WO2022148459A1 - Classe de nouveaux agents de dégradation de protéine smad3 et leur application - Google Patents

Classe de nouveaux agents de dégradation de protéine smad3 et leur application Download PDF

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WO2022148459A1
WO2022148459A1 PCT/CN2022/071013 CN2022071013W WO2022148459A1 WO 2022148459 A1 WO2022148459 A1 WO 2022148459A1 CN 2022071013 W CN2022071013 W CN 2022071013W WO 2022148459 A1 WO2022148459 A1 WO 2022148459A1
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alkyl
haloalkyl
compound
independently selected
halogen
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PCT/CN2022/071013
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Chinese (zh)
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马欣
陈永峰
赵存良
王兆伏
张玉华
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和径医药科技（上海）有限公司
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Priority claimed from CN202111371038.6A external-priority patent/CN116253724A/zh
Application filed by 和径医药科技（上海）有限公司 filed Critical 和径医药科技（上海）有限公司
Priority to CN202280006894.8A priority Critical patent/CN116368131A/zh
Publication of WO2022148459A1 publication Critical patent/WO2022148459A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicinal chemistry. Specifically, it relates to a new type of PROTAC molecule targeting Smad3 protein, a preparation method thereof, and a pharmaceutical composition comprising the compound.
  • the ubiquitin-proteasome pathway is a common way of degrading endogenous proteins.
  • the proteins that need to be degraded are first modified by ubiquitination, and then decomposed by the proteasome into smaller polypeptides, amino acids, and reusable ubiquitins.
  • PROTAC pro teolysis targeting c himeras
  • protein degradation targeting chimeras is a hot research field emerging in recent years [1] .
  • PROTAC molecules can generally be divided into three parts, one end is a small molecule fragment (warhead) that binds to a specific target protein, the other end is an E3 ligase ligand with ubiquitination function (E3 ligase ligand), and the two Linkers that are connected together.
  • PROTAC molecules utilize the cellular protein ubiquitination degradation pathway to selectively degrade target proteins. Specifically, since the two ends of the PROTAC molecule are the ligand fragments of the target protein and the E3 ligase, the PROTAC molecule can bind to the target protein and the E3 ligase at the same time, which promotes the ubiquitination of the target protein, which is further processed by the proteasome. Identify and degrade.
  • the reported PROTAC molecules are not only applied to some common kinase targets in the tumor field, such as EGFR [3] , ALK [4] , CDK [5] , etc., but also to BRD4 in the epigenetic field [2,6 ] ] , HDAC [7] , and nuclear receptors AR [8] , ER [9] and so on.
  • the proteins of the Smad family can be divided into three subgroups: R-Smad (receptor-regulated Smad), Co-Smad (common-mediated Smad) and I-Smad (inhibitory Smad) according to their molecular structure and different biological functions. They act as transporters in the transforming growth factor beta (TGF- ⁇ ) signaling pathway, and participate in mediating extracellular TGF- ⁇ signaling to the nucleus to regulate the expression of related target genes.
  • TGF- ⁇ transforming growth factor beta
  • TGF- ⁇ After TGF- ⁇ binds to the type II receptor on the cell membrane, it recruits and activates the type I receptor (ALK5), and then phosphorylates R-Smad in the cell; the phosphorylated R-Smad forms with Co-Smad and other transcription factors
  • the complex enters the nucleus to regulate the transcription of downstream genes [10] .
  • TGF- ⁇ is a key factor in promoting renal fibrosis.
  • the transcription factor complex formed after Smad3 is activated by TGF- ⁇ can directly bind to a series of collagen formation gene promoter regions to promote the formation of matrix layer.
  • Knockout of Smad3 gene in mice can inhibit fibrosis in various kidney diseases [13-16] .
  • Overexpression of Smad7 in mouse models of kidney disease to inhibit Smad3 activity can also effectively delay the process of kidney injury [17] .
  • a specific small molecule inhibitor of Smad3, SIS3, can effectively inhibit the progression of renal fibrosis in mouse models of diabetic nephropathy and obstructive nephropathy [18,19] .
  • Smad3 plays an important role in the progression of various tumors [20] .
  • Smad3 gene knockout and pharmacological inhibition have significant effects on cancer growth, invasion and tumor growth.
  • Metastasis produced a significant inhibitory effect [21] .
  • the purpose of the present invention is to provide a PROTAC molecule capable of degrading Smad3 protein.
  • the present invention provides compounds of formula (I), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof Object:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L is NR
  • R" is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • X 1 is CR X1 or N
  • X 2 is CR X2 or N
  • X 3 is CR X3 or N
  • X 4 is CR X4 or N
  • X 5 is CR X5 or N
  • R X1 , R X2 , R X3 , R X4 and R X5 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • Y 1 is CR Y1 or N
  • Y2 is O, S or NR Y2 ;
  • R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R Y2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1 and R 2 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R1 and R2 are connected, and together with the atoms to which they are connected form
  • Z 1 is CR Z1 or N
  • Z 2 is CR Z2 or N
  • Z 3 is CR Z3 or N
  • Z 4 is CR Z4 or N
  • R Z1 , R Z2 , R Z3 and R Z4 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 1 is CR 1 R 1 ';
  • L 2 is O, S, NR 2 "or CR 2 R 2 ';
  • L 3 is O, S, NR 3 " or CR 3 R 3 ';
  • L 4 is O, S, NR 4 "or CR 4 R 4 ';
  • L 5 is O, S, NR 5 "or CR 5 R 5 ';
  • L 6 is O, S, NR 6 ′′ or CR 6 R 6 ′
  • L 7 is O, S, NR 7 ′′ or CR 7 R 7 ′
  • L 1 , L 5 and L 6 are each independently absent;
  • L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene base or 5-7 membered heteroarylene;
  • L 2 and L 4 are connected, and together with L 2 , L 3 and L 4 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5 -7-membered heteroarylene;
  • L 3 and L 5 are connected and together with L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5 -7-membered heteroarylene;
  • Or -L 2 -L 3 -L 4 - represents a C 5-7 cycloalkylene group, a 5-7 membered heterocyclylene group, a C 6-10 arylene group or a 5-7 membered heteroarylene group;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 , and R 7 ′ are independently is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 3 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 4 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 5 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 7 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • the condition is that two adjacent atoms cannot be heteroatoms at the same time.
  • the present invention provides methods for the preparation of compounds of the present invention.
  • the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.
  • the compounds of the present invention are provided in a therapeutically effective amount.
  • the compounds of the present invention are provided in a prophylactically effective amount.
  • the present invention provides use of a compound of the present invention or a pharmaceutical composition of the present invention in the manufacture of a medicament for the treatment and/or prevention of Smad3 protein-mediated diseases.
  • the present invention provides a method of treating and/or preventing a Smad3 protein-mediated disease in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutical composition thereof.
  • the present invention provides a compound of the present invention or a pharmaceutical composition thereof for use in the treatment and/or prevention of Smad3 protein-mediated diseases.
  • the disease mediated by the Smad3 protein mentioned above is selected from autoimmune diseases and inflammation, tissue fibrosis and tumors, and the like.
  • Figure 1 is a Western blot of the degradation of Smad3 protein by representative compounds of the present invention.
  • C 1-6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1 -2 , C2-6 , C2-5 , C2-4 , C2-3 , C3-6 , C3-5 , C3-4 , C4-6 , C4-5 , and C5 -6 alkyl.
  • C 1-6 alkyl refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl”.
  • C 1-4 alkyl groups are particularly preferred. Examples of such alkyl groups include, but are not limited to: methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tertiary Butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butyl (C 5 ), tert-amyl (C 5 ) and n-hexyl (C 6 ).
  • each of the alkyl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, suitable substituents are as follows definition.
  • Halo or halogen refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • the halogen group is F, Cl, or Br.
  • the halogen group is F or Cl.
  • the halogen group is F.
  • C 1-6 haloalkyl refers to the aforementioned "C 1-6 alkyl” substituted with one or more halogen groups.
  • C 1-4 haloalkyl is particularly preferred, more preferably C 1-2 haloalkyl.
  • Exemplary such haloalkyl groups include, but are not limited to : -CF3 , -CH2F , -CHF2 , -CHFCH2F , -CH2CHF2 , -CF2CF3 , -CCl3 , -CH2Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.
  • C 5-7 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having 5 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, C5-6 cycloalkyl and C6 cycloalkyl are preferred. Cycloalkyl also includes ring systems in which the aforementioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to indicate The number of carbons in a cycloalkyl system.
  • cycloalkyl groups include, but are not limited to: cyclopentyl (C 5 ), cyclopentenyl (C 5 ), bicyclo[1.1.1]pent-1-yl (C 5 ), cyclohexyl (C 5 ) 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptyl (C 7 ) Heptatrienyl (C 7 ), and the like.
  • each of the cycloalkyl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate
  • the basis is defined as follows.
  • 5-7 membered heterocyclyl alternatively refers to a 5- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 5- to 6-membered heterocyclyl groups are preferred , which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms.
  • Heterocyclyl also includes ring systems in which the aforementioned heterocyclyl ring is fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases, the ring The number of members continues to indicate the number of ring members in a heterocyclyl ring system.
  • each of the heterocyclyl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate
  • the basis is defined as follows.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-diketone.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolane, oxasulfuranyl, disulfuranyl, and oxa oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiahexyl, dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl.
  • Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclyl groups) fused to a C6 aryl ring include, but are not limited to: indoline, isoindolyl , dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like.
  • Exemplary 6 -membered heterocyclyl groups fused to a C aryl ring include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and many more.
  • C 6-10 aryl refers to a monocyclic or polycyclic (eg, bicyclic or tricyclic) 4n+2 aromatic ring system (eg, having 6-10 ring carbon atoms and zero heteroatoms) 6 or 10 pi electrons shared by a cyclic arrangement).
  • an aryl group has six ring carbon atoms (" C6 aryl”; eg, phenyl).
  • aryl groups have ten ring carbon atoms (" C10 aryl”; eg, naphthyl, eg, 1-naphthyl and 2-naphthyl).
  • C6 aryl groups are preferred.
  • Aryl also includes ring systems in which the aforementioned aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said aryl ring, in which case the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system.
  • each of the aryl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, suitable substituents are as follows definition.
  • 5-7 membered heteroaryl refers to a 5- to 7-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (eg, having shared in a cyclic arrangement 6 or 10 pi electrons) wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • the point of attachment may be a carbon or nitrogen atom as valence allows.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the carbon atom is The numbers continue to indicate the number of carbon atoms in the heteroaryl ring system.
  • 5- to 6-membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms.
  • each of the heteroaryl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate
  • the basis is defined as follows.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacyclotrienyl, oxeptrienyl, and thiacyclotrienyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Indanyl and purine groups.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pteridyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl .
  • C 5-7 -membered cycloalkylene represents the above-mentioned "C 5-7 ring"Alkyl”
  • 5-7 membered heterocyclyl represents the above-mentioned "C 5-7 ring"Alkyl”
  • 5-7 membered heterocyclyl represents the above-mentioned "C 5-7 ring"Alkyl”
  • 5-7 membered heterocyclyl represents the above-mentioned "C 5-7 membered heterocyclyl”
  • C 6-10 aryl represents the above-mentioned heterocyclyl
  • C 6-10 aryl represents the above-mentioned
  • Each of R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R aa groups are combined to form a heterocyclyl or Heteroaryl rings in which each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R dd groups group replacement;
  • Each of Rcc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two Rcc groups are combined to form a heterocycle yl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R dd group substitution;
  • R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbon cyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups;
  • Each of Rff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two Rff groups are combined to form a heterocyclyl group or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently separated by 0, 1, 2, 3, 4, or 5 R gg group substitution;
  • pharmaceutically acceptable salt means, within the scope of sound medical judgment, suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergy, etc., and with reasonable benefit/risk those salts in commensurate proportions.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by Berge et al. in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases.
  • non-toxic acid addition salts examples include salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or salts formed with organic acids such as acetic, oxalic, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Also included are salts formed using methods conventional in the art, eg, ion exchange methods.
  • salts include: adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphor acid salt, camphorsulfonate, citrate, cypionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerin Phosphate, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobate, Lactate, Laurate, Lauryl Sulfate , malate, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoic acid Salt, Pectin Acetate, Persulfate, 3-Phenyl
  • Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations with counter ions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrates, lower alkyl sulfonates and aryl sulfonates.
  • Subjects for administration include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and/or non-human animals, eg, mammals, eg, primates (eg, cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep , goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "human", “patient” and “subject” are used interchangeably herein.
  • treatment includes the effect that occurs when a subject has a particular disease, disorder or condition, which reduces the severity of, or delays or slows down, the disease, disorder or condition or development of a disorder ("therapeutic treatment”), and also includes effects that occur before a subject begins to suffer from a particular disease, disorder or condition ("prophylactic treatment").
  • Combination and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention.
  • a compound of the present invention may be administered concurrently or sequentially with another therapeutic agent in separate unit dosage forms, or concurrently with another therapeutic agent in a single unit dosage form.
  • compounds of the present invention refers to compounds of formula (X) and formula (I) to (V) below (including subsets of each formula), or tautomers, stereoisomers, Prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates.
