WO2024083257A1 - Agent de dégradation de protéine sos1 et son utilisation - Google Patents

Agent de dégradation de protéine sos1 et son utilisation Download PDF

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WO2024083257A1
WO2024083257A1 PCT/CN2023/125976 CN2023125976W WO2024083257A1 WO 2024083257 A1 WO2024083257 A1 WO 2024083257A1 CN 2023125976 W CN2023125976 W CN 2023125976W WO 2024083257 A1 WO2024083257 A1 WO 2024083257A1
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alkyl
group
membered
independently
cycloalkyl
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PCT/CN2023/125976
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Chinese (zh)
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叶正清
冯焱
李世强
丁陈利
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上海领泰生物医药科技有限公司
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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
    • A61K31/495—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/34—Phthalazines with nitrogen atoms directly attached to carbon atoms of the nitrogen-containing ring, e.g. hydrazine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medical technology, and in particular, relates to a SOS1 protein degradation agent and application thereof.
  • SOS1 (son of sevenless homolog 1) protein is a regulatory protein widely expressed in cells. As a key protein in the signaling pathway, SOS1 plays an important regulatory role in many signal transduction pathways in cells, such as participating in the regulation of Ras and Rac signaling pathways. SOS1 is composed of 1333 amino acids and contains a proline-rich domain (PxxP) at its C-terminus, which can bind to growth factor receptor-bound protein 2 (Grb2) in the Ras pathway to form a complex of Grb2 and SOS1, thereby bringing SOS1 to the vicinity of Ras protein on the cell membrane.
  • PxxP proline-rich domain
  • Rhb2 growth factor receptor-bound protein 2
  • SOS1 catalyzes the binding of Ras to GTP, promotes the activation of Ras, and then activates multiple downstream signaling pathways, such as Ras-Raf-Mek-Erk and Ras-PI3K-AKT-mTOR.
  • PxxP can also bind to the SH3 (Src homology 3) domain of proteins such as E3B1 in the Rac pathway to form an EPS8-E3B1-SOS1 complex.
  • the EPS8-E3B1-SOS1 complex connects to actin filaments through EPS8, causing the conversion of GTP, thereby activating Rac and subsequently activating signaling pathways such as JNK and MAPK.
  • Ras mutant genes are considered to be the main oncogenes with a high incidence in human cancer. Studies have shown that 20-30% of tumor patients have Ras mutations, of which KRas mutations account for 85%, NRas and HRas account for 12% and 3%, respectively. However, due to the picomolar affinity of GTP for its binding site and the smooth surface of Ras protein, which lacks other suitable binding pockets, it is considered extremely challenging to directly act on Ras to inhibit its activity.
  • SOS1 Abnormal expression or mutation of SOS1 is also closely related to the occurrence of clinical diseases. Studies have shown that SOS1 mutations exist in NS patients and CFC patients. HGF1 is a rare autosomal dominant genetic disease, and its cause is also related to the mutation of the PxxP domain of SOS1. In addition, abnormal expression or mutation of SOS1 is also related to the occurrence of cancer.
  • WO2018172250A1, WO2020173935A1, WO2019201848A1, WO2020180768A1, WO2020180770A1, WO2019122129A1 and EP3558979A1 disclose several types of SOS1 inhibitors, but so far, there are no reports on SOS1 degraders.
  • Proteolysis Targeting Chimeria is a technology different from traditional small molecule inhibitors.
  • PROTAC is a heterogeneous bifunctional molecule, one end of which is a small molecule inhibitor that can recognize the target protein through a connecting chain, and the other end is an E3 ubiquitin ligase ligand that can recognize E3 ubiquitin ligase.
  • This bifunctional molecule recognizes the target protein and E3 ubiquitin ligase in the body, pulls the target protein and E3 ubiquitin ligase closer to form a ternary complex, and after ubiquitination of the target protein, it degrades the target protein through the ubiquitin-proteasome pathway in the body.
  • PROTAC Compared with traditional small molecule inhibitors, on the one hand, PROTAC only needs to connect the target protein to the E3 ubiquitin ligase. The enzyme is brought closer to the substrate, causing the substrate to degrade. This mode of action allows this technology to be applied to some undruggable targets. On the other hand, since the target protein can be released after being degraded and continue to participate in the degradation process of the next protein, this degradation with catalytic effect allows a smaller PROTAC drug dose to achieve efficient degradation.
  • the present invention provides a new SOS1 protein degrader and its application, which can effectively bind to or inhibit the SOS1 target protein, and further, can effectively and specifically degrade the SOS1 protein.
  • the present invention solves the above technical problems through the following methods.
  • the present invention provides a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or pharmaceutically acceptable salts thereof: SLE I
  • L is a connecting chain, which connects S and E through a covalent bond
  • E is the E3 ubiquitin ligase ligand
  • X is CH or N
  • R 1 is hydrogen, halogen, OH, thiol, CN, NO 2 , NR a R b , C 1 -C 6 alkyl, C 1 -C 6 alkylthiol, C 1 -C 6 heteroalkyl, C 1 -C 6 alkoxy, -O(C 1 -C 6 heteroalkyl), -S(C 1 -C 6 alkyl), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 12 aryl, 5-10 membered heteroaryl, -COOR c , -NHS(O)(R d ), -NHS(O) 2 (R d ), -NHC(O)-(C 1 -C 6 alkyl), -NHC(O)-NR a R b , -NH-(CH 2 ) k
  • each Ra and Rb is independently hydrogen, C1 - C6 alkyl, C1 - C6 heteroalkyl, 3-8 membered heterocycloalkyl or C3 - C8 cycloalkyl;
  • R c is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or C 3 -C 8 cycloalkyl;
  • R d and R e' are independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl;
  • R aa is C 1 -C 6 alkyl, 3-8 membered heterocycloalkyl or C 3 -C 8 cycloalkyl;
  • k 1 or 2;
  • i 0, 1 or 2;
  • R f' is a 4-7 membered heterocycloalkyl group, a 5-10 membered heteroaryl group or a C 1 -C 6 alkylsulfonyl group;
  • z 0, 1, or 2;
  • C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl mentioned above are optionally replaced by 1, 2 or 3 selected from deuterium, halogen, OH, oxo, CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylsulfonyl, phenyl, benzyl, 5-10 membered heteroaryl, -(CH 2 )-(5-8 membered heteroaryl),
  • A1 is C4 - C12 cycloalkyl, 3-8 membered heterocycloalkyl, C6 - C12 aryl, 5-10 membered heteroaryl, C4 - C12 cycloalkyl substituted with 1, 2, 3, 4 or 5 Rc " , 3-8 membered heterocycloalkyl substituted with 1, 2, 3, 4 or 5 Rd " , C 6 -C 12 aryl substituted by 2, 3, 4 or 5 R c' or 5-10 membered heteroaryl substituted by 1, 2, 3, 4 or 5 R d' ,
  • each of R o' , R g , R h and R i is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, -NR k R j or C 1 -C 6 alkyl substituted with one or more R l ;
  • each Re and Rf is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, -NR k R j or C 1 -C 6 alkyl substituted with one or more R l ;
  • Each R k and R j is independently hydrogen or C 1 -C 6 alkyl
  • Each R1 is independently -NRmRn ,
  • R m and R n are independently deuterium, hydrogen or C 1 -C 6 alkyl
  • R c'' and R d'' is independently hydrogen, C 1 -C 6 alkyl, 3-8 membered heterocycloalkyl or C 3 -C 8 cycloalkyl;
  • R g' is hydrogen or C 1 -C 6 alkyl
  • A2 is H, C3 - C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6- C10 aryl, 5-10 membered heteroaryl, C4 -C12 cycloalkyl substituted by 1, 2 , 3, 4 or 5 Re" , 3-10 membered heterocycloalkyl substituted by 1, 2, 3, 4 or 5 Rf " , C6 - C10 aryl substituted by 1, 2, 3, 4 or 5 Rg " , or 5-8 membered heteroaryl substituted by 1, 2, 3, 4 or 5 Rh” ;
  • each of Re “ , Rf “ , Rg “ and Rh “ is independently hydrogen, halogen, OH, oxo, CN, NO2 , C2 - C6 alkenyl, C2 - C6 alkynyl, C3- C8 cycloalkyl, 4-10 membered heterocycloalkyl, C6 - C10 aryl, 5-10 membered heteroaryl, -C1 - C6 alkyl( NRzRza ) , -C(O) Rv , -C(O)NRvRw, -CH2C (O) NRvRw , -C (O) ORv , -NRzRza, -NHC(O) Rz , -NHC ( O) ORz , -NHS ( O ) 2Rz , -O( CH2 ) s- ( C3 - C8 cycloalkyl), -O( CH2 ) s -pheny
  • each R v and R w is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, phenyl or -(CH 2 ) 2 NR x R y , R x and R y are independently hydrogen, C 1 -C 4 alkyl or -(CH 2 ) 2 N(CH 3 ) 2 ;
  • each R z and R za is independently hydrogen, C 1 -C 4 alkyl, 5-10 membered heteroaryl, C 3 -C 8 cycloalkyl, hydroxy substituted C 1 -C 4 alkyl, methoxy substituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or phenyl;
  • Each s is independently 0, 1, 2 or 3;
  • the C1 - C6 alkyl, C1- C6 alkoxy, C2 -C6 alkenyl, C2 - C6 alkynyl, C3 - C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6 - C10 aryl, 5-10 membered heteroaryl are optionally substituted with 1, 2 or 3 substituents selected from halogen, OH, oxo, CN, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, phenyl, 5-10 membered heteroaryl, -C(O) NRi'Rj ' , -NRk'Rl ' and -NRs'Rt ' ;
  • R i' and R j' are independently hydrogen or C 1 -C 6 alkyl
  • R k' and R l' are independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkylsulfonyl, phenyl, 5-10 membered heteroaryl, -CH 2 -C(O)-R m , -C(O)R p or 4-7 membered heterocycloalkyl, and the alkyl, alkynyl, alkenyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl are independently optionally substituted with 1, 2 or 3 selected from C 1 -C 6 haloalkyl, OH, oxo, phenyl, CN, C 1 -C 6 alkoxy and 5-10 membered heteroaryl, the heteroaryl is optionally substituted with methyl; R m is 9-10 membered bicyclic heteroary
  • -NR s' R t' is R s' and R t' and the nitrogen atom form a 4-7 membered monocyclic azacycloalkyl or a 6-10 membered spirocyclic azacycloalkyl, the heterocycloalkyl further comprising up to two heteroatoms selected from N and O, and the heterocycloalkyl is optionally substituted by 1, 2 or 3 substituents selected from OH, oxo, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and -C(O)OR z , the R z is C 1 -C 6 alkyl, halogen, -N(C 1 -C 6 alkyl) 2 , -CH 2 N(C 1 -C 6 alkyl) 2 or -C(O)NR s" R t" , R s" and R t" are independently hydrogen, C 1 -C 6 alkyl, 3-8 membered heterocycloalky
  • R4 is hydrogen, oxo, C1 - C6 alkyl, C1 - C6 heteroalkyl, N( C1 - C6 alkyl) 1-2 , C1 - C6 alkoxy, C3 - C8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the alkyl, heteroalkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, CN, OH, C1 - C6 alkoxy, C3 - C8 cycloalkyl, 3-8 membered heterocycloalkyl or halogen;
  • R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, N(C 1 -C 6 alkyl) 1-2 , C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the alkyl, heteroalkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, CN, OH, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl or halogen;
  • the heteroalkyl group mentioned above is a heteroalkyl group whose heteroatom or heteroatom group is selected from one or more of N, O, S, -C(O)-, -S(O)-, -S(O) 2 -, -C(O)O-, -OC(O)-), C(O)NH-, -NHC(O)-, vinylene and ethynylene, and whose number of heteroatoms is 1, 2 or 3.
  • the S is also
  • a 1 is optionally substituted
  • L′ is a bond, —(CH 2 ) k′ —, —O(CH 2 ) k′ —, or —CH ⁇ CH—(CH 2 ) n —, wherein k′ is 1 or 2, and n is 0, 1 or 2.
  • A2 is optionally substituted
  • X is CH or N
  • R 1 , R 4 and R 5 are independently hydrogen, CN, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, N(C 1 -C 6 alkyl) 1-2 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl substituted by one or more Ra1 , or C 1 -C 6 alkoxy substituted by one or more Ra2 ;
  • R a1 and R a2 are independently deuterium or halogen
  • n 1, 2 or 3;
  • A1 is C6- C12 aryl, 5-10 membered heteroaryl, C6 - C12 aryl substituted by 1, 2, 3 or 4 Rc ' , or 5-10 membered heteroaryl substituted by 1, 2, 3 or 4 Rd ' ;
  • each R c' and R d' is independently CN, C 1 -C 6 alkyl, -NR e R f , halogen, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 1 -C 6 alkyl(SO 2 )-, C 1 -C 6 alkyl substituted with 1, 2, 3, 4 or 5 R g , C 6 -C 10 aryl substituted with 1, 2, 3, 4 or 5 R h , or 5-10 membered heteroaryl substituted with 1, 2, 3, 4 or 5 R i ;
  • Each of Re , Rf , Rg and Rh is independently hydrogen, deuterium, halogen, C1 - C6 alkyl, -NRkRj or C1 - C6 alkyl substituted with one or more R1.
  • Alkyl; R k and R j are independently hydrogen or C 1 -C 6 alkyl;
  • Each R l is independently -NR m R n , R m and R n are independently deuterium, hydrogen or C 1 -C 6 alkyl;
  • the heteroalkyl group is a heteroatom or a heteroatom group selected from one or more of N, O, S, -C(O)-, -S(O)-, -S(O) 2 -, -C(O)O-, -OC(O)-), C(O)NH-, -NHC(O)-, vinylene and ethynylene, and the number of heteroatoms is 1, 2 or 3 heteroalkyl groups.
  • the C 3 -C 8 cycloalkyl group may independently be a C 3 -C 6 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the C 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 1-2 and the C 1 -C 6 alkyl substituted by one or more Ra1 may independently be C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
  • the C 1 -C 6 heteroalkyl group may independently be a C 1 -C 4 heteroalkyl group containing 1 or 2 heteroatoms selected from N, O and S, for example, CH 3 OCH 2 -, CH 3 CH 2 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 3 NHCH 2 -, CH 3 CH 2 NHCH 2 -, CH 3 NHCH 2 CH 2 -, CH 3 SCH 2 -, CH 3 CH 2 SCH 2 -, CH 3 SCH 2 CH 2 - or CH 3 OCH 2 OCH 2 -.
  • the C 1 -C 6 alkoxy group may independently be a C 1 -C 4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy.
  • the halogen in Ra1 and Ra2 , can independently be F, Cl, Br or I.
  • the C 6 -C 12 aryl group or the C 6 -C 12 aryl group substituted by 1, 2, 3 or 4 R c's may independently be phenyl or naphthyl.
  • the 5-10 membered heteroaryl or the 5-10 membered heteroaryl substituted by 1, 2, 3 or 4 R d' can independently be furanyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, indolyl or
  • the C 1 -C 6 alkyl, C 1 -C 6 alkyl(SO 2 )-, or the C 1 -C 6 alkyl substituted by 1, 2, 3, 4 or 5 R g may independently be C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
  • the C 6 -C 10 aryl group or the C 6 -C 10 aryl group substituted with 1, 2, 3, 4 or 5 R h may independently be phenyl or naphthyl.
  • the halogen in each of R c' and R d' , can independently be F, Cl, Br or I.
  • the 5-10 membered heteroaryl or the 5-10 membered heteroaryl substituted by 1, 2, 3, 4 or 5 R i can be independently furanyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, pyrazolyl, pyrimidinyl, indolyl or
  • the halogen in each of Re , Rf , Rg and Rh , can independently be F, Cl, Br or I.
  • the C1 - C6 alkyl or the C1 - C6 alkyl substituted by one or more R1 may be independently C1 - C4 alkyl, such as methyl , ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
  • each R1 is independently hydrogen, CN, C1 - C6 alkyl, C1 - C6 heteroalkyl, C3 - C8 cycloalkyl or C1 - C6 alkoxy, such as hydrogen, C1 - C3 alkyl or C1 - C3 alkoxy, also such as hydrogen, methyl or methoxy.
  • R 4 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkoxy, N(C 1 -C 6 alkyl) 1-2 , C 1 -C 6 alkyl substituted by one or more Ra1 , Ra1 is independently deuterium or halogen; for example, C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by 3 deuteriums or C 1 -C 3 alkyl substituted by 3 fluorines, for example, methyl, -CD 3 or -CH 2 CF 3 .
  • R 5 is C 1 -C 6 alkyl, such as C 1 -C 3 alkyl, and also such as methyl.
  • m is 1 or 2.
  • each R c' is independently CN, amino, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl(SO 2 )-, or C 1 -C 6 alkyl substituted by 1, 2, 3, 4 or 5 halogen; for example CN, C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by 1 , 2 or 3 fluorine; for example CN, methyl, -CHF 2 , -CF 3 or amino.
  • each R d′ is independently C 6 -C 12 aryl (eg, phenyl) or C 6 -C 12 aryl (eg, phenyl) substituted with one or more R h .
  • each R h is independently hydrogen, halogen, C 1 -C 6 alkyl substituted by one or more R l , such as hydrogen, halogen, C 1 -C 3 alkyl substituted by one or more R l ; also such as hydrogen, Cl or methyl substituted by one or more R l .
