1-4 Alkyl) optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
Y 2 each independently selected from N, CH or CR Y ；
R Y Selected from H, halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
R x selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
R 2 selected from C 1-6 Alkyl, C 1-6 Alkoxy, - (CH) 2 ) q -3 to 12 membered heterocycle or- (CH) 2 ) q -C 3-10 Carbocycles, said CH 2 Optionally further substituted with 0 to 4R 2a A substitution, said heterocycle containing from 1 to 4 heteroatoms selected from O, S, N;
R 2a each independently selected from H, halogen, = O, OH, cyano, COOH, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocycle or 3-to 12-membered heterocycle, said alkyl, alkoxy, carbocycle, heterocycle optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl;
R 4 selected from C 1-6 Alkyl, C 3-10 Carbocyclyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl or 5 to 10 membered heteroaryl, said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl optionally being further substituted with 0 to 5R 4a A substitution, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
R 4a each independently selected from H, halogen, = O, OH, cyano, CF 3 、COOH、NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 6-10 Aryl or 5-to 10-membered heteroaryl, said alkyl, alkoxy, alkylthio, alkynyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, said heterocycloalkyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
R 3 、R 5 each independently selected from H, halogen, OH, cyano, COOH, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkynyl, C 2-6 Alkenyl, C 4-7 Heterocyclyl, C 3-6 Cycloalkyloxy or C 3-6 Cycloalkyl, said alkyl, alkoxy, alkylthio, alkynyl, alkenyl, heterocyclyl, cycloalkyloxy or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 4-7 Heterocyclyl or C 3-6 Substituted cycloalkyl;
k is selected from
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Q is each independently selected from the group consisting of bond, -O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 3-12 membered heterocyclyl, said heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
R q selected from H or C 1-6 An alkyl group;
a is selected from C 3-10 Carbocyclyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
f are each independently selected from C 3-20 Carbocyclyl, C 6-20 Aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
R k2 each independently selected from the group consisting of bond, -CO-, -SO 2 -, -SO-or-C (R) k3 ) 2 -；
R k1 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k3 each independently selected from H, F,Cl、Br、I、OH、＝O、NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
or two R k3 And the carbon atoms or ring skeletons directly linked to each other together form a 3-8 membered carbocycle or 3-8 membered heterocycle, said carbocycle or heterocycle optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;
R k4 each independently selected from H, OH, NH 2 、CN、CONH 2 、C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
M 1 selected from the group consisting of bond, -C (=O) NH-, -NHC (=O) -, -CH 2 -C(＝O)NH-、-C(＝O)CH 2 NH-, 5-6 membered heteroaryl, said heteroaryl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, CF 3 、NH 2 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Substituted with an alkoxy substituent, said heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
M 2 selected from-NHC (=o) -C 1-6 Alkyl, -NHC (=o) -C 3-6 Cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl being anyOptionally further 0 to 4 are selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
M 3 selected from-NH-or-O-;
R k10 selected from C 1-6 Alkyl optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, C 1-6 Alkyl or C 3-6 Substituted cycloalkyl;
R k11 each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylthio or-O-C (=o) -C 1-6 Alkyl, said alkyl, alkoxy or alkylthio being optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k12 、R k13 each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k14 selected from 5-6 membered heteroaryl, optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl substituent, said heteroaryl containing 1 to 4 heteroatoms selected from N, O, S;
g is selected from 6-10 membered aryl or 5-10 membered heteroaryl, said aryl or heteroaryl optionally further being 0 to 4 selected from H, F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted with a cycloalkyl substituent, said heteroaryl containing 1 to 14 heteroatoms selected from N, O, S;
n1, n2, n3 are each independently selected from 0, 1, 2 or 3;
p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.
As a second embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
l is selected from the group consisting of-Cy 1-Cy2-Ak2-Cy3-Cy4-Ak 4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak 5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak 1-2-Ak 2-Ak3-Cy3-Cy4-Ak 5-; -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak 5-; -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5- -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak 5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak 5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak2-Ak 3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -1-Ak 2-Ak3-Ak4-Ak 2-Cy3-Cy4-Ak 5-; -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak 2-Cy 5-Cy1-Cy 2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5- -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy 2-Ak3-Ak4-Ak5-Cy3-Cy 4-; -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy 3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy 4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4- Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;
Ak1, ak2, ak3, ak4, ak5 are each independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 )q-NR L C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-(CH 2 ) q -、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -or a bond, said-CH 2 Optionally further 0 to 2 are selected from H, halogen, OH, CN, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Substituted by alkyl;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from the group consisting of a bond, 4-7 membered heteromonocyclic ring, 4-10 membered heterobicyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered heterocycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic ring, heterofused ring, heterospiro ring or heterobridged ring optionally further being selected from 0 to 4 from H, F, cl, br, I, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing from 1 to 4 heteroatoms selected from O, S, N, optionally further substituted with 0, 1, or 2 = O when the heteroatom is selected from S;
q is each independently selected from 0, 1, 2, 3 or 4;
R L each independently selected from H or C 1-6 An alkyl group;
B is selected from
a is selected from 0, 1, 2, 3 or 4;
X 1 selected from bonds, O or NR x ；
R x Selected from H or C 1-4 An alkyl group;
Y 1 each independently selected from N, CH or C (C) 1-4 An alkyl group);
R Y selected from H, halogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R 2a each independently selected from H, halogen, = O, OH, cyano, CF 3 、C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycle or 3-to 6-membered heterocycle, said alkyl, alkoxy, carbocycle, heterocycle optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R 3 、R 5 each independently selected from H, halogen, OH, cyano, COOH, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 2-4 Alkynyl, C 2-4 Alkenyl, C 4-7 Heterocyclyl, C 3-6 Cycloalkyloxy or C 3-6 Cycloalkyl, said alkyl, alkoxy, alkylthio, alkynyl, alkenyl, heterocyclyl, cycloalkyloxy or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R 4 selected from C 6-10 Carbocyclyl, 6-to 10-membered heterocyclyl, C 6-10 Aryl or 5-to 10-membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroaryl optionally being further substituted with 0 to 5R 4a A substitution, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
R 4a each independently selected from H, halogen, = O, OH, cyano, CF 3 、NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 Alkynyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, phenyl or 5-to 6-membered heteroaryl, said alkyl, alkoxy, alkylthio, alkynyl, alkenyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl, C 1-4 Substituted with an alkoxy substituent, said heterocycloalkyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
the remaining groups are as defined in the first embodiment of the invention.
As a third embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from the group consisting of a bond, a 4-7 membered nitrogen containing heteromonocyclic ring, a 4-10 membered nitrogen containing heteromonocyclic ring, a 5-12 membered nitrogen containing heterospiro ring, a 7-10 membered nitrogen containing heterobridged ring, a 3-7 membered monocycloalkyl, a 4-10 membered cycloalkyl, a 5-12 membered spirocycloalkyl, a 7-10 membered bridged cycloalkyl, a 5-10 membered heteroaryl or a 6-10 membered aryl, said heteromonocyclic ring, heterofused ring, heterobridged ring, heterospiro ring, cycloalkyl, aryl or heteroaryl optionally being further substituted with 0 to 4 members selected from H, F, cl, br, I, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteromonocyclic, heterobicyclic, heterobridged, heterospiro or heteroaryl group containing from 1 to 4 heteroatoms selected from O, S, N, optionally further substituted with 0, 1 or 2 = O when the heteroatoms are selected from S;
R L each independently selected from H or C 1-4 An alkyl group;
R 1 selected from H, F, cl, br, I, OH, NH 2 、-NHCH 3 、-N(CH 3 ) 2 Cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy optionally further being 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R a each independently selected from H, F, cl, br, I, OH, NH 2 、-NHCH 3 、-N(CH 3 ) 2 (c) =o, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy optionally further being 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、-NHCH 3 、-N(CH 3 ) 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
Alternatively, any two R a Directly connecting to form cyclopropyl and cyclobutyl;
R 2a each independently selected from H, F, cl, br, I, = O, OH, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentylOptionally further cyclohexyl is 0 to 4 selected from H, F, cl, br, I, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R 4 selected from one of the following substituted or unsubstituted: phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, indazole, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, pyridinyl, when substituted, are optionally further substituted with 0 to 5R 4a Substitution;
R 4a each independently selected from H, halogen, OH, NH 2 Cyano, CF 3 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 2-4 Alkynyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl or 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, alkylthio, alkynyl, alkenyl, cycloalkyl, heterocycloalkyl optionally being further substituted by 0 to 4 members selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl, C 1-4 Substituted with an alkoxy substituent, said heterocycloalkyl containing 1 to 2 heteroatoms selected from O, S, N;
R 3 、R 5 each independently selected from H, F, cl, br, I, OH, cyano, CF 3 Methyl, ethyl, cyclopropyl, cyclopropyloxy or methoxy;
R x selected from H, methyl or ethyl;
Y 1 each independently selected from N or CH;
R Y selected from H, F, cl, br, I, methyl, ethyl, cyclopropyl;
k is selected from
/>
M 2 selected from-NHC (=o) -C 1-4 Alkyl, -NHC (=o) -C 3-6 Cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
R k10 selected from C 1-4 Alkyl optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, C 1-4 Alkyl or C 3-6 Substituted cycloalkyl;
R k11 each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-4 Alkyl, C 1-4 Alkoxy or C 1-4 Alkylthio or-O-C (=o) -C 1-4 Alkyl, said alkyl, alkoxy or alkylthio being optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k12 、R k13 each independently selected from H, C 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
q is each independently selected from-O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 4-7 membered heterocyclyl, said heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Substituted by alkoxy, said heterocyclyl containing 1 to 4 substituents selected from O, S, NA heteroatom;
R q selected from H or C 1-4 An alkyl group;
R k1 、R k3 each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CF 3 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, NH 2 Is substituted by a substituent of (2);
or two R k3 And the carbon atoms or ring skeletons directly linked to each other together form a 3-6 membered carbocycle or a 3-7 membered heterocycle, said carbocycle or heterocycle optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;
R k4 each independently selected from H, OH, NH 2 、CF 3 、CN、C 1-4 An alkyl group;
R k5 each independently selected from CO, CH 2 、SO 2 、
R k6 Each independently selected from CO, CH, SO, SO 2 、CH 2 Or N;
R k7 each independently selected from CO, CH, N, CH 2 、O、S、N(CH 3 ) Or NH;
R k8 each independently selected from C, N or CH;
R k9 each independently selected from bond, CO, CH 2 、CH 2 CH 2 Or SO 2 ；
A. H1 or H2 are each independently selected from C 3-8 A carbocycle, benzene ring, 4-7 membered heterocycle or 5-6 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
e is each independently selected from C 3-8 Carbocycle, benzene ring, 4-7 membered heterocycleAn 8-12 membered heterocyclyl, 7-12 membered heteroaryl or 5-6 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
f is each independently selected from 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 5-10 membered bridged cycloalkyl, 4-7 membered heteromonocyclic, 4-10 membered heteroacene, 5-12 membered heterospirocyclic, 5-10 membered heterobridged ring, C 6-14 An aryl or 5-10 membered heteroaryl group, said heteromonocyclic, heterobicyclic, heterospiro, heterobridged, or heteroaryl group containing 1 to 4 heteroatoms selected from O, S, N;
the remaining groups are as defined in either of the first and second embodiments of the invention.
As a fourth embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
R L Selected from H, methyl or ethyl;
q is each independently selected from 0, 1 or 2;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclyl, azacyclohexenyl, piperidine, morpholine, piperazine, phenyl, cyclopropyl-and-cyclopropyl, cyclopropyl-and-cyclobutyl, cyclobutyl-and-cyclopentyl, cyclobutyl-and-cyclohexyl, cyclopentyl-and-cyclopentyl, cyclopentyl-and-cyclohexyl, cyclohexyl-and-cyclohexyl, cyclopropyl-and-cyclobutyl, cyclopropyl-and-spirocyclopentyl, cyclopropyl-and-spirocyclohexyl, cyclobutyl-and-spirobutyl, cyclobutyl-and-spirocyclopentyl, cyclobutyl-and-spirocyclohexyl, cyclopentyl-and-spirocyclopentyl, cyclopentyl-and-spirocyclohexyl, cyclohexyl-and-spirocyclohexyl, cyclopropyl-and-azacyclobutyl, cyclopropyl-and-azacyclohexyl, cyclopropyl-and-piperidine, cyclobutyl-and-azacyclobutyl, cyclobutyl-and-azacyclopentyl, cyclopentyl-and-azacyclohexyl, cyclopentyl-and-azacyclohexyl A group, a cyclopentylpiperidine, a cyclohexylazetidinyl group, a cyclohexylpiperidine, an azetidinyl group, a azetidinoazacyclopentyl, azetidinoazacyclohexyl, azetidinopiperidine, azetidinoazacyclobutyl, azetidine, azacyclopentyl-azacyclopentyl-, azacyclopentyl-azacyclohexyl-, azacyclopentyl-piperidine-, azacyclohexyl-azacyclobutyl-, azacyclohexyl-azacyclopentyl-, azacyclohexyl-, azacyclohexyl-piperidine-, cyclobutyl-spiroazetidinyl-, cyclobutyl-spiroazacyclopentyl-, cyclobutyl-spiroazetidinyl-, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl cyclohexyl spiro-azetidine, azetidinyl spiro-azetidine, azacyclopentyl spiroazacyclopentyl, azacyclopentyl spiroazacyclohexyl, azacyclohexyl spiroazacyclobutyl, azacyclohexyl spiroazacyclopentyl, azacyclohexyl spiroazacyclohexyl, cyclobutylspiropiperidine, cyclopentyl spiropiperidine, cyclohexyl spiropiperidine, azacyclobutylspiropiperidine, azacyclopentyl spiropiperidine, azacyclohexyl spiropiperidine, azanyl spiropiperidine, 
When substituted, optionally further substituted with 0 to 4 members selected from H, F, cl, br, I, OH, NH 2 、COOH、CN、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
b is selected from
b is selected from 0, 1, 2, 3 or 4;
R 1 selected from H, F, cl, br, I, OH, cyano, methyl, ethyl, propyl, isopropyl;
R 4a each independently selected from H, F, cl, br, I, OH, NH 2 Cyano, CF 3 Methyl, ethyl, isopropyl, methoxy, ethoxy, -OCF 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl;
R 2a each independently selected from H, F, cl, br, I, = O, OH, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy;
R 3 、R 5 each independently selected from H, methyl, ethyl, cyclopropyl, methoxy, or F;
R x selected from H, methyl or ethyl;
k is selected from
/>
M1 is selected from the group consisting of bond, -C (=O) NH-, -CH 2 -C(＝O)NH-、-C(＝O)CH 2 NH-, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl;
M 2 selected from-NHC (=O) -CH 3 -NHC (=o) -cyclopropyl, -NHC (=o) -cyclobutyl, azetidinyl, benzazetidinyl, said cyclopropyl, cyclobutyl, azetidinyl, benzazetidinyl or benzazetidinyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k10 selected from methyl, ethyl, isopropyl, propyl, tert-butyl, said methyl, ethyl, isopropyl, propyl, tert-butyl optionally further being 0 to 4 selected from H, F, cl, br, I, =o, OH, C 1-4 Alkyl or C 3-6 Substituted cycloalkyl;
R k11 each independently selected from H, F, cl, br, I, =o, OH, SH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio or-O-C (=o) -CH 3 Said methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio optionally further being 0 to 4 groups selected from H, F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k12 、R k13 each independently selected from H, methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl, optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
e is each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl;
Each a is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl;
f is each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridinyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, azacyclopentyl, piperidinyl, morpholinyl, pyridonyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl or pyrazinopyrazinyl;
R k7 Each independently selected from CH 2 、O、N(CH 3 ) Or NH;
p1 or p2 are each independently selected from 0, 1 or 2;
the remaining groups are as defined in any of the first, second and third embodiments of the invention.
