CN113912589B

CN113912589B - Compounds that inhibit and induce protein degradation

Info

Publication number: CN113912589B
Application number: CN202110771189.4A
Authority: CN
Inventors: 甘乐凌; 连敬堂; 马明阳; 付明月; 王俊恒; 周丽莹; 刘亚男
Original assignee: Beijing Tide Pharmaceutical Co Ltd
Current assignee: Beijing Tide Pharmaceutical Co Ltd
Priority date: 2020-07-08
Filing date: 2021-07-08
Publication date: 2023-10-20
Anticipated expiration: 2041-07-08
Also published as: CN117327059A; CN113912589A

Abstract

The present invention relates to compounds of formula (I), and pharmaceutical compositions containing said compounds, useful for inhibiting and inducing degradation of ErBb2, ER and AR proteins, useful for treating tumors associated with high expression of ErBb2, ER and AR proteins, such as lung cancer, breast cancer, prostate cancer, and the like. The invention also relates to the preparation and application of the compound.

Description

Compounds that inhibit and induce protein degradation

Technical Field

The invention relates to the field of medicines, and in particular provides a compound capable of inhibiting and inducing protein degradation, a preparation method and application thereof; specifically, the proteins include ErBb2, ER and AR.

Background

Ubiquitin-proteinase system (UPS) is a multicomponent system for degradation of intracellular proteins, and is involved in important physiological and biochemical processes such as cell growth and differentiation, DNA replication and repair, cell metabolism, immune response and the like. Ubiquitin-proteasome pathway mediated protein degradation is an important mechanism of body regulating intracellular protein level and function, playing an important role in maintaining protein homeostasis in vivo. Through the intracellular ubiquitin-proteasome approach, erBb2, ER and AR proteins are induced to degrade, and a new idea is provided for treating diseases related to the high expression of the proteins.

Erb-B2 (tyrosine kinase receptor 2) is a 185kDa cell membrane receptor encoded by the proto-oncogene erbB-2 and is a subtype of the epidermal growth factor receptor (epidermal growth factor receptor, EGFR), human epidermal growth factor receptor 2 (HER 2). It is currently known that more than 30% of human tumors have amplified/over-expressed HER2 gene (e.g., breast, ovarian, endometrial, fallopian tube, gastric, and prostate cancers), and that over-expression of HER2 is associated with tumor development and invasion, increasing the risk of metastasis, and altering the sensitivity of tumors to hormones and chemotherapeutic drugs. Therefore, the overexpression of the HER2 gene is not only related to the occurrence and development of tumors, but also is an important clinical treatment monitoring and prognosis index and an important target point for selecting tumor targeted therapeutic drugs. The current HER2 targeting drug is mainly used for treating breast cancer and also has wide application in treating non-small cell lung cancer and gastric cancer.

ER (Estrogen receptor ) is present in cells of target organs and can specifically bind to estrogen to form hormone-receptor complexes, thereby allowing the hormone to exert its biological effects. Antiestrogen therapy is one of the main methods of treating breast cancer today, since Estrogen Receptors (ERs) are found in high expression in about 70% of breast cancer patients' tumor tissues, and tumor growth is stimulated by estrogen.

AR (Androgen receptor) is a nuclear receptor with testosterone as a main ligand, and exerts various biological effects on target cells after binding to Androgen. It is currently known that AR is one of the key drivers for prostate cancer, and thus anti-androgen therapy is an important therapeutic approach for prostate cancer, and that AR also has a certain potential value in the treatment of breast cancer.

Thus, the present invention provides compounds capable of inhibiting ErBb2, ER and AR proteins, and/or inducing degradation of ErBb2, ER and AR proteins, and methods of making and using the same.

Disclosure of Invention

In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof:

wherein, the liquid crystal display device comprises a liquid crystal display device,

represents a single bond or a double bond;

indicating that the attachment site to the other part of the molecule may be located at the available position of the ring;

Z ₁ o, S, N or C atom, optionally substituted with one or two R _Z1 Substitution; or Z is ₁ Is not present, thus Z ₄ To Z ₂ 、Z ₃ Or with Z ₁ C atoms in attached aromatic rings and not attached Z ₄ And Z of (2) ₁ Z is connected to ₂ And the C atom on the aromatic ring is attached to R; or Z is ₁ 、Z ₂ And Z ₃ Are all absent, thus Z ₄ Is connected to Z ₁ Or Z is ₃ One of the C atoms on the attached aromatic ring, and the other C atom on the aromatic ring is attached to R;

Z ₂ o, S, N or C atom, optionally substituted with one or two R _Z2 Substitution;

Z ₃ o, S, N or C atom, optionally substituted with one or two R _Z3 Substitution; provided that whenIn the case of double bonds, Z ₂ Is an N or C atom, Z ₃ Is an N or C atom;

Z ₄ is N or CR _Z4 ；

Z ₅ Is N or CR _Z5 ；

R _a 、R _b And R is _c Independently H, halogen, - (CH) ₂ ) _0-5 -OR’、-(CH ₂ ) _0-5 -NR’R”、C _1-6 Alkyl or C _1-6 A haloalkyl group; or R is _a 、R _b Together the C atoms to which they are attached form c= O, C _3-7 Cycloalkyl or 4-8 membered heterocyclyl; or R is _a And R is _c Together the C atoms to which they are attached form C _3-7 Cycloalkyl or 4-8 membered heterocyclyl; or R is _a And R is _c Forming a chemical bond;

R _N1 h, C of a shape of H, C _1-6 Alkyl or C _1-6 A haloalkyl group; preferably H;

R _Z1 is absent, H, CN, halogen, - (CH) ₂ ) _0-5 -OR’、-(CH ₂ ) _0-5 -NR’R”、C _1-6 Alkyl, C _1-6 Haloalkyl, - (CH) ₂ ) _0-5 -C _3-7 Cycloalkyl or- (CH) ₂ ) _0-5 -4-8 membered heterocyclyl; or two R _Z1 And Z is ₁ Together form c= O, C _3-7 Cycloalkyl or 4-8 membered heterocyclyl;

R _Z2 is absent, H, CN, halogen, - (CH) ₂ ) _0-5 -OR’、-(CH ₂ ) _0-5 -NR’R”、C _1-6 Alkyl, C _1-6 Haloalkyl, - (CH) ₂ ) _0-5 -C _3-7 Cycloalkyl or- (CH) ₂ ) _0-5 -4-8 membered heterocyclic ringA base; or two R _Z2 And Z is ₂ Together form c= O, C _3-7 Cycloalkyl or 4-8 membered heterocyclyl;

R _Z3 is absent, H, CN, halogen, - (CH) ₂ ) _0-5 -OR’、-(CH ₂ ) _0-5 -NR’R”、C _1-6 Alkyl, C _1-6 Haloalkyl, - (CH) ₂ ) _0-5 -C _3-7 Cycloalkyl or- (CH) ₂ ) _0-5 -4-8 membered heterocyclyl; or two R _Z3 And Z is ₃ Together form c= O, C _3-7 Cycloalkyl or 4-8 membered heterocyclyl;

R _Z4 h, CN, halogen, - (CH) ₂ ) _0-5 -OR’、-(CH ₂ ) _0-5 -NR’R”、C _1-6 Alkyl or C _1-6 A haloalkyl group;

R _Z5 h, CN, halogen, - (CH) ₂ ) _0-5 -OR’、-(CH ₂ ) _0-5 -NR’R”、C _1-6 Alkyl, C _1-6 Haloalkyl, - (CH) ₂ ) _0-5 -C _3-7 Cycloalkyl or- (CH) ₂ ) _0-5 -4-8 membered heterocyclyl;

or Z is ₄ The ring in which it is located is absent;

wherein R is H, CN, halogen, - (CH) ₂ ) _0-5 -OR’、-(CH ₂ ) _0-5 -NR’R”、-C _1-6 Alkyl, C _1-6 Haloalkyl, - (CH) ₂ ) _0-5 -C _3-7 Cycloalkyl, - (CH) ₂ ) _0-5 -4-8 membered heterocyclyl, C _2-6 Alkenyl, C _2-6 Alkynyl, - (CH) ₂ ) _0-5 -C _3-10 Halogenated cycloalkyl, - (CH) ₂ ) _0-5 -C _6-10 Aryl or- (CH) ₂ ) _0-5 -a 5-14 membered heteroaryl;

r' is H, C _1-6 Alkyl, C _1-6 Haloalkyl or- (CH) ₂ ) _0-5 -C _3-7 Cycloalkyl;

r' is H, C _1-6 Alkyl or C _1-6 A haloalkyl group;

or R ', R' together with the N atom to which they are attached form a 4-8 membered heterocyclyl or a 5-14 membered heteroaryl;

L ₁ selected from the group consisting of chemical bonds, -O-, -S (O) _p -、-S(O)(＝NR ^* )-、-NR ^# -、-CR ^# R ^# ’-、-C _a R ^# R ^# ’-C _b R ^# R ^# ’-、-N＝S(O)(R ^* ) -or-S (O) (R ^* )＝N-；

L ₂ Selected from the group consisting of chemical bonds, -O-, -S (O) _p -、-S(O)(＝NR ^* )-、-NR ^# -、-CR ^# R ^# ’-、-C _a R ^# R ^# ’-C _b R ^# R ^# ’-、-N＝S(O)(R ^* ) -or-S (O) (R ^* ) =n-; and when L ₂ When the bond with I is a double bond, L ₂ Selected from-N=, -S (O) (R) ^* )＝、-CR ^# =or-C _a R ^# R ^# ’-C _b R ^# ＝；

Wherein C is _a R ^# R ^# ' or C _b R ^# R ^# ' either of which may be O, S (O) _p 、S(O)(＝NR ^* ) Or NR (NR) ^# Replacement, and when C _a R ^# R ^# ' or C _b R ^# R ^# ' either of which is O, S or NR ^# C at the time of replacement _a R ^# R ^# ' or C _b R ^# R ^# ' the other one can also be S (O) _q Replacement;

e is independently selected from: chemical bond, -C _c R ^# R ^# ’-C _d R ^# R ^# ’-C _e R ^# R ^# ’、

Wherein C is _c R ^# R ^# ’、C _d R ^# R ^# ' or C _e R ^# R ^# ' any one of, or C _c R ^# R ^# ' and C _e R ^# R ^# ' both may be covered O, S (O) _p 、S(O)(＝NR ^* ) Or NR (NR) ^# Replacement, and when C _c R ^# R ^# ’、C _d R ^# R ^# ' or C _e R ^# R ^# ' either of which is O, S or NR ^# At the time of replacement, the other or two adjacent C' s _c R ^# R ^# ’、C _d R ^# R ^# ' or C _e R ^# R ^# ' can also be S (O) _q Replacement;

or two E units may form a-CH ₂ CH ₂ OCH ₂ CH ₂ -、-OCH ₂ CH ₂ CH ₂ CH ₂ -、-CH ₂ CH ₂ CH ₂ CH ₂ O-、

Wherein, the liquid crystal display device comprises a liquid crystal display device,representation and L ₁ Or L ₂ Is a connection point of (2);

H ₁ and H ₂ Is N or C atom, H ₃ O, S, N or C atom, and H ₁ And H ₃ 、H ₂ And H ₃ Are not simultaneously heteroatoms;

H ₄ and H ₅ Is an N or C atom;

H ₆ 、H ₇ 、H ₈ and H ₉ Is a C or N atom;

p is 0, 1 or 2;

q is 1 or 2;

R ^* h, C of a shape of H, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _3-10 Halogenated cycloalkyl, 3-10 membered heterocyclic group, C _6-10 Aryl or 5-14 membered heteroaryl;

R ^# is H, halogen or C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _3-10 Halogenated cycloalkyl, 3-10 membered heterocyclic group, C _6-10 Aryl or 5-14 membered heteroaryl;

R ^# ' H, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _3-10 Halogenated cycloalkyl, 3-10 membered heterocyclic group, C _6-10 Aryl or 5-14 membered heteroaryl;

or R on adjacent atoms ^# And R is ^# Can form a chemical bond, R on adjacent atoms ^# ' and R ^# ' chemical bonds may be formed; r on adjacent atoms ^# And R is ^# ' chemical bonds may be formed;

alternatively, R on the same or different atoms ^# And R is ^# ' may together form =o, or optionally R _x Substituted C _3-7 Cycloalkyl, 4-8 membered heterocyclyl, C _6-10 Aryl or 5-6 membered heteroaryl, wherein R is _x H, CN, halogen, C _1-6 Alkyl or C _1-6 A haloalkyl group;

m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

R _s1 selected from H, CN, halogen, - (CH) ₂ ) _0-5 -OR’、-(CH ₂ ) _0-5 -NR’R”、C _1-6 Alkyl, C _1-6 Haloalkyl, - (CH) ₂ ) _0-5 -4-8 membered heterocyclyl, C _2-6 Alkenyl, C _2-6 Alkynyl, - (CH) ₂ ) _0-5 -C _3-7 Cycloalkyl, - (CH) ₂ ) _0-5 -C _3-10 Halogenated cycloalkyl, - (CH) ₂ ) _0-5 -C _6-10 Aryl, - (CH) ₂ ) _0-5 -5-14 membered heteroaryl, -C (O) R, -S (O) R or-S (O) ₂ R；

s1 is 0, 1, 2 or 3;

i is selected from the following:

wherein the method comprises the steps ofRepresents the position of attachment to the remainder of the molecule;

R ₁ to R ₈ Independently selected from H, halogen, -OR ', -NR ' R ', C _1-6 Alkyl or C _1-6 A haloalkyl group; and R is ₁ And R is R ₂ Can combine to form =o; r is R ₃ And R is R ₄ Can combine to form =o;

one part of a and b is a single bond, and the other part is a double bond;

the above alkyl, alkylene, haloalkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl or L ₁ 、E、L ₂ Contains OH, NH and NH ₂ 、CH、CH ₂ 、CH ₃ Each of which is optionally substituted at each occurrence by 1, 2, 3 or more R ^s Substitution, wherein said R ^s Independently at each occurrence selected from: halogen, hydroxy, amino, cyano, nitro, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _3-10 Halogenated cycloalkyl, 3-10 membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, -OR ^a’ 、-OC(O)R ^a’ 、-C(O)R ^a’ 、-C(O)OR ^a’ 、-C(O)NR ^a’ R ^b’ 、-S(O) _n R ^a’ 、-S(O) _n OR ^a’ 、-S(O) _n NR ^a’ R ^b’ 、-NR ^a’ R ^b’ 、-NR ^a’ C(O)R ^b’ 、-NR ^a’ -C(O)OR ^b’ 、-NR ^a’ -S(O) _n -R ^b’ 、-NR ^a’ C(O)NR ^a’ R ^b’ 、-C _1-6 Alkylene group-R ^a’ 、-C _1-6 alkylene-OR ^a’ 、-C _1-6 alkylene-OC (O) R ^a’ 、-C _1-6 alkylene-C (O) OR ^a’ 、-C _1-6 alkylene-S (O) _n R ^a’ 、-C _1-6 alkylene-S (O) _n OR ^a’ 、-C _1-6 alkylene-OC (O) NR ^a’ R ^b’ 、-C _1-6 alkylene-C (O) NR ^a’ R ^b’ 、-C _1-6 alkylene-NR ^a’ -C(O)NR ^a’ R ^b’ 、-C _1-6 alkylene-OS (O) _n R ^a’ 、-C _1-6 alkylene-S (O) _n NR ^a’ R ^b’ 、-C _1-6 alkylene-NR ^a’ -S(O) _n NR ^a’ R ^b’ 、-C _1-6 alkylene-NR ^a’ R ^b’ and-O-C _1-6 alkylene-NR ^a’ R ^b’ And wherein R is a substituent ^s The hydroxy, amino, alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl groups are further optionally substituted with 1, 2, 3, or more substituents independently selected from the group consisting of: halogen, OH, amino, cyano, nitro, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkyl hydroxy, C _3-6 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 An aralkyl group;

n is each occurrence independently 1 or 2;

R ^a’ and R is ^b’ Each at each occurrence is independently selected from H, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 alkyl-O-, C _1-6 alkyl-S-, C _3-10 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 Aralkyl groups.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient.