  • each R l is independently -NR m R n
  • R m and R n are independently hydrogen or C 1 -C 6 alkyl, preferably hydrogen or C 1 -C 3 alkyl; for example -NHCH 3 or -N(CH 3 ) 2 .
  • Each R c' is independently CN, amino, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted with 1, 2, 3, 4 or 5 halogens;
  • Each R d' is independently a C 6 -C 12 aryl group or a C 6 -C 12 aryl group substituted with one or more R h ;
  • Each R h is independently hydrogen, halogen, or C 1 -C 6 alkyl substituted with one or more R l ;
  • Each R1 is independently -NRmRn , and Rm and Rn are independently hydrogen or C1 - C6 alkyl.
  • X is CH or N
  • Each R 1 is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • n 1 or 2;
  • R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted by one or more Ra1 , Ra1 independently being deuterium or halogen;
  • R 5 is hydrogen or C 1 -C 6 alkyl
  • each R c' is independently CN, amino, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl(SO 2 )-, or C 1 -C 6 alkyl substituted with 1, 2, 3, 4 or 5 halogens;
  • Each R d' is independently a C 6 -C 12 aryl group or a C 6 -C 12 aryl group substituted with one or more R h ;
  • Each R h is independently hydrogen, halogen or C 1 -C 6 alkyl substituted with one or more R l ;
  • Each R1 is independently -NRmRn , and Rm and Rn are independently hydrogen or C1 - C6 alkyl.
  • X is CH or N
  • Each R 1 is independently hydrogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy;
  • R 4 is C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by 3 deuteriums, or C 1 -C 3 alkyl substituted by 3 fluorines;
  • R 5 is C 1 -C 3 alkyl
  • n 1 or 2;
  • Each R c' is independently CN, C 1 -C 3 alkyl, C 1 -C 3 alkyl(SO 2 )-, C 1 -C 3 alkyl substituted with 1, 2 or 3 fluorine groups;
  • Each R d' is independently phenyl or phenyl substituted with one or more R h ;
  • Each R h is independently hydrogen, halogen, C 1 -C 3 alkyl substituted with one or more R l ;
  • Each R1 is independently -NRmRn , and Rm and Rn are independently hydrogen or C1 - C3 alkyl.
  • X is CH or N
  • Each R 1 is independently hydrogen, methyl or methoxy
  • R 4 is methyl, -CD 3 or -CH 2 CF 3 ;
  • R5 is methyl
  • n 1 or 2;
  • A1 is C6 - C12 aryl, 5-10 membered heteroaryl, C6- C12 aryl substituted by one or more Rc ' , or 5-10 membered heteroaryl substituted by one or more Rd' ;
  • the C6 - C12 aryl or the C6 - C12 aryl substituted by one or more Rc ' is phenyl;
  • the 5-10 membered heteroaryl or the 5-10 membered heteroaryl substituted by one or more Rd' is
  • R c' is independently CN, methyl, -CHF 2 , -CF 3 , CH 3 SO 2 - or amino;
  • R d' is independently phenyl or phenyl substituted with one or more R h ;
  • R h is independently hydrogen, Cl or methyl substituted by one or more R l ;
  • R l is -NHCH 3 or -N(CH 3 ) 2 .
  • the S is S':
  • the S' is S'-1:
  • X, R 1 , A 1 , R 4 , R 5 and m are as defined in any of the preceding schemes.
  • the S is S-1 or S-2:
  • the S-1 is S-1-1 or S-1-2:
  • W and Y are independently 1, 2, 3, 4 or 5;
  • R 1 , R 4 , R 5 , R c' and R h are as defined in any of the preceding schemes.
  • the S-2 is S-2-1 or S-2-2:
  • W and Y are independently 1, 2, 3, 4 or 5;
  • the S-2 is N-(2-aminoethyl)-2
  • R 1 , R 4 , R 5 , R c' and R h are as defined in any of the preceding schemes.
  • S is:
  • L is a bond
  • L is -( CH2 ) j- , and one or more methylene groups in said -( CH2 ) j- are optionally selected from -NR3'- , -O-, -S-, -S(O)-, -S(O)NR3'- , -NR3'S (O) - , -S(O) 2- , -S(O )2NR3'-, -NR3 'S (O) 2- , -NR4'S ( O)2NR3'-, -CR1'R2'- , -C(O)-, -C(O)O-, -OC(O) - , -NR3'C(O) O- , -OC(O)NR3'- , -C(O)NR3'- , -NR3'C(O) -, -NR4'C (O)NR3 ' -, -
  • L is -(CH 2 ) j -, wherein one or more methylene groups in said -(CH 2 ) j - are optionally selected from -NR 3'- , -O-, -CR 1' R 2'- , -C(O)-, -S(O)-, -S(O) 2 -, -C(O)O-, -OC(O)-, -C(O)NR 3'- , -NR 3'C (O)-, -S(O) 2 NR 3'- , -NR 3'S (O) 2 -, vinylene, ethynylene, phenyl, 8-10 membered bicyclic arylene, 3-7 membered saturated or partially unsaturated cycloalkylene, 5-11 membered saturated or partially unsaturated spirocycloalkylene, 5-11 membered saturated or partially unsaturated condensed cycl
  • the alkyl, spirocycloalkylene, fused cycloalkylene and heteroarylene groups are independently optionally substituted with one or more substituents selected from halogen, oxo, -NR 3' R 4' , -OR 3' , nitro, -CN, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl and 3-10 membered heterocycloalkyl; the alkyl, cycloalkyl and heterocycloalkyl groups are optionally substituted with one or more substituents selected from halogen, -OH, -NH 2 , -CN, C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl; R 1' and R 2' are each independently halogen, -OH, -NH 2 , C 1 -C 4 alkyl, C 1 -C 4 chloroalkyl, C 1 -C 4 hydroxyalkyl, -O(C 1 -C 4 al
  • L is -(CH 2 ) j -, wherein one or more methylene groups in said -(CH 2 ) j - are optionally selected from -NR 3'- , -O-, -CR 1' R 2'- , -C(O)-, -S(O)-, -S(O) 2 -, -C(O)O-, -OC(O)-, -C(O)NR 3'- , -NR 3'C (O)-, -S(O) 2 NR 3'- , -NR 3'S (O) 2 -, vinylene, ethynylene, phenyl, 8-10 membered bicyclic arylene, 3-7 membered saturated or partially unsaturated monocyclic cycloalkylene, 5-11 membered saturated or partially unsaturated spirocycloalkylene, 5-11 membered saturated or partially unsaturated conden
  • L is -(CH 2 ) j -, wherein one, two, three, four or five methylene groups in said -(CH 2 ) j - are optionally selected from -NH-, -NCH 3 -, -O-, -C(CH 3 ) 2 -, -CHF-, -CHCF 3 -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH 3 -, -NHC(O)-, -NCH 3 C(O)-, vinylene, ethynylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, oxiranediylene, oxetanediylene, oxolanylene, oxhexylene, aziridinediylene
  • L is -(CH 2 ) j -, and one, two, three, four or five methylene groups in said -(CH 2 ) j - are optionally selected from -NH-, -NCH 3 -, -O-, -C(CH 3 ) 2 -, -CHF-, -CHCF 3 -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH 3 -, -NHC(O)-, -NCH 3 C(O)-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, oxiranediylene, oxetanediylene, oxolanylene, oxhexylene, aziridinediyl, aziridinediyl, piperidiny
  • L is -(CH 2 ) j -, and one, two, three, four or five methylene groups in said -(CH 2 ) j - are optionally selected from -O-, -NH-, -NCH 3 -, -C(O)-, -C(O)NH-, -NHC(O)-, -NCH 3 C(O)-, -C(O)NCH 3 -, cyclohexylene, aziridinyl, aziridinyl, azipentyl, piperidinyl, piperazinyl, and j is 4, 5, 6, 7, 8, 9 or 10.
  • L is selected from -(CH 2 ) j-1 -C(O)-, wherein the methylene group in -(CH 2 ) j-1 -C(O)- is as defined in L above, optionally substituted by one or more groups, and j is as defined in L above.
  • L is selected from
  • L is any of the following structures:
  • said L is LA
  • the LA the LA:
  • Ring A is a bond, C 3 -C 12 cycloalkylene (e.g. The a end connected to S, and the a terminal is connected to X"') or a 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S (e.g.
  • the cycloalkylene and heterocycloalkylene are optionally substituted by a substituent selected from halogen, oxo, cyano, amino, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl or -O-(C 1 -C 6 alkyl);
  • Ring B is a bond, C 3 -C 12 cycloalkylene (e.g., wherein the c-terminal is connected to X"' and the d-terminal is connected to L 3 ) or a 3-12 membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S (e.g.
  • the cycloalkylene and heterocycloalkylene are optionally substituted by a substituent selected from halogen, oxo, cyano, amino, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl or -O-(C 1 -C 6 alkyl);
  • Ring C is C 3 -C 12 cycloalkylene (e.g. wherein the e end is connected to L3 , and the f end is connected to X”) or a 3-12 membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S (e.g.
  • cycloalkylene and heterocycloalkylene are optionally substituted by a substituent selected from halogen, oxo, cyano, amino, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl or -O-(C 1 -C 6 alkyl);
  • L 3 is -(CH 2 ) k , one or two methylene groups in L 3 are optionally replaced by -O-, -NH-, -C ⁇ C-, -N(C 1 -C 6 alkyl)-, -N(C 1 -C 6 haloalkyl)-, -C(O)-, -N(C 1 -C 6 hydroxyalkyl)- or -N(C 3 -C 8 cycloalkyl)-, and k is 0, 1, 2, 3, 4, 5, 6 or 7;
  • Ring A is a bond, a C 3 -C 12 cycloalkylene group, or a 3-12-membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S, wherein the cycloalkylene group and the heterocycloalkylene group are optionally substituted with a substituent selected from halogen, oxo, cyano, amino, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl or -O-(C 1 -C 6 alkyl);
  • Ring B is a bond, a C 3 -C 12 cycloalkylene group, or a 3-12-membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S, wherein the cycloalkylene group and the heterocycloalkylene group are optionally substituted with a substituent selected from halogen, oxo, cyano, amino, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl or -O-(C 1 -C 6 alkyl);
  • Ring C is C 3 -C 12 cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, and the cycloalkylene and heterocycloalkylene are optionally substituted by a substituent selected from halogen, oxo, cyano, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl or -O-(C 1 -C 6 alkyl);
  • L 3 is -(CH 2 ) k , one or two methylene groups in L 3 are optionally replaced by -O-, -NH-, -N(C 1 -C 6 alkyl)-, -N(C 1 -C 6 haloalkyl)-, -N(C 1 -C 6 hydroxyalkyl)- or -N(C 3 -C 8 cycloalkyl)-, and k is 0, 1, 2, 3 or 4;
  • L 3 is -(CH 2 ) k , one or two methylene groups in said L 3 are optionally replaced by -O-, -NH-, -C ⁇ C-, -N(C 1 -C 6 alkyl)-, -N(C 1 -C 6 haloalkyl)-, -N(C 1 -C 6 hydroxyalkyl)- or -N(C 3 -C 8 cycloalkyl)-, and k is 0, 1, 2, 3, 4, 5 , 6 or 7.
  • ring A is a bond.
  • ring A is a 3-7 membered saturated or partially unsaturated cycloalkylene group, a 4-11 membered saturated or partially unsaturated spirocycloalkylene group, a 4-11 membered saturated or partially unsaturated fused cycloalkylene group, an 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene group, a 4-7 membered saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated fused heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently
  • ring A is a 3-6-membered saturated cycloalkylene group or a 4-7-membered saturated monocyclic heterocycloalkylene group having 1 or 2 heteroatoms independently selected from nitrogen atoms.
  • ring A is a cyclohexylene group (e.g., cyclohexane-1,4-diyl, e.g., trans-cyclohexane-1,4-diyl), a piperidinylene group (e.g., piperidine-1,4-diyl) or a piperazinylene group (e.g., piperazine-1,4-diyl).
  • a cyclohexylene group e.g., cyclohexane-1,4-diyl, e.g., trans-cyclohexane-1,4-diyl
  • a piperidinylene group e.g., piperidine-1,4-diyl
  • a piperazinylene group e.g., piperazine-1,4-diyl
  • ring A is The a end is connected to S, and the b end is connected to X''.
  • ring A is The a end is connected to S, and the b end is connected to X''.
  • ring A is The a end is connected to S, and the b end is connected to X''.
  • ring B is a bond.
  • ring B is a 3-7 membered saturated or partially unsaturated cycloalkylene group, a 4-11 membered saturated or partially unsaturated spirocycloalkylene group, a 4-11 membered saturated or partially unsaturated fused cycloalkylene group, an 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene group, a 4-7 membered saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated fused heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently
  • ring B is a 4-7 membered saturated monocyclic heterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, a 7-11 membered spiroheterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, or a condensed heterocycloalkylene group.
  • ring B is a piperidinylene group (eg, piperidine-1,4-diyl) or a piperazinylene group (eg, piperazine-1,4-diyl).
  • ring B is The c-terminal is connected to X'', and the d-terminal is connected to L3 .
  • ring B is The c-terminal is connected to X'', and the d-terminal is connected to L3 .
  • ring C is a 3-7 membered saturated or partially unsaturated cycloalkylene group, a 4-11 membered saturated or partially unsaturated spirocycloalkylene group, a 4-11 membered saturated or partially unsaturated fused cycloalkylene group, an 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene group, a 4-7 membered saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated fused heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently
  • ring C is a 4-7 membered saturated monocyclic heterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, a 7-11 membered spiroheterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, or a condensed heterocycloalkylene group.
  • ring C is piperidinyl (e.g., piperidine-1,4-diyl), piperazinyl (e.g., piperazine-1,4-diyl), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example )or (For example ).
  • piperidinyl e.g., piperidine-1,4-diyl
  • piperazinyl e.g., piperazine-1,4-diyl
  • ring C is The e end is connected to L3 , and the f end is connected to X".
  • ring C is The e end is connected to L3 , and the f end is connected to X".
  • ring A in LA is a 3-6 membered saturated cycloalkylene group;
  • ring B is a 4-7 membered saturated monocyclic heterocycloalkylene group containing 1 or 2 nitrogen heteroatoms;
  • ring C is a 4-7 membered saturated monocyclic heterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, a 7-11 membered spiroheteroalkylene group containing 1 or 2 nitrogen heteroatoms, or a condensed heterocycloalkylene group;
  • X" is a bond or -C(O)-;
  • L3 is -( CH2 ) k , and k is 1, 2, 3, 4 or 5 (for example, k is 1, 2, 3 or 4).
  • X" is a bond or -C(O)-.
  • X" is a bond
  • X" is -C(O)-.
  • X" is -C(O)CH 2 O-.
  • X'' is a bond or -C(O)-.
  • X'' is a bond.
  • X'' is -C(O)-.
  • k is 1, 2, 3, 4 or 5.
  • L 3 is -(CH 2 ) k
  • k is 1, 2, 3, 4 or 5.
  • L 3 is -(CH 2 ) k , one or two methylene groups in said L 3 are optionally replaced by -O-, -NH-, -C ⁇ C- or -N(C 1 -C 6 alkyl)- (eg -N(CH 3 )-), and k is 1, 2, 3, 4 or 5.
  • k is 1, 2, 3 or 4.
  • L 3 is -(CH 2 ) k -, wherein one or two CH 2 contained in said L 3 are independently optionally replaced by -O-, -NH- or -N(C 1 -C 6 alkyl)- (e.g. -N(CH 3 )-), or one -CH 2 CH 2 - contained in said L 3 is optionally replaced by -C ⁇ C-; k is 1, 2, 3 or 4.
  • L 3 is -(CH 2 ) k -, one methylene group in said L 3 is optionally replaced by -O-, -NH- or -N(C 1 -C 6 alkyl)- (eg -N(CH 3 )-); k is 1, 2, 3 or 4.
  • the LA is LA-1:
  • Ring A, Ring B, Ring C, L 3 , and X are as defined and described in LA.
  • the LA is LA-2:
  • ring A is wherein the a end is connected to S, and the b end is connected to X"'; 1, 2, 3 or 4 hydrogen atoms in the ring A are optionally substituted by F;
  • X'' is -C(O)-
  • Ring B is wherein the c-terminus is connected to X'', and the d-terminus is connected to L 3 ; 1, 2, 3 or 4 hydrogen atoms in the ring B are optionally substituted by F;
  • L 3 is -(CH 2 ) k -, wherein one or two CH 2 groups contained in L 3 are independently optionally replaced by -O-, -NH- or -N(C 1 -C 6 alkyl)- (e.g. -N(CH 3 )-), or one -CH 2 CH 2 - contained in L 3 is optionally replaced by -C ⁇ C-; k is 1, 2, 3 or 4;
  • Ring C is wherein the e end is connected to L 3 , and the f end is connected to X"; 1, 2, 3 or 4 hydrogen atoms in the ring C are optionally replaced by F;
  • X" is -C(O)-.
  • ring A is The a end is connected to S, and the b end is connected to X''.
  • ring B is The c-terminal is connected to X'', and the d-terminal is connected to L3 .
  • L 3 is -(CH 2 ) k -, wherein one or two CH 2 contained in L 3 are independently optionally replaced by -O-, -NH- or -N(CH 3 )-; k is 1, 2, 3 or 4.