  • the present invention relates to a compound of formula (X), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L is NR
  • R" is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • X 1 is CR X1 or N
  • X 2 is CR X2 or N
  • X 3 is CR X3 or N
  • X 4 is CR X4 or N
  • X 5 is CR X5 or N
  • R X1 , R X2 , R X3 , R X4 and R X5 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • Y 1 is CR Y1 or N;
  • Y 2 is O, S or NR Y2 ;
  • R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R Y2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1 and R 2 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R1 and R2 are connected, and together with the atoms to which they are connected form
  • Z 1 is CR Z1 or N
  • Z 2 is CR Z2 or N
  • Z 3 is CR Z3 or N
  • Z 4 is CR Z4 or N
  • R Z1 , R Z2 , R Z3 and R Z4 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 1 is CR 1 R 1 ';
  • L 2 is O, S, NR 2 "or CR 2 R 2 ';
  • L 3 is O, S, NR 3 " or CR 3 R 3 ';
  • L 4 is O, S, NR 4 "or CR 4 R 4 ';
  • L 5 is O, S, NR 5 " or CR 5 R 5 ';
  • L 6 is O, S, NR 6 " or CR 6 R 6 ';
  • L 7 is O, S , NR 7 "or CR 7 R 7 ';
  • L 1 , L 5 and L 6 are each independently absent;
  • L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene base or 5-7 membered heteroarylene;
  • L 2 and L 4 are connected, and together with L 2 , L 3 and L 4 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5 -7-membered heteroarylene;
  • L 3 and L 5 are connected and together with L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5 -7-membered heteroarylene;
  • Or -L 2 -L 3 -L 4 - represents a C 5-7 cycloalkylene group, a 5-7 membered heterocyclylene group, a C 6-10 arylene group or a 5-7 membered heteroarylene group;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 , and R 7 ′ are independently is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 3 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 4 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 5 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 7 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • Ra is selected from D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; n is 0, 1, 2, 3 or 4.
  • n is preferably 0 or 1
  • Ra is preferably fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -CH 2 CH 2 F, - CH2CHF2 , -CH2CF3 , monobromo - substituted ethyl or dibromo - substituted ethyl.
  • the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L is NR
  • R" is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • X 1 is CR X1 or N
  • X 2 is CR X2 or N
  • X 3 is CR X3 or N
  • X 4 is CR X4 or N
  • X 5 is CR X5 or N
  • R X1 , R X2 , R X3 , R X4 and R X5 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • Y 1 is CR Y1 or N;
  • Y 2 is O, S or NR Y2 ;
  • R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R Y2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1 and R 2 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R1 and R2 are connected, and together with the atoms to which they are connected form
  • Z 1 is CR Z1 or N
  • Z 2 is CR Z2 or N
  • Z 3 is CR Z3 or N
  • Z 4 is CR Z4 or N
  • R Z1 , R Z2 , R Z3 and R Z4 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 1 is CR 1 R 1 ';
  • L 2 is O, S, NR 2 "or CR 2 R 2 ';
  • L 3 is O, S, NR 3 " or CR 3 R 3 ';
  • L 4 is O, S, NR 4 "or CR 4 R 4 ';
  • L 5 is O, S, NR 5 "or CR 5 R 5 ';
  • L 6 is O, S, NR 6 " or CR 6 R 6 ';
  • L 7 is O, S, NR 7 "or CR 7 R 7 ';
  • L 1 , L 5 and L 6 are each independently absent;
  • L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene base or 5-7 membered heteroarylene;
  • L 2 and L 4 are connected, and together with L 2 , L 3 and L 4 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5 -7-membered heteroarylene;
  • L 3 and L 5 are connected and together with L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5 -7-membered heteroarylene;
  • Or -L 2 -L 3 -L 4 - represents a C 5-7 cycloalkylene group, a 5-7 membered heterocyclylene group, a C 6-10 arylene group or a 5-7 membered heteroarylene group;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 , and R 7 ′ are independently is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 3 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 4 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 5 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 7 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • the condition is that two adjacent atoms cannot be heteroatoms at the same time.
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; in another specific embodiment, R and R' are independently is selected from H, D, halogen and C 1-6 alkyl; in another specific embodiment, R and R' are independently selected from H, D and halogen; in another specific embodiment, R and R' are independently is selected from H and D.
  • L is NR"; in another embodiment, L is NH.
  • R" is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; in another specific embodiment, R " is C 1-6 alkyl or C 1 -6 haloalkyl; in another specific embodiment, R" is C 1-6 alkyl; in another specific embodiment, R" is C 1-6 haloalkyl.
  • X1 is CR X1 ; in another embodiment, X1 is CH ; in another embodiment, X1 is N ;
  • X2 is CR X2 ; in another embodiment, X2 is CH ; in another embodiment, X2 is N ;
  • X3 is CR X3 ; in another embodiment, X3 is CH; in another embodiment, X3 is N;
  • X4 is CR X4 ; in another embodiment, X4 is CH; in another embodiment, X4 is N;
  • X5 is CR X5 ; in another embodiment, X5 is CH ; in another embodiment, X5 is N.
  • R X1 , R X2 , R X3 , R X4 and R X5 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; in another particular In an embodiment, R X1 , R X2 , R X3 , R X4 and R X5 are independently selected from H, D, halogen or C 1-6 alkyl; in another specific embodiment, R X1 , R X2 , R X3 , R X4 and R X5 are independently selected from H or D; in another specific embodiment, R X1 , R X2 , R X3 , R X4 and R X5 are independently C 1-6 alkyl; in another In specific embodiments, R X1 , R X2 , R X3 , R X4 and R X5 are independently C 1-6 haloalkyl.
  • Y1 is CR Y1 ; in another embodiment, Y1 is CH; in another embodiment, Y1 is N.
  • Y2 is O; in another embodiment, Y2 is S; in another embodiment, Y2 is NR Y2 ; in another embodiment, Y2 is NMe; In one embodiment, Y2 is NH.
  • R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; in another specific embodiment, R Y1 is independently selected from H, D, halogen or C 1-6 alkyl; in another specific embodiment, R Y1 is independently selected from H or D; in another specific embodiment, R Y1 is C 1-6 alkyl; in another specific embodiment, R Y1 is C 1-6 alkyl; In a specific embodiment, R Y1 is C 1-6 haloalkyl.
  • R Y2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl; in another specific embodiment, R Y2 is selected from H or C 1-6 alkyl; in another specific embodiment, R Y2 is selected from H; in another specific embodiment, R Y2 is C 1-6 alkyl; in another specific embodiment, R Y2 is C 1-6 haloalkyl.
  • R1 and R2 are H ; in another embodiment, R1 and R2 are D ; in another embodiment, R1 and R2 are halogen ; in another embodiment , R 1 and R 2 are C 1-6 alkyl; in another embodiment, R 1 and R 2 are C 1-6 haloalkyl.
  • R 1 and R 2 are linked, and together with the atoms to which they are linked form
  • Z1 is CR Z1 ; in another specific embodiment, Z1 is CH ; in another specific embodiment, Z1 is N ;
  • Z2 is CR Z2 ; in another specific embodiment, Z2 is CH ; in another specific embodiment, Z2 is N ;
  • Z3 is CR Z3 ; in another specific embodiment, Z3 is CH ; in another specific embodiment, Z3 is N ;
  • Z4 is CR Z4 ; in another specific embodiment, Z4 is CH; in another specific embodiment, Z4 is N.
  • R Z1 , R Z2 , R Z3 and R Z4 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; in another specific embodiment , R Z1 , R Z2 , R Z3 and R Z4 are independently selected from H, D, halogen or C 1-6 alkyl; in another specific embodiment, R Z1 , R Z2 , R Z3 and R Z4 are independently is selected from H, D or halogen; in another specific embodiment, R Z1 , R Z2 , R Z3 and R Z4 are independently selected from H or D.
  • L1 is CR1R1 ' ; in another embodiment, L1 is CH2 ; in another embodiment, L1 is absent ;
  • the substituents of L 2 and L 5 are linked and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5-7 membered heteroarylene; in another embodiment, the substituents of L 2 and L 5 are linked and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene; in another embodiment, the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form a 5-7 membered heterocyclylene; in another embodiment, the substituents of L 2 and L 5 are linked and together with L 2 , L 3 , L 4 and L 5 form a C 6-10 arylene; in another embodiment, L 2 and L The substituents of 5 are attached and together with L 2 , L 3 , L 4 and L 5 form a 5-7 membered heteroarylene; in another embodiment, the substituents of L
  • the substituents of L 2 and L 4 are linked and together with L 2 , L 3 and L 4 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6- 10 arylene or 5-7 membered heteroarylene; in another embodiment, the substituents of L 2 and L 4 are connected and together with L 2 , L 3 and L 4 form a C 5-7 cycloalkane In another embodiment, the substituents of L 2 and L 4 are connected and together with L 2 , L 3 and L 4 form a 5-7 membered heterocyclylene group; in another embodiment, L 2 and The substituents of L 4 are connected and together with L 2 , L 3 and L 4 form a C 6-10 arylene; in another embodiment, the substituents of L 2 and L 4 are connected and together with L 2 , L 3 and L 4 together form a 5-7 membered heteroarylene; in another embodiment, the substituents of L 2 and L 4 are linked and together with L 2 , L 3 and L 4 form C 5-7
  • the substituents of L 3 and L 5 are linked and together with L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6- 10 arylene or 5-7 membered heteroarylene; in another embodiment, the substituents of L 3 and L 5 are connected and together with L 3 , L 4 and L 5 form C 5-7 cycloalkane In another embodiment, the substituents of L 3 and L 5 are connected and together with L 3 , L 4 and L 5 form a 5-7 membered heterocyclylene group; in another embodiment, L 3 and The substituents of L 5 are connected and together with L 3 , L 4 and L 5 form a C 6-10 arylene; in another embodiment, the substituents of L 3 and L 5 are connected and together with L 3 , L 4 and L 5 together form a 5-7 membered heteroarylene; in another embodiment, the substituents of L 3 and L 5 are connected and together with L 3 , L 4 and L 5 form 1,3
  • -L 2 -L 3 -L 4 - represents C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5-7 membered heterocyclylene Aryl; in another embodiment, -L 2 -L 3 -L 4 - represents C 5-7 cycloalkylene; in another embodiment, -L 2 -L 3 -L 4 - represents 5- 7-membered heterocyclylene; in another embodiment, -L 2 -L 3 -L 4 - represents a C 6-10 arylene; in another embodiment, -L 2 -L 3 -L 4 - represents a 5-7 membered heteroarylene; in another embodiment, -L 2 -L 3 -L 4 - represents 1,4-phenylene; in another embodiment, -L 2 -L 3 - L 4 - represents 2,5-pyridylene; in another embodiment, -L 2 -L 3 -L 4 - represents 2,5-pyrimidiny
  • -L 3 -L 4 -L 5 - represents C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5-7 membered heterocyclylene Aryl; in another embodiment, -L 3 -L 4 -L 5 - represents C 5-7 cycloalkylene; in another embodiment, -L 3 -L 4 -L 5 - represents 5- 7-membered heterocyclylene; in another embodiment, -L 3 -L 4 -L 5 - represents a C 6-10 arylene; in another embodiment, -L 3 -L 4 -L 5 - represents a 5-7 membered heteroarylene; in another embodiment, -L 3 -L 4 -L 5 - represents 1,4-phenylene; in another embodiment, -L 3 -L 4 - L 5 -represents 2,5-pyridylene; in another embodiment, -L 3 -L 4 -L 5 -represents 2,5-
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 and R 7 ′ are independently selected from H, D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; in another embodiment, R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ', R 6 , R 6 ', R 7 and R 7 ' are independently selected from H, D, halogen or C 1-6 alkyl; In another embodiment, R1, R1 ' , R2, R2 ' , R3 , R3 ', R4 , R4 ', R5 , R5 ', R6 , R6 ', R 7 and R7 ' are independently selected from H, D or halogen; in another embodiment,
  • R 2 " is H; in another embodiment, R 2 " is C 1-6 alkyl; in another embodiment, R 2 " is C 1-6 haloalkyl;
  • R 3 " is H; in another embodiment, R 3 " is C 1-6 alkyl; in another embodiment, R 3 " is C 1-6 haloalkyl;
  • R 4 " is H; in another embodiment, R 4 " is C 1-6 alkyl; in another embodiment, R 4 " is C 1-6 haloalkyl;
  • R 5 " is H; in another embodiment, R 5 " is C 1-6 alkyl; in another embodiment, R 5 " is C 1-6 haloalkyl;
  • R 6 " is H; in another embodiment, R 6 " is C 1-6 alkyl; in another embodiment, R 6 " is C 1-6 haloalkyl;
  • R 7 " is H; in another embodiment, R 7 " is C 1-6 alkyl; in another embodiment, R 7 " is C 1-6 haloalkyl.
  • any technical solution in any of the above specific embodiments or any combination thereof may be combined with any technical solution in other specific embodiments or any combination thereof.
  • any technical solution of W or any combination thereof can be carried out with any technical solution of L, X 1 -X 5 , Y 1 -Y 2 , R 1 -R 2 and L 1 -L 7 or any combination thereof. combination.
  • the present invention is intended to include all the combinations of these technical solutions, and is not listed one by one due to space limitations.
  • Y 1 is CR Y1 , preferably CH.
  • Y 2 is O or S, preferably O.
  • Z 1 , Z 2 , Z 3 and Z 4 are respectively CR Z1 , CR Z2 , CR Z3 and CR Z4 , preferably all CH; preferably, Z 1 , Z 2 , Z 3 and Z 4 are respectively CH, CH, CH, and N.