In another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient, which also contains an additional therapeutic agent.

In another aspect, the invention provides kits comprising a compound of the invention, and other therapeutic agent, together with a pharmaceutically acceptable carrier, adjuvant or vehicle.

In another aspect, the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment and/or prophylaxis of cancer.

In another aspect, the invention provides a method of treating and/or preventing cancer in a subject comprising administering to the subject a compound of the invention or a composition of the invention.

In another aspect, the present invention provides a compound of the invention or a composition of the invention for use in the treatment and/or prevention of cancer.

In specific embodiments, the cancer is selected from lung cancer, breast cancer, gastric cancer, prostate cancer, in particular from HER2 positive metastatic breast cancer, HER2 overexpressed metastatic gastric or gastroesophageal junction adenocarcinoma, non-small cell lung cancer with an Epidermal Growth Factor Receptor (EGFR) gene sensitive mutation, locally advanced or metastatic squamous histological type non-small cell lung cancer with disease progression during or after platinum-containing chemotherapy, metastatic advanced breast cancer, castration-resistant prostate cancer.

Furthermore, the compounds, compositions or medicaments of the invention are useful as an adjunct treatment for HER2 over-expressing breast cancer.

Furthermore, the compounds, compositions or medicaments of the invention are useful as treatment of Estrogen Receptor (ER) induced breast cancer.

Furthermore, the compounds, compositions or medicaments of the invention are useful as treatment of Androgen Receptor (AR) induced breast cancer or prostate cancer.

Other objects and advantages of the present invention will be apparent to those skilled in the art from the detailed description, examples, and claims that follow.

Drawings

FIG. 1 shows the results of an experiment of the degradation of the ErBb2 protein of the breast cancer cell line (BT 474) by the compounds of the invention.

FIG. 2 is the results of an experiment of degradation of LNCaP cell AR protein by Compounds A1-8.

Definition of the definition

Chemical definition

The definition of specific functional groups and chemical terms is described in more detail below.

When numerical ranges are listed, it is intended to include each and every value and subrange within the range. For example "C _1-6 Alkyl "includes C ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ 、C ₆ 、C _1-6 、C _1-5 、C _1-4 、C _1-3 、C _1-2 、C _2-6 、C _2-5 、C _2-4 、C _2-3 、C _3-6 、C _3-5 、C _3-4 、C _4-6 、C _4-5 And C _5-6 An alkyl group.

“C _1-6 Alkyl "refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C _1-4 Alkyl groups are preferred. C (C) _1-6 Examples of alkyl groups include: methyl (C) ₁ ) Ethyl (C) ₂ ) N-propyl (C) ₃ ) Isopropyl (C) ₃ ) N-butyl (C) ₄ ) Tert-butyl (C) ₄ ) Sec-butyl (C) ₄ ) Isobutyl (C) ₄ ) N-pentyl (C) ₅ ) 3-pentyl (C) ₅ ) Amyl (C) ₅ ) Neopentyl (C) ₅ ) 3-methyl-2-butyl (C) ₅ ) Tert-amyl (C) ₅ ) And n-hexyl (C) ₆ ). The term "C _1-6 Alkyl "also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: me (-CH) ₃ )、Et(-CH ₂ CH ₃ )、iPr(-CH(CH ₃ ) ₂ )、nPr(-CH ₂ CH ₂ CH ₃ )、n-Bu(-CH ₂ CH ₂ CH ₂ CH ₃ ) Or i-Bu (-CH) ₂ CH(CH ₃ ) ₂ )。

“C _2-6 Alkenyl "refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C _2-4 Alkenyl groups are preferred. C (C) _2-6 Examples of alkenyl groups include: vinyl (C) ₂ ) 1-propenyl (C) ₃ ) 2-propenyl (C) ₃ ) 1-butenyl (C) ₄ ) 2-butenyl (C) ₄ ) Butadiene group (C) ₄ ) Pentenyl (C) ₅ ) Pentadienyl (C) ₅ ) Hexenyl (C) ₆ ) And so on. The term "C _2-6 Alkenyl "also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C _2-6 Alkynyl "refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C _2-4 Alkynyl groups are preferred. C (C) _2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C) ₂ ) 1-propynyl (C) ₃ ) 2-propynyl (C) ₃ ) 1-butynyl (C) ₄ ) 2-butynyl (C) ₄ ) Pentynyl (C) ₅ ) Hexynyl (C) ₆ ) And so on. The term "C _2-6 Alkynyl "also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C _1-6 Alkylene, C _2-6 Alkenylene or C _2-6 Alkynylene "refers to" C "as defined above _1-6 Alkyl, C _2-6 Alkenyl or C _2-6 Alkynyl "divalent radicals.

“C _1-6 Alkylene "means removal of C _1-6 The other hydrogen of the alkyl group forms a divalent group and may be substituted or unsubstituted. In some embodiments, C _1-4 Alkylene groups are particularly preferred. Unsubstituted alkylene groups include, but are not limited to: methylene (-CH) ₂ (-), ethylene (-CH) ₂ CH ₂ (-), propylene (-CH) ₂ CH ₂ CH ₂ -) and butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ -) pentylene (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₂ (-), hexylene (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ (-), etc. Exemplary substituted alkylene groups, for example, alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH (CH) ₃ )-、-C(CH ₃ ) ₂ (-), substituted ethylene (-CH (CH) ₃ )CH ₂ -、-CH ₂ CH(CH ₃ )-、-C(CH ₃ ) ₂ CH ₂ -、-CH ₂ C(CH ₃ ) _2- ) Substituted propylene (-CH (CH) ₃ )CH ₂ CH ₂ -、-CH ₂ CH(CH ₃ )CH ₂ -、-CH ₂ CH ₂ CH(CH ₃ )-、-C(CH ₃ ) ₂ CH ₂ CH ₂ -、-CH ₂ C(CH ₃ ) ₂ CH ₂ -、-CH ₂ CH ₂ C(CH ₃ ) ₂ (-), etc.

“C _2-6 Alkenylene "means removal of C _2-6 The other hydrogen of the alkenyl group forms a divalent group and may be substituted or unsubstituted. In some embodiments, C _2-4 Alkenylene is particularly preferred. Exemplary unsubstituted alkenylenes include, but are not limited to: ethenylene (-ch=ch-) and propenylene (e.g., -ch=chch) ₂ -、-CH ₂ -ch=ch-). Exemplary substituted alkenylenes, such as alkenylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted ethylene (-C (CH) ₃ )＝CH-、-CH＝C(CH ₃ ) (-), substituted propenylene (-C (CH) ₃ )＝CHCH ₂ -、-CH＝C(CH ₃ )CH ₂ -、-CH＝CHCH(CH ₃ )-、-CH＝CHC(CH ₃ ) ₂ -、-CH(CH ₃ )-CH＝CH-、-C(CH ₃ ) ₂ -CH＝CH-、-CH ₂ -C(CH ₃ )＝CH-、-CH ₂ -CH＝C(CH ₃ ) (-), etc.

“C _2-6 Alkynylene "refers to removal of C _2-6 The other hydrogen of the alkynyl group forms a divalent group and may be substituted or unsubstituted. In some embodiments, C _2-4 Alkynylene groups are particularly preferred. Exemplary such alkynylene groups include, but are not limited to: ethynylene (-C.ident.C-), substituted or unsubstituted propynylene (-C.ident.CCH) ₂ (-), etc.

“C _1-6 Heteroalkyl "means C as defined herein _1-6 Alkyl, and within the parent chain it further contains one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein one or more heteroatoms are between adjacent carbon atoms within the parent carbon chain, and/or one or more heteroatoms are between a carbon atom and the parent molecule, i.e., between the points of attachment. C (C) _1-6 The point of attachment of the heteroalkyl group to the parent molecule may be a carbon atom or a heteroatom.

“C _2-6 Alkylene "means removal of C _1-6 The other hydrogen of the heteroalkyl group is a divalent group and may be substituted or unsubstituted. C (C) _1-6 The point of attachment of the alkylene group to the remainder of the parent molecule may be two carbon atoms, may be two heteroatoms, or may be one carbon atom and one heteroatom.

"halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

Thus, "C _1-6 Haloalkyl "means" C "as described above _1-6 Alkyl ", substituted with one or more halo groups. In some embodiments, C _1-4 Haloalkyl is particularly preferred, more preferably C _1-2 A haloalkyl group. Exemplary such haloalkyl groups include, but are not limited to: -CF ₃ 、-CH ₂ F、-CHF ₂ 、-CHFCH ₂ F、-CH ₂ CHF ₂ 、-CF ₂ CF ₃ 、-CCl ₃ 、-CH ₂ Cl、-CHCl ₂ 2, 2-trifluoro-1, 1-dimethyl-ethyl, and the like. The haloalkyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C _3-10 Cycloalkyl "refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C _3-7 Cycloalkyl and C _3-6 Cycloalkyl is particularly preferred, more preferably C _5-6 Cycloalkyl groups. Cycloalkyl also includes ring systems in which the cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary such cycloalkyl groups include, but are not limited to: cyclopropyl (C) ₃ ) Cyclopropenyl (C) ₃ ) Cyclobutyl (C) ₄ ) Cyclobutenyl (C) ₄ ) Cyclopentyl (C) ₅ ) Cyclopentenyl (C) ₅ ) Cyclohexyl (C) ₆ ) Cyclohexenyl (C) ₆ ) Cyclohexadienyl (C) ₆ ) Cycloheptyl (C) ₇ ) Cycloheptenyl (C) ₇ ) Cycloheptadienyl (C) ₇ ) Cycloheptatrienyl (C) ₇ ) And so on. Cycloalkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C _3-10 Halogenated cycloalkyl "means" C "as described above _3-10 Cycloalkyl ", substituted with one or more halo groups.

"3-12 membered heterocyclyl" refers to a group of a 3 to 12 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon. In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as the valence permits. In some embodiments, a 4-12 membered heterocyclic group is preferred, which is a 4-12 membered non-aromatic ring system having a ring carbon atom and 1 to 5 ring heteroatoms; in some embodiments, 3-10 membered heterocyclyl is preferred, which is a 3-10 membered non-aromatic ring system having a ring carbon atom and 1 to 5 ring heteroatoms; in some embodiments, 3-8 membered is preferredHeterocyclyl, which is a 3 to 8 membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms; preferably a 3-6 membered heterocyclic group which is a 3 to 6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; preferably a 4-8 membered heterocyclic group which is a 4-to 8-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; more preferably a 5-6 membered heterocyclic group which is a 5-to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms. Heterocyclyl further includes ring systems in which the above heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or ring systems in which the above heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridinyl, oxetanyl, thietanyl (thio). Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolanyl, oxathiolanyl (oxathiolanyl), dithiolanyl (disulfuranyl) and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6 membered heterocyclyl groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl (thianyl). Exemplary 6 membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiocyclohexenyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepanyl, oxepinyl, and thiepanyl. Exemplary embodiments And C of (C) ₆ Aryl ring fused 5-membered heterocyclyl groups (also referred to herein as 5, 6-bicyclic heterocyclyl groups) include, but are not limited to: indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary AND C ₆ Aryl ring fused 6 membered heterocyclyl (also referred to herein as 6, 6-bicyclic heterocyclyl) groups include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"4-12 membered heterocyclylene" and "5-6 membered heterocyclylene" represent the above-described "4-12 membered heterocyclyl" and "5-6 membered heterocyclyl", respectively, wherein the other hydrogen is removed to form a divalent group, and may be substituted or unsubstituted.

“C _6-10 Aryl "refers to a group of a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) having 6 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C ₆ Aryl "; for example, phenyl). In some embodiments, aryl groups have ten ring carbon atoms ("C ₁₀ Aryl "; for example, naphthyl groups, such as 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the above aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C _6-12 Aralkyl "means a group-R ', where R is an alkyl moiety, R' is an aryl moiety, and the alkyl and aryl groups have 6 to 12 carbon atoms in total.

"5-14 membered heteroaryl" refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as the valency permits. The heteroaryl bicyclic ring system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, a 5-10 membered heteroaryl group is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (e.g., 1,2, 4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: a pyridyl group. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetrazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azetidinyl, oxepinyl, and thiepinyl. Exemplary 5, 6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazole, benzothienyl, isobenzothienyl, benzofuranyl, benzisotofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiadiazolyl, indenazinyl and purinyl. Exemplary 6, 6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl. Heteroaryl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"oxo" means =o.

Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like as defined herein are optionally substituted groups.

Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO ₂ 、-N ₃ 、-SO ₂ H、-SO ₃ H、-OH、-OR ^aa 、-ON(R ^bb ) ₂ 、-N(R ^bb ) ₂ 、-N(R ^bb ) ₃ ⁺ X ^- 、-N(OR ^cc )R ^bb 、-SH、-SR ^aa 、-SSR ^cc 、-C(＝O)R ^aa 、-CO ₂ H、-CHO、-C(OR ^cc ) ₂ 、-CO ₂ R ^aa 、-OC(＝O)R ^aa 、-OCO ₂ R ^aa 、-C(＝O)N(R ^bb ) ₂ 、-OC(＝O)N(R ^bb ) ₂ 、-NR ^bb C(＝O)R ^aa 、-NR ^bb CO ₂ R ^aa 、-NR ^bb C(＝O)N(R ^bb ) ₂ 、-C(＝NR ^bb )R ^aa 、-C(＝NR ^bb )OR ^aa 、-OC(＝NR ^bb )R ^aa 、-OC(＝NR ^bb )OR ^aa 、-C(＝NR ^bb )N(R ^bb ) ₂ 、-OC(＝NR ^bb )N(R ^bb ) ₂ 、-NR ^bb C(＝NR ^bb )N(R ^bb ) ₂ 、-C(＝O)NR ^bb SO ₂ R ^aa 、-NR ^bb SO ₂ R ^aa 、-SO ₂ N(R ^bb ) ₂ 、-SO ₂ R ^aa 、-SO ₂ OR ^aa 、-OSO ₂ R ^aa 、-S(＝O)R ^aa 、-OS(＝O)R ^aa 、-Si(R ^aa ) ₃ 、-OSi(R ^aa ) ₃ 、-C(＝S)N(R ^bb ) ₂ 、-C(＝O)SR ^aa 、-C(＝S)SR ^aa 、-SC(＝S)SR ^aa 、-SC(＝O)SR ^aa 、-OC(＝O)SR ^aa 、-SC(＝O)OR ^aa 、-SC(＝O)R ^aa 、-P(＝O) ₂ R ^aa 、-OP(＝O) ₂ R ^aa 、-P(＝O)(R ^aa ) ₂ 、-OP(＝O)(R ^aa ) ₂ 、-OP(＝O)(OR ^cc ) ₂ 、-P(＝O) ₂ N(R ^bb ) ₂ 、-OP(＝O) ₂ N(R ^bb ) ₂ 、-P(＝O)(NR ^bb ) ₂ 、-OP(＝O)(NR ^bb ) ₂ 、-NR ^bb P(＝O)(OR ^cc ) ₂ 、-NR ^bb P(＝O)(NR ^bb ) ₂ 、-P(R ^cc ) ₂ 、-P(R ^cc ) ₃ 、-OP(R ^cc ) ₂ 、-OP(R ^cc ) ₃ 、-B(R ^aa ) ₂ 、-B(OR ^cc ) ₂ 、-BR ^aa (OR ^cc ) Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R ^dd Group substitution;

or two geminal hydrogen-cover groups on carbon atom=o, =s, =nn (R ^bb ) ₂ 、＝NNR ^bb C(＝O)R ^aa 、＝NNR ^bb C(＝O)OR ^aa 、＝NNR ^bb S(＝O) ₂ R ^aa 、＝NR ^bb Or=nor ^cc Substitution;