  • L 3 is -(CH 2 ) k -, wherein one or two CH 2 contained in L 3 are independently optionally replaced by -O-; k is 1, 2, 3 or 4.
  • k is 3 or 4, preferably 4.
  • L 3 is -(CH 2 ) k -, wherein one CH 2 contained in L 3 is optionally replaced by -O-; k is 4.
  • L 3 in LA, LA-1 and LA-2, L 3 may be -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -,
  • the k" end is connected to ring B, and the k' end is connected to ring C.
  • L 3 may be -(CH 2 ) 4 -,
  • ring C is The e end is connected to L3 , and the f end is connected to X".
  • the LA-2 is any of the following structures:
  • the LA-2 is any of the following structures:
  • the LA is LA-3:
  • ring A is wherein the a end is connected to S, and the b end is connected to X"'; 1, 2, 3 or 4 hydrogen atoms in the ring A are optionally substituted by F;
  • X'' is -C(O)-
  • Ring B is wherein the c-terminus is connected to X'', and the d-terminus is connected to L 3 ; 1, 2, 3 or 4 hydrogen atoms in the ring B are optionally substituted by F;
  • L 3 is -(CH 2 ) k -, wherein one CH 2 contained in L 3 is optionally replaced by -O-, -NH- or -N(C 1 -C 6 alkyl)- (eg -N(CH 3 )-); k is 1 or 2;
  • Ring C is wherein the e end is connected to L 3 , and the f end is connected to X"; 1, 2, 3 or 4 hydrogen atoms in the ring C are optionally replaced by F;
  • X" is -C(O)-.
  • ring A is Preferably The a end is connected to S, and the b end is connected to X''.
  • ring B is The c-terminal is connected to X'', and the d-terminal is connected to L3 .
  • L 3 is -(CH 2 ) k -, and k is 1 or 2.
  • ring C is The c-terminal is connected to X'', and the d-terminal is connected to L3 .
  • the LA-3 is any of the following structures:
  • the LA-3 is any of the following structures:
  • the LA is LA-4:
  • ring A is wherein the a end is connected to S, and the b end is connected to X"'; 1, 2, 3 or 4 hydrogen atoms in the ring A are optionally substituted by F;
  • X"' is a bond, -C(O)NH- or -C(O)NCH 3 -;
  • Ring B is a bond
  • L 3 is -(CH 2 ) k , one or two methylene groups in L 3 are optionally replaced by -O-, -NH-, -C(O)-, -C ⁇ C- or -N(C 1 -C 6 alkyl)-, and k is 0, 1, 2, 3, 4, 5, 6 or 7;
  • Ring C is wherein the e end is connected to L 3 , and the f end is connected to X"; 1, 2, 3 or 4 hydrogen atoms in the ring C are optionally replaced by F;
  • X" is -C(O)-.
  • ring A is The a end is connected to S, and the b end is connected to X''.
  • L 3 is -CH 2 -, The k" end is connected to ring B, and the k' end is connected to ring C.
  • ring C is The e end is connected to L3 , and the f end is connected to X".
  • the LA-4 is any of the following structures:
  • the LA-4 is any of the following structures:
  • the LA is LA-5:
  • Ring A, X'', Ring B, L3 and Ring C are as defined in LA-2 or LA-3;
  • X" is -C(O)CH 2 O-, and the -C(O)- in X" is connected to the ring C.
  • ring A is The a end is connected to S, and the b end is connected to X''.
  • ring B is The c-terminal is connected to X'', and the d-terminal is connected to L3 .
  • L 3 is -(CH 2 ) k , and k is 1 or 2, preferably 1.
  • ring C is The e end is connected to L3 , and the f end is connected to X".
  • the LA is
  • L is LB:
  • Ring A" is connected to S;
  • Ring A", Ring B” and Ring C" are independently a bond, C3 - C12 cycloalkylene, C3 - C12 cycloalkenylene or 3-12 membered heterocycloalkylene, wherein the cycloalkylene and heterocycloalkylene are optionally substituted with a substituent selected from halogen, oxo, cyano, amino , hydroxy, C1- C6 alkyl, C1 - C6 heteroalkyl, C1 - C6 haloalkyl, C1 - C6 hydroxyalkyl, C3 - C8 cycloalkyl, 3-8 membered heterocycloalkyl or -O-( C1 - C6 alkyl);
  • the C 1 -C 6 alkylene group in -NH-(C 1 -C 6 alkylene)- or -NH-(C 1 -C 6 alkylene)- may be substituted by one or more Rx', wherein the Rx' is a C 1 -C 6 alkyl group, or two Rx' located on the same carbon atom are connected to the carbon atom to form a C 3 -C 8 cycloalkyl group;
  • La is -(CH 2 ) k'- , one or two methylene groups in La" are optionally replaced by -O-, -NH-, -C ⁇ C-, -N(C 1 -C 6 alkyl)-, -N(C 1 -C 6 haloalkyl)-, -C(O)-, -N(C 1 -C 6 hydroxyalkyl)- or -N(C 3 -C 8 cycloalkyl)-, and k' is 0, 1, 2, 3, 4, 5, 6 or 7;
  • the heterocycloalkylene group is a heterocycloalkylene group whose heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.
  • the C3 - C12 cycloalkylene group may independently be a C3 - C6 monocyclic cycloalkylene group, a C7 - C11 bicyclic spirocyclic cycloalkylene group, a C7 - C11 bridged cycloalkylene group or a C7 - C11 bicyclic cycloalkylene group, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, spiro[3.3]hexylene, spiro[3.4]heptylene, spiro[3.5]octylene, spiro[4.4]octylene, spiro[4.5]nonylene, spiro[5.5]decylene, bicyclo[3.3.0]octylene or hexahydroindanylene.
  • the C 3 -C 12 cycloalkenylene in the ring A", ring B" and ring C" can independently be a C 3 -C 6 monocyclic cycloalkenylene, a C 7 -C 11 bicyclic spirocyclic cycloalkenylene, a C 7 -C 11 bridged cycloalkenylene or a C 7 -C 11 bicyclic cycloalkenylene, such as cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene,
  • the 3-12 membered heterocycloalkylene group in the ring A", ring B" and ring C" can independently be a C3 - C6 monocyclic heterocycloalkylene group, a C7 - C11 bicyclic spirocyclic heterocycloalkylene group, a C7 - C11 bridged heterocycloalkylene group or a C7 -C11 heterocycloalkylene group.
  • 11 -cycloheterocycloalkylene for example, azetidinylene, oxetanylene, tetrahydrofuranylene, tetrahydropyrrolylene, tetrahydropyranylene, piperidinylene, morpholinylene or piperazinylene, 2,7-diaza[3.5]nonanylene, 7-aza[3.5]nonanylene, 2-aza[3.5]nonanylene, 2,6-diaza[3,3]-hexylene, 2-aza[3,3]-hexylene, 3-aza[5,5]undecylene or 3,9-diaza[5,5]undecylene.
  • the C 1 -C 6 alkyl in the substituents in the ring A", ring B" and ring C" or the C 1 -C 6 alkyl in -O-(C 1 -C 6 alkyl) may independently be C 1 -C 4 alkyl , such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
  • the halogen in the substituent in the ring A", ring B" and ring C" can independently be F, Cl, Br or I.
  • the C 1 -C 6 heteroalkyl group in the substituent in the ring A", ring B" and ring C" may independently be a C 1 -C 4 heteroalkyl group containing 1 or 2 heteroatoms selected from N, O and S, such as CH 3 OCH 2 -, CH 3 CH 2 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 3 NHCH 2 -, CH 3 CH 2 NHCH 2 -, CH 3 NHCH 2 CH 2 -, CH 3 SCH 2 -, CH 3 CH 2 SCH 2 -, CH 3 SCH 2 CH 2 - or CH 3 OCH 2 OCH 2 -.
  • the C1 - C6 haloalkyl in the substituent may independently be C1 - C4 haloalkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl substituted with 1, 2 or 3 halogens, and the halogen may be F, Cl, Br or I.
  • the C 1 -C 6 hydroxyalkyl in the substituents in the ring A", ring B" and ring C" may independently be C 1 -C 4 hydroxyalkyl, such as hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxy-isopropyl, hydroxy-n-butyl, hydroxy-sec-butyl, hydroxy-isobutyl or hydroxy-tert-butyl.
  • the C 3 -C 8 cycloalkyl in the substituents in the ring A", ring B" and ring C" may independently be C 3 -C 6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the 3-8 membered heterocycloalkyl group in the substituent may independently be a 4-6 membered heterocycloalkyl group, such as azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl or piperazinyl.
  • the C 1 -C 6 alkylene in -O-(C 1 -C 6 alkylene), -S-(C 1 -C 6 alkylene) or -NH-(C 1 -C 6 alkylene) may independently be C 1 -C 4 alkylene, such as methylene, ethylene, n-propylene, isopropylene, sec - butylene, n-butylene, isobutylene or tert-butylene.
  • the C 1 -C 6 alkyl group in the Rx', can be independently a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
  • the C 1 -C 6 alkyl in -N(C 1 -C 6 alkyl)- in said substituted group may be C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
  • the C 1 -C 6 haloalkyl in the -N(C 1 -C 6 haloalkyl) in the substituted group may be a C 1 -C 4 haloalkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl substituted with 1, 2 or 3 halogens, and the halogens may independently be F, Cl, Br or I.
  • the C1 - C6 hydroxyalkyl in the -N(C1-C6 hydroxyalkyl)- in the substituted group may be a C1 -C4 hydroxyalkyl , such as hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxyisopropyl, hydroxy-n-butyl, hydroxy-sec-butyl, hydroxyisobutyl or hydroxy-tert-butyl.
  • the C 3 -C 8 cycloalkyl in -N(C 3 -C 8 cycloalkyl)- in the substituted group may be a C 3 -C 6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • ring A" is C 3 -C 12 cycloalkylene, C 3 -C 12 cycloalkenylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S.
  • ring A" is a C5 - C6 monocyclic cycloalkylene, a C5 - C6 monocyclic cycloalkenylene, a 5-6-membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S, or a 7-8-membered bridged ring containing 1-2 heteroatoms selected from N, O and S.
  • Cycloheterocycloalkylene preferably C 5 -C 6 monocyclic cycloalkylene, C 5 -C 6 monocyclic cycloalkenylene, or 5-6 membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S.
  • ring A" is C3 - C12 cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S, such as C5 -C6 monocyclic cycloalkylene or 5-6 membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S, more such as piperidinylene, piperazinylene, cyclohexylene or cyclohexenylene.
  • ring B" is C3 - C12 cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, such as C5 -C6 monocyclic cycloalkylene or 5-6 membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, more such as piperidinylene, cyclohexylene or piperazinylene.
  • ring C" is a 3-12-membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S, such as a 5-6-membered monocyclic heterocycloalkylene group or a 7-11-membered spirocyclic heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S, more preferably a piperidinylene group, a piperazinylene group, a 2,7-diaza[3.5]nonanylene group, a 7-aza[3.5]nonanylene group, a 2-aza[3.5]nonanylene group, a 2,6-diaza[3,3]-hexylene group, a 2-aza[3,3]-hexylene group, a 3-aza[5,5]undecylene group or a 3,9-diaza[5,5]undecylene group.
  • X"" is -C(O)-, -O-(C 1 -C 6 alkylene), -S-(C 1 -C 6 alkylene) or -NH-(C 1 -C 6 alkylene), the C 1 -C 6 alkylene in the -O-(C 1 -C 6 alkylene), -S-(C 1 -C 6 alkylene) or -NH-(C 1 -C 6 alkylene) may be substituted by one or more Rx', wherein the Rx' is a C 1 -C 6 alkyl, or two Rx' on the same carbon atom are connected to the carbon atom to form a C 3 -C 8 cycloalkyl.
  • Rx' is a C 1 -C 6 alkyl, or two Rx' on the same carbon atom are connected to the carbon atom to form a C 3 -C 8 cycloalkyl.
  • La is -(CH 2 ) k'-
  • one or two methylene groups in La" are optionally substituted by -O-, -NH, or -N(Me)-
  • k' is 0, 1, 2, 3, 4, 5 or 6.
  • X'' is -C(O)-.
  • ring A" is C3 - C12 cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S, such as C5 -C6 monocyclic cycloalkylene or 5-6 membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O and S; more preferably piperidinylene, piperazinylene, cyclohexylene or cyclohexenylene;
  • Ring B is C3 - C12 cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, such as C5 -C6 monocyclic cycloalkylene or 5-6 membered monocyclic heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S; more preferably piperidinylene, cyclohexylene or piperazinylene;
  • Ring C" is a 3-12-membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S, for example a 5-6-membered monocyclic heterocycloalkylene group or a 7-11-membered spirocyclic heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S; more preferably a piperidinylene group, a piperazinylene group, a 2,7-diaza[3.5]nonylene group, a 7-aza[3.5]nonylene group, a 2-aza[3.5]nonylene group, a 2,6-diaza[3,3]-hexylene group, a 2-aza[3,3]-hexylene group, a 3-aza[5,5]undecylene group or a 3,9-diaza[5,5]undecylene group;
  • X"" is -C(O)-, -O-(C 1 -C 6 alkylene), -S-(C 1 -C 6 alkylene) or -NH-(C 1 -C 6 alkylene), wherein the C 1 -C 6 alkylene in -O-(C 1 -C 6 alkylene), -S-(C 1 -C 6 alkylene) or -NH-(C 1 -C 6 alkylene) may be substituted by one or more Rx', wherein Rx' is C 1 -C 6 alkyl, or two Rx' located on the same carbon atom are connected to the carbon atom to form a C 3 -C 8 cycloalkyl;
  • La is -(CH 2 ) k' , one or two methylene groups in La” are optionally replaced by -O-, -NH or -N(Me)-, and k' is 0, 1, 2, 3, 4, 5 or 6;
  • X'' is -C(O)-.
  • ring C" is a 5-6 membered monocyclic heterocycloalkylene or a 7-11 membered spirocyclic heterocycloalkylene containing 1-2 N heteroatoms, wherein the N atom is connected to X"', and the definitions of ring A", ring B", La", X"" and X"' are as described in any scheme.
  • ring A" is a C 5 -C 6 monocyclic cycloalkylene or a 5-6-membered monocyclic heterocycloalkylene containing 1-2 N;
  • Ring B is a C 5 -C 6 monocyclic cycloalkylene group or a 5-6-membered monocyclic heterocycloalkylene group containing 1-2 N heteroatoms;
  • Ring C", La", X"" and X"' are as defined in any of the previous schemes.
  • LB is LB-1:
  • Ring A" is Preferably The a side is connected to X””.
  • Ring B" is Preferably The b side is connected to X””.
  • La is -CH2- , -CH2CH2- , -CH2CH2CH2- , -CH2CH2CH2CH2- , -CH2CH2OCH2- , or -CH2OCH2CH2- , preferably * -CH2- , * -CH2CH2- , * -CH2CH2CH2- , * -CH2CH2CH2CH2- , * -CH2CH2OCH2- , or * -CH2OCH2CH2- , wherein the * side is connected to ring B " .
  • ring C" is Preferably The d side is connected to X''.
  • LB is
  • the E is a small molecule ligand of E3 ubiquitin ligase CRBN, VHL, XAIP or MDM2.
  • the E is E1:
  • each R 1a is independently halogen, optionally substituted C 1 -C 6 acyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted 3-12 membered heterocycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5-10 membered heteroaryl, -CN or -O(CH 2 ) x R 1a1 ;
  • R 1a is -O(CH 2 ) x R 1a1 ;
  • R 1b is unsubstituted isopropyl, -(CH 2 )C(O)OMe, or -(CH 2 ) 2 OH;
  • R 1c is a substituted C 1 -C 6 alkyl group
  • R 1d is hydrogen, optionally substituted C 1 -C 6 acyl, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
  • R 1a1 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted 3-12 membered heterocycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5-10 membered heteroaryl, -OR 1a2 , -N(R 1a3 )2, or -SR 1a2 ;
  • Each R 1a2 is independently hydrogen, optionally substituted C 1 -C 6 acyl, optionally substituted C 1 -C 6 alkyl, an oxygen protecting group or a sulfur protecting group;
  • Each R 1a3 is independently hydrogen, optionally substituted C 1 -C 6 acyl, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
  • n 1, 2, 3 or 4;
  • x is 0, 1, 2, 3, 4, 5 or 6, and when R 1b is isopropyl, R 1c is methyl, R 1c is hydrogen, and n is 1, R 1a is not methyl or hydroxymethyl.
  • the E1 is E1a, E1b or E1c:
  • R1 is as defined above.