  • L2 is O, S or CR2R2 ';
  • L3 is O, S or CR3R3 ' ;
  • L4 is O, S or CR4R4 ' ;
  • L5 is O, S or CR 5 R 5 ′;
  • L 6 is O, S or CR 6 R 6 ′.
  • the present invention relates to the above-mentioned compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which are Compound of formula:
  • the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which are of formula (II) or (II-a) compound:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L is NR
  • R" is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • X 1 is CR X1 or N
  • X 2 is CR X2 or N; preferably N
  • X 3 is CR X3 or N
  • X 4 is CR X4 or N
  • X 5 is CR X5 ;
  • R X1 , R X2 , R X3 , R X4 and R X5 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • Y 1 is CR Y1 or N
  • Y2 is O, S or NR Y2 ;
  • R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R Y2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • Z 1 is CR Z1 or N
  • Z 2 is CR Z2 or N
  • Z 3 is CR Z3 or N
  • Z 4 is CR Z4 or N
  • R Z1 , R Z2 , R Z3 and R Z4 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 2 is O, S, NR 2 "or CR 2 R 2 ';
  • L 3 is O, S, NR 3 " or CR 3 R 3 ';
  • L 4 is O, S, NR 4 "or CR 4 R 4 ';
  • L 5 is O, S, NR 5 "or CR 5 R 5 ';
  • L 1 and L 6 are CR 1 R 1 ' and CR 6 R 6 ', respectively;
  • L 1 , L 5 and L 6 are each independently absent;
  • L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene base or 5-7 membered heteroarylene;
  • L 2 and L 4 are connected, and together with L 2 , L 3 and L 4 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5 -7-membered heteroarylene;
  • L 3 and L 5 are connected and together with L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5 -7-membered heteroarylene;
  • Or -L 2 -L 3 -L 4 - represents a C 5-7 cycloalkylene group, a 5-7 membered heterocyclylene group, a C 6-10 arylene group or a 5-7 membered heteroarylene group;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 3 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 4 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 5 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • the condition is that two adjacent atoms cannot be heteroatoms at the same time.
  • the present invention relates to a compound of formula (II) above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a tautomer, stereoisomer, prodrug, crystalline form thereof ,in:
  • R and R' are independently selected from H or D;
  • L is NH
  • X1 is CR X1 or N ;
  • X2 is CR X2 or N ; preferably N;
  • X3 is CR X3 or N
  • X4 is CR X4 or N
  • X5 is CR X5 ;
  • R X1 , R X2 , R X3 , R X4 and R X5 are independently selected from H or D;
  • Y 1 is CR Y1 or N
  • Y2 is O, S or NR Y2 ;
  • R Y1 is independently selected from H or D;
  • R Y2 is selected from H or C 1-6 alkyl
  • Z1 is CR Z1 or N ;
  • Z2 is CR Z2 or N ;
  • Z 3 is CR Z3 or N
  • Z 4 is CR Z4 or N
  • R Z1 , R Z2 , R Z3 and R Z4 are independently selected from H or D;
  • L 2 is O, NR 2 "or CR 2 R 2 ';
  • L 3 is O, NR 3 "or CR 3 R 3 ';
  • L 4 is O, NR 4 "or CR 4 R 4 ';
  • L 1 , L 5 and L 6 are CR 1 R 1 ', CR 5 R 5 ' and CR 6 R 6 ', respectively;
  • L 1 , L 5 and L 6 are each independently absent;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D;
  • R 2 " is selected from H or C 1-6 alkyl
  • R 3 " is selected from H or C 1-6 alkyl
  • R 4 " is selected from H or C 1-6 alkyl
  • the condition is that two adjacent atoms cannot be heteroatoms at the same time.
  • the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which are of formula (II-1) or (II-1-a) compound:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • X1 is CR X1 or N ;
  • X2 is CR X2 or N ; preferably N;
  • X3 is CR X3 or N
  • X4 is CR X4 or N
  • X5 is CR X5 ;
  • R X1 , R X2 , R X3 , R X4 and R X5 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • Y1 is CR Y1 ;
  • Y2 is O, S or NR Y2 ;
  • R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R Y2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • Z 4 is CR Z4 or N
  • R Z4 is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 2 is O, S, NR 2 ′′ or CR 2 R 2 ′;
  • L 3 is O, S or CR 3 R 3 ';
  • L 4 is O, S or CR 4 R 4 ';
  • L 1 , L 5 and L 6 are CR 1 R 1 ′, CR 5 R 5 ′ and CR 6 R 6 ′, respectively; or L 5 is absent;
  • L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene or C 6-10 arylene base;
  • L 2 and L 4 are connected, and together with L 2 , L 3 and L 4 form a C 5-7 cycloalkylene group, a 5-7 membered heterocyclylene group or a C 6-10 arylene group ;
  • Or -L 2 -L 3 -L 4 - represents C 5-7 cycloalkylene, C 6-10 arylene or
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • the condition is that two adjacent atoms cannot be heteroatoms at the same time.
  • the present invention relates to a compound of formula (II-1) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:
  • R and R' are independently selected from H or D;
  • X1 is CR X1 or N ;
  • X2 is CR X2 or N ; preferably N;
  • X3 is CR X3 or N
  • X4 is CR X4 or N
  • X5 is CR X5 ;
  • R X1 , R X2 , R X3 , R X4 and R X5 are independently selected from H or D;
  • Y1 is CR Y1 ;
  • Y2 is O, S or NR Y2 ;
  • R Y1 is independently selected from H or D;
  • R Y2 is selected from H or C 1-6 alkyl
  • Z 4 is CR Z4 or N
  • R Z4 is selected from H or D
  • L 2 is O, NR 2 "or CR 2 R 2 ';
  • L 3 is O or CR 3 R 3 ';
  • L 4 is O or CR 4 R 4 ';
  • L 1 , L 5 and L 6 are CR 1 R 1 ', CR 5 R 5 ' and CR 6 R 6 ', respectively; or L 5 is absent;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D;
  • R 2 " is selected from H or C 1-6 alkyl
  • the condition is that two adjacent atoms cannot be heteroatoms at the same time.
  • the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which are of formula (II-2) or (II-2-a) compound:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • Y1 is CR Y1 ;
  • Y2 is O, S or NR Y2 ;
  • R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R Y2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • Z 4 is CR Z4 or N
  • R Z4 is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 2 is O, S, NR 2 ′′ or CR 2 R 2 ′;
  • L 3 is O, S or CR 3 R 3 ';
  • L 1 , L 4 , L 5 and L 6 are CR 1 R 1 ', CR 4 R 4 ', CR 5 R 5 ' and CR 6 R 6 ', respectively;
  • L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene or C 6-10 arylene base;
  • L 2 and L 4 are connected, and together with L 2 , L 3 and L 4 form a C 5-7 cycloalkylene group, a 5-7 membered heterocyclylene group or a C 6-10 arylene group ;
  • Or -L 2 -L 3 -L 4 - represents C 5-7 cycloalkylene, C 6-10 arylene or
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • the condition is that two adjacent atoms cannot be heteroatoms at the same time.
  • the present invention relates to a compound of formula (II-2) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof.
  • compounds including:
  • R and R' are independently selected from H or D;
  • Y1 is CR Y1 ;
  • Y2 is O, S or NR Y2 ;
  • R Y1 is independently selected from H or D;
  • R Y2 is selected from H or C 1-6 alkyl
  • Z 4 is CR Z4 or N
  • R Z4 is selected from H or D
  • L 2 is O, NR 2 "or CR 2 R 2 ';
  • L 3 is O or CR 3 R 3 ';
  • L 1 , L 4 , L 5 and L 6 are CR 1 R 1 ', CR 4 R 4 ', CR 5 R 5 ' and CR 6 R 6 ', respectively;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D;
  • R 2 " is selected from H or C 1-6 alkyl
  • the condition is that two adjacent atoms cannot be heteroatoms at the same time.
  • the present invention relates to a compound of formula (II-2) above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • Y1 is CR Y1 ;
  • R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • Y 2 is O or S
  • Z 4 is CR Z4 or N
  • R Z4 is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 1 , L 2 , L 3 , L 4 , L 5 and L 6 are CR 1 R 1 ′, CR 2 R 2 ′, CR 3 R 3 ′, CR 4 R 4 ′, CR 5 R 5 ′ and CR, respectively 6R6 ' ;
  • L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene or C 6-10 arylene base;
  • Or -L 2 -L 3 -L 4 - represents a C 5-7 cycloalkylene group, a 5-7 membered heterocyclic group or a C 6-10 arylene group;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • the present invention relates to a compound of formula (II-2) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof.
  • compounds including:
  • R and R' are independently selected from H or D;
  • Y1 is CR Y1 ;
  • R Y1 is independently selected from H or D;
  • Y 2 is O or S
  • Z 4 is CR Z4 or N
  • R Z4 is selected from H or D
  • L 1 , L 2 , L 3 , L 4 , L 5 and L 6 are CR 1 R 1 ′, CR 2 R 2 ′, CR 3 R 3 ′, CR 4 R 4 ′, CR 5 R 5 ′ and CR, respectively 6R6 ' ;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D;
  • the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which are of formula (III-3) or (III-a) compound:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 2 is O, S, NR 2 ′′ or CR 2 R 2 ′;
  • L 3 is O, S, NR 3 "or CR 3 R 3 ';
  • L 4 is O, S, NR 4 "or CR 4 R 4 ';
  • L 5 is O, S, NR 5 "or CR 5 R 5 ';
  • L 1 and L 6 are CR 1 R 1 ' and CR 6 R 6 ', respectively;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 3 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 4 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 5 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • the condition is that two adjacent atoms cannot be heteroatoms at the same time.
  • the present invention relates to a compound of formula (III-3) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:
  • L 2 is O or CR 2 R 2 ';
  • L 3 is O, NR 3 "or CR 3 R 3 ';
  • L 1 , L 4 , L 5 and L 6 are CR 1 R 1 ', CR 4 R 4 ', CR 5 R 5 ' and CR 6 R 6 ', respectively;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D;
  • R 3 " is selected from H or C 1-6 alkyl
  • the condition is that two adjacent atoms cannot be heteroatoms at the same time.
  • the present invention relates to a compound of formula (III-3) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 3 is O, S or CR 3 R 3 ';
  • L 1 , L 2 , L 4 , L 5 and L 6 are CR 1 R 1 ′, CR 2 R 2 ′, CR 4 R 4 ′, CR 5 R 5 ′ and CR 6 R 6 ′, respectively;
  • R 1 , R 1 ', R 2 , R 2 ', R 4 , R 4 ', R 5 , R 5 ', R 6 and R 6 ' are independently selected from H, D, halogen, C 1-6 alkanes group or C 1-6 haloalkyl;
  • the present invention relates to a compound of formula (III-3) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:
  • L 3 is O or CR 3 R 3 ';
  • L 1 , L 2 , L 4 , L 5 and L 6 are CR 1 R 1 ′, CR 2 R 2 ′, CR 4 R 4 ′, CR 5 R 5 ′ and CR 6 R 6 ′, respectively;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D.
  • the present invention relates to a compound of formula (III-3) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 3 is O or S
  • L 1 , L 2 , L 4 , L 5 and L 6 are CR 1 R 1 ′, CR 2 R 2 ′, CR 4 R 4 ′, CR 5 R 5 ′ and CR 6 R 6 ′, respectively;
  • R 1 , R 1 ', R 2 , R 2 ', R 4 , R 4 ', R 5 , R 5 ', R 6 and R 6 ' are independently selected from H, D, halogen, C 1-6 alkanes group or C 1-6 haloalkyl;
  • the present invention relates to a compound of formula (III-3) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:
  • L 1 , L 2 , L 4 , L 5 and L 6 are CR 1 R 1 ′, CR 2 R 2 ′, CR 4 R 4 ′, CR 5 R 5 ′ and CR 6 R 6 ′, respectively;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D.
  • the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which are of formula (IV-3) or (IV-3-a) compound:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 2 is O, S, NR 2 ′′ or CR 2 R 2 ′;
  • L 3 is O, S, NR 3 "or CR 3 R 3 ';
  • L 4 is O, S, NR 4 "or CR 4 R 4 ';
  • L 5 is O, S, NR 5 "or CR 5 R 5 ';
  • L 1 and L 6 are CR 1 R 1 ' and CR 6 R 6 ', respectively;
  • L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene base or 5-7 membered heteroarylene;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 3 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 4 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 5 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • the condition is that two adjacent atoms cannot be heteroatoms at the same time.
  • the present invention relates to a compound of formula (IV-3) above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:
  • L 2 is O or CR 2 R 2 ';
  • L 3 is O or CR 3 R 3 ';
  • L 4 is O or CR 4 R 4 ';
  • L 1 , L 5 and L 6 are CR 1 R 1 ', CR 5 R 5 ' and CR 6 R 6 ', respectively;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D;
  • the condition is that two adjacent atoms cannot be O at the same time.
  • the present invention relates to a compound of formula (IV-3) above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 2 is O, S or CR 2 R 2 ';
  • L 3 is O, S or CR 3 R 3 ';
  • L 1 , L 4 , L 5 and L 6 are CR 1 R 1 ', CR 4 R 4 ', CR 5 R 5 ' and CR 6 R 6 ', respectively;
  • L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene or C 6-10 arylene base;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • the condition is that two adjacent atoms cannot be heteroatoms at the same time.