R ^aa independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ^aa The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R ^dd Group substitution;

R ^bb independently selected from: hydrogen, -OH, -OR ^aa 、-N(R ^cc ) ₂ 、-CN、-C(＝O)R ^aa 、-C(＝O)N(R ^cc ) ₂ 、-CO ₂ R ^aa 、-SO ₂ R ^aa 、-C(＝NR ^cc )OR ^aa 、-C(＝NR ^cc )N(R ^cc ) ₂ 、-SO ₂ N(R ^cc ) ₂ 、-SO ₂ R ^cc 、-SO ₂ OR ^cc 、-SOR ^aa 、-C(＝S)N(R ^cc ) ₂ 、-C(＝O)SR ^cc 、-C(＝S)SR ^cc 、-P(＝O) ₂ R ^aa 、-P(＝O)(R ^aa ) ₂ 、-P(＝O) ₂ N(R ^cc ) ₂ 、-P(＝O)(NR ^cc ) ₂ Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ^bb The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R ^dd Group substitution;

R ^cc independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ^cc The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R ^dd Group substitution;

R ^dd independently selected from: halogen, -CN, -NO ₂ 、-N ₃ 、-SO ₂ H、-SO ₃ H、-OH、-OR ^ee 、-ON(R ^ff ) ₂ 、-N(R ^ff ) ₂ ,、-N(R ^ff ) ₃ ⁺ X ^- 、-N(OR ^ee )R ^ff 、-SH、-SR ^ee 、-SSR ^ee 、-C(＝O)R ^ee 、-CO ₂ H、-CO ₂ R ^ee 、-OC(＝O)R ^ee 、-OCO ₂ R ^ee 、-C(＝O)N(R ^ff ) ₂ 、-OC(＝O)N(R ^ff ) ₂ 、-NR ^ff C(＝O)R ^ee 、-NR ^ff CO ₂ R ^ee 、-NR ^ff C(＝O)N(R ^ff ) ₂ 、-C(＝NR ^ff )OR ^ee 、-OC(＝NR ^ff )R ^ee 、-OC(＝NR ^ff )OR ^ee 、-C(＝NR ^ff )N(R ^ff ) ₂ 、-OC(＝NR ^ff )N(R ^ff ) ₂ 、-NR ^ff C(＝NR ^ff )N(R ^ff ) ₂ 、-NR ^ff SO ₂ R ^ee 、-SO ₂ N(R ^ff ) ₂ 、-SO ₂ R ^ee 、-SO ₂ OR ^ee 、-OSO ₂ R ^ee 、-S(＝O)R ^ee 、-Si(R ^ee ) ₃ 、-OSi(R ^ee ) ₃ 、-C(＝S)N(R ^ff ) ₂ 、-C(＝O)SR ^ee 、-C(＝S)SR ^ee 、-SC(＝S)SR ^ee 、-P(＝O) ₂ R ^ee 、-P(＝O)(R ^ee ) ₂ 、-OP(＝O)(R ^ee ) ₂ 、-OP(＝O)(OR ^ee ) ₂ Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R ^gg Substituted by a group, or by two gem R ^dd Substituents may combine to form =o or =s;

R ^ee independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R ^gg Group substitution;

R ^ff independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ^ff The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R ^gg Group substitution;

R ^gg independently is: halogen, -CN, -NO ₂ 、-N ₃ 、-SO ₂ H、-SO ₃ H、-OH、-OC _1-6 Alkyl, -ON (C) _1-6 Alkyl group ₂ 、-N(C _1-6 Alkyl group ₂ 、-N(C _1-6 Alkyl group ₃ ⁺ X ^- 、-NH(C _1-6 Alkyl group ₂ ⁺ X ^- 、-NH ₂ (C _1-6 Alkyl group ⁺ X ^- 、-NH ₃ ⁺ X ^- 、-N(OC _1-6 Alkyl) (C) _1-6 Alkyl), -N (OH) (C _1-6 Alkyl), -NH (OH), -SH, -SC _1-6 Alkyl, -SS (C) _1-6 Alkyl), -C (=o) (C _1-6 Alkyl) -CO ₂ H、-CO ₂ (C _1-6 Alkyl), -OC (=o) (C _1-6 Alkyl), -OCO ₂ (C _1-6 Alkyl), -C (=O) NH ₂ 、-C(＝O)N(C _1-6 Alkyl group ₂ 、-OC(＝O)NH(C _1-6 Alkyl), -NHC (=o) (C _1-6 Alkyl), -N (C) _1-6 Alkyl) C (=O) (C _1-6 Alkyl), -NHCO ₂ (C _1-6 Alkyl), -NHC (=o) N (C) _1-6 Alkyl group ₂ 、-NHC(＝O)NH(C _1-6 Alkyl), -NHC (=o) NH ₂ 、-C(＝NH)O(C _1-6 Alkyl), -OC (=nh) (C _1-6 Alkyl), -OC (=nh) OC _1-6 Alkyl, -C (=nh) N (C _1-6 Alkyl group ₂ 、-C(＝NH)NH(C _1-6 Alkyl), -C (=nh) NH ₂ 、-OC(＝NH)N(C _1-6 Alkyl group ₂ 、-OC(NH)NH(C _1-6 Alkyl), -OC (NH) NH ₂ 、-NHC(NH)N(C _1-6 Alkyl group ₂ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ (C _1-6 Alkyl), -SO ₂ N(C _1-6 Alkyl group ₂ 、-SO ₂ NH(C _1-6 Alkyl), -SO ₂ NH ₂ 、-SO ₂ C _1-6 Alkyl, -SO ₂ OC _1-6 Alkyl, -OSO ₂ C _1-6 Alkyl, -SOC _1-6 Alkyl, -Si (C) _1-6 Alkyl group ₃ 、-OSi(C _1-6 Alkyl group ₃ 、-C(＝S)N(C _1-6 Alkyl group ₂ 、C(＝S)NH(C _1-6 Alkyl), C (=S) NH ₂ 、-C(＝O)S(C _1-6 Alkyl), -C (=S) SC _1-6 Alkyl, -SC (=s) SC _1-6 Alkyl, -P (=o) ₂ (C _1-6 Alkyl), -P (=o) (C _1-6 Alkyl group ₂ 、-OP(＝O)(C _1-6 Alkyl group ₂ 、-OP(＝O)(OC _1-6 Alkyl group ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₃ -C ₇ Cycloalkyl, C ₆ -C ₁₀ Aryl, C ₃ -C ₇ Heterocyclyl, C ₅ -C ₁₀ Heteroaryl; or two gem R ^gg Substituents may combine to form =o or =s; wherein X is ^- Is a counter ion.

Exemplary substituents on nitrogen atoms include, but are not limited to: hydrogen, -OH, -OR ^aa 、-N(R ^cc ) ₂ 、-CN、-C(＝O)R ^aa 、-C(＝O)N(R ^cc ) ₂ 、-CO ₂ R ^aa 、-SO ₂ R ^aa 、-C(＝NR ^bb )R ^aa 、-C(＝NR ^cc )OR ^aa 、-C(＝NR ^cc )N(R ^cc ) ₂ 、-SO ₂ N(R ^cc ) ₂ 、-SO ₂ R ^cc 、-SO ₂ OR ^cc 、-SOR ^aa 、-C(＝S)N(R ^cc ) ₂ 、-C(＝O)SR ^cc 、-C(＝S)SR ^cc 、-P(＝O) ₂ R ^aa 、-P(＝O)(R ^aa ) ₂ 、-P(＝O) ₂ N(R ^cc ) ₂ 、-P(＝O)(NR ^cc ) ₂ Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R's attached to a nitrogen atom ^cc The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R ^dd Substituted with radicals, and wherein R ^aa 、R ^bb 、R ^cc And R is ^dd As described above.

Other definitions

The term "cancer" includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and pharynx (mouth), lip, tongue, oral cavity, pharynx, small intestine, colorectal, large intestine, rectum, brain and central nervous system cancers, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, renal carcinoma, myelodisorders, lymphomas, hodgkin's disease, hairy cell carcinoma and leukemia. More specifically, cancers include, but are not limited to, HER2 positive metastatic breast cancer, HER2 overexpressed metastatic gastric or gastroesophageal junction adenocarcinoma, non-small cell lung cancer with an Epidermal Growth Factor Receptor (EGFR) gene sensitive mutation, locally advanced or metastatic squamous histological type non-small cell lung cancer with disease progression during or after platinum-containing chemotherapy, metastatic advanced breast cancer, castration-resistant prostate cancer.

The term "treating" as used herein relates to reversing, alleviating, inhibiting the progression or prevention of a disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein relates to the action of a verb treatment, the latter as just defined.

The term "pharmaceutically acceptable salts" as used herein means those carboxylate salts, amino acid addition salts of the compounds of the invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, and effective for their intended use, including (if possible) zwitterionic forms of the compounds of the invention.

Pharmaceutically acceptable base addition salts are formed with metals or amines, for example alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.

The base addition salts of the acidic compounds may be prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt, in a conventional manner. The free acid can be regenerated by contacting the salt form with the acid in a conventional manner, isolating the free acid. The free acid forms differ somewhat in certain physical properties from their respective salt forms, such as solubility in polar solvents, but for the purposes of the present invention, the salts are also equivalent to their respective free acids.

The salt may be a sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide prepared from an inorganic acid, an acid such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, isethionate, and the like. Salts may also be prepared from organic acids, such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzates, dinitrobenzoates, naphthoates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, methanesulfonates, and the like. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Salts of amino acids, such as arginine salts, gluconate salts, galacturonate salts, and the like are also contemplated (see, e.g., berge s.m. et al., "Pharmaceutical Salts," j.pharm.sci.,1977;66:1-19, incorporated herein by reference).

The "subject" to be administered includes, but is not limited to: a human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle aged adults, or senior adults)) and/or a non-human animal, e.g., a mammal, e.g., a primate (e.g., cynomolgus monkey, rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, and/or dog. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.

"disease," "disorder," and "condition" are used interchangeably herein.

As used herein, unless otherwise indicated, the term "treating" includes an effect that occurs when a subject has a particular disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as an effect that occurs before the subject begins to have the particular disease, disorder, or condition ("prophylactic treatment").

In general, an "effective amount" of a compound refers to an amount sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of the compounds of the present invention may vary depending on the following factors: for example, biological targets, pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age health and symptoms of the subject. The effective amount includes a therapeutically effective amount and a prophylactically effective amount.

As used herein, unless otherwise indicated, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to that amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.

As used herein, unless otherwise indicated, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" may include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic effect of other prophylactic agents.

"combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, the compounds of the invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form.

Detailed description of the preferred embodiments

Herein, "the compounds of the present invention" refers to compounds of the following formula (I) (including sub-formulae, e.g., formula (I-a-1), (I-B-2), (I-G-6), etc.), pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof.

Compounds are named herein using standard nomenclature. Compounds having asymmetric centers, it is to be understood (unless otherwise indicated) that all optical isomers and mixtures thereof are encompassed. Furthermore, unless otherwise specified, all isomeric compounds encompassed by the present invention may occur with carbon-carbon double bonds in the form of Z and E. Compounds that exist in different tautomeric forms, one of the compounds is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.

In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:

represents a single bond or a double bond;

Z ₄ is N or CR _Z4 ；

Z ₅ Is N or CR _Z5 ；

R _Z2 is absent, H, CN, halogen, - (CH) ₂ ) _0-5 -OR’、-(CH ₂ ) _0-5 -NR’R”、C _1-6 Alkyl, C _1-6 Haloalkyl, - (CH) ₂ ) _0-5 -C _3-7 Cycloalkyl or- (CH) ₂ ) _0-5 -4-8 membered heterocyclyl; or two R _Z2 And Z is ₂ Together form c= O, C _3-7 Cycloalkyl or 4-8 membered heterocyclyl;

or Z is ₄ The ring in which it is located is absent;

r' is H, C _1-6 Alkyl, C _1-6 Haloalkyl or- (CH) ₂ ) _0-5 -C _3-7 Cycloalkyl;

r' is H, C _1-6 Alkyl or C _1-6 A haloalkyl group;

H ₄ and H ₅ Is an N or C atom;

H ₆ 、H ₇ 、H ₈ And H ₉ Is a C or N atom;

p is 0, 1 or 2;

q is 1 or 2;

R ^# ' H, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _3-10 Halogenated cycloalkyl and 3-10 membered heterocycleRadical, C _6-10 Aryl or 5-14 membered heteroaryl;

m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

s1 is 0, 1, 2 or 3;

i is selected from the following:

wherein the method comprises the steps ofRepresents the position of attachment to the remainder of the molecule; />

one part of a and b is a single bond, and the other part is a double bond;

n is each occurrence independently 1 or 2;

In one embodiment of the present invention, in one embodiment,represents a single bond; in another embodiment, +_a->Representing a double bond.

Z ₁

In a specific embodiment, Z ₁ Is an O atom; in another embodiment, Z ₁ Is an S atom; in another embodiment, Z ₁ Is an N atom; in another embodiment, Z ₁ Is CAn atom; in another embodiment, Z ₁ Is covered by one R _Z1 Substitution; in another embodiment, Z ₁ Is covered by two R _Z1 Substitution; in another embodiment, Z ₁ Is not present.

Z ₂

In a specific embodiment, Z ₂ Is an O atom; in another embodiment, Z ₂ Is an S atom; in another embodiment, Z ₂ Is an N atom; in another embodiment, Z ₂ Is a C atom; in another embodiment, Z ₂ Is covered by one R _Z2 Substitution; in another embodiment, Z ₂ Is covered by two R _Z2 And (3) substitution.

Z ₃

In a specific embodiment, Z ₃ Is an O atom; in another embodiment, Z ₃ Is an S atom; in another embodiment, Z ₃ Is an N atom; in another embodiment, Z ₃ Is a C atom; in another embodiment, Z ₃ Is covered by one R _Z3 Substitution; in another embodiment, Z ₃ Is covered by two R _Z3 And (3) substitution.

In a specific embodiment, Z ₁ 、Z ₂ And Z ₃ None exist.

Z ₄

In a specific embodiment, Z ₄ Is N; in another embodiment, Z ₄ Is CR (CR) _Z4 。

Z ₅

In a specific embodiment, Z ₅ Is N; in another embodiment, Z ₅ Is CR (CR) _Z5 。

R _a 、R _b And R is _c

In a specific embodiment, R _a Is H; in another embodiment, R _a Is halogen; in another embodiment, R _a Is OR'.The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R _a Is NR 'R'; in another embodiment, R _a Is C _1-6 An alkyl group; in another embodiment, R _a Is C _1-6 A haloalkyl group.

In a specific embodiment, R _b Is H; in another embodiment, R _b Is halogen; in another embodiment, R _b Is OR'; in another embodiment, R _b Is NR 'R'; in another embodiment, R _b Is C _1-6 An alkyl group; in another embodiment, R _b Is C _1-6 A haloalkyl group.