  • the E is E2:
  • X 101 is a bond, -CH 2 -, -CHCF 3 -, -S(O) 2 -, -S(O)-, -P(O)R 100 -, -P(O)OR 100 -, -P(O)N(R 100 ) 2 , -C(O)-, -C(S)-, or
  • X 201 is C or Si
  • X 301 is -CH 2 -, -O-, -S-, -C(R 100 ) 2 - or -Si(R 100 ) 2 -;
  • R 101 is selected from hydrogen, deuterium, halogen, -CN, -OR 100 , -SR 100 , -S(O)R 100 , -S(O) 2 R 100 , -N(R 100 ) 2 , -P(O)(OR 100 ) 2 , -P(O)[N(R 100 ) 2 ](OR 100 ), -P(O)[N(R 100 ) 2 ] 2 , -Si(OH) 2 (R 100 )-, -Si(OH)(R 100 ) 2 -, -Si(R 100 ) 3 -, or optionally substituted C 1 -C 4 alkyl;
  • R 201 is selected from hydrogen, -R 601 , halogen, -CN, -NO 2 , -OR 100 , -SR 100 , -S(O)R 100 , -S(O) 2 R 100 , -N(R 100 ) 2 , -S(O) 2 N(R 100 ) 2 , -C(O)R 100 , -C(O)OR 100 , -C(O)N(R 100 ) 2 , -OC(O)R 100 , -OC(O)N(R 100 ) 2 , -NR 100 C(O)OR 100 , -NR 100 C(O)R 100 , -NR100C (O)N( R100 ) 2 , -OP(O)( R100 ) 2 , -OP(O)( OR100 ) 2 , -OP(O)( OR100 ) 2 , -OP(O)( OR100 )[N( R100 ) 2 ],
  • L 101 is a bond or a C 1 -C 4 alkylene group, in which one or two methylene groups are optionally replaced by -O-, -C(O)-, -C(S)-, -C(R 100 ) 2 -, -CH(R 100 )-, -C(F) 2 -, -N(R 100 )-, -S-, -S(O) 2 -, or -CH ⁇ CH;
  • Ring B is a 6-membered heteroaryl group containing 1-2 N atoms, a phenyl group, a 5-7-membered saturated or partially unsaturated C 3 -C 12 cycloalkyl group, a 5-7-membered saturated or partially unsaturated heterocycloalkyl group containing 1-2 atoms selected from N, O and S, or a 5-membered heteroaryl group containing 1-3 atoms selected from N, O and S;
  • R 301 is selected from hydrogen, halogen, -OR 100 , -SR 100 or -N(R 100 ) 2 ;
  • R 401 is hydrogen, -R 601 , -halogen, -CN, nitro, -OR 100 , -SR 100 , -N(R 100 ) 2 , -S(O)R 100 , -S(O) 2 R 100 , -N(R 100 ) 2 , -S(O) 2 N(R 100 ) 2 , -C(O)R 100 , -C(O)OR 100 , -C(O)N(R 100 ) 2 , -OC(O)R 100 , -OC(O)N(R 100 ) 2 , -NR 100 C(O)OR 100 , -NR 100 C(O)R 100 , -NR 100 C(O)N(R 100 ) 2 , or -NR 100 S(O) 2R100 ;
  • R 501 is hydrogen, -CN or C 1 -C 4 alkyl
  • R 601 is an optionally substituted C 1 -C 6 alkyl group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocycloalkyl group containing 1-2 heteroatoms selected from N, O or S, or a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S;
  • R 100 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, phenyl, a saturated or partially unsaturated 4-7 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S, a 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, or two R 100 attached to the same N atom together with the N atom to which they are attached form a saturated or partially unsaturated 5-6 membered heteroaryl containing 0-3 heteroatoms selected from N, O and S in addition to the N atom;
  • n 0, 1, 2, 3 or 4.
  • the E is E3:
  • X 101' is a bond, -CH 2 -, -CHCF 3 -, -S(O) 2 -, -S(O)-, -P(O)R 100' -, -P(O)OR 100' -, -P(O)N(R 100' ) 2 , -C(O)-, -C(S)-, or
  • X 201' is C, N or Si
  • X 301' is -CH 2 -, -O-, -S-, -C(R 100' ) 2 - or -Si(R 100' ) 2 -;
  • R 101' is hydrogen, deuterium, halogen, -CN, -OR 100' , -SR 100' , -S(O)R 100' , -S(O) 2 R 100' , -N(R 100' ) 2 , -P(O)(OR 100' ) 2 , -P(O)[N(R 100' ) 2 ](OR 100' ), -P(O)[N(R 100' ) 2 ] 2 , -Si(OH) 2 (R 100' ), -Si(OH)(R 100' ) 2 , -Si(R 100' ) 3 , or optionally substituted C 1 -C 4 alkyl;
  • R 201' is selected from hydrogen, -R 601' , halogen, -CN, -NO 2 , -OR 100' , -SR 100' , -S(O)R 100' , -S(O) 2 R 100' , -N(R 100' ) 2 , -S(O) 2 NR 100' , -C(O)R 100' , -C(O)OR 100' , -C(O)N(R 100' ) 2 , -OC(O)R 100' , -OC(O)N(R 100' ) 2 , -NR 100' C(O)OR 100' , -NR 100' C(O)R 100' , -NR 100' C(O)N(R 100' ) 2 , -OP(O)(R 100' ) 2 , -OP(O)(OR 100' ) 2 , -OP(O)(OR 100' ) [N(R 100'
  • Ring B' is a 6-membered heteroaryl group containing 1-2 N atoms, a phenyl group, a saturated or partially unsaturated C 5 -C 7 cycloalkyl group, a saturated or partially unsaturated 5-7-membered heterocycloalkyl group containing 1-2 heteroatoms selected from N, O and S, or a 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S;
  • R 301' and R 401' are independently hydrogen, -R 601' , halogen, -CN, -NO 2 , -OR 100' , -SR 100' , -S(O)R 100' , -S(O) 2 R 100' , -N(R 100' ) 2 , -S(O) 2 NR 100' , -C(O)R 100' , -C(O)OR 100' , -C(O)N(R 100' ) 2 , -OC(O)R 100' , -OC(O)N(R 100' ) 2 , -NR 100' C(O)OR 100' , -NR 100' C(O)R 100' , -NR 100' C(O)N(R 100' ) 2 or -NR 100' S(O) 2 R 100' ;
  • R 501' is hydrogen, -CN or C 1 -C 4 alkyl
  • R 601′ is an optionally substituted C 1 -C 6 alkyl group, a phenyl group, a saturated or partially unsaturated 4-7 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N, O and S, or a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S;
  • R 100' is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, phenyl, a saturated or partially unsaturated 4-7 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S, a 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, or two R 100' attached to the same N atom together with the N atom to which they are attached form a saturated or partially unsaturated 5-6 membered heteroaryl containing 0-3 heteroatoms selected from N, O and S in addition to the N atom;
  • P" is 0 or 1
  • n'' 0, 1 or 2;
  • n'' is 0, 1, 2, 3 or 4.
  • the E is E4:
  • X 101 is a bond, -CH 2 -, -CHCF 3 -, -S(O) 2 -, -S(O)-, -P(O)R 100 -, -P(O)OR 100 -, -P(O)N(R 100 ) 2 , -C(O)-, -C(S)-, or
  • X 201 is C, N or Si
  • X 301 is -CH 2 -, -O-, -S-, -C(R 100 ) 2 - or -Si(R 100 ) 2 -;
  • R 101 is selected from hydrogen, deuterium, halogen, -CN, -OR 100 , -SR 100 , -S(O)R 100 , -S(O) 2 R 100 , -N(R 100 ) 2 , -P(O)(OR 100 ) 2 , -P(O)[N(R 100 ) 2 ](OR 100 ), -P(O)[N(R 100 ) 2 ] 2 , -Si(OH) 2 (R 100 )-, -Si(OH)(R 100 ) 2 -, -Si(R 100 ) 3 -, or optionally substituted C 1 -C 4 alkyl;
  • R 201 is selected from hydrogen, -R 601 , halogen, -CN, -NO 2 , -OR 100 , -SR 100 , -S(O)R 100 , -S(O) 2 R 100 , -N(R 100 ) 2 , -S(O) 2 NR 100 , -C(O)R 100 , -C(O)OR 100 , -C(O)N(R 100 ) 2 , -OC(O)R 100 , -OC(O)N(R 100 ) 2 , -NR 100 C(O)OR 100 , -NR 100 C(O)R 100 , -NR 100 C(O)N(R 100 ) 2 , -OP(O)(R 100 ) 2 , -OP(O)(OR 100 ) 2 100 ) 2 , -OP(O)(OR 100 ) 2 100 ) 2 , -OP(O)(OR 100 )[N(R 100 )
  • R 601 is an optionally substituted C 1 -C 6 alkyl group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocycloalkyl group containing 1-2 heteroatoms selected from N, O or S, or a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S;
  • R 100 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, phenyl, 4-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, or two R 100 together with the N atom to which they are attached form a group containing 0-3 heteroatoms selected from N, O or S in addition to the attached N atom;
  • Ring E, Ring F and Ring G are independently 6-membered heteroaryl containing 1-2 N atoms, phenyl, 5-7-membered saturated or partially unsaturated cycloalkyl, 5-7-membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms selected from N, O, S, or 1-3 heteroatoms selected from A 5-membered heteroaryl group selected from N, O, and S heteroatoms; wherein among ring E, ring F, and ring G, ring E and ring F may share one atom to form a spiro ring or share two or more atoms to form a fused ring or a bridged ring, and ring F and ring G may share one atom to form a spiro ring or share two or more atoms to form a fused ring or a bridged ring;
  • m" is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
  • E is E5:
  • Each of X 101 , X 601 and X 701 is independently a bond, -CH 2 -, -CHCF 3 -, -S(O) 2 -, -S(O)-, -P(O)R 100 -, -P(O)OR 100 -, -P(O)N(R 100 ) 2 , -C(O)-, -C(S)-, or
  • Each of X 301 and X 501 is independently a bond, -C(R 100 ) 2 -, -NR 100 -, -O-, -S-, or -Si(R 100 ) 2 -;
  • Each R 100 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, phenyl, saturated or oligomeric residues containing 1-2 heteroatoms selected from N, O and S. and a partially unsaturated 4-7 membered heterocycloalkyl, a 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, or two R 100 attached to the same N atom together with the N atom to which they are attached form a saturated or partially unsaturated 5-6 membered heteroaryl containing 0-3 heteroatoms selected from N, O and S in addition to the N atom;
  • Each R 601 is independently an optionally substituted C 1 -C 6 alkyl group, a phenyl group, a saturated or partially unsaturated 4-7 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N, O or S, or a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S;
  • each R 701 is independently hydrogen, deuterium, halogen, -CN, -OR 100 , -SR 100 , -S(O)R 100 , -S(O) 2 R 100 , -N(R 100 ) 2 , -P(O)(OR 100 ) 2 , -P(O)[N(R 100 ) 2 ](OR 100 ), -P(O)[N(R 100 ) 2 ] 2 , -Si(OH) 2 (R 100 )-, -Si(OH)(R 100 ) 2 -, -Si(R 100 ) 3 -, or optionally substituted C1-C4 alkyl; or
  • R 701 and X 101 , R 701 and X 301 may also form together with the atoms to which they are attached a saturated or partially unsaturated 5-7 membered carbon ring or a heterocyclic ring containing 1-3 heteroatoms selected from boron, N, O, Si and S;
  • R 701 on the same carbon atom together with the atom to which they are attached form a 3-6 membered carbocyclic ring or a 4-7 membered heterocyclic ring containing 1-2 heteroatoms selected from boron, N, O, Si and S;
  • R 701 on adjacent carbon atoms together with the atoms to which they are attached form a saturated or partially unsaturated 3-7 membered carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms selected from boron, N, O, Si and S, or a saturated or partially unsaturated 7-13 membered bridged heterocyclic ring or spiroheterocyclic ring containing 1-3 heteroatoms selected from boron, N, O, Si and S;
  • Ring D is independently a 6-membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, a phenyl group, a saturated or partially unsaturated 5-7-membered cycloalkyl group, a saturated or partially unsaturated 5-7-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O and S, or a 5-membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S;
  • n 0, 1, 2, 3 or 4;
  • q is 0, 1, 2, 3, or 4.
  • E is E6, E6a, E6b, E6c, E6d, E6e, E6f, E6g, E6h or E6i:
  • Y is a bond, Y 1 , O, NH, NR 2 , C(O)O, C(O)NR 2 ', Y 1 -O, Y 1 -NH, Y 1 -NR 2 , Y 1 -C(O), Y1-C(O)O, Y 1 -OC(O), Y 1 -C(O)NR 2 ′ or Y 1 -NR 2 ′C(O), wherein Y 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;
  • X is C(O) or C(R 3 ) 2 ;
  • Each R 1 is independently halogen, nitro, NH 2 , OH, C(O)OH, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl or C(O)-3-8 membered heterocycloalkyl, and R 2 may be optionally substituted by one or more halogen, N(R a ) 2 , NHC(O)R a , NHC(O)OR a , OR b , C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl, wherein the C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl may be optionally substituted by one or more halogen, NH 2 , CN, nitro, OH, C(O)OH, C 1 -C 6 alkyl, C
  • R 2 ' is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl or 3-8 membered heterocycloalkyl, and when R 2 'is not H, it may be optionally substituted by one or more halogen, N(R a ) 2 , NHC(O)R a , NHC(O)OR a , OR b , C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, wherein said C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl may be optionally substituted by another one or more halogen, NH 2 , CN, nitro, OH, C(O)OH, C 1 -C 6 alkyl, C 1 -C 6
  • Each R 3 is independently H or C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is optionally substituted with C 6 -C 10 aryl or 5-10 membered heteroaryl;
  • Each R 3 ′ is independently C 1 -C 3 alkyl
  • Each R 4 is independently H or C 1 -C 3 alkyl; or two R 4 together with the carbon atom to which they are attached form C(O), C 3 -C 6 cycloalkyl, or a 4-membered, 5-membered or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O;
  • R 5 is H, C 1 -C 3 alkyl, F or Cl;
  • Each Ra is independently H or C1 - C6 alkyl
  • R b is H or tosyl
  • t is 0 or 1;
  • n 0, 1, 2, or 3;
  • n 0, 1 or 2.
  • Ring A, X, X 1 , X 2 , Y, R 1 , R 3 , R 3′ , R 4 , R 5 , t, m and n are as defined in WO 2017/007612 and US 2018/0134684, and are incorporated herein by reference in their entirety.
  • E is E7, E7b, E7c, E7d or E7e:
  • W is CH 2 , CR a R b , C(S), C(O) or SO 2 ;
  • X is H 2 , CH 2 , O or S
  • Y is NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocycloalkyl, O or S;
  • Z is CH 2 , O or S, and in E7c, Z cannot be CH 2 at the same time;
  • G and G' are independently hydrogen, C 1 -C 6 alkyl, OH, -CH 2 -heterocycloalkyl optionally substituted by R', or -CH 2 -phenyl optionally substituted by R';
  • Q 1 , Q 2 , Q 3 , and Q 4 are independently carbon, nitrogen, or nitrogen oxide;
  • A is hydrogen, C 1 -C 6 alkyl, cycloalkyl or halogen
  • R, Ra and Rb are independently hydrogen, hydroxyl, halogen, -NH2 , -N( C1 - C6 alkyl) 1-2 , C1 - C6 alkyl, C1- C6 alkoxy, C1 -C6 haloalkyl , -CONR'R", -OR', -NR'R", -SR ', -SO2R', -SO2NR'R” , -CR'R", -CR'NR'R", aryl, heteroaryl, C3- C8 cycloalkyl, 3-8 membered heterocycloalkyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -Cl, -F, -Br, -I, -CF3 , -CN, -NR'SO2 NR′R′′, —NR′C(O)NR′R′′, —C(O
  • R' and R" are independently a bond, hydrogen, C1 - C6 alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl;
  • n′′ is an integer from 1 to 4.
  • ----- is a bond, which may be an R stereoisomer, an S stereoisomer or a non-stereoisomer.
  • E is E7a:
  • W is CH 2 , CR a R b , C(S), C(O) or SO 2 ;
  • X is H 2 , CH 2 , O or S
  • Z is H 2 , CH 2 , O or S
  • G is selected from hydrogen, C 1 -C 6 alkyl, OH, -CH 2 -heterocycloalkyl optionally substituted by R′, -CH 2 -phenyl optionally substituted by R′;
  • Q 1 , Q 2 , Q 3 , and Q 4 are each independently carbon, nitrogen, or nitrogen oxide;
  • A is hydrogen, C 1 -C 6 alkyl, cycloalkyl or halogen
  • R is independently selected from hydrogen, hydroxy, halogen, -NH2 , -N( C1 - C6 alkyl) 1-2 , C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl , -CONR'R", -OR', -NR'R ", -SR', -SO2R', -SO2NR'R", -CR'R", -CR'NR'R", aryl, heteroaryl, C3- C8 cycloalkyl, 3-8 membered heterocycloalkyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -Cl, -F, -Br, -I, -CF3 , -CN, -NR'SO2 NR′R′′, —NR′C(O)NR′R′′, —C(O)NR′C(
  • R' and R" are each independently selected from a bond, hydrogen, C1 - C6 alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl;
  • n′′ is an integer from 1 to 4.
  • ----- is a bond, which may be an R stereoisomer, an S stereoisomer or a non-stereoisomer.
  • W is CH2 or C(O).
  • X is O or S.
  • X is O.
  • Z is O.
  • G is hydrogen
  • Q 1 , Q 2 , Q 3 , and Q 4 are each independently carbon or nitrogen.
  • Q 1 is carbon
  • Q 2 is carbon
  • Q 3 is carbon
  • Q 4 is carbon
  • Q 1 , Q 2 , Q 3 , and Q 4 are carbon.
  • A is hydrogen
  • R is hydrogen
  • said E is E7a';
  • said E is E7a"
  • E is E7a-1:
  • Q 1 , Q 2 , Q 3 and Q 4 are each independently carbon or nitrogen;
  • W is C(O) or CH 2 ;
  • A is hydrogen, C 1 -C 6 alkyl or halogen (for example, A is hydrogen);
  • R is selected from hydrogen, hydroxy, halogen, -NH 2 , -N(C 1 -C 6 alkyl) 1-2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl;
  • n′′ is 1, 2, 3 or 4;
  • ----- is a bond, which may be an R stereoisomer, an S stereoisomer or a non-stereoisomer.
