CN112812100A - Compound capable of degrading BTK kinase, preparation method and pharmaceutical application thereof - Google Patents
Compound capable of degrading BTK kinase, preparation method and pharmaceutical application thereof Download PDFInfo
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- CN112812100A CN112812100A CN202011152071.5A CN202011152071A CN112812100A CN 112812100 A CN112812100 A CN 112812100A CN 202011152071 A CN202011152071 A CN 202011152071A CN 112812100 A CN112812100 A CN 112812100A
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- substituted
- membered
- ring
- amino
- alkyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 128
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 230000000593 degrading effect Effects 0.000 title description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 60
- 239000013078 crystal Substances 0.000 claims abstract description 56
- 229940002612 prodrug Drugs 0.000 claims abstract description 56
- 239000000651 prodrug Substances 0.000 claims abstract description 56
- 239000012453 solvate Substances 0.000 claims abstract description 52
- 239000002207 metabolite Substances 0.000 claims abstract description 51
- 201000010099 disease Diseases 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 9
- -1 cyclobutylcyclobutyl Chemical group 0.000 claims description 202
- 125000000623 heterocyclic group Chemical group 0.000 claims description 84
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 56
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 56
- 229910052794 bromium Inorganic materials 0.000 claims description 54
- 229910052801 chlorine Inorganic materials 0.000 claims description 54
- 229910052731 fluorine Inorganic materials 0.000 claims description 54
- 229910052739 hydrogen Inorganic materials 0.000 claims description 53
- 229910052740 iodine Inorganic materials 0.000 claims description 53
- 125000001072 heteroaryl group Chemical group 0.000 claims description 44
- 125000001424 substituent group Chemical group 0.000 claims description 43
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical group OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 claims description 36
- 125000005842 heteroatom Chemical group 0.000 claims description 35
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 34
- 229910052717 sulfur Inorganic materials 0.000 claims description 34
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 229910052757 nitrogen Inorganic materials 0.000 claims description 32
- 125000002393 azetidinyl group Chemical group 0.000 claims description 31
- 229910052760 oxygen Inorganic materials 0.000 claims description 31
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 18
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- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
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- 125000003003 spiro group Chemical group 0.000 claims description 14
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 10
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- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- JUXAVSAMVBLDKO-UHFFFAOYSA-N 1-(1-azabicyclo[2.2.2]octan-3-yl)-3-[3-(1h-indol-3-yl)-1-oxo-1-spiro[1,2-dihydroindene-3,4'-piperidine]-1'-ylpropan-2-yl]urea Chemical compound C1N(CC2)CCC2C1NC(=O)NC(C(=O)N1CCC2(C3=CC=CC=C3CC2)CC1)CC1=CNC2=CC=CC=C12 JUXAVSAMVBLDKO-UHFFFAOYSA-N 0.000 claims description 4
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- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 4
- 101100518409 Schizosaccharomyces pombe (strain 972 / ATCC 24843) orc1 gene Proteins 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 4
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- APXRHPDHORGIEB-UHFFFAOYSA-N 1H-pyrazolo[4,3-d]pyrimidine Chemical class N1=CN=C2C=NNC2=C1 APXRHPDHORGIEB-UHFFFAOYSA-N 0.000 claims description 3
- DDZGQYREBDXECY-UHFFFAOYSA-N 1h-pyrazolo[3,4-b]pyrazine Chemical class C1=CN=C2C=NNC2=N1 DDZGQYREBDXECY-UHFFFAOYSA-N 0.000 claims description 3
- UNRJKSOCYAGRFG-UHFFFAOYSA-N 2,3,4,4a-tetrahydro-1H-cyclopenta[b]pyridine Chemical compound N1CCCC2C=CC=C12 UNRJKSOCYAGRFG-UHFFFAOYSA-N 0.000 claims description 3
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 3
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
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- 150000005235 imidazopyrazines Chemical class 0.000 claims description 3
- 150000005237 imidazopyrimidines Chemical class 0.000 claims description 3
- ITMRVWWUAHLHPJ-UHFFFAOYSA-N n-cyclopropylpiperidin-1-amine Chemical compound C1CC1NN1CCCCC1 ITMRVWWUAHLHPJ-UHFFFAOYSA-N 0.000 claims description 3
- 150000003217 pyrazoles Chemical class 0.000 claims description 3
- 150000004944 pyrrolopyrimidines Chemical class 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
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- 230000015556 catabolic process Effects 0.000 claims description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 2
- 238000006731 degradation reaction Methods 0.000 claims description 2
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- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 7
- 125000005843 halogen group Chemical group 0.000 claims 6
- 238000004519 manufacturing process Methods 0.000 claims 2
- DSSKLTAHHALFRW-UHFFFAOYSA-N N-cyclohexylpiperidine Chemical compound C1CCCCC1N1CCCCC1 DSSKLTAHHALFRW-UHFFFAOYSA-N 0.000 claims 1
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- 230000005496 eutectics Effects 0.000 abstract description 8
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- 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
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000018883 protein targeting Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 239000000523 sample Substances 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
- 238000000926 separation method Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- ZQRYPCAUVKVMLZ-HTQZYQBOSA-N tert-butyl (3r,4r)-4-amino-3-fluoropiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](F)C1 ZQRYPCAUVKVMLZ-HTQZYQBOSA-N 0.000 description 1
- SRCROGUSYNRTRE-UHFFFAOYSA-N tert-butyl 3-formylpyrrole-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C=CC(C=O)=C1 SRCROGUSYNRTRE-UHFFFAOYSA-N 0.000 description 1
- LZRDHSFPLUWYAX-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)CC1 LZRDHSFPLUWYAX-UHFFFAOYSA-N 0.000 description 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-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
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 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
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 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
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention relates to a compound shown in a general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application in BTK related diseases such as tumors or autoimmune system diseases. B-L-K (I).
Description
Technical Field
The invention relates to a compound shown in a general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application in BTK related diseases such as tumors or autoimmune system diseases.
Background
Bruton's Tyrosine Kinase (BTK) is a member of the non-receptor protein tyrosine kinase Tec family, is a key regulator in the B cell antigen receptor (BCR) signaling pathway, and is distributed in the lymphatic, hematopoietic, and blood systems. BTK mutations cause activation of signal pathways such as proliferation, differentiation and angiogenesis of downstream tumor cells, leading to X-linked agammaglobulinemia, non-hodgkin's lymphoma (NHL) and many B-cell malignancies, including Chronic Lymphocytic Leukemia (CLL), mantle cell lymphoma and diffuse large B-cell lymphoma. Because the BTK is mainly expressed in B cells and marrow cells, the BTK is a target with better targeting and safety.
PROTAC (protein targeting chimera) molecules are bifunctional compounds capable of simultaneously combining targeting proteins and E3 ubiquitin ligase, and the compounds can be recognized by proteasomes of cells to cause degradation of the targeting proteins and effectively reduce the content of the targeting proteins in the cells. By introducing ligands capable of binding different target proteins into the ProTAC molecule, the application of the PROTAC technology to the treatment of various diseases becomes possible, and the technology has attracted much attention in recent years.
Disclosure of Invention
The invention develops a BTK inhibitor which has novel structure, good drug effect, high bioavailability and higher safety and is used for treating BTK related diseases such as tumors or autoimmune system diseases.
The invention develops a PROTAC compound of a BTK inhibitor and E3 ubiquitin ligase, which has novel structure, good drug effect, high bioavailability and higher safety and can inhibit or degrade BTK, and is used for treating BTK related diseases such as tumors or autoimmune system diseases.
The invention relates to a compound as shown in a general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein
B-L-K (I)
L is selected from-Ak 1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak 5-;
ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from CH2O, NH or a key;
cy1, Cy2, Cy3 and Cy4 are each independentlyIs selected from 3 to 12 membered heterocycle, 3 to 12 membered cycloalkyl, 6 to 10 membered aryl or a bond, said heterocycle, cycloalkyl or aryl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2、oxo、CF3、COOH、CN、C1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy substituted C1-4Alkyl or C1-4Alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;
when Ak1, Ak2, Ak3, Ak4 or Ak5 is O, the B can not be directly connected;
when Ak1, Ak2, Ak3, Ak4 or Ak5 are not bonds, the bonds can not be directly connected with each other;
when 4 or more of Ak1, Cy1, Ak2, Cy2, Ak3, Cy3, Ak4, Cy4 and Ak5 are not bonds, at least one of Cy1, Cy2, Cy3 and Cy4 is not piperidine, piperazine, pyrimidine or pyridine;
b is selected from B1-W1-B2-W2-B3-W3-B4;
b1 is selected from 6-membered heteroaromatic ring or phenyl further optionally substituted with 0 to 4Rb1(iii) substituted, said heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S, N;
w1 is selected from-O-, -S-, -NH-, -NHCO-or-CONH-;
w2 is selected from the group consisting of a bond, -CO-, -O-, -S-, -NH-, -NHCO-, and-CONH-;
w3 is selected from the group consisting of a bond, -CO-, -O-, -S-, -NH-, -NHCO-, and-CONH-;
b2 is selected from 6-membered heteroaromatic ring or phenyl optionally further optionally substituted with 0 to 4Rb2(iii) substituted, said heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S, N;
b3 is selected from an 8-10 membered heteroaryl ring or a 5-6 membered heteroaryl ring, said heteroaryl ring or heteroaryl ring optionally further optionally substituted with 0 to 4Rb3(iii) substituted, said hetero-fused or hetero-aromatic ring containing from 1 to 4 heteroatoms selected from O, S, N;
when B3 is selected from an 8-10 membered fused ring, W2 is not a bond;
b4 is selected from a bond or a 4-10 membered saturated heterocyclic ring selected from monocyclic, fused or spiro ringThe saturated heterocycle, monocyclic, fused ring or spiro ring is optionally further optionally substituted with 0 to 4Rb4Substituted, said saturated heterocycle containing 1 to 2 heteroatoms selected from O, S, N;
Rb1、Rb2、Rb3or Rb4Each independently selected from H, F, Cl, Br, I, OH, NH2、CN、CF3、COOH、CONH2、C1-4Alkyl, hydroxy substituted C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4Alkoxy, said alkyl and alkoxy being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2、CN、CONH2、C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
Ring E is selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1 to 2 heteroatoms selected from O, S, N;
Rk2is selected from CH2、C=O、S=O、SO2;
Rk1、Rk3Or Rk4Each independently selected from H, F, Cl, Br, I, OH, NH2、CN、COOH、C1-4Alkyl or C1-4An alkoxy group;
Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
Cy1, Cy2, Cy3 and Cy4 are each independently selected from the group consisting of 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle, 7-membered heterocycle, 8-membered heterocycle, 9-membered heterocycle, 10-membered heterocycle, 11-membered heterocycle, 12-membered heterocycle, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl6-membered cycloalkyl, 7-membered cycloalkyl, 8-membered cycloalkyl, 9-membered cycloalkyl, 10-membered cycloalkyl, 11-membered cycloalkyl, 12-membered cycloalkyl, 6-to 10-membered aryl or a bond, preferably a bond, 4-membered heteromonocyclic ring, 5-membered heteromonocyclic ring, 6-membered heteromonocyclic ring, 7-membered heteromonocyclic ring, 5-membered hetero-fused ring, 6-membered hetero-fused ring, 8-membered hetero-fused ring, 9-membered hetero-fused ring, 10-membered hetero-fused ring, 6-membered hetero-spiro ring, 7-membered hetero-spiro ring, 8-membered hetero-fused ring, 9-membered hetero-bridged ring, 10-membered hetero-bridged ring, 4-membered monocycloalkyl, 5-membered monocycloalkyl, 6-membered monocycloalkyl, 7-membered monocycloalkyl, 5-membered co-cycloalkyl, 6-membered co-cycloalkyl, 7-membered co-cycloalkyl, 9-co-cycloalkyl, 10-membered co-cycloalkyl, 6-membered co-cycloalkyl spirocyclic, 7-membered spirocycloalkyl, 8-membered spirocycloalkyl, 9-membered spirocycloalkyl, 10-membered spirocycloalkyl, 11-membered spirocycloalkyl, 12-membered spirocycloalkyl, 7-membered bridged cycloalkyl, 8-membered bridged cycloalkyl, 9-membered bridged cycloalkyl, 10-membered bridged cycloalkyl or 6-10-membered aryl, said aryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospirocyclic or heterobridged ring optionally further substituted by 0, 1,2, 3 or 4 substituents selected from H, F, Cl, Br, I, OH, NH2、oxo、CF3、COOH、CN、C1-4Alkyl, hydroxy substituted C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4(ii) alkoxy, said heteromonocyclic, heterobicyclic, heterospirocyclic, or heterobridged ring containing 1,2, 3, or 4 heteroatoms selected from O, S, N;
b1 is selected from 6-membered heteroaromatic ring or phenyl, preferably phenyl or pyridyl, said heteroaromatic ring, phenyl or pyridyl further optionally substituted with 0 to 4Rb1(iii) substituted, said heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S, N;
w1 is selected from-O-, -NHCO-, or-CONH-;
b2 is selected from 6-membered heteroaromatic ring or phenyl, preferably phenyl or pyridyl, said heteroaromatic ring, phenyl or pyridyl further optionally substituted with 0 to 4Rb2(iii) substituted, said heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S, N;
b3 is selected from an 8-10 membered fused ring or a 5-6 membered heteroaromatic ring, which when substituted is optionally furtherIs selected from 0 to 4Rb3(iii) substituted, said hetero-fused or hetero-aromatic ring containing from 1 to 4 heteroatoms selected from O, S, N;
or B3 may be selected from one of the following substituted or unsubstituted groups: imidazopyrimidines, pyrazolopyrimidines, pyrrolopyrimidines, imidazopyrazines, pyrazolopyrazines, imidazotetrahydropyrimidines, pyrazolotetrahydropyrimidines, pyrazoles or imidazoles, when substituted, optionally further optionally substituted with 0 to 4Rb3Substituted;
b4 is selected from a bond or a 4-10 membered saturated heterocyclic ring selected from monocyclic, fused or spiro ring optionally further optionally substituted with 0 to 4Rb4Substituted, said saturated heterocycle containing 1 to 2 heteroatoms selected from O, S, N;