In a specific embodiment, R _c Is H; in another embodiment, R _c Is halogen; in another embodiment, R _c Is OR'; in another embodiment, R _c Is NR 'R'; in another embodiment, R _c Is C _1-6 An alkyl group; in another embodiment, R _c Is C _1-6 A haloalkyl group.

In a specific embodiment, R _a 、R _b And the C atoms to which they are attached together form c=o; in another embodiment, R _a 、R _b Together the C atoms to which they are attached form C _3-7 Cycloalkyl; in another embodiment, R _a 、R _b And the C atoms to which they are attached together form a 4-8 membered heterocyclic group; in another embodiment, R _a And R is _c Forming a chemical bond; in another embodiment, R _a And R is _c Together the C atoms to which they are attached form C _3-7 Cycloalkyl or 4-8 membered heterocyclyl.

R _N1

In a specific embodiment, R _N1 Is H; in another embodiment, R _N1 Is C _1-6 An alkyl group; in another embodiment, R _N1 Is C _1-6 A haloalkyl group.

R _Z1

In a specific embodiment, R _Z1 Absence of; in another embodiment, R _Z1 Is H; in another embodiment, R _Z1 Is CN; in another embodiment, R _Z1 Is halogen; in another embodiment, R _Z1 Is- (CH) ₂ ) _0-5 -OR'; in another embodiment, R _Z1 Is- (CH) ₂ ) _0-5 -NR' R "; in another embodiment, R _Z1 Is C _1-6 An alkyl group; in another embodiment, R _Z1 Is C _1-6 A haloalkyl group; in another embodiment, R _Z1 Is- (CH) ₂ ) _0-5 -C _3-7 Cycloalkyl; in another embodiment, R _Z1 Is- (CH) ₂ ) _0-5 -4-8 membered heterocyclyl; in another embodiment, two R' s _Z1 And Z is ₁ Together, c=o; in another embodiment, two R' s _Z1 And Z is ₁ Together form C _3-7 Cycloalkyl; in another embodiment, two R' s _Z1 And Z is ₁ Together forming a 4-8 membered heterocyclic group.

R _Z2

In a specific embodiment, R _Z2 Absence of; in another embodiment, R _Z2 Is H; in another embodiment, R _Z2 Is CN; in another embodiment, R _Z2 Is halogen; in another embodiment, R _Z2 Is- (CH) ₂ ) _0-5 -OR'; in another embodiment, R _Z2 Is- (CH) ₂ ) _0-5 -NR' R "; in another embodiment, R _Z2 Is C _1-6 An alkyl group; in another embodiment, R _Z2 Is C _1-6 A haloalkyl group; in another embodiment, R _Z2 Is- (CH) ₂ ) _0-5 -C _3-7 Cycloalkyl; in another embodiment, R _Z2 Is- (CH) ₂ ) _0-5 -4-8 membered heterocyclic ringA base; in another embodiment, two R' s _Z2 And Z is ₂ Together, c=o; in another embodiment, two R' s _Z2 And Z is ₂ Together form C _3-7 Cycloalkyl; in another embodiment, two R' s _Z2 And Z is ₂ Together forming a 4-8 membered heterocyclic group.

R _Z3

In a specific embodiment, R _Z3 Absence of; in another embodiment, R _Z3 Is H; in another embodiment, R _Z3 Is CN; in another embodiment, R _Z3 Is halogen; in another embodiment, R _Z3 Is- (CH) ₂ ) _0-5 -OR'; in another embodiment, R _Z3 Is- (CH) ₂ ) _0-5 -NR' R "; in another embodiment, R _Z3 Is C _1-6 An alkyl group; in another embodiment, R _Z3 Is C _1-6 A haloalkyl group; in another embodiment, R _Z3 Is- (CH) ₂ ) _0-5 -C _3-7 Cycloalkyl; in another embodiment, R _Z3 Is- (CH) ₂ ) _0-5 -4-8 membered heterocyclyl; in another embodiment, two R' s _Z3 And Z is ₃ Together, c=o; in another embodiment, two R' s _Z3 And Z is ₃ Together form C _3-7 Cycloalkyl; in another embodiment, two R' s _Z3 And Z is ₃ Together forming a 4-8 membered heterocyclic group.

R _Z4

In a specific embodiment, R _Z4 Is H; in another embodiment, R _Z4 Is CN; in another embodiment, R _Z4 Is halogen; in another embodiment, R _Z4 Is- (CH) ₂ ) _0-5 -OR'; in another embodiment, R _Z4 Is- (CH) ₂ ) _0-5 -NR' R "; in another embodiment, R _Z4 Is C _1-6 An alkyl group; in another embodimentIn embodiments, R _Z4 Is C _1-6 A haloalkyl group.

R _Z5

In a specific embodiment, R _Z5 Is H; in another embodiment, R _Z5 Is CN; in another embodiment, R _Z5 Is halogen; in another embodiment, R _Z5 Is- (CH) ₂ ) _0-5 -OR'; in another embodiment, R _Z5 Is- (CH) ₂ ) _0-5 -NR' R "; in another embodiment, R _Z5 Is C _1-6 An alkyl group; in another embodiment, R _Z5 Is C _1-6 A haloalkyl group; in another embodiment, R _Z5 Is- (CH) ₂ ) _0-5 -C _3-7 Cycloalkyl; in another embodiment, R _Z5 Is- (CH) ₂ ) _0-5 -4-8 membered heterocyclyl.

In a specific embodiment, Z ₄ The ring in which it is located is not present.

L ₁

In a specific embodiment, L ₁ Is a chemical bond; in another embodiment, L ₁ is-O-; in another embodiment, L ₁ is-S (O) _p -; in another embodiment, L ₁ is-S (O) (=NR) ^* ) -; in another embodiment, L ₁ is-NR ^# -; in another embodiment, L ₁ is-CR ^# R ^# 's' -; in another embodiment, L ₁ is-C _a R ^# R ^# ’-C _b R ^# R ^# 's' -; in another embodiment, L ₁ Is-n=s (O) (R ^* ) -; in another embodiment, L ₁ is-S (O) (R ^* )＝N-。

L ₂

In a specific embodiment, L ₂ Is a chemical bond; in another embodiment, L ₂ is-O-; in another embodiment ，L ₂ is-S (O) _p -; in another embodiment, L ₂ is-S (O) (=NR) ^* ) -; in another embodiment, L ₂ is-NR ^# -; in another embodiment, L ₂ is-CR ^# R ^# 's' -; in another embodiment, L ₂ is-C _a R ^# R ^# ’-C _b R ^# R ^# 's' -; in another embodiment, L ₂ Is-n=s (O) (R ^* ) -; in another embodiment, L ₂ is-S (O) (R ^* ) =n-; in another embodiment, L ₂ Is-n=; in another embodiment, L ₂ is-S (O) (R ^* ) =; in another embodiment, L ₂ is-CR ^# =; in another embodiment, L ₂ is-C _a R ^# R ^# ’-C _b R ^# ＝。

In another embodiment, L ₁ Or L ₂ C in (C) _a R ^# R ^# ' or C _b R ^# R ^# ' either of which may be O, S (O) _p 、S(O)(＝NR ^* ) Or NR (NR) ^# Replacement, and when C _a R ^# R ^# ' or C _b R ^# R ^# ' either of which is O, S or NR ^# C at the time of replacement _a R ^# R ^# ' or C _b R ^# R ^# ' the other one can also be S (O) _q And (5) replacing.

E

In a specific embodiment, E is a bond; in another embodiment, E is-C _c R ^# R ^# ’-C _d R ^# R ^# ’-C _e R ^# R ^# 'A'; in another embodiment, E isIn another embodiment E is +.>In another embodiment E is +.>In another embodiment, E isIn another embodiment E is +. >

In another embodiment, C _c R ^# R ^# ’、C _d R ^# R ^# ' or C _e R ^# R ^# ' any one of, or C _c R ^# R ^# ' and C _e R ^# R ^# ' both may be covered O, S (O) _p 、S(O)(＝NR ^* ) Or NR (NR) ^# Replacement, and when C _c R ^# R ^# ’、C _d R ^# R ^# ' or C _e R ^# R ^# ' either of which is O, S or NR ^# At the time of replacement, the other or two adjacent C' s _c R ^# R ^# ’、C _d R ^# R ^# ' or C _e R ^# R ^# ' can also be S (O) _q Replacement;

in another embodiment, two E units may form a-CH ₂ CH ₂ OCH ₂ CH ₂ -; in another embodiment, two E units may form-OCH ₂ CH ₂ CH ₂ CH ₂ -; in another embodiment, two E units may form a-CH ₂ CH ₂ CH ₂ CH ₂ O-; in another embodiment, two E units may formIn another embodiment, two E units may be formedGet->In another embodiment, two E units may form +.>In another embodiment, two E units may form +.>In another embodiment, two E units may form +.>In another embodiment, two E units may form +.>

In another embodiment, at L ₁ 、L ₂ Or E, R on adjacent atoms ^# And R is ^# Can form a chemical bond, R on adjacent atoms ^# ' and R ^# ' chemical bond can be formed, R on adjacent atoms ^# And R is ^# ' chemical bonds may be formed;

in another embodiment, at L ₁ 、L ₂ Or E in the same atom R ^# And R is ^# ' may together form =o, or optionally R _x Substituted C _3-7 Cycloalkyl, 4-8 membered heterocyclyl, C _6-10 Aryl or 5-6 membered heteroaryl; in another embodiment, at L ₁ 、L ₂ Or E, R on different atoms ^# And R is ^# ' may together form an optionally R _x Substituted C _3-7 Cycloalkyl, 4-8 membered heterocyclyl, C _6-10 Aryl or 5-6 membered heteroaryl.

m

In a specific embodiment, m is 0; in another specific embodiment, m is 1; in another specific embodiment, m is 2; in another specific embodiment, m is 3; in another specific embodiment, m is 4; in another specific embodiment, m is 5; in another specific embodiment, m is 6; in another specific embodiment, m is 7; in another specific embodiment, m is 8; in another specific embodiment, m is 9; in another embodiment, m is 10.

I

In one embodiment, I isIn another embodiment, I is +.>In another embodiment, I is In another embodiment, I is +.>In another embodiment, I is +.>In another embodiment, I is +.>In another embodiment, I is +.>In another embodiment, I is

In a more particular embodiment of the above embodiments, R ₁ To R ₈ Independently H; more particularly of the above embodimentsIn particular embodiments, R ₁ To R ₈ Independently halogen; in a more particular embodiment of the above embodiments, R ₁ To R ₈ Independently is-OR'; in a more particular embodiment of the above embodiments, R ₁ To R ₈ Independently is-NR 'R'; in a more particular embodiment of the above embodiments, R ₁ To R ₈ Independently C _1-6 An alkyl group; in a more particular embodiment of the above embodiments, R ₁ To R ₈ Independently C _1-6 A haloalkyl group; in a more particular embodiment of the above embodiments, R ₁ And R is R ₂ Bonding formation = O; in a more particular embodiment of the above embodiments, R ₃ And R is R ₄ Bonding formation = O.

In a more specific embodiment of the above specific embodiments, a is a single bond and b is a double bond; in a more specific embodiment of the above specific embodiments, b is a single bond and a is a double bond.

Any one of the above embodiments or any combination thereof may be combined with any one of the other embodiments or any combination thereof. For example, Z ₁ Any one of the aspects or any combination thereof, can be combined with Z ₂ -Z ₅ 、R _a -R _c 、R _N1 、R _Z1 -R _Z5 Any one of the aspects or any combination thereof. The invention is intended to include all such combinations, limited to the extent that they are not listed.

In a more specific embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,

selected from the following groups:

/>

and one or more H atoms in the above groups may be substituted with a D atom;

preferably, the method comprises the steps of,

selected from->

L ₁ and L ₂ Independently selected from the group consisting of chemical bonds, -O-, -S (O) ₂ -、-S(O)(＝NH)-、-S(O)(＝NMe)-、-NH-、-N(Me)-、/>-N(CF ₃ )-、-CH ₂ -、-CH(OMe)-、-CH(Cl)-、-CH(F)-、-CF ₂ -、-CH(CF ₃ )-、-C(O)-、-CH ₂ CH ₂ -、-CH＝CH-、-C≡C-、-OCH ₂ -、-CH ₂ O-、-SCH ₂ -、-CH ₂ S-、-S(O)CH ₂ -、-CH ₂ S(O)-、-S(O) ₂ CH ₂ -、-CH ₂ S(O) ₂ -、-NHCH ₂ -、-N(Me)CH ₂ -、-CH ₂ NH-、-CH ₂ N(Me)-、-C(O)CH ₂ -、-CH ₂ C(O)-、-C(O)CMe ₂ -、-CMe ₂ C(O)-、-OC(O)-、-C(O)O-、-SC(O)-、-C(O)S-、-NHC(O)-、-N(Me)C(O)-、-C(O)NH-、-C(O)N(Me)-、-S(O)＝NH-、-NH＝S(O)-、-N＝S(O)Me-、-S(O)Me＝N-、/>

And one or more H atoms in the above groups may be substituted with a D atom.

e is selected from chemical bond, -CH ₂ CH ₂ CH ₂ -、-CH ₂ CH＝CH-、-CH＝CHCH ₂ -、-CH ₂ C≡C-、-C≡CCH ₂ -、-CH ₂ CH ₂ C(O)-、-CH ₂ C(O)CH ₂ -、-C(O)CH ₂ CH ₂ -、-CH ₂ CH ₂ S(O) ₂ -、-CH ₂ S(O) ₂ CH ₂ -、-S(O) ₂ CH ₂ CH ₂ -、-C(O)CH＝CH-、-C(O)C≡C-、-CH ₂ CH ₂ O-、-CH ₂ OCH ₂ -、-OCH ₂ CH ₂ -、-CH ₂ CH ₂ S-、-CH ₂ SCH ₂ -、-SCH ₂ CH ₂ -、-C(O)CH ₂ O-、-OCH ₂ C(O)-、-CH ₂ C(O)O-、-C(O)CH ₂ S-、-SCH ₂ C(O)-、-CH ₂ C(O)S-、-OC(O)CH ₂ -、-C(O)OCH ₂ -、-CH ₂ OC(O)-、-SC(O)CH ₂ -、-C(O)SCH ₂ -、-CH ₂ SC(O)-、-CH ₂ CH ₂ NH-、-CH ₂ NHCH ₂ -、-NHCH ₂ CH ₂ -、-CH ₂ CH ₂ NMe-、-CH ₂ NMeCH ₂ -、-NMeCH ₂ CH ₂ -、-C(O)CH ₂ NH-、-NHCH ₂ C(O)-、-CH ₂ C(O)NH-、-NHC(O)CH ₂ -、-C(O)NHCH ₂ -、-CH ₂ NHC(O)-、/>

Either two E units, or two E' units may form a-CH ₂ CH ₂ OCH ₂ CH ₂ -、-OCH ₂ CH ₂ CH ₂ CH ₂ -、-CH ₂ CH ₂ CH ₂ CH ₂ O-、

And one or more H atoms in the above groups may be substituted with a D atom.

