CN115490673A

CN115490673A - 3, 3-disubstituted indolone compounds and application thereof

Info

Publication number: CN115490673A
Application number: CN202211272924.8A
Authority: CN
Inventors: 高峰; 姜蕊; 刘彬; 高宇; 郭永起; 吴卓
Original assignee: Suzhou Puhe Pharmaceutical Technology Co ltd
Current assignee: Suzhou Puhe Pharmaceutical Technology Co ltd
Priority date: 2022-01-11
Filing date: 2022-10-20
Publication date: 2022-12-20

Abstract

The invention provides a3, 3-disubstituted indolone compound and application thereof, and provides a compound shown in formula (I), or pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorphism, hydrate or solvate thereof. The invention also provides a preparation method of the compound, a pharmaceutical composition containing the compound, and an effect of the compound in preventing and treating related cancers, such as breast cancer, ovarian cancer, uterine cancer, cervical cancer or endometrial cancer.

Description

3, 3-disubstituted indolone compounds and application thereof

Cross Reference to Related Applications

This application claims priority to PCT/CN2022/071338 filed on 11/1/2022, which is hereby incorporated by reference in its entirety.

Technical Field

The invention belongs to the field of medicines, and relates to a3, 3-disubstituted indolone compound, or pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof. The invention also relates to a preparation method of the compound, a pharmaceutical composition containing the compound, and an effect of the compound in preventing and treating related cancers, such as breast cancer, ovarian cancer, uterine cancer, cervical cancer, endometrial cancer and the like.

Background

Breast cancer is a malignant disease caused by uncontrolled growth of breast cells, and has a high incidence in various countries around the world. Although clinical diagnosis and treatment of breast cancer have been improved greatly with the development of medical technology, according to the standard diagnosis and treatment guideline for advanced breast cancer in China (2020 edition), the 5-year survival rate of patients with advanced breast cancer is only 20%, and the overall median survival time is only 2-3 years (Chinese journal of tumor, 2020, 42 (10): 781-797). According to the reports, about 27.24 million new breast Cancer patients are reported in China each year, and about 7.07 million patients die of breast Cancer each year (CA Cancer J Clin.2016; 66; approximately 28.42 million new breast Cancer patients in the United states annually, and approximately 4.41 million patients annually die of breast Cancer (CA Cancer J Clin.2021; 71-33.

Breast cancer can be divided into various subtypes according to the expression backgrounds of Estrogen Receptor (ER), progestogen Receptor (PR), and human epithelial growth factor receptor 2 (her2). Among the various subtypes, ER-positive patients account for approximately 79% of all breast Cancer patients (CA Cancer J Clin.2019;69 438-451), and estrogen drives proliferation and survival of breast Cancer cells by acting on ER receptors. Currently, endocrine therapy targeting the ER signaling pathway is the primary therapeutic approach for the treatment of ER positive tumors, including the estrogen-competitive drug tamoxifen, the aromatase inhibitor letrozole, which inhibits estrogen production, the ER receptor antagonist/degrader fulvestrant, and the like. Although these drugs show good therapeutic effects, some patients are still insensitive to the drug, while most develop resistance after administration (Nat Rev Clin Oncol,2015Sep 12 (9): 541-52) (Nat Rev Clin Oncol,2019May 16 (5): 296-311.) (Cancer cell.2018Sep10;34 (3): 427-438.e6.. Current data show that resistance typically occurs within 7 years after administration (Sci Transl Med.2021Jul21;13 (603): eabf 1383.) (Nat Rev Clin Oncol,2019May 16 (5): 296-311.) (Ann Oncol.2018Aug1;29 (8): 1634-1657.).

In addition, there have been new mechanistic therapeutic drugs in recent years, such as the CDK4/6 inhibitor Pabociclib, which is used in the treatment of ER +/HER 2-breast cancer patients (Nat Rev Clin Oncol,2016Jul 13 (7): 417-30.), as well as the PI3 K.alpha.inhibitor Albizinix, which is used in the treatment of hormone receptor positive/HER 2-breast cancer (Nat Rev Clin Oncol,2019Aug 16 (8): 466.. The two drugs are mild in action when taken alone and generally need to be combined with endocrine therapy, for example, palbociclib is combined with letrozole, while arbepril is generally combined with fulvestrant; at the same time, these two classes of drugs are approved for HER 2-patients and not for all ER positive patients; moreover, resistance to both drugs often occurs after administration. Overall, there is still an urgent need for effective therapeutic agents in ER + breast cancer patients.