As a fifth embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
b is selected from
R 1 Selected from H, F, cl, br, methyl, ethyl, propyl, isopropyl;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups:
k is selected from one of the following structural fragments:
the remaining groups are as defined in any of the first, second, third, fourth or fifth embodiments of the invention.
As a sixth embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
b is selected from
L is selected from the group consisting of-Cy 1-, -Cy1-Ak1-Ak2-Ak3-Ak 4-; -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak 4-; -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak 3-, -Cy1-Ak1-Cy2-Ak 3-, -Cy1-Ak 2-Ak3-, -Cy2-Cy3-Ak3-Ak4- -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy 4-, -Cy1-Ak1-Cy2-Ak 3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Ak 3-; -Ak1-Ak2-Cy3-Ak3-Ak4-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy 4-Cy5-, -Ak1-Cy2-Ak2-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak 4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5- -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak 5-; -Ak1-Cy2-Ak 3-Ak4-Ak5-, -Ak1-Cy2-Ak 3-Ak4-, -Ak1-Cy2-Ak 3-;
Ak1, ak2, ak3, ak4, ak5 are each independently selected from the group consisting of-O-, -OCH 2 -、-CH 2 O-、-OCH 2 CH 2 -、-CH 2 CH 2 O-、-C≡C-、-C(CH 3 ) 2 -、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-N(CH 3 )-、-NH-、-CH 2 N(CH 3 )-、-CH 2 NH-、-NHCH 2 -、-CH 2 CH 2 N(CH 3 )-、-CH 2 CH 2 NH-、-NHCH 2 CH 2 -、-C(＝O)-、-C(＝O)CH 2 -、-C(＝O)CH 2 NH-、-CH 2 C (=o) NH-, -C (=o) NH-or-NHC (=o) -;
the remaining groups are as defined in any of the first, second, third, fourth, fifth or sixth embodiments of the invention.
As a seventh embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,
b is selected from
L is selected from the group consisting of-Cy 1-, -Cy1-Ak1-Cy2-, -Ak1-Ak2-Cy3-Ak3-, -Ak1-Ak2-Cy3-Ak 4-, ak1-Cy2-Ak2-, -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;
or L is selected from the group consisting of-Ak 1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-;
ak1, ak2, ak3, ak4, ak5 are each independently selected from the group consisting of-O-, -OCH 2 -、-CH 2 O-、-OCH 2 CH 2 -、-CH 2 CH 2 O-、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -, -C (=O) -or-C (=O) CH 2 -；
The remaining groups are as defined in any of the first, second, third, fourth, fifth or sixth embodiments of the invention.
As an eighth embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
Cy1, cy2 or Cy3 are each independently selected from a bond or one of the following substituted or unsubstituted groups:
/>
the remaining groups are as defined in any of the first, second, third, fourth, fifth, sixth or seventh embodiments of the invention.
As a ninth embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
l is selected from a bond or a group wherein the left side of the group is attached to B;
the remaining groups are as defined in any of the first, second, third, fourth, fifth, sixth, seventh or eight embodiments of the invention.
As a tenth embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,
b is selected from
/>
K is selected from one of the following structural fragments:
the remaining groups are as defined in any of the first, second, third, fourth, fifth, sixth, seventh, eighth or nine embodiments of the present invention.
As an eleventh embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,
k is selected from one of the following structural fragments:
the remaining groups are as defined in any of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiments of the invention.
The present invention relates to a compound or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from one of the following structures:
table AK groups
The present invention relates to a pharmaceutical composition comprising a compound of the invention described above or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.
The invention relates to application of the compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic thereof in preparing medicines for treating diseases related to KRAS G12D activity or expression quantity.
The invention relates to an application of the compound or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectic crystals thereof in preparing medicines for treating and inhibiting or degrading KRAS G12D related diseases.
The invention relates to the use of the above-mentioned compounds of the invention or stereoisomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, characterized in that the disease is selected from cancers.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the invention each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include 16 O、 17 O and 18 isotopes of O, sulfur include 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen include 14 N and 15 isotopes of N, fluorine include 17 F and F 19 Isotopes of F, chlorine include 35 Cl and Cl 37 Isotopes of Cl, bromine include 79 Br and 81 Br。
"halogen" means F, cl, br or I.
"halo substituted" means F, cl, br or I substituted, including but not limited to 1 to 10 substituents selected from F, cl, br or I, 1 to 6 substituents selected from F, cl, br or I, 1 to 4 substituents selected from F, cl, br or I. "halo substituted" is simply referred to as "halo".
"alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group including, but not limited to, alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; alkyl groups appearing herein are defined in accordance with the present definition. The alkyl group may be monovalent, divalent, trivalent, or tetravalent.
"heteroalkyl" refers to a substituted or unsubstituted alkyl in which 1 or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms are replaced with a heteroatom (including but not limited to N, O or S). Non-limiting examples include-X (CH 2 )v-X(CH 2 )v-X(CH 2 ) v-H (v is an integer from 1 to 5, X are each independently selected from bonds or heteroatoms including, but not limited to N, O or S, and at least 1X is selected from heteroatoms, and N or S in the heteroatoms may be oxidized to various oxidation states). The heteroalkyl group may be monovalent, divalent, trivalent, or tetravalent.
"alkylene" means a substituted or unsubstituted straight and branched chain divalent saturated hydrocarbon radical, including- (CH) 2 ) v - (v is an integer of 1 to 10), alkylene examples include, but are not limited to, methylene, ethylene, propylene, butylene and the like.
"heteroalkylene" means a substituted or unsubstituted alkylene in which 1 or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms are replaced with a heteroatom (including but not limited to N, O or S). Non-limiting examples include-X (CH 2 )v-X(CH 2 )v-X(CH 2 ) v-, v is an integer from 1 to 5, X is each independently selected from a bond, N, O or S, and at least 1X is selected from N, O or S.
"cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Cycloalkyl groups as herein presented are defined as described above. Cycloalkyl groups may be monovalent, divalent, trivalent, or tetravalent.
"heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group including, but not limited to, 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O or S, optionally substituted N, S in the ring of the heterocycloalkyl group being oxidizable to various oxidation states. Heterocycloalkyl groups can be attached to heteroatoms or carbon atoms, heterocycloalkyl groups can be attached to aromatic or non-aromatic rings, and heterocycloalkyl groups can be attached to bridged or spiro rings, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocyclylalkyl can be monovalent, divalent, trivalent, or tetravalent
"alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbyl groups having at least 1, typically 1, 2 or 3 carbon-carbon double bonds, the backbone including but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms, alkenyl examples including but not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-pentadienyl, 1, 4-pentadienyl and the like; alkenyl groups appear herein, the definition of which is consistent with the definition. Alkenyl groups may be monovalent, divalent, trivalent, or tetravalent.
"alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbyl groups having at least 1, typically 1, 2 or 3 carbon-carbon triple bonds, including but not limited to 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms in the backbone, alkynyl embodiments including but not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 4-decynyl, and the like; alkynyl groups may be monovalent, divalent, trivalent or tetravalent.
"alkoxy" refers to a substituted or unsubstituted-O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy and cyclobutoxy.
"carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered bicyclic ring, or a 10 to 15 membered tricyclic ring system, to which carbocyclyl may be attached, optionally in the form of a monocyclic, bridged, or spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring,
"carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent, or tetravalent.
"heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring that may be a 3-to 8-membered monocyclic, 4-to 12-membered bicyclic, or 10-to 15-membered tricyclic ring system and that contains 1 or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O or S, and N, S optionally substituted in the ring of the heterocyclyl can be oxidized to various oxidation states. The heterocyclic groups being bound to hetero atoms or carbon atoms, the heterocyclic groups being bound to aromatic rings or The heterocyclic group may be attached to a bridged or spiro ring on a non-aromatic ring, non-limiting examples include an oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, dihydrofuryl, dihydropyranyl, dithianyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, benzodihydropyranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyrimidinyl, benzopiperazinyl, piperazinyl, 2. 3. The heterocyclic groups]Octyl and azabicyclo [5.2.0]Nonylalkyl oxatricyclo [5.3.1.1 ]]Dodecyl, azaadamantyl, oxaspiro [3.3 ]]Heptyl radical, 
"Spiro" or "spirocyclic group" refers to a polycyclic group having one atom (referred to as a spiro atom) shared between substituted or unsubstituted monocyclic rings, the number of ring atoms in the spirocyclic ring system including, but not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more of the rings may contain 0 or more (including, but not limited to, 1, 2, 3, or 4) double bonds, and optionally may contain 0 to 5 members selected from N, O or S (=O) n Is a heteroatom of (2).
"fused ring" or "fused ring group" refers to a polycyclic group wherein each ring in the system shares an adjacent pair of atoms with the other rings in the system, wherein one or more of the rings may contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to those selected from N, S (=o) n Or O, n is 0, 1 or 2). The number of ring atoms in the fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include: 
"fused" or "fused-ring" groups may be monovalent, divalent, trivalent, or tetravalent.
"bridged ring" or "bridged ring radical" refers to a substituted or unsubstituted polycyclic group containing any two atoms not directly attached, which may contain 0 or more double bonds, and any ring in the ring system may contain 0 to 5 groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S (=o) n Or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include
"carbospiro", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spiro" ring system consisting of only carbon atoms. "carbospiro", "spirocarbocyclyl" or "carbospirocyclyl" as referred to herein are defined in accordance with spirocyclic rings.
"carbon-fused", "fused carbocyclyl" or "carbon-fused cyclic" refers to a "fused ring" in which the ring system has only carbon atoms. "carbo-cyclic", "carbocyclyl" or "carbo-cyclic" as used herein is defined as consistent with a carbo-cyclic group.
"carbon bridged ring", "bridged carbocyclyl" or "carbon bridged cyclyl" refers to a "bridged ring" in which the ring system has only carbon atoms. "carbobridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbobridged ring radical" as used herein is defined as being identical to a bridged ring.
"heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic" refers to a "heterocyclyl" or "heterocycle" of a monocyclic system, and the heterocyclic groups, "monocyclic heterocyclyl" or "heteromonocyclic" appearing herein are defined as identical to heterocycles.
"heterobicyclic", "heterobicyclic radical", "fused-to-heterocyclic radical" or "heterobicyclic radical" refers to a "fused ring" containing a heteroatom. The "heteroacene", "heteroacenyl", "fused-ring heterocyclyl" or "heteroacenyl" as presented herein are defined in accordance with the fused ring.
"Heterospiro", "spirocyclic heterocyclyl" or "Heterospiro" refers to a "spiro" containing heteroatoms. As used herein, a heterospiro, "spiroheterocyclyl," or "heterospiro" is defined as a spiro.
"heterobridged", "bridged heterocyclyl" or "heterobridged heterocyclyl" refers to a "bridged ring" that contains a heteroatom. The term "heterobridged ring," as used herein, refers to a bridged ring, or a bridged ring.
"aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic having a single ring or fused ringsThe number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring attached to the parent structure is an aryl ring, non-limiting examples of which include benzene rings, naphthalene rings,
The "aryl" or "aromatic ring" may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment site is located on the aryl ring.
"heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group and contains 1 to 5 optional heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (=o) n N is 0, 1, 2), the number of ring atoms in the heteroaromatic ring including, but not limited to, 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include 
Heteroaryl groups as herein appear, the definition of which is consistent with the definition. Heteroaryl groups may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment sites are located on the heteroaryl ring.
"5 membered ring and 5 membered heteroaryl ring" refers to a fused heteroaryl ring of 5 and 5 members, at least 1 of the 2 rings containing more than 1 heteroatom (including but not limited to O, S or N), the entire group having aromaticity, non-limiting examples including pyrrolopyrrole rings, pyrazolopyrrole rings, pyrazolopyrazole rings, pyrrolofuran rings, pyrazolofuran rings, pyrrolothiene rings, pyrazolothiophene rings.