  • the present invention relates to a compound of formula (IV-3) above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:
  • L 2 is O or CR 2 R 2 ';
  • L 3 is O or CR 3 R 3 ';
  • L 1 , L 4 , L 5 and L 6 are CR 1 R 1 ', CR 4 R 4 ', CR 5 R 5 ' and CR 6 R 6 ', respectively;
  • L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form 1,4-phenylene, 2,5-pyridylene, 1,4-pyrazolyl , 1,3-pyrazolylidene, 1,3-pyrrolidene, 1,4-triazolylidene, 2,5-thiadiazolylidene or tetrazolylidene;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D;
  • the condition is that two adjacent atoms cannot be O at the same time.
  • the present invention relates to a compound of formula (IV-3) above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 3 is O, S or CR 3 R 3 ';
  • L 1 , L 2 , L 4 , L 5 and L 6 are CR 1 R 1 ′, CR 2 R 2 ′, CR 4 R 4 ′, CR 5 R 5 ′ and CR 6 R 6 ′, respectively;
  • L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene or C 6-10 arylene base;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • the present invention relates to a compound of formula (IV-3) above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:
  • L 3 is O or CR 3 R 3 ';
  • L 1 , L 2 , L 4 , L 5 and L 6 are CR 1 R 1 ′, CR 2 R 2 ′, CR 4 R 4 ′, CR 5 R 5 ′ and CR 6 R 6 ′, respectively;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D.
  • the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which are of formula (V-2) or (V-2-a) compound:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • Y1 is CR Y1 ;
  • Y2 is O, S or NR Y2 ;
  • R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R Y2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • L 1 is CR 1 R 1 ';
  • L 5 is CR 5 R 5 '
  • L 6 is CR 6 R 6 ' or absent
  • L 7 is O, S, NR 7 "or CR 7 R 7 ';
  • L 2 and L 5 are connected and together with L 2 , L 3 , L 4 and L 5 form C 6-10 arylene, 5-7 membered heteroarylene or Preferably C 6-10 arylene or 5-7 membered heteroarylene;
  • Or -L 2 -L 3 -L 4 - represents C 6-10 arylene, 5-7 membered heteroarylene or
  • R 1 , R 1 ', R 5 , R 5 ', R 6 , R 6 ', R 7 and R 7 ' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkane base;
  • R 7 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention relates to a compound of formula (V-2) above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:
  • R and R' are independently selected from H or D;
  • Y1 is CR Y1 ;
  • Y 2 is O or S
  • R Y1 is independently selected from H or D;
  • L 1 is CR 1 R 1 ';
  • L 5 is CR 5 R 5 '
  • L 6 is CR 6 R 6 ' or absent
  • L 7 is O, S, NR 7 "or CR 7 R 7 ';
  • R 1 , R 1 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 and R 7 ′ are independently selected from H or D;
  • R 7 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention relates to a compound of formula (V-2) above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • Y1 is CR Y1 ;
  • Y2 is O, S or NR Y2 ;
  • R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R Y2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • L 1 is CR 1 R 1 ';
  • L 5 is CR 5 R 5 '
  • L 6 is CR 6 R 6 ′
  • L 7 is S or NR 7 ";
  • L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form a C 6-10 arylene group or a 5-7 membered heteroarylene group;
  • Or -L 2 -L 3 -L 4 - represents a C 6-10 arylene group or a 5-7 membered heteroarylene group;
  • R 1 , R 1 ', R 5 , R 5 ', R 6 and R 6 ' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 7 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention relates to a compound of formula (V-2) above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:
  • R and R' are independently selected from H or D;
  • Y1 is CR Y1 ;
  • Y 2 is O or S
  • R Y1 is independently selected from H or D;
  • L 1 is CR 1 R 1 ';
  • L 5 is CR 5 R 5 '
  • L 6 is CR 6 R 6 ′
  • L 7 is S or NH
  • R 1 , R 1 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D.
  • the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which are of formula (V-3) or (V-3-a) compound:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 2 is O, S, NR 2 ′′ or CR 2 R 2 ′;
  • L 3 is O, S, NR 3 "or CR 3 R 3 ';
  • L 4 is O, S, NR 4 "or CR 4 R 4 ';
  • L 5 is O, S, NR 5 "or CR 5 R 5 ';
  • L 6 is O, S, NR 6 "or CR 6 R 6 ';
  • L 1 and L 7 are CR 1 R 1 ' and CR 7 R 7 ', respectively;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 , and R 7 ′ are independently is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 3 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 4 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 5 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • the condition is that two adjacent atoms cannot be heteroatoms at the same time.
  • the present invention relates to a compound of formula (V-3) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof.
  • compounds including:
  • L 2 is O or CR 2 R 2 ';
  • L 3 is O or CR 3 R 3 ';
  • L 4 is O or CR 4 R 4 ';
  • L 1 , L 5 , L 6 and L 7 are CR 1 R 1 ', CR 5 R 5 ', CR 6 R 6 ' and CR 7 R 7 ', respectively;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 , and R 7 ′ are independently is selected from H or D;
  • the condition is that two adjacent atoms cannot be O at the same time.
  • the present invention relates to a compound of formula (V-3) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof.
  • compounds including:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 2 is O or S
  • L 1 , L 3 , L 4 and L 5 are CR 1 R 1 ', CR 3 R 3 ', CR 4 R 4 ' and CR 5 R 5 ', respectively;
  • R 1 , R 1 ', R 3 , R 3 ', R 4 , R 4 ', R 5 and R 5 ' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkane base;
  • the present invention relates to a compound of formula (V-3) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof.
  • compounds including:
  • L 2 is O
  • L 1 , L 3 , L 4 and L 5 are CR 1 R 1 ', CR 3 R 3 ', CR 4 R 4 ' and CR 5 R 5 ', respectively;
  • R 1 , R 1 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 and R 5 ′ are independently selected from H or D.
  • the present invention relates to a compound of formula (V-3) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof.
  • compounds including:
  • R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • L 2 is O, S or CR 2 R 2 ';
  • L 3 is O, S or CR 3 R 3 ';
  • L 1 , L 4 , L 5 , L 6 and L 7 are CR 1 R 1 ′, CR 4 R 4 ′, CR 5 R 5 ′, CR 6 R 6 ′ and CR 7 R 7 ′, respectively;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 , and R 7 ′ are independently is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • the condition is that two adjacent atoms cannot be heteroatoms at the same time.
  • the present invention relates to a compound of formula (V-3) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof.
  • compounds including:
  • L 2 is O or CR 2 R 2 ';
  • L 3 is O or CR 3 R 3 ';
  • L 1 , L 4 , L 5 , L 6 and L 7 are CR 1 R 1 ', CR 4 R 4 ', CR 5 R 5 ', CR 6 R 6 ' and CR 7 R 7 ', respectively;
  • R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 , and R 7 ′ are independently is selected from H or D;
  • the condition is that two adjacent atoms cannot be O at the same time.
  • the present invention relates to the following compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof:
  • the present invention relates to the following compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof:
  • the compounds of the present invention may contain one or more asymmetric centers, and thus may exist in various stereoisomeric, eg, enantiomeric and/or diastereomeric forms.
  • the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (eg, cis and trans isomers), or may be in the form of a mixture of stereoisomers, Include racemic mixtures and mixtures enriched in one or more stereoisomers.
  • Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and chiral salt formation and crystallization; or preferred isomers can be separated by prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • Tautomer means that one functional group in some compounds changes its structure into another functional group isomer, and can rapidly convert into each other, becoming two isomers in dynamic equilibrium, and the two isomers are in dynamic equilibrium. isomers are called tautomers.
  • organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are called "solvates”. When the solvent is water, the complex is called a "hydrate”.
  • the present invention encompasses all solvates of the compounds of the present invention.
  • solvate refers to a solvent-bound compound or salt form thereof usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds described herein can be prepared, eg, in crystalline forms, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.
  • hydrate refers to a compound that is combined with water. Typically, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined.
  • a hydrate of a compound can be represented, for example, by the general formula R ⁇ xH2O, where R is the compound and x is a number greater than zero.
  • a given compound can form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R 0.5 H 2 ) O)) and polyhydrates (x is a number greater than 1, eg, dihydrate (R ⁇ 2H2O) and hexahydrate (R ⁇ 6H2O)).
  • monohydrate x is 1
  • lower hydrate x is a number greater than 0 and less than 1, for example, hemihydrate (R 0.5 H 2 ) O
  • polyhydrates x is a number greater than 1, eg, dihydrate (R ⁇ 2H2O) and hexahydrate (R ⁇ 6H2O)
  • the compounds of the present invention may be in amorphous or crystalline form (crystalline or polymorphic). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the present invention.
  • the term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) of a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature and other factors can cause one crystalline form to dominate. Various polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the present invention also includes isotopically-labeled compounds that are equivalent to those described in formula (I), but with one or more atoms replaced by an atom having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may be introduced into the compounds of the present invention include isotopes of hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H , 13C , 11C , 14C , 15N , 18 , respectively O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs containing the above isotopes and/or other isotopes of other atoms are within the scope of the present invention.
  • Certain isotopically-labeled compounds of the invention, such as those into which radioactive isotopes (eg, 3H and14C ) have been incorporated, are useful in drug and/or substrate tissue distribution assays. Tritium, ie 3 H, and carbon-14, ie 14 C isotopes are particularly preferred because of their ease of preparation and detection.
  • isotopically labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents in carrying out the processes disclosed in the following Schemes and/or Examples and Preparations labeled reagents.
  • prodrugs are also included within the context of the present invention.
  • the term "prodrug” as used herein refers to a compound that is converted in vivo to its active form having a medical effect by, for example, hydrolysis in blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra, "Improved oral drug delivery: solution limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each cited This article is for reference.
  • a prodrug is any covalently bonded compound of the invention which, when administered to a patient, releases the parent compound in vivo.
  • Prodrugs are typically prepared by modifying functional groups in a manner such that the modification can be cleaved, either by routine manipulation or in vivo, to yield the parent compound.
  • Prodrugs include, for example, compounds of the present invention wherein a hydroxyl, amino or sulfhydryl group is bonded to any group that, when administered to a patient, can be cleaved to form a hydroxyl, amino or sulfhydryl group.
  • prodrugs include, but are not limited to, acetate/amide, formate/amide and benzoate/amide derivatives of the hydroxy, sulfhydryl and amino functional groups of compounds of formula (I).
  • esters such as methyl esters, ethyl esters, and the like can be used.
  • the esters themselves may be active and/or hydrolyzable under human in vivo conditions.
  • Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups which are readily cleaved in humans to release the parent acid or salt thereof.
  • compositions, formulations and kits are provided.
  • the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the active ingredient.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.
  • a pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin.
  • buffer substances such as phosphates
  • glycine such as sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block segment polymers, polyethylene glycol, and lanolin.
  • kits eg, pharmaceutical packages.
  • kits can include a compound of the present invention, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packs or other) containing the compounds of the present invention, other therapeutic agents. suitable container).
  • kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the present invention and/or other therapeutic agent.
  • a compound of the present invention and other therapeutic agent provided in a first container and a second container are combined to form one unit dosage form.
  • compositions provided by the present invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration Drugs, administration via implants, or other modes of administration.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , intrameningeal administration, intralesional administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the amount of compound actually administered can be determined by the physician depending on the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .
  • the compounds provided herein are administered to subjects at risk of developing the disorders, typically on the advice and supervision of a physician, at dosage levels as described above.
  • Subjects at risk of developing a particular disorder typically include subjects with a family history of the disorder, or those identified by genetic testing or screening as being particularly susceptible to developing the disorder.
  • Chronic administration refers to administration of a compound or a pharmaceutical composition thereof over an extended period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely, For example, the rest of the subject's life.
  • chronic administration is intended to provide a constant level of the compound in the blood over an extended period of time, eg, within a therapeutic window.
  • the pharmaceutical composition may be administered as a bolus injection, eg, in order to rapidly increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic level of the active ingredient, eg, intramuscular or subcutaneous bolus doses provide slow release of the active ingredient, whereas boluses delivered directly into the vein (eg, by IV infusion) can be more effective. It is delivered rapidly, resulting in a rapid increase in the concentration of the active ingredient in the blood to an effective level.
  • the pharmaceutical composition may be administered as a continuous infusion, eg, by IV infusion, to provide a steady state concentration of the active ingredient in the body of the subject.
  • a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.
  • Oral compositions can take the form of bulk liquid solutions or suspensions or bulk powders. More generally, however, the compositions are presented in unit dosage form for ease of precise dosing.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable for producing the desired therapeutic effect in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, and the like.
  • the compound will generally be the minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various components useful in forming the desired administration form. carriers or excipients and processing aids.
  • a typical regimen is one to five oral doses, especially two to four oral doses, typically three oral doses per day.
  • each dose provides about 0.01 to about 20 mg/kg of a compound of the invention, with preferred doses each providing about 0.1 to about 10 mg/kg, especially about 1 to about 5 mg/kg.
  • transdermal doses are typically selected in amounts of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.
  • injection dose levels are in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour.
  • a preloaded bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be administered.
  • the maximum total dose cannot exceed approximately 2 g/day.
  • Liquid forms suitable for oral administration can include suitable aqueous or non-aqueous carriers as well as buffering agents, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • Solid forms may include, for example, any of the following components, or compounds of similar properties: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or cornstarch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, peppermint, water Methyl cylate or orange flavoring.
  • binders such as microcrystalline cellulose, tragacanth, or gelatin
  • excipients such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or cornstarch
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound is typically the minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient.
  • the active ingredient When formulated as an ointment, the active ingredient is typically combined with a paraffinic or water-miscible ointment base.