-L ₁ -(E) _m -L ₂ -selected from-NH- (CH) ₂ ) _n1 -CH ₂ -、-NH-(CH ₂ ) _n1 -NH-、-NH-(CH ₂ ) _n1 -CH＝、-NH-(CH ₂ ) _n1 -N＝、-NH-(CH ₂ ) _n1 -O-NH-、-NH-(CH ₂ ) _n1 -O-N＝、-NH-(CH ₂ CH ₂ O) _n2 -(CH ₂ ) _n3 -、-NH-(CH ₂ OCH ₂ ) _n2 -(CH ₂ ) _n3 -、-NH-(OCH ₂ CH ₂ ) _n2 -(CH ₂ ) _n3 -、-NH-(CH ₂ CH ₂ O) _n2 -NH-、-NH-(CH ₂ OCH ₂ ) _n2 -NH-、-NH-(OCH ₂ CH ₂ ) _n2 -NH-、-NH-(CH ₂ CH ₂ O) _n2 -CH＝、-NH-(CH ₂ OCH ₂ ) _n2 -CH＝、-NH-(OCH ₂ CH ₂ ) _n2 -CH＝、-NH-(CH ₂ CH ₂ O) _n2 -N＝、-NH-(CH ₂ OCH ₂ ) _n2 -N＝、-NH-(OCH ₂ CH ₂ ) _n2 -N＝、-NH-CH ₂ -CH＝N-NH-C(O)-(CH ₂ ) _n4 -or-NH-CH ₂ -CH＝N-NH-C(O)-NH-；

Wherein n1=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; preferably 2, 3, 4, 5 or 6; preferably 3, 4 or 5;

n2=0, 1, 2, 3, 4 or 5; preferably 1, 2, 3 or 4; preferably 1, 2 or 3;

n3=0, 1, 2 or 3; preferably 1 or 2;

n4=0, 1, 2 or 3; preferably 1 or 2.

I is selected from:

preferably, I is selected from:

in a more specific embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein said compound of formula (I) has the following general structure:

/>

wherein Y is defined as Z ₁ The same, and the other groups are as defined above.

In a more specific embodiment, the present invention provides a compound of the general formula (I-A-1), (I-B-1), (I-C-1), (I-D-1), (I-E-1), (I-F-1), (I-G-1) or (I-H-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein

Y is selected from CH ₂ Or c=o;

-L ₁ -(E) _m -L ₂ -selected from-NH- (CH) ₂ ) _n1 -CH ₂ -、-NH-(CH ₂ ) _n1 -NH-、-NH-(CH ₂ CH ₂ O) _n2 -(CH ₂ ) _n3 -、-NH-(CH ₂ OCH ₂ ) _n2 -(CH ₂ ) _n3 -、-NH-(OCH ₂ CH ₂ ) _n2 -(CH ₂ ) _n3 -、-NH-(CH ₂ CH ₂ O) _n2 -NH-、-NH-(CH ₂ OCH ₂ ) _n2 -NH-、-NH-(OCH ₂ CH ₂ ) _n2 -NH-、-NH-CH ₂ -CH＝N-NH-C(O)-(CH ₂ ) _n4 -or-NH-CH ₂ -CH＝N-NH-C(O)-NH-；

n2=0, 1, 2, 3, 4 or 5; preferably 1, 2, 3 or 4; preferably 1, 2 or 3;

n3=0, 1, 2 or 3; preferably 1 or 2;

n4=0, 1, 2 or 3; preferably 1 or 2.

In a more specific embodiment, the present invention provides compounds of formula (I) are compounds of formula (I-A-2), (I-B-2), (I-C-2), (I-D-2), (I-E-2), (I-F-2), (I-G-2) or (I-H-2), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof, wherein

Y is selected from CH ₂ Or c=o;

-L ₁ -(E) _m -L ₂ -selected from-NH- (CH) ₂ ) _n1 -CH ₂ -、-NH-(CH ₂ ) _n1 -NH-、-NH-(CH ₂ ) _n1 -O-NH-、-NH-(CH ₂ CH ₂ O) _n2 -(CH ₂ ) _n3 -、-NH-(CH ₂ OCH ₂ ) _n2 -(CH ₂ ) _n3 -、-NH-(OCH ₂ CH ₂ ) _n2 -(CH ₂ ) _n3 -、-NH-(CH ₂ CH ₂ O) _n2 -NH-、-NH-(CH ₂ OCH ₂ ) _n2 -NH-and-NH- (OCH) ₂ CH ₂ ) _n2 -NH-；

n2=0, 1, 2, 3, 4 or 5; preferably 1, 2, 3 or 4; preferably 1, 2 or 3

n3=0, 1, 2 or 3; preferably 1 or 2.

In a more specific embodiment, the present invention provides a compound of the general formula (I-A-3), (I-B-3), (I-C-3), (I-D-3), (I-E-3), (I-F-3), (I-G-3) or (I-H-3), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein

Y is selected from CH ₂ Or c=o;

-L ₁ -(E) _m -L ₂ -selected from-NH- (CH) ₂ ) _n1 -CH＝、-NH-(CH ₂ ) _n1 -N＝、-NH-(CH ₂ ) _n1 -O-N＝、-NH-(CH ₂ CH ₂ O) _n2 -CH＝、-NH-(CH ₂ OCH ₂ ) _n2 -CH＝、-NH-(OCH ₂ CH ₂ ) _n2 -CH＝、-NH-(CH ₂ CH ₂ O) _n2 -N＝、-NH-(CH ₂ OCH ₂ ) _n2 -n=and-NH- (OCH) ₂ CH ₂ ) _n2 -N＝；

n2=0, 1, 2, 3, 4 or 5; preferably 1, 2, 3 or 4; preferably 1, 2 or 3.

In a more specific embodiment, the present invention provides a compound of the general formula (I-A-4), (I-B-4), (I-C-4), (I-D-4), (I-E-4), (I-F-4), (I-G-4) or (I-H-4), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein

Y is selected from CH ₂ Or c=o;

n2=0, 1, 2, 3, 4 or 5; preferably 1, 2, 3 or 4; preferably 1, 2 or 3.

In this more specific embodiment, preferably R ₁ And R is R ₂ Bond formation = O, and R ₃ And R is ₄ Is H; preferably, R ₁ is-OH and R ₂ 、R ₃ And R is ₄ Is H; preferably, R ₁ is-OH, R ₃ And R is R ₄ Bond formation = O, and R ₂ H.

In a more specific embodiment, the present invention provides compounds of formula (I) are compounds of formula (I-A-5), (I-B-5), (I-C-5), (I-D-5), (I-E-5), (I-F-5), (I-G-5) or (I-H-5), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof, wherein

Y is selected from CH ₂ Or c=o;

n2=0, 1, 2, 3, 4 or 5; preferably 1, 2, 3 or 4; preferably 1, 2 or 3

n3=0, 1, 2 or 3; preferably 1 or 2.

In a more specific embodiment, the present invention provides a compound of the general formula (I-A-6), (I-B-6), (I-C-6), (I-D-6), (I-E-6), (I-F-6), (I-G-6) or (I-H-6), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein

Y is selected from CH ₂ Or c=o;

n2=0, 1, 2, 3, 4 or 5; preferably 1, 2, 3 or 4; preferably 1, 2 or 3.

In a more specific embodiment, the present invention provides a compound of the general formula (I-A-7), (I-B-7), (I-C-7), (I-D-7), (I-E-7), (I-F-7), (I-G-7) or (I-H-7), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein

Y is selected from CH ₂ Or c=o;

n2=0, 1, 2, 3, 4 or 5; preferably 1, 2, 3 or 4; preferably 1, 2 or 3.

In a more specific embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, said compound being selected from the group consisting of:

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in a more specific embodiment, the present invention relates to all of the compounds of the above general formula, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variations thereof, and mixtures thereof, wherein m is 0, 1, 3, 4, 5, 6, 7, 8, 9 or 10; preferably, m is 0, 1, 3, 4, 5, 6, 7 or 8; preferably, m is 0, 1, 3, 4, 5 or 6; preferably, m is 0, 1, 3, 4 or 5.

The compounds of the invention may include one or more asymmetric centers and thus may exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers may be separated from the mixtures by methods known to those skilled in the art, including: chiral High Pressure Liquid Chromatography (HPLC), formation and crystallization of chiral salts; alternatively, preferred isomers may be prepared by asymmetric synthesis.

Those skilled in the art will appreciate that the organic compound may form a complex with a solvent in or from which it reacts or from which it precipitates or crystallizes. These complexes are referred to as "solvates". When the solvent is water, the complex is referred to as a "hydrate". The present invention encompasses all solvates of the compounds of the present invention.

The term "solvate" refers to a form of a compound or salt thereof that is bound to a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "solvate" includes both solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates and methanolates.

The term "hydrate" refers to a compound that binds to water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, the hydrates of the compounds can be used, for example, of the formula R x H ₂ O represents, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, e.g., hemihydrate (r.0.5H) ₂ O)) and polyhydrates (x is a number greater than 1, e.g., dihydrate (r.2h) ₂ O) and hexahydrate (R.6H) ₂ O))。

The compounds of the present invention may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the present invention. The term "polymorph" refers to a crystalline form (or salt, hydrate or solvate thereof) of a compound of a particular crystal stacking arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can lead to a crystalline form predominating. Various polymorphs of a compound can be prepared by crystallization under different conditions.

The invention also includes isotopically-labelled compounds (isotopically-variant) which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively, for example ² H、 ³ H、 ¹³ C、 ¹¹ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ¹⁷ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and F ³⁶ Cl. The compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs thereof, which contain the isotopes described above and/or other isotopes of other atoms, are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, e.g., for incorporation of a radioisotope (e.g. ³ H and ¹⁴ c) Those useful in drug and/or substrate tissue distribution assays. Tritium, i.e. tritium ³ H and carbon-14 ¹⁴ The C isotopes are particularly preferred because they are easy to prepare and detect. Further, substitution by heavier isotopes, e.g. deuterium, i.e ² H may be preferred in some cases because higher metabolic stability may provide therapeutic benefits, such as extended in vivo half-life or reduced dosage requirements. Isotopically-labeled compounds of formula (I) of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and/or examples and preparations below by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent.

In addition, prodrugs are also included within the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo by hydrolysis, e.g. in blood, into its active form having a medical effect. Pharmaceutically acceptable prodrugs are described in t.higuchi and v.stilla, prodrugs as Novel Delivery Systems, a.c. s.symposium Series vol.14, edward b.roche, ed., bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press,1987, and d.fleisher, s.ramon and h.barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs ", advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each of which is incorporated herein by reference.

Prodrugs are any covalently bonded compounds of the invention which, when administered to a patient, release the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in such a way that the modification may be performed by conventional procedures or cleavage in vivo to yield the parent compound. Prodrugs include, for example, compounds of the invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, may cleave to form the hydroxy, amino, or sulfhydryl group. Representative examples of prodrugs therefore include, but are not limited to, acetate, formate and benzoate/amide derivatives of hydroxy, mercapto and amino functional groups of compounds of formula (I). In addition, in the case of carboxylic acid (-COOH), esters such as methyl ester, ethyl ester, and the like can be used. The esters themselves may be active and/or may be hydrolysed under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups which readily decompose in the human body to release the parent acid or salt thereof.

The invention also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms are within the scope of the invention.

Pharmaceutical compositions and kits

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

Pharmaceutically acceptable excipients for use in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the co-formulated compounds. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

The invention also includes kits (e.g., pharmaceutical packages). Kits provided can include a compound of the invention, other therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packages or other suitable containers) containing a compound of the invention, other therapeutic agent. In some embodiments, the provided kits may also optionally include a third container containing pharmaceutically acceptable excipients for diluting or suspending the compounds of the invention and/or other therapeutic agents. In some embodiments, the compounds of the invention and other therapeutic agents provided in the first and second containers are combined to form one unit dosage form.

Administration of drugs

The pharmaceutical compositions provided herein may be administered by a number of routes including, but not limited to: oral, parenteral, inhalation, topical, rectal, nasal, buccal, vaginal, by implantation or other means of administration. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intramuscularly, and intracranial injection or infusion techniques.

Typically, an effective amount of a compound provided herein is administered. The amount of the compound actually administered may be determined by a physician, according to the circumstances involved, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

When used to prevent a disorder of the present invention, a subject at risk of developing the disorder is administered a compound provided herein, typically based on physician recommendations and administered under the supervision of a physician, at a dosage level as described above. Subjects at risk for developing a particular disorder generally include subjects having a family history of the disorder, or those subjects determined by genetic testing or screening to be particularly susceptible to developing the disorder.

The pharmaceutical compositions provided herein may also be administered chronically ("chronically"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over a prolonged period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue administration indefinitely, e.g., for the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, e.g., within a therapeutic window.

Various methods of administration may be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus, e.g., in order to increase the concentration of the compound in the blood to an effective level. Bolus doses depend on the targeted systemic level of active ingredient through the body, e.g., intramuscular or subcutaneous bolus doses cause slow release of the active ingredient, whereas bolus injections delivered directly to veins (e.g., by IV intravenous drip) can be delivered more rapidly, causing the concentration of the active ingredient in the blood to rise rapidly to effective levels. In other embodiments, the pharmaceutical composition may be administered in the form of a continuous infusion, for example, by IV intravenous drip, thereby providing a steady state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.

Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. More typically, however, the compositions are provided in unit dosage form in order to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable for producing the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules and the like. In such compositions, the compound is typically a minor component (about 0.1 to about 50 wt.%, or preferably about 1 to about 40 wt.%) with the remainder being various carriers or excipients and processing aids useful for forming the desired administration form.

For oral doses, a typical regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these modes of dosing, each dose provides from about 0.01 to about 20mg/kg of a compound of the invention, with preferred doses each providing from about 0.1 to about 10mg/kg, especially from about 1 to about 5mg/kg.

In order to provide similar blood levels to, or lower than, the use of an injected dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

From about 1 to about 120 hours, especially 24 to 96 hours, the injection dosage level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. To achieve adequate steady state levels, a preloaded bolus of about 0.1mg/kg to about 10mg/kg or more may also be administered. For human patients of 40 to 80kg, the maximum total dose cannot exceed about 2 g/day.

Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous carriers, buffers, suspending and dispersing agents, colorants, flavors, and the like. Solid forms may include, for example, any of the following components, or compounds having similar properties: binders, for example microcrystalline cellulose, gum tragacanth or gelatin; excipients, for example starch or lactose, disintegrants, for example alginic acid, primogel or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or a flavoring agent, for example, peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based on sterile saline or phosphate buffered saline for injectable use, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, the remainder being an injectable excipient or the like.

Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as ointments, the active ingredients are typically combined with a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope provided by the present invention.

The compounds of the invention may also be administered via a transdermal device. Transdermal administration may thus be achieved using a reservoir (reservoir) or porous membrane type, or a variety of solid matrix patches.

The above components of the compositions for oral administration, injection or topical administration are merely representative. Other materials and processing techniques, etc. are set forth in Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania, section 8, incorporated herein by reference.

The compounds of the present invention may also be administered in sustained release form, or from a sustained release delivery system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α -, β -and γ -cyclodextrins consisting of 6, 7 and 8 α -1, 4-linked glucose units, respectively, optionally including one or more substituents on the linked sugar moiety, including but not limited to: methylated, hydroxyalkylated, acylated and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β -cyclodextrin, e.g., sulfobutyl ether β -cyclodextrin, also known as Captisol. See, for example, U.S.5,376,645. In some embodiments, the formulation comprises hexapropyl- β -cyclodextrin (e.g., 10-50% in water).

Treatment of

As described herein, EGFR kinases are known to play a role in tumorigenesis and many other diseases. We have found that the compounds of the present invention have potent anti-tumour activity which is believed to be obtained by inhibition of EGFR kinase.