"5-and 6-membered heteroaryl ring" refers to a fused 5-and 6-membered heteroaryl ring, at least 1 of the 2 fused rings containing more than 1 heteroatom (including but not limited to O, S or N), the entire group having aromaticity, non-limiting examples including benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl rings.
"substituted" or "substituted" means substituted with 1 or more (including but not limited to 2, 3, 4, or 5) substituents including but not limited to H, F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spirocyclic, and cyclic, hydroxyalkyl, =o, carbonyl, aldehyde, carboxylic acid, formate, - (CH) 2 ) m -C(＝O)-R a 、-O-(CH 2 ) m -C(＝O)-R a 、-(CH 2 ) m -C(＝O)-NR b R c 、-(CH 2 ) m S(＝O) n R a 、-(CH 2 ) m -alkenyl-R a 、OR d Or- (CH) 2 ) m -alkynyl-R a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or-NR b R c Etc., wherein R is b And R is R c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally R b And R is R c Can form five-membered or six-membered cycloalkyl or heterocyclyl, R a And R is R d Each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spirocyclic, or fused ring.
"containing 1 to 5 heteroatoms selected from O, S, N" means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, N.
"0 to X substituents selected from …" means substituted with 0, 1, 2, 3 … X substituents selected from …, X being selected from any integer between 1 and 10. For example, "0 to 4 substituents selected from …" means substituted with 0, 1, 2, 3 or 4 substituents selected from …. For example, "0 to 5 substituents selected from …" means substituted with 0, 1, 2, 3, 4 or 5 substituents selected from …. By "the hetero-bridge ring is optionally further substituted with 0 to 4 substituents selected from H or F" is meant that the hetero-bridge ring is optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H or F.
The X-Y membered ring (X is selected from integers less than Y and greater than 3 and Y is selected from any integer between 4 and 12) includes X+1, X+2, X+3, X+4 … Y membered rings. The ring includes heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" means 4-, 5-, 6-or 7-membered heteromonocyclic ring, and "5-10 membered heteromonocyclic ring" means 5-, 6-, 7-, 8-, 9-or 10-membered heteromonocyclic ring.
"optional" 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. Such as: "alkyl optionally substituted with F" means that the alkyl may be, but is not necessarily, substituted with F, and is intended to include both cases where the alkyl is substituted with F and cases where the alkyl is not substituted with F.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.
"pharmaceutical composition" refers to one or more compounds of the present invention, or stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and mixtures of other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance that is added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.
"prodrug" means a compound of the invention which is converted into a biologically active form by in vivo metabolism. Prodrugs of the invention are prepared by modifying amino or carboxyl groups in the compounds of the invention, which modifications may be removed by conventional procedures or in vivo to give the parent compound. When the prodrugs of the invention are administered to a mammalian subject, the prodrugs are cleaved to form the free amino or carboxyl groups.
"co-crystals" refers to crystals of Active Pharmaceutical Ingredient (API) and co-crystal former (CCF) that are bound by hydrogen bonds or other non-covalent bonds, wherein the pure states of the API and CCF are both solid at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.
"animal" is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
"tautomer" refers to a functional group isomer produced by rapid movement of an atom in a molecule at two positions, such as keto-enol isomers and amide-imine alcohol isomers.
"optional" 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 and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group, and cases where the heterocyclic group is not substituted with an alkyl group.
“IC 50 "is specified forThe concentration of the drug or inhibitor required to inhibit half of the biological process (or some component of the process such as an enzyme, receptor, cell, etc.).
Detailed Description
For the purpose of the present invention, starting from commercially available chemicals and/or compounds described in the chemical literature, the compounds "commercially available chemicals" used in the reactions described herein are prepared from standard commercial sources, including Shanghai Allatin Biotechnology Co., ltd, shanghai Michelin Biochemical Co., sigma-Aldrich, alfa Elisa (China) chemical Co., ltd, boschiza (Shanghai) chemical industry development Co., an Naiji chemical, shanghai Tetan technology Co., kelong chemical, bailingwei Co., etc., according to organic synthesis techniques known to those skilled in the art.
The following examples illustrate the technical aspects of the present invention in detail, but the scope of the present invention is not limited thereto.
The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art starting from commercially available chemicals and/or compounds described in the chemical literature. "commercially available chemicals" are obtained from regular commercial sources and include: taitan technology, an Naiji chemistry, shanghai de moer, chengdu Kelong chemical, shaoguan chemical technology, nanjing medical stone, ming Kangde and Budweiser technologies.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was performed using a (Bruker Avance III and Bruker Avance 300) magnetonuclear apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS);
MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X14.6mm, 3.5. Mu.M);
the thin layer chromatography silica gel plate is prepared from tobacco stage yellow sea HSGF254 or Qingdao GF254 silica gel plate, the Thin Layer Chromatography (TLC) adopts silica gel plate with specification of 0.15-0.20 mm, and the thin layer chromatography separation and purification product adopts specification of 0.4mm-
0.5mm；
Column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.
SEM:
THP:/>
Boc: a tert-butoxycarbonyl group; ms: />
TBS:/>
MTBE methyl tert-butyl ether; bn: -herba cistanches>
DIPEA: n, N-diisopropylethylamine; DMAc: n, N-dimethylacetamide; DMSO: dimethyl sulfoxide; DCM: dichloromethane; cbz:>
NMP: n-methylpyrrolidone; DMF: n, N-dimethylformamide; HATU:2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (CAS: 148893-10-1); pd (dppf) Cl 2 : [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride; mCPBA: m-chloroperoxybenzoic acid; csF: cesium fluoride.
Example 1:2- (2, 6-Dioxopiperidin-3-yl) -5- (4- ((4- (3- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) piperidin-1-yl) methyl) piperidin-1-yl) isoindoline-1, 3-dione (compound 1)
The first step: 1B preparation
1A (1.0 g,1.11 mmol) was dissolved in 10mL of dichloromethane, 5mL of 4N hydrochloric acid in dioxane was added, stirring was performed at room temperature for 1h, and crude 1B (0.84 g, yield 99.94%) was obtained by concentration under reduced pressure, and was used directly in the next step. .
Ms m/z(ESI):597.4[M+2] + /2
And a second step of: preparation of 1C
1B (0.84 g,1.11 mmol) was dissolved in 10mL of MAc, N-t-butoxycarbonyl-4-piperidone (0.44 g,2.22 mmol) was added, and after adding 0.1mL of glacial acetic acid and 150mg of anhydrous magnesium sulfate, the reaction was continued at room temperature for 2 hours, and sodium triacetoxyborohydride (0.71 g,3.33 mmol) was added to the reaction for 2 hours. Saturated aqueous sodium bicarbonate was added to quench, extraction was performed with ethyl acetate (50 ml×3), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give 1C as a pale yellow solid (0.5 g, yield 47.91%).
And a third step of: preparation of 1D
1C (0.35 g,0.37 mmol) was dissolved in 10mL of dichloromethane, 2mL of 4N hydrochloric acid in dioxane was added, stirring was performed at room temperature for 1h, and crude 1D (0.31 g, yield: 99.73%) was obtained by concentration under reduced pressure.
Fourth step: 1E preparation
1D (0.31 g,0.37 mmol) was dissolved in 10mL of DMAc, N-t-butoxycarbonyl-4-piperidinecarbaldehyde (0.16 g,0.74 mmol) was added, and after adding 80mg of glacial acetic acid and anhydrous magnesium sulfate, the reaction was continued at room temperature for 2 hours, and sodium triacetoxyborohydride (0.235 g,1.11 mmol) was added thereto, and the reaction was continued for 2 hours. Saturated aqueous sodium hydrogencarbonate was added to quench, extraction was performed with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give 1E as a pale yellow solid (0.19 g, yield 49.5%).
Ms m/z(ESI):1037.6[M+H]
Fifth step: preparation of 1F
1E (0.19 g,0.18 mmol) was dissolved in 10mL of dichloromethane, 2mL of 4N dioxane solution of hydrochloric acid was added, stirred at room temperature for 1h, and concentrated under reduced pressure to give crude 1F (0.16 g, yield: 94.84%).
Ms m/z(ESI):469.4[M+2] + /2
Sixth step: preparation of 1G
1F (0.16 g,0.17 mmol) was dissolved in 5mL DMSO, DIPEA was added and stirred under nitrogen at 80deg.C for 3h. Water (20 mL) was added to the reaction, extraction was performed with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography to give 1G (0.11G, yield: 54.22%).
Ms m/z(ESI):597.4[M+2] + /2
Seventh step: preparation of Compound 1
1G (0.11G, 0.092 mmol) was dissolved in 5mL DMF under nitrogen, followed by the addition of CsF (0.14G, 0.92 mmol) at room temperature. Stirring was continued for 4 hours. 30mL of water was added, extraction was performed with ethyl acetate (40 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by preparative HPLC to give Compound 1 (10 mg, yield: 10.48%).
The preparation method comprises the following steps:
the instrument is SHIMADZU LC-20AP; preparation of column Phenomenex C18; mobile phase A:10mM NH 4 HCO 3 An aqueous solution; b: acetonitrile; the elution method comprises the steps of gradient elution of 40 to 70 percent of solution A of B for 10 minutes; the flow rate is 25mL/min; column temperature, room temperature; the detection wavelength is 210nm;
Ms m/z(ESI):519.3[M+2] + /2
1 H NMR(400MHz,CD 3 OD)δ9.08(s,1H),7.90–7.82(m,1H),7.67(d,1H),7.39–7.28(m,3H),7.27–7.19(m,2H),5.56–5.37(m,1H),5.06(dd,1H),4.66–4.44(m,4H),4.14–4.03(m,2H),3.90–3.79(m,2H),3.78–3.63(m,4H),3.62–3.44(m,3H),3.11–2.54(m,11H),2.53–2.04(m,10H),2.03–1.54(m,9H),1.48–1.34(m,2H).
example 2:2- (2, 6-Dioxopiperidin-3-yl) -5- (4- (3- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) piperidin-1-yl isoindoline-1, 3-dione (compound 2)
The first step: preparation of 2A
1D (0.14 g,0.17 mmol) was dissolved in 5mL DMSO, DIPEA was added and stirred under nitrogen at 80deg.C for 3h. Water (20 mL) was added to the reaction, extraction was performed with ethyl acetate (50 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure, and 2A (0.10 g, yield: 53.66%) was obtained by separation and purification through silica gel chromatography
Ms m/z(ESI):548.8[M+2] + /2
And a second step of: preparation of Compound 2
2A (0.10 g,0.091 mmol) was dissolved in 5mL DMF under nitrogen, followed by the addition of CsF (0.069 g,0.45 mmol) at room temperature and stirring was continued for 4 hours. 30mL of water was added, extraction was performed with ethyl acetate (40 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by preparative HPLC to give the trifluoroacetate salt of Compound 2 (9 mg, yield: 10.52%)
Ms m/z(ESI):470.7[M+2] + /2
HPLC preparation conditions: the instrument is SHIMADZU LC-20AP; preparation of the column: phenomnex C18; mobile phase A:0.1% tfa in water; b: acetonitrile; the elution method comprises the steps of gradient elution of solution A from 12% to 42% B for 15 minutes; the flow rate is 25mL/min; the column temperature is room temperature detection wavelength is 210nm;
example 3:2- (2, 6-Dioxypiperidin-3-yl) -5- (4- ((3- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) methyl) piperidin-1-yl) isoindoline-1, 3-dione (compound 3)
The first step: preparation of 3A
1B (0.40 g,0.53 mmol) was dissolved in 10mL of DMAc, N-t-butoxycarbonyl-4-carbaldehyde (0.17 g,0.8 mmol) was added, and after adding 0.1mL of glacial acetic acid and 100mg of anhydrous magnesium sulfate, the reaction was continued at room temperature for 2 hours, and sodium triacetoxyborohydride (0.34 g,1.59 mmol) was added to the reaction, and the reaction was continued for 2 hours. Saturated aqueous sodium hydrogencarbonate was added to quench, extraction was performed with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography to give 3A (0.25 g, yield 49.43%).
And a second step of: preparation of 3B
3A (0.25 g,0.26 mmol) was dissolved in 10mL of dichloromethane, 2mL of 4N hydrochloric acid in dioxane was added, stirred at room temperature for 1h, and concentrated under reduced pressure to give crude 3B, which was used directly in the next step without further purification (0.20 g, yield: 90.06%).
And a third step of: preparation of 3C
3B (0.25 g,0.29 mmol) was dissolved in 5mL DMSO, DIPEA was added and stirred for 3h at 80℃under nitrogen. Water (20 mL) was added to the reaction, extraction was performed with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography to give 3C (0.10 g, yield: 31.06%).
Ms m/z(ESI):555.8[M+2]+/2
Fourth step: preparation of Compound 3
3C (0.10 g,0.09 mmol) was dissolved in 5mL of LDMF under nitrogen, followed by addition of CsF (0.068 g,0.45 mmol) at room temperature. Stirring was continued for 4 hours. 30mL of water was added, extraction was performed with ethyl acetate (40 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by preparative HPLC to give compound 3 (30 mg, yield: 34.94%).
The preparation method comprises the steps of preparing SHIMADZU LC-20AP; preparation of column Phenomenex C18; mobile phase A:10mM NH 4 HCO 3 An aqueous solution; b: acetonitrile; the elution method comprises the steps of gradient elution of 40 to 70 percent of solution A of B for 10 minutes; the flow rate is 25mL/min; column temperature, room temperature; the detection wavelength is 210nm;
1 H NMR(400MHz,DMSO-d 6 )δ11.04(br.s,1H),10.17(br.s,1H),9.05(s,1H),8.00–7.93(m,1H),7.66(d,1H),7.45(t,1H),7.38(d,1H),7.30–7.27(m,1H),7.25(dd,1H),7.17(d,1H),5.37–5.17(m,1H),5.06(dd,1H),4.51–4.41(m,1H),4.34–4.26(m,1H),4.15–3.98(m,4H),3.91(s,1H),3.73–3.66(m,2H),3.41–3.32(m,2H),3.16–2.78(m,7H),2.64–2.52(m,2H),2.30–2.22(m,2H),2.17–1.70(m,12H),1.64–1.54(m,2H),1.30–1.18(m,2H).