  • E is E7a-2:
  • W is CH2 or C(O);
  • A is hydrogen, methyl, Cl or F (e.g. A is hydrogen);
  • R is each independently selected from hydrogen, hydroxy, NH 2 , C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • n′′ is 1, 2, 3 or 4;
  • ----- is a bond, which may be an R stereoisomer, an S stereoisomer or a non-stereoisomer.
  • the carbon atom to which the ----- bond is attached has chirality, it is in the R configuration, the S configuration, or a mixture thereof (eg, a mixture of 40%-60% R configuration and 60%-40% S configuration).
  • E is any of the following structures:
  • the carbon atoms marked with * are in R configuration, S configuration or a mixture thereof (eg, a mixture of 40%-60% R configuration and 60%-40% S configuration).
  • E is the following structure:
  • the carbon atoms marked with * are in R configuration, S configuration or a mixture thereof (eg, a mixture of 40%-60% R configuration and 60%-40% S configuration).
  • E is the following structure:
  • the carbon atoms marked with * are in R configuration, S configuration or a mixture thereof (eg, a mixture of 40%-60% R configuration and 60%-40% S configuration).
  • E is any of the following structures:
  • E is E8, E8a, E8b, E8c, E8d, E8e, E8f, E8g, E8h, E8i, E8j, E8k, E8l, E8m, E8n, E8o, E8p, E8q, E8s, E8t, E8u, E8v, E8w, E8x, E8y, E8z, E8aa, E8bb or E8cc:
  • W is independently selected from CH 2 , CHR, C(O) or SO 2 ;
  • Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are independently carbon, N, or N substituted by R', or nitrogen oxide;
  • R 1 is absent, or is hydrogen, hydroxyl, cyano, C 1 -C 3 alkyl, or C(O);
  • R 2 is absent, or is hydrogen, hydroxyl, cyano, C 1 -C 3 alkyl, CHF 2 , CF 3 , CHO or C(O)NH 2 ;
  • R3 is hydrogen, alkyl (e.g., C1 - C6 alkyl or C1 - C3 alkyl), optionally substituted alkyl (e.g., C1 - C6 alkyl or C1 - C3 alkyl), alkoxy (e.g., C1 - C6 alkoxy or C1 - C3 alkoxy), or optionally substituted alkoxy (e.g., C1 - C6 alkoxy or C1 - C3 alkoxy);
  • R4 is selected from hydrogen, alkyl or optionally substituted alkyl
  • R 5 or R 6 is independently hydrogen, halogen, C(O)R', cyano, hydroxyl or CF 3 ;
  • X is carbon, nitrogen or C(O);
  • X1 is carbon, nitrogen or C(O);
  • R' is hydrogen, halogen, amine, alkyl (e.g., C 1 -C 3 alkyl), optionally substituted alkyl (e.g., C 1 -C 3 alkyl), alkoxy (e.g., C 1 -C 3 alkoxy), optionally substituted alkoxy (e.g., C 1 -C 3 alkoxy), NR 2 R 3 , C(O)OR 2 or optionally substituted phenyl;
  • R is H, OH, lower alkyl, lower alkoxy, cyano, halogenated lower alkoxy or halogenated lower alkyl;
  • n 0, 1, 2, 3 or 4;
  • a single bond or a double bond
  • E is E9a, E9b, E9c, E9d, E9e, E9f, E9g, E9h, E9i, E9j, E9k, E9l, E9m, E9n, E9o, E9p, E9q, E9r or E9s:
  • W is independently selected from CH 2 , CHR, C ⁇ O, SO 2 , NH and N-alkyl;
  • R 1 is selected from H, CN, C 1 -C 3 alkyl
  • R2 is H or C1 - C3 alkyl
  • R4 is methyl or ethyl
  • R5 is H or halogen
  • R6 is H or halogen
  • R is H
  • R’ is H
  • Q 1 and Q 2 are independently CH, CH 2 , CH(C 1 -C 3 alkyl), N, NH or N(C 1 -C 3 alkyl);
  • E is E10, E10a or E10b:
  • X A is C(O) or C(R 3A ) 2 ;
  • Z is NR 3A or C(R 3A ) 2 ;
  • Each R 1A is independently halogen, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • Each R 3A is independently hydrogen or C 1 -C 3 alkyl
  • R 3' is independently C 1 -C 3 alkyl
  • Each R 4A is independently hydrogen or C 1 -C 3 alkyl, or two R 4A together with the carbon atom to which they are attached form C(O), C 3 -C 6 cycloalkyl, or together form a 3-membered, 4-membered, 5-membered or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O;
  • R 5A is selected from hydrogen, C 1 -C 3 alkyl or halogen
  • Each R 6A is independently hydrogen or C 1 -C 3 alkyl, or two R 6A together with the carbon atom to which they are attached form C(O), C 3 -C 6 cycloalkyl, or together form a 3-membered, 4-membered, 5-membered or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O;
  • n 0, 1, 2 or 3;
  • n 0, 1 or 2;
  • a1 is 0 or 1.
  • E is E11:
  • Each R 1A is independently halogen, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • Each R 3A is independently hydrogen or C 1 -C 3 alkyl
  • R 3' is independently C 1 -C 3 alkyl
  • R 4A is hydrogen or C 1 -C 3 alkyl; or two R 4A together with the carbon atoms to which they are attached form C(O), C 3 -C 6 cycloalkyl, or together form a 4-membered, 5-membered or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O;
  • n 0, 1, 2 or 3;
  • n 0, 1 or 2;
  • a1 is 0 or 1.
  • E is E12:
  • Each R 2' is independently halogen, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • Each R 4' is independently halogen, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • Each R 5' is independently halogen, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • n1 0, 1, 2, 3, 4, 5 or 6;
  • n2 is 0, 1, 2, 3 or 4;
  • n3 0, 1 or 2.
  • E is E13:
  • R 3A is hydrogen or C1-C3 alkyl
  • Each R 3' is a C 1 -C 3 alkyl group
  • Each R 6' is independently halogen, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • n1 0, 1, 2, 3, 4 or 5;
  • n1 0, 1, 2, 3, 4 or 5.
  • E is E14, E14a, E14b, E14c, E14d or E14e:
  • Ar is aryl, cycloalkyl, heterocycloalkyl or heteroaryl
  • R', R", R'" are independently H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted ether, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylated aryl, or substituted or unsubstituted amine; r is an integer from 1 to 6;
  • R 1 , R 2 , and R 3 are independently H, halogen, hydroxy, azide, alkoxy, thiol, imino, amino, phosphonate, phosphate, carbonyl, carboxyl, cyano, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, substituted or unsubstituted amine, substituted or unsubstituted amide, nitro, ester, morpholino, dioxolane, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstitute
  • R 1 and R 2 combine to form a 5-7 membered heterocyclic ring, and when R 1 and R 2 combine to form a 5-7 membered heterocyclic ring, Ar and the 5-7 membered heterocyclic ring do not form a fused ring, but are substituents of the 5-7 membered heterocyclic ring;
  • R 4 and R 5 are independently hydrogen, halogen, hydroxyl, azide, ether, alkoxy, thiol, alkylthio, sulfonyl, sulfonylamide, ketone, aldehyde, ester, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted enone, unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, heterocyclyl, or a combination thereof;
  • R8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, or a combination thereof;
  • x 0, 1, or 2;
  • y is an integer from 1 to 6.
  • E is E15, E15a, E15b, E15c, E15d, E15e, E15f, E15g or E15h:
  • E15a, E15b, E15c, E15d, E15e, E15f, E15g and E15h are E15, E15a, E15b, E15c, E15d, E15e, E15f, E15g and E15h:
  • Ring B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • L 101 is a bond or a C 1 -C 6 alkyl group
  • A is C, S, substituted or unsubstituted C 1 -C 8 alkyl or a combination thereof;
  • G 100 is C, S, N, substituted or unsubstituted C 1 -C 8 alkyl or a combination thereof;
  • R101 , R201 and R301 are hydrogen, halogen, hydroxy, azide, alkoxy, mercapto, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, cyano, silyl, ether, alkylthio, sulfonyl, sulfonylamino, ketone, aldehyde, substituted or unsubstituted amine, substituted or unsubstituted amide, nitro, ester, morpholino, dioxolane, substituted or unsubstituted alkyl, substituted or unsubstituted alkyl halide, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl; substituted or unsubsti
  • R 401 and R 501 are independently hydrogen, halogen, hydroxy, azide, ether, alkoxy, thiol, alkylthio, sulfonyl, sulfonylamino, ketone, aldehyde, ester, substituted or unsubstituted alkyl, substituted or unsubstituted alkyl halide, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, heterocycloalkyl, and combinations thereof;
  • R 601 and R 701 are independently oxo, hydrogen, C 1 -C 8 alkyl, or R 601 and R 701 are combined together to form oxo;
  • R 801 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyl halide, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkaryl, and combinations thereof;
  • x 0, 1 or 2;
  • E is E16, E16a or E16b:
  • W 101 is CR 601 R 701 , C(O), C(S), C ⁇ CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH or P(O)NH 2 ;
  • W 201 is CR 801 R 901 , C(O), C(S), C ⁇ CH 2 , SO 2 , S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH or P(O)NH 2 ;
  • X 100 is independently selected from NH, NR 301 , CH 2 , CHR 301 , C(R 301 ) 2 , O or S;
  • n 0, 1, 2 or 3;
  • n" is 0, 1, 2 or 3; when When it is a double bond, n" is 0, 1 or 2;
  • R 101 is selected from:
  • R 201 is alkyl, hydrogen, heteroalkyl, aryl, heteroaryl or heterocycloalkyl
  • R 101 and R 201 combine to form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl or heteroaryl group, wherein the heterocycloalkyl or heteroaryl group is optionally substituted with one or more substituents selected from R 501 and R 120 ;
  • R 101* is selected from:
  • R 301 is selected from the group consisting of: alkyl, -C(O)H, C(O)OH, -C(O)alkyl, -C(O)Oalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heteroalkyl;
  • R 401 is selected from alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azido, amino, cyano, -NH(alkyl), -N(alkyl) 2 , -NHS(O) 2 (alkyl), -N(alkyl)SO 2alkyl , -NHSO 2 (aryl, heteroaryl or heterocycloalkyl), -N(alkyl)SO 2 (aryl, heteroaryl or heterocycloalkyl), -NHSO 2 (alkenyl), -N(alkyl)SO 2 (alkenyl), -NHSO 2 (alkynyl), -N(alkyl)SO 2 (alkynyl) or haloalkyl, aryl, heteroaryl, heteroalkyl and cycloalkyl;
  • R 501 and R 140 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azido, amino, cyano, -NH(alkyl), -N(alkyl) 2 , -NHS(O) 2 (alkyl), -N(alkyl)SO 2 (alkyl), -NHSO 2 (aryl, heteroaryl or heterocycloalkyl), -N(alkyl)SO 2 (aryl), heteroaryl or heterocycloalkyl), -NHSO 2 (alkenyl), -N(alkyl)SO 2 (alkenyl), -NHSO 2 (alkynyl), -N(alkyl)SO 2 (alkynyl), or haloalkyl, aryl, heteroaryl, heteroalkyl and cycloalkyl;
  • R 501 is independently selected from C(O)R 401 , cyano, aryl, aryloxy, heterocycloalkyl, heteroaryl, arylalkyl, alkoxy, hydroxy, O-aralkyl or cycloalkyl;
  • R 601 , R 701 , R 801 , R 901 , R 1001 , or R 110 are independently selected from hydrogen, alkyl, heteroalkyl, hydroxy, alkoxy, amine, -NH(alkyl) and -N(alkyl) 2 ;
  • R 601 and R 701 together with the carbon atoms to which they are attached form a 3-, 4-, 5- or 6-membered spirocarbocyclic ring, or a 4-, 5- or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;
  • R 801 and R 901 together with the carbon atoms to which they are attached form a 3-, 4-, 5- or 6-membered spirocarbocyclic ring; or form a 4-, 5- or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;
  • R 1001 and R 110 together with the carbon atoms to which they are attached form a 3-, 4-, 5- or 6-membered spirocarbocyclic ring; or form a 4-, 5- or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;
  • R 601 and R 801 together form one or two carbon bridged rings
  • R 601 and R 1001 together form 1 or 2 carbon bridged rings
  • R 801 and R 1001 together form 1 or 2 carbon bridged rings
  • R 601 and R 140 together form a 3, 4, 5 or 6 carbon-fused ring
  • R 140 and R 1001 together form a 3, 4, 5 or 6 carbon-fused ring
  • R 801 and R 140 together form 1 or 2 carbon bridged rings
  • R 401 and R 140 together form a 3, 4, 5 or 6 carbon fused ring, wherein said R 501 is located on the carbon alpha to R 140 , or together form 1, 2, 3 or 4 carbon bridged rings, wherein said R 501 is not located on the carbon alpha to R 140 ;
  • R 120 is L 100 ;
  • R 170 is selected from:
  • Y 100 is selected from N, CH or CR 101 ; wherein 0, 1, 2 or 3 Y 100 are N;
  • R 101 is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, hydroxy, aryl, heteroaryl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -C(O)Oalkyl, -C(O)OH, NO 2 , F, Cl, Br, I, CF 3 , NH 2 , NH(alkyl), N(alkyl) 2 , or heteroalkyl.
  • E is E17, E17a, E17b or E17c:
  • W 1 is CR 6 R 7 , C ⁇ O, C ⁇ S, C ⁇ CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH or P(O)H 2 ;
  • W 2 is CR 8 R 9 , C ⁇ O, C ⁇ S, C ⁇ CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH or P(O)H 2 ;
  • X, X 1 are independently selected from NH, NR 3 , CH 2 , CHR 3 , C(R 3 ) 2 , O or S;
  • n 0, 1, 2 or 3;
  • n" is 0, 1, 2 or 3; When it is a double bond, n" is 0, 1 or 2;
  • R1 is or R 1* , wherein X is O or N, and when X is O, R 2 is absent;
  • Ring A is phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl, and the phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted by R 12 ;
  • Ring B is absent, phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted by R 5 or R 12 ;
  • R2 is alkyl, H, aliphatic, heteroaliphatic, aryl, heteroaryl or heterocycloalkyl;
  • R 1* is an arbitrarily substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylamino, alkoxy, ester, sulfonyl or acylamino group;
  • R3 is alkyl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, alkenyl or alkynyl;
  • R 4 is alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azido, amino, -NHalkyl, -N(alkyl) 2 , -NHSO 2 Alkyl, -N(alkyl) SO2alkyl , -NHSO2aryl , -N(alkyl) SO2aryl , -NHSO2alkenyl , -N(alkyl) SO2alkenyl , -NHSO2alkynyl , -N(alkyl) SO2alkynyl , or halogenated alkane;
  • R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are independently selected from hydrogen, alkyl, aliphatic, heteroaliphatic, hydroxy, alkoxy, amine, -NH(aliphatic, including alkyl) and -N(aliphatic, including alkyl) 2 ;
  • R 6 , R 7 together with the carbon atoms to which they are bound form a 3-, 4-, 5- or 6-membered spirocarbocyclic ring, or a 4-, 5- or 6-membered spiroheterocyclic ring, wherein the heteroatom is 1 or 2 N or O;
  • R 8 , R 9 together with the carbon atoms to which they are bound form a 3-, 4-, 5- or 6-membered spirocarbocyclic ring, or a 4-, 5- or 6-membered spiroheterocyclic ring, wherein the heteroatom is 1 or 2 N or O;
  • R 10 , R 11 together with the carbon atoms to which they are bound form a 3-, 4-, 5- or 6-membered spirocarbocyclic ring, or a 4-, 5- or 6-membered spiroheterocyclic ring, wherein the heteroatom is 1 or 2 N or O;
  • R 6 and R 8 form 1 or 2 carbon bridge rings
  • R 6 and R 10 form 1 or 2 carbon bridged rings
  • R 8 and R 10 form 1 or 2 carbon bridged rings
  • R 14 and R 6 form a 3, 4, 5 or 6 carbon-fused ring
  • R 14 and R 10 form a 3, 4, 5 or 6 carbon-condensed ring
  • R 14 and R 8 form 1 or 2 carbon bridged rings
  • R 14 and R 4 form a 3, 4, 5 or 6 carbon fused ring, and R 4 is on the carbon alpha to which R 14 is attached, or form a 1, 2, 3 or 4 carbon bridged ring, and R 4 is not on the carbon alpha to which R 14 is attached;
  • R 12 is a chain connecting the target ligand
  • R 5 and R 14 are independently selected from hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azido, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl) 2 , -NHSO 2 (aliphatic, including alkyl), -N(aliphatic, including alkyl)SO 2 alkyl, -NHSO 2 (aryl, heteroaryl or heterocyclic), C(O)R 4 , -N(alkyl)SO 2 (aryl, heteroaryl or heterocyclic), -NHSO 2 alkenyl, -N(alkyl)SO 2 alkenyl, -NHSO 2 alkynyl, -N(alkyl)SO 2 alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl and carbocyclic;
  • each R 5 may be optionally replaced by one or more selected from alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azido, amino, -NH alkyl, -N(alkyl) 2 , aryl, heterocycloalkyl, heteroaryl, haloalkyl, and cycloalkyl;
  • R 1 , R 4 , R 10 , R 11 , R 14 , R 16 , W 1 , W 2 , X, and n are as defined in WO2018/237026, the entire contents of which are incorporated herein by reference.