Thus, the compounds of the present invention have value as antitumor agents. In particular, the compounds of the present invention have value as antiproliferative, apoptotic and/or anti-invasive agents in the inhibition and/or treatment of solid and/or liquid neoplastic diseases. In particular, the compounds of the invention are expected to be useful in the prevention or treatment of those tumors that are sensitive to EGFR inhibition. Furthermore, the compounds of the invention are expected to be useful in the prevention or treatment of those tumors mediated alone or in part by EGFR. Thus, the compounds are useful for producing EGFR enzyme inhibition in warm-blooded animals in need of such treatment.

Inhibitors of EGFR kinase, as described herein, include cancers such as ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute Myelogenous Leukemia (AML), multiple myeloma, melanoma, mesothelioma.

Anticancer effects useful for treating cancer in a patient include, but are not limited to, anti-tumor effects, response rates, time to disease progression, and survival rates. The anti-tumor effects of the methods of treatment of the present invention include, but are not limited to, inhibition of tumor growth, delay of tumor growth, regression of tumor, shrinkage of tumor, prolonged regrowth of tumor after cessation of treatment, and slowing of disease progression. Anticancer effects include prophylactic treatment and treatment of existing diseases.

EGFR kinase inhibitors or pharmaceutically acceptable salts thereof are also useful in the treatment of patients with cancers including, but not limited to, blood cancers such as leukemia, multiple myeloma; lymphomas such as hodgkin's disease, non-hodgkin's lymphomas (including mantle cell lymphomas) and myelodysplastic syndrome, as well as solid tumors and metastases thereof (metastases), such as breast cancer, lung cancer (non-small cell lung cancer (NSCL), small Cell Lung Cancer (SCLC), squamous cell carcinoma), endometrial cancer, central nervous system tumors (such as gliomas, dysplastic neuroepithelial tumors, glioblastoma multiforme, mixed gliomas, medulloblastomas, retinoblastomas, neuroblastomas, germ cell tumors and teratomas, gastrointestinal cancers (such as gastric cancer), esophageal cancer, hepatocellular (liver) carcinoma, cholangiocarcinomas, colorectal and rectal cancer, small intestine cancers, pancreatic cancer, skin cancers such as melanoma (especially metastatic melanoma), thyroid cancer, head and neck cancer and salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, uterine cancer, vulval cancer, bladder cancer, renal cancer (including renal cell carcinoma, ming's and eosinophilic cell carcinoma), chondromas, sarcomas such as osteosarcoma, leiomyosarcoma, gisarcoma, sarcomas of the gastrointestinal tract tissue (GIST) and leiomyosarcoma, sarcomas of the gastrointestinal tract, and paediatricoma.

The effective amount of the compound of the present invention is generally in the range of 0.01mg to 50mg compound per kilogram of patient body weight, preferably 0.1mg to 25mg compound per kilogram of patient body weight, in single or multiple administrations. In general, the compounds of the invention may be administered to the patient in need of such treatment in a daily dosage range of from about 1mg to about 3500mg, preferably from 10mg to 1000mg, per patient. For example, the daily dose per patient may be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900 or 1000mg. The administration may be one or more times daily, weekly (or at intervals of days), or on an intermittent schedule. For example, the compounds may be administered on a weekly basis (e.g., once a week), once or more times a day, indefinitely or for a few weeks, e.g., 4-10 weeks. Alternatively, the administration may be continued for several days (e.g., 2-10 days) and then several days (e.g., 1-30 days) without administration of the compound, with the cycle being repeated indefinitely or for a given number of cycles, e.g., 4-10 cycles. For example, the compounds of the invention may be administered daily for 5 days, then intermittently for 9 days, then daily for another 5 days, then intermittently for 9 days, and so on, with the cycle being repeated indefinitely or for a total of 4-10 times.

Combination therapy

The treatment defined herein may be applied as a sole treatment or may include conventional surgery or radiation or chemotherapy in addition to the compounds of the invention. Thus, the compounds of the present invention may also be used in combination with existing therapeutic agents for the treatment of cancer.

In addition to treatment with the compounds of the invention, conventional surgery or radiation therapy or chemotherapy or immunotherapy are involved. Such chemotherapy may be administered simultaneously, sequentially, or separately with the compounds of the invention, and may contain one or more of the following types of antineoplastic agents:

(i) Antiproliferative/antineoplastic agents used in medical oncology and combinations thereof, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates, e.g., fluoropyrimidines (e.g., 5-fluorouracil and tegafur), raltitrexed, methotrexate, cytarabine, hydroxyurea); antitumor antibiotics (e.g., anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin C, actinomycin, mithramycin); antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, vinorelbine; and taxanes such as paclitaxel, taxotere, polo kinase inhibitors); topoisomerase inhibitors (e.g., epipodophyllotoxins (e.g., etoposide, teniposide), amsacrine, topotecan, camptothecins);

(ii) Cytostatic agents, such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, ioxifene (iodoxyfene)), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorozole), exemestane), 5 alpha-reductase inhibitors (e.g., finasteride);

(iii) Anti-invasive agents (anti-invasions), such as inhibitors of the c-Src kinase family, [ such as 4- (6-chloro-2, 3-methylenedioxyanilino) -7- [2- (4-methylpiperazin-1-yl) ethoxy ] -5-tetrahydropyran-4-yloxy quinazoline [ AZD0530 (secatinib) ], N- (2-chloro-6-methylphenyl) -2- {6- [4- (2-hydroxyethyl) piperazin-1-yl ] -2-methylpyrimidin-4-ylamino } thiazole-5-carboxamide (dasatinib, BMS-354825) and bosutinib (SKI-606), and metalloproteinase inhibitors (such as marimastat), inhibitors of urokinase plasminogen activator receptor function or antibodies to heparanase (hepatanase);

(iv) Inhibitors of growth factor function: such inhibitors include, for example, growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB 2 antibody trastuzumab [ herceptin ], anti-EGFR antibody panitumumab, anti-erbB 1 antibody cetuximab [ Erbitux, C225]; such inhibitors also include tyrosine kinase inhibitors such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinylpropoxy) -quinazolin-4-amine (gefitinib, ZD 1839), N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI 774), 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinylpropoxy) -quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors (e.g., lapatinib), inhibitors of the hepatocyte growth factor family, inhibitors of the insulin growth factor family, inhibitors of the platelet derived growth factor family such as imatinib and/or nilotinib (AMN 107), inhibitors of serine/threonine kinases (e.g., ras/Raf signaling inhibitors such as farnesyl transferase inhibitors such as, for example, BAY 43-6, R90062), and F777762 (SCH 773) Cell signaling inhibitors through mkk and/or AKT kinase, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase (aurora kinase) inhibitors (e.g. AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528, AX 39459), cyclin dependent kinase inhibitors, e.g. CDK2 and/or CDK4 inhibitors;

(v) Anti-angiogenic agents, such as agents that inhibit the action of vascular endothelial growth factor, [ such as the anti-human vascular endothelial growth factor antibody bevacizumab (avastin) and for example VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD 6474), vatalanib (PTK 787), sunitinib (SU 11248), axitinib (AG-013136), pazopanib (GW 786034), 4- (4-fluoro-2-methylindol-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD 2171), and compounds that act by other mechanisms (such as ranolamine, inhibitors of integrin αvβ3 function and angiostatin (angiostatin)) ];

(vi) Vascular damaging agents such as combretastatin A4;

(vii) Endothelin receptor antagonists such as ziprasidtan (ZD 4054) or atrasentan;

(viii) Antisense therapeutics, such as those directed to the targets listed above, e.g., ISIS2503 (an anti-ras antisense therapeutic);

(ix) Gene therapy methods, including, for example, methods of replacing an abnormal gene (e.g., abnormal p53 or abnormal BRCA1 or BRCA 2); GDEPT (gene-directed enzyme prodrug therapy) methods, such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase; methods of increasing patient resistance to chemotherapy or radiation therapy, such as multiple resistance gene therapy; and

(x) Immunotherapeutic methods, including, for example, in vitro and in vivo methods of increasing the immunogenicity of a patient's tumor cells, such as transfection with cytokines (e.g., interleukin 2, interleukin 4, or granulocyte macrophage colony stimulating factor); methods of reducing T cell inefficiency; methods of using transfected immune cells (e.g., cytokine-transfected dendritic cells); methods of using cytokine-transfected tumor cell lines; methods of using anti-idiotype antibodies; methods of reducing the function of immunosuppressive cells (e.g., regulatory T cells, myeloid-derived (myeoid-derived) suppressor cells, or IDO (indoleamine 2, 3-deoxyenzyme) expressing dendritic cells); and methods of using a cancer vaccine composed of proteins or peptides derived from a tumor associated antigen (e.g., NY-ESO-1, mAGE-3, WT1, or Her 2/neu).

Examples

The materials or reagents used herein are commercially available or prepared by synthetic methods generally known in the art.

Example 1: synthesis of Y13-2

The following synthetic route was adopted:

step 1: synthesis of Y13-1

A25 mL single vial was charged with glutaraldehyde (800 mg of 50% aqueous solution), DCM (12 mL) and Na ₂ SO ₄ (3g) Stirring at room temperature for 0.5h. LPTN (1.16 g,2 mmol) and AcOH (0.12 g,2 mmol) were added and stirred at room temperature for 0.5h. The system was cooled to below 0deg.C, sodium cyanoborohydride (0.125 g) was added to the system at 0deg.C in four batches three minutes apart, and reacted at 0deg.C for 2h. The reaction solution is slowly added into NaHCO at 0 DEG C ₃ In (100 mL) solution, EA (100 mLx 3) was extracted. The EA phases were combined, washed with saturated NaCl (100 mL), na ₂ SO ₄ Drying, filtering and spin drying. The residue was dissolved with 5mL of DCM and chromatographed on silica gel (DCM/MeOH), collecting the product and concentrating to 0.48g of a yellow solid.

(ESI-MS，m/z):[M+H] ⁺ 665.19。

Step 2: synthesis of Y13-2

To a 25mL single vial was added Y13-1 (0.4 g,0.6 mmol), meOH (5 mL), DMF (1.5 mL), lenalidomide (0.156 g,0.6 mmol) and AcOH (0.036 g,0.6 mmol), and the mixture was stirred at room temperature for 0.5h. Sodium cyanoborohydride (0.076 g,1.2 mmol) was added to the system at room temperature in 4 portions 3 minutes apart and reacted overnight at room temperature. The reaction solution was slowly added to NaHCO at 0 ℃ ₃ In (100 mL) solution, EA (50 mLx 3) was extracted. The EA phases were combined, washed with saturated NaCl (50 mL), na ₂ SO ₄ Drying, filtering, spin drying, dissolving with DMSO, and preparing at medium pressure in reverse direction, wherein the system is H ₂ O (0.08% TFA)/ACN. The product was collected, the acetonitrile was removed by spinning, and NaHCO was used ₃ The pH was adjusted to be slightly alkaline, the aqueous phase was extracted with DCM (100 mL X3), the DCM phases were combined, na ₂ SO ₄ Drying, filtering and spin drying. Beating with MeOH/DCM/MTBE (5 mL) for 20 min, filtered to give 0.18g of a yellow solid.

(ESI-MS，m/z):[M+H] ⁺ 908.29。

¹ H NMR(400MHz，DMSO-d ₆ ):δ11.01(s，1H)，9.85(s，1H)，8.72(d，J＝1.6Hz，1H)，8.56(s，1H)，8.13(dd，J＝2.0，8.8Hz，1H)，8.01(d，J＝2.8Hz，1H)，7.81(d，J＝8.8Hz，1H)，7.74(dd，J＝2.8，8.8Hz，1H)，7.51-7.46(m，1H)，7.33-7.16(m，5H)，7.06(d，J＝3.6Hz，1H)，6.90(dd，J＝0.8，7.6Hz，1H)，6.66(d，J＝8.0Hz，1H)，6.55(d，J＝3.2Hz，1H)，5.51(t，J＝4.2Hz，1H)，5.26(s，2H)，5.11(dd，J＝4.2，13.2Hz，1H)，4.20(d，J＝16.8Hz，1H)，4.10(d，J＝16.8Hz，1H)，3.79(s，2H)，3.36(t，J＝6.8Hz，2H)，3.10-3.03(m，5H)，2.97-2.87(m，3H)，2.65-2.56(m，1H)，2.52(t，J＝2.0Hz，2H)，2.34-2.22(m，1H)，2.05-1.98(m，1H)，1.62-1.50(m，4H)，1.42-1.34(m，2H)。

Example 2: synthesis of Y15-2

The following synthetic route was adopted:

step 1: synthesis of F2-1

A250 mL single port flask was charged with A3-1 (5 g), DMF (65 mL) and DIEA (7 g) and the temperature of the system was raised to 100 ℃. Diglycolamine (1.9 g) was dissolved in 10mL of DMF and added slowly dropwise to the system at 100deg.C, and reacted at 100deg.C for 2 hours after the addition. The temperature of the system was reduced to room temperature, DMF was distilled off under reduced pressure, 100mL of water was added, DCM (100 mLx 3) was added, the DCM phases were combined, washed with saturated NaCl (100 mL), na ₂ SO ₄ Drying, filtering and spin drying. The residue was dissolved with 5mL of DCM and chromatographed on silica gel (DCM/MeOH), collecting the product and concentrating to 2.5g of a yellow solid.

(ESI-MS，m/z):[M+H]+362.14。

Step 2: synthesis of Y15-1

To a 100mL single flask was added F2-1 (2.5 g), DCM (50 mL), tsCl (1.45 g) and DIEA (1.79 g), and the mixture was stirred at room temperature for 16h. The raw materials are more left, K is added ₂ CO ₃ (1.9 g), and reacted at room temperature for 6 hours. The remaining starting material was more, tsCl (1.4 g) and DMAP (0.1 g) were added and stirred overnight at room temperature. 100mL of DCM was added for dilution, the DCM phase was washed with 100mL of water, 100mL of saturated brine, na ₂ SO ₄ And (5) drying. The mixture was filtered, dried, and the residue was dissolved in 5mL DCM, chromatographed on silica gel (PE/EA), and the product was collected and concentrated to 0.78g of a yellow solid.

(ESI-MS，m/z):[M+H]+516.14。

Step 3: synthesis of Y15-2

A25 mL single flask was charged with Y15-1 (0.78 g), DMF (5 mL), LPTN (0.88 g) and NaI (0.25 g) and stirred at room temperature for 3h. The raw materials are remained more, and the temperature of the system is raised to 80 ℃ for reaction for 4 hours. The system was cooled to room temperature, quenched with 50mL of water, extracted with EA (50 mL. Times.3), the EA phases combined, washed with saturated NaCl (50 mL), na ₂ SO ₄ Drying, filtering and spin drying. The residue was dissolved with 5mL DCM, chromatographed on silica gel (PE/EA/EtOH), and the product was collected and concentrated to 0.41g of a yellow solid.