Endocrine therapy resistant patients generally remain ER positive, including patients with mutations in some ER (e.g., Y537S and D538G), resulting in sustained activation of the ER signal (Cancer cell.2020Apr 13 (4): 496-513.) (Nat Rev Clin Oncol,2015Oct 12 (10): 573-83.. In the application, we used the ER + MCF breast cancer cell line (resistant or only partially responsive to tamoxifen, fulvestrant, palbociclib, etc.) and the ER-MDA-MB-231 breast cancer cell line to detect a series of molecules and find some new molecules which selectively kill ER + cells and have the potential to overcome drug resistance.

Disclosure of Invention

In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variation, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:

wherein, the first and the second end of the pipe are connected with each other,

R ₁ is selected from C _3-10 Cycloalkyl, C _5-12 And a cycloalkyl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl; optionally substituted with 1,2,3,4 or 5R #;

r # is independently selected from H, halogen, -OH, -NH ₂ 、-CN、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, O-C _1-6 Alkyl, O-C _1-6 Haloalkyl, C _3-7 Cycloalkyl or 3-7 membered heterocyclyl; or two R # on the same carbon atom together form C = O, C = S, C _3-7 Cycloalkyl or 3-7 membered heterocyclyl;

R ₂ is H, or together with the carbon atom to which it is attached and a gem-hydrogen forms C = O or C = S;

R ₃ 、R ₄ 、R ₅ and R ₆ Each independently selected from H, halogen, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, -O-C _1-6 Alkyl or-O-C _1-6 A haloalkyl group;

R ₇ selected from H, halogen, -OH, -CN、-NH ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, O-C _1-6 Alkyl or O-C _1-6 A haloalkyl group.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant or vehicle.

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

In another aspect, the present invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment and/or prevention of cancer, preferably, the cancer is an ER-positive cancer.

In another aspect, the present invention provides a method of treating and/or preventing cancer in a subject, comprising administering to said subject a compound of the present invention or a pharmaceutical composition of the present invention, preferably, said cancer is an ER-positive cancer.

In another aspect, the present invention provides a compound of the invention or a pharmaceutical composition of the invention for use in the treatment and/or prevention of cancer, preferably said cancer is an ER-positive cancer.

In a particular embodiment, the invention is for the treatment and/or prevention of cancer. In another specific embodiment, the invention is used for the treatment and/or prevention of ER-positive cancer. In another embodiment, the present invention is used for the treatment and/or prevention of breast cancer, ovarian cancer, uterine cancer, cervical cancer or endometrial cancer.

Definition of

Chemical definition

Definitions of specific functional groups and chemical terms are described in more detail below.

When a range of values is recited, it is intended to include each value and every subrange within the range. E.g. "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 chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C _1-4 Alkyl and C _1-2 Alkyl groups are preferred. 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 group (C) ₅ ) 3-pentyl radical (C) ₅ ) Pentyl group (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 wherein 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, 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 _2-6 Examples of alkenyl groups include: vinyl radical (C) ₂ ) 1-propenyl group (C) ₃ ) 2-propenyl (C) ₃ ) 1-butenyl (C) ₄ ) 2-butenyl (C) ₄ ) Butadienyl radical (C) ₄ ) Pentenyl (C) ₅ ) Pentadienyl (C) ₅ ) Hexenyl (C) ₆ ) And so on. The term "C _2-6 Alkenyl radical"also includes heteroalkenyl 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 alkenyl group may be optionally substituted with one or more substituents, for example, 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 _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 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). An alkynyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C _1-6 Alkylene "means removal of C _1-6 Another hydrogen of the alkyl group forms a divalent group and may be substituted or unsubstituted. In some embodiments, C _1-4 Alkylene radical, C _2-4 Alkylene and C _1-3 Alkylene groups are preferred. Unsubstituted said alkylene groups include, but are not limited to: methylene (-CH) ₂ -) ethylene (-CH ₂ CH ₂ -) propylene (-CH) ₂ CH ₂ CH ₂ -) butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ -), pentylene (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₂ -) and hexylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -) and the like. Exemplary substituted said alkylene groups, for example, said 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 byEthylene (-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 -) and the like.

“C _0-6 Alkylene "means a bond and the above-mentioned" C _1-6 Alkylene groups ".