or B4 may be selected from one of the following substituted or unsubstituted groups: azetidinyl, azepinyl, piperidine, cyclopropyloazetidinyl, cyclobutylazetidinyl, cyclobutyloazetidinyl, cyclopentaizetidinyl, cyclopentaietidinyl, cyclohexyloazetidinyl, cyclobutyloazetidinyl, cyclohexyloazetidinyl, or cyclohexyloazetidinyl aoctetidinyl, when substituted, optionally substituted with 0 to 4Rb4Substituted;
Ring E is selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1 to 2 heteroatoms selected from O, S, N;
or ring E may be selected from a benzene ring, pyridine, thiophene, furan, pyrrole, thiazole, oxazole, imidazole or pyrazole;
Rk2is selected from CH2、C=O、S=O、SO2;
Rk1、Rk3Or Rk4Each independently selected from H, F, Cl, Br, I, OH, NH2、CN、COOH、C1-4Alkyl or C1-4An alkoxy group;
Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
Cy1, Cy2, Cy3 and Cy4 are each independently selected from the group consisting of 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle, 7-membered heterocycle, 8-membered heterocycle, 9-membered heterocycle, 10-membered heterocycle, 11-membered heterocycle, 12-membered heterocycle, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 8-membered cycloalkyl, 9-membered cycloalkyl, 10-membered cycloalkyl, 11-membered cycloalkyl, 12-membered cycloalkyl, 6-to 10-membered aryl or a bond, preferably a bond, 4-membered heteromonocycle, 5-membered heteromonocycle, 6-membered heteromonocycle, 7-membered heteromonocycle, 9-membered heteromonocycle, 10-membered heteromonocycle, 11-membered heteromonocycle, 12-membered heteromonocycle, 7-membered heterospiro cycle, 8-membered heterobridged ring, 9-membered heterobridged ring, 9-membered heterospiro ring, 10-membered heterospiro ring, 11-membered heterospiro ring, 12-membered heterospiro ring, 10-membered heterobridged ring, 4-membered monocycloalkyl, 5-membered monocycloalkyl, 6-membered monocycloalkyl, 7-membered monocycloalkyl, 5-membered benzocycloalkyl, 6-membered benzocycloalkyl, 7-membered benzocycloalkyl, 8-membered benzocycloalkyl, 9-membered benzocycloalkyl, 6-membered spirocycloalkyl, 7-membered spirocycloalkyl, 8-membered spirocycloalkyl, 10-membered spirocycloalkyl, 11-membered spirocycloalkyl, 12-membered spirocycloalkyl, 7-membered bridged cycloalkyl, 8-membered bridged cycloalkyl, 9-membered bridged cycloalkyl, 10-membered bridged cycloalkyl or 6-10-membered aryl, which aryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospirocyclic or heterobridged ring is optionally further substituted with 0, 1,2, 3 or 4 substituents selected from H, F, Cl, Br, I, OH, NH2、oxo、CF3、COOH、CN、C1-4Alkyl, hydroxy substituted C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4(ii) alkoxy, said heteromonocyclic, heterobicyclic, heterospirocyclic, or heterobridged ring containing 1,2, 3, or 4 heteroatoms selected from O, S, N;
or Cy1, Cy2, Cy3 and Cy4 may each independently be selected from one of the following substituted or unsubstituted groups: a bond, phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylmethylcyclohexylcyclohexyl, cyclopropylcyclobutylyl, cyclopropylcyclopentylyl, cyclopropylcyclohexylyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylpirocyclopentyl, cyclopentylpirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, azetidinyl, piperidine, morpholine, piperazine, pyrrole, pyrazole, imidazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, tetrazole, cyclopropylazacyclobutyl, cyclopropylazacyclopentyl, cyclopropylazacyclohexyl, cyclopropylaminopiperidine, cyclobutylazetidinylbutyl, cyclobutylazacyclopentyl, Cyclobutyl and azacyclopentyl, cyclobutyl and azacyclohexyl, cyclobutyl and piperidine, cyclopentaazacyclobutyl, cyclopentaazacyclopentyl, cyclopentaazacyclohexyl, cyclopentaptoazacyclopentyl, cyclohexylaozacyclohexyl, azetidinyl, azetidinoazetidinyl, azetidinyl, cyclopentaazetidinyl, azetidinyl, azacyclohexylo-piperidine, cyclobutyl spiroazetidinyl, cyclobutyl spiroazepinyl, azetidinyl, azacyclohexylo, azetidinyl, cyclobutyl spiroazepinyl, cyclopentadipinyl, azetidinyl, and the like, Cyclopentyl spiroazacyclobutanesA group selected from the group consisting of cyclopentyl spiroazacyclopentyl, cyclopentyl spiroazacyclohexyl, cyclohexyl spiroazetidinyl, cyclohexyl spiroazacyclopentyl, cyclohexyl spiroazetidinyl, azetidinyl spiroazetidinyl, cyclobutyl spiropiperidine, cyclopentyl spiropiperidine, cyclohexyl spiropiperidine, azetidinyl spiropiperidine,When substituted, is optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2、oxo、CF3、COOH、CN、C1-4Alkyl, hydroxy substituted C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
b1 is selected from phenyl or pyridyl further optionally substituted with 0 to 4Rb1Substituted;
w1 is selected from-O-, -NHCO-, or-CONH-;
b2 is selected from phenyl or pyridyl further optionally substituted with 0 to 4Rb2Substituted;
b3 is selected from one of the following substituted or unsubstituted groups: imidazopyrimidines, pyrazolopyrimidines, pyrrolopyrimidines, imidazopyrazines, pyrazolopyrazines, imidazotetrahydropyrimidines, pyrazolotetrahydropyrimidines, pyrazoles or imidazoles, when substituted, optionally further optionally substituted with 0 to 4Rb3Substituted;
when B3 is selected from an 8-10 membered fused ring, W2 is not a bond;
b4 is selected from a bond or a 4-10 membered saturated heterocyclic ring selected from monocyclic, fused or spiro ring optionally further optionally substituted with 0 to 4Rb4Substituted, said saturated heterocyclic ring containing 1 to 2A heteroatom selected from O, S, N;
or B4 may be selected from one of the following substituted or unsubstituted groups: azetidinyl, azepinyl, piperidine, cyclopropyloazetidinyl, cyclobutylazetidinyl, cyclobutyloazetidinyl, cyclopentaizetidinyl, cyclopentaietidinyl, cyclohexyloazetidinyl, cyclobutyloazetidinyl, cyclohexyloazetidinyl, or cyclohexyloazetidinyl aoctetidinyl, when substituted, optionally substituted with 0 to 4Rb4Substituted;
Rb1、Rb2、Rb3Or Rb4Each independently selected from H, F, Cl, Br, I, OH, NH2、CN、CF3、COOH、CONH2、C1-4Alkyl, hydroxy substitutionC of (A)1-4Alkyl, halogen substituted C1-4Alkyl or C1-4Alkoxy, said alkyl and alkoxy being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2、CN、CONH2、C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
or Rb1、Rb2、Rb3Or Rb4Can be respectively and independently selected from H, F, Cl, Br, I, OH and NH2、CN、CONH2、CF3COOH, hydroxymethyl, methyl or methoxy, said methyl or methoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I;
n1, n2, n3 are each independently selected from 0, 1,2, 3 or 4;
Rk2Is selected from CH2、C=O、S=O、SO2;
Or Rk2May be selected from CH2Or C ═ O;
Rk1、Rk3or Rk4Each independently selectsFrom H, F, Cl, Br, I, OH, NH2、CN、COOH、C1-4Alkyl or C1-4An alkoxy group;
or Rk1、Rk3Or Rk4Each independently selected from H, F, Cl, Br, I, OH or NH2;
p1 or p2 are each independently selected from 0, 1,2, 3 or 4.
Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
Cy1, Cy2, Cy3 and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: a bond, phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylmethylcyclohexylcyclohexyl, cyclopropylcyclobutylyl, cyclopropylcyclopentylyl, cyclopropylcyclohexylyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylpirocyclopentyl, cyclopentylpirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, azetidinyl, piperidine, morpholine, piperazine, pyrrole, pyrazole, imidazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, tetrazole, cyclopropylazacyclobutyl, cyclopropylazacyclopentyl, cyclopropylazacyclohexyl, cyclopropylaminopiperidine, cyclobutylazetidinylbutyl, cyclobutylazacyclopentyl, Cyclobutyl-and-azacyclopentyl, cyclobutyl-and-azacyclohexyl, cyclobutyl-and-piperidine, cyclopenta-azacyclobutyl, cyclopenta-azacyclopentyl, cyclopenta-azacyclohexyl, cyclopenta-piperidine, cyclohexylo-azacyclobutyl, cyclohexylo-azacyclopentyl, cyclohexylo-azacyclohexyl, cyclohexylo-azetidinyl, azetidinyl-and-azacyclopentyl, cyclopenta-azacyclohexyl, cyclopenta-piperidine, azetidinyl, cyclopenta-,Azetidinyl-and-cyclohexylyl, azetidinyl-and-piperidino, azepinyl-and-azetidinyl, azepinyl-and-cyclopentazacyclohexylyl, azepinyl-and-piperidino, azepinyl-and-azetidinyl, azepinyl-and-cyclohexylyl, azacyclohexylyl-and-piperidino, cyclobutyl-spiroazetidinyl, cyclopentyl-spiroazetidinyl, cyclohexyl-spiroazetidinyl, azetidinyl, Azacyclopentyl spiroazacyclohexyl, azacyclohexyl spiroazetidinyl, azacyclohexyl spiropiperidine, cyclopentylspiropiperidine, cyclohexylspiropiperidine, azetidinylspiropiperidine, azacyclopentylspiropiperidine, azacyclohexylspiropiperidine, azacycloazetidinyl spiropiperidine, azacyclobutylspiropiperidine, azacyclobutylpiperidine, azacyclopentylspiropiperidine, azacyclobutylpiperidine,when substituted, is optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2、oxo、CF3、COOH、CN、C1-4Alkyl, hydroxy substituted C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
B4 is selected from one of the following substituted or unsubstituted groups: azetidinyl, azepinyl, piperidine, cyclopropyloazetidinyl, cyclobutylazetidinyl, cyclobutyloazetidinyl, cyclopentaizetidinyl, cyclopentaietidinyl, cyclohexyloazetidinyl, cyclobutyloazetidinyl, cyclohexyloazetidinyl, or cyclohexyloazetidinyl aoctetidinyl, when substituted, optionally substituted with 0 to 4Rb4Substituted;
Rb1、Rb2、Rb3Or Rb4Each independently selected from H, F, Cl, Br, I, OH, NH2、CN、CONH2、CF3COOH, hydroxymethyl, methyl or methoxy, said methyl or methoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I;
n1, n2, n3 are each independently selected from 0, 1,2, 3 or 4;
Rk2Is selected from CH2Or C ═ O;
Rk1、Rk3or Rk4Each independently selected from H, F, Cl, Br, I, OH or NH2;
p1 or p2 are each independently selected from 0, 1 or 2;
Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
B4 is selected from one of the following substituted or unsubstituted groups: azetidinyl, piperidine, cyclopropyloazetidinyl, cyclopropylOptionally substituted with 0 to 4R when substituted, of cyanoazacyclohexyl, cyclopropylazapiperidine, cyclobutylazacyclobutyl, cyclobutylazacyclopentyl, cyclobutylazacyclohexyl, cyclobutylpiperidine, cyclopentazacyclobutyl, cyclopentazacyclopentyl, cyclopentazacyclohexyl, cyclopentazacyclopentyl, cyclohexylazacyclobutyl, cyclohexylazacyclopentyl, cyclohexylazacyclohexyl, cyclohexylspiroazetidinyl, cyclobutylspiroazacyclopentyl, cyclobutylspiroazacyclohexyl, cyclohexylspiroazetidinyl or cyclohexylspiroazacyclopentylb4Substituted;
Rb1、Rb2、Rb3or Rb4Each independently selected from H, F, Cl, Br, I, OH, NH2、CN、CONH2、CF3COOH, hydroxymethyl, methyl or methoxy, said methyl or methoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I;
n1, n2, n3 are each independently selected from 0, 1,2, 3 or 4;
The left side of the L is connected with the B, and the right side of the L is connected with the K;
Rk2Is selected from CH2Or C ═ O;
Rk1、Rk3or Rk4Each independently selected from H, F, Cl, Br, I, OH or NH2;
p1 or p2 are each independently selected from 0, 1 or 2;
Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
B4 is selected from one of the following substituted or unsubstituted groups: azetidinyl, azepinyl, piperidine, cyclopropyloazetidinyl, cyclobutylazetidinyl, cyclobutyloazetidinyl, cyclopentaizetidinyl, cyclopentaietidinyl, cyclohexyloazetidinyl, cyclobutyloazetidinyl, cyclohexyloazetidinyl, or cyclohexyloazetidinyl aoctetidinyl, when substituted, optionally substituted with 0 to 4Rb4Substituted;
Rb4each independently selected from H, F, Cl, Br, I, OH, NH2、CN、CONH2、CF3COOH, hydroxymethyl, methyl or methoxy, said methyl or methoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I;
The left side of the L is connected with the B, and the right side of the L is connected with the K;
Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
B4 is selected from one of the following substituted or unsubstituted groups: azetidinyl, piperidine, cyclopropyloazetidinyl, cyclonexidineButyl-and-azetidinyl, cyclobutyl-and-azetidinyl, cyclopentyl-and-azetidinyl, cyclopentylpiperidinyl, cyclohexyl-and-azetidinyl, cyclohexyl-and-piperidinyl, cyclobutyl-spiroazetidinyl, cyclohexyl-spiroazetidinyl or cyclohexyl-spiroazetidinyl, when substituted, optionally substituted with 0 to 4Rb4Substituted;
Rb4each independently selected from H, F, Cl, Br, I, OH, NH2、CN、CONH2、CF3COOH, hydroxymethyl, methyl or methoxy, said methyl or methoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I;
The left side of the L is connected with the B, and the right side of the L is connected with the K;
Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
B4 is selected from one of the following substituted or unsubstituted groups: azetidinyl, azepinyl, piperidine, cyclopropyloazetidinyl, cyclobutylazetidinyl, cyclopentaizetidinyl, cyclopentaietidinyl, cyclohexyloazetidinyl, cyclobutylazetidinyl, cyclobutyloazetidinylAn azacyclopentyl, cyclobutyl spiroazacyclohexyl, cyclohexyl spiroazetidinyl or cyclohexyl spiroazacyclopentyl, when substituted, optionally substituted with 0 to 4Rb4Substituted;
Rb4each independently selected from H, F, Cl, Br, I, OH, NH2、CN、CONH2、CF3COOH, hydroxymethyl, methyl or methoxy, said methyl or methoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I;
The left side of the L is connected with the B, and the right side of the L is connected with the K;
Some embodiments of the invention relate to a compound of formula (Ia), (Ib), (Ic), or (Id) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein
B-Cy1-K(Ia)
B-Cy1-Cy2-K(Ib)
B-Cy1-Cy2-Cy3-K(Ic)
B-Cy1-Cy2-Cy3-Cy4-K(Id)
B4 is selected from 4-to 6-membered azamonocyclic ring, 5-to 10-membered azabicyclic ring, 6-to 10-membered azaspiro ring or 4-to 6-membered monocycloalkyl, said cycloalkyl, heteromonocyclic, heterobicyclic or heterospiro ring being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2、CN、CF3、COOH、CONH2、C1-4Alkyl, hydroxy substituted C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4Alkoxy, said heteromonocyclic, heterocyclic, or heterospirocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;
cy1, Cy2, Cy3 and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: 4 to 6 membered azamonocyclic, 5 to 10 membered azabicyclic, 6 to 10 membered azaspiro, 4 to 6 membered monocycloalkyl or phenyl, said phenyl, cycloalkyl, heteromonocyclic, heterocyclic or heterospiro ring optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, O,NH2、oxo、CF3、COOH、CN、C1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy substituted C1-4Alkyl or C1-4Alkoxy, said heteromonocyclic, heterocyclic, or heterospirocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;
Some embodiments of the invention relate to a compound of formula (Ia), (Ib), (Ic), or (Id) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein
Some embodiments of the present invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from one of the following structures:
some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
Rk2Is selected from CH2、C=O、S=O、SO2;
Rk1、Rk3Or Rk4Each independently selected from H, F, Cl, Br, I, OH, NH2、CN、COOH、C1-4Alkyl or C1-4An alkoxy group;
Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
Rk2Is selected from CH2Or C ═ O;
Rk1、Rk3or Rk4Each independently selected from H, F, Cl, Br, I, OH or NH2;
p1 or p2 are each independently selected from 0, 1 or 2.
Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
b4 is selected from one of the following substituted or unsubstituted groups: azetidinyl, azepinyl, piperidine, cyclopropyloazetidinyl, cyclobutylazetidinyl, cyclobutyloazetidinyl, cyclopentaizetidinyl, cyclopentaietidinyl, cyclohexyloazetidinyl, cyclobutyloazetidinyl, cyclohexyloazetidinyl, or cyclohexyloazetidinyl aoctetidinyl, when substituted, optionally substituted with 0 to 4Rb4Substituted;
Rb4each independently selected from H, F, Cl, Br, I, OH, NH2、CN、CONH2、CF3COOH, hydroxymethyl, methyl or methoxy, said methyl or methoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I.
Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
l is selected from-Cy 1-, -Cy1-Cy2-, -Cy1-Cy2-Cy 3-or-Cy 1-Cy2-Cy3-Cy 4-.
Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
l is selected from-CH2-Cy1-、-Cy1-CH2-Cy2-。
Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
l is selected from-CH2-Cy1-、-Cy1-CH2-Cy2-;
Cy1 and Cy2 are each independently selected from azetidinyl, azacyclopentyl and piperidine.
Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
cy1, Cy2, Cy3 and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: a bond, phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclopropylcyclobutylyl, cyclopropylcyclopentylyl, cyclopropylcyclohexylyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylpirocyclopentyl, cyclopentylpirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, azetidinyl, piperidine, morpholine, piperazine, pyrrole, pyrazole, imidazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, tetrazole, cyclopropylazacyclobutyl, cyclopropylazacyclopentyl, cyclopropylazepinylHeterocyclohexyl, cyclopropylazapiperidine, cyclobutylazacyclobutyl, cyclobutylazacyclopentyl, cyclobutylazacyclohexyl, cyclobutylpiperidine, cyclopentazacyclobutyl, cyclopentazacyclopentyl, cyclopentazacyclohexapeptide, cyclopentazacyclopiperidyl, cyclohexylazacyclobutyl, cyclohexylazacyclohexapeptide, azetidinyl, azetidinoazetidinyl, azetidinyl, azacyclohexylazapiperidine, azetidinyl, and a, Cyclobutyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, cyclobutyl spiroazetidinyl, azetidinyl spiroazetidinyl, cyclobutyl spiropiperidine, cyclopentyl spiropiperidine, cyclohexyl spiropiperidine, azetidinyl spiroazetidinyl,when substituted, is optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2、oxo、CF3、COOH、CN、C1-4Alkyl, hydroxy substituted C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4Substituted by a substituent of alkoxy.
Some embodiments of the invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
The left side of L is connected with B, and the right side of L is connected with K.
Some embodiments of the invention relate to a compound of formula (I), (Ia), (Ib), (Ic), or (Id) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the salt is selected from the group consisting of trifluoroacetate.
The invention relates to a pharmaceutical composition, which comprises the compound or the stereoisomer, the solvate, the prodrug, the metabolite, the pharmaceutically acceptable salt or the eutectic crystal thereof, and a pharmaceutically acceptable carrier.
The invention relates to application of the compound or stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof in preparing a medicament for treating diseases related to BTK activity or expression.
The invention relates to application of the compound or stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof in preparing a medicament for treating diseases related to inhibiting or degrading BTK.
The invention relates to application of the compound or stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, which is characterized in that the disease is selected from tumor or autoimmune disease.
The invention relates to application of the compound or stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, which is characterized in that tumors are selected from non-Hodgkin lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma and B cell lymphoma, and autoimmune diseases are selected from rheumatoid arthritis or psoriasis.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
Where carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I are involved in the radicals and compounds of the invention, including their isotopes, and where carbon, hydrogen, oxygen, sulfur or nitrogen are involved in the radicals and compounds of the invention, optionally further substituted with one or more of their corresponding isotopes, where isotopes of carbon include12C、13C and14c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including16O、17O and18isotopes of O, sulfur including32S、33S、34S and36isotopes of S, nitrogen include14N and15isotopes of N, F include17F and19isotopes of F, chlorine including35Cl and37cl, isotopes of bromine including79Br and81Br。
"alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; the alkyl can be optionally further substituted by 0 to 6 groups selected from F, Cl, Br, I, hydroxyl and mercaptoRadical, nitro radical, cyano radical, amino radical, alkylamino radical, amido radical, alkenyl radical, alkynyl radical, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Alkoxy, 3-to 8-membered carbocyclyl, 3-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy, 3-to 8-membered heterocyclyloxy, carboxy, or carboxylate, wherein alkyl is as defined herein.
"alkoxy" means-O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. The alkyl group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy, or carboxylate. Alkoxy groups, as used herein, are defined in accordance with the present definition.
"heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3 to 8 membered monocyclic, 4 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring system and contain 1 to 3 heteroatoms selected from N, O or S, preferably a 3 to 8 membered heterocyclyl, the optionally substituted N, S in the ring of the heterocyclyl may be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or carbon atom to which the heterocyclic group may be attached a bridged or spiro ring, non-limiting examples of which include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepinyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, perinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, dihydrofuryl, dihydropyranyl, dithiapentyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydropyridinyl, chromanyl, azabicyclo [3.2.1] octanyl, Azabicyclo [5.2.0] nonanyl, oxatricyclo [5.3.1.1] dodecyl, azaadamantyl and oxaspiro [3.3] heptanyl. The heterocyclic group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, ═ O, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate. Heterocyclyl groups, as found herein, are defined in accordance with this definition.
"spiro" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (called spiro atom) between substituted or unsubstituted monocyclic rings, which may contain 0 to 5 double bonds, and may contain 0 to 5 substituents selected from N, O or S (═ O)nA heteroatom of (a). Preferably 6 to 14, more preferably 6 to 12, more preferably 6 to 10, non-limiting examples of which include:
when substituted, the substituents may be 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH), carbonyl, carboxylate, or carboxylate2)m-C(=O)-Ra、-O-(CH2)m-C(=O)-Ra、-(CH2)m-C(=O)-NRbRc、-(CH2)mS(=O)nRa、-(CH2)m-alkenyl-Ra、ORdOr- (CH)2)m-alkynyl-Ra(wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NRbRcEtc. wherein R isbAnd RcIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trisFluoromethanesulfonyl, alternatively, RbAnd RcFive or six membered cycloalkyl or heterocyclyl groups may be formed. RaAnd RdEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring. Heterocyclyl groups, as found herein, are defined in accordance with this definition.
"fused" refers to a polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain 0 or more double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 rings selected from N, S (═ O)nOr a heteroatom of O. Preferably 5 to 20, more preferably 5 to 14, more preferably 5 to 12, and even more preferably 5 to 10 yuan. Non-limiting examples include:
when substituted, the substituents may be 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH), carbonyl, carboxylate, or carboxylate2)m-C(=O)-Ra、-O-(CH2)m-C(=O)-Ra、-(CH2)m-C(=O)-NRbRc、-(CH2)mS(=O)nRa、-(CH2)m-alkenyl-Ra、ORdOr- (CH)2)m-alkynyl-Ra(wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NRbRcEtc. wherein R isbAnd RcIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, and alkaneOxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, RbAnd RcFive or six membered cycloalkyl or heterocyclyl groups may be formed. RaAnd RdEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring. Heterocyclyl groups, as found herein, are defined in accordance with this definition.
"bridged ring" means any two polycyclic group of carbon atoms not directly attached, which may contain 0 or more double bonds, and which may be substituted or unsubstituted, and any ring in the fused ring system may contain 0 to 5 rings selected from N, S (═ O)nOr an O heteroatom or group (where n is 1, 2). The ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, further preferably 5 to 12, and further preferably 5 to 10. Non-limiting examples include And adamantane. When substituted, the substituents may be 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH), carbonyl, carboxylate, or carboxylate2)m-C(=O)-Ra、-O-(CH2)m-C(=O)-Ra、-(CH2)m-C(=O)-NRbRc、-(CH2)mS(=O)nRa、-(CH2)m-alkenyl-Ra、ORdOr- (CH)2)m-alkynyl-Ra(wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NRbRcEtc. wherein R isbAnd RcIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and mixtures thereof,Heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively, RbAnd RcFive or six membered cycloalkyl or heterocyclyl groups may be formed. RaAnd RdEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring. Heterocyclyl groups, as found herein, are defined in accordance with this definition.
"Heteromonocyclic" refers to "heterocyclyl" or "heterocycle" of a monocyclic ring system, heterocyclyl groups appearing herein, the definition of which is consistent with the present definition.
"fused ring" means a "fused ring" containing a heteroatom. Heterocyclyl groups, as found herein, are defined in accordance with this definition.
"Heterospirocyclic" refers to "spirocyclic" rings containing heteroatoms. Heterocyclyl groups, as found herein, are defined in accordance with this definition.
"heterobridged ring" refers to a "bridged ring" containing a heteroatom. Heterocyclyl groups, as found herein, are defined in accordance with this definition.
"heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted 5 to 14 membered aromatic ring and contains 1 to 5 substituents selected from N, O or S (═ O)nA hetero atom or group, preferably a 5-to 10-membered heteroaromatic ring, further preferably 5-to 6-membered. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholine, thiomorpholine, 1, 3-dithiane, benzimidazole, perindopyl, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together to the parent structure is a heteroaryl ring, non-limiting examples of which include
When substituted, the substituents may be 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroAryl, heterocyclyl, bridged cyclic, spiro cyclic, fused cyclic, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH)2)m-C(=O)-Ra、-O-(CH2)m-C(=O)-Ra、-(CH2)m-C(=O)-NRbRc、-(CH2)mS(=O)nRa、-(CH2)m-alkenyl-Ra、ORdOr- (CH)2)m-alkynyl-Ra(wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NRbRcEtc. wherein R isbAnd RcIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, RbAnd RcFive or six membered cycloalkyl or heterocyclyl groups may be formed. RaAnd RdEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring. Heterocyclyl groups, as found herein, are defined in accordance with this definition.
"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 group may, but need not, be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group 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 obtained by reaction with a non-toxic inorganic or organic base, and the free base obtained by reaction with a non-toxic inorganic or organic acid.
"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and 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 an organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance 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.
By "prodrug" is meant a compound of the invention that is metabolically convertible in vivo to a biologically active compound. Prodrugs of the invention are prepared by modifying an amino or carboxyl group in a compound of the invention, which modification may be removed by routine manipulation or in vivo, to yield the parent compound. When a prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
"cocrystal" refers to a crystal of an Active Pharmaceutical Ingredient (API) and a cocrystal former (CCF) bound by hydrogen bonding or other non-covalent bonds, wherein the API and CCF are both solid in their pure state at room temperature and a fixed stoichiometric ratio exists between the components. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent co-crystal 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 resulting from the different arrangement of atoms in a molecule, including cis, trans isomers, enantiomers and conformational isomers.
"optional" or "optionally" or "selective" or "selectively" 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, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group, and the case where the heterocyclic group is not substituted with an alkyl group.
IC50(semi-inhibitory concentration of inhibitor measured): the concentration required for 50% inhibition of gabapentin binding to calcium ion channels was tested for the test compound.
Detailed Description
The following examples illustrate the technical solutions of the present invention in detail, but the scope of the present invention includes but 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 compounds described in the commercial chemicals and/or chemical literature. "commercial chemicals" are obtained from regular commercial sources, and suppliers include: tatan science and technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical engineering, Shaoshao chemical technology, Nanjing Yashi, Yaogongkang and Bailingwei science and technology.
References and monographs in this field detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide articles describing the preparation for reference. These references and monographs include: "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; sandler et al, "Organic Functional Group precursors," 2nd ed, Academic Press, New York, 1983; h.o.house, "Modern Synthetic Reactions", 2nd ed., w.a.benjamin, inc.menlo Park, calif.1972; gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; march, "Advanced Organic Chemistry: Reactions, mechanics and Structure", 4th Ed., Wiley-Interscience, New York, 1992; fuhrhop, J.and Penzlin G. "Organic Synthesis: hubs, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-; hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-; march, J. "Advanced Organic Chemistry: Reactions, mechanics, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-; otera, J. (editor) "Modern carbon Chemistry" (2000) Wiley-VCH, ISBN: 3-527-; patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-; solomons, T.W.G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-; stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73volumes.
Specific and similar reactants can be selectively identified by an index of known chemicals prepared by the chemical abstracts society of america, which is available in most public and university libraries and online. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis plants, many of which standard chemical supply plants (e.g., those listed above) provide custom synthesis services. References to the preparation and selection of pharmaceutically acceptable Salts of the compounds described herein are P.H.Stahl & C.G.Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich,2002.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS);
MS measurement (Agilent 6120B (ESI)) and Agilent 6120B (APCI));
HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6mm, 3.5. mu.M);
the thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of silica gel plate used by Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of thin layer chromatography separation and purification product is 0.4mm-0.5 mm;
the column chromatography generally uses 200-mesh and 300-mesh silica gel of the Tibet yellow sea silica gel as a carrier;
DMSO, DMSO: dimethyl sulfoxide; DIPEA: n, N' -diisopropylethylamine; ph is phenyl; DCM: dichloromethane; boc is tert-butyloxycarbonyl;
intermediate 1: (2-chloro-4-phenoxyphenyl) (4- (piperidin-4-ylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (intermediate 1)
(2-chloro-4-phenoxyphenyl)(4-(piperidin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
The first step is as follows: 2-chloro-4-phenoxybenzoic acid methyl ester (1B)
Methyl 2-chloro-4-phenoxybenzoate
To methyl 2-chloro-4-fluorobenzoate (1A) (7.5g,40mmol) was added 100mL of DMF, and phenol (4.5g,48mmol) and cesium carbonate (20g,61mmol) were added, respectively, and the mixture was heated to 90 ℃ for reaction for 3 h. The reaction mixture was cooled to room temperature, 400mL of ethyl acetate was added to the reaction mixture, and the reaction mixture was washed with 400mL of water, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4:1) to give methyl 2-chloro-4-phenoxybenzoate (1B) (7.5g, yield: 72%).
LCMS m/z=263.1[M+1]+
The second step is that: (2-chloro-4-phenoxyphenyl) (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (1C)
(2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
Adding 2-chloro-4-phenoxybenzoic acid methyl ester (1B) (4.5g,17mmol) into 100mL of anhydrous tetrahydrofuran under nitrogen atmosphere, cooling to-70 ℃, slowly dropwise adding a 2.5mol/L n-hexane solution (12mL,30mmol) of n-butyllithium, keeping the temperature of the reaction system lower than-60 ℃ in the dropwise adding process, and continuously stirring for 1h at the temperature. Then, a solution of 5-bromo-4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (3.2g,14mmol) in 50mL of tetrahydrofuran was slowly added dropwise to the above reaction system, and the temperature of the system was kept below-60 ℃ during the dropwise addition, and the reaction was carried out for 1 hour. After completion of the reaction, 2N hydrochloric acid was slowly dropped at-60 ℃ until the pH of the reaction solution became 5, the reaction solution was warmed to room temperature and stirred for 10 minutes, the mixture was directly concentrated to an oily substance, 200mL of ethyl acetate was added to the crude product, which was washed with 300mL of water, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10:1) to give (2-chloro-4-phenoxyphenyl) (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (1C) (1.6g, yield: 30%).
1H NMR(400MHz,DMSO-d6)δ13.41(s,1H),8.74(s,1H),8.12(s,1H),7.59(d,1H),7.53–7.44(m,2H),7.26(t,1H),7.22–7.14(m,3H),7.02(dd,1H).
LCMS m/z=384.1[M+1]+
The third step: 4- [ [ [5- (2-chloro-4-phenoxy-benzoyl) -7H-pyrrolo [2,3-D ] pyrimidin-4-yl ] amino ] piperidine-1-carboxylic acid tert-butyl ester (1D)
tert-butyl4-[[5-(2-chloro-4-phenoxy-benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]piperidine-1-carboxylate
(2-chloro-4-phenoxyphenyl) (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (1C) (0.6g,1.56mmol) was dissolved in 15mL of isopropanol in an autoclave, 1.5mL of DIPEA and tert-butyl 4-aminopiperidine-1-carboxylate (310mg, 1.55mmol) were added, and the reaction was stirred at 130 ℃ for 5 hours. The reaction mixture was cooled to room temperature, 50mL of water was added, extraction was performed with 100mL of ethyl acetate, the organic phase was washed with 100mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give tert-butyl 4- [ [ [5- (2-chloro-4-phenoxy-benzoyl) -7H-pyrrolo [2,3-D ] pyrimidin-4-yl ] amino ] piperidine-1-carboxylate (1D) (0.72g, yield: 85.0%).