Ms m/z(ESI):477.7[M+2] + /2
Example 4:2- (2, 6-Dioxopiperidin-3-yl) -5- (7- ((3- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) methyl) -2-azaspiro [3.5] non-2-yl) isoindoline-1, 3-dione (compound 4)
The first step: preparation of 4A
1B (0.40 g,0.53 mmol) was dissolved in 10mL of DMAc, 7-formyl-2-azaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester (0.13 g,0.53 mmol) was added, and the reaction was continued at room temperature for 2 hours with the addition of 0.1mL of glacial acetic acid and 100mg of anhydrous magnesium sulfate, followed by addition of sodium triacetoxyborohydride (0.34 g,1.59 mmol) to the reaction for 2 hours. Saturated aqueous sodium bicarbonate was added to quench, extraction was performed with ethyl acetate (50 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography to give 4A. (0.26 g, 49.34% yield)
Ms m/z(ESI):994.5[M+H] +
And a second step of: preparation of 4B
4A (0.26 g,0.26 mmol) was dissolved in 10mL of dichloromethane, 2mL of 4N dioxane solution of hydrochloric acid was added, stirring was performed at room temperature for 1h, and crude 4B (0.23 g, yield: 98.93%) was obtained by concentrating under reduced pressure.
Ms m/z(ESI):447.9[M+2] + /2
And a third step of: preparation of 4C
4B (0.23 g,0.26 mmol) was dissolved in 5mL DMSO, 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (0.14 g,0.52 mmol), DIPEA (0.17 g,1.32 mmol) was added and stirred under nitrogen for 3h at 80 ℃. Water (20 mL) was added to the reaction, the mixture was extracted with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give 4C (0.1 g, yield: 33.43%).
Ms m/z(ESI):575.9[M+2] + /2
Fourth step: preparation of Compound 4
4C (0.09 g,0.078 mmol) was dissolved in 5mL DMF under nitrogen, followed by the addition of CsF (0.059 g,0.39 mmol) at room temperature. Stirring was continued for 4 hours. 30mL of water was added, extraction was performed with ethyl acetate (40 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by preparative HPLC to give Compound 4 (10 mg, yield: 12.9%).
The preparation method comprises the steps of preparing SHIMADZU LC-20AP; preparation of column Phenomenex C18; mobile phase A:10mM NH 4 HCO 3 An aqueous solution; b: acetonitrile; the elution method comprises the steps of gradient elution of 40 to 70 percent of solution A of B for 10 minutes; the flow rate is 25mL/min; column temperature, room temperature; the detection wavelength is 210nm;
Ms m/z(ESI):497.7[M+2] + /2
1 H NMR(400MHz,CD 3 OD)δ9.03(s,1H),7.88(dd,1H),7.64(d,1H),7.39–7.30(d,2H),7.23
(d,1H),6.83(d,1H),6.66(dd,1H),5.43–5.23(m,1H),5.07(dd,1H),4.65–4.51(m,2H),4.37–
4.22(m,2H),3.84–3.69(m,6H),3.46–3.37(m,2H),3.35(s,1H),3.30–3.15(m,3H),3.08–
2.99(m,1H),2.94–2.66(m,3H),2.43–1.86(m,15H),1.75–1.50(m,5H),1.22–1.08(m,2H).
example 5:2- (2, 6-Dioxopiperidin-3-yl) -5- (3- ((3- (7- (8-ethynyl-7-) -fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) methyl) azetidin-1-yl) isoindoline-1, 3-dione (compound 5)
The first step: preparation of 5A
1B (0.40 g,0.53 mmol) was dissolved in 10mL of DMAc, tert-butyl 3-formylazetidine-1-carboxylate (0.14 g,0.77 mmol) was added, and after adding 0.1mL of glacial acetic acid and 100mg of anhydrous magnesium sulfate, the reaction was continued at room temperature for 2 hours, and sodium triacetoxyborohydride (0.34 g,1.59 mmol) was added to the reaction for 2 hours. Saturated aqueous sodium bicarbonate was added to quench, extraction was performed with ethyl acetate (50 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography to give 5A. (0.188 g, 46.08% yield)
Ms m/z(ESI):926.5[M+H] +
And a second step of: preparation of 5B
5A (0.16 g,0.17 mmol) was dissolved in 10mL of methylene chloride, trifluoroacetic acid (0.13 mL,1.7 mmol) was added, stirred at room temperature for 1h, and concentrated under reduced pressure to give crude 5B (0.14 g, yield: 99%) which was used directly in the next step without further purification. Ms m/z (ESI) 413.8[ M+2 ]] + /2
And a third step of: preparation of 5C
5B (0.14 g,0.17 mmol) was dissolved in 5mL DMSO, 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (0.094 g,0.34 mmol), DIPEA (0.11 g,0.85 mmol) was added and stirred under nitrogen for 3h at 80 ℃. Water (20 mL) was added to the reaction, extraction was performed with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography to give 5C (0.1 g, yield: 54.35%).
Ms m/z(ESI):1082.5[M+H] +
Fourth step: preparation of Compound 5
4C (0.10 g,0.092 mmol) was dissolved in 5mL DMF under nitrogen, followed by the addition of CsF (0.070 g,0.46 mmol) at room temperature. Stirring was continued for 4 hours. 30mL of water was added, extraction was performed with ethyl acetate (40 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by preparative HPLC to give compound 5 (15 mg, yield: 17.6%).
The preparation method comprises the steps of preparing SHIMADZU LC-20AP; preparation of column Phenomenex C18; mobile phase A:10mM NH 4 HCO 3 An aqueous solution; b: acetonitrile; the elution method comprises the steps of gradient elution of 40 to 70 percent of solution A of B for 10 minutes; the flow rate is 25mL/min; column temperature, room temperature; the detection wavelength is 210nm;
Ms m/z(ESI):497.7[M+2] + /2
1 H NMR(400MHz,DMSO-d 6 )δ11.05(s,1H),10.13(s,1H),9.05(s,1H),7.97(dd,1H),7.64(d,1H),7.46(t,1H),7.39(d,1H),7.17(d,1H),6.80(d,1H),6.67(dd,1H),5.38–5.19(m,1H),5.05(dd,1H),4.51–4.31(m,1H),4.33–4.25(m,1H),4.22–4.08(m,3H),4.06–3.99(m,1H),3.92(s,1H),3.83–3.75(m,2H),3.76–3.67(m,1H),3.66–3.58(m,1H),3.46–3.38(m,2H),3.13–2.95(m,4H),2.94–2.77(m,2H),2.74–2.65(m,2H),2.62–2.53(m,2H),2.17–2.95(m,4H),1.93–1.71(m,5H),1.65–1.57(m,2H).
compound 6:2- (2, 6-Dioxypiperidin-3-yl) -5- (2- ((3- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) methyl) -7-isoindol-dione (compound 6)
The first step: preparation of 6B
Methoxymethyltriphenyl phosphorus chloride (1.72 g,5.01 mmol) was dissolved in 50mL of THF, liHMDS (5.34 mL,5.34 mmol) was added at 0deg.C under nitrogen, followed by stirring at room temperature for 30min, and 2-oxo-7-azaspiro [3.5 ] was added ]Nonane-7-carboxylic acid tert-butyl ester (0.8 g,3.34 mmol). Stirring was continued for 2h after addition. 40mLNH was added 4 The reaction was quenched with aqueous Cl, extracted with ethyl acetate (80 mL x 3), washed with 50mL water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the crude product was isolated by column chromatography over silica gelPure (petroleum ether/ethyl acetate (v/v=3:1)) gave 6B (0.53 g, 59.35% yield).
Ms m/z(ESI):212.1[M-55] +
And a second step of: preparation of 6C 6B (0.53 g,1.98 mmol) was added to 10mL of acetonitrile and 2mL of water, 0.3mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1h. The pH was adjusted to 9 to 10 with aqueous sodium hydrogencarbonate, the system was concentrated, extracted with ethyl acetate (20 mL. Times.3), washed with 10mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatographed to give 6C, (0.28 g, yield 55.82%)
Ms m/z(ESI):198.2[M-55] +
And a third step of: preparation of 6D
1B (0.40 g,0.53 mmol) was dissolved in 10mL of DMAc, 6C (0.13 g,0.53 mmol) was added, and after adding 0.1mL of glacial acetic acid and 100mg of anhydrous magnesium sulfate, the reaction was continued at room temperature for 2 hours, and sodium triacetoxyborohydride (0.34 g,1.59 mmol) was added to the reaction, and the reaction was continued for 2 hours. Saturated aqueous sodium bicarbonate was added to quench, extraction was performed with ethyl acetate (50 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography to give 6D. (0.22 g, 40.6% yield)
Ms m/z(ESI):497.9[M+2] + /2
Fourth step: preparation of 6E
6D (0.22 g,0.22 mmol) was dissolved in 10mL of dichloromethane, trifluoroacetic acid (0.16 mL,2.2 mmol) was added, stirred at room temperature for 1h, and concentrated under reduced pressure to give crude 6E (0.19 g, yield: 96.58%) which was used directly in the next step without further purification. Ms m/z (ESI): 447.9[ M+2 ]] + /2
Fifth step: preparation of 6F
6E (0.19 g,0.21 mmol) was dissolved in 5mL DMSO, 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (0.12 g,0.42 mmol) was added and DIPEA (0.14 g,0.15 mmol) was stirred under nitrogen for 3h at 80 ℃. Water (20 mL) was added to the reaction, extraction was performed with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography to give 6F (0.16 g, yield: 66.36%).
Ms m/z(ESI):575.9[M+2] + /2
Sixth step: preparation of Compound 6
6F (0.16 g,0.14 mmol) was dissolved in 5mL of LDMF under nitrogen, followed by addition of CsF (0.21 g,1.4 mmol) at room temperature. Stirring was continued for 4 hours. 30mL of water was added, extraction was performed with ethyl acetate (40 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure and then purified by column chromatography of the residue to give Compound 6 as a yellow solid (0.11 g, yield: 79%).
Ms m/z(ESI):497.8[M+2] + /2
1 H NMR(400MHz,DMSO-d 6 )δ11.06(s,1H),10.13(s,1H),9.05(s,1H),7.97(dd,1H),7.64(d,1H),7.46(t,1H),7.39(d,1H),7.35–7.29(m,1H),7.28–7.21(m,1H),7.21–7.12(m,1H),5.39–5.19(m,1H),5.06(dd,1H),4.52–4.23(m,2H),4.19–3.98(m,2H),3.91(s,1H),3.74–3.55(m,2H),3.52–3.44(m,2H),3.43–3.30(m,4H),3.21–2.97(m,3H),2.94–2.79(m,2H),2.64–2.39(m,4H),2.19–1.64(m,14H),1.63–1.47(m,6H).
Example 7: (2S, 4R) -1- ((S) -2- (7- (4- ((1R, 5S) -3- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) methyl) piperidin-1-yl-7-oxoheptanamide-3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (compound 7)
The first step: preparation of 7B
7A (0.50 g,1.12 mmol) and 7-methoxy-7-oxoheptanoic acid (0.20 g,1.12 mmol) were dissolved in 10mL DMF, HATU (0.64 g,1.68 mmol) and N, N-diisopropylethylamine (0.29 g,2.24 mmol) were added and the reaction was continued for 3h. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give 7B (0.4 g, yield 59.45%).
And a second step of: preparation of 7C
7B (0.30 g,0.50 mmol) was dissolved in 3mL of methanol and 2mL of water, lithium hydroxide (0.012 g,0.50 mmol) was added thereto, stirred at room temperature for 5 hours, concentrated under reduced pressure, pH was adjusted to 4, and the mixture was separated and purified by reverse phase column chromatography to give 7C (0.22 g, yield: 74.99%).
Ms m/z(ESI):587.3[M+H] +
And a third step of: preparation of 7D
3B (0.10 g,0.12 mmol) and 7C (0.07 g,0.12 mmol) were dissolved in 5mL DMF and HATU (0.068 g,0.18 mmol) were added and the reaction was continued for 2h with N, N-diisopropylethylamine (0.031 g,0.24 mmol). The crude product was concentrated under reduced pressure, and purified by silica gel chromatography to give 7D (0.12 g, yield 70.28%).
Ms m/z(ESI):712.0[M+2] + /2
Fourth step: preparation of Compound 7
7D (0.10 g,0.07 mmol) was dissolved in 5mL DMF under nitrogen, followed by addition of CsF (0.053 g,0.35 mmol) at room temperature. Stirring was continued for 22 hours. The residue was purified by preparative HPLC to give compound 7 (24 mg, yield: 27.07%).