“C _2-6 Alkenylene "means removal of C _2-6 Another hydrogen of the alkenyl group forms a divalent radical and may be substituted or unsubstituted. In some embodiments, C _2-4 Alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to: vinylidene (-CH = CH-) and propenylene (e.g., -CH = CHCH) ₂ -、-CH ₂ -CH = CH-. Exemplary substituted alkenylene groups, for example, alkenylene 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 ) -) and the like.

“C _2-6 Alkynylene "means removal of C _2-6 Another hydrogen of the alkynyl group forms a divalent radical 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 [ identical to ] C-), substituted or unsubstituted propynyl (-C [ identical to ] CCH) ₂ -) and the like.

"halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

Thus, "C _1-6 Haloalkyl "means" C "as defined 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 said 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 can 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 A cycloalkyl group. Cycloalkyl also includes ring systems in which the aforementioned 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 group (C) ₃ ) Cyclobutyl (C) ₄ ) Cyclobutenyl (C) ₄ ) Cyclopentyl (C) ₅ ) Cyclopentenyl group (C) ₅ ) Cyclohexyl (C) ₆ ) Cyclohexenyl (C) ₆ ) Cyclohexyldienyl (C) ₆ ) Cycloheptyl (C) ₇ ) Cycloheptenyl (C) ₇ ) Cycloheptadienyl (C) ₇ ) Cycloheptatrienyl (C) ₇ ) And so on. A cycloalkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"5-10 membered heterocyclyl" means a saturated or unsaturated group having a ring carbon atom and 1 to 5 ring heteroatoms in a 5 to 10 membered non-aromatic ring system, wherein each heteroatom is presentIndependently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. "3-7 membered heterocyclyl" refers to a saturated or unsaturated group of a3 to 7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the point of attachment may be carbon or a nitrogen atom, as valency permits. In some embodiments, a 3-6 membered heterocyclic group is preferred, which is a3 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 5-8 membered heterocyclic group which is a4 to 8 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferred are 5-6 membered heterocyclic groups which are 5 to 6 membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems wherein the aforementioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or ring systems wherein the aforementioned 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 heterocyclic groups containing one heteroatom include, but are not limited to: aziridinyl, oxacyclopropaneyl, thiacyclopropanyl (thiorenyl). 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 heterocyclic groups containing two heteroatoms include, but are not limited to: dioxolanyl, oxathiolanyl (oxathiolanyl), dithiolanyl (disulphuryl), and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl and thiacyclohexyl (thianyl). Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl radicalMorpholinyl, dithiacyclohexane, dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinanyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepane, oxepanyl and thiepane. Exemplary with C ₆ Aryl ring fused 5-membered heterocyclyl (also referred to herein as 5, 6-bicyclic heterocyclyl) includes, but is not limited to: indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolonyl, and the like. Exemplary with C ₆ Aryl ring fused 6-membered heterocyclyl (also referred to herein as 6, 6-bicyclic heterocyclyl) includes, but is not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Heterocyclyl also includes heterocyclic groups as described above which share one or two atoms with a cycloalkyl, heterocyclyl, aryl or heteroaryl group to form a bridged or spiro ring, where the shared atoms may be carbon or nitrogen atoms as valency permits. Heterocyclyl also includes the above-described heterocyclyl and heterocyclyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

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

"5-10 membered heteroaryl" refers to a group having a 5-10 membered monocyclic or bicyclic 4n +2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) with 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 valency permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6 membered heteroaryl is preferred, which is a 5-6 membered monocyclic or bicyclic 4n +2 aromatic ring system 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: a tetrazolyl group. 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: azepinyl, oxacycloheptyl, and thiacycloheptyl trienyl groups. Exemplary 5, 6-bicyclic heteroaryls include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisothiafuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indezinyl, and purinyl. Exemplary 6, 6-bicyclic heteroaryls include, but are not limited to: naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl. The heteroaryl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C _5-12 Cyclocycloalkyl "refers to a 5-12 membered cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other, including 5-12 membered saturated and cyclocycloalkyl and 5-12 membered partially saturated and cyclocycloalkyl. Preferably 5-to 10-membered acyclic cycloalkyl. 5-12 membered saturated fused cycloalkyl, meaning that the fused ring group is a fully saturated carbocyclic ring, specific examples include, but are not limited to: bicyclo [3.1.0]Hexane radical, bicyclo [4.1.0 ]]Heptylalkyl, bicyclo [2.2.0]Hexane radical, bicyclo [3.2.0]Heptylalkyl, bicyclo [4.2.0]Octyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthyl and the like. 5-12 membered partially saturated fused cycloalkyl, meaning that at least one ring in the fused ring is a partially saturated carbocyclic ring, specific examples include, but are not limited to: bicyclo [3.1.0]Hex-2-enyl, bicyclo [4.1.0]Hept-3-enyl, bicyclo [3.2.0]Hept-3-enyl, bicyclo [4.2.0]Oct-3-enyl, 1,2,3 a-tetrahydrocyclopentadienyl, 2, 3a,4,7 a-hexahydro-1H-indenyl, 1,2,3, 4a,5,6,8 a-octahydronaphthyl, 1,2,4a,5,6,8 a-hexahydronaphthyl, and the like.