1H NMR(400MHz,DMSO-d6)δ12.71(s,1H),8.81(d,1H),8.25(s,1H),7.62(s,1H),7.58(d,1H),7.52–7.44(m,2H),7.29–7.22(m,1H),7.21–7.15(m,3H),7.02(dd,1H),4.45–4.21(m,1H),3.89–3.78(m,2H),3.20–2.98(m,2H),2.08–1.97(m,2H),1.51–1.35(m,11H).
The fourth step: (2-chloro-4-phenoxyphenyl) (4- (piperidin-4-ylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (intermediate 1)
(2-chloro-4-phenoxyphenyl)(4-(piperidin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
Tert-butyl 4- [ [ [5- (2-chloro-4-phenoxy-benzoyl) -7H-pyrrolo [2,3-D ] pyrimidin-4-yl ] amino ] piperidine-1-carboxylate (1D) (720mg,1.31mmol) was dissolved in 20mL DCM, 5mL trifluoroacetic acid was added, and the mixture was stirred at room temperature for 4H. After the reaction was completed, the system was directly spin-dried, 100mL of a saturated aqueous solution of sodium bicarbonate was added, extraction was carried out with 50mL of dichloromethane three times, the organic phase was dried over anhydrous sodium sulfate, and concentration under reduced pressure was carried out to obtain a crude product of (2-chloro-4-phenoxyphenyl) (4- (piperidin-4-ylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (intermediate 1) (528 mg).
LCMS m/z=448.1[M+1]+
Intermediate 2: 5-amino-3- (4- (2, 4-difluorophenoxy) phenyl) -1- (piperidin-4-yl) -1H-pyrazole-4-carboxamide (intermediate 2)
5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide
The first step is as follows: 4- (2- (tert-Butoxycarbonyl) hydrazino) piperidine-1-carboxylic acid benzyl ester (2B)
benzyl 4-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1-carboxylate
Benzyl 4-oxopiperidine-1-carboxylate (2A) (35g,0.15mol) and tert-butyl hydrazinoformate (20g, 0.15mol) were added to 300mL tetrahydrofuran and the reaction was refluxed for 3 h. The reaction solution was cooled to room temperature, sodium cyanoborohydride (10g,0.16mol) was added thereto, stirring was continued for 5min, and p-toluenesulfonic acid monohydrate (29g,0.152mol) in 100mL of tetrahydrofuran was slowly added thereto, and the reaction was carried out at room temperature for 16 h. The reaction mixture was concentrated to an oil, 1000mL of ethyl acetate was added to dilute the reaction mixture, the reaction mixture was washed with 1000mL of saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2:1) to give benzyl 4- (2- (tert-butoxycarbonyl) hydrazino) piperidine-1-carboxylate (2B) (33g, yield: 63%).
LCMS m/z=350.1[M+1]+
The second step is that: 4-hydrazinylpiperidine-1-carboxylic acid benzyl ester hydrochloride (2C)
benzyl 4-hydrazinylpiperidine-1-carboxylate hydrochloride
Benzyl 4- (2- (tert-butoxycarbonyl) hydrazino) piperidine-1-carboxylate (2B) (33g, 0.094mol) was charged into a reaction flask, dissolved in 200mL of methanol, added in portions with 200mL of 4N 1, 4-dioxane hydrochloride solution, and reacted at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give 4-hydrazinylpiperidine-1-carboxylic acid benzyl ester hydrochloride (2C) (20 g).
LCMS m/z=250.2[M+1]+
The third step: benzyl 4- [ 5-amino-4-cyano-3- [4- (2, 4-difluorophenoxy) phenyl ] pyrazol-1-yl ] piperidine-1-carboxylate (2D)
benzyl4-[5-amino-4-cyano-3-[4-(2,4-difluorophenoxy)phenyl]pyrazol-1-yl]piperidine-1-carboxylate
2- ((4- (2, 4-Difluorophenoxy) phenyl) (methoxy) methylene) malononitrile (synthesis method see WO2014068527) (4.2g, 13.5mmol) was dissolved in 50mL ethanol, followed by the addition of 4-hydrazinylpiperidine-1-carboxylic acid benzyl ester hydrochloride (2C) (3.7g), DIPEA (2.6g,20mmol) and stirring at room temperature for 16 h. To the reaction solution, 20mL of a saturated sodium chloride solution was slowly added, extraction was performed twice with 100mL of ethyl acetate, the organic phase was washed with 50mL of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give benzyl 4- [ 5-amino-4-cyano-3- [4- (2, 4-difluorophenoxy) phenyl ] pyrazol-1-yl ] piperidine-1-carboxylate (2D) (5.0g, two-step total yield from compound 2B: 54%).
LCMS m/z=530.3[M+1]+
The fourth step: 5-amino-3- (4- (2, 4-difluorophenoxy) phenyl) -1- (piperidin-4-yl) -1H-pyrazole-4-carboxamide (intermediate 2)
5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide
Benzyl 4- [ 5-amino-4-cyano-3- [4- (2, 4-difluorophenoxy) phenyl ] pyrazol-1-yl ] piperidine-1-carboxylate (2D) (5.0g,9.43mmol) was dissolved in 100mL of ethanol, 100mL of 4N sodium hydroxide solution was added, and stirring was performed at 140 ℃ for 24h under reflux. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, 50mL of water was added, extracted with ethyl acetate (200mL x3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 5-amino-3- (4- (2, 4-difluorophenoxy) phenyl) -1- (piperidin-4-yl) -1H-pyrazole-4-carboxamide (intermediate 2) (2.6 g).
LCMS m/z=414.3[M+1]+
Intermediate 3: 5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1- (piperidin-4-yl) -1H-pyrazole-4-carboxamide (intermediate 3)
5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide
The first step is as follows: 4- (5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -4-cyano-1H-pyrazol-1-yl) piperidine-1-carboxylic acid benzyl ester (3B)
benzyl 4-(5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate
2- ((4- ((5-Chloropyridin-2-yl) oxy) phenyl) (ethoxy) methylene) malononitrile (3A) (synthesis method WO2019091441) (2.0g,6.15mmol) was dissolved in 30mL of dichloromethane, and triethylamine (2.0mL) and 4-hydrazinylpiperidine-1-carboxylic acid benzyl ester hydrochloride (2C) (1.3g) were added in this order at room temperature, and stirred at room temperature for 6 h. To the reaction solution was added 150mL of water, followed by extraction with dichloromethane (50mL × 3), organic phases were combined, the organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1-10:1) to give benzyl 4- (5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -4-cyano-1H-pyrazol-1-yl) piperidine-1-carboxylate (3B) (1.8g, total yield of two steps from compound 2B: 56%).
LCMS m/z=529.2[M+1]+
The second step is that: 5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1- (piperidin-4-yl) -1H-pyrazole-4-carboxamide (intermediate 3)
5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide
Benzyl 4- (5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -4-cyano-1H-pyrazol-1-yl) piperidine-1-carboxylate (3B) (1.8g,3.41mmol) was dissolved in 50mL of 90% by mass concentrated sulfuric acid, reacted at room temperature for 1H, warmed to 60 ℃ and stirred for 2H. The reaction was cooled to room temperature, slowly poured into ice water (300mL), adjusted to pH 10 with 28% by mass aqueous ammonia, the aqueous phase was extracted with dichloromethane (100mL × 6), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1- (piperidin-4-yl) -1H-pyrazole-4-carboxamide (intermediate 3) (1.1 g).
LCMS m/z=413.2[M+1]+
Example 1:
trifluoroacetic acid salt of 5- [3- [3- [3- [4- [ [5- (2-chloro-4-phenoxy-benzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl ] amino ] -1-piperidinyl ] azetidin-1-yl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione (compound 1)
5-[3-[3-[4-[[5-(2-chloro-4-phenoxy-benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-1-piperidyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione trifluoroacetate
The first step is as follows: 3- [4- [ [5- (2-chloro-4-phenoxy-benzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl ] amino ] -1-piperidinyl ] azetidine-1-carboxylic acid tert-butyl ester (1a)
tert-butyl 3-[4-[[5-(2-chloro-4-phenoxy-benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-1-piperidyl]azetidine-1-carboxylate
The crude (2-chloro-4-phenoxyphenyl) (4- (piperidin-4-ylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (intermediate 1) (300mg) was dissolved in 25mL of 1, 2-dichloroethane, tert-butyl 3-oxoazetidine-1-carboxylate (229mg,1.34mmol) was added, and after stirring at room temperature for 10 minutes, sodium triacetoxyborohydride (568mg, 2.68mmol) was added and the mixture was stirred at room temperature for 16 hours. To the reaction solution was slowly added 30mL of a saturated sodium bicarbonate solution, extracted three times with 30mL of DCM, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 3- [4- [ [5- (2-chloro-4-phenoxy-benzoyl) -7H-pyrrolo [2,3-D ] pyrimidin-4-yl ] amino ] -1-piperidinyl ] azetidine-1-carboxylate (1a) (320mg, two-step total yield from compound 1D: 71%).
LCMS m/z=603.3[M+1]+
The second step is that: trifluoroacetate salt of [4- [ [1- (azetidin-3-yl) -4-piperidinyl ] amino ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] - (2-chloro-4-phenoxy-phenyl) methanone (1b)
[4-[[1-(azetidin-3-yl)-4-piperidyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-(2-chloro-4-phenoxy-phenyl)methanone trifluoroacetate
Tert-butyl 3- [4- [ [5- (2-chloro-4-phenoxy-benzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl ] amino ] -1-piperidinyl ] azetidine-1-carboxylate (1a) (300mg,0.50mmol) was dissolved in 20mL DCM and 8mL trifluoroacetic acid was added and stirred at room temperature for 4 hours. After the reaction, the system was directly spin-dried to obtain trifluoroacetate (450mg) of crude [4- [ [1- (azetidin-3-yl) -4-piperidinyl ] amino ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] - (2-chloro-4-phenoxy-phenyl) methanone (1 b).
LCMS m/z=503.2[M+1]+
The third step: 3- [3- [4- [ [5- (2-chloro-4-phenoxy-benzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl ] amino ] -1-piperidinyl ] azetidin-1-yl ] azetidine-1-carboxylic acid tert-butyl ester (1c)
tert-butyl 3-[3-[4-[[5-(2-chloro-4-phenoxy-benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-1-piperidyl]azetidin-1-yl]azetidine-1-carboxylate
The trifluoroacetate salt (450mg) of the above crude [4- [ [1- (azetidin-3-yl) -4-piperidinyl ] amino ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] - (2-chloro-4-phenoxy-phenyl) methanone (1b) was dissolved in 30mL of 1, 2-dichloroethane, tert-butyl 3-oxoazetidine-1-carboxylate (160mg,0.94mmol) was added, and after stirring at room temperature for 10 minutes, sodium triacetoxyborohydride (400mg, 1.89mmol) was added, and stirring at room temperature for 16 hours. 30mL of a saturated sodium bicarbonate solution was slowly added to the reaction system, and the mixture was extracted three times with 30mL of DCM, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 3- [3- [4- [ [5- (2-chloro-4-phenoxy-benzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl ] amino ] -1-piperidinyl ] azetidin-1-yl ] azetidin-1-carboxylate (1c) (240mg, two-step total yield from Compound 1 a: 73%).
LCMS m/z=658.3[M+1]+
The fourth step: trifluoroacetate salt of [4- [ [1- [1- (azetidin-3-yl) azetidin-3-yl ] -4-piperidinyl ] amino ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] - (2-chloro-4-phenoxy-phenyl) methanone (1d)
[4-[[1-[1-(azetidin-3-yl)azetidin-3-yl]-4-piperidyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-(2-chloro-4-phenoxy-phenyl)methanone trifluoroacetate
Tert-butyl 3- [3- [4- [ [5- (2-chloro-4-phenoxy-benzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl ] amino ] -1-piperidinyl ] azetidin-1-yl ] azetidine-1-carboxylate (1c) (236mg,0.36mmol) was dissolved in 20mL DCM and 8mL trifluoroacetic acid was added and stirred at room temperature for 4 hours. The reaction system was directly spin-dried to obtain trifluoroacetate (350mg) of crude [4- [ [1- [1- (azetidin-3-yl) azetidin-3-yl ] -4-piperidinyl ] amino ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] - (2-chloro-4-phenoxy-phenyl) methanone (1 d).
LCMS m/z=558.3[M+1]+
The fifth step: trifluoroacetic acid salt of 5- [3- [3- [3- [4- [ [5- (2-chloro-4-phenoxy-benzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl ] amino ] -1-piperidinyl ] azetidin-1-yl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione (compound 1)
5-[3-[3-[4-[[5-(2-chloro-4-phenoxy-benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-1-piperidyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione trifluoroacetate
The trifluoroacetate salt (235mg) of the crude [4- [ [1- [1- (azetidin-3-yl) azetidin-3-yl ] -4-piperidinyl ] amino ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] - (2-chloro-4-phenoxy-phenyl) methanone (1d) above was dissolved in 15mL DMSO, 1.5mL DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (synthesis see WO2017197056) (150mg, 0.54mmol) were added and the reaction stirred at 80 ℃ for 5 hours. The reaction mixture was cooled to room temperature, 50mL of water was added, extraction was performed with 100mL of ethyl acetate, the organic phase was washed with 100mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1), to give trifluoroacetate salt of 5- [3- [3- [4- [ [5- (2-chloro-4-phenoxy-benzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl ] amino ] -1-piperidinyl ] azetidin-1-yl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione (compound 1) (97.4 mg).
1H NMR(400MHz,CDCl3)δ9.11(s,1H),8.34(s,1H),7.63(d,1H),7.46–7.37(m,3H),7.34(s,1H),7.25–7.20(m,1H),7.13–7.06(m,3H),6.96(dd,1H),6.77(d,1H),6.52(dd,1H),4.92(dd,1H),4.39–4.24(m,1H),4.08–3.99(m,2H),3.93–3.84(m,2H),3.78–3.67(m,1H),3.63–3.53(m,2H),3.34–3.04(m,3H),2.93–2.65(m,5H),2.48–2.06(m,5H),1.98–1.80(m,2H).
LCMS m/z=814.3[M+1]+
Example 1-1:
5- [3- [3- [4- [ [5- (2-chloro-4-phenoxy-benzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl ] amino ] -1-piperidinyl ] azetidin-1-yl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione (compound 1)
5-[3-[3-[4-[[5-(2-chloro-4-phenoxy-benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-1-piperidyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione
The trifluoroacetate salt (70mg) of 5- [3- [3- [4- [ [5- (2-chloro-4-phenoxy-benzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl ] amino ] -1-piperidinyl ] azetidin-1-yl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione (compound 1) was dissolved in 10mL of dichloromethane, washed with 28% by mass concentrated aqueous ammonia (10mLx5), the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5- [3- [3- [4- [ [5- (2-chloro-4-phenoxy-benzoyl) -7H-pyrrolo [ 2-chloro-4-phenoxy-benzoyl ] -2 3-d ] pyrimidin-4-yl ] amino ] -1-piperidinyl ] azetidin-1-yl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione (Compound 1) (40 mg).
1H NMR(400MHz,CDCl3)δ9.10(s,1H),8.33(s,1H),7.63(d,1H),7.47–7.36(m,3H),7.33(s,1H),7.26–7.19(m,1H),7.14–7.05(m,3H),6.96(dd,1H),6.77(d,1H),6.52(dd,1H),4.92(dd,1H),4.38–4.20(m,1H),4.08–3.98(m,2H),3.93–3.82(m,2H),3.78–3.66(m,1H),3.63–3.52(m,2H),3.32–2.96(m,3H),2.93–2.64(m,5H),2.42–2.06(m,5H),1.96–1.80(m,2H).