  • E is E18, E18a, E18b, E18c, E18d, E18e, E18f, E18g, E18h, E18i, E18g, E18k, E18l or E18m:
  • X1 is -C(R) 2 , -O-, -NR-, -CF2- , -C(O)-, -C(S)- or
  • X2 and X3 are independently -CH2- , -C(O)-, -C(S)-, -C(R) 2C (O)- or
  • Z1 and Z2 are independently a carbon atom or a nitrogen atom
  • Ring A x is selected from phenyl, 4-6 membered saturated or partially unsaturated cycloalkyl or heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S;
  • Rx is hydrogen, deuterium , -Rz, halogen, -CN, -NO2 , -OR, -SR, -N(R) 2 , -S(O)R, -S(O) 2R , -S(O) 2N (R) 2 , -CF(R) 2- , -CF2R- , -CF3- , -C(R) 2 (OR)-, -C(R) 2 [N(R) 2 ]-, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)N(R) 2 , -C(S) NR2 , -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) 2 , -NRS(O) 2R , -C(R) 2
  • R x together with the atoms to which they are attached form an optionally substituted 5-8 membered partially unsaturated or aryl-fused heterocycloalkyl containing 0-2 heteroatoms selected from N, O or S;
  • Each R is independently hydrogen, or optionally substituted C 1 -C 6 alkyl, phenyl, 4-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, 5-6 membered heteroaryl ring containing 1-4 heteroatoms selected from N, O or S; or
  • R y is hydrogen or
  • Ring Bx is phenyl, 4-10 membered saturated or partially unsaturated monocyclic or bicyclic cycloalkyl, or heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, or 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, and the ring Bx is further optionally substituted by 1-2 oxo groups;
  • each R w is independently hydrogen, deuterated, R z , halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -S(O)R, -S(O) 2 R, -S(O) 2 N(R) 2 , -CF(R) 2 -, -CF 2 R-, -CF 3 -, -C(R) 2 (OR)-, -C(R) 2 [N(R) 2 ]-, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)N(R) 2 , -C(S)NR 2 , -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) 2 , -NRS(O) 2 R, -C(R) 2 N
  • Each R z is independently C 1 -C 6 alkyl, phenyl, 4-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S, 5-6 membered heteroaryl ring containing 1-4 heteroatoms selected from N, O and S;
  • x 0, 1, 2, 3, or 4;
  • y is 0, 1, or 2;
  • w 0, 1, 2, 3, or 4.
  • E is E19, E19a, E19b, E19c, E19d, E19e, E19f, E19g, E19h or E19i:
  • R5 is H, methyl or F
  • R 16a , R 16b , R 16c and R 16d are independently H, halogen or C 1 -C 4 alkyl.
  • E19, E19a, E19b, E19c, E19d, E19e, E19f, E19g, E19h and E19i A 1 , A 2 , A 3 , Z, G and R 5 are as defined and described in WO 2017/176958 (which is incorporated herein by reference in its entirety).
  • E is E20, E20a, E20b, E20c, E20d, E20e or E20f:
  • L 1 is selected from: a bond
  • X 1 , X 2 , X 3 and X 4 are independently selected from nitrogen or CR 4 , and at most two of X 1 , X 2 , X 3 and X 4 are simultaneously selected from nitrogen;
  • Z2 and Z3 are selected from -CH2- or -C(O)- and at least one of Z1 and Z2 is selected from -C(O)-;
  • o is selected from 0, 1, 2, 3 or 4;
  • Each R 4 is independently hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl;
  • Each R 5 is independently hydrogen, C 1 -C 6 alkyl or -C(O)-alkyl;
  • Each R 8 is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; or two R 8 together with the atoms to which they are attached form a cyclopropyl group.
  • E is E21:
  • X" is C or N
  • Y" is C, N, O or S
  • Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are independently CR 3 ′′ or N;
  • R 3 is independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl (e.g. morpholinyl, e.g.
  • n 1, 2 or 3;
  • R 1 is independently hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, -O (C 1 -C 6 alkyl), wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1-3 groups independently selected from hydroxyl, halogen, cyano and amino;
  • R 2 ′′ is hydrogen, deuterium, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, wherein the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl are optionally substituted with 1 to 3 groups independently selected from hydroxy, halogen, cyano and amino.
  • one or two of Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 in E21 are N, and the others are independently CR 3 ”.
  • Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 in E21 are independently CR 3 ”.
  • X" in E21 is N.
  • X" in E21 is C.
  • Y" in E21 is N.
  • R 1 ′′ in E21 is independently hydrogen, deuterium, -F, -Cl, or C 1 -C 6 alkyl, and the alkyl is optionally substituted by 1-3 halogens; preferably R 1 ′′ is hydrogen.
  • R 2 ′′ in E21 is hydrogen or C 1 -C 6 alkyl, and the alkyl is optionally substituted by 1 to 3 halogens; preferably R 2 ′′ is hydrogen.
  • R 3 ′′ in E21 is independently hydrogen, deuterium, halogen, -O(C 1 -C 6 alkyl), or C 1 -C 6 alkyl, and the alkyl is optionally substituted by 1-3 halogens; preferably R 3 ′′ is independently hydrogen, deuterium, F, Cl, methyl, methoxy, ethoxy, trifluoromethoxy, 2-hydroxypropan-2-yl or trifluoromethyl.
  • m in E21 is 2.
  • the E21 has the following structure
  • the E21 has the following structure:
  • R 1 ′′, R 2 ′′, R 3 ′′ and m′′ are as defined in E21 above.
  • the E21 has the following structure
  • R 1 ′′, R 2 ′′ and R 3 ′′ are as defined in E21 above.
  • the E21 has the following structure:
  • R 3 is as defined in E21 above.
  • the E21 has the following structure
  • the E21 has the following structure
  • R 1 ′′, R 2 ′′, R 3 ′′ and m′′ are as defined in E21 above.
  • the E21 has the following structure:
  • R 1 ′′, R 2 ′′ and R 3 ′′ are as defined in E21-1 above.
  • the E21 has the following structure
  • R 3 is as defined in E21 above.
  • the E21 has the following structure:
  • R 3 is as defined in E21 above.
  • the E21 has the following structure:
  • R 3 is as defined in E21 above.
  • R 3 ′′ is hydrogen, halogen (e.g., F or Cl), C 1 -C 6 alkyl or -O(C 1 -C 6 alkyl) (e.g., -OCH 3 ), and the C 1 -C 6 alkyl and -O(C 1 -C 6 alkyl) are optionally substituted with 1-3 halogens (e.g., F).
  • halogen e.g., F or Cl
  • C 1 -C 6 alkyl or -O(C 1 -C 6 alkyl) e.g., -OCH 3
  • 1-3 halogens e.g., F
  • R 3 ′′ is hydrogen, F, Cl, CF 3 , -OCF 3 , or -OCH 3 .
  • R 3 ′′ is halogen (eg, F or Cl) or —O(C 1 -C 6 alkyl) (eg, —OCH 3 ).
  • the E21-1h is any of the following structures:
  • the E21-1h is any of the following structures:
  • the E21-1i is the following structure:
  • the E21-1j is any of the following structures:
  • the E21 is any of the following structures:
  • the E21 is selected from
  • the E21 has the following structure:
  • the E21 has the following structure:
  • the E21 has the following structure:
  • the E21 has the following structure:
  • the E21 has the following structure:
  • the E21 has the following structure
  • the E21 has the following structure
  • R 1 ′′, R 2 ′′, R 3 ′′ and m′′ are as defined in E21 above.
  • the E21 has the following structure
  • R 1 ′′, R 2 ′′ and R 3 ′′ are as defined in E21 above.
  • the E21 has the following structure
  • R 3 is as defined in E21 above.
  • the E21 has the following structure
  • the E21 has the following structure
  • R 1 ′′, R 2 ′′, R 3 ′′ and m′′ are as defined in E21-1 above.
  • the E21 has the following structure
  • R 1 ′′, R 2 ′′ and R 3 ′′ are as defined in E21 above.
  • the E21 has the following structure
  • R 3 is as defined in E21 above.
  • the E21 is selected from
  • the E21 is selected from
  • the E21 is any of the following structures:
  • E is E22:
  • R 1′ is optionally substituted C 1 -C 6 alkyl, optionally substituted -(CH 2 ) n OH, optionally substituted -(CH 2 ) n SH, optionally substituted -(CH 2 ) n -O-(C 1 -C 6 alkyl), optionally substituted -(CH 2 ) n -WC(O)CW-(C 0 -C 6 alkyl), wherein each W is independently hydrogen or C 1 -C 3 alkyl, optionally substituted -(CH 2 ) n C(O)OH, optionally substituted -(CH 2 ) n C(O)-(C 1 -C 6 alkyl), optionally substituted -(CH 2 ) n NHC(O)-R 1 , optionally substituted -(CH 2 ) n C(O)-NR 1 R 2 , optionally substituted -(CH 2 ) n OC(O)-NR 1 R 2 , -(CH 2 O
  • R1 and R2 are independently hydrogen or C1 - C6 alkyl, which is optionally substituted by 1 or 2 hydroxyl groups or by 1, 2 or 3 halogens (preferably F);
  • R s is C 1 -C 6 alkyl, optionally substituted aryl, heteroaryl, heterocycloalkyl or -(CH 2 ) m NR 1 R 2 ;
  • X and X' are independently C(O), C(S), S(O), S(O) 2 (preferably X and X' are both C(O));
  • R2 ′ is optionally substituted -( CH2 ) n -C(O) u ( NR1 ) v ( SO2 ) walkyl , optionally substituted -( CH2 ) n -C(O) u ( NR1 ) v ( SO2 ) wNR1NR2N , optionally substituted -( CH2 ) n -C(O) u ( NR1 ) v ( SO2 ) w - aryl , optionally substituted -( CH2 ) n -C(O) u ( NR1 ) v ( SO2 ) w -heteroaryl, optionally substituted -( CH2 ) n -C(O) u ( NR1 ) v ( SO2 ) w -heteroaryl, optionally substituted -( CH2 ) n -C(O) u ( NR1 ) v ( SO2 ) w
  • R 3′ is optionally substituted alkyl, optionally substituted -(CH 2 ) n (O) u (NR 1 ) v (SO 2 ) w -alkyl, optionally substituted -(CH 2 ) n C(O) u (NR 1 ) v (SO 2 ) w -NR 1N R 2N , optionally substituted -(CH 2 ) n C(O) u (NR 1 ) v (SO 2 ) w -C(O)NR 1 R 2 , optionally substituted -(CH 2 ) n C(O) u (NR 1 ) v (SO 2 ) w -aryl, optionally substituted -(CH 2 ) n C(O) u (NR 1 ) v (SO 2 ) w -heteroaryl, optionally substituted -(CH 2 ) n C(O) u (NR 1 ) v (SO 2 ) w -heter
  • R 1N and R 2N are independently hydrogen, optionally substituted -(CH 2 ) n -aryl, optionally substituted -(CH 2 ) n -heteroaryl, optionally substituted -(CH 2 ) n -heterocycloalkyl, C 1 -C 6 alkyl, said C 1 -C 6 alkyl being optionally substituted by 1 or 2 hydroxyl groups or optionally substituted by 1, 2 or 3 halogen groups;
  • V is O, S or NR 1 ;
  • R 1 and R 1' are independently hydrogen or C 1 -C 3 alkyl
  • n is independently 0, 1, 2, 3, 4, 5 or 6;
  • n' is independently 1 or
  • n is independently 0, 1, 2, 3, 4, 5 or 6;
  • n' is independently 0 or 1;
  • u is independently 0 or 1;
  • v is independently 1 or 1;
  • w is independently 0 or 1.
  • E is E23, E23a, E23b, E23c, E23d or E23e:
  • R 1' , R 2' , R 3' , and X are as defined in E22;
  • R7 is H or optionally substituted alkyl
  • J is O or NR 8 ;
  • R8 is H, CN, an arbitrarily substituted alkyl group or an arbitrarily substituted alkoxy group
  • M is aryl, heteroaryl, heterocyclic or The aryl, heteroaryl and heterocyclic groups may be substituted arbitrarily;
  • R 9 and R 10 are independently selected from H, alkyl, cycloalkyl, hydroxyalkyl, thioalkyl, disulfide bond connected to ULM, heteroaryl or haloalkyl, and the alkyl, cycloalkyl, hydroxyalkyl, thioalkyl, disulfide bond connected to ULM, heteroaryl or haloalkyl may be arbitrarily substituted; or R 9 and R 10 together with the carbon atom to which they are attached form an arbitrarily substituted cycloalkyl;
  • R 11 is heterocycloalkyl, alkoxy, heteroaryl, aryl or The heterocycloalkyl, alkoxy, heteroaryl and aryl groups may be substituted at will;
  • R 12 is H or an arbitrarily substituted alkyl group
  • R 13 is H, alkyl, alkyl-C ⁇ O, (cycloalkyl)alkyl-C ⁇ O, aralkyl-C ⁇ O, aryl-C ⁇ O, (heterocycloalkyl)-C ⁇ O, aralkyl or alkoxy-C ⁇ O, and the alkyl, alkyl-C ⁇ O, (cycloalkyl)alkyl-C ⁇ O, aralkyl-C ⁇ O, aryl-C ⁇ O, (heterocycloalkyl)-C ⁇ O, aralkyl or alkoxy-C ⁇ O may be arbitrarily substituted;
  • R 14 is H, haloalkyl, cycloalkyl, alkyl or heterocycloalkyl, and the cycloalkyl, alkyl or heterocycloalkyl may be arbitrarily substituted;
  • R 15 is H, heteroaryl, haloalkyl, aryl, alkoxy or heterocycloalkyl, and the heteroaryl, haloalkyl, aryl, alkoxy or heterocycloalkyl may be arbitrarily substituted;
  • R 16 is halogen, alkyl, haloalkyl, CN or haloalkoxy, and the alkyl, haloalkyl or haloalkoxy may be arbitrarily substituted;
  • R 17 is H, halogen, cycloalkyl, alkyl, alkenyl or haloalkyl, and the cycloalkyl, alkyl and alkenyl may be arbitrarily substituted;
  • R23 is H or OH
  • Z 1 , Z 2 , Z 3 and Z 4 are independently selected from C or N;
  • X is O or S
  • Y is H, methyl or ethyl
  • o 0, 1, 2, 3, or 4.
  • R 1' , R 2' , R 3' , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 14, R 15 , R 16 , R 17 , R 23 , R 25 , E, M, o, X, Y, Z 1 , Z 2 , Z 3 and Z 4 are as defined and described in US 2016/0272639, the entire contents of which are incorporated herein by reference.
  • E is E23a:
  • R 1' is a hydroxyl group
  • R 2' is -NH-CH 2 -aryl-HET
  • R 3′ is selected from optionally substituted alkyl, -(CH)R CR3′ -NH-C(O)-R 3p1 or -(CH)R CR3′ -R 3p2 ;
  • R CR3' is an optionally substituted C 1 -C 4 alkyl group
  • R 3p1 is optionally substituted C 1 -C 6 alkyl, optionally substituted oxetanyl, -(CH 2 ) n OCH 3 , phenyl optionally substituted by -O(CH 2 CH 3 ) or morpholinyl connected to the carbonyl at the 2- or 3-position, wherein n is 1 or 2;
  • R 3p2 is or optionally substituted phenyl
  • HET is selected from optionally substituted thiazole, oxazole, isoxazole or isothiazole;
  • RHET is selected from hydrogen, halogen, cyano, optionally substituted C1 - C6 alkyl, optionally substituted C1 - C6 alkoxy, and optionally substituted aryl.
  • E is E23c
  • Each R 5 and R 6 is independently -OH, -SH or an optionally substituted alkyl group, or R 5 , R 6 and the carbon atom to which they are attached form a carbonyl group;
  • R 7 is H or optionally substituted alkyl
  • J is O or NR 8 ;
  • R 8 is H, CN, optionally substituted alkyl or optionally substituted alkoxy;
  • M is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl or
  • each R 9 and R 10 are independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, disulfide-linked ULM, or optionally substituted heteroaryl or haloalkyl; or R 9 , R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl;
  • R 11 is optionally substituted heterocycloalkyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted substituted aryl or
  • R 12 is H or optionally substituted alkyl
  • R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocycloalkyl)carbonyl or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate,
  • each R 14 is independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted heterocycloalkyl;
  • R 15 is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocycloalkyl;
  • each R 16 is independently halogen, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy;
  • Each R 25 is independently H or optionally substituted alkyl; or two R 25 groups may be taken together to form oxo or optionally substituted cycloalkyl;
  • R23 is H or OH
  • Z 1 , Z 2 , Z 3 and Z 4 are independently C or N;
  • o 0, 1, 2, 3, or 4.
  • E is E23d:
  • X is O or S
  • Y is H, methyl or ethyl
  • R 17 is H, methyl, ethyl, hydroxymethyl or cyclopropyl
  • M is optionally substituted heteroaryl, optionally substituted aryl.