  • the active ingredient may be formulated in a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and typically include other components for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope of the present invention.
  • transdermal administration can be accomplished using reservoir or porous membrane types, or patches of various solid matrices.
  • compositions for oral administration, injection or topical administration are only representative. Additional materials and processing techniques, etc. are described in Section 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.
  • the compounds of the present invention can also be administered in sustained release form, or from a sustained release drug delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ - and ⁇ -cyclodextrins consisting of 6, 7 and 8 ⁇ -1,4-linked glucose units, respectively, which optionally include a or more substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions.
  • the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, a sulfobutyl ether beta-cyclodextrin, also known as Captisol. See, eg, U.S. 5,376,645.
  • the formulation includes hexapropyl-beta-cyclodextrin (eg, in water, 10-50%).
  • the compounds of the present invention may be used in combination with one or more other active ingredients in pharmaceutical compositions or methods for the treatment of the diseases and disorders described herein.
  • additional active ingredients include other therapeutic agents or agents that moderate the adverse effects of the therapeutic agent against the intended disease target.
  • the combination can be used to increase efficacy, ameliorate symptoms of other diseases, reduce one or more adverse effects, or reduce the required dose of a compound of the present invention.
  • the additional active ingredients may be formulated in separate pharmaceutical compositions from the compounds of the present invention or may be included with the compounds of the present invention in a single pharmaceutical composition.
  • the additional active ingredient may be administered concurrently with, prior to or subsequent to administration of the compounds of the present invention.
  • the present invention also provides the preparation method of formula I compound and its intermediate, and described scheme comprises:
  • the raw material amine 1 (or its salt) and the acid 2 are condensed into the target product I under the action of a condensing agent (such as HATU) and a base (such as N,N-diisopropylethylamine (DIPEA)).
  • a condensing agent such as HATU
  • DIPEA N,N-diisopropylethylamine
  • the raw material amine 3 (or its salt) and compound 4 undergo a nucleophilic substitution reaction under the action of a base (such as triethylamine, N,N-diisopropylethylamine, etc.) to obtain the target product II.
  • a base such as triethylamine, N,N-diisopropylethylamine, etc.
  • the raw materials in the following synthetic steps, for the non-commercial reagents, the synthetic steps have been provided.
  • the batches corresponding to the raw materials in each step are not necessarily the same as those described in the synthesis method.
  • Step 1 4-Alkynyl-1-pentanol 1-1 (5.00 g, 59.44 mmol) and tetrabutylammonium bromide (6.32 g, 19.62 mmol) were added to toluene (170 mL) at 0°C, then Sodium hydroxide (61.2 g, 535.45 mmol) and tert-butyl bromoacetate (34.78 g, 178.32 mmol) were sequentially added, then slowly warmed to room temperature and stirred at room temperature for 5 hours.
  • reaction mixture was diluted with water (50 mL), then extracted with ethyl acetate (2 ⁇ 50 mL), the organic layers were combined, washed with saturated sodium chloride solution (2 ⁇ 40 mL), and dried by adding anhydrous sodium sulfate, Filter to obtain crude product.
  • Step 2 Compound 1-2 (1 g, 5.04 mmol) and 4-bromo-1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-isoindoline 1-3 (850.22mg, 2.52mmol) was added to N,N-dimethylformamide (8mL), followed by triethylamine (4.59g, 45.40mmol), cuprous iodide (48.03mg, 252.2 ⁇ mol) and bis(triphenylphosphine)palladium(II) dichloride (178 mg, 252.2 ⁇ mol), and the reaction system was microwaved at 80° C. for 1 hour.
  • Step 3 At room temperature, the above compound 1-4 (0.97 g, 2.1 mmol) was dissolved in dichloromethane (4 mL), and then trifluoroacetic acid (1.54 g, 13.51 mmol) was slowly added dropwise, and stirred at room temperature for 1 hour . After the reaction was completed, under reduced pressure, dichloromethane and trifluoroacetic acid were removed by concentration to obtain the crude compound Int-1 (0.58 g, yield 69%).
  • Step 1 Under argon protection, wet palladium/carbon (300 mg, 10% Pd/C) was added to a solution of compound 1-4 (0.3 g, 0.66 mmol) in tetrahydrofuran (10 mL), after three hydrogen replacements, 50 psi Under hydrogen, it was stirred at 40°C for 12 hours. After the reaction was completed, filtered, the filter cake was washed three times with ethyl acetate (3 ⁇ 15 mL), the filtrates were combined and concentrated under reduced pressure to obtain crude compound 2-1 (0.3 g, yield 99.6%) as a colorless oil. used directly in the next reaction. LCMS[M-tBu+H] + 401.0.
  • Step 2 Compound 2-1 (0.3 g, 657.2 ⁇ mol) was dissolved in dichloromethane (6 mL) at room temperature, then trifluoroacetic acid (3.09 g, 27.13 mmol, 2 mL) was added and stirred for 2 hours. The reaction mixture was concentrated to give crude compound Int-2 (0.26 g) as a colorless oil. used directly in the next reaction. LCMS[M+H] + 401.1.
  • Step 1 At room temperature, to a solution of 3-alkynyl-1-butanol 3-1 (5 g, 71.34 mmol, 5.40 mL) in tetrahydrofuran (80 mL) was added potassium tert-butoxide (400.24 mg, 3.57 mmol), followed by tert-Butyl acrylate (11.89 g, 92.74 mmol, 13.46 mL) was added dropwise, followed by stirring at room temperature for 12 hours. TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain a crude product.
  • potassium tert-butoxide 400.24 mg, 3.57 mmol
  • tert-Butyl acrylate 11.89 g, 92.74 mmol, 13.46 mL
  • Step 2 At room temperature, compound 3-2 (1.18 g, 5.93 mmol), 4-bromo-1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-iso Indoline 1-3 (1 g, 2.97 mmol), bis(triphenylphosphine)palladium(II) dichloride (208.20 mg, 296.63 ⁇ mol), cuprous iodide (56.49 mg, 296.63 ⁇ mol) and triethyl
  • the amine (5.40 g, 53.39 mmol, 7.43 mL) was dissolved in N,N-dimethylformamide (10 mL), and the reaction was carried out at 80° C. for 1 hour with a microwave after nitrogen substitution.
  • Step 3 Compound 3-3 (0.3 g, 660.1 ⁇ mol) was dissolved in tetrahydrofuran (10 mL), and under argon protection, wet palladium/carbon (500 mg, 10% Pd/C) was added, and after hydrogen replacement three times, the mixture was heated at 40 °C, stirring at 50 psi for 12 hours. After the reaction was completed, filtered, the filter cake was washed three times with ethyl acetate (3 ⁇ 15 mL), the filtrates were combined and concentrated under reduced pressure to obtain compound 3-4 (0.3 g, yield 99.1%) as a brown oil.
  • Step 4 Compound 3-4 (0.3 g, 654.3 ⁇ mol) was dissolved in dichloromethane (6 mL) at room temperature, then trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL) was added and stirred for 3 hours. The reaction mixture was concentrated to give crude compound Int-3 (0.26 g). used directly in the next reaction. LCMS[M+H] + 403.1.
  • Step 1 To compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline 5-1 (500 mg, 1.82 mmol) and 7 - To a solution of tert-butyl bromoheptanoate (580 mg, 2.2 mmol) in NMP (10 mL), N,N-diisopropylethylamine (306 mg, 2.4 mmol) was added, and the mixture was heated and stirred at 40° C. for 5 hours. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was extracted twice.
  • Step 2 Compound 5-2 (100 mg, 0.22 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.8 mL) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was spin-dried to obtain compound Int-5 (80 mg), which was directly used in the next step. LCMS[M+H] + 403.2.
  • Step 1 Sodium hydride (2.88 g, 72.1 mmol, 60% purity) was added portionwise to 3-bromopropyne (5.45 g, 36.6 mmol, 3.95 mL, 80% purity) in anhydrous tetrahydrofuran ( 50 mL) solution, then the reaction was stirred at 0 °C for 1 hour. 1,4-Butanediol 6-1 (10.0 g, 110.9 mmol, 9.80 mL) was added, and the reaction was stirred at room temperature for 12 hours.
  • Step 2 To a solution of compound 6-2 (1.50 g, 11.7 mmol) in 1,2-dichloroethane (10 mL) was added 2,2,6,6-tetramethylpiperidine oxide (TEMPO) (184.0 mg, 1.17 mmol), potassium chloride (87.2 mg, 1.17 mmol) and ferric nitrate nonahydrate (472.8 mg, 1.17 mmol), then the reaction was stirred at room temperature for 5 h under O 2 protection. The reaction mixture was filtered through celite and concentrated to give crude compound 6-3 (1.50 g, yield 90.1%) as a yellow oil. used directly in the next reaction.
  • TEMPO 2,2,6,6-tetramethylpiperidine oxide
  • Step 3 To compound 6-3 (500 mg, 3.52 mmol), benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 (788.7 mg, 3.52 mmol) in N,N- To the dimethylformamide (5 mL) solution, HATU (1.47 g, 3.87 mmol) and N,N-diisopropylethylamine (1.36 g, 10.5 mmol, 1.84 mL) were added, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (2 x 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and filtered to give crude product.
  • Step 1 At 0°C, add tert-butyl acrylate (30.32 g, 236.55 mmol) and 1,3-propanediol 8-1 (20 g, 262.83 mmol) into the reaction flask, and slowly add sodium hydroxide solid (315.37 mmol) mg, 7.88 mmol), then slowly warmed to room temperature and stirred for 24 hours.
  • the resulting reaction mixture was diluted with water (50 mL), then extracted with ethyl acetate (2 ⁇ 50 mL), the organic layers were combined, washed with saturated sodium chloride solution (2 ⁇ 10 mL), dried over anhydrous sodium sulfate, filtered, Concentration under reduced pressure gave crude product.
  • Step 2 At room temperature, compound 8-2 (10 g, 48.96 mmol) was dissolved in anhydrous dichloromethane (200 mL), and p-toluenesulfonyl chloride (14.00 g, 73.43 mmol), 4-dimethylaminopyridine ( 299.04 mg, 2.45 mmol) and triethylamine (14.86 g, 146.87 mmol), and then the reaction was stirred at room temperature for 18 hours.
  • Step 3 At room temperature, sodium azide (108.82 mg, 1.67 mmol) was added to a solution of compound 8-3 (0.5 g, 1.39 mmol) in N,N-dimethylformamide (5 mL), at 60° C. Stir for 12 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (2 ⁇ 20 mL). The organic layers were combined and concentrated under reduced pressure to obtain crude compound 8-4 (0.31 g, yield 96.9%).
  • Step 4 Under argon protection, wet palladium/carbon (310 mg, 10% Pd/C) was added to a solution of compound 8-4 (0.31 g, 1.35 mmol) in methanol (5 mL), after three hydrogen replacements, 50 psi Under hydrogen, it was stirred at room temperature for 12 hours. After the completion of the reaction, filter, and the filter cake was washed with ethyl acetate three times (3 ⁇ 15 mL), the filtrates were combined and concentrated under reduced pressure to obtain compound 8-5 (0.32 g) as a colorless oil. used directly in the next reaction.
  • Step 5 At room temperature, compound 8-5 (242.86 mg, 1.19 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (205.88 mg, 1.59 mmol) was added. , 277.46 ⁇ L), and stirred at 90 °C for 0.5 h. Then compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (0.22 g, 796.47 ⁇ mol) was added, followed by Stir at 90°C for 12 hours.
  • reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (2 ⁇ 15 mL). The organic layers were combined and concentrated under reduced pressure to obtain the crude product.
  • the crude product was purified by reverse-phase preparative HPLC (formic acid system) to give compound 8-6 (0.12 g, yield 32.8%) as a green oil.
  • Step 6 Compound 8-6 (0.12 g, 261.16 ⁇ mol) was dissolved in dichloromethane (6 mL), then trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain crude compound Int-8 (0.105 g, yield 99.7%). used directly in the next reaction. LCMS[M+H] + 404.1.
  • Step 1 At room temperature, compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline 5-1 (0.2 g, 729.32 ⁇ mol) was dissolved in N,N-dimethylformamide (5 mL), and then compound 8-3 (313.71 mg, 875.18 ⁇ mol), potassium bicarbonate (109.52 mg, 1.09 mmol), and sodium iodide (12.11 mg) were added in sequence. , 80.77 ⁇ mol), and the resulting reaction solution was stirred at 80° C. for 16 hours.
  • Step 2 Compound 9-1 (0.4 g, 868.67 ⁇ mol) was dissolved in dichloromethane (4 mL) at room temperature, trifluoroacetic acid (4.11 g, 36.02 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain the crude compound Int-9 (0.426 g).
  • Step 1 Compound 2-(benzyloxy)ethanol (5.00 g, 32.85 mmol) was added to tert-butanol (50 mL) at room temperature, followed by potassium tert-butoxide (4.42 g, 39.42 mmol) and compound 4- tert-Butyl bromobutyrate 10-1 (7.33 g, 32.85 mmol), and the reaction was stirred for 2 hours.
  • the reaction mixture was diluted with water (100 mL), then extracted with ethyl acetate (2 x 80 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain crude product.
  • Step 2 Compound 10-2 (0.68 g, 2.31 mmol) was dissolved in methanol (10 mL), under argon protection, wet palladium/carbon (300 mg, 10% Pd/C) was added, and after hydrogen replacement three times, 15 psi hydrogen Stir at room temperature for 12 hours. After the reaction was completed, filtered, the filter cake was washed three times with ethyl acetate (3 ⁇ 15 mL), the filtrates were combined and concentrated under reduced pressure to obtain compound 10-3 (0.47 g, yield 99.6%) as a colorless oil. used directly in the next reaction.