(ESI-MS，m/z):[M+H] ⁺ 924.26。

1H NMR(400MHz，DMSO-d ₆ ):δ11.10(s，1H)，9.85(s，1H)，8.70(d，J＝1.2Hz，1H)，8.56(s，1H)，8.11(dd，J＝1.6，8.8Hz，1H)，8.02(d，J＝2.8Hz，1H)，7.78(d，J＝8.8Hz，1H)，7.74(dd，J＝2.4，8.8Hz，1H)，7.54-7.46(m，2H)，7.35-7.27(m，3H)，7.22-7.17(m，1H)，7.08(d，J＝8.8Hz，1H)，7.04(d，J＝3.2Hz，1H)，6.99(d，J＝6.8Hz，1H)，6.58(dd，J＝6.0，6.0Hz，1H)，6.54(d，J＝3.2Hz，1H)，5.27(s，2H)，5.04(dd，J＝5.2，12.8Hz，1H)，3.84(s，2H)，3.61(dd，J＝5.2，11.2Hz，4H)，3.45(dd，J＝5.2，11.2Hz，2H)，3.33(t，J＝6.8Hz，2H)，3.05(s，3H)，2.99(t，J＝6.8Hz，2H)，2.91-2.82(m，1H)，2.75(t，J＝5.6Hz，2H)，2.60-2.51(m，2H)，2.04-1.97(m，1H)。

Example 3: synthesis of Y16-4

The following synthetic route was adopted:

Step 1: synthesis of Y16-2

A250 mL single port flask was charged with A3-1 (5 g), DMF (65 mL) and DIEA (7 g) and the temperature of the system was raised to 100 ℃. 5-amino-1-pentanol (1.87 g) was dissolved in 10mL of DMF and added slowly dropwise to the system at 100deg.C, and reacted at 100deg.C for 2 hours after the addition. The temperature of the system was reduced to room temperature, DMF was distilled off under reduced pressure, 100mL of water was added, DCM (100 mLx 3) was added, the DCM phases were combined, washed with saturated NaCl (100 mL), na ₂ SO ₄ Drying, filtering and spin drying. The residue was dissolved with 5mL of DCM and chromatographed on silica gel (DCM/MeOH), collecting the product and concentrating to 2.14g of a yellow solid.

(ESI-MS，m/z):[M+H] ⁺ 360.16。

Step 2: synthesis of Y16-3

To a 100mL single flask were added Y16-2 (2 g), DCM (40 mL) and DIEA (1.79 g), msCl (1.45 g) was dissolved in DCM (10 mL), and the mixture was added dropwise at room temperature and stirred at room temperature for 4h after the addition. 100mL of DCM was added for dilution, the DCM phase was washed with 100mL of water, 100mL of saturated brine, na ₂ SO ₄ And (5) drying. The mixture was filtered, dried, and the residue was dissolved in 5mL DCM, chromatographed on silica gel (PE/EA), and the product was collected and concentrated to 1.78g of a yellow solid.

(ESI-MS，m/z):[M+H] ⁺ 438.13。

Step 3: synthesis of Y16-4

A100 mL single flask was charged with Y16-3 (1.75 g), DMF (35 mL), LPTN (2.32 g) and NaI (0.66 g) and reacted at 90℃for 6h. The system was cooled to room temperature, quenched with 300mL of water, and extracted with EA (300 mL. Times.3). The EA phases were combined, washed with saturated NaCl (50 mL), na ₂ SO ₄ Drying, filtering and spin drying. The residue was dissolved with 5mL DCM, chromatographed on silica gel (PE/EA/EtOH), the product was collected and concentrated to a yellow solid, which was slurried with MeOH/DCM/EA for 0.5h and filtered to 0.6g of a yellow solid.

(ESI-MS，m/z):[M+H] ⁺ 922.29。

¹ H NMR(400MHz，DMSO-d ₆ ):δ11.09(s，1H)，9.85(s，1H)，8.70(d，J＝1.6Hz，1H)，8.53(s，1H)，8.12(dd，J＝1.6，8.4Hz，1H)，8.01(d，J＝2.4Hz，1H)，7.78(d，J＝9.2Hz，1H)，7.73(dd，J＝2.4，8.8Hz，1H)，7.52-7.45(m，2H)，7.35-7.27(m，3H)，7.21-7.16(m，1H)，7.05(d，J＝3.2Hz，1H)，6.99-6.96(m，2H)，6.66(d，J＝8.0Hz，1H)，6.55(d，J＝3.2Hz，1H)，6.45(dd，J＝6.0，6.0Hz，1H)，5.26(s，2H)，5.03(dd，J＝5.2，12.8Hz，1H)，3.79(s，2H)，3.36(t，J＝6.8Hz，2H)，3.26-3.21(m，2H)，3.05(s，3H)，2.93(t，J＝6.8Hz，2H)，2.88-2.82(m，1H)，2.60-2.46(m，4H)，2.05-1.98(m，1H)，1.61-1.55(m，4H)，1.40-1.32(m，2H)。

Example 4: synthesis of A1-6

The following synthetic route was adopted:

step 1: synthesis of A1-12

To the reaction flask, 30.0g of A1-11 and 300mL of ethanol were added and dissolved with stirring. 8.1g of hydrazine hydrate is added dropwise into the reaction liquid, and the reaction is carried out for 30min at room temperature after the dripping. After the reaction is finished, filtering, pumping a filter cake, and soaking and washing with ethanol; the filtrates were combined and concentrated to dryness under reduced pressure at 50℃with external bath to give 19.0g of an oily product. (the yield of the product exceeds the theoretical yield, partial residual solvent exists, and the product is directly put into the next step)

Step 2: synthesis of A1-2

Into the reaction flask were added 20.0g of A1-12 and 160mL of THF and dissolved with stirring. 40.0mL NaHCO was added to the reaction solution ₃ The aqueous solution was cooled to 0 ℃. To the reaction mixture was added dropwise 30.0g (Boc) ₂ O, reaction at room temperature for 16h. After the completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. To the concentrated residue was added water and ethyl acetate for extraction, and the aqueous phase was discarded. The organic phase was washed with saturated aqueous sodium chloride and the aqueous phase was discarded. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give an oil which was purified by passing through a column to give 7.5g of a pure product.

Step 3: synthesis of A1-3

Into the reaction flask, 20.4g of A1-2 and 40.8ml of THF were added and dissolved with stirring. 81.6mL of AcOH was added dropwise to the reaction mixture, and after the addition, 40.8mL of water was added to the reaction mixture to react at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. To the concentrated residue was added ethyl acetate, washed with water and the aqueous phase was discarded. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and the concentrated residue was purified by column to give 9.2g of a product.

Step 4: synthesis of A1-4

Into the reaction flask were added 2.03g of A1-3, 2.30g of lenalidomide, 10.0mL of methanol, 4.00g of molecular sieve, and 5.0mL of DMF, and the mixture was stirred and dispersed. To the reaction solution, 0.60g of acetic acid was added, and the reaction solution was stirred at room temperature, 1.90g of sodium cyanoborohydride was added in portions, and the mixture was reacted at room temperature for 16 hours. After the completion of the reaction, water was added to the reaction mixture to quench the reaction mixture. The solution was concentrated under reduced pressure to remove most of the methanol. The solution was continued to be extracted with water and DCM. The combined organic phases were washed with water and the aqueous phase was discarded. The organic phase was washed with saturated sodium chloride and the aqueous phase was discarded. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness under reduced pressure, and purified by passing through a column of DCM/MEOH to give 2.8g of a white solid product.

Step 5: synthesis of A1-5

To the reaction flask was added 1.0g of A1-4 and 15.0mL of DCM and dissolved with stirring. The internal temperature of the reaction solution is reduced to 0 ℃, the temperature is controlled to be 0-5 ℃, 5.0mL of HCl/dioxane is added dropwise, and the reaction is carried out for 16 hours at room temperature after the dripping. After the reaction, the reaction solution was concentrated to dryness under reduced pressure and then directly put into the next step.

Step 6: synthesis of A1-6

400mg of A1-5, 10mL of methanol, 424mg of estrone and 515mg of anhydrous sodium acetate were added to the reaction flask, and the mixture was stirred and dispersed, and the internal temperature was raised to 50℃to react for 16 hours. After the completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. To the concentrated residue was added water and ethyl acetate for extraction, and the aqueous phase was discarded. The organic phases were combined, washed with saturated aqueous sodium chloride solution and the aqueous phase was discarded. The organic phase was dried over anhydrous sodium sulfate, filtered and the filter cake was discarded. The filtrate was dissolved with a small amount of DCM and purified by passing DCM/MeOH through a column to give 280.0mg of A1-6Q (enantiomer 1) as a white solid and 60.0mg of A1-6H (enantiomer 2) as a white solid.

A1-6Q (enantiomer 1) (ESI-MS, M/z): [ M+H ]] ⁺ 631.35

A1-6Q: ¹ H NMR(400MHz，CD ₃ OD-d ₄ ):δ7.32-7.28(m，1H)，7.08-7.03(m，2H)，6.82-6.80(m，1H)，6.56-6.52(m，1H)，6.48-6.46(m，1H)，4.96-4.89(m，1H)，4.52-4.46(m，1H)，4.34-4.30(m，1H)，4.08-3.96(m，2H)，3.58(s，3H)，3.28-3.22(m，2H)，2.81-2.76(m，2H)，2.49-2.28(m，5H)，2.23-2.13(m，2H)，2.03-1.68(m，7H)，1.50-1.28(m，7H)，0.89(s，3H)。

A1-6H (enantiomer 2): (ESI-MS, M/z): [ M+H ]] ⁺ 631.35

A1-6H: ¹ H NMR(400MHz，CD ₃ OD-d ₄ ):δ7.32-7.28(m，1H)，7.08-7.03(m，2H)，6.82-6.80(m，1H)，6.56-6.52(m，1H)，6.48-6.46(m，1H)，4.99-4.89(m，1H)，4.43-4.31(m，2H)，4.08-3.76(m，2H)，3.72(s，3H)，3.28-3.22(m，2H)，2.81-2.76(m，2H)，2.49-2.28(m，5H)，2.23-2.13(m，2H)，2.03-1.68(m，7H)，1.50-1.28(m，7H)，0.89(s，3H)。

Example 5: synthesis of A1-7

The following synthetic route was used:

compounds A1-5 were prepared as in example 4.

Into the reaction flask were charged 0.78g of A1-5, 7.00mL of THF, 1.10g of estrone and 0.50g of anhydrous sodium acetate, and the mixture was stirred and dispersed. The reaction solution was then added dropwise with 0.53g of DIEA at room temperature, and the mixture was reacted at room temperature for 16 hours. After the completion of the reaction, water and ethyl acetate were added to the reaction mixture to extract, and the aqueous phase was discarded. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filter cake discarded. The filtrate was concentrated under reduced pressure at 40℃in an external bath and the concentrated residue was purified by passing through a column with DCM/MeOH to give 0.9g of an off-white solid product.

(ESI-MS，m/z):[M+H] ⁺ 599.32

¹ H NMR(400MHz，CD ₃ OD-d ₄ ):δ7.34-7.30(m，1H)，7.08-7.01(m，2H)，6.85-6.82(m，1H)，6.56-6.52(m，1H)，6.48-6.46(m，1H)，5.19-5.08(m，1H)，4.28-4.26(m，2H)，4.08-3.96(m，2H)，3.28-3.22(m，2H)，2.92-2.72(m，4H)，2.49-2.28(m，3H)，2.21-1.98(m，3H)，1.92-1.68(m，7H)，1.52-1.28(m，6H)，0.89(s，3H)。

Example 6: synthesis of A3-5

The following synthetic route was used:

step 1: synthesis of A2-1

To a single-necked flask, 50.00g of SM1 and 400.00mL of THF were added and dissolved with stirring. 100.00mL NaHCO was added ₃ (aq), internal temperature was lowered to 0℃and 103.85g (Boc) was added dropwise ₂ O, controlling the temperature to be 0-5 ℃, and reacting overnight at room temperature after finishing dripping. After the reaction, the mixture was concentrated to dryness under reduced pressure. Water was added, EA was added to extract 2 times, and the organic phase was washed with saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. Concentrating the organic phase under reduced pressureDried to give 82.50g of the product.

Step 2: synthesis of A2-2

Into a reaction flask were charged 62.00g of A2-1, 49.30g of SM2, 119.00g of PPh ₃ And 620.00mL DCM under nitrogen, and stirring to disperse. And (3) cooling the internal temperature of the reaction solution to 0 ℃, slowly dripping DIAD into the reaction solution, controlling the temperature to 0 ℃, naturally heating to room temperature after dripping, and reacting for 16 hours. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure at 40℃under external bath control. To the concentrated residue was added DCM/meoh=2/1, stirred for 0.5h, filtered. The filtrate was concentrated to dryness under reduced pressure to give 100.0g of oil, which was taken directly to the next step without purification, in 100% yield.

Step 3: synthesis of A2-3

30.00g of A2-2, 300.00mL of absolute ethyl alcohol and 6.50g of hydrazine hydrate are added into a reaction bottle, stirred and dispersed, and the reaction is carried out for 15min at room temperature. And after the reaction is finished, filtering, leaching a filter cake by using ethanol, pumping, and concentrating the filtrate under reduced pressure. The concentrated residue was dissolved in DCM, washed with aqueous sodium carbonate solution, the aqueous phase was discarded and extracted with 0.5M aqueous hydrochloric acid. The aqueous phases were combined, made basic with aqueous sodium carbonate and extracted with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 12.5g of a product.

Step 4: synthesis of A2-7

To the reaction flask were added 11.40g of A2-3, 100.00mL of DCM and 8.30g of DIEA, dissolved with stirring, and cooled to 0deg.C. 6.20g CbzCl is added dropwise into the reaction solution at the temperature of 0 ℃, and the reaction solution is naturally warmed to room temperature after the completion of the addition, and then the reaction is carried out for 16 hours. After the reaction, purified water was added dropwise to the reaction mixture to wash the mixture, and the aqueous phase was discarded. The organic phase was washed with saturated aqueous NaCl solution and the aqueous phase was discarded. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure at 40 ℃ in an external bath. To the concentrated residue was added a small amount of DCM for dissolution and 0-50% DCM/MeOH for purification in a medium pressure preparative column to give 12.0g of a white solid. The yield exceeds the theoretical value, and partial solvent is possibly remained, and the solvent is not treated once and is directly put into the next step.

Step 5: synthesis of A2-8

To the reaction flask, 12.0g of A2-7 and 120.0mL of ethyl acetate were added and dissolved at room temperature with stirring, and the temperature was lowered to 0 ℃. 30.0mL of HCl (dioxane) is added dropwise to the reaction solution at the temperature of 0 ℃, and the mixture is naturally warmed to room temperature after the completion of the addition, and then the reaction is carried out for 3 hours. After the reaction, no solid is separated out, the external bath is controlled to be at 38 ℃ and the solution is concentrated to be dry under reduced pressure, thus obtaining 12.0g of product.

Step 6: synthesis of A3-1

To the reaction flask, 20.10g of SM1 and 100.00mL of glacial acetic acid were added and dispersed with stirring. The temperature in the reaction solution was raised to 60 ℃, 12.10g of glacial acetic acid (20 mL) solution of acetic anhydride was added dropwise to the reaction solution, and during the temperature raising, the reaction solution was partially dissolved (continuous temperature raising during the dropwise addition, the reaction solution was fully dissolved). After the completion of the dropping, 18.76g of SM2 and 13.20g of anhydrous sodium acetate were added to the reaction solution at an internal temperature of 60℃and the reaction was carried out at 110℃with an internal temperature of 110℃for 2 hours. After the reaction, slowly cooling to room temperature, stirring for 1h in a cold bath, filtering, and pumping out a filter cake to obtain 22.0g of a purple solid product.

Step 7: synthesis of A3-3

To the reaction flask were added 7.6g of A3-1, 12.0g of A2-8, 14.3g of DIEA and 120.0mL of NMP, and the mixture was dissolved with stirring. The reaction solution was heated to 80℃and reacted for 16 hours. After the reaction, the reaction solution was naturally warmed to room temperature. The reaction solution was poured into water, EA was added thereto for extraction, and the aqueous phase was discarded. The organic phase was washed with water and the aqueous phase was discarded. The organic phase was washed with saturated aqueous NaCl solution and the aqueous phase was discarded. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure at 40 ℃ in an external bath. To the concentrated residue was added a small amount of DCM for dissolution and 0-10% DCM/MeOH for purification in a medium pressure preparative column to give 2.5g of a yellow solid product.