  • E is E23d-1
  • Y is H, methyl or ethyl
  • R 9 is H
  • R10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl or cyclohexyl;
  • R 11 is optionally substituted amide, optionally substituted isoindolinone, optionally substituted isoxazole, optionally substituted heterocycle;
  • R17 is H, methyl, ethyl, hydroxymethyl or cyclopropyl.
  • E is a specific compound of Examples 1 to 208 in CN108601764 (the entire text of which is incorporated herein by reference).
  • E is E24:
  • X 1 and X 2 are independently a bond, O, NR Y3 , CR Y3 RY4 , C ⁇ O, C ⁇ S, SO or SO 2 ;
  • R Y3 and R Y4 are independently hydrogen, C 1 -C 6 alkyl optionally substituted by 1 or more halogens, or C 1 -C 6 alkoxy optionally substituted by 0 to 3 R ps ;
  • R p is 0, 1, 2 or 3 selected from hydrogen, halogen, hydroxyl, C 1 -C 3 alkyl or C( ⁇ O);
  • W 3 is selected from optionally substituted T, optionally substituted -TN(R 1a R 1b )X 3 , optionally substituted -TN(R 1a R 1b ), optionally substituted optionally substituted -T-aryl, optionally substituted -T-heteroaryl, optionally substituted -T-bicyclic heteroaryl, optionally substituted -T-heterocycloalkyl, optionally substituted -T-bicyclic heterocycloalkyl, optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl, or optionally substituted -NR 1 -T-heterocycloalkyl;
  • X 3 is C(O), R 1 , R 1a or R 1b ;
  • each R 1 , R 1a or R 1b is independently selected from hydrogen, C1-C6 alkyl optionally substituted by one or more halogen or hydroxyl, RY3 C(O), RY3 C(S), RY3 S(O), RY3 S(O) 2 , N( RY3 RY4) C(O), N( RY3 RY4) C(S), N( RY3 RY4) S(O) or N( RY3 RY4) S(O) 2 ;
  • T is selected from optionally substituted alkyl, -(CH 2 ) n -, each methylene group optionally substituted by a substituent selected from halogen, hydroxyl, an optionally substituted amino acid side chain, methyl, an optionally substituted alkoxy, a C 1 -C 6 alkyl group optionally substituted by one or more halogens, -C(O)NR 1 R 1a or NR 1 R 1a ;
  • R 1 and R 1a may optionally form an optionally substituted heterocycloalkyl
  • n 0, 1, 2, 3, 4, 5 or 6;
  • R 14a and R 14b are independently hydrogen, haloalkyl or optionally substituted alkyl
  • W 5 is optionally substituted phenyl or optionally substituted heteroaryl
  • R 15 is optionally substituted hydrogen, cyano, halogen, hydroxyl, nitro, NR 14a R 14b , OR 14a , CONR 14a R 14b , NR 14a CONR 14b , SO 2 NR 14a R 14b , NR 14a SO 2 R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl.
  • E is E25 or E25a:
  • W3 is an optionally substituted aryl, an optionally substituted heteroaryl or
  • R9 and R10 are independently hydrogen, haloalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl or optionally substituted heteroaryl, or R9 and R10 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl;
  • R 11 is optionally substituted heterocycloalkyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,
  • R 12 is independently hydrogen or optionally substituted alkyl
  • R 13 is independently hydrogen, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocycloalkyl)carbonyl or optionally substituted aralkyl;
  • R 14a and R 14b are independently hydrogen, haloalkyl or optionally substituted alkyl
  • W5 is selected from optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl
  • R 15 is optionally substituted hydrogen, cyano, halogen, hydroxyl, nitro, NR 14a R 14b , OR 14a , CONR 14a R 14b , NR 14a CONR 14b , SO 2 NR 14a R 14b , NR 14a SO 2 R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;
  • Each R 16 is independently halogen, cyano, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxyl or optionally substituted haloalkyl;
  • o 0, 1, 2, 3, or 4;
  • R 18 is independently halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl or haloalkoxy;
  • p 0, 1, 2, 3 or 4.
  • E is 26, E26a or E26b
  • R 1 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl;
  • R 14a is hydrogen, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;
  • X is CH 2 or C(O);
  • R 15 is selected from hydrogen, halogen, CN, hydroxy, nitro, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;
  • R 3 is absent or is an optionally substituted 5-6 membered heteroaryl.
  • E is E27, E27a, E27b, E27c, E27d, E27e, E27f and E27g:
  • X is selected from carbon, oxygen, sulfur, sulfoxide, sulfone and NR a ;
  • Ra is independently H or an alkyl group having a carbon number of 1 to 6;
  • Y and Z are independently carbon or nitrogen
  • A, A' and A" are independently selected from C, N, O and S, and may also be one or two atoms forming a fused bicyclic, or 6,5 and 5,5-fused aromatic bicyclic groups;
  • R 1 , R 2 are independently aryl or heteroaryl, heteroaryl having one or two heteroatoms independently selected from sulfur and nitrogen, wherein the aryl or heteroaryl may be monocyclic or bicyclic, or unsubstituted or substituted with one to three substituents independently selected from halogen, -CN, C1 to C6 alkyl, C3 to C6 cycloalkyl, -OH, alkoxy having 1 to 6 carbons, alkoxy substituted with fluorine having 1 to 6 carbons, sulfoxide having 1 to 6 carbons, sulfone having 1 to 6 carbons, ketone having 2 to 6 carbons, amide having 2 to 6 carbons, and dialkylamine having 2 to 6 carbons;
  • R 3 and R 4 are independently selected from H, methyl and C 1 -C 6 alkyl
  • R 5 is aryl or heteroaryl, heteroaryl having one or two heteroatoms independently selected from sulfur or nitrogen, wherein the aryl or heteroaryl can be monocyclic or bicyclic, or unsubstituted or substituted with one to three substituents independently selected from: halogen, -CN, C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, -OH, alkoxy having 1 to 6 carbons, fluorine-substituted alkoxy having 1 to 6 carbons, sulfoxide having 1 to 6 carbons, sulfone having 1 to 6 carbons, ketone having 2 to 6 carbons, amide having 2 to 6 carbons, N(C 2 -C 6 alkyl) 2 , alkyl ether (C 2 to C 6 ), alkyl ketone (C 3 to C 6 ), morpholinyl, alkyl ester (C 3 to C 6 ) or alkyl cyanide (C 3 to C 6 );
  • Rb is selected from alkyl, cycloalkyl, mono-, di- or tri-substituted aryl or heteroaryl, 4-morpholinyl, 1-(3-oxopiperazinyl), 1-piperidinyl, 4- NRc -morpholinyl, 4- Rc -1-piperidinyl and 3- Rc -1-piperidinyl, wherein:
  • R c is selected from alkyl, fluoro-substituted alkyl, cyanoalkyl, hydroxy-substituted alkyl, cycloalkyl, alkoxyalkyl, amidealkyl, alkylsulfone, alkylsulfoxide, alkylamide, aryl, heteroaryl, mono-, di- or tri-substituted aryl or heteroaryl, CH 2 CH 2 R d and CH 2 CH 2 CH 2 R d , wherein:
  • R d is selected from alkoxy, alkyl sulfone, alkyl sulfoxide, N-substituted carboxamide, -NHC(O)-alkyl, -NH-SO 2 -alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
  • R7 is selected from H, C1 - C6 alkyl, cycloalkyl, fluorine-substituted alkyl, cyano-substituted alkyl, 5- or 6-membered heteroaryl or aryl, and substituted 5- or 6-membered heteroaryl or aryl;
  • R 8 is selected from -Re - C(O) -Rf , -Re -alkoxy, -Re -aryl, -Re - heteroaryl and -Re - C(O)-Rf - C(O) -Rg , wherein:
  • R e is an alkylene group having 1 to 6 carbons or a bond
  • Rf is a substituted 4- to 7-membered heterocyclic ring
  • Rg is selected from aryl, heteroaryl, substituted aryl or heteroaryl, and 4 to 7 membered heterocyclic ring;
  • R 9 is selected from mono-, di- or tri-substituents on the fused bicyclic aromatic ring, wherein the substituents are independently selected from halogen, alkene, alkyne, alkyl, unsubstituted or alkyl substituted with Cl or F;
  • R 10 is selected from aryl and heteroaryl, wherein the heteroaryl may contain one or two heteroatoms such as sulfur or nitrogen, the aryl or heteroaryl may be monocyclic or bicyclic, the aryl or heteroaryl may be unsubstituted or substituted with one to three substituents, the substituents include halogen, F, Cl, -CN, alkene, alkyne, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, -OH, alkoxy having 1 to 6 carbons, alkoxy substituted with fluorine having 1 to 6 carbons, sulfoxide having 1 to 6 carbons, sulfone having 1 to 6 carbons, or ketone having 2 to 6 carbons;
  • R 11 is -C(O)-N(R h )(R i ), wherein R h and R i are selected from the following: H, C 1 to C 6 alkyl, alkoxy substituted alkyl, sulfone substituted alkyl, aryl, heteroaryl, monosubstituted, disubstituted or trisubstituted aryl or heteroaryl, alkylcarboxylic acid, heteroarylcarboxylic acid, alkylcarboxylic acid, Fluorine-substituted alkyl carboxylic acid, aryl-substituted cycloalkyl and heteroaryl-substituted cycloalkyl; wherein R h and R i are independently H, 4-hydroxycyclohexane, monohydroxy and dihydroxy substituted alkyl (e.g., C 3 to C 6 alkyl), 3-hydroxycyclobutane, phenyl-4-carboxylic acid or substituted phenyl
  • R 12 and R 13 are independently H, lower alkyl (e.g., C 1 to C 6 alkyl), lower alkenyl (e.g., C 2 to C 6 alkenyl), lower alkynyl (e.g., C 2 to C 6 alkynyl), cycloalkyl (e.g., 4, 5, and 6-membered ring cycloalkyl), substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, or 5- and 6-membered aryl and heteroaryl, and R 12 and R 13 may be linked to form 5- and 6-membered rings with or without substitution on the ring;
  • lower alkyl e.g., C 1 to C 6 alkyl
  • lower alkenyl e.g., C 2 to C 6 alkenyl
  • lower alkynyl e.g., C 2 to C 6 alkynyl
  • cycloalkyl e.g., 4, 5, and 6-member
  • R 14 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl;
  • R15 is CN
  • R 16 is C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl in which one or more hydrogen is replaced by fluorine, an alkyl or cycloalkyl in which one CH 2 is replaced by S( ⁇ O), -S or -S( ⁇ O) 2 , an alkyl or cycloalkyl in which the terminal CH 3 is replaced by S( ⁇ O) 2 N(alkyl)(alkyl), -C( ⁇ O)N(alkyl)(alkyl), -N(alkyl)S( ⁇ O) 2 (alkyl), -C( ⁇ O ) 2 (alkyl), -O(alkyl) alkyl or cycloalkyl in which hydrogen is replaced by hydroxyl; C 1 -C 6 alkyl or alkyl-cycloalkyl, a 3 to 7 membere
  • R 17 is selected from (CH 2 ) n C(O)NR k R l , wherein R k and R l are independently selected from H, C 1 -C 6 alkyl, hydroxylated C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 alkyl in which one or more hydrogens are replaced by fluorine, C 1 -C 6 alkyl in which one carbon is replaced by S(O) or S(O)(O), C 1 -C 6 alkoxyalkyl in which one or more hydrogens are replaced by fluorine, C 1 -C 6 alkyl in which one or more hydrogens are replaced by cyano, 5- and 6-membered aryl or heteroaryl, C 1 -C 6 alkylaryl, and C 1 -C 6 alkylalkylheteroaryl, wherein the aryl or heteroaryl may be further substituted; and n is an integer from 0 to 6;
  • R 18 is selected from substituted aryl, heteroaryl, alkyl, cycloalkyl, wherein the substitution is preferably -N(C 1 -C 4 alkyl)(cycloalkyl), -N(C 1 -C 4 alkyl)alkyl-cycloalkyl, and -N(C 1 -C 4 alkyl)[(alkyl)-(heterocyclic substituted)-cycloalkyl];
  • R 19 is selected from aryl, heteroaryl and bicyclic heteroaryl, and these aryl or heteroaryl groups may be substituted by halogen, C1-6 alkyl, C1-6 cycloalkyl, CF 3 , F, CN, alkyne, alkyl sulfone, and the halogen substitution may be monosubstituted or trisubstituted;
  • R 20 and R 21 are independently selected from C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxylated C 1 -C 6 alkoxy and fluorine-substituted C 1 -C 6 alkoxy, wherein R 20 and R 21 may also be connected to form a 5-, 6- and 7-membered carbocyclic or heterocyclic ring, which may be further substituted;
  • R 22 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, carboxylic acid, carboxylic acid ester, amide, reverse amide, sulfonamide, reverse sulfonamide, N-acylurea and nitrogen-containing 5-membered heterocyclic ring, which may be further substituted by C 1 -C 6 alkyl, alkoxy, fluorine-substituted alkyl, CN and alkyl sulfone;
  • R 23 is selected from aryl, heteroaryl, -O-aryl, -O-heteroaryl, -O-alkyl, -O-alkyl-cycloalkyl, -NH-alkyl, -NH-alkyl-cycloalkyl, -N(H)-aryl, -N(H)-heteroaryl, -N(alkyl)-aryl and -N(alkyl)-heteroaryl, wherein the aryl or heteroaryl may be halogen, C 1 -C 6 alkyl, hydroxylated C 1 -C 6 alkyl, cycloalkyl, fluorinated C 1 -C 6 alkyl, CN, alkoxy, alkyl sulfone, amide and sulfonamide substitution;
  • R 24 is selected from -CH 2 -(C 1 -C 6 alkyl), -CH 2 -cycloalkyl, -CH 2 -aryl and CH 2 -heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl may be substituted with halogen, alkoxy, hydroxylated alkyl, cyano-substituted alkyl, cycloalkyl and substituted cycloalkyl;
  • R 25 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl-cycloalkyl, alkoxy-substituted alkyl, hydroxylated alkyl, aryl, heteroaryl, substituted aryl or heteroaryl, 5-, 6- and 7-membered nitrogen-containing saturated heterocyclic rings and 5,6-fused and 6,6-fused nitrogen-containing saturated heterocyclic rings, and these saturated heterocyclic rings may be substituted by C 1 -C 6 alkyl, fluorine-substituted C 1 -C 6 alkyl, alkoxy, aryl and heteroaryl;
  • R 26 is selected from C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein the alkyl or cycloalkyl may be substituted with -OH, alkoxy, fluorine-substituted alkoxy, fluorine-substituted alkyl, -NH 2 , -NH-alkyl, NH-C(O)alkyl, -NH-S(O) 2 -alkyl and -S(O) 2 -alkyl;
  • R 27 is selected from aryl, heteroaryl and bicyclic heteroaryl, wherein the aryl or heteroaryl may be substituted by C 1 -C 6 alkyl, alkoxy, NH 2 , NH-alkyl, halogen or -CN, and the substitution may be independently mono-, di- and tri-substituted;
  • R 28 is selected from aryl, 5- and 6-membered heteroaryl, bicyclic heteroaryl, cycloalkyl and saturated heterocycle (e.g. piperidine, piperidone, tetrahydropyran, N-acyl-piperidine), wherein the cycloalkyl, saturated heterocycle, aryl or heteroaryl may be further mono-, di- or tri-substituted with substituents selected from -OH, alkoxy, halogen, -CN, alkylsulfone and fluoro-substituted alkyl; and
  • aryl, 5- and 6-membered heteroaryl, bicyclic heteroaryl, cycloalkyl and saturated heterocycle e.g. piperidine, piperidone, tetrahydropyran, N-acyl-piperidine
  • substituents selected from -OH, alkoxy, halogen, -CN, alkylsulfone and fluoro-substituted alkyl
  • R 1" is selected from the group consisting of alkyl, aryl-substituted alkyl, alkoxy-substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl and alkoxy-substituted cycloalkyl.