  • Step 3 Compound 10-3 (0.47 g, 2.30 mmol) was dissolved in anhydrous dichloromethane (10 mL), 4-dimethylaminopyridine (14.06 mg, 115.05 ⁇ mol), triethylamine (698.49 mg, 6.90 mmol) and p-toluenesulfonyl chloride (658.01 mg, 3.45 mmol), and the reaction was stirred at room temperature for 12 hours. The reaction mixture was concentrated to give crude product. The crude product was separated and purified by reversed-phase medium pressure column (formic acid system) to obtain compound 10-4 (0.60 g, yield 72.8%). used directly in the next reaction. LCMS[M+Na] + 381.1.
  • Step 4 Compound 10-4 (520 mg, 1.45 mmol) was added to N,N-dimethylformamide (10 mL), then sodium azide (113.17 mg, 1.74 mmol) was added, and the mixture was stirred at 60°C 12 hours. The reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (2 ⁇ 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain crude compound 10-5 (330 mg, yield 99.2%). used directly in the next reaction.
  • Step 5 Under argon protection, wet palladium/carbon (300 mg, 10% Pd) was added to a solution of compound 10-5 (330 mg, 1.44 mmol) in methanol (5 mL), and after hydrogen replacement three times, at room temperature under 50 psi Stir for 12 hours. Filtration, the filter cake was washed with methanol (2 ⁇ 10 mL), the organic layers were combined and spun dry to obtain crude compound 10-6 (200 mg, yield 68.4%) as colorless oil. used directly in the next reaction.
  • Step 6 1,3-Dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (113.24 mg, 409.95 ⁇ mol) was added to N , N-dimethylformamide (5 mL), then N,N-diisopropylethylamine (105.97 mg, 819.90 ⁇ mol) was added, and the mixture was stirred at 90° C. for 0.5 h, and then compound 10-6 (100 mg, 491.94umol), the reaction was stirred at 90°C for 12 hours.
  • Step 7 Compound 10-7 (60 mg, 130.58 ⁇ mol) was added to anhydrous dichloromethane (6 mL), trifluoroacetic acid (3.08 g, 27.01 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude compound Int-10 (52 mg, yield 98.7%) as a yellow solid. used directly in the next reaction.
  • Step 1 Compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline 5-1 (382.52 mg, 1.39 mmol) was added N,N-dimethylformamide (5 mL), then compound 10-4 (0.60 g, 1.67 mmol), KHCO 3 (209.48 mg, 2.09 mmol) and NaI (23.21 mg, 154.83 umol) were added, and the mixture was placed in Stir at 80°C for 16 hours.
  • Step 2 Compound 11-1 (0.64 mg, 1.39 mmol) was dissolved in anhydrous dichloromethane (9 mL), trifluoroacetic acid (4.62 g, 40.52 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude compound Int-11 (0.56 g, 99.6% yield). used directly in the next reaction. LCMS[M+H] + 405.0.
  • Step 1 At room temperature, compound 4-(benzyloxy)-1-butanol 12-1 (5.00 g, 27.74 mmol), tert-butyl bromoacetate (10.82 g, 55.48 mmol), 37% aqueous sodium hydroxide solution (29.99 g, 277.40 mmol) and tetrabutylammonium bromide (894.25 mg, 2.77 mmol) were added to dichloromethane (100 mL) and stirred for 12 hours. The reaction mixture was diluted with water (200 mL), then extracted with dichloromethane (2 x 100 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and filtered to give the crude product.
  • compound 4-(benzyloxy)-1-butanol 12-1 5.00 g, 27.74 mmol
  • tert-butyl bromoacetate 10.82 g, 55.48 mmol
  • Step 2 Compound 12-2 (0.5 g, 1.65 mmol) was dissolved in methanol (8 mL), under argon protection, wet palladium/carbon (300 mg, 10% Pd/C) was added, and after hydrogen replacement three times, at 15 psi Under hydrogen, it was stirred at room temperature for 12 hours. After the reaction was completed, filtered, the filter cake was washed three times with ethyl acetate (3 ⁇ 15 mL), the filtrates were combined and concentrated under reduced pressure to obtain compound 12-3 (0.336 g, yield 99.9%) as a colorless oil.
  • Step 3 Compound 12-3 (330.40 mg, 1.62 mmol) was dissolved in anhydrous dichloromethane (10 mL), then 4-dimethylaminopyridine (9.87 mg, 80.78 ⁇ mol), triethylamine (490.43 mg) were added , 4.85 mmol) and p-toluenesulfonyl chloride (462.00 mg, 2.42 mmol), and the reaction was stirred at room temperature for 12 hours. The reaction mixture was concentrated to give crude product. The crude product was purified by reverse-phase medium pressure preparative column (formic acid system) to obtain compound 12-4 (0.50 g, yield 86.3%). used directly in the next reaction. LCMS[M+ NH4 ] + 376.1.
  • Step 4 Compound 12-4 (1.00 g, 2.79 mmol) was added to N,N-dimethylformamide (10 mL), then sodium azide (217.64 mg, 3.35 mmol) was added, and the mixture was heated at 60 °C Stir for 12 hours. The reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (2 ⁇ 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to give crude compound 12-5 (0.64 g) as a yellow oil. used directly in the next reaction.
  • Step 5 Under argon protection, wet palladium/carbon (400 mg, 10% Pd/C) was added to a solution of crude compound 12-5 (640 mg, 2.79 mmol) in methanol (10 mL), and after hydrogen replacement three times, Stir at 50 psi for 12 hours at room temperature. The reaction mixture was filtered, then the filter cake was rinsed with ethyl acetate (3 ⁇ 50 mL), and the organic layers were combined to give crude compound 12-6 (430 mg, 75.8% yield) as a yellow oil. used directly in the next reaction.
  • Step 6 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (380 mg, 1.87 mmol) was added to N, N-dimethylformamide (10 mL), then N,N-diisopropylethylamine (322.14 mg, 2.49 mmol) was added, and the mixture was stirred at 90° C. for 0.5 hour, and then compound 12-6 (344.2 mg, 1.25 mmol), and the reaction was stirred at 90°C for 12 hours.
  • Step 7 Compound 12-7 (0.18 g, 391.74 ⁇ mol) was added to anhydrous dichloromethane (9 mL), then trifluoroacetic acid (4.62 g, 40.52 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude compound Int-12 (0.16 g). used directly in the next reaction.
  • step 1
  • Step 2 Compound 13-1 (0.53 g, 1.15 mmol) was added to anhydrous dichloromethane (9 mL), then trifluoroacetic acid (4.62 g, 40.52 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain crude compound Int-13 (0.46 g, yield 98.8%). used directly in the next reaction.
  • Step 1 To tert-butyl (3-(methylamino)propyl)carbamate 14-1 (2.00 g, 10.6 mmol) and ethyl 3-bromopropionate (2.31 g, 12.7 mmol, 1.63 mmol) at room temperature mL) in N,N-dimethylformamide (30 mL), was added N,N-diisopropylethylamine (4.12 g, 31.8 mmol, 5.55 mL), and the reaction was stirred at 85° C. for 12 hours. The reaction solution was diluted with water (50 mL), and then extracted with ethyl acetate (2 ⁇ 50 mL).
  • Step 2 To a solution of compound 14-2 (1.00 g, 3.47 mmol) in ethanol (5 mL) was added lithium hydroxide monohydrate (727.5 mg, 17.3 mmol) at room temperature, and the reaction was stirred at room temperature for 12 hours. The reaction solution was concentrated, adjusted to pH about 3 with 1M hydrochloric acid, extracted with ethyl acetate (2 ⁇ 20 mL), and concentrated to give compound 14-3 (900 mg, yield 99.7%) as a white solid. used directly in the next reaction.
  • Step 3 To compound 14-3 (250 mg, 960.3 ⁇ mol), benzofuran-2-yl(pyridin-3-yl)methanamine (6-4 (215.3 mg, 960.3 ⁇ mol) in N,N at room temperature - In dimethylformamide (5 mL) solution, HATU (401.6 mg, 1.06 mmol) and N,N-diisopropylethylamine (372.3 mg, 2.88 mmol, 501.8 ⁇ L) were added. Stirred at room temperature for 12 hours. The mixture was diluted with water (20 mL), then extracted with ethyl acetate (2 ⁇ 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the crude product. The crude product was purified by reverse phase column (formic acid system) to obtain compound 14- 4 (250 mg, 55.8% yield), white solid. LCMS [M+H] + 467.3.
  • Step 4 Compound 14-4 (150 mg, 321.4 ⁇ mol) was added to dichloromethane (6 mL) at room temperature, followed by trifluoroacetic acid (3.08 g, 27.0 mmol, 2 mL), and stirred for 0.5 hour. The reaction mixture was concentrated to give crude compound Int-14 (120 mg). used directly in the next reaction. LCMS[M+H] + 367.1.
  • Step 1 Compound benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 dihydrochloride (435 mg, 1.46 mmol) was dissolved in DMF (5 mL), potassium carbonate (300 mg, 2.17 mmol) was added and ethyl bromoacetate (290 mg, 1.75 mmol), heated and stirred at 55°C for 16 hours. Ethyl acetate and water were added, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product.
  • Step 1 Compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (353 mg, 1.28 mmol) was dissolved in In DMF (8 mL), N-tert-butoxycarbonyl-1,4-butanediamine (350 mg, 1.86 mmol) and N,N-diisopropylethylamine (0.46 mL, 2.8 mmol) were added successively, 100°C Heat and stir for 18 hours. The reaction was cooled to room temperature and quenched by the addition of water.
  • Step 2 Compound 16-1 (100 mg, 0.22 mmol) was dissolved in 4M HCl/dioxane (5 mL, 20 mmol) and stirred at room temperature for 3 hours. The solvent was spin-dried to obtain compound Int-16 (95 mg) as a yellow oil. LCMS[M+H] + 345.5.
  • Step 1 Compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline 5-1 (300 mg, 1.09 mmol) was dissolved in In DMF (6 mL), tert-butyl N-(4-bromobutyl)carbamate (330 mg, 1.3 mmol), sodium bicarbonate (460 mg, 5.45 mmol) and potassium iodide (50 mg, 0.3 mmol) were sequentially added, and heated at 55°C Stir for 16 hours. The reaction was cooled to room temperature, water and ethyl acetate were added, and extraction was performed.
  • Step 2 Compound 17-1 (120 mg, 0.27 mmol) was dissolved in 4M HCl/dioxane (5 mL, 20 mmol) and stirred at room temperature for 3 hours. The solvent was spin-dried to obtain compound Int-17 (82 mg) as a white solid. LCMS[M+H] + 346.2.
  • Step 1 Compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-bromoisoindoline 1-3 (675 mg, 2 mmol) and N- tert-Butoxycarbonyl-4-pentyn-1-amine (730 mg, 4 mmol) was dissolved in DMF (8 mL), followed by triethylamine (2.0 g, 20 mmol), cuprous iodide (76 mg, 0.4 mmol) and Bis(triphenylphosphine)palladium(II) dichloride (280 mg, 0.4 mmol) was heated to 80°C under nitrogen protection and stirred for 3 hours.
  • Step 2 At room temperature, 10% palladium/carbon (110 mg) was added to a suspension of compound 18-1 (220 mg, 0.5 mmol) in 95% ethanol (20 mL), the temperature was raised to 40 °C, and the reaction was carried out under 1 atmosphere of hydrogen. 16 hours. The reaction solution was filtered, and the filtrate was spin-dried to obtain the product 18-2 (200 mg, yield 95%) as a colorless oil.
  • Step 3 Compound 18-2 (200 mg, 0.45 mmol) was dissolved in 4M HCl/dioxane (5 mL, 20 mmol) and stirred at room temperature for 3 hours. The solvent was spin-dried to obtain compound Int-18 (155 mg, yield 90%) as a colorless oil. LCMS[M+H] + 344.7.
  • Step 1 Compound benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 dihydrochloride (100 mg, 336 ⁇ mol) was dissolved in acetonitrile (2 mL) and water (2 mL) at room temperature, followed by Add tert-butyl 3-bromopropionate (106 mg, 505 ⁇ mol), potassium carbonate (186 mg, 1.35 mmol), heat at 90° C. and stir for 16 hours. After the reaction was detected by LCMS, it was filtered, purified by reverse-phase C18 medium pressure preparative column, concentrated and lyophilized to obtain compound 19-1 as a pale yellow solid. LCMS[M+H] + 353.6.
  • Step 2 The compound 19-1 obtained above was dissolved in DCM (5 mL), then trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was detected by LCMS, the solvent was replaced with acetonitrile three times, concentrated to dryness, and water was added for lyophilization to obtain the trifluoroacetic acid salt of compound Int-19 (35.0 mg, yield 21.1%) as a pale yellow solid. LCMS[M+H] + 297.5.
  • Step 1 Compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (100 mg, 362 ⁇ mol) at room temperature Dissolved in DMF (5 mL), N-tert-butoxycarbonyl-1,3-propanediamine (126 mg, 724 ⁇ mol) and potassium carbonate (200 mg, 1.45 mmol) were added successively, heated at 90° C. and stirred for 16 hours. After the reaction was detected by LCMS, the mixture was filtered, purified by reverse-phase C18 medium pressure preparative column, concentrated and lyophilized to obtain compound 20-1 as a pale yellow solid.