The divalent group formed by removing another hydrogen from the above-defined alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is collectively referred to as "subunit". The cyclic groups such as cycloalkyl, heterocyclic group, aryl and heteroaryl are collectively referred to as "cyclic group".

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

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 Substituted by groups;

or two gem-hydrogens on carbon atoms are replaced by a group = 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 each is 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 Substituted by groups;

R ^bb each 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 Substitution of radicals;

R ^cc each is independently selected from the group consisting of 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 Substituted by groups;

R ^dd each 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 radicals, or two geminal R ^dd Substituents may combine to form = O or = S;

R ^ee is 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 Substituted by groups;

R ^ff each is independently selected from the group consisting of 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 Substituted by groups;

R ^gg is independently from each other: halogen, -CN, -NO ₂ 、-N ₃ 、-SO ₂ H、-SO ₃ H、-OH、-OC _1-6 Alkyl, -ON (C) _1-6 Alkyl radical) ₂ 、-N(C _1-6 Alkyl radical) ₂ 、-N(C _1-6 Alkyl radical) ₃ ⁺ X ^- 、-NH(C _1-6 Alkyl radical) ₂ ⁺ X ^- 、-NH ₂ (C _1-6 Alkyl radical) ⁺ 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 radical) 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 radical) 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 radical) ₂ 、-C(＝NH)NH(C _1-6 Alkyl), -C (= NH) NH ₂ 、-OC(＝NH)N(C _1-6 Alkyl radical) ₂ 、-OC(NH)NH(C _1-6 Alkyl), -OC (NH) NH ₂ 、-NHC(NH)N(C _1-6 Alkyl radical) ₂ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ (C _1-6 Alkyl), -SO ₂ N(C _1-6 Alkyl radical) 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 radical) ₃ 、-OSi(C _1-6 Alkyl radical) ₃ 、-C(＝S)N(C _1-6 Alkyl radical) 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 group, -SC (= S) SC _1-6 Alkyl, -P (= O) ₂ (C _1-6 Alkyl), -P (= O) (C) _1-6 Alkyl radical) ₂ 、-OP(＝O)(C _1-6 Alkyl radical) ₂ 、-OP(＝O)(OC _1-6 Alkyl radical) ₂ 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₇ Cycloalkyl radical, C ₆ -C ₁₀ Aryl radical, C ₃ -C ₇ Heterocyclic group, C ₅ -C ₁₀ A heteroaryl group; or two geminal R ^gg Substituents may combine to form = O or = S; wherein, X ^- Are counter ions.

Exemplary substituents on the nitrogen atom 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 Is substituted by radicals, and wherein R ^aa 、R ^bb 、R ^cc And R ^dd As described above.

Other definitions

The term "cancer" includes, but is not limited to, the following cancers: breast cancer, ovarian cancer, uterine cancer, cervical cancer or endometrial cancer.

The term "treating" as used herein relates to reversing, alleviating, inhibiting the progression of, or preventing the 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 the verb treatment, the latter being as just defined.

The term "pharmaceutically acceptable salts" as used herein refers to those carboxylic acid salts, amino acid addition salts, of the compounds of the present 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, and are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use, including the zwitterionic forms, where possible, of the compounds of the invention.

Pharmaceutically acceptable base addition salts are formed with metals or amines, such as 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.

Base addition salts of 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 may be regenerated by contacting the salt form with an acid and separating the free acid in a conventional manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but the salts are also equivalent to their respective free acids for the purposes of this invention.

The salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids 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, lauryl sulfonate, 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 acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoic acid basin, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate, mesylate, and the like. Pharmaceutically acceptable salts can include cations based on the 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. Also contemplated are Salts of amino acids, such as arginate, gluconate, galacturonate, and the like (see, e.g., berge s.m.et al, "Pharmaceutical Salts," j.pharm.sci.,1977, 66, incorporated herein by reference.