The preparation method comprises the steps of preparing SHIMADZU LC-20AP; preparation of column Phenomenex C18; mobile phase A:10mM NH 4 HCO 3 An aqueous solution; b: acetonitrile; the elution method comprises the steps of gradient elution of 30 to 60 percent of solution A of B for 10 minutes; the flow rate is 25mL/min; column temperature, room temperature; the detection wavelength is 210nm;
Ms m/z(ESI):423.0[M+3] + /3
1 H NMR(400MHz,DMSO-d 6 )δ10.13(s,1H),9.04(s,1H),8.98(s,1H),8.34(d,1H),7.97(dd,1H),7.77(d,1H),7.51–7.32(m,6H),7.17(d,1H),5.38–5.18(m,1H),5.08(d,1H),4.97–4.85(m,1H),4.54–4.34(m,4H),4.34–4.22(m,2H),4.15–3.98(m,2H),3.94–3.81(m,2H),3.74–3.55(m,4H),3.39–3.30(m,2H),3.16–2.93(m,4H),2.87–2.76(m,1H),2.45(s,3H),2.32–2.19(m,5H),2.17–1.95(m,5H),1.92–1.66(m,9H),1.63–1.43(m,6H),1.37(d,3H),1.33–1.21(m,3H),1.14–0.89(m,11H).
example 8:2- (2, 6-Dioxopiperidin-3-yl) -5- (4- ((1R, 5S) -3- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) -methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) methyl) - (1, 4' -bipiperidinyl) -1-isoindole-1, 3-dione (compound 8)
The first step: preparation of 8A
3B (0.245 g,0.29 mmol) was dissolved in 10mL of DMAc, N-t-butoxycarbonyl-4-piperidone (0.087 g,0.43 mmol) was added, and after adding 0.1mL of glacial acetic acid and 60mg of anhydrous magnesium sulfate, the reaction was continued at room temperature for 2 hours, and sodium triacetoxyborohydride (0.18 g,0.87 mmol) was added to the reaction for 2 hours. Saturated aqueous sodium hydrogencarbonate was added to quench, extraction was performed with ethyl acetate (15 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography to give 8A (0.12 g, yield 39.81%).
And a second step of: preparation of 8B
8A (0.1 g,0.096 mmol) was dissolved in 10mL of acetonitrile, 2mL of 4N dioxane solution of hydrochloric acid was added, stirred at room temperature for 3 hours, and concentrated under reduced pressure to give crude 8B, which was used directly in the next step without further purification (0.08 g, yield: 88.91%).
And a third step of: preparation of 8C
8B (0.08 g,0.085 mmol) was dissolved in 5mL DMSO, DIPEA was added and stirred under nitrogen at 80deg.C for 3h. Water (20 mL) was added to the reaction, extraction was performed with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography to give 8C (0.04 g, yield: 39.43%).
Ms m/z(ESI):597.4[M+2] + /2
Fourth step: preparation of Compound 8C (0.04 g,0.034 mmol) was dissolved in 5mL DMF under nitrogen, followed by addition of CsF (0.026 g,0.17 mmol) at room temperature. Stirring was continued for 4 hours. 30mL of water was added, extraction was performed with ethyl acetate (40 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by column chromatography (DCM: meOH=10:1) to give Compound 8 (20 mg, yield: 56.72%).
Ms m/z(ESI):519.3[M+2] + /2
Synthesis of intermediate M:
the first step: preparation of M-2
M-1 (5 g,21.46 mmol) was dissolved in 60mL of DMF, HATU (12.24 g,32.18 mmol), N, N-diisopropylethylamine (5.53 g,42.92 mmol) and ammonium chloride (11.48 g,214.60 mmol) were added separately and the reaction was continued at room temperature for 3h. The reaction solution was slowly poured into 120mL of ice water and stirred at room temperature for 10min, and the precipitated solid was filtered, dried and concentrated under reduced pressure to give M-2 (4.9 g, yield 98.39%).
LCMS m/z＝233.1[M+H] +
And a second step of: preparation of M-3
M-2 (4.9 g,21.12 mmol) was dissolved in 100mL of tetrahydrofuran, and triphosgene (9.4 g,31.68 mmol) was added thereto, followed by reaction at 65℃for 3 hours. The reaction was cooled to room temperature, and concentrated under reduced pressure to give M-3 (4.7 g, yield 86.23%)
LCMS m/z＝259.1[M+H] +
And a third step of: preparation of M-4
M-3 (1.5 g,5.81 mmol) was dissolved in 30mL of toluene, phosphorus oxychloride (4.45 g,29.07 mmol) was added, and N, N-diisopropylethylamine (2.25 g,17.44 mmol) was reacted at 110℃for 5h. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give M-4, which was used directly in the next reaction.
Fourth step: preparation of M-5
M-4 was dissolved in 30mL of dry dichloromethane, N-diisopropylethylamine (2.25 g,17.44 mmol), intermediate 1 (1.23 g,5.81 mmol) was slowly added under ice bath, and after the addition was completed, the reaction was slowly warmed to room temperature and reacted for 2 hours, and after concentrating under reduced pressure, the residue was chromatographed on a silica gel column to give M-5 (0.71 g, 26.00% in two steps).
LCMS m/z＝471.1[M+H] +
Fifth step: preparation of M-6
Intermediate 2 (0.4 g,2.51 mmol) was dissolved in DMF 15mL, cesium carbonate (0.55 g,1.70 mmol), triethylenediamine (0.03 g,0.26 mmol) was added
Molecular sieves 500mg, under nitrogen protection, at room temperature for 10min, dissolving M-5 (0.4 g,0.85 mmol) in DMF 2mL, slowly adding to the reaction solution, reacting for 4h at room temperature after the addition, slowly adding 40mL of water, extracting twice with ethyl acetate (40 mL. Times.2), combining ethyl acetate layers, washing ethyl acetate layer with water (40 mL. Times.2) twice, washing once with saturated saline (40 mL. Times.1), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and subjecting the residue to column chromatography with silica gel chromatography to give M-6 (0.36 g, yield 71.42%)
LCMS m/z＝594.1[M+H] +
Sixth step: preparation of M-7
M-6 (0.36 g,0.60 mmol) was dissolved in a mixture of 15mL of 1, 4-dioxane and 3mL of water, and intermediate 3 (0.62 g,1.20 mmol), cesium carbonate (0.39 g,1.20 mmol), pd (dppf) Cl was added 2 DCM (0.10 g,0.12 mmol), 100℃for 5h under nitrogen protection, cool the reaction to room temperature, add 40mL of ethyl acetate and 25mL of water, extract the aqueous phase once more with ethyl acetate (40 mL. Times.1), combine ethyl acetate layers, wash the ethyl acetate layer once with saturated brine (40 mL. Times.1), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then column chromatography the residue on a silica gel column to give M-7 (0.24 g, 44.03% yield)
LCMS m/z＝900.1[M+H] +
Seventh step: preparation of intermediate M
M-7 (0.15 g,0.16 mmol) was dissolved in 10mL of methylene chloride, 0.5mL of trifluoroacetic acid was added, and after completion of the addition, the reaction was carried out at room temperature for 3 hours, and intermediate M (103 mg, 81%) was directly obtained after concentration under reduced pressure.
LCMS m/z＝756.1[M+H] +
Example 9:2- (2, 6-Dioxypiperidin-3-yl) -5- (4- ((1R, 5S) -3- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octyl-8-yl) methyl) piperidin-1-yl) isoindoline-1, 3-dione
The first step: preparation of 9A
Intermediate M (0.7 g,0.93 mmol) was dissolved in 10mL of DMAc, N-t-butoxycarbonyl-4-piperidinecarbaldehyde (0.3 g,1.40 mmol) was added, and after adding 0.1mL of glacial acetic acid and 500mg of anhydrous magnesium sulfate, the reaction was continued at room temperature for 2 hours, and sodium triacetoxyborohydride (0.59 g,2.79 mmol) was added to the reaction for 2 hours. Saturated aqueous sodium hydrogencarbonate was added to quench, extraction was performed with ethyl acetate (15 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography to give 9A (0.5 g, yield 56.40%).
And a second step of: preparation of 9B
9A (0.3 g,0.31 mmol) was dissolved in 10mL of acetonitrile, 2mL of 4N dioxane solution of hydrochloric acid was added, stirred at room temperature for 3h, and concentrated under reduced pressure to give crude 9B, which was used directly in the next step (0.2 g, yield: 75.53%).
And a third step of: preparation of 9C
9B (0.20 g,0.23 mmol) was dissolved in 5mL DMSO, DIPEA was added and stirred for 3h at 80℃under nitrogen. Water (20 mL) was added to the reaction, the mixture was extracted with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography to give 9C (0.08 g, yield: 31.35%).
Ms m/z(ESI):556.3[M+2] + /2
Fourth step: preparation of Compound 9
9C (0.08 g,0.072 mmol) was dissolved in 5mL DMF under nitrogen, followed by the addition of CsF (0.026 g,0.17 mmol) at room temperature. Stirring was continued for 4 hours. 30mL of water was added, extraction was performed with ethyl acetate (40 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by column chromatography (DCM: meOH=10:1) to give Compound 9 (20 mg, yield: 29.17%).
1 H NMR(400MHz,DMSO-d 6 )δ11.05(s,1H),10.10(s,1H),7.96(dd,1H),7.75(d,1H),7.66(d,1H),7.45(t,1H),7.38–7.30(m,2H),7.29–7.24(m,1H),7.16(t,1H),7.09–7.04(m,1H),5.40–5.18(m,1H),5.06(dd,1H),4.35–4.17(m,2H),4.16–3.96(m,4H),3.83(s,1H),3.59–3.47(m,2H),3.37–3.30(m,2H),3.19–2.95(m,5H),2.94–2.80(m,2H),2.64–2.50(m,2H),2.31–2.14(m,3H),2.10–1.98(m,3H),1.97–1.73(m,8H),1.70–1.59(m,2H),1.32–1.17(m,2H).
Ms m/z(ESI):477.3[M+2] + /2
Example 10: (2S, 4R) -1- ((2S) -2- (2- (4- ((3- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) methyl) piperidin-1-yl) carboxamide-3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (compound 10)
The first step: preparation of 10B
10A (1.0 g,2.25 mmol) was dissolved in 10mL DCM, triethylamine (0.45 g,4.47 mmol) was added and chloroacetyl chloride (0.25 g,2.25 mmol) was added dropwise for a further 2h at room temperature. The crude product was concentrated under reduced pressure, and purified by silica gel chromatography to give 10B (0.8 g, yield 68.24%).
Ms m/z(ESI):521.2[M+H] +
And a second step of: preparation of 10C
10B (0.063 g,0.12 mmol) and 3B (0.1 g,0.12 mmol) were dissolved in 10mL DCM, stirred for 72h at 35℃and concentrated under reduced pressure, the residue was chromatographed on silica gel to give 10C (40 mg, yield: 24.93%).
And a third step of: preparation of Compound 10) 10C (0.04 g,0.03 mmol) was dissolved in 5mL DMF under nitrogen, followed by addition of CsF (0.026 g,0.17 mmol) at room temperature. Stirring was continued for 4 hours. 30mL of water was added, extraction was performed with ethyl acetate (40 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by preparative TLC to give compound 10 (20 mg, yield: 56.44%).
Ms m/z(ESI):591.8[M+2] + /2
Synthesis of intermediate N:
the first step: preparation of N-2
N-1 (25.0 g,113.6 mmol) was dissolved in 150mL of methanol and concentrated sulfuric acid (15.0 mL) was slowly added and the system was heated to 90℃under nitrogen and stirred for 5 hours. The reaction solution was cooled to room temperature, slowly added to ice water, filtered, and the cake was washed with water and dried to give N-2 (23.0 g, yield 87%).
Ms m/z(ESI):234.0[M+H] +
And a second step of: preparation of N-3
To a 500mL single flask under nitrogen protection, methyl 2-bromo-5-fluoropyridine-4-carboxylate N-2 (8.0 g,34 mmol) and cyclopropylboronic acid (3.82 g,44 mmol) were added, dissolved in 200mL toluene and 20mL water, then palladium acetate (385 mg,1.7 mmol), tricyclohexylphosphorus (1.08 g,3.43 mmol) and potassium phosphate (25.4 g,120 mmol) were added, nitrogen was replaced three times, the temperature was raised to 100℃for reaction for 8 hours, the reaction solution was filtered to remove the residue, the filtrate was concentrated under reduced pressure to give a crude product, and the crude product was purified by silica gel column chromatography to give compound N-3 (4.0 g, yield 60%).
LCMS m/z＝196.1[M+H] +
And a third step of: preparation of N-4
N-3 (2.7 g,13.8 mmol) was added to 30mL of methylene chloride and dissolved with stirring, then m-chloroperoxybenzoic acid (6 g,34.6 mmol) was added, and the reaction was left to stir at room temperature for 4 hours. The reaction was quenched with saturated aqueous sodium hydrogencarbonate (50 mL), extracted with dichloromethane (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and chromatographed on a silica gel column (petroleum ether: ethyl acetate=5:1) to give N-4 (1.6 g, yield: 54.8%).
Ms m/z(ESI):212.1[M+1] +
Fourth step: preparation of N-5
N-4 (1.6 g,7.6 mmol) was dissolved in toluene (30 mL), phosphorus oxychloride (3.5 g,22.8 mmol) was then added dropwise at 0℃and after the addition was completed, the reaction solution was stirred at 100℃for 3 hours. The reaction solution was cooled to room temperature, quenched by adding to ice water with stirring, extracted with ethyl acetate (50 mL. Times.3), and the obtained organic phase was washed with saturated aqueous sodium hydrogencarbonate, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and subjected to silica gel column chromatography to give N-5 (1.1 g, yield: 63.2%).
Ms m/z(ESI):230.0[M+H] +
Fifth step: preparation of N-6
N-5 (1.1 g,4.8 mmol) was dissolved in a mixed solvent of acetonitrile (30 mL) and water (6 mL), lithium hydroxide monohydrate (1.0 g,24 mmol) was added, and the reaction was stirred at room temperature for 4 hours. Then, after ph=2 was adjusted with 1N hydrochloric acid, further 30mL of water was added for dilution, followed by extraction with ethyl acetate (30 ml×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product N-6 (0.82 g, yield 79.4%). Without further purification, it was used directly in the next reaction.
Ms m/z(ESI):216.1[M+H] +
Sixth step: preparation of N-7
The crude product N-6 (0.82 g,3.8 mmol) obtained in the previous step was dissolved in toluene (30 mL) under nitrogen atmosphere, triethylamine (1.15 g,11.4 mmol) and diphenyl azide phosphate (1.57 g,5.7 mmol) were added, and after stirring at room temperature for 30 minutes, tert-butanol (5 mL) was added and the mixture was stirred at 110℃for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, then added with water (50 mL), extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to give N-7 (0.9 g, yield: 82.6%).