  • Step 2 The obtained compound 20-1 was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was detected by LCMS, the solvent was replaced with acetonitrile three times, concentrated to dryness, and water was added for lyophilization to obtain the trifluoroacetic acid salt of compound Int-20 (28.5 mg, yield 18.4%) as a yellow solid. LCMS[M+H] + 331.5.
  • Step 1 At room temperature, compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline 5-1 (200 mg, 729 ⁇ mol) Dissolved in DMF (5 mL), N-tert-butoxycarbonyl-3-bromo-1-propylamine (226 mg, 948 ⁇ mol), sodium bicarbonate (123 mg, 1.46 mmol) and potassium iodide (10.9 mg, 72.9 ⁇ mol) were added successively , heated at 60°C and stirred for 16 hours. After the reaction was detected by LCMS, it was filtered, purified by reverse-phase C18 medium pressure preparative column, concentrated and lyophilized to obtain compound 21-1 as a pale yellow solid.
  • Step 2 The obtained compound 21-1 was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was detected by LCMS, the solvent was replaced with acetonitrile three times, concentrated to dryness, and water was added for lyophilization to obtain the trifluoroacetic acid salt of compound Int-21 (148.5 mg, yield 47.4%) as a yellow solid. LCMS[M+H] + 332.6.
  • Step 1 To compound benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 dihydrochloride (270 mg, 0.91 mmol) and tert-butyl 2-bromoethylcarbamate (245 mg, 1.1 mmol) ) in N-methylpyrrolidone solution (5 mL), cesium carbonate (700 mg, 2.15 mmol) was added, and the reaction mixture was heated and stirred at 90° C. for 16 hours. The reactant was cooled to room temperature, ethyl acetate and water were added, extracted, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried to obtain the crude product.
  • cesium carbonate 700 mg, 2.15 mmol
  • Step 2 Compound 22-1 (60 mg, 0.16 mmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL, 1.94 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Spin-dried under reduced pressure to obtain compound Int-22 (78 mg) as a yellow oil, which was directly used in the next reaction. LCMS[M+H] + 268.4.
  • Step 1 Compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (275 mg, 1.0 mmol) was dissolved in To N-methylpyrrolidone (4 mL), tert-butyl 4-aminobutyrate (206 mg, 1.3 mmol) and N,N-diisopropylethylamine (0.4 mL, 2.4 mmol) were added in sequence, and the reaction mixture was heated at 100°C Stir for 18 hours.
  • Step 2 Compound 23-1 (100 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.65 mL) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was spin-dried to obtain compound Int-23 (85 mg) as a yellow oil, which was directly used in the next step. LCMS[M+H] + 360.5.
  • Step 1 Dissolve 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline 5-1 (200 mg, 0.73 mmol) in N , N-dimethylformamide (4 mL), tert-butyl 4-bromobutyrate (195 mg, 0.87 mmol), sodium bicarbonate (307 mg, 3.65 mmol) and potassium iodide (30 mg, 0.18 mmol) were added successively, and the reaction The mixture was stirred with heating at 55°C for 16 hours. The reaction was cooled to room temperature and quenched by the addition of water.
  • Step 2 Compound 24-1 (120 mg, 0.29 mmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL, 1.94 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Spin-dried under reduced pressure to obtain compound Int-24 (78 mg) as a yellow oil, which was directly used in the next reaction.
  • Step 1 Compound benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 dihydrochloride (297 mg, 1 mmol) and tert-butyl 3-bromopropylcarbamate (357 mg, 1.5 mmol) , dissolved in N-methylpyrrolidone (5 mL), cesium carbonate (815 mg, 2.5 mmol) and potassium iodide (50 mg, 0.3 mmol) were added, and the mixture was heated to 90° C. and stirred for 18 hours. After the reaction was completed, it was cooled to room temperature and filtered. Ethyl acetate and water were added, shaken, and allowed to stand to separate the layers.
  • Step 2 Compound 25-1 (260 mg, 0.62 mmol) was dissolved in dichloromethane (1.0 mL), 4M HCl in 1,4-dioxane solution (3 mL, 12 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Spin-dried under reduced pressure to obtain crude compound Int-25 (118 mg) as a yellow oil. used directly in the next reaction. LCMS[M+H] + 282.5.
  • Step 1-2 In a similar manner to Intermediate 28, by using tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate as starting material, compound 29-2 was obtained as a colorless oil. used directly in the next reaction. LCMS[M+H] + 385.7.
  • Step 3 Compound 29-2 (50 mg, 0.10 mmol) was dissolved in N-methylpyrrolidone (4 mL), followed by adding tert-butyl bromoacetate (0.18 mL, 0.12 mmol), and sodium iodide (15 mg, 0.1 mmol) , potassium carbonate (35 mg, 0.25 mmol), and the mixture was heated to 55°C and stirred for 3 hours. The reaction was cooled to room temperature and filtered, and the filtrate was purified by reverse-phase preparative HPLC to give compound 29-3 (25 mg, yield 50%) as a yellow oil. LCMS[M+H] + 499.7.
  • Step 4 Compound 29-3 (25 mg, 0.05 mmol) was dissolved in dichloromethane (1.5 mL), trifluoroacetic acid (0.5 mL, 6.7 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Spin to dryness under reduced pressure to obtain the crude compound Int-29 (20 mg, yield 74.1%) as a yellow oil, which is directly used in the next reaction. LCMS[M+H] + 443.5.
  • Step 1 Compound 1-tert-butoxycarbonyl-4-piperidineacetic acid (124 mg, 0.42 mmol), benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 dihydrochloride (137 mg, 0.56 mmol) and N,N-diisopropylethylamine (0.4 mL, 2.4 mmol) were dissolved in N,N-dimethylformamide (4 mL), HATU (242 mg, 0.64 mmol) was added, and the mixture was stirred at room temperature for 18 hours post-filtering. Ethyl acetate and water were added, and the mixture was left to stand for separation after extraction.
  • Step 2 Compound 30-1 (175 mg, 0.39 mmol) was dissolved in dichloromethane (3.0 mL), trifluoroacetic acid (1 mL, 13.1 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Spin to dryness under reduced pressure to obtain the crude compound 30-2 trifluoroacetate (180 mg) as a colorless oil, which was directly used in the next reaction. LCMS[M+H] + 350.8.
  • Step 3 Compound 30-2 (80 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (4 mL), followed by adding tert-butyl 2-bromoethylcarbamate (58 mg, 0.26 mmol), potassium carbonate (50 mg, 0.37 mmol) and potassium iodide (10 mg, 0.06 mmol), the mixture was heated to 55°C and stirred for 3 hours. The reaction was cooled to room temperature, ethyl acetate and water were added, and extraction was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried.
  • tert-butyl 2-bromoethylcarbamate 58 mg, 0.26 mmol
  • potassium carbonate 50 mg, 0.37 mmol
  • potassium iodide 10 mg, 0.06 mmol
  • Step 4 Compound 30-3 (36 mg, 0.073 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL, 13.1 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Spin to dryness under reduced pressure to obtain crude compound Int-30 (22 mg) as a yellow oil. used directly in the next reaction. LCMS[M+H] + 393.5.
  • Step 1 Dissolve benzofuran (5.0 g, 42.33 mmol) in anhydrous tetrahydrofuran (100 mL) at -78 °C, slowly add n-butyllithium (2.5 M, 17.78 mL, 44.44 mmol) dropwise, and then slowly warm up to room temperature and stirred for 0.5 hour. The temperature of the system was lowered to -78°C again, isonicotinaldehyde 32-1 (4.53 g, 42.33 mmol) was added dropwise, the temperature was slowly raised to room temperature after dropping, and the mixture was stirred for 3 hours.
  • n-butyllithium 2.5 M, 17.78 mL, 44.44 mmol
  • Step 2 Compound 32-2 (9.0 g, 39.96 mmol) was added to thionyl chloride (50 mL) at room temperature and stirred for 3 hours. TLC detected new substances, and the reaction solution was directly spin-dried to obtain a crude compound 32-3 (10.6 g), which was directly used in the next reaction.
  • Step 3 At room temperature, the crude compound 32-3 (9.74 g, 39.97 mmol) was added to a mixed solution of tetrahydrofuran (10 mL) and ammonia water (50 mL), and stirred for 3 hours. The reaction mixture was diluted with water (200 mL), then extracted with ethyl acetate (2 x 200 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude compound 32-4 (1.92 g, 19.4% yield). used directly in the next reaction. LCMS[M+H] + 225.1.
  • Step 4 At room temperature, 7-((tert-butoxycarbonyl)amino)heptanoic acid (1.64 g, 6.69 mmol) was dissolved in N,N-dimethylformamide (35 mL), and then compound 32-4 was added sequentially (1.5 g, 6.69 mmol), HATU (2.80 g, 7.36 mmol) and N,N-diisopropylethylamine (3.5 mL, 20.07 mmol) and stirred for 2 hours. The reaction mixture was diluted with water (50 mL), then extracted with ethyl acetate (3 x 50 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was purified by reverse phase preparation (formic acid system) to give compound 32-5 (1.74 g, yield 57.5%). LCMS[M+H] + 452.3.
  • Step 5 Compound 32-5 (1.6 g, 3.54 mmol) was dissolved in dichloromethane (32 mL) at room temperature, then trifluoroacetic acid (8 mL, 108.05 mmol) was added, and the mixture was stirred for 2 hours. The reaction solution was spun dry to obtain the crude compound Int-32 (3.33 g). used directly in the next reaction. LCMS[M+H] + 352.1.
  • Step 1 Under nitrogen protection, boron trifluoride ether (529 mg, 3.73 mmol) was added to 4-bromophenylacetic acid 33-1 (5.0 g, 23.3 mmol) and tertiary 2,2,2-trichloroethylimide A solution of butyl ester (10.2 g, 46.7 mmol) in tetrahydrofuran (50 mL) was stirred at room temperature for 16 hours. To the reaction mixture was added NaHCO3 (500 mg) to quench the reaction, diluted with water (100 mL), then extracted with ethyl acetate (2 x 50 mL), the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The obtained crude product was separated and purified by reverse phase column (formic acid system) to obtain compound 33-2 (3.50 g, yield 55.4%) as a yellow oil. used directly in the next reaction.
  • boron trifluoride ether 529 mg, 3.73 m
  • Step 2 Under nitrogen protection, compound 33-2 (3.00 g, 11.06 mmol), 2-vinylisoindoline-1,3-dione (1.92 g, 11.06 mmol), palladium acetate (74.52 mg, 331.92 ⁇ mol), triphenylphosphine (336.75 mg, 1.11 mmol) and N,N-diisopropylethylamine (4.29 g, 33.19 mmol) were added to acetonitrile (50 mL) and stirred at 90° C. for 16 hours. After cooling, the reaction mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was separated and purified by reverse phase column (formic acid system) to obtain compound 33-3 (1.80 g, yield 44.8%) as a yellow solid.
  • Step 3 Under argon protection, wet palladium/carbon (100 mg, 10% Pd) was added to a mixed solution of compound 33-3 (1.8 g, 4.95 mmol) in methanol (15 mL) and ethyl acetate (15 mL), After three hydrogen replacements, the mixture was stirred at room temperature at 50 psi for 12 hours. After the reaction was completed, it was filtered, and the filter cake was washed twice with methanol. The filtrates were combined and concentrated under reduced pressure to give crude compound 33-4 (1.80 g) as a yellow oil. LCMS[M+Na] + 388.1.
  • Step 4 Compound 33-4 (500 mg, 1.37 mmol) was added to ethanol (5 mL), then 85% hydrazine hydrate (177.29 mg, 3.01 mmol) was added, and the mixture was stirred at 85° C. for 12 hours. After the completion of the reaction, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound 33-5 (370 mg) as a white solid. used directly in the next reaction. LCMS[M+H] + 236.1.
  • Step 5 Combine N,N-diisopropylethylamine (247.1 mg, 1.91 mmol) and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4- Fluorisoindoline 7-2 (264.0 mg, 0.96 mmol) was added to N,N-dimethylformamide (10 mL), stirred at 90°C for 0.5 h, and then compound 33-5 (270 mg, 1.15 mmol) was added , and stirred at 90 °C for 12 hours. After cooling, the reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (3 x 20 mL).
  • Step 6 Compound 33-6 (95 mg, 193.3 ⁇ mol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (3.08 g, 27.01 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was spun dry to obtain crude compound Int-33 (80 mg, yield 95.0%) as a yellow oil. used directly in the next reaction. LCMS[M+H] + 436.2.
  • N,N-Diisopropylethylamine 320.5 mg, 2.48 mmol was added to compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoro
  • a solution of isoindoline 7-2 (342.5 mg, 1.24 mmol) in N,N-dimethylformamide (10 mL) was stirred at 90°C for 0.5 h, and then 2-(4-(aminomethyl)benzene was added base)acetic acid 34-1 (300.0 mg, 1.49 mmol), stirred at 90°C for 12 hours.
  • Step 1 At room temperature, 3-bromophenylacetic acid 35-1 (5 g, 23.25 mmol) was dissolved in anhydrous methanol (50 mL), then concentrated sulfuric acid (920 mg, 9.38 mmol, 0.5 mL) was slowly added, and the reaction system was heated up Stir to 80°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (2 ⁇ 80 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution (80 mL), and the layers were separated. The organic phase was washed with anhydrous sodium sulfate. dry. Filtration and concentration gave crude compound 35-2 (5.5 g) as a yellow oil. used directly in the next reaction.