The "subject" to which the drug is administered includes, but is not limited to: a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an older adult)) and/or a non-human animal, e.g., a mammal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a cow, a pig, a horse, a sheep, a goat, a rodent, a cat, and/or a 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 specified, the term "treatment" includes effects that occur when a subject suffers from 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"), and also includes effects that occur before the subject begins to suffer from the particular disease, disorder or condition ("prophylactic treatment").

Generally, an "effective amount" of a compound is 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 a compound of the present invention may vary depending on the following factors: for example, biological targets, pharmacokinetics of the compound, disease to be treated, mode of administration, and age health and condition of the subject. An effective amount includes a therapeutically effective amount and a prophylactically effective amount.

As used herein, unless otherwise specified, 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 the amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves the 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 specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with a disease, disorder or condition, or prevent the 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 the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can 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 present invention may be administered simultaneously or sequentially with the other therapeutic agent in separate unit dosage forms, or simultaneously with the other therapeutic agent in a single unit dosage form.

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

Detailed description of the preferred embodiments

Herein, "compound of the present invention" refers to a compound of formula (I) below (including sub-formulae, for example, formula (I-1), formula (I-2), formula (II-1), formula (II-2), formula (III-1), formula (III-2), and the like), or a pharmaceutically acceptable salt, isotopic variation, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, and a mixture thereof.

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

wherein the content of the first and second substances,

R ₁ is selected from C _3-10 Cycloalkyl radical, C _5-12 And a heterocycloalkyl group, a 5-10 membered heteroaryl group or a 5-10 membered heterocyclic group; optionally substituted with 1,2,3,4 or 5R #;

R ₂ is H, or together with the attached carbon atom and gem hydrogen forms C = O or C = S;

R ₇ selected from H, halogen, -OH, -CN, -NH ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, O-C _1-6 Alkyl or O-C _1-6 A haloalkyl group.

R ₁

In one embodiment, R ₁ Is C _3-10 A cycloalkyl group; in another embodiment, R ₁ Is C _5-12 And a cycloalkyl group; in another embodiment, R ₁ Is a 5-10 membered heteroaryl; in a further embodiment of the method according to the invention,R ₁ is a 5-10 membered heterocyclic group; in another embodiment, R ₁ Is C _5-10 And a cycloalkyl group; in another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is C _5-10 A cycloalkyl group; in another embodiment, R ₁ Is C _3-7 A cycloalkyl group; in another embodiment, R ₁ Is C _5-6 A cycloalkyl group.

In one embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

In another embodiment, R ₁ Is composed of

R ₂

In one embodiment, R ₂ Is H; in another embodiment, R ₂ Together with the attached carbon atom and the gem-hydrogen form C = O; in another embodiment, R ₂ Together with the carbon atom to which it is attached and the gem-hydrogen form C = S.

R ₃

In one embodiment, R ₃ Is H; in another embodiment, R ₃ Is halogen; in another embodiment, R ₃ Is C _1-6 An alkyl group; in another embodiment, R ₃ Is C _1-4 An alkyl group; in another embodiment, R ₃ Is C _1-2 An alkyl group; in another embodiment, R ₃ Is C _2-6 An alkenyl group; in another embodiment, R ₃ Is C _2-6 An alkynyl group; in another embodiment, R ₃ Is C _1-6 A haloalkyl group; in another embodiment, R ₃ Is C _1-4 A haloalkyl group; in another embodiment, R ₃ Is C _1-2 A haloalkyl group; in another embodiment, R ₃ is-O-C _1-6 An alkyl group; in another embodiment, R ₃ is-O-C _1-4 An alkyl group; in another embodiment, R ₃ is-O-C _1-2 An alkyl group; in another embodiment, R ₃ is-O-C _1-6 A haloalkyl group; in another embodiment, R ₃ is-O-C _1-4 A haloalkyl group; in another embodiment, R ₃ is-O-C _1-2 A haloalkyl group.