Ms m/z(ESI):287.1[M+H] +
Seventh step: preparation of N-8
N-7 (0.9 g,4.0 mmol) was dissolved in acetonitrile (10 mL), and hydrogen chloride (4N in Dioxane) (3 mL) was added thereto, and the reaction was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, then 30mL of aqueous sodium hydrogencarbonate solution was added, followed by extraction with ethyl acetate (30 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, and then filtered, followed by concentration under reduced pressure to give crude product N-8 (0.55 g, yield: 93.4%).
Ms m/z(ESI):187.1[M+H] +
Eighth step: preparation of N-9
N-8 (0.55 g,2.95 mmol) and p-toluenesulfonic acid monohydrate (28 mg,0.15 mmol) were dissolved in acetonitrile (10 mL) under nitrogen atmosphere, and NIS (N-iodosuccinimide) (1.0 g,4.43 mmol) was added thereto, and the mixture was stirred at 70℃for 20 hours. After cooling to room temperature, the reaction was quenched by addition of saturated aqueous sodium thiosulfate (10 mL), extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and chromatographed on a silica gel column to give N-9 (0.75 g, yield: 81.4%).
Ms m/z(ESI):313.0[M+H] +
Ninth step: preparation of N-10
N-9 (0.75 g,2.4 mmol), pd (dppf) Cl 2 DCM (0.2 g,0.24 mmol) and triethylamine (1.2 g,12 mmol) were dissolved in absolute ethanol (15 mL), the reaction was replaced with carbon monoxide atmosphere, and the temperature was raised to 80℃and stirred for 15 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and a residue was obtained by silica gel column chromatography to give N-10 (0.55 g, yield: 88.6%).
Ms m/z(ESI):259.1[M+H] +
Tenth step: preparation of N-11
N-10 (0.55 g,2.13 mmol) was dissolved in tetrahydrofuran (10 mL), and 2, 2-trichloroacetyl isocyanate (0.48 g,2.56 mmol) was slowly added dropwise to the system at room temperature, and after the addition was completed, the reaction was left at room temperature and stirred for 30 minutes. The reaction solution was then concentrated under reduced pressure to give a residue, which was slurried with methyl tert-butyl ether and filtered to give N-11 (0.81 g, yield: 85%).
Ms m/z(ESI):448.0[M+H] +
Eleventh step: preparation of N-12
N-11 (0.81 g,1.8 mmol) was dissolved in anhydrous methanol (15 mL), and after stirring and dissolution, an ammonia-methanol solution (3 mL) was added to the system, the reaction was continued under stirring at room temperature for 1 hour, a large amount of white solid was precipitated, the reaction solution was filtered, and the obtained solid was slurried with methyl tert-butyl ether, and the solid obtained by filtration was N-12 (0.41 g, yield: 89.6%).
Ms m/z(ESI):256.0[M+H] +
Twelfth step: preparation of N-13
N-12 (0.4 g,1.56 mmol) and N, N-diisopropylethylamine (0.6 g,4.68 mmol) were dissolved in toluene (20 mL) under nitrogen atmosphere, and phosphorus oxychloride (0.7 g,4.68 mmol) was slowly added to the system. Placed at 100℃and stirred for 5 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure to obtain a residue, the residue was dissolved in 20mL of methylene chloride, 2mL of N, N-diisopropylethylamine was added, and after stirring and dissolution at 0℃intermediate 1 (0.43 g,2.03 mmol) was added to the system. The reaction was continued to stir at 0℃for 3 hours. The reaction solution was concentrated directly to give a residue which was subjected to silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give N-13 (0.4 g, yield: 56%).
Ms m/z(ESI):468.1[M+H] +
Thirteenth step: preparation of N-14
N-13 (0.4 g,0.85 mmol) and intermediate 2 (0.27 g,1.7 mmol) were dissolved in an overdry 1, 4-dioxane solution (20 mL) under nitrogen, followed by N, N-diisopropylethylamine (0.55 g,4.25 mmol). The reaction was stirred at 90℃for 16 hours. The solvent was removed under reduced pressure and the residue was chromatographed on a column of silica gel (DCM: meoh=15:1) to give N-14 (0.3 g, yield: 59.7%).
Ms m/z(ESI):591.2[M+H] +
Fourteenth step: preparation of N-15
N-14 (0.3 g,0.5 mmol), intermediate 3 (0.39 g,0.75 mmol), pd (dppf) Cl under nitrogen 2 DCM (84 mg,0.1 mmol) and cesium carbonate (0.5 g,1.53 mmol) were added to a mixed solvent of 1, 4-dioxane (5 mL) and water (1.5 mL). The reaction was stirred at 100℃for 3 hours. After the reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, 30mL of water was added, extraction was performed with ethyl acetate (20 mL. Times.3), and the organic phase was combined with anhydrous sulfuric acidAfter drying sodium, filtration and concentration under reduced pressure, the residue was subjected to silica gel column chromatography to give N-15 (260 mg, yield: 54%).
Ms m/z(ESI):471.3[(M+2H)/2] +
Fifteenth step: preparation of N-16
Compound N-15 (260 mg,0.28 mmol) was dissolved in 3mL of DMF under nitrogen, followed by the addition of CsF (210 mg,1.4 mmol) at room temperature. Stirring was continued for 4 hours. 30mL of water was added, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by silica gel column chromatography to give N-16 (160 mg, yield: 72.8%)
Ms m/z(ESI):785.4[M+H] +
Sixteenth step: preparation of intermediate N
Intermediate N-16 (0.15 g,0.19 mmol) was dissolved in 2mL of acetonitrile, 2mL of 4N dioxane hydrochloride solution was added, stirring was performed at room temperature for 15min, the solvent was removed under reduced pressure, the residue was dissolved with dichloromethane, washed with 5mL of saturated aqueous sodium bicarbonate solution, the organic phase was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument: SHIMADZU LC-20AP; chromatographic column: phenomenex C18; mobile phase: ais 0.05.05% NH) 4 HCO 3 in H 2 O; b is acetonitrile; eluent Phase B from 40to 60in 15min; the flow rate is 25mL/min; column temperature, room temperature; the intermediate N (70 mg, yield 57.5%) was isolated and purified at a detection wavelength of 210 nm.
Ms m/z(ESI):641.3[M+H] +
Example 11:5- (4- ((3- (5-cyclopropyl-7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octyl-8-yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (compound 11)
The first step: preparation of 11A
Intermediate N (0.2 g,0.31 mmol) was dissolved in 10mL of DMAc, N-t-butoxycarbonyl-4-piperidinecarbaldehyde (0.13 g,0.62 mmol) was added, and the mixture was reacted at room temperature for 2 hours with the addition of 0.1mL of glacial acetic acid and 100mg of anhydrous magnesium sulfate, and then sodium triacetoxyborohydride (0.2 g,0.93 mmol) was added to the reaction to continue the reaction for 2 hours. Saturated aqueous sodium hydrogencarbonate was added to quench, extraction was performed with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography to give 11A as a pale yellow solid (0.19 g, yield 69.29%).
Ms m/z(ESI):838.5[M+H] +
And a second step of: preparation of 11B
11A (0.19 g,0.23 mmol) was dissolved in 10mL of methylene chloride, 2mL of 4N dioxane solution of hydrochloric acid was added, and the mixture was stirred at room temperature for 1h, followed by concentration under reduced pressure to give crude 11B (0.16 g, yield: 94.28%).
Ms m/z(ESI):369.8[M+2] + /2
And a third step of: preparation of Compound 11
11B (0.14 g,0.19 mmol) was dissolved in 5mL DMSO, 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (0.10 g,0.38 mmol), DIPEA (0.12 g,0.95 mmol) was added and stirred under nitrogen for 3h at 80 ℃. Water (20 mL) was added to the reaction, the mixture was extracted with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give compound 11 (30 mg, yield: 15.88%).
Ms m/z(ESI):497.9[M+2] + /2
Synthesis of intermediate P:
the first step: preparation of P-2
Compound P-1 (10.0 g,58.5 mmol) was dissolved in 100mL of methanol under nitrogen, concentrated sulfuric acid (8.0 mL) was slowly added, and the mixture was heated to 90℃and stirred for 5 hours. The solvent was removed under reduced pressure, and then the residue was cooled to room temperature, and slowly added to ice water, then ph=8 was adjusted with saturated sodium bicarbonate, the aqueous phase was extracted with 200ml×3 of ethyl acetate, the organic phases were combined, then washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography to give P-2 (9.3 g, yield 86%).
Ms m/z(ESI):186.0[M+H] +
And a second step of: preparation of P-3
P-2 (9.3 g,50.3 mmol) was added to 100mL of methylene chloride and dissolved with stirring, then m-chloroperoxybenzoic acid (34.7 g,201.1 mmol) was added, the reaction was left at room temperature and stirred for 4 hours, a saturated aqueous solution of sodium hydrogencarbonate (100 mL) was added, extracted with methylene chloride (150 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the residue after concentration under reduced pressure was separated and purified by silica gel column chromatography to give P-3 (6.2 g, yield: 61%).
Ms m/z(ESI):202.0[M+1] +
And a third step of: preparation of P-4
P-3 (6.2 g,30.8 mmol) was dissolved in toluene (100 mL), and phosphorus oxychloride (14.2 g,92.5 mmol) was added dropwise at 0℃and after the addition was completed, the reaction solution was stirred at 100℃for 3 hours. The reaction solution was cooled to room temperature, quenched by adding ice water with stirring, extracted with ethyl acetate (100 mL. Times.3), and the obtained organic phase was washed with a saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography to give P-4 (5.2 g, yield: 77%).
Ms m/z(ESI):220.0[M+H] +
Fourth step: preparation of P-5
P-4 (5.2 g,23.7 mmol) was dissolved in a mixed solvent of acetonitrile (100 mL) and water (20 mL), lithium hydroxide monohydrate (5.0 g,118.7 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Then, after ph=2 was adjusted with 1N hydrochloric acid, 50mL of water was added to dilute, ethyl acetate was used for extraction (100 ml×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product P-5, which was directly used for the next reaction.
Ms m/z(ESI):206.1[M+H] +
Fifth step: preparation of P-6
The crude product P-5 (428 mg,2.09 mmol) obtained in the previous step was dissolved in toluene (6 mL) under nitrogen atmosphere, triethylamine (0.9 mL,6.27 mmol) and diphenyl azide phosphate (0.7 mL,3.13 mmol) were added thereto, and after stirring at room temperature for 30 minutes, tert-butanol (6 mL) was added thereto, and the reaction mixture was stirred at 110℃for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, then added with water (30 mL), extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to give P-6 (344 mg, yield: 60%).
Ms m/z(ESI):277.1[M+H] +
Sixth step: preparation of P-7
P-6 (344 mg,1.25 mmol) was dissolved in acetonitrile (3 mL), followed by addition of hydrogen chloride (4N in Dioxane) (3 mL) and stirring at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, diluted with 15mL of water, extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product P-7 (247 mg).
Ms m/z(ESI):177.1[M+H] +
Seventh step: preparation of P-8
P-7 (247 mg) and P-toluenesulfonic acid monohydrate (13.34 mg,0.07 mmol) were dissolved in acetonitrile (5.5 mL) under nitrogen atmosphere, and N-iodosuccinimide (379 mg,1.68 mmol) was added thereto and stirred at 70℃for 20 hours. After the reaction solution was cooled to room temperature, the reaction was quenched by addition of a saturated aqueous sodium thiosulfate solution (15 mL), extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was chromatographed on a silica gel column to give P-8 (333 mg, two-step yield: 88%).
Ms m/z(ESI):303.0[M+H] +
Eighth step: preparation of P-9
P-8 (333 mg,1.103 mmol), pd (dppf) Cl 2 DCM (90 mg,0.11 mmol) and triethylamine (0.77 mL,5.5 mmol) were dissolved in absolute ethanol (8 mL) and after the reaction was replaced with carbon monoxide atmosphere, the mixture was stirred at 80℃for 15 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and then, P-9 was obtained by separation and purification through silica gel column chromatography (216 mg, yield: 79%).
Ms m/z(ESI):249.1[M+H] +
Ninth step: preparation of P-10
P-9 (216 mg,0.871 mmol) was dissolved in tetrahydrofuran (5 mL), and 2, 2-trichloroacetyl isocyanate (0.16 mL,1.31 mmol) was slowly added dropwise to the system at room temperature, and after the addition was completed, the mixture was stirred at room temperature for 30 minutes. The reaction solution was then concentrated under reduced pressure to give a residue, which was slurried with methyl tert-butyl ether and filtered to give P-10 (560 mg).
Ms m/z(ESI):438.0[M+H] +
Tenth step: preparation of P-11
P-10 (560 mg) was dissolved in anhydrous methanol (15 mL), and after stirring and dissolution, ammonia-methanol solution (1 mL) was added, the reaction was continued under stirring at room temperature for 1 hour, a large amount of white solid was precipitated, the reaction solution was filtered, the obtained solid was slurried with methyl tert-butyl ether, and crude solid P-11 (472 mg) was obtained by filtration, and was directly used for the next reaction.
Ms m/z(ESI):246.0[M+H] +
Eleventh step: preparation of P-12
P-11 (472 mg) and N, N-diisopropylethylamine (0.96 mL,5.8 mmol) were dissolved in toluene (20 mL) under nitrogen, and phosphorus oxychloride (0.55 mL,5.8 mmol) was slowly added and stirred at 100℃for 5 hours. After the reaction solution was cooled to room temperature, the concentrated solution was filtered under reduced pressure to obtain a residue, i.e., crude product P-12, which was directly used for the next reaction.
Twelfth step: preparation of P-13
The crude product P-12 obtained in the previous step was dissolved in 20mL of methylene chloride, 3.5mL of N, N-diisopropylethylamine (1.3 mL,7.72 mmol) was added, and after dissolving the mixture in stirring at 0℃intermediate 1 (409 mg,1.93 mmol) was added to the system. The reaction was continued to stir at 0℃for 3 hours. The reaction solution was concentrated directly, and the obtained residue was purified by silica gel column chromatography to give P-13 (287 mg, four-step yield: 72%).