LCMS m/z=814.3[M+1]+
Example 2:
trifluoroacetic acid salt of 5- (3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidin ] -1' -yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 2)
5-(3-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
The first step is as follows: 4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidine ] -1' -carboxylic acid tert-butyl ester (2a)
tert-butyl 4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-[1,4'-bipiperidine]-1'-carboxylate
The crude (2-chloro-4-phenoxyphenyl) (4- (piperidin-4-ylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (intermediate 1) (300mg) was dissolved in 25mL of 1, 2-dichloroethane, and tert-butyl 4-oxopiperidine-1-carboxylate (267mg,1.34mmol) was added thereto, followed by stirring at room temperature for 10 minutes, followed by addition of sodium triacetoxyborohydride (568mg, 2.68mmol), and stirring at room temperature for 16 hours. To the reaction solution was slowly added 30mL of a saturated sodium bicarbonate solution, extracted three times with 30mL of DCM, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-D ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidine ] -1' -carboxylate (2a) (310mg, two-step total yield from compound 1D: 66%).
LCMS m/z=631.3[M+1]+
The second step is that: trifluoroacetate salt of (4- ([1,4' -bipiperidin ] -4-ylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (2b)
(4-([1,4'-bipiperidin]-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone trifluoroacetate
Tert-butyl 4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidine ] -1' -carboxylate (2a) (300mg,0.48mmol) was dissolved in 20mL of DCM, and 8mL of trifluoroacetic acid was added and stirred at room temperature for 4 hours. After the reaction, the system was directly spin-dried to obtain the trifluoroacetate salt (450mg) of crude (4- ([1,4' -bipiperidin ] -4-ylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (2 b).
LCMS m/z=531.3[M+1]+
The third step: 3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidine ] -1' -yl) azetidine-1-carboxylic acid tert-butyl ester (2c)
tert-butyl 3-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-[1,4'-bipiperidin]-1'-yl)azetidine-1-carboxylate
The trifluoroacetate salt (430mg) of the above crude product of (4- ([1,4' -bipiperidin ] -4-ylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (2b) was dissolved in 30mL of 1, 2-dichloroethane, and tert-butyl 3-azetidine-1-carboxylate (160mg,0.93mmol) was added, followed by stirring at room temperature for 10 minutes, followed by addition of sodium triacetoxyborohydride (400mg, 1.89mmol), and stirring at room temperature for 16 hours. To the reaction system, 30mL of a saturated sodium bicarbonate solution was slowly added, extraction was carried out three times with 30mL of DCM, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidin ] -1' -yl) azetidine-1-carboxylate (2c) (250mg, two-step total yield from compound 2 a: 80%).
LCMS m/z=686.3[M+1]+
The fourth step: trifluoroacetic acid salt of (4- (((1'- (azetidin-3-yl) - [1,4' -bipiperidine ] -4-yl ] amino ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (2d)
(4-((1'-(azetidin-3-yl)-[1,4'-bipiperidin]-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone trifluoroacetate
Tert-butyl 3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidin ] -1' -yl) azetidine-1-carboxylate (2c) (250mg,0.36mmol) was dissolved in 20mL DCM and 8mL trifluoroacetic acid was added and stirred at room temperature for 4 hours. The reaction system was directly spin-dried to give the crude product (trifluoroacetate salt of (4- (((1'- (azetidin-3-yl) - [1,4' -bipiperidine ] -4-yl ] amino ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (2d) (350 mg).
LCMS m/z=586.3[M+1]+
The fifth step: trifluoroacetic acid salt of 5- (3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidin ] -1' -yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 2)
5-(3-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
The trifluoroacetate salt (350mg) of (4- (((1'- (azetidin-3-yl) - [1,4' -bispiperidine ] -4-yl ] amino ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (2d) was dissolved in 15mL of DMSO, 1.5mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (see synthetic method WO2017197056) (150mg, 0.54mmol) were added, the reaction mixture was stirred at 80 ℃ for 5 hours, the reaction mixture was cooled to room temperature, 50mL of water was added, extraction was performed with 100mL of ethyl acetate, the organic phase was washed with 100mL of water, dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) (15: 1) to give the trifluoroacetate salt of 5- (3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidin ] -1' -yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 2) (120 mg).
1H NMR(400MHz,CDCl3)δ9.09(s,1H),8.33(s,1H),7.63(d,1H),7.46–7.37(m,3H),7.32(s,1H),7.25–7.19(m,1H),7.13–7.05(m,3H),6.96(dd,1H),6.78(d,1H),6.51(dd,1H),4.92(dd,1H),4.35–4.17(m,1H),4.12–4.05(m,2H),3.92–3.82(m,2H),3.40–3.29(m,1H),3.09–2.39(m,10H),2.32–2.07(m,3H),2.01–1.77(m,6H),1.77–1.57(m,2H).
LCMS m/z=842.3[M+1]+
Example 3:
5-amino-3- [4- (2, 4-difluorophenoxy) phenyl ] -1- [1- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo ] -isoindolin-5-yl ] azetidin-3-yl ] -4-piperidinyl ] pyrazole-4-carboxamide (Compound 3)
5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-[1-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]azetidin-3-yl]-4-piperidyl]pyrazole-4-carboxamide
The first step is as follows: 3- [4- [ 5-amino-4-carbamoyl ] -3- [4- (2, 4-difluorophenoxy) phenyl ] pyrazol-1-yl ] -1-piperidinyl ] azetidine-1-carboxylic acid tert-butyl ester (3a)
tert-butyl 3-[4-[5-amino-4-carbamoyl-3-[4-(2,4-difluorophenoxy)phenyl]pyrazol-1-yl]-1-piperidyl]azetidine-1-carboxylate
The crude 5-amino-3- (4- (2, 4-difluorophenoxy) phenyl) -1- (piperidin-4-yl) -1H-pyrazole-4-carboxamide (intermediate 2) (400mg) was dissolved in 15mL of DMF, and tert-butyl 3-oxoazetidine-1-carboxylate (497mg,2.90mmol), 0.5mL of acetic acid and 2g of anhydrous magnesium sulfate were added in this order, and after heating to 70 ℃ and stirring for 3 hours, the reaction mixture was cooled to room temperature, sodium cyanoborohydride (304mg, 4.84mmol) was added, and the mixture was stirred at room temperature for 16 hours. To the reaction solution was slowly added 20mL of a saturated sodium bicarbonate solution, extracted twice with 60mL of ethyl acetate, the organic phase was washed with 50mL of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 3- [4- [ 5-amino-4-carbamoyl ] -3- [4- (2, 4-difluorophenoxy) phenyl ] pyrazol-1-yl ] -1-piperidinyl ] azetidine-1-carboxylate (3a) (250mg, total yield in two steps from compound 2D: 30%).
LCMS m/z=569.3[M+1]+
The second step is that: 5-amino-1- [1- (azetidin-3-yl) -4-piperidinyl ] -3- [4- (2, 4-difluorophenoxy) phenyl ] pyrazole-4-carboxamide (3b)
5-amino-1-[1-(azetidin-3-yl)-4-piperidyl]-3-[4-(2,4-difluorophenoxy)phenyl]pyrazole-4-carboxamide
Tert-butyl 3- [4- [ 5-amino-4-carbamoyl ] -3- [4- (2, 4-difluorophenoxy) phenyl ] pyrazol-1-yl ] -1-piperidinyl ] azetidine-1-carboxylate (3a) (150mg,0.26mmol) was dissolved in 5mL of DCM, 2mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 4 hours. After the reaction, the system is directly dried by spinning, then is dissolved by 50mL of DCM, the pH value is adjusted to 10 by saturated sodium bicarbonate solution, the mixture is extracted three times by 50mL of dichloromethane, dried by anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product of 5-amino-1- [1- (azetidin-3-yl) -4-piperidyl ] -3- [4- (2, 4-difluorophenoxy) phenyl ] pyrazole-4-formamide (3b) (110mg) is obtained.
LCMS m/z=469.3[M+1]+
The third step: 3- [3- [4- [ 5-amino-4-carbamoyl ] -3- [4- (2, 4-difluorophenoxy) phenyl ] pyrazol-1-yl ] -1-piperidinyl ] azetidin-1-yl ] azetidine-1-carboxylic acid tert-butyl ester (3c)
tert-butyl 3-[3-[4-[5-amino-4-carbamoyl-3-[4-(2,4-difluorophenoxy)phenyl]pyrazol-1-yl]-1-piperidyl]azetidin-1-yl]azetidine-1-carboxylate
The crude 5-amino-1- [1- (azetidin-3-yl) -4-piperidinyl ] -3- [4- (2, 4-difluorophenoxy) phenyl ] pyrazole-4-carboxamide (3b) (110mg) was dissolved in 10mL of 1, 2-dichloroethane, and tert-butyl 3-oxoazetidine-1-carboxylate (80mg,0.47mmol) was added, followed by stirring at room temperature for 60 minutes, sodium triacetoxyborohydride (249mg, 1.17mmol) was added, and the mixture was stirred at room temperature for 16 hours. To the reaction system, 30mL of a saturated sodium bicarbonate solution was slowly added, extraction was carried out three times with 30mL of DCM, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 3- [3- [4- [ 5-amino-4-carbamoyl ] -3- [4- (2, 4-difluorophenoxy) phenyl ] pyrazol-1-yl ] -1-piperidinyl ] azetidin-1-yl ] azetidine-1-carboxylate (3c) (100mg, total yield of two steps from compound 3 a: 62%).
LCMS m/z=624.3[M+1]+
The fourth step: 5-amino-1- [1- [1- [1- (azetidin-3-yl) azetidin-3-yl ] -4-piperidinyl ] -3- [4- (2, 4-difluorophenoxy) phenyl ] pyrazole-4-carboxamide (3d)
5-amino-1-[1-[1-(azetidin-3-yl)azetidin-3-yl]-4-piperidyl]-3-[4-(2,4-difluorophenoxy)phenyl]pyrazole-4-carboxamide
Tert-butyl 3- [3- [4- [ 5-amino-4-carbamoyl ] -3- [4- (2, 4-difluorophenoxy) phenyl ] pyrazol-1-yl ] -1-piperidinyl ] azetidin-1-yl ] azetidine-1-carboxylate (3c) (100mg,0.16mmol) was dissolved in 2mL of DCM, and 2mL of trifluoroacetic acid was added and stirred at room temperature for 4 hours. The reaction system was directly spin dried, dissolved with 50mL of DCM, adjusted to pH 10 with saturated sodium bicarbonate solution, extracted three times with 50mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 5-amino-1- [1- [1- [1- (azetidin-3-yl) azetidin-3-yl ] -4-piperidinyl ] -3- [4- (2, 4-difluorophenoxy) phenyl ] pyrazole-4-carboxamide (3d) (77 mg).
LCMS m/z=524.3[M+1]+
The fifth step: 5-amino-3- [4- (2, 4-difluorophenoxy) phenyl ] -1- [1- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo ] -isoindolin-5-yl ] azetidin-3-yl ] -4-piperidinyl ] pyrazole-4-carboxamide (Compound 3)
5-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1-[1-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]azetidin-3-yl]-4-piperidyl]pyrazole-4-carboxamide
The crude 5-amino-1- [1- [1- [1- (azetidin-3-yl) azetidin-3-yl ] -4-piperidinyl ] -3- [4- (2, 4-difluorophenoxy) phenyl ] pyrazole-4-carboxamide (3d) (77mg) was dissolved in 10mL DMSO, 1.5mL DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (synthesis see WO2017197056) (44mg, 0.16mmol) were added and the reaction stirred at 80 ℃ for 5 hours. The reaction mixture was cooled to room temperature, 50mL of water was added, extraction was performed with 100mL of ethyl acetate, the organic phase was washed with 100mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1), to give 5-amino-3- [4- (2, 4-difluorophenoxy) phenyl ] -1- [1- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo ] -isoindolin-5-yl ] azetidin-3-yl ] -4-piperidinyl ] pyrazole-4-carboxamide (Compound 3) (20mg, two-step total yield from Compound 3 c: 16%).
1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),7.64(d,1H),7.55–7.44(m,3H),7.41–7.31(m,1H),7.20–7.11(m,1H),7.06–6.98(m,2H),6.81–6.76(m,1H),6.66(dd,1H),6.30(s,2H),5.05(dd,1H),4.18–3.98(m,3H),3.86–3.76(m,2H),3.68–3.58(m,1H),3.46–3.39(m,2H),3.02–2.74(m,6H),2.65–2.52(m,2H),2.08–1.85(m,5H),1.84–1.72(m,2H).
LCMS m/z=780.4[M+1]+
Example 4
5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1- (1'- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) - [1,4' -bipiperidin ] -4-yl) -1H-pyrazole-4-carboxamide (Compound 4)
5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,4'-bipiperidin]-4-yl)-1H-pyrazole-4-carboxamide
The first step is as follows: 4- (5-amino-4-carbamoyl-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1H-pyrazol-1-yl) - [1,4 '-bipiperidine ] -1' -carboxylic acid tert-butyl ester (4a)
tert-butyl4-(5-amino-4-carbamoyl-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)-[1,4'-bipiperidine]-1'-carboxylate
The crude 5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1- (piperidin-4-yl) -1H-pyrazole-4-carboxamide (intermediate 3) (900mg) was dissolved in 30mL of 1, 2-dichloroethane/DMSO (v/v ═ 10/1), tert-butyl 4-oxopiperidine-1-carboxylate (1.3g,6.53mmol), glacial acetic acid (0.32mL) and anhydrous magnesium sulfate (1.4g) were added successively at room temperature, the mixture was warmed to 70 ℃ and stirred for 6 hours, the reaction mixture was cooled to room temperature, sodium cyanoborohydride (545mg,8.67mmol) was added, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was filtered with suction, 50mL of water was added to the filtrate, the pH of the aqueous phase was adjusted to 10 with 2N sodium hydroxide solution, extraction was performed with dichloromethane (40mL × 3), the organic phases were combined, the organic phase was washed with water (20mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-8:1) to give 4- (5-amino-4-carbamoyl-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1H-pyrazol-1-yl) - [1,4 '-bipiperidine ] -1' -carboxylic acid tert-butyl ester (4a) (410 mg).
LCMS m/z=596.3[M+1]+
The second step is that: 1- ([1,4' -bipiperidin ] -4-yl) -5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1H-pyrazole-4-carboxamide (4b)
1-([1,4'-bipiperidin]-4-yl)-5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1H-pyrazole-4-carboxamide
Tert-butyl 4- (5-amino-4-carbamoyl-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1H-pyrazol-1-yl) - [1,4 '-bipiperidine ] -1' -carboxylate (4a) (100mg,0.17mmol) was dissolved in 3mL of dichloromethane, and 2mL of trifluoroacetic acid was added to react at room temperature for 2 hours. The reaction solution was adjusted to pH 10 with 2N sodium hydroxide solution, the aqueous phase was extracted with methylene chloride (10 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 1- ([1,4' -bipiperidin ] -4-yl) -5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1H-pyrazole-4-carboxamide (4b) (74mg, yield: 88%).
LCMS m/z=496.2[M+1]+
The third step: 5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1- (1'- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) - [1,4' -bipiperidin ] -4-yl) -1H-pyrazole-4-carboxamide (Compound 4)
5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,4'-bipiperidin]-4-yl)-1H-pyrazole-4-carboxamide
1- ([1,4' -bipiperidin ] -4-yl) -5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1H-pyrazole-4-carboxamide (4b) (73mg,0.15mmol) was dissolved in 5mL DMSO, 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (synthesis method see WO2017197056) (0.10g,0.36mmol) and diisopropylethylamine (0.20g,1.55mmol) were added at room temperature, and the reaction was warmed to 80 ℃ for 4 hours. The reaction solution was poured into 20mL of water, the aqueous phase was extracted with dichloromethane/methanol (v/v) ═ 10:1 (30mL × 3), the organic phases were combined, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) to give 5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1- (1'- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) - [1,4' -bipiperidin ] -4-yl) -1H-pyrazole-4-carboxamide (compound 4) (50mg, yield: 44%).