In one embodiment, R ₃ is-CF ₃ (ii) a In another embodiment, R ₃ is-CH ₃ 。

R ₄

In one embodiment, R ₄ Is H; in another embodiment, R ₄ Is halogen; in another embodiment, R ₄ Is C _1-6 An alkyl group; in another embodiment, R ₄ Is C _1-4 An alkyl group; in another embodiment, R ₄ Is C _1-2 An alkyl group; in another embodiment, R ₄ Is C _2-6 An alkenyl group; in another embodiment, R ₄ Is C _2-6 An alkynyl group; in another embodiment, R ₄ Is C _1-6 A haloalkyl group; in another embodiment, R ₄ is-O-C _1-6 An alkyl group; in another embodiment, R ₄ is-O-C _1-4 An alkyl group; in another embodiment, R ₄ is-O-C _1-2 An alkyl group; in another embodiment, R ₄ is-O-C _1-6 A haloalkyl group; in another embodiment, R ₄ is-O-C _1-4 A haloalkyl group; in another embodiment, R ₄ is-O-C _1-2 A haloalkyl group.

In one embodiment, R ₄ is-OCH ₃ 。

R ₅

In one embodiment, R ₅ Is H; in another embodiment, R ₅ Is halogen; in another embodiment, R ₅ Is C _1-6 An alkyl group; in another embodiment, R ₅ Is C _1-4 An alkyl group; in another embodiment, R ₅ Is C _1-2 An alkyl group; in thatIn another embodiment, R ₅ Is C _2-6 An alkenyl group; in another embodiment, R ₅ Is C _2-6 An alkynyl group; in another embodiment, R ₅ Is C _1-6 A haloalkyl group; in another embodiment, R ₅ is-O-C _1-6 An alkyl group; in another embodiment, R ₅ is-O-C _1-4 An alkyl group; in another embodiment, R ₅ is-O-C _1-2 An alkyl group; in another embodiment, R ₅ is-O-C _1-6 A haloalkyl group; in another embodiment, R ₅ is-O-C _1-4 A haloalkyl group; in another embodiment, R ₅ is-O-C _1-2 A haloalkyl group.

R ₆

In one embodiment, R ₆ Is H; in another embodiment, R ₆ Is halogen; in another embodiment, R ₆ Is C _1-6 An alkyl group; in another embodiment, R ₆ Is C _1-4 An alkyl group; in another embodiment, R ₆ Is C _1-2 An alkyl group; in another embodiment, R ₆ Is C _2-6 An alkenyl group; in another embodiment, R ₆ Is C _2-6 Alkynyl; in another embodiment, R ₆ Is C _1-6 A haloalkyl group; in another embodiment, R ₆ is-O-C _1-6 An alkyl group; in another embodiment, R ₆ is-O-C _1-4 An alkyl group; in another embodiment, R ₆ is-O-C _1-2 An alkyl group; in another embodiment, R ₆ is-O-C _1-6 A haloalkyl group; in another embodiment, R ₆ is-O-C _1-4 A haloalkyl group; in another embodiment, R ₆ is-O-C _1-2 A haloalkyl group.

R ₇

In one embodiment, R ₇ Is H; in a further embodiment of the method according to the invention,R ₇ is halogen; in another embodiment, R ₇ is-OH; in another embodiment, R ₇ is-CN; in another embodiment, R ₇ is-NH ₂ (ii) a In another embodiment, R ₇ Is C _1-6 An alkyl group; in another embodiment, R ₇ Is C _1-4 An alkyl group; in another embodiment, R ₇ Is C _1-2 An alkyl group; in another embodiment, R ₇ Is C _2-6 An alkenyl group; in another embodiment, R ₇ Is C _2-6 Alkynyl; in another embodiment, R ₇ Is C _1-6 A haloalkyl group; in another embodiment, R ₇ is-O-C _1-6 An alkyl group; in another embodiment, R ₇ is-O-C _1-4 An alkyl group; in another embodiment, R ₇ is-O-C _1-2 An alkyl group; in another embodiment, R ₇ is-O-C _1-6 A haloalkyl group; in another embodiment, R ₇ is-O-C _1-4 A haloalkyl group; in another embodiment, R ₇ is-O-C _1-2 A haloalkyl group.

R _s

In one embodiment, R _s Is H; in another embodiment, R _s Is C _1-4 An alkyl group; in another embodiment, R _s Is C _1-2 An alkyl group; in another embodiment, R _s Is C _1-4 A haloalkyl group; in another embodiment, R _s Is C _1-2 A haloalkyl group; in another embodiment, R _s Is O-C _1-4 An alkyl group; in another embodiment, R _s Is O-C _1-2 An alkyl group; in another embodiment, R _s Is O-C _1-4 A haloalkyl group; in another embodiment, R _s Is O-C _1-2 A haloalkyl group.