Step 8: synthesis of A3-4

To the reaction flask were added 2.5g of A3-3, 10.0mL of AcOH and 10.0mL of HBr (40% aqueous HBr) and dissolved with stirring. The internal temperature of the reaction solution is heated to 40 ℃, and the reaction is carried out for 48 hours with heat preservation. After the reaction is finished, the internal temperature is reduced to room temperature. The reaction solution was concentrated to dryness under reduced pressure at 40℃under external bath control. To the concentrated residue was added water and MTBE washed and the organic phase was discarded. Saturated NaHCO is added into the water phase ₃ The pH of the aqueous solution was adjusted to 7-8, and DCM was added to the aqueous phase for extraction. The DCMs were combined, washed with saturated aqueous NaCl solution and the aqueous phase was discarded. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure at 40℃in an external bath to give 1.2g of a yellow solid product.

Step 9: synthesis of A3-5

Into the reaction flask, 1.2g of A3-4, 10.0mL of THF, 1.7g of estrone and 0.8g of NaOAc were added and dispersed with stirring, and reacted at room temperature for 16 hours. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure at 40℃in an external bath. To the concentrated residue was added water and EA extracted and the aqueous phase was discarded. The EA was combined, washed with saturated aqueous NaCl solution and the aqueous phase was discarded. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure at 40 ℃ in an external bath. To the concentrated residue was added a small amount of DCM for dissolution and 0-10% DCM/MeOH for purification in a medium pressure preparative column to give 0.5g of a yellow solid product.

(ESI-MS，m/z):[M+H] ⁺ 629.30

¹ H NMR(400MHz，CD ₃ OD-d ₄ ):δ7.54(dd，J＝7.2，8.8Hz，1H)，7.10-7.04(m，3H)，6.54(dd，J＝2.8，8.8Hz，1H)，6.48(d，J＝2.8Hz，1H)，5.06-5.01(m，1H)，4.14(t，J＝4.8Hz，2H)，3.78-3.69(m，4H)，3.51-3.47(m，2H)，2.89-2.65(m，5H)，2.52-2.29(m，3H)，2.21-1.97(m，3H)，1.93-1.77(m，2H)，1.58-1.23(m，6H)，0.90(s，3H)。

Example 7: synthesis of A1-8

The following synthetic route was used:

compounds A1-5 were prepared as in example 4.

Into the reaction flask were charged 1.05g of A1-5, 8.00mL of THF, 1.57g of androstenedione and 0.68g of anhydrous sodium acetate, and the mixture was stirred and dispersed. The reaction solution was then added dropwise with 0.71g of DIEA at room temperature, and the mixture was reacted at room temperature for 16 hours. After the completion of the reaction, water and ethyl acetate were added to the reaction mixture to extract, and the aqueous phase was discarded. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filter cake discarded. The filtrate was concentrated under reduced pressure at 40℃with external bath to give 0.8g of an off-white solid product.

(ESI-MS，m/z):[M+H]+615.35。

¹ H NMR(400MHz，DMSO-d ₆ ):δ11.00(s，1H)，7.26(t，J＝7.7Hz，1H)，6.91(dd，J＝7.3Hz，1H)，6.74(m，1H)，5.70(s，1H)，5.58(s，1H)，5.11(m，1H)，4.17(m，2H)，3.99(m，2H)，3.14(dd，J＝6.5Hz，2H)，3.0-1.2(m，20H)，1.16(s，5H)，0.82(m，4H)。

Example 8: synthesis of A1-9

The following synthetic route was used:

/>

compounds A1-5 were prepared as in example 4.

To the reaction flask were added 0.70g of A1-5, 7.00mL of THF, 1.05g of testosterone and 0.50g of anhydrous sodium acetate, and the mixture was stirred and dispersed. The reaction was allowed to proceed at room temperature, 0.50g of DIEA was added dropwise to the reaction mixture, and the mixture was reacted at room temperature for 16 hours. After the completion of the reaction, water and ethyl acetate were added to the reaction mixture to extract, and the aqueous phase was discarded. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filter cake discarded. The filtrate was concentrated under reduced pressure at 25℃in an external bath, and the concentrated residue was purified by passing through a PE/EA column to give 0.7g of an off-white solid product.

(ESI-MS，m/z):[M+H]+617.37。

¹ H NMR(400MHz，DMSO-d ₆ ):δ11.00(s，1H)，7.26(t，J＝7.7Hz，1H)，6.92(dd，J＝7.3Hz，1H)，6.73(d，J＝8.0Hz，1H)，5.68(d，J＝1Hz，1H)，5.57(s，1H)，5.11(m，1H)，4.43(d，J＝2.3Hz，1H)，4.10(m，2H)，3.97(m，2H)，3.42(s，1H)，3.13(t，J＝6.2Hz，1H)，2.63(s，2H)，3.0-0.5(m，33H)。

Example 9: synthesis of A1-10

The following synthetic route was used:

compounds A1-5 were prepared as in example 4.

Into the reaction flask were added 0.85g of A1-5, 7.00mL of THF, 1.35g of 11-ketotestosterone and 0.55g of anhydrous sodium acetate, and the mixture was stirred and dispersed. The reaction solution was then added dropwise with 0.58g of DIEA at room temperature, and the mixture was reacted at room temperature for 16 hours. After the completion of the reaction, water and ethyl acetate were added to the reaction mixture to extract, and the aqueous phase was discarded. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filter cake discarded. The filtrate was concentrated under reduced pressure at 25℃with external bath to give 0.8g of an off-white solid product.

(ESI-MS，m/z):[M+H]+63。

¹ HNMR(400MHz，DMSO-d ₆ ):δ10.99(s，1H)，7.26(t，J＝7.7Hz，1H)，6.92(m，1H)，6.74(m，1H)，5.70(d，J＝1.7Hz，1H)，5.11(dd，J＝8.2Hz，1H)，4..46(d，J＝4.7Hz，1H)，4.24-4.01(m，2H)，3.98(t，J＝6.5Hz，2H)，3.66(d，J＝5.0Hz，1H)，3.14(d，J＝6.2Hz，2H)，3.0-0.5(m，31H)。

Example 10: synthesis of A1-15

The following synthetic route was used:

compounds A1-5 were prepared as in example 4.

To the reaction flask were added 0.85g of A1-5, 7.00mL of THF, 1.30g of trans-dehydroandrosterone and 0.55g of anhydrous sodium acetate, and the mixture was stirred and dispersed. The reaction solution was then added dropwise with 0.13g of DIEA at room temperature, and the mixture was reacted at room temperature for 16 hours. After the completion of the reaction, water and ethyl acetate were added to the reaction mixture to extract, and the aqueous phase was discarded. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filter cake discarded. The filtrate was concentrated under reduced pressure at 25℃with external bath to give 0.75g of an off-white solid product.

(ESI-MS，m/z):[M+H]+617.37。

¹ H NMR(400MHz，DMSO-d ₆ ):δ10.99(s，1H)，7.26(t，J＝7.6Hz，1H)，6.92(d，J＝7.4Hz，1H)，6.73(m，J＝2.0Hz，1H)，5.58(s，1H)，5.11(d，J＝2.9Hz，1H)，5.08(s，1H)，4.59(m，1H)，4.14(m，2H)，3.95(t，J＝57Hz，2H)，3.14-3.07(m，3H).3.0-0.5(m，33H)。

In vitro efficacy evaluation of drugs

Experimental example 1: degradation of the ErBb2 protein of the breast cancer cell line (BT 474)

The degradation of the breast cancer cell line (BT 474) ErBb2 protein by the compounds of the invention was tested using western immunoblotting (WB) method.

The experimental procedure was as follows:

(1) Drug treatment and total protein extraction

Cells were plated and at 37 degrees, 5% CO ₂ Culturing in an incubator for 3d; changing to medium containing different concentration of compound, 37 deg.C, 5% CO ₂ Incubating the incubator for 4 hours; extracting total cell proteins by using RIPA lysate;

(2) Protein quantification

Protein quantification is carried out by using a Brandford method, total protein is regulated to the same concentration by lysate, loading buffer solution is added, after denaturation for 20min by a metal bath at 100 ℃, the sample is rapidly placed on ice and subjected to instantaneous centrifugation, and the sample is stored at 4 ℃ or sub-packaged and stored at minus 80 ℃.

(3) WB experiment

Loading total cell proteins into running gel (SDS-PAGE electrophoresis), separating proteins with different molecular weights, wherein the protein electrophoresis program is 100V for 10min;200V,60min. Transferring the protein to a PVDF membrane, wherein the transfer conditions are determined according to different molecular weights, and the transfer conditions are 200mA and 70min, wherein the transfer solution of internal reference beta-tubulin or GAPDH contains 20% of methanol; the target protein ErBb2 transfer solution contains 10% methanol and 0.1% SDS, and the transfer condition is 200mA for 120min.5% skimmed milk powder is sealed at normal temperature for 1h. The primary antibody is incubated at normal temperature for 2h or at 4 ℃ overnight. TBST washes 10min 3. The secondary antibody is incubated for 1h at normal temperature. TBST washes 10min 3.ECL color development and photographing.

Experimental results: the degradation experimental results of the compound of the invention on ErBb2 protein are shown in figure 1: the results show that the representative compounds Y13-2, Y15-2 and Y16-4 all show significant protein degradation, with a maximum degradation rate of about 50%, wherein the Y15-2 protein degradation is most significant and the protein degradation rate is 46% at a concentration of 1 nM.

Conclusion of experiment: the compound can effectively degrade ErBb2 protein in a breast cancer cell line BT474, and the dose-effect relationship between the drug concentration and the protein degradation rate is obvious.

Experimental example 2: proliferation inhibition of breast cancer cell line (BT 474)

The proliferation inhibition of breast cancer cell lines (BT 474) by the compounds of the invention was tested using the CCK8 assay.

Experimental operation: BT474 cells were plated, changed to assay medium after 24h, and compounds at different concentrations were added. At 37 degrees, 5% CO ₂ Culturing in an incubator for 3d. Cell proliferation was detected by addition of CCK 8.

Experimental results: the results of representative compounds Y13-2, Y15-2 and Y16-4 are shown in Table 1, wherein the maximum inhibition rate and IC of compound Y13-2 ₅₀ Values were 69% and 142.3nM, respectively; maximum inhibition and IC of Compound Y15-2 ₅₀ Values were 62% and 32.0nM, respectively; maximum inhibition and IC of Compound Y16-4 ₅₀ The values were 58% and 296.3nM, respectively.

TABLE 1

Compounds of formula (I)	Maximum inhibition rate	IC50(nM)
			Y13-2	69％	142.3
Y15-2	62％	32.0
			Y16-4	58％	296.3

Conclusion of experiment: the compound can effectively inhibit the proliferation of BT474 cells, wherein the proliferation inhibition effect of Y15-2 on the BT474 cells is most obvious. This is consistent with the results of the above protein degradation, indicating that the compounds of the invention inhibit proliferation of breast cancer cells by degrading the ErBb2 protein.

Experimental example 3: degradation of LNCaP cellular AR proteins

The degradation of LNCaP cell AR proteins by the compounds of the invention was examined using the Western immunoblotting (WB) method.

Experimental operation:

(1) Cell plating:

LNCaP cells were taken and observed in good condition by microscopic examination, and in logarithmic growth phase, the culture solution was discarded by an electric pipette in an ultra clean bench, and then 4ml PBS was rinsed 3 times. Adding 2ml of 0.25% pancreatin into CO ₂ The incubator digests for 10 minutes. The digestion was stopped by adding 4ml of culture medium, and the cells were completely blown off by pipetting with an electric pipette. Collecting into 15ml centrifuge tube, centrifuging at 1000rpm/min for 5min, re-suspending with 3ml culture medium, and counting cell number with cell counter (LNCaP: 4×10) ⁶ X 3 ml) and adjust it to 4 x 10 ⁵ cell/ml. And (5) blowing and uniformly mixing the cells. The cell suspension is inoculated into two 6-well plates respectively, each of which is 2ml, and then placed into 37 ℃ and 5% CO ₂ The cell culture was continued for 48 hours in the incubator.

(2) Drug administration treatment:

taking the compound of the invention stored at the temperature of minus 20 ℃ and adopting a culture medium to carry out serial concentration gradient dilution. And the culture medium in (1) was replaced with it for further culture for 24 hours. To observe the effect of vehicle effect, DMSO negative control groups were set, while one negative control group with medium alone was set for each 6-well plate.

(3) Protein extraction and quantification:

extracting total cell proteins by RIPA, quantifying the proteins by a Brandford method, adjusting the total proteins to the same concentration, adding a loading buffer, denaturing in a 100-DEG C metal bath for 10min, rapidly placing on ice, performing instantaneous centrifugation, and placing a sample at 4℃ for preservation.

(4) WB experiment:

separating proteins by SDS-PAGE, wherein the protein electrophoresis program is 100V for 10min;200V,60min. Transferring the protein to PVDF film under the conditions of 20% methanol and 200mA and 80min.5% skimmed milk powder is sealed at normal temperature for 1h. The primary antibody is incubated at normal temperature for 2h or at 4 ℃ overnight. TBST wash membranes for 5 min.3. The secondary antibody is incubated for 1h at normal temperature. TBST wash membranes for 5 min.3. ECL color development and photographing.

Experimental results: the results of compounds A1-8 are shown in FIG. 2. Wherein, when LNCaP cells are treated with concentration of more than 10uM, the expression of Jie Xiong hormone receptor (AR) can be reduced to different degrees, and the degradation rate can reach 42.37% at 30 uM.

The foregoing is a further detailed description of the invention in connection with the preferred embodiments, and it is not intended that the invention be limited to the specific embodiments described. It will be apparent to those skilled in the art that several simple deductions or substitutions may be made without departing from the spirit of the invention, and these should be considered to be within the scope of the invention.

Claims

1. A compound of the general formula (I-H-1), or a pharmaceutically acceptable salt thereof:

y is selected from CH ₂ Or c=o;

-L ₁ -(E) _m -L ₂ -selected from-NH- (CH) ₂ ) ₄ -CH ₂ -or-NH- (CH) ₂ CH ₂ O) ₁ -(CH ₂ ) ₂ -。

2. A compound of general formula (I-H-1) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

3. a pharmaceutical composition comprising a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

4. The pharmaceutical composition of claim 3, further comprising an additional therapeutic agent.

5. Use of a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and/or prevention of cancer.

6. The use of claim 5, wherein the cancer is selected from lung cancer, breast cancer, gastric cancer, prostate cancer.

7. The use of claim 5, wherein the cancer is selected from HER2 positive metastatic breast cancer, HER2 overexpressed metastatic gastric adenocarcinoma or gastroesophageal junction adenocarcinoma, non-small cell lung cancer with an Epidermal Growth Factor Receptor (EGFR) gene sensitive mutation, locally advanced or metastatic squamous histological type non-small cell lung cancer with disease progression during or after platinum-containing chemotherapy, metastatic advanced breast cancer, castration-resistant prostate cancer.

8. The use of claim 5, wherein the medicament is for use as an adjunct treatment for HER2 over-expressing breast cancer.

9. The use of claim 5, wherein the cancer is selected from the group consisting of estrogen receptor-induced breast cancer, androgen receptor-induced breast cancer, and androgen receptor-induced prostate cancer.