1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.25–8.20(m,1H),7.97(dd,1H),7.66(d,1H),7.57–7.50(m,2H),7.35–7.31(m,1H),7.28–7.18(m,3H),7.14(dd,1H),6.30(s,2H),5.06(dd,1H),4.18–4.03(m,3H),3.06–2.81(m,5H),2.70–2.53(m,3H),2.37–2.19(m,2H),2.07–1.75(m,7H),1.61–1.45(m,2H).
LCMS m/z=752.3[M+1]+
Example 5
5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1- (1'- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) - [1,4' -bipiperidin ] -4-yl) -1H-pyrazole-4-carboxamide (Compound 5)
5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(1'-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)-[1,4'-bipiperidin]-4-yl)-1H-pyrazole-4-carboxamide
The first step is as follows: 3- (4- (5-amino-4-carbamoyl-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1H-pyrazol-1-yl) - [1,4 '-bipiperidin ] -1' -yl) azetidine-1-carboxylic acid tert-butyl ester (5a)
tert-butyl
3-(4-(5-amino-4-carbamoyl-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidine-1-carboxylate
1- ([1,4' -bipiperidin ] -4-yl) -5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1H-pyrazole-4-carboxamide (4b) (171mg,0.34mmol) was dissolved in 30mL of 1, 2-dichloroethane/DMSO (v/v ═ 10/1), tert-butyl 3-oxoazetidine-1-carboxylate (173mg,1.01mmol), glacial acetic acid (0.05mL) and anhydrous magnesium sulfate (250mg) were added in this order at room temperature, the temperature was raised to 70 ℃ and stirred for 5 hours, after cooling to room temperature, sodium cyanoborohydride (84mg,1.34mmol) was added and stirred at room temperature for 16 hours. The reaction solution was suction-filtered, 50mL of water was added to the filtrate, the pH of the aqueous phase was adjusted to 10 with 2N sodium hydroxide solution, extraction was performed with dichloromethane (40mL × 3), the organic phases were combined, the organic phase was washed with water (20mL × 2), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-8:1) to give tert-butyl 3- (4- (5-amino-4-carbamoyl-3- (4- ((5-chloropyridinyl-2-yl) oxy) phenyl) -1H-pyrazol-1-yl) - [1,4 '-bipiperidine ] -1' -yl) azetidine-1-carboxylate (5a) (90mg, yield: 41%).
LCMS m/z=651.4[M+1]+
The second step is that: 5-amino-1- (1'- (azetidin-3-yl) - [1,4' -bipiperidine ] -4-yl) -3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1H-pyrazole-4-carboxamide (5b)
5-amino-1-(1'-(azetidin-3-yl)-[1,4'-bipiperidin]-4-yl)-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1H-pyrazole-4-carboxamide
Tert-butyl 3- (4- (5-amino-4-carbamoyl-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1H-pyrazol-1-yl) - [1,4 '-bipiperidin ] -1' -yl) azetidine-1-carboxylate (5a) (90mg,0.14mmol) was dissolved in 4mL dichloromethane, and 2mL trifluoroacetic acid was added to react at room temperature for 2 hours. The pH was adjusted to 10 with 2N sodium hydroxide solution, the aqueous phase was extracted with dichloromethane (20 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-amino-1- (1'- (azetidin-3-yl) - [1,4' -bipiperidin ] -4-yl) -3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1H-pyrazole-4-carboxamide (5b) (73mg, yield: 92%).
LCMS m/z=551.4[M+1]+
The third step: 5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1- (1'- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) - [1,4' -bipiperidin ] -4-yl) -1H-pyrazole-4-carboxamide (Compound 5)
5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(1'-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)-[1,4'-bipiperidin]-4-yl)-1H-pyrazole-4-carboxamide
5-amino-1- (1'- (azetidin-3-yl) - [1,4' -bipiperidine ] -4-yl) -3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1H-pyrazole-4-carboxamide (5b) (73mg,0.13mmol) was dissolved in 4mL of DMSO, 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (see WO2017197056 for synthesis) (53mg,0.19mmol) and diisopropylethylamine (84mg,0.65mmol) were added at room temperature, and the mixture was warmed to 80 ℃ for 4 hours. The reaction solution was poured into 20mL of water, the aqueous phase was extracted with dichloromethane/methanol (v/v) ═ 10:1 (30mL × 3), the organic phases were combined, the organic phase was washed with 50mL of water, and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) to give 5-amino-3- (4- ((5-chloropyridin-2-yl) oxy) phenyl) -1- (1'- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) - [1,4' -bipiperidin ] -4-yl) -1H-pyrazole-4-carboxamide (compound 5) (25mg, yield: 24%).
1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.23(d,1H),7.98(dd,1H),7.65(d,1H),7.58–7.50(m,2H),7.25–7.17(m,2H),7.14(d,1H),6.79(d,1H),6.65(dd,1H),6.30(s,2H),5.05(dd,1H),4.17–4.05(m,3H),3.88–3.78(m,2H),3.38–3.30(m,1H),3.08–2.80(m,5H),2.70–2.52(m,2H),2.38–2.19(m,3H),2.08–1.65(m,9H),1.58–1.41(m,2H).
LCMS m/z=404.3[M/2+1]+
Example 6:
5- (3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 6)
5-(3-((4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
The first step is as follows: 3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) azetidine-1-carboxylic acid tert-butyl ester (6a)
tert-butyl3-((4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)azetidine-1-carboxylate
The crude (2-chloro-4-phenoxyphenyl) (4- (piperidin-4-ylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (intermediate 1) (200mg) was dissolved in 10mL of DCE, 3-formylazetidine-1-carboxylic acid tert-butyl ester (92mg,0.5mmol) and acetic acid (0.05mL,0.875mmol) were added, the reaction stirred at room temperature for 1H, sodium triacetoxyborohydride (286mg,1.35mmol) was added, and the reaction stirred at room temperature for 16H. The reaction mixture was quenched with 10mL of water, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-D ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) azetidine-1-carboxylate (6a) (220mg, two-step yield from compound 1D: 72%).
The second step is that: (4- ((1- (azetidin-3-ylmethyl) piperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (6b)
(4-((1-(azetidin-3-ylmethyl)piperidin-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone
Tert-butyl 3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) azetidine-1-carboxylate (6a) (220mg,0.36mmol) was dissolved in 10mL DCM and 2.0mL trifluoroacetic acid was added and the reaction stirred at rt for 2H. The reaction system was concentrated under reduced pressure, the residue was dissolved in 10mL of DCM, 10mL of water was added, 1mol/L NaOH solution was added dropwise to adjust pH to 12, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30 mL. times.3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude (4- ((1- (azetidin-3-ylmethyl) piperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (6b) (35 mg).
The third step: 5- (3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 6)
5-(3-((4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
The crude (4- ((1- (azetidin-3-ylmethyl) piperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (6b) (35mg) was dissolved in 2mL of DMSO, 0.2mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (synthesis see WO2017197056) (21mg, 0.08mmol) were added and the reaction stirred at 80 ℃ for 5H. The reaction solution was cooled to room temperature, 5mL of water was added, and the filtrate was collected, the cake was washed with 20mL of water, the solid was dissolved in 30mL of dichloromethane, dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1) after concentration under reduced pressure to give 5- (3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 6) (15mg, two-step yield from compound 6 a: 5%).
1H NMR(400MHz,CDCl3)δ9.08(d,1H),8.39–8.30(m,1H),7.63(d,1H),7.47–7.36(m,3H),7.36–7.31(m,1H),7.26–7.19(m,1H),7.13–7.05(m,3H),6.96(dd,1H),6.80(d,1H),6.49(dd,1H),4.93(dd,1H),4.35–4.20(m,1H),4.20–4.11(m,2H),3.77–3.68(m,2H),3.15–3.00(m,1H),2.95–2.65(m,7H),2.51–2.34(m,2H),2.24–2.07(m,3H),1.90–1.76(m,2H).
LCMS m/z=773.3[M+1]+
Example 7:
5- (3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) pyrrolidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 7)
5-(3-((4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
The first step is as follows: 3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester (7a)
tert-butyl3-((4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate
The crude (2-chloro-4-phenoxyphenyl) (4- (piperidin-4-ylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (intermediate 1) (300mg) described above was dissolved in 20mL of DCE, tert-butyl 3-formylpyrrole-1-carboxylate (147mg,0.74mmol) and acetic acid (0.05mL,0.875mmol) were added, the reaction stirred at room temperature for 1H, sodium triacetoxyborohydride (426mg,2.01mmol) was added, and the reaction stirred at room temperature for 16H. To the reaction solution, 20mL of water was added to quench the reaction, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-D ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) pyrrolidine-1-carboxylate (7a) (280mg, two-step yield from compound 1D: 60%).
The second step is that: (2-chloro-4-phenoxyphenyl) (4- ((1- (pyrrolidin-3-ylmethyl) piperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (7b)
(2-chloro-4-phenoxyphenyl)(4-((1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
Tert-butyl 3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) pyrrolidine-1-carboxylate (7a) (280mg,0.44mmol) was dissolved in 10mL DCM and 3.0mL trifluoroacetic acid was added and the reaction stirred at rt for 2H. The reaction system was concentrated under reduced pressure, the residue was dissolved in 20mL of DCM, 20mL of water was added, 1mol/L of NaOH solution was added dropwise to adjust pH to 12, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30 mL. times.3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude (2-chloro-4-phenoxyphenyl) (4- ((1- (pyrrolidin-3-ylmethyl) piperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (7b) (200 mg).
The third step: 5- (3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) pyrrolidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 7)
5-(3-((4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
The crude (2-chloro-4-phenoxyphenyl) (4- ((1- (pyrrolidin-3-ylmethyl) piperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (7b) (200mg) was dissolved in 10mL of DMSO, 1mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (synthesis see WO2017197056) (135mg, 0.49mmol) were added, and the reaction was stirred at 80 ℃ for 5H. The reaction mixture was cooled to room temperature, 10mL of water was added, and the mixture was filtered, and the filter cake was collected, washed with 50mL of water, the solid was dissolved in 50mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give 5- (3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) pyrrolidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 7) (55mg, two-step yield from compound 7 a: 16%).
1H NMR(400MHz,CDCl3)δ9.04(d,1H),8.34(s,1H),7.65(d,1H),7.49–7.35(m,3H),7.31(s,1H),7.26–7.19(m,1H),7.14–7.05(m,3H),6.99–6.93(m,2H),6.70(dd,1H),4.93(dd,1H),4.32–4.18(m,1H),3.63–3.54(m,1H),3.54–3.36(m,2H),3.25–3.16(m,1H),2.97–2.62(m,5H),2.54–2.27(m,4H),2.27–2.06(m,4H),1.92–1.72(m,4H).
LCMS m/z=787.3[M+1]+
Example 8:
5- (4- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 8)
5-(4-((4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
The first step is as follows: 4- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (8a)
tert-butyl4-((4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)piperidine-1-carboxylate
The crude (2-chloro-4-phenoxyphenyl) (4- (piperidin-4-ylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (intermediate 1) (200mg) was dissolved in 10mL of DCE, tert-butyl 4-formylpiperidine-1-carboxylate (106mg,0.5mmol) and acetic acid (0.05mL,0.875mmol) were added, the reaction stirred at room temperature for 1H, sodium triacetoxyborohydride (286mg,1.35mmol) was added, and the reaction stirred at room temperature for 16H. To the reaction solution was added 10mL of water to quench the reaction, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 4- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-D ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) piperidine-1-carboxylate (8a) (168mg, two-step yield from compound 1D: 52%).
The third step: (2-chloro-4-phenoxyphenyl) (4- ((1- (piperidin-4-ylmethyl) piperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (8b)
(2-chloro-4-phenoxyphenyl)(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
Tert-butyl 4- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) piperidine-1-carboxylate (8a) (168mg,0.26mmol) was dissolved in 10mL DCM and 2.0mL trifluoroacetic acid was added and the reaction stirred at rt for 2H. The reaction system was concentrated under reduced pressure, the residue was dissolved in 10mL of DCM, 10mL of water was added, 1mol/L NaOH solution was added dropwise to adjust pH to 12, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30 mL. times.3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude (2-chloro-4-phenoxyphenyl) (4- ((1- (piperidin-4-ylmethyl) piperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (8b) (71 mg).
The third step: 5- (4- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 8)
5-(4-((4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
The crude (2-chloro-4-phenoxyphenyl) (4- ((1- (piperidin-4-ylmethyl) piperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (8b) (71mg) was dissolved in 5mL of DMSO, 0.5mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (see WO2017197056 for synthesis) (40mg, 0.14mmol) were added, and the reaction was stirred at 80 ℃ for 5H. The reaction solution was cooled to room temperature, 10mL of water was added, and the filtrate was collected, the cake was washed with 30mL of water, the solid was dissolved in 30mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give 5- (4- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 8) (50mg, two-step yield from compound 8 a: 24%).
1H NMR(400MHz,CDCl3)δ9.16–9.04(m,1H),8.33(s,1H),7.66(d,1H),7.46–7.37(m,3H),7.33(s,1H),7.29–7.26(m,1H),7.26–7.18(m,1H),7.13–7.06(m,3H),7.03(dd,1H),6.96(dd,1H),4.94(dd,1H),4.38–4.22(m,1H),3.99–3.89(m,2H),3.03–2.89(m,4H),2.89–2.65(m,3H),2.46–2.32(m,2H),2.32–2.17(m,2H),2.17–2.07(m,2H),2.03–1.83(m,6H),1.40–1.28(m,2H).
LCMS m/z=801.3[M+1]+
Example 9:
trifluoroacetate salt of 5- (3- ((3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) azetidin-1-yl) methyl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 9)
5-(3-((3-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionetrifluoroacetate
The first step is as follows: 3- ((3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) azetidin-1-yl) methyl) azetidine-1-carboxylic acid tert-butyl ester (9a)
tert-butyl3-((3-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)azetidin-1-yl)methyl)azetidine-1-carboxylate
The trifluoroacetate salt (0.50g) of the above crude [4- [ [1- (azetidin-3-yl) -4-piperidinyl ] amino ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] - (2-chloro-4-phenoxy-phenyl) methanone (1b) was dissolved in 20mL of DCE, tert-butyl 3-formylazetidine-1-carboxylate (0.37g,2.0mmol) was added, stirring was carried out at room temperature for 10min, sodium triacetoxyborohydride (0.42g, 2.0mmol) was added, and the reaction was stirred at room temperature for 12H. To the reaction solution, 50mL of a saturated sodium bicarbonate solution was slowly dropped, extracted with 30mL of dichloromethane, dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 3- ((3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) azetidin-1-yl) methyl) azetidine-1-carboxylate (9a) (0.1g, two-step yield from compound 1 a: 27%).
LC-MS m/z=672.3[M+1]+
The second step is that: (4- ((1- (1- (azetidin-3-ylmethyl) azetidin-3-yl) piperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (9b)
(4-((1-(1-(azetidin-3-ylmethyl)azetidin-3-yl)piperidin-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone
Tert-butyl 3- ((3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) azetidin-1-yl) methyl) azetidine-1-carboxylate (9a) (0.1g,0.15mmol) was dissolved in 15mL DCM and 5mL trifluoroacetic acid was added and stirred at room temperature for 3H. 30mL of saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution, and the mixture was extracted with 30mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of (4- ((1- (1- (azetidin-3-ylmethyl) azetidin-3-yl) piperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (9b) (0.05 g).