Ring A

In one embodiment, ring a is a 3-7 membered heterocyclyl; in another embodiment, ring a is 5-10 membered heteroaryl; in another embodiment, ring a is a 5-6 membered heterocyclyl; in another embodiment, ring a is a 5-6 membered heteroaryl;

in one embodiment, ring a is optionally substituted with 1R #; in another embodiment, ring a is optionally substituted with 2R #; in another embodiment, ring a is optionally substituted with 3R #.

Ring B

In one embodiment, ring B is C _6-10 An aryl group; in another embodiment, ring B is C _5-10 A heteroaryl group.

In one embodiment, ring B is optionally substituted with 1R #; in another embodiment, ring B is optionally substituted with 2R #; in another embodiment, ring B is optionally substituted with 3R #.

Ring C

In one embodiment, ring C is C _6-10 An aryl group; in another embodiment, ring C is C _5-10 A heteroaryl group.

In one embodiment, ring C is optionally substituted with 1R #; in another embodiment, ring C is optionally substituted with 2R #; in another embodiment, ring C is optionally substituted with 3R #.

R#

In one embodiment, R # is H; in another embodiment, R # is halo; in another embodiment, R # is-OH; in another embodiment, R # is-NH ₂ (ii) a In another embodiment, R # is — CN; in another embodiment, R # is C _1-6 An alkyl group; in another embodiment, R # is C _1-4 An alkyl group; in another embodiment, R # is C _1-2 An alkyl group; in another embodiment, R # is C _2-6 An alkenyl group; in another embodiment, R # is C _2-6 An alkynyl group; in another embodiment, R # is C _1-6 Halogenated alkyl radical(ii) a In another embodiment, R # is C _1-4 A haloalkyl group; in another embodiment, R # is C _1-2 A haloalkyl group; in another embodiment, R # is O-C _1-6 An alkyl group; in another embodiment, R # is O-C _1-6 A haloalkyl group; in another embodiment, R # is C _3-7 A cycloalkyl group; in another embodiment, R # is C _3-5 A cycloalkyl group; in another embodiment, R # is a 3-7 membered heterocyclyl; in another embodiment, R # is a 5-6 membered heterocyclyl.

In a specific embodiment, two R # s on the same carbon atom together form C = O; in another embodiment, two R # on the same carbon atom together form C = S; in another embodiment, two R # s on the same carbon atom are taken together to form C _3-7 A cycloalkyl group; in another embodiment, two R # s on the same carbon atom are taken together to form C _3-5 A cycloalkyl group; in another embodiment, two R #, on the same carbon atom, taken together form a 3-7 membered heterocyclyl; in another embodiment, two R #, on the same carbon atom, together form a 5-6 membered heterocyclyl.

In one embodiment, R # is F; in another embodiment, R # is-CH ₃ (ii) a In another embodiment, R # is cyclopropane; in another embodiment, R # is-OCF ₃ 。

Any of the above embodiments, or any combination thereof, may be combined with any of the other embodiments, or any combination thereof. For example, R ₁ Any one or any combination of (1) can be combined with R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R _s Any of the technical schemes of ring A, ring B, ring C, R #, and the like, or any combination thereof. The present invention is intended to include all combinations of these solutions, not to be limited to space, but to be listed one by one.

In a more specific embodiment, the present invention provides a compound of formula (I-1) or (I-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:

wherein the content of the first and second substances,

R ₁ is selected from C _3-10 Cycloalkyl radical, C _5-12 And a cycloalkyl group or a 5-to 10-membered heteroaryl group; optionally substituted with 1,2 or 3R #;

r # is selected from H, halogen, -OH, -NH ₂ 、-CN、C _1-6 Alkyl radical, C _1-6 Haloalkyl, O-C _1-6 Alkyl, O-C _1-6 Haloalkyl, C _3-7 Cycloalkyl or 3-7 membered heterocyclyl; or two R # on the same carbon atom together form C = O, C = S, C _3-7 Cycloalkyl or 3-7 membered heterocyclyl;

R ₃ selected from H, halogen, C _1-6 Alkyl or C _1-6 A haloalkyl group;

R ₄ selected from H, halogen, -O-C _1-6 Alkyl or-O-C _1-6 A haloalkyl group;

R ₅ is H or halogen;

R ₆ is H or halogen;

R ₇ is-OH, -CN or-NH ₂ 。

In a more specific embodiment, the present invention provides a compound of formula (I-1) or (I-2) as described above, or a pharmaceutically acceptable salt, isotopic variation, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,