Ms m/z(ESI):458.2[M+H] +
Thirteenth step: preparation of P-14
P-13 (287 mg,0.627 mmol) and intermediate 2 (200 mg, 1.255 mmol) were dissolved in an overdry 1, 4-dioxane solution (20 mL) and then N, N-diisopropylethylamine (1.03 mL,6.27 mmol) was added. The reaction was stirred at 90℃for 16 hours under nitrogen. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give P-14 (241 mg, yield: 66%).
Ms m/z(ESI):581.4[M+H] +
Fourteenth step: preparation of P-15
P-14 (241 mg, 0.418 mmol), intermediate 3 (425 mg,0.83 mmol), pd (dppf) Cl under nitrogen 2 DCM (34 mg,0.0415 mmol) and cesium carbonate (406 mg,1.245 mmol) were added to a mixed solvent of 1, 4-dioxane (9 mL) and water (3 mL). The reaction was stirred at 100℃for 3 hours. After the reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, 30mL of water was added, and then ethyl acetate (20 mL. Times.3) was used for extraction, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give P-15 (269 mg, yield: 70%).
Ms m/z(ESI):466.4[(M+2H)/2] +
Fifteenth step: preparation of P-16
P-15 (279 mg,0.289 mmol) was dissolved in 3mL of DMF under nitrogen, followed by the addition of CsF (220 mg, 1.4476 mmol) at room temperature. Stirring was continued for 4 hours. 50mL of ethyl acetate was added to dilute, the organic phase was washed with saturated brine, the organic phase was dried and concentrated, and the residue was separated and purified by column chromatography to give P-16 (134 mg, yield: 60%).
Ms m/z(ESI):775.3[M+H] +
Sixteenth step: preparation of intermediate P
P-16 (3.44 g,4.44 mmol) was dissolved in 13mL of acetonitrile, then 13mL of 1, 4-dioxane solution of hydrochloric acid was added, stirring was performed at room temperature for 15 minutes, after a large amount of white solid had been precipitated in the reaction system, the solvent was removed under reduced pressure, the residue was diluted with 50mL of a mixed solution of methylene chloride and methanol (10:1), then the pH of the system was adjusted to be alkaline with saturated sodium bicarbonate solution, and the organic phase was separated. The aqueous phase was extracted with 100mL×3 of a mixture of dichloromethane and methanol (10:1), the organic phases were combined, dried, concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument: SHIMADZU LC-20AP; column chromatography: phenomnex C18; mobile phase: ais0.05% NH) 4 HCO 3 in H 2 O; b is acetonitrile; eluent Phase B from 40to 60in 15min; the flow rate is 25mL/min; column temperature, room temperature; the detection wavelength was 210 nm) to give intermediate P (530 mg, yield 18.9%).
LCMS m/z＝631.3[M+H] +
1 H NMR(400MHz,CD 3 OD)δ7.89–7.82(m,1H),7.37–7.28(m,2H),7.27–7.21(m,1H),5.44–5.24(m,1H),4.41–4.07(m,4H),4.03(s,3H),3.73–3.64(m,2H),3.63–3.46(m,2H),3.42–3.19(m,4H),3.12–3.01(m,1H),2.44–2.12(m,3H),2.10–2,17(m,7H).
Example 12:2- (2, 6-Dioxypiperidin-3-yl) -5- (4- (3- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -5-methoxypyridine [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octyl-8-methyl) piperidin-1-yl) isoindole-1, 3-dione (compound 12)
The first step: preparation of 12A
Intermediate P (0.2 g,0.32 mmol) was dissolved in 10mL of DMAc, N-t-butoxycarbonyl-4-piperidinecarbaldehyde (0.14 g,0.64 mmol) was added, and after reacting at room temperature for 2 hours with 100mg of glacial acetic acid and anhydrous magnesium sulfate, sodium triacetoxyborohydride (0.2 g,0.96 mmol) was added and the reaction was continued for 2 hours. Saturated aqueous sodium hydrogencarbonate was added to quench, extraction was performed with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography to give 12A as a pale yellow solid (0.18 g, yield 67.94%).
Ms m/z(ESI):828.3[M+H] +
And a second step of: preparation of 12B
12A (0.18 g,0.22 mmol) was dissolved in 10mL of dichloromethane, 2mL of 4N dioxane solution of hydrochloric acid was added, stirred at room temperature for 1h, and concentrated under reduced pressure to give crude 12B (0.15 g, yield: 93.68%) which was used directly in the next step.
Ms m/z(ESI):364.8[M+2] + /2
And a third step of: preparation of Compound 12
12B (0.11 g,0.15 mmol) was dissolved in 5mL DMSO, 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (0.083 g,0.3 mmol) was added and DIPEA (0.1 g,0.75 mmol) was stirred under nitrogen for 3h at 80 ℃. Water (20 mL) was added to the reaction, extraction was performed with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography to give compound 12 (20 mg, yield: 13.55%).
Ms m/z(ESI):492.9[M+2] + /2
Cell proliferation inhibition assay
ASPC-1 cell culture conditions: RPMI-1640+10% FBS+1% diabody, cultured at 37 ℃,5% CO 2 In the incubator. ASPC-1 cells in exponential growth phase were collected on the first day in 96-well plates with a plating density of 1000 plates/well at 37℃and 5% CO at 80. Mu.L per well 2 Culturing overnight in incubator, and plating while spreading T 0 And (3) a hole. The next day, 20. Mu.L of compound was added to each well to give final DMSO concentration of 0.5% per well at 37deg.C, 5% CO 2 Culturing in incubator for 6 days. The next day of dosing while detecting T using CellTiter-Glo kit 0 Board, denoted RLU 0 . After the incubation, 25 μl of detection solution (Cell 4 usability Assay, promega) was added to each well, mixed for 2 minutes, incubated at room temperature for 10 minutes, and chemiluminescent readings were detected using a Nivo multi-label analyzer (PerkinElmer). Results the proliferation inhibition ratio of each concentration of the compound was calculated by the treatment of formula (1), and curve fitting was performed using four parameters using GraphPad Prism software, and the concentration GI of the compound at which the proliferation inhibition ratio was 50% was calculated 50 Values. RLU (radio link Unit) compound For drug treatment group readings, RLU control Mean value of the solvent control group. The test results are shown in Table 1.
Inhibition％＝(1-(RLU compound -RLU 0 )/(RLU control -RLU 0 ) 100% x (1)
TABLE 1 proliferation-inhibiting Activity GI of the Compounds of the invention 50 Value of
| Numbering of compounds | GI 50 (nM) |
| Compound 3 | A |
| Compound 4 | A |
| Compound 6 | A |
Note that: a is less than or equal to 200nM,200< B is less than or equal to 1000nM, and C is less than or equal to 1000nM.
Conclusion: the compounds of the present invention have good proliferation inhibitory activity against ASPC-1 cells.
Claims (14)
1. A compound or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein the compound is selected from compounds shown in a general formula (I),
B-L-K(I)；
l is selected from a bond or-C 1-50 Hydrocarbyl-, having from 0 to 20 methylene units in said hydrocarbyl optionally further replaced by-Ak-, -Cy-;
each-Ak-is independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(＝O)-、-NR L (CH 2 ) q C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-(CH 2 ) q -、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -、-CH＝CH-、-Si(R L ) 2 -、-Si(OH)(R L )-、-Si(OH) 2 -、-P(＝O)(OR L )-、-P(＝O)(R L )-、-S-、-S(＝O)-、-S(＝O) 2 -or a bond, said-CH 2 Optionally further 0 to 2 are selected from H, halogen, OH, CN, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Substituted by alkyl;
q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;
R L each independently selected from H, C 1-6 Alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl;
each-Cy-is independently selected from the group consisting of a bond, 4-8 membered heteromonocyclic ring, 4-10 membered heterobicyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered heterocycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl, or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic ring, heterofused ring, heterospiro ring, or heterobridged ring optionally further being 0 to 4 selected from H, F, cl, br, I, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing from 1 to 4 heteroatoms selected from O, S, N, optionally further substituted with 0, 1, or 2 = O when the heteroatom is selected from S;
b is selected from
R 1 Selected from H, halogen, OH, cyano, CF 3 、NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, said alkylOr alkoxy optionally further substituted with 0 to 4 groups selected from halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
ring W is selected from 7-to 12-membered heterocyclic ring or C 7-10 A carbocycle, said heterocycle or carbocycle being selected from one of the following groups, saturated or partially saturated: a monocyclic, parallel, bridged or spiro ring, said heterocyclic or carbocyclic ring optionally being further substituted with 0 to 4R a A substitution, said heterocycle containing from 1 to 4 heteroatoms selected from O, S, N;
R a each independently selected from H, halogen, OH, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 (v), =o, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
alternatively, any two R a Directly connected to form C 3-6 Carbocycles or 3-to 8-membered heterocycles, said carbocycles or heterocycles optionally being further substituted with 1 to 4 groups selected from halogen, OH, cyano, CF 3 、COOH、NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
Z 1 、Z 2 each independently selected from C or N;
when Z is 1 When selected from N, X 2 Selected from the group consisting of a bond;
when Z is 1 When selected from C, X 2 Selected from bonds or NR x ；
X 1 Each independently selected from bond, O, -OCH 2 -、-CH 2 O-or NR x ；
Y 1 Each independently selected from N, CH or C (C) 1-4 Alkyl) optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
Y 2 each independently selected from N, CH or CR Y ；
R Y Selected from H, halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
R x selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
R 2 selected from C 1-6 Alkyl, C 1-6 Alkoxy, - (CH) 2 ) q -3 to 12 membered heterocycle or- (CH) 2 ) q -C 3-10 Carbocycles, said CH 2 Optionally further substituted with 0 to 4R 2a A substitution, said heterocycle containing from 1 to 4 heteroatoms selected from O, S, N;
R 2a each independently selected from H, halogen, = O, OH, cyano, COOH, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocycle or 3-to 12-membered heterocycle, said alkyl, alkoxy, carbocycle, heterocycle optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl;
R 4 selected from C 1-6 Alkyl, C 3-10 Carbocyclyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl or 5 to 10 membered heteroaryl, said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl optionally being further substituted with 0 to 5R 4a A substitution, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
R 4a each independently selected from H, halogen, = O, OH, cyano, CF 3 、COOH、NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 6-10 Aryl or 5-to 10-membered heteroaryl, said alkyl, alkoxy, alkylthio, alkynyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, said heterocycloalkyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
R 3 、R 5 each independently selected from H, halogen, OH, cyano, COOH, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkynyl, C 2-6 Alkenyl, C 4-7 Heterocyclyl, C 3-6 Cycloalkyloxy or C 3-6 Cycloalkyl, said alkyl, alkoxy, alkylthio, alkynyl, alkenyl, heterocyclyl, cycloalkyloxy or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 4-7 Heterocyclyl or C 3-6 Substituted cycloalkyl;
k is selected from
Q is each independently selected from the group consisting of bond, -O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 3-12 membered heterocyclyl, said heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I,OH、＝O、NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
R q selected from H or C 1-6 An alkyl group;
a is selected from C 3-10 Carbocyclyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
f are each independently selected from C 3-20 Carbocyclyl, C 6-20 Aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
R k2 each independently selected from the group consisting of bond, -CO-, -SO 2 -, -SO-or-C (R) k3 ) 2 -；
R k1 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k3 each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
or two R k3 And the carbon atoms or ring skeletons directly linked to each other together form a 3-8 membered carbocycle or 3-8 membered heterocycle, said carbocycle or heterocycle optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;
R k4 each independently selected from H, OH, NH 2 、CN、CONH 2 、C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
M 1 selected from the group consisting of bond, -C (=O) NH-, -NHC (=O) -, -CH 2 -C(＝O)NH-、-C(＝O)CH 2 NH-, 5-6 membered heteroaryl, said heteroaryl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, CF 3 、NH 2 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 A substituent of an alkoxy group, said heteroaryl group containing 1 to 4 heteroatoms selected from O, S, N;
M 2 selected from-NHC (=o) -C 1-6 Alkyl, -NHC (=o) -C 3-6 Cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
M 3 selected from-NH-or-O-;
R k10 selected from C 1-6 Alkyl optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, C 1-6 Alkyl or C 3-6 Substituted cycloalkyl;
R k11 each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylthio or-O-C (=o) -C 1-6 Alkyl, saidAlkyl, alkoxy or alkylthio are optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k12 、R k13 each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k14 selected from 5-6 membered heteroaryl, optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl substituent, said heteroaryl containing 1 to 4 heteroatoms selected from N, O, S;
g is selected from 6-10 membered aryl or 5-10 membered heteroaryl, said aryl or heteroaryl optionally further being 0 to 4 selected from H, F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl substituent, said heteroaryl containing 1 to 4 heteroatoms selected from N, O, S;
n1, n2, n3 are each independently selected from 0, 1, 2 or 3;
p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.