  • Step 2 Under nitrogen protection, methyl 3-bromophenylacetate 35-2 (2.5 g, 10.91 mmol), (2-(9-borabicyclo[3.3.1]nonan-9-yl)ethyl)amino tert-Butyl formate 35-3 (5.79 g, 21.83 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex ((891.25 mg, 1.09 mmol) and cesium carbonate (7.11g, 21.83mmol) was dissolved in the mixed solvent of dioxane (50mL) and water (5mL), and the reaction system was warming up to 100 ° C and stirred for 2 hours.
  • dioxane 50mL
  • water 5mL
  • Step 3 Compound 35-4 (0.5 g, 1.70 mmol) was dissolved in methanol (5 mL), 4M aqueous potassium hydroxide solution (10 mL) was added, and the reaction system was stirred at 85° C. for 3 hours. Cool to room temperature, add dropwise 1M hydrochloric acid (40 mL) to neutralize potassium hydroxide, add water (20 mL) to dilute, and extract with ethyl acetate (2 ⁇ 20 mL). The combined organic phases were washed twice with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration gave crude compound 35-5 (1.1 g) as a pale yellow oil. LCMS[M+K] + 318.0.
  • Step 4 Compound 35-5 (249.12 mg, 891.8 ⁇ mol), benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 (200 mg, 891.8 ⁇ mol), HATU (373.01 mg, 981.0 ⁇ mol) and N,N-diisopropylethylamine (345.79 mg, 2.68 mmol) were added to N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (2 x 20 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave crude product.
  • Step 5 Compound 35-6 (0.15 g, 308.91 ⁇ mol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (770.00 mg, 6.75 mmol, 500.0 ⁇ L) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude compound Int-35 as trifluoroacetate salt (0.2 g) as a brown oil. LCMS[M+H] + 386.1.
  • Step 1 2-Hydroxybenzaldehyde (2.17 g, 17.80 mmol) was added to 2-bromo-1-(pyridin-2-yl)ethanone 36-1 (5.00 g, 17.80 mmol) in N,N-dimethylene
  • potassium carbonate (4.92 g, 35.59 mmol) was added, and the mixture was stirred at room temperature for 12 hours.
  • the reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (3 x 20 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product.
  • the crude product was separated and purified by reverse phase column to obtain compound 36-2 (3.10 g, yield 78.0%) as a brown solid.
  • Step 2 Compound 36-2 (1.50 g, 6.72 mmol), tert-butylsulfinamide (741.13 mg, 6.11 mmol) and tetraethyl titanate (2.79 g, 12.23 mmol) were added to dichloromethane (50 mL) , and stirred at 40°C for 12 hours. The reaction mixture was diluted with water (80 mL), then extracted with dichloromethane (2 x 40 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product.
  • Step 3 Sodium borohydride (69.54 mg, 1.84 mmol) was added to a solution of compound 36-3 (300 mg, 919.08 ⁇ mol) in methanol (5 mL) at 0°C, followed by stirring at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with water (5 mL). Diluted with water (10 mL), then extracted with ethyl acetate (2 x 10 mL), the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude compound 36-4 (540 mg) as a blue solid. used directly in the next reaction. LCMS[M+H] + 329.0.
  • Step 4 Compound 36-4 (70 mg, 213.14 ⁇ mol) was added to a solution of 4M HCl in methanol (4 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated and diluted with water (10 mL), adjusted to pH 8 with saturated sodium bicarbonate solution, then extracted with ethyl acetate (2 ⁇ 10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filter and concentrate. The crude compound Int-36 (40 mg, 83.7% yield) was obtained as a red oil. used directly in the next reaction. LCMS[M+H] + 225.0.
  • Step 1 n-Butyllithium (2.5M, 4.11 mL) was slowly added dropwise to nitrogen-protected 1-methylindole 37-1 (1.22 g, 9.34 mmol) in anhydrous tetrahydrofuran (10 mL) at -78°C ) solution, the temperature was naturally raised to room temperature after dropping, and stirred for 0.5 hours. It was cooled to -78°C again, and a solution of nicotinaldehyde (1.00 g, 9.34 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise, and the mixture was naturally warmed to room temperature after dropping, and stirred for 3 hours.
  • Step 2 Active manganese dioxide (3.06 g, 35.25 mmol) was added to a solution of compound 37-2 (700 mg, 2.94 mmol) in anhydrous dichloromethane (20 mL) at room temperature, and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to give crude compound 37-3 (700 mg) as a yellow gum. used directly in the next reaction. LCMS[M+H] + 237.0.
  • Step 1 Compound 3-bromoxynil 38-1 (546 mg, 3 mmol) and tert-butyl acrylate (1.15 g, 9 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by adding tetrabutyl Ammonium bromide TBAB (1.16 g, 3.6 mmol), potassium carbonate (1.24 g, 9 mmol) and palladium acetate (34 mg, 0.15 mmol). It was heated to 120°C and stirred for 16 hours under nitrogen protection. After the reaction was completed, the reaction mixture was cooled to room temperature, ethyl acetate (50 mL) and water (20 mL) were added, extracted, and the layers were separated.
  • Step 2 Compound 38-2 (180 mg, 0.78 mmol) was dissolved in methanol (5 mL), 7M NH3/ MeOH (2 mL, 14.0 mmol) was added followed by Raney Ni (0.5 g). Hydrogenate with hydrogen balloon for 16 hours at room temperature. Filtration and concentration of the filtrate gave crude compound 38-3 (190 mg) as a colorless oil. used directly in the next reaction. LCMS[M+H] + 236.6.
  • Step 3 Compound 38-3 (160 mg, 0.69 mmol) and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7 -2 (190 mg, 0.69 mmol) was dissolved in N-methylpyrrolidone (4 mL), diisopropylethylamine (268 mg, 3.0 mmol) was added, and the mixture was heated and stirred at 90°C for 16 hours. After the reaction was completed, the reactant was cooled to room temperature, ethyl acetate (20 mL) and water (10 mL) were added, extracted, and the layers were separated.
  • Step 4 Compound 38-4 (130 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL, 6.7 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, it was spin-dried under reduced pressure to obtain the crude compound Int-38 (95 mg) as a yellow oil. used directly in the next reaction. LCMS[M+H] + 436.5.
  • Step 1 Methanesulfonyl chloride (246.75 mg, 2.15 mmol) was added dropwise to compound 8-2 (400 mg, 1.96 mmol) and triethylamine (594.46 mg, 5.87 mmol) in anhydrous dichloromethane (10 mL) at 0°C ) solution, and stirred at room temperature for 0.5 hours after dropping. After the reaction was completed, it was concentrated under reduced pressure to obtain the crude compound 43-1 (520 mg), which was directly used in the next reaction. LCMS[M+ NH4 ] + 300.0.
  • Step 2 Compound 43-1 (145.90 mg, 516.72 ⁇ mol) was dissolved in N,N-dimethylformamide (5 mL), Int-42 (100 mg, 344.48 ⁇ mol) and potassium carbonate (71.41 mg, 516.72 ⁇ mol) were added sequentially ⁇ mol) and stirred at room temperature for 4 hours. TLC detected the formation of new substances. The reaction mixture was diluted with water (10 mL), then extracted with ethyl acetate (2 x 10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by reverse phase column to obtain compound 43-2 (30 mg, yield 18.3%) as a white solid. used directly in the next reaction. LCMS[M+Na] + 499.3.
  • Step 3 Compound 43-2 (30 mg, 62.95 ⁇ mol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1.54 g, 13.51 mmol) was added, and the mixture was stirred at room temperature for 2 hours. TLC detected that the reaction was complete, and concentrated to obtain crude compound Int-43 (26 mg, yield 98.2%) as a yellow oil. used directly in the next reaction.
  • Step 1 Compound benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 (253.59 mg, 1.13 mmol), 3-(((tert-butoxycarbonyl)amino)methyl)phenylacetic acid 44-1 (300 mg, 1.13 mmol), HATU (472.95 mg, 1.24 mmol) and N,N-diisopropylethylamine (438.44 mg, 3.39 mmol) were dissolved in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hours.
  • Step 2 Compound 44-2 (500 mg, 1.06 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1.40 g, 12.28 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain the crude compound Int-44 (1.11 g) as a brown oil. used directly in the next reaction. LCMS[M+H] + 372.2.
  • Step 1 To 7-hydroxyheptanoic acid 47-1 (300 mg, 2.05 mmol), benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 (460.22 mg, 2.05 mmol) in N at room temperature , N-dimethylformamide (4 mL) solution was added HATU (858.34 mg, 2.26 mmol) and N,N-diisopropylethylamine (795.70 mg, 6.16 mmol, 1.07 mL). Stir at room temperature for 12 hours. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (3 ⁇ 5 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by reverse phase column to obtain compound 47-2 (309 mg, yield 42.7%) as a brown solid. LCMS[M+H] + 353.2.
  • Step 2 To a solution of compound 47-2 (150 mg, 425.62 ⁇ mol) and triethylamine (129.20 mg, 1.28 mmol, 177.72 ⁇ L) in anhydrous dichloromethane (5 mL) at 0° C. under the protection of N 2 , add dropwise Methanesulfonyl chloride (300 mg, 2.62 mmol, 202.70 ⁇ L), the reaction mixture was stirred at room temperature for 1 hour, TLC showed the reaction was complete. The reaction mixture was concentrated to give crude compound Int-47 (183 mg, yield 99.9%) as a brown solid. used directly in the next reaction.
  • Step 1 To a solution of compound 48-1 (3.00 g, 15.85 mmol) and triethylamine (4.81 g, 47.56 mmol) in anhydrous dichloromethane (50 mL) under the protection of N 2 at 0 °C, methanesulfonic acid was added dropwise. Acid chloride (2.0 g, 17.44 mmol), the reaction mixture was stirred at room temperature for 0.5 h, TLC showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution (20 mL). The reaction mixture was then diluted with water (50 mL), extracted with dichloromethane (2 x 40 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude compound 48-2 (3.9 g, yield 92.0%) as a yellow oil. used directly in the next reaction. LCMS[M+Na] + 290.0.
  • Step 2 Compound 48-2 (138.14 mg, 516.72 ⁇ mol) was dissolved in N,N-dimethylformamide (4 mL), Int-42 (100 mg, 344.48 ⁇ mol) and potassium carbonate (71.41 mg, 516.72 ⁇ mol) were added sequentially ) and stirred at room temperature for 12 hours.
  • the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (2 ⁇ 10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by reverse phase column to obtain compound 48-3 (55 mg, yield 34.6%) as a yellow solid.
  • Step 3 Compound 48-3 (55 mg, 119.17 ⁇ mol) was added to anhydrous dichloromethane (6 mL), then trifluoroacetic acid (3.08 g, 27.01 mmol) was added, and the mixture was stirred at room temperature for 2 hours. TLC detected that the reaction was complete, and the reaction solution was concentrated to obtain crude compound 48-4 (87 mg) as a yellow solid. used directly in the next reaction.
  • Step 4 Compound 48-4 (70.00 mg, 147.2 ⁇ mol) was dissolved in tert-butanol (4 mL), followed by adding triethylamine (19.60 mg, 193.69 ⁇ mol) and tert-butyl acrylate (37.24 mg, 290.55 ⁇ mol), at 80° C. Heat and stir for 10 hours. After cooling, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (2 x 20 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by reverse phase column to obtain compound 48-5 (30 mg, yield 41.6%) as a yellow oil.
  • Step 5 Compound 48-5 (30 mg, 61.28 ⁇ mol) was added to anhydrous dichloromethane (3 mL), then trifluoroacetic acid (1.54 g, 13.51 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude compound Int-48 (26 mg, yield 77.5%) as a yellow oil. used directly in the next reaction.
  • Step 1 At room temperature, benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 (674.77 mg, 3.01 mmol) and 4-hydroxymethylphenylacetic acid 51-1 (0.5 g, 3.01 mmol) were combined ) was dissolved in N,N-dimethylformamide (5 mL), then HATU (1.26 g, 3.31 mmol) and N,N-diisopropylethylamine (1.17 g, 9.03 mmol) were added, and the mixture was stirred at room temperature for 2 hours .
  • Step 2 To a solution of compound 51-2 (100 mg, 268.52 ⁇ mol) in dichloromethane (2 mL) at room temperature, manganese dioxide (280.14 mg, 3.22 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain the crude compound Int-51 (85 mg), which was directly used in the next reaction. LCMS[M+H] + 371.0.

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Abstract

La présente invention concerne un composé représenté par la formule (X), ou un tautomère, un stéréoisomère, un promédicament, une forme cristalline, un sel pharmaceutiquement acceptable, un hydrate ou un solvate de celui-ci, et une composition pharmaceutique comprenant le composé, et une utilisation correspondante.
PCT/CN2022/071013 2021-01-11 2022-01-10 Classe de nouveaux agents de dégradation de protéine smad3 et leur application WO2022148459A1 (fr)

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WO2009145899A1 (fr) * 2008-05-30 2009-12-03 Celgene Corporation Composés consistant en isoindolines substituées en position 5
CN105085620A (zh) * 2015-06-25 2015-11-25 中山大学附属第一医院 一种靶向泛素化降解Smad3的化合物
WO2017201449A1 (fr) * 2016-05-20 2017-11-23 Genentech, Inc. Conjugués anticorps-protac et procédés d'utilisation
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