The third step: trifluoroacetate salt of 5- (3- ((3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) azetidin-1-yl) methyl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 9)
5-(3-((3-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionetrifluoroacetate
The crude (4- ((1- (1- (azetidin-3-ylmethyl) azetidin-3-yl) piperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (9b) (0.05g) was dissolved in 5mL DMSO, 1.0mL DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (synthesis WO2017197056) (0.1g, 0.36mmol) were added and the reaction was stirred at 90 ℃ for 5H. The reaction mixture was cooled to room temperature, diluted with 50mL of ethyl acetate, and the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product which was subjected to Pre-HPLC (Instrument and preparative column: liquid phase preparative on Glison GX-281, model Sunfire C18, 5 μm, inner diameter. times. length. 30 mm. times.150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted with a 5% gradient 60% (elution time 15min) and lyophilized to give the trifluoroacetate salt of 5- (3- ((3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) azetidin-1-yl) methyl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 9) (10 mg).
1H NMR(400MHz,DMSO-d6)δ11.15–11.00(m,1H),8.91–8.82(m,1H),8.30–8.23(m,1H),7.97–7.87(m,1H),7.70–7.62(m,2H),7.58(d,1H),7.52–7.44(m,2H),7.30–7.22(m,1H),7.22–7.14(m,3H),7.04(d,1H),6.82–6.77(m,1H),6.66(d,1H),5.05(dd,1H),4.34–4.02(m,7H),3.86–3.78(m,2H),3.52–3.48(m,1H),3.08–2.80(m,6H),2.70–2.52(m,4H),2.25–2.10(m,2H),2.06–1.96(m,1H),1.80–1.60(m,2H).
LCMS m/z=828.3[M+1]+
Example 10:
trifluoroacetate salt of 5- (3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidin ] -1' -yl) methyl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 10)
5-(3-((4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-[1,4'-bipiperidin]-1'-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
The first step is as follows: 3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidin ] -1' -yl) methyl) azetidine-1-carboxylic acid tert-butyl ester (10a)
tert-butyl3-((4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-[1,4'-bipiperidin]-1'-yl)methyl)azetidine-1-carboxylate
The trifluoroacetate salt (0.3g) of crude (4- ([1,4' -bipiperidin ] -4-ylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (2b) was dissolved in 20mL of DCE, 3-formylazetidine-1-carboxylic acid tert-butyl ester (0.2g,1.08mmol) was added, stirring was carried out at room temperature for 10min, sodium triacetoxyborohydride (0.21g, 1.0mmol) was added, and the reaction was stirred at room temperature for 12H. To the reaction solution, 50mL of a saturated sodium bicarbonate solution was slowly dropped, extracted with 30mL of dichloromethane, dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give tert-butyl 3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bispiperidin ] -1' -yl) methyl) azetidine-1-carboxylate (10a) (0.35g, two-step yield from compound 2 a: > 99%).
LC-MS m/z=700.3[M+1]+
The second step is that: (4- ((1'- (azetidin-3-ylmethyl) - [1,4' -bipiperidine ] -4-yl ] amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (10b)
(4-((1'-(azetidin-3-ylmethyl)-[1,4'-bipiperidin]-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone
Tert-butyl 3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidin ] -1' -yl) methyl) azetidine-1-carboxylate (10a) (0.35g,0.50mmol) was dissolved in 15mL DCM and 5mL trifluoroacetic acid was added and stirred at room temperature for 3H. 30mL of a saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution, and the mixture was extracted with 30mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product (4- ((1'- (azetidin-3-ylmethyl) - [1,4' -bipiperidin ] -4-yl ] amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (10b) (0.45 g).
The third step: trifluoroacetate salt of 5- (3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidin ] -1' -yl) methyl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 10)
5-(3-((4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-[1,4'-bipiperidin]-1'-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
The crude (4- ((1'- (azetidin-3-ylmethyl) - [1,4' -bispiperidine ] -4-yl ] amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (10b) (0.1g) was dissolved in 10mL of DMSO, 1.0mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (see WO2017197056 for the synthetic method) (0.1g, 0.36mmol) were added, the reaction was stirred at 90 ℃ for 5H, the reaction was cooled to room temperature, diluted with 50mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and passed through a Pre-HPLC (apparatus and preparative column: A liquid phase was prepared using Glison GX-281, the preparation column is of the type Sunfire C18, 5 μm, internal diameter × length 30mm × 150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted with a 5% gradient 60% (elution time 15min) and lyophilized to give the trifluoroacetate salt of 5- (3- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidin ] -1' -yl) methyl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 10) (8 mg).
1H NMR(400MHz,DMSO-d6)δ12.84(br.s,1H),11.06(s,1H),8.81(br.s,1H),8.29(s,1H),7.73–7.64(m,2H),7.58(d,1H),7.53–7.45(m,2H),7.30–7.23(m,1H),7.22–7.15(m,3H),7.04(dd,1H),6.81(s,1H),6.71–6.64(m,1H),5.06(dd,1H),4.48–4.30(m,1H),4.30–4.16(m,2H),3.89–3.79(m,2H),3.70–3.53(m,6H),3.32–3.18(m,4H),3.11–2.95(m,2H),2.95–2.82(m,1H),2.70–2.52(m,2H),2.46–2.22(m,4H),2.08–1.71(m,5H).
LCMS m/z=856.3[M+1]+
Example 11:
trifluoroacetate salt of 5- (4- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidin ] -1' -yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 11)
5-(4-((4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-[1,4'-bipiperidin]-1'-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
The first step is as follows: 4- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bispiperidine ] -1' -yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (11a)
tert-butyl4-((4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-[1,4'-bipiperidin]-1'-yl)methyl)piperidine-1-carboxylate
The trifluoroacetate salt (0.3g) of the above crude product of (4- ([1,4' -bipiperidin ] -4-ylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (2b) was dissolved in 20mL of DCE, and tert-butyl 4-formylpiperidine-1-carboxylate (0.3g,1.4mmol) was added, followed by stirring at room temperature for 10min, sodium triacetoxyborohydride (0.42g, 2.0mmol) was added, and the reaction was stirred at room temperature for 12 hours. To the reaction solution was slowly dropped 50mL of a saturated sodium bicarbonate solution, extracted with 30mL of dichloromethane, dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 4- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidin ] -1' -yl) methyl) piperidine-1-carboxylate (11a) (0.3g, two-step yield from compound 2 a: > 99%).
LC-MS m/z=728.4[M+1]+
The second step is that: (2-chloro-4-phenoxyphenyl) (4- ((1'- (piperidin-4-ylmethyl) - [1,4' -bispiperidine ] -4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (11b)
(2-chloro-4-phenoxyphenyl)(4-((1'-(piperidin-4-ylmethyl)-[1,4'-bipiperidin]-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
Tert-butyl 4- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidin ] -1' -yl) methyl) piperidine-1-carboxylate (11a) (0.3g,0.41mmol) was dissolved in 15mL DCM and 5mL trifluoroacetic acid was added and stirred at room temperature for 3H. 30mL of a saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution, and the mixture was extracted with 30mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of (2-chloro-4-phenoxyphenyl) (4- ((1'- (piperidin-4-ylmethyl) - [1,4' -bispiperidin ] -4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (11b) (0.2 g).
The third step: trifluoroacetate salt of 5- (4- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidin ] -1' -yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 11)
5-(4-((4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-[1,4'-bipiperidin]-1'-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate
The crude (2-chloro-4-phenoxyphenyl) (4- ((1'- (piperidin-4-ylmethyl) - [1,4' -bipiperidin ] -4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (11b) (0.2g) was dissolved in 10mL of DMSO, 1.0mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (see WO2017197056 for synthesis) (0.2g, 0.72mmol) were added and the reaction was stirred at 90 ℃ for 5H. The reaction mixture was cooled to room temperature, diluted with 50mL of ethyl acetate, and the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product which was subjected to Pre-HPLC (Instrument and preparative column: liquid phase preparative on Glison GX-281, model Sunfire C18, 5 μm, inner diameter. times. length. 30 mm. times.150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethyl sulfoxide, and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% TFA). Gradient elution method: acetonitrile was eluted with a 5% gradient 60% (elution time 15min) and lyophilized to give the trifluoroacetate salt of 5- (4- ((4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) - [1,4 '-bipiperidin ] -1' -yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 11) (150 mg).
1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.31(s,1H),7.74–7.64(m,2H),7.60(d,1H),7.53–7.45(m,2H),7.39–7.33(m,1H),7.31–7.23(m,2H),7.23–7.15(m,3H),7.05(dd,1H),5.08(dd,1H),4.48–4.32(m,1H),4.18–4.08(m,2H),3.80–3.67(m,2H),3.66–3.46(m,3H),3.39–3.21(m,2H),3.10–2.96(m,5H),2.96–2.83(m,1H),2.66–2.52(m,2H),2.48–2.24(m,4H),2.24–1.96(m,5H),1.96–1.78(m,4H),1.36–1.20(m,2H).
LCMS m/z=884.3[M+1]+
Example 12:
trifluoroacetate salt of Trans-5- (3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -3-fluoropiperidin-1-yl) - [1,3 '-diazacyclobutan ] -1' -yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 12)
Trans-5-(3-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-fluoropiperidin-1-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionetrifluoroacetate
The first step is as follows: trans-4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester (12a)
Trans-tert-butyl4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-fluoropiperidine-1-carboxylate
Trans-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (393mg,1.80mmol) (see WO2016127358 for a synthetic method) and (2-chloro-4-phenoxyphenyl) (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (1C) (576mg, 1.50mmol) were dissolved in 30mL of isopropanol and 1mL of DIPEA was added and reacted for 5H under reflux. The reaction mixture was cooled to room temperature, 50mL of water was added, extraction was performed with 100mL of ethyl acetate, the organic phase was washed with 100mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give Trans-4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester (12a) (700mg, yield from compound 1C: 83%).
LCMS m/z=566.2[M+1]+
The second step is that: trifluoroacetate salt of Trans- (2-chloro-4-phenoxyphenyl) (4- ((3-fluoropiperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (12b)
Trans-(2-chloro-4-phenoxyphenyl)(4-((3-fluoropiperidin-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone trifluoroacetate
Tert-butyl Trans-4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -3-fluoropiperidine-1-carboxylate (12a) (700mg,1.24mmol) was dissolved in 30mL of DCM, 10mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 4 hours. The reaction system was concentrated under reduced pressure to give a crude product of Trans- (2-chloro-4-phenoxyphenyl) (4- ((3-fluoropiperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (12b) as a trifluoroacetate salt (810 mg).
LCMS m/z=466.2[M+1]+
The third step: trans-3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -3-fluoropiperidin-1-yl) azetidine-1-carboxylic acid tert-butyl ester (12c)
Trans-tert-butyl3-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-fluoropiperidin-1-yl)azetidine-1-carboxylate
The trifluoroacetate salt (0.8g) of the above crude Trans- (2-chloro-4-phenoxyphenyl) (4- ((3-fluoropiperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (12b) was dissolved in 35mL DCE, and tert-butyl 3-oxoazetidine-1-carboxylate (423mg,2.47mmol) was added, followed by stirring at room temperature for 20min, sodium triacetoxyborohydride (1.02g, 4.81mmol) was added, and the mixture was stirred at room temperature for 18H. To the reaction solution, 50mL of a saturated sodium bicarbonate solution was slowly added, extraction was performed 3 times with 80mL of DCM, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give Trans-3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -3-fluoropiperidin-1-yl) azetidin-1-carboxylic acid tert-butyl ester (12c) (700mg, two-step yield from compound 12 a: 92%).
LCMS m/z=621.3[M+1]+
The fourth step: trifluoroacetate salt of Trans- (4- ((1- (azetidin-3-yl) -3-fluoropiperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (12d)
Trans-(4-((1-(azetidin-3-yl)-3-fluoropiperidin-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone trifluoroacetate
Trans-3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -3-fluoropiperidin-1-yl) azetidine-1-carboxylic acid tert-butyl ester (12c) (500mg,0.81mmol) was dissolved in 25mL of dichloromethane, 10mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2H. The reaction system was concentrated under reduced pressure to give crude Trans- (4- ((1- (azetidin-3-yl) -3-fluoropiperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (12d) as the trifluoroacetate salt (0.61 g).
LCMS m/z=521.3[M+1]+
The fifth step: trans-3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -3-fluoropiperidin-1-yl) - [1,3 '-diazacyclobutane ] -1' -carboxylic acid tert-butyl ester (12e)
Trans-tert-butyl3-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-fluoropiperidin-1-yl)-[1,3'-biazetidine]-1'-carboxylate
The trifluoroacetate salt (0.6g) of the above crude Trans- (4- ((1- (azetidin-3-yl) -3-fluoropiperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (12d) was dissolved in 40mL DCE, solid sodium bicarbonate (202mg, 2.40mmol) was added and stirred at room temperature for 20min, tert-butyl 3-oxoazetidine-1-carboxylate (329mg,1.92mmol) was added and stirred at room temperature for 10min, sodium triacetoxyborohydride (814mg, 3.84mmol) was added and stirred at room temperature for 16H. To the reaction system, 60mL of a sodium hydrogencarbonate solution was slowly added, extraction was performed with DCM (80mL × 3), the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1) to give Trans-3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -3-fluoropiperidin-1-yl) - [1,3 '-diazacyclobutane ] -1' -carboxylic acid tert-butyl ester (12e) (310mg, two-step yield from compound 12 c: 58%).
LCMS m/z=676.2[M+1]+
And a sixth step: trifluoroacetate salt of Trans- (4- ((1- ([1,3' -diazacyclobut ] -3-yl) -3-fluoropiperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (12f)
Trans-(4-((1-([1,3'-biazetidin]-3-yl)-3-fluoropiperidin-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone trifluoroacetate
Trans-3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -3-fluoropiperidin-1-yl) - [1,3 '-diazacyclobutane ] -1' -carboxylic acid tert-butyl ester (12e) (300mg,0.44mmol) was dissolved in 20mL of methanol, 8mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2H. The reaction system was concentrated under reduced pressure to give a crude product of Trans- (4- ((1- ([1,3' -diazacyclobut ] -3-yl) -3-fluoropiperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (12f) as a trifluoroacetate (0.35 g).
LCMS m/z=576.3[M+1]+
The seventh step: trifluoroacetate salt of Trans-5- (3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -3-fluoropiperidin-1-yl) - [1,3 '-diazacyclobutan ] -1' -yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 12)
Trans-5-(3-(4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-fluoropiperidin-1-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionetrifluoroacetate
The trifluoroacetate salt (0.35g) of the crude Trans- (4- ((1- ([1,3' -diazacyclobut ] -3-yl) -3-fluoropiperidin-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (2-chloro-4-phenoxyphenyl) methanone (12f) described above was dissolved in 15mL DMSO, 1.5mL DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (synthesis see WO2017197056) (245mg, 0.89mmol) were added and the reaction stirred at 80 ℃ for 5H. The reaction mixture was cooled to room temperature, 50mL of water was added, the mixture was filtered, the filter cake was collected, the filtrate was washed with 10mL of water, the solid was dissolved in 100mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1), to give trifluoroacetate salt of Trans-5- (3- (4- ((5- (2-chloro-4-phenoxybenzoyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -3-fluoropiperidin-1-yl) - [1,3 '-diazacyclobutan ] -1' -yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 12) (120 mg).