2. The compound of claim 1, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
l is selected from the group consisting of-Cy 1-Cy2-Ak2-Cy3-Cy4-Ak 4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak 5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak 1-2-Ak 2-Ak3-Cy3-Cy4-Ak 5-; -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak 5-; -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5- -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak 5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak 5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak2-Ak 3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -1-Ak 2-Ak3-Ak4-Ak 2-Cy3-Cy4-Ak 5-; -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak 2-Cy 5-Cy1-Cy 2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5- -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy 2-Ak3-Ak4-Ak5-Cy3-Cy 4-; -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy 3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy 4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4- Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;
Ak1, ak2, ak3, ak4, ak5 are each independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 )q-NR L C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-(CH 2 ) q -、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -or a bond, said-CH 2 Optionally further 0 to 2 are selected from H, halogen, OH, CN, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano groups are takenSubstituted C 1-4 Substituted by alkyl;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from the group consisting of a bond, 4-7 membered heteromonocyclic ring, 4-10 membered heterobicyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered heterocycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic ring, heterofused ring, heterospiro ring or heterobridged ring optionally further being selected from 0 to 4 from H, F, cl, br, I, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing from 1 to 4 heteroatoms selected from O, S, N, optionally further substituted with 0, 1, or 2 = O when the heteroatom is selected from S;
q is each independently selected from 0, 1, 2, 3 or 4;
R L each independently selected from H or C 1-6 An alkyl group;
B is selected from
a is selected from 0, 1, 2, 3 or 4;
X 1 selected from bonds, O or NR x ；
R x Selected from H or C 1-4 An alkyl group;
Y 1 each independently selected from N, CH or C (C) 1-4 An alkyl group);
R Y selected from H, halogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R 2a each independently selected from H, halogen, = O, OH, cyano, CF 3 、C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycles or 3 to6 membered heterocyclic ring, said alkyl, alkoxy, carbocycle, heterocyclic ring optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R 3 、R 5 each independently selected from H, halogen, OH, cyano, COOH, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 2-4 Alkynyl, C 2-4 Alkenyl, C 4-7 Heterocyclyl, C 3-6 Cycloalkyloxy or C 3-6 Cycloalkyl, said alkyl, alkoxy, alkylthio, alkynyl, alkenyl, heterocyclyl, cycloalkyloxy or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R 4 selected from C 6-10 Carbocyclyl, 6-to 10-membered heterocyclyl, C 6-10 Aryl or 5-to 10-membered heteroaryl, said carbocyclyl, heterocyclyl, aryl or heteroaryl optionally being further substituted with 0 to 5R 4a A substitution, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
R 4a each independently selected from H, halogen, = O, OH, cyano, CF 3 、NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 Alkynyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, phenyl or 5-to 6-membered heteroaryl, said alkyl, alkoxy, alkylthio, alkynyl, alkenyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl, C 1-4 The alkoxy substituent is substituted, and the heterocycloalkyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N.
3. The compound of claim 2, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from the group consisting of a bond, a 4-7 membered nitrogen containing heteromonocyclic ring, a 4-10 membered nitrogen containing heteromonocyclic ring, a 5-12 membered nitrogen containing heterospiro ring, a 7-10 membered nitrogen containing heterobridged ring, a 3-7 membered monocycloalkyl, a 4-10 membered cycloalkyl, a 5-12 membered spirocycloalkyl, a 7-10 membered bridged cycloalkyl, a 5-10 membered heteroaryl or a 6-10 membered aryl, said heteromonocyclic ring, heterofused ring, heterobridged ring, heterospiro ring, cycloalkyl, aryl or heteroaryl optionally being further substituted with 0 to 4 members selected from H, F, cl, br, I, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteromonocyclic, heterobicyclic, heterobridged, heterospiro or heteroaryl group containing from 1 to 4 heteroatoms selected from O, S, N, optionally further substituted with 0, 1 or 2 = O when the heteroatoms are selected from S;
R L each independently selected from H or C 1-4 An alkyl group;
R 1 selected from H, F, cl, br, I, OH, NH 2 、-NHCH 3 、-N(CH 3 ) 2 Cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, saidOptionally further 0 to 4 methyl, ethyl, propyl, isopropyl, methoxy, ethoxy groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R a each independently selected from H, F, cl, br, I, OH, NH 2 、-NHCH 3 、-N(CH 3 ) 2 (c) =o, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy optionally further being 0 to 4 groups selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、-NHCH 3 、-N(CH 3 ) 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
Alternatively, any two R a Directly connecting to form cyclopropyl and cyclobutyl;
R 2a each independently selected from H, F, cl, br, I, = O, OH, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further being 0 to 4 selected from H, F, cl, br, I, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R 4 selected from one of the following substituted or unsubstituted: phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, indazole, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, pyridinyl, when substituted, are optionally further substituted with 0 to 5R 4a Substitution;
R 4a each independently selected from H, halogen, OH, NH 2 Cyano, CF 3 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio group、C 2-4 Alkynyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl or 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, alkylthio, alkynyl, alkenyl, cycloalkyl, heterocycloalkyl optionally being further substituted by 0 to 4 members selected from H, halogen, OH, cyano, CF 3 、COOH、NH 2 、C 1-4 Alkyl, C 1-4 Substituted with an alkoxy substituent, said heterocycloalkyl containing 1 to 2 heteroatoms selected from O, S, N;
R 3 、R 5 each independently selected from H, F, cl, br, I, OH, cyano, CF 3 Methyl, ethyl, cyclopropyl, cyclopropyloxy or methoxy;
R x selected from H, methyl or ethyl;
Y 1 each independently selected from N or CH;
R Y selected from H, F, cl, br, I, methyl, ethyl, cyclopropyl;
k is selected from
M 2 selected from-NHC (=o) -C 1-4 Alkyl, -NHC (=o) -C 3-6 Cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
R k10 selected from C 1-4 Alkyl optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, C 1-4 Alkyl or C 3-6 Substituted cycloalkyl;
R k11 each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-4 Alkyl, C 1-4 Alkoxy or C 1-4 Alkylthio or-O-C (=o) -C 1-4 Alkyl, said alkyl, alkoxy or alkylthio being optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k12 、R k13 each independently selected from H, C 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
q is each independently selected from-O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 4-7 membered heterocyclyl, said heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
R q selected from H or C 1-4 An alkyl group;
R k1 、R k3 each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CF 3 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, NH 2 Is substituted by a substituent of (2);
or two R k3 And the carbon atoms or ring skeletons directly linked to each other together form a 3-6 membered carbocyclic ring or a 3-7 membered heterocyclic ring, said carbocyclic ring or heterocyclic ring optionally being further substituted with 0 to 4 members selected from H, F, cl, br, I, OH、＝O、NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;
R k4 each independently selected from H, OH, NH 2 、CF 3 、CN、C 1-4 An alkyl group;
R k5 Each independently selected from CO, CH 2 、SO 2 、
R k6 Each independently selected from CO, CH, SO, SO 2 、CH 2 Or N;
R k7 each independently selected from CO, CH, N, CH 2 、O、S、N(CH 3 ) Or NH;
R k8 each independently selected from C, N or CH;
R k9 each independently selected from bond, CO, CH 2 、CH 2 CH 2 Or SO 2 ；
A. H1 or H2 are each independently selected from C 3-8 A carbocycle, benzene ring, 4-7 membered heterocycle or 5-6 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
e is each independently selected from C 3-8 A carbocycle, a benzene ring, a 4-7 membered heterocycle, an 8-12 membered heterocyclyl, a 7-12 membered heteroaryl or a 5-6 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
f is each independently selected from 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 5-10 membered bridged cycloalkyl, 4-7 membered heteromonocyclic, 4-10 membered heteroacene, 5-12 membered heterospirocyclic, 5-10 membered heterobridged ring, C 6-14 Aryl or 5-10 membered heteroaryl, said heteromonocyclic, heterobicyclic, heterospiro, heterobridged or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N.
4. The compound of claim 3, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
R L selected from H, methyl or ethyl;
q is each independently selected from 0, 1 or 2;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexenyl, piperidine, morpholine, piperazine, phenyl, cyclopropyl-and-cyclopropyl, cyclopropyl-and-cyclobutyl, cyclobutyl-and-cyclopentyl, cyclobutyl-and-cyclohexyl, cyclopentyl-and-cyclopentyl, cyclopentyl-and-cyclohexyl, cyclohexyl-and-cyclohexyl, cyclopropyl-and-cyclobutyl, cyclopropyl-and-spirobutyl, cyclopropyl-and-spirocyclopentyl, cyclopropyl-and-spirocyclohexyl, cyclobutyl-and-spirobutyl, cyclobutyl-and-spiropentyl, cyclobutyl-and-spirohexyl, cyclopentyl-and-spirocyclohexyl, cyclohexyl-and-spirocyclohexyl, cyclopropyl-and-azacyclobutyl, cyclopropyl-and-azacyclohexyl, cyclopropyl-and-piperidine, cyclobutyl-and-azacyclobutyl, cyclobutyl-and-azacyclopentyl cyclobutyl azetidine, cyclobutyl piperidine, cyclopentyl azetidine, cyclopentyl piperidine, cyclohexyl azetidine, cyclohexyl-azetidinyl, azetidinyl-hexyl cyclohexyl-azacyclopentyl, cyclohexyl-azacyclohexyl, cyclohexyl-azapiperidine azetidinoazetidines, azetidinoazelohexyl, azetidines, azetidin, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, Cyclohexyl spiro-azetidine, azetidinyl spiro-azetidine, cyclohexyl, azetidine azacyclopentyl spiroazetidinyl, azacyclopentyl spiroazetidinyl azacyclopentyl spiro-azacyclohexyl Azacyclohexaspiroazetidine, azacyclohexaspiroazetidine, cyclobutylspiropiperidine, cyclopentylpiropiperidine, cyclohexylspiropiperidine, azetidinylpiropiperidine, azacyclopentylpiropiperidine, azacyclohexylspiropiperidine,
When substituted, optionally further substituted with 0 to 4 members selected from H, F, cl, br, I, OH, NH 2 、COOH、CN、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
b is selected from
b is selected from 0, 1, 2, 3 or 4;
R 1 selected from H, F, cl, br, I, OH, cyano, methyl, ethyl, propyl, isopropyl;
R 4a each independently selected from H, F, cl, br, I, OH, NH 2 Cyano, CF 3 Methyl, ethyl, isopropyl, methoxy, ethoxy, -OCF 3 Cyclopropyl, cyclobutyl, and ringAmyl, cyclohexyl and ethynyl;
R 2a each independently selected from H, F, cl, br, I, = O, OH, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy;
R 3 、R 5 Each independently selected from H, methyl, ethyl, cyclopropyl, methoxy, or F;
R x selected from H, methyl or ethyl;
k is selected from
/>
/>
M1 is selected from the group consisting of bond, -C (=O) NH-, -CH 2 -C(＝O)NH-、-C(＝O)CH 2 NH-, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl;
M 2 selected from-NHC (=O) -CH 3 -NHC (=o) -cyclopropyl, -NHC (=o) -cyclobutyl, azetidinyl, benzazetidinyl, said cyclopropyl, cyclobutyl, azetidinyl, benzazetidinyl or benzazetidinyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k10 selected from methyl, ethyl, isopropyl, propyl, tert-butyl, said methyl, ethyl, isopropyl, propyl, tert-butyl optionally further being 0 to 4 selected from H, F, cl, br, I, =o, OH, C 1-4 Alkyl or C 3-6 Substituted cycloalkyl;
R k11 are each independently selected fromH. F, cl, br, I, =o, OH, SH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio or-O-C (=o) -CH 3 Said methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio optionally further being 0 to 4 groups selected from H, F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k12 、R k13 each independently selected from H, methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl, optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
e is each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl;
each a is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl;
f is each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridinyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, azacyclopentyl, piperidinyl, morpholinyl, pyridonyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl or pyrazinopyrazinyl;
R k7 Each independently selected from CH 2 、O、N(CH 3 ) Or NH;
p1 or p2 are each independently selected from 0, 1 or 2.
5. The compound of claim 4, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
b is selected from
R 1 Selected from H, F, cl, br, methyl, ethyl, propyl, isopropyl;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups:
6. The compound of claim 5, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
b is selected from
L is selected from the group consisting of-Cy 1-, -Cy1-Ak1-Cy2-, -Ak1-Ak2-Cy3-Ak3-, -Ak1-Ak2-Cy3-Ak 4-, ak1-Cy2-Ak2-, -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;
or L is selected from the group consisting of-Ak 1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-;
ak1, ak2, ak3, ak4, ak5 are each independently selected from the group consisting of-O-, -OCH 2 -、-CH 2 O-、-OCH 2 CH 2 -、-CH 2 CH 2 O-、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -, -C (=O) -or-C (=O) CH 2 -。
7. The compound of claim 6, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
l is selected from a bond or a group wherein the left side of the group is attached to B;
8. the compound of claim 7, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
b is selected from
/>
K is selected from one of the following structural fragments:
9. the compound of claim 8, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
k is selected from one of the following structural fragments:
10. the compound of claim 1, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the following structures:
11. a pharmaceutical composition comprising a compound of any one of claims 1-10, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.
12. Use of a compound according to any one of claims 1-10, or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with KRAS G12D activity or expression level.
13. Use of a compound according to any one of claims 1-10, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of a medicament for the treatment and inhibition or degradation of KRAS G12D-related diseases.
14. The use according to claim 12 or 13, wherein the disease is selected from cancer.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024083258A1 (en) * | 2022-10-21 | 2024-04-25 | 上海领泰生物医药科技有限公司 | Kras g12c degradation agent, and preparation method and use therefor |
| WO2024083256A1 (en) * | 2022-10-21 | 2024-04-25 | 上海领泰生物医药科技有限公司 | Pan-kras degrading agent, and preparation method therefor and use thereof |
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- 2022-12-21 CN CN202211628220.XA patent/CN116375742A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024083258A1 (en) * | 2022-10-21 | 2024-04-25 | 上海领泰生物医药科技有限公司 | Kras g12c degradation agent, and preparation method and use therefor |
| WO2024083256A1 (en) * | 2022-10-21 | 2024-04-25 | 上海领泰生物医药科技有限公司 | Pan-kras degrading agent, and preparation method therefor and use thereof |
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| Date | Code | Title | Description |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20231221 Address after: 856099 Xingfu Jiayuan Economic Development Zone, Gyerba, Nedong District, Shannan City, Tibet Autonomous Region Applicant after: Tibet Haisike Pharmaceutical Co.,Ltd. Address before: No.17 Sanxiang Avenue, Zedang Town, Shannan City, Tibet Autonomous Region Applicant before: HAISCO PHARMACEUTICAL Group Inc. |