  • E is E28, E28a, E28b, E28c, E28d, E28e, E28f, E28g, E28h or E28i, (MDM2)
  • R 1' and R 2' are independently F, Cl, Br, I, ethynyl, cyano, nitro or CF 3 ;
  • R 3′ is selected from —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 F, —OCH 2 CH 2 OCH 3 and —OCH(CH 3 ) 2 ;
  • R 4′ is selected from hydrogen, halogen, methyl, —CF 3 , —OCH 3 , —C(CH 3 ) 3 , —CH(CH 3 ) 2 , -cyclopropyl, cyano, —C(CH 3 ) 2 OH, —C(CH 3 ) 2 OCH 2 CH 3 , —C(CH 3 ) 2 OCH 2 OH, —C(CH 3 ) 2 CH 2 OCH 2 CH 3 , —C(CH 3 ) 2 CH 2 OCH 2 CH 2 OH, —C(CH 3 ) 2 CN, —C(CH 3 ) 2 C(O)CH 3 , —C(CH 3 ) 2 C(O)NHCH 3 , —C(CH 3 ) 2 C(O)N(CH 3 ) 2 , —SCH 3 , —SCH 2 CH 3 , —S(O) 2 CH 3 , -S(O) 2 CH 2 CH 3 , -NHC(
  • R 5′ is selected from halogen, cyclopropyl, —S(O) 2 CH 3 , —S(O) 2 CH 2 CH 3 , pyrrolidinyl, —NH 2 , —N(CH 3 ) 2 , and —NHC(CH 3 ) 3 ;
  • R 6' is selected from hydrogen, wherein the * in R 6' is a connection point to L; or R 4' may also be connected to L;
  • R 7' is halogen, and the number of R 7' can be one or more;
  • R 8' is hydrogen, F, Cl, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy, isopropoxy, hydroxyl, other C 1 -C 6 alkyl, other C 1 -C 6 alkenyl or other C 1 -C 6 alkynyl, and the number of R 8' can be one or more;
  • R 9′ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cycloalkyl;
  • Z is hydrogen, -OCH 3 , -OCH 2 CH 3 or halogen
  • R10′ and R11′ are independently hydrogen, ( CH2 ) n -R′, ( CH2 ) n -NR′R′′, ( CH2 ) n -NR′C(O)R′′, ( CH2 ) n- NR′S(O) 2R ′′, ( CH2 ) n -C(O)OH, ( CH2 ) n -C(O)OR′, ( CH2 ) n -C(O)NR′R′′, ( CH2 ) n- OR′, ( CH2 ) n- SR′, ( CH2 ) n- SOR′, ( CH2 ) n -CH(OH)-R′, ( CH2 ) n -C(O)R′, ( CH2 ) n -S(O) 2R ′, ( CH2 ) n -S(O)NR′R ′′ , ( CH2 ) n -S(O ) 2NR′R′′, ( CH2CH
  • n and p are independently 0, 1, 2, 3, 4, 5 or 6;
  • R 12′ is independently —O-alkyl, —O-alkyl-alkoxy, —C(O)-alkyl, —C(OH)-alkyl-alkoxy, —C(O)-NH-alkyl, —C(O)-N-(alkyl) 1-2 , —S(O)-alkyl, S(O) 2 -alkyl, —C(O)-cyclic amine, —O-aryl-alkyl or —O-aryl-alkoxy;
  • R 1" is hydrogen, alkyl optionally substituted by aryl or alkoxy, or cycloalkyl optionally substituted by aryl or alkoxy.
  • E is E29:
  • R 1 is independently H, C 1 -C 4 -alkyl, C 1 -C 4 -alkenyl, C 1 -C 4 -alkynyl or C 3 -C 10 -cycloalkyl, which is unsubstituted or substituted;
  • R 2 is independently H, C 1 -C 4 -alkenyl, C 1 -C 4 -alkenyl, C 1 -C 4 -alkynyl or C 3 -C 10 -cycloalkyl, which is unsubstituted or substituted;
  • R 3 is independently H, -CF 3 , -C 2 H 5 , C 1 -C 4 -alkyl, C 1 -C 4 -alkenyl, C 1 -C 4 -alkynyl, -CH 2 -Z, or any of R 2 and R 3 together form a heterocycle;
  • each Z is independently H, -OH, F, Cl, -CH 3 , -CF 3 , -CH 2 Cl, -CH 2 F, or -CH 2 OH;
  • R 4 is independently C 1 -C 16 straight or branched alkyl, C 1 -C 16 -alkenyl, C 1 -C 16 -alkynyl, C 3 -C 10 -cycloalkyl, -(CH 2 ) 0-6 -Z 1 , -(CH 2 ) 0-6 -aryl or -(CH 2 ) 0-6 -het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted;
  • R5 is independently H, C1-10 -alkyl, aryl, phenyl, C3-7 -cycloalkyl, -( CH2 ) 1-6 - C3-7 -cycloalkyl, -C1-10 -alkyl-aryl, -( CH2 )0-6- C3-7-cycloalkyl-(CH2)0-6-phenyl, -(CH2)0-4-CH[(CH2)1-4-phenyl]2, indanyl, -C(O)-C1-10-alkyl, -C(O)-(CH2)1-6 - C3-7 - cycloalkyl , -C ( O ) - ( CH2 ) 0-6 -phenyl, -( CH2 ) 0-6 - C(O)-phenyl, -( CH2 ) 0-6 -het, or -C(O)-( CH2 ) 1-6 -het, or R 5 is selected from the residue
  • Z 1 is independently selected from -N(R 10 )-C(O)-C 1-10 -alkyl, -N(R 10 )-C(O)-(CH 2 ) 0-6 -C 3-7 -cycloalkyl, -N(R 10 )-C(O)-(CH 2 ) 0-6 -phenyl, -N(R 10 )-C(O)(CH 2 ) 1-6 -het, -C(O)-N(R 11 )(R 12 ), -C(O)-OC 1-10 -alkyl, -C(O)-O-(CH 2 ) 1-6 -C 3-7 -cycloalkyl, -C(O)-O-(CH 2 ) 0-6 -phenyl, -C(O)-O-(CH 2 ) 1-6 -het, -OC(O)-C 1-10 -alkyl, -OC(O)-(CH 2 ) 1-6
  • het is independently a 5-7 membered heterocyclic ring or an 8-12 membered fused ring system containing 1-4 heteroatoms selected from N, O and S, which includes at least a 5-7 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O and S, said heterocyclic ring or fused ring system being unsubstituted or substituted on the carbon or nitrogen atom;
  • R 10 is H, -CH 3 , -CF 3 , -CH 2 OH or -CH 2 Cl;
  • R 11 and R 12 are independently H, C 1-4 -alkyl, C 3-7 -cycloalkyl, -(CH 2 ) 1-6 -C 3-7 -cycloalkyl or (CH 2 ) 0-6 -phenyl, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted; or R 11 and R 12 together with nitrogen form het, and
  • n is independently an integer from 0 to 5;
  • X is selected from -CH and N;
  • Ra and Rb are independently C0-8 -alkyl, wherein one or more carbon atoms in the alkyl chain are optionally replaced by a heteroatom selected from O, S or N, and wherein each alkyl group is independently unsubstituted or substituted;
  • R d is selected from Re-Q-(R f ) p (R g ) q and Ar 1 -D-Ar 2 ;
  • R c is H or any of R c and R d together form a cycloalkyl or het; wherein if R c and R d form a cycloalkyl or het, R 5 is attached to the formed ring at a C or N atom;
  • p and q are independently selected from 0 or 1;
  • Re is selected from C 1-8 -alkyl and alkylene, and each Re is unsubstituted or substituted;
  • Q is selected from N, O, S, S(O) and S(O) 2 ;
  • Ar 1 and Ar 2 are independently selected from substituted or unsubstituted aryl and het;
  • Rf and Rg are independently selected from H, -C1-10 -alkyl, C1-10 -alkylaryl, -OH, -OC1-10 -alkyl, -( CH2 ) 0-6 - C3-7 -cycloalkyl, -O-( CH2 ) 0-6 -aryl, phenyl, aryl , phenyl-phenyl, -( CH2 ) 1-6 -het, -O-( CH2 ) 1-6- het, -OR13, -C(O) -R13 , -C(O)-N( R13 )( R14 ), -N( R13 )( R14 ) , -SR13 , -S(O)-R13, -S(O) 2 -R13 , -S(O) 2 - NR13R14 , -NR13 - S(O) 2 - R14 , -SC t-10
  • D is -CO-, -C(O)-C 1-7 -alkylene or arylene, -CF 2 -, -O-, -S(O) r , 1,3-dioxolane or C 1-7 -alkyl-OH, wherein r is 0-2; wherein the alkyl, alkylene or arylene is unsubstituted or substituted with one or more halogen, OH, -OC 1-6 -alkyl, -SC 1-6 - alkyl or -CF 3 ; or each D is independently N(R h );
  • R h is H, unsubstituted or substituted C 1-7 -alkyl, aryl, unsubstituted or substituted -O-(C 1-7 -cycloalkyl), -C(O)-C 1-10 -alkyl, -C(O)-C 0-10 -alkyl-aryl, -COC 01-10 -alkyl, -COC 0-10 -alkyl-aryl, -SO 2 -C 1-10 -alkyl or -SO 2 -(C 0-10 -alkylaryl);
  • R 6 , R 7 , R 8 and R 9 are independently H, —C 1-10 -alkyl, —C 1-10 -alkoxy, aryl-C 1-10 -alkoxy, —OH, —OC 1-10 -alkyl, —(CH 2 ) 0-6 -C 3-7 -cycloalkyl, —O—(CH 2 ) 0-6 -aryl, phenyl, —(CH 2 ) 1-6 -het, —O—(CH 2 ) 1-6 -het, —OR 13 , —C(O)—R 13 , —C(O)—N(R 13 )(R 14 ), —N(R 13 )(R 14 ), —SR 13 , —S(O)—R 13 , —S(O) 2 -R 13 , —S(O) 2 -NR 13 R 14 or —NR 13 -S(O) 2 -R 14 ; wherein each
  • R13 and R14 are independently H, C1-10 -alkyl, -( CH2 ) 0-6 - C3-7 -cycloalkyl, -( CH2 ) 0-6- (CH) 0-1- (aryl) 1-2 , -C(O) -C1-10 -alkyl, -C(O)-( CH2 ) 1-6 - C3-7 -cycloalkyl, -C(O)-O-( CH2 )0-6-aryl, -C(O)-(CH2) 0-6 - O-fluorenyl, -C(O)-NH-(CH2) 0-6 -aryl , -C(O)-(CH2) 0-6 -aryl , -C(O)-( CH2 ) 0-6 - het, -C(S) -C1-10 -alkyl, -C(S)-( CH2 )0-6-cycloalkyl,
  • the alkyl in R 13 and R 14 is unsubstituted or substituted and, when substituted, is substituted by one or more substituents selected from the group consisting of C 1-10 -alkyl, halogen, OH, -OC 1-6 -alkyl, -SC 1-6 -alkyl and -CF 3 ; and the substituted phenyl or aryl in R 13 and R 14 is substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, C 1-4 -alkyl, C 1-4 -alkoxy, nitro, -CN, -OC(O)-C 1-4 -alkyl and -C(O)-OC 1-4 -aryl;
  • E is E30, E30a, E30b, E30c or E30d:
  • R1 is hydrogen or alkyl
  • R2 is hydrogen or alkyl
  • R3 is hydrogen, alkyl, cycloalkyl or heterocycloalkyl
  • R 5 and R 6 are independently hydrogen, alkyl, cycloalkyl or heterocycloalkyl; or R 5 , R 6 together with the atoms to which they are attached form a pyrrole ring or a piperidine ring and are optionally fused with 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings, and each of the rings is further optionally fused to another cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;
  • R5 and R3 together with the atoms to which they are attached form a 5-8 membered ring and are optionally fused to 1 or 2 cycloalkyl, heterocycloalkyl, aryl, heteroaryl rings;
  • R4 is selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl or bicyclic aryl, arylalkyl, heteroaryl or bicyclic heteroaryl or heteroarylalkyl, and is further optionally substituted with 1-3 alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl or bicyclic aryl, arylalkyl, heteroaryl or bicyclic heteroaryl, heteroarylalkyl substituents.
  • E is E31
  • A1 and A2 are independently selected from optionally substituted monocyclic rings, fused rings, aryl groups and heteroaryl groups;
  • R is H or Me.
  • E is E32
  • R 1 is selected from alkyl, cycloalkyl and heterocycloalkyl, and most preferably is selected from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl; R 2 is selected from -OPh or H.
  • E is E33,
  • R 1 is H, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 NH 2 or -CH 2 CH 2 NH 2 ;
  • X is S or CH 2 ;
  • n 1, 2 or 3;
  • R2 is:
  • R3 and R4 are independently selected from H or Me.
  • E is E34
  • R1 is selected from H or Me
  • R2 is selected from H or
  • E is E35
  • R1 is selected from:
  • R2 is selected from:
  • E is E36
  • n 0, 1 or 2, preferably 2;
  • Z does not exist or is O
  • R1 is selected from:
  • R 10 is hydrogen, alkyl or aryl
  • X is selected from CH2 and O;
  • Z does not exist or is O
  • R3 and R4 are independently selected from H or Me
  • R1 is selected from:
  • R 10 is H, alkyl or aryl
  • Z does not exist or is O
  • R1 is selected from:
  • R 10 is H, alkyl or aryl
  • X is CH2 and O
  • middle is a nitrogen-containing heteroaryl group
  • R2 is H, alkyl or acyl.
  • E is E39,
  • R2 is selected from alkyl, cycloalkyl and heterocycloalkyl; more preferably selected from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl, most preferably selected from cyclohexyl;
  • Ar is an aryl or heteroaryl group.
  • R1 is selected from halogen (e.g., fluorine), cyano,
  • X is selected from O or CH 2 .
  • E is E41
  • R is alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, or halogen (in variable substitution positions).
  • E36 It is a 6-membered nitrogen-containing heteroaryl group.
  • E is E43
  • X is selected from CH 2 , O, NH or S.
  • E is E44, E44a or E44b
  • n 1 or 2;
  • R 2 , R 3 and R 4 are independently H or methyl
  • X is independently O or S
  • R1 is:
  • E is E45
  • R3 and R4 are independently hydrogen or methyl
  • E is E46 or E46a
  • R2 is H or methyl
  • N 0, 1 or 2.
  • E is EA:
  • Ring D is connected to L;
  • ring D is
  • Q 1 , Q 1 ′, Q 2 , Q 2 ′, Q 3 , Q 3 ′, Q 4 , Q 4 ′, Q 5 , Q 5 ′, Q 6 or Q 6 ′ is independently CH or N;
  • RB and RB ' are independently hydrogen, deuterium, hydroxyl, halogen, CN, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 -C6 heteroalkyl, -O-( C1 - C6 heteroalkyl), C2 - C6 alkenyl , C2 -C6 alkynyl , -CONRCRD , -ORC , -NRCRD , -SRC , -SO2RC , -SO2NRCRD , -CRCRD , -CRRCNRCRD, C6 - C10aryl , C5 -C10heteroaryl , C3 - C8cycloalkyl , 3-8 membered heterocycloalkyl, -P(O)( ORC )RD, -P(O) RCRD , -OP(O)( ORC ) RD , -Cl, -F
  • RC and RD are independently a bond, hydrogen, deuterium, C1 - C6 haloalkyl, C1- C6 alkyl, C1 -C6 heteroalkyl, C3 - C8 cycloalkyl, C6 - C10 aryl, C5 - C10 heteroaryl, or 3-8 membered heterocycloalkyl;
  • n′′ and n′′′ are independently 1, 2, 3 or 4;
  • t 0, 1, or 2;
  • P1 is CH2 , O or S
  • W is CRERF , C(S), C(O) or SO2 ;
  • RE and RF are independently hydrogen, C1 - C6 alkyl, C1 - C6 heteroalkyl, C3 - C8 cycloalkyl or 3-8 membered heterocycloalkyl;

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Abstract

La présente invention concerne un agent de dégradation de protéine SOS1 et son utilisation. Spécifiquement, la présente invention concerne une formule (I) pour un composé S-L-E, et un stéréoisomère, un énantiomère, un diastéréomère, un composé deutéré, un hydrate, un solvate, un promédicament ou un sel pharmaceutiquement acceptable de celui-ci tel que représenté. Le S-L-E est tel que représenté dans la formule (I). Le composé est de structure nouvelle et a un bon effet de dégradation sur la protéine SOS1.
PCT/CN2023/125976 2022-10-21 2023-10-23 Agent de dégradation de protéine sos1 et son utilisation WO2024083257A1 (fr)

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CN202310842205 2023-07-11
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109071552A (zh) * 2016-04-22 2018-12-21 达纳－法伯癌症研究所公司 细胞周期蛋白依赖性激酶4/6(cdk4/6)通过cdk4/6抑制剂与e3连接酶配体的缀合的降解及使用方法
WO2022170952A1 (fr) * 2021-02-09 2022-08-18 苏州阿尔脉生物科技有限公司 Dérivé de pyridazinone polycyclique servant d'inhibiteur de sos1, son procédé de préparation et son utilisation
CN115135315A (zh) * 2019-12-20 2022-09-30 米拉蒂治疗股份有限公司 Sos1抑制剂
WO2022271679A1 (fr) * 2021-06-21 2022-12-29 Mirati Therapeutics, Inc. Inhibiteurs de sos1
CN116768861A (zh) * 2022-06-23 2023-09-19 北京福元医药股份有限公司 Sos1蛋白降解靶向嵌合体及其组合物、制剂和用途
WO2023178130A1 (fr) * 2022-03-16 2023-09-21 Biotheryx, Inc. Agents de dégradation de protéine sos1, compositions pharmaceutiques et applications thérapeutiques

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109071552A (zh) * 2016-04-22 2018-12-21 达纳－法伯癌症研究所公司 细胞周期蛋白依赖性激酶4/6(cdk4/6)通过cdk4/6抑制剂与e3连接酶配体的缀合的降解及使用方法
CN115135315A (zh) * 2019-12-20 2022-09-30 米拉蒂治疗股份有限公司 Sos1抑制剂
WO2022170952A1 (fr) * 2021-02-09 2022-08-18 苏州阿尔脉生物科技有限公司 Dérivé de pyridazinone polycyclique servant d'inhibiteur de sos1, son procédé de préparation et son utilisation
WO2022271679A1 (fr) * 2021-06-21 2022-12-29 Mirati Therapeutics, Inc. Inhibiteurs de sos1
WO2023178130A1 (fr) * 2022-03-16 2023-09-21 Biotheryx, Inc. Agents de dégradation de protéine sos1, compositions pharmaceutiques et applications thérapeutiques
CN116768861A (zh) * 2022-06-23 2023-09-19 北京福元医药股份有限公司 Sos1蛋白降解靶向嵌合体及其组合物、制剂和用途

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