1H NMR(400MHz,CDCl3)δ9.26–9.14(m,1H),8.35(s,1H),7.62(d,1H),7.46–7.38(m,3H),7.35(s,1H),7.25–7.19(m,1H),7.13–7.06(m,3H),6.96(dd,1H),6.77(d,1H),6.51(dd,1H),4.92(dd,1H),4.86–4.63(m,1H),4.62–4.46(m,1H),4.08–3.98(m,2H),3.91–3.81(m,2H),3.74–3.64(m,1H),3.61–3.51(m,2H),3.24–3.15(m,1H),3.13–3.03(m,2H),3.03–2.91(m,1H),2.91–2.64(m,4H),2.43–2.21(m,3H),2.17–2.06(m,1H),1.87–1.72(m,1H).
LCMS m/z=832.3[M+1]+
Seventhly, the method comprises the following steps: effect (must fill)
1. Cell proliferation inhibition assay
When SU-DHL-4 cells were grown to 5X 106Mino cells grown to 2X 10 cells/mL6At counts/mL, cells were plated.
The cells in the dish/bottle were mixed well with a pipette, transferred to a 15mL (50mL) sterile centrifuge tube, centrifuged at 1500rpm for 3 minutes, removed after centrifugation, and the supernatant discarded. The centrifuge tube was added with 5mL of medium to resuspend the cells and counted. According to the counting result, SU-DHL-4 cells are diluted to 20000/90 mu L, Mino cells are diluted to 5000/90 mu L, and then the cells are plated by a row gun, wherein 90 mu L of each well is formed, the cells in the sample adding groove are uniformly mixed during plating, and the cell information is marked on a 96-well plate.
SU-DHL-4 cells: P13I was mixed with 10mM stock of test compound at an initial dose of 10000nM and diluted 3-fold in9 gradients. Compound concentration: 10000. 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52 nM. A dilution mode: mu.L of compound stock + 495. mu.L of medium in well 1, and 80. mu.L of medium containing 1% DMSO + 40. mu.L of dilution from well 2 to well 9.
And (3) Mino cells: P13I was mixed with 10mM stock of test compound at an initial dose of 10000nM and diluted 5-fold in 6-step dilutions. The administration concentration is as follows: 10000. 2000, 400, 80, 16, 3.2 nM. A dilution mode: mu.L of compound stock + 495. mu.L of medium in well 1, and 80. mu.L of medium containing 1% DMSO + 20. mu.L of dilution from well 2 to well 6.
10 μ L/well of compound was added to the well of the 96-well plate plated with cells. Each concentration was set to 3 more wells, the last column was DMSO vehicle control, at 37 ℃, 5% CO2Under the condition ofThe culture was continued for 72 hours.
After 72 hours, 100. mu.L of detection reagent (Cell Viability Assay, Promega, G7573) was added to each well, mixed for 2 minutes, incubated at room temperature for 10 minutes, and read by chemiluminescence with a microplate reader.
Cell proliferation inhibition assay (IC)50): using origin9.2 software, the IC of compounds to inhibit cell proliferation was calculated50The value is obtained.
TABLE 1 IC for inhibition of Mino cell proliferation50Value of
Serial number | Compound numbering | IC50(nM) |
1 | Trifluoroacetic acid salt of Compound 1 | 67 |
2 | Compound 3 | 102 |
3 | Compound 4 | 43 |
4 | Trifluoroacetic acid salt of Compound 9 | 109 |
5 | Trifluoroacetic acid salt of Compound 11 | 126 |
6 | Trifluoroacetic acid salt of Compound 12 | 19 |
IC for inhibiting proliferation of SU-DHL-4 cells50The results are shown in Table 2.
TABLE 2 IC inhibition of SU-DHL-4 cells50Value of
Serial number | Compound numbering | IC50(nM) |
1 | Compound 1 | 679 |
And (4) conclusion: the compound synthesized by the technology has obvious inhibition effect on the proliferation of Mino cells (mantle cell lymphoma cells) and SU-DHL-4 cells (human B lymphoma cells), and the embodiment of the invention comprises trifluoroacetate of compound 2, trifluoroacetate of compound 10 and activity inhibition IC of compounds 6-7 on the Mino cells (mantle cell lymphoma cells)50Activity inhibition IC of example Compounds of the invention on SU-DHL-4 cells (human B lymphoma cells) at 10-1000nM50The activity of the compound is 100-1500nM, and the specific values of the activity of the partial compound are shown in tables 1 and 2.
2. Pharmacokinetic testing of rats
Purpose of the experiment: in this test, the test substance is administered to SD rats via single-dose vein and gavage, and the in vivo pharmacokinetics of the test substance in rats is evaluated by measuring the concentration of the test substance in the plasma of rats.
Test animals: male SD rats, about 200g, 6-8 weeks old, 6 per compound. Purchased from Woods laboratories Inc.
The test method comprises the following steps: on the day of the experiment, 6 SD rats were randomly grouped by body weight. The food is fasted for 12-14 h before administration for 1 day, and is fed for 4h after administration.
Doses are in free base.
Sampling
Before and after administration isoflurane anaesthesia 0.1ml of blood was drawn through the eye orbit and placed in an EDTAK2 centrifuge tube. Centrifuging at 5000rpm and 4 deg.C for 10min, and collecting plasma.
Plasma time points were collected in groups G1& G2: 0,5min,15min,30min,1,2,4,6,8 and 24 h.
All samples were stored at-80 ℃ before analytical testing. The samples were tested by HPLC-MS/MS.
Injecting: compound was administered i.g. (gavage).
And (4) conclusion: the compound synthesized by the technology of the invention has certain oral bioavailability in rats.
3. Pharmacokinetic testing of rats
Purpose of the experiment: in this test, the test substance is administered to SD rats via single-dose vein and gavage, and the concentration of the test substance in the plasma of the rats is measured to evaluate the pharmacokinetic characteristics and bioavailability of the test substance in the rats.
Test animals: male SD rats, about 200g, 6-8 weeks old, 6 per compound. Purchased from Woods laboratories Inc.
The test method comprises the following steps: on the day of the experiment, 6 SD rats were randomly grouped by body weight. The food is fasted for 12-14 h before administration for 1 day, and is fed for 4h after administration.
Doses are in free base.
Sampling
Before and after administration isoflurane anaesthesia 0.1ml of blood was drawn through the eye orbit and placed in an EDTAK2 centrifuge tube. Centrifuging at 5000rpm and 4 deg.C for 10min, and collecting plasma.
Plasma time points were collected in groups G1& G2: 0,5min,15min,30min,1,2,4,6,8 and 24 h.
All samples were stored at-80 ℃ before analytical testing. The samples were tested by HPLC-MS/MS.
Table 3 pharmacokinetic parameters of the compounds in rat plasma
Test compounds | Mode of administration | AUC0-t(ng/ml·h) | F(%) |
Compound 1 | i.g.(20mg/kg) | 6801±304 | 16.0±0.72 |
Injecting: compound was administered i.g. (gavage).
And (4) conclusion: the compound synthesized by the technology of the invention has certain oral bioavailability in rat bodies.
Claims (19)
1. A compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
B-L-K (I);
L is selected from-Ak 1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak 5-;
ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from CH2O, NH or a key;
cy1, Cy2, Cy3 and Cy4 are each independently selected from 3 to 12 membered heterocyclic ring, 3 to 12 membered cycloalkyl, 6 to 10 membered aryl or bond, said heterocyclic, cycloalkyl or aryl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2、oxo、CF3、COOH、CN、C1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy substituted C1-4Alkyl or C1-4Alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;
when Ak1, Ak2, Ak3, Ak4 or Ak5 is O, the B can not be directly connected;
when Ak1, Ak2, Ak3, Ak4 or Ak5 are not bonds, the bonds can not be directly connected with each other;
when 4 or more of Ak1, Cy1, Ak2, Cy2, Ak3, Cy3, Ak4, Cy4 and Ak5 are not bonds, at least one of Cy1, Cy2, Cy3 and Cy4 is not piperidine, piperazine, pyrimidine or pyridine;
b is selected from B1-W1-B2-W2-B3-W3-B4;
b1 is selected from 6-membered heteroaromatic ring or phenyl further optionally substituted with 0 to 4Rb1(iii) substituted, said heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S, N;
w1 is selected from-O-, -S-, -NH-, -NHCO-or-CONH-;
w2 is selected from the group consisting of a bond, -CO-, -O-, -S-, -NH-, -NHCO-, and-CONH-;
w3 is selected from the group consisting of a bond, -CO-, -O-, -S-, -NH-, -NHCO-, and-CONH-;
b2 is selected from 6-membered heteroaromatic ring or phenyl optionally further optionally substituted with 0 to 4Rb2(iii) substituted, said heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S, N;
b3 is selected from an 8-10 membered heteroaryl ring or a 5-6 membered heteroaryl ring, said heteroaryl ring or heteroaryl ring optionally further optionally substituted with 0 to 4Rb3(iii) substituted, said hetero-fused or hetero-aromatic ring containing from 1 to 4 heteroatoms selected from O, S, N;
when B3 is selected from an 8-10 membered fused ring, W2 is not a bond;
b4 is selected from a bond or a 4-10 membered saturated heterocyclic ring selected from monocyclic, fused or spiro ring optionally further optionally substituted with 0 to 4Rb4Substituted, said saturated heterocycle containing 1 to 2 heteroatoms selected from O, S, N;
Rb1、Rb2、Rb3or Rb4Each independently selected from H, F, Cl, Br, I, OH, NH2、CN、CF3、COOH、CONH2、C1-4Alkyl, hydroxy substituted C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4Alkoxy, said alkyl and alkoxy being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2、CN、CONH2、C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
Ring E is selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1 to 2 heteroatoms selected from O, S, N;
Rk2is selected from CH2、C=O、S=O、SO2;
Rk1、Rk3Or Rk4Each independently selected from H, F, Cl, Br, I, OH, NH2、CN、COOH、C1-4Alkyl or C1-4An alkoxy group;
2. A compound according to claim 1 or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
Cy1, Cy2, Cy3 and Cy4 are each independently selected from a bond, 4-7 membered heteromonocyclic ring, 5-10 membered heterobicyclic ring, 6-12 membered heterospirocyclic ring, 7-10 membered heterobridged ring, 4-7 membered monocycloalkyl, 5-10 membered benzocycloalkyl, 6-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl or 6-10 membered aryl, said aryl, cycloalkyl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2、oxo、CF3、COOH、CN、C1-4Alkyl, hydroxy substituted C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4Alkoxy, said hetero-monocyclic, hetero-fused ring, hetero-spiro ring or hetero-bridged ring containing 1 to 4 heteroatoms selected from O, S, N;
b1 is selected from phenyl or pyridyl further optionally substituted with 0 to 4Rb1Substituted;
w1 is selected from-O-, -NHCO-, or-CONH-;
b2 is selected from phenyl or pyridyl further optionally substituted with 0 to 4Rb2Substituted;
b3 is selected from one of the following substituted or unsubstituted groups: imidazopyrimidines, pyrazolopyrimidines, pyrrolopyrimidines, imidazopyrazines, pyrazolopyrazines, imidazotetrahydropyrimidines, pyrazolotetrahydropyrimidines, pyrazoles or imidazoles, when substituted, optionally further optionally substituted with 0 to 4Rb3Substituted;
ring E is selected from the group consisting of benzene ring, pyridine, thiophene, furan, pyrrole, thiazole, oxazole, imidazole or pyrazole.
4. A compound according to claim 3 or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
Cy1, Cy2, Cy3 and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: a bond, phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylmethylcyclohexylcyclohexyl, cyclopropylcyclobutylyl, cyclopropylcyclopentylyl, cyclopropylcyclohexylyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylpirocyclopentyl, cyclopentylpirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, azetidinyl, piperidine, morpholine, piperazine, pyrrole, pyrazole, imidazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, tetrazole, cyclopropylazacyclobutyl, cyclopropylazacyclopentyl, cyclopropylazacyclohexyl, cyclopropylaminopiperidine, cyclobutylazetidinylbutyl, cyclobutylazacyclopentyl, Cyclobutyl and azacyclopentyl, cyclobutyl and azacyclohexyl, cyclobutyl and azacyclopentyl, cyclopenta-azetidinyl, cyclopenta-piperidine, cyclohexylo-azetidinyl, cyclopenta-azetidinyl, azetidinylCyclohexylazacyclopentazacyclopentyl, azacyclohexylazapiperidine, cyclobutyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, azetidinyl spiroazetidinyl, cyclohexylspiropiperidinyl, azetidinyl, An azacyclopentyl spiropiperidine, an azacyclohexyl spiropiperidine,When substituted, is optionally substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2、oxo、CF3、COOH、CN、C1-4Alkyl, hydroxy substituted C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
B4 is selected from one of the following substituted or unsubstituted groups: azetidinyl, azepinyl, piperidine, cyclopropyloazetidinyl, cyclobutylazetidinyl, cyclopentoazetidinyl, cyclopentaizetidinyl, cyclopentaietidinyl, and the like,Cyclohexylazacyclobutyl, cyclohexylazacyclopentyl, cyclohexylazacyclohexyl, cyclohexylpiperidine, cyclobutyl spiroazetidinyl, cyclohexyl spiroazetidinyl or cyclohexylspiroazetidinyl, when substituted, optionally substituted by 0 to 4Rb4Substituted;
Rb1、Rb2、Rb3or Rb4Each independently selected from H, F, Cl, Br, I, OH, NH2、CN、CONH2、CF3COOH, hydroxymethyl, methyl or methoxy, said methyl or methoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I;
n1, n2, n3 are each independently selected from 0, 1,2, 3 or 4;
Rk2Is selected from CH2Or C ═ O;
Rk1、Rk3or Rk4Each independently selected from H, F, Cl, Br, I, OH or NH2;
p1 or p2 are each independently selected from 0, 1 or 2.
5. The compound of claim 4 or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
The left side of the L is connected with the B, and the right side of the L is connected with the K;
11. A compound according to claim 3, wherein the compound is selected from compounds of formula (Ia), (Ib), (Ic) or (Id),
B-Cy1-K(Ia)
B-Cy1-Cy2-K(Ib)
B-Cy1-Cy2-Cy3-K(Ic)
B-Cy1-Cy2-Cy3-Cy4-K(Id)
B4 is selected from 4-to 6-membered azamonocyclic ring, 5-to 10-membered azabicyclic ring, 6-to 10-membered azaspiro ring or 4-to 6-membered monocycloalkyl, said cycloalkyl, heteromonocyclic, heterobicyclic or heterospiro ring being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2、CN、CF3、COOH、CONH2、C1-4Alkyl, hydroxy substituted C1-4Alkyl, halogen substituted C1-4Alkyl or C1-4Alkoxy, said heteromonocyclic, heterocyclic, or heterospirocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;
cy1, Cy2, Cy3 and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: 4 to 6 membered azamonocyclic, 5 to 10 membered azabicyclic, 6 to 10 membered azaspiro, 4 to 6 membered monocycloalkyl or phenyl, said phenyl, cycloalkyl, heteromonocyclic, heterocyclic or heterospiro ring optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2、oxo、CF3、COOH、CN、C1-4Alkyl, halogen substituted C1-4Alkyl, hydroxy substituted C1-4Alkyl or C1-4Alkoxy, said heteromonocyclic, heterocyclic, or heterospirocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;
14. a compound according to any one of claims 1 to 13, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the salt is selected from trifluoroacetate salt.
15. A pharmaceutical composition comprising a compound of any one of claims 1-14, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.
16. Use of a compound according to any one of claims 1-14, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with BTK activity or expression.
17. Use of a compound according to any one of claims 1-12, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with inhibition or degradation of BTK.
18. The use according to any one of claims 16 to 17, wherein the disease is selected from a tumour or an autoimmune disease.
19. The use according to claim 18, wherein the neoplasm is selected from the group consisting of non-hodgkin's lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, B-cell lymphoma, and the autoimmune disease is selected from the group consisting of rheumatoid arthritis and psoriasis.
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