R ₁ is selected from C _3-10 Cycloalkyl radical, C _5-10 A heterocyclic cycloalkyl group,

R _s Selected from H, C _1-4 Alkyl radical, C _1-4 Haloalkyl, O-C _1-4 Alkyl or O-C _1-4 A haloalkyl group;

ring A is selected from 3-7 membered heterocyclyl or 5-10 membered heteroaryl;

ring B is C _6-10 Aryl or C _5-10 A heteroaryl group;

ring C being C _6-10 Aryl or C _5-10 A heteroaryl group;

ring a, ring B, and ring C are optionally substituted with 1,2, or 3R #;

r # is selected from H, halogen, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-5 Cycloalkyl or 3-7 membered heterocyclyl; or two R # on the same carbon atom together form C = O, C = S, C _3-5 Cycloalkyl or 3-7 membered heterocyclyl;

R ₂ is H, or together with the attached carbon atom and gem-hydrogen forms C = O;

R ₃ is selected from C _1-2 Alkyl or C _1-2 A haloalkyl group;

R ₄ selected from H or-O-C _1-2 An alkyl group;

R ₅ is H;

R ₆ is H;

R ₇ is-OH.

R ₁ is selected from

R ₃ is selected from-CF ₃ or-CH ₃ ；

R ₄ Is selected from H or-OCH ₃ ；

R ₅ Is H;

R ₆ is H;

R ₇ is-OH.

In a more specific embodiment, the present invention provides a compound of (II), (II-1), or (II-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:

R ₁ is selected from C _3-10 Cycloalkyl radical, C _5-10 And a cycloalkylalkyl group or a 5-to 10-membered heteroaryl group; optionally substituted with 1,2 or 3R #;

R ₃ is selected from C _1-6 Alkyl or C _1-6 A haloalkyl group;

R ₄ selected from H, C _1-6 Alkyl radical, C _1-6 Haloalkyl, -O-C _1-6 Alkyl or-O-C _1-6 A haloalkyl group.

In a more specific embodiment, the present invention provides the above-described compound of (II), (II-1) or (II-2), or a pharmaceutically acceptable salt, isotopic variation, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

R ₁ is selected from C _3-10 Cycloalkyl, C _5-10 A heterocyclic cycloalkyl group,

ring A is selected from 3-7 membered heterocyclyl or 5-10 membered heteroaryl;

ring B is C _6-10 Aryl or C _5-10 A heteroaryl group;

ring C being C _6-10 Aryl or C _5-10 A heteroaryl group;

ring a, ring B, and ring C are optionally substituted with 1,2, or 3R #;

R ₃ is selected from C _1-4 Alkyl or C _1-4 A haloalkyl group;

R ₄ selected from H, -O-C _1-4 Alkyl or-O-C _1-4 A haloalkyl group.

R ₁ is selected from C _5-10 Cycloalkyl radical, C _5-10 A heterocyclic cycloalkyl group,

R _s Selected from H, C _1-2 Alkyl or O-C _1-2 A haloalkyl group;

ring A is selected from 5-6 membered heterocyclyl or 5-6 membered heteroaryl;

ring B is C _6-10 An aryl group;

ring C is C _6-10 An aryl group;

ring a, ring B, and ring C are optionally substituted with 1,2, or 3R #;

r # is selected from H, halogen, C _1-2 Alkyl or C _3-5 A cycloalkyl group; or two R # on the same carbon atom together form C = O or C _3-5 A cycloalkyl group;

R ₂ is H, or together with the carbon atom to which it is attached and a gem-hydrogen forms C = O;

R ₃ is selected from C _1-4 Alkyl or C _1-4 A haloalkyl group;

R ₄ selected from H or-O-C _1-2 An alkyl group.

R ₁ is selected from

R ₃ is selected from-CF ₃ or-CH ₃ ；

R ₄ Is selected from H or-OCH ₃ 。

In a more specific embodiment, the present invention provides a compound of formula (III), (III-1), or (III-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:

wherein the content of the first and second substances,

R ₁ is selected from C _3-10 Cycloalkyl or 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl may be optionally substituted with 1,2 or 3R #;

r # is selected from H, halogen, -OH, -NH ₂ 、-CN、O-C _1-4 Alkyl, O-C _1-4 Haloalkyl, C _3-5 Cycloalkyl or 3-7 membered heterocyclyl; or two R # on the same carbon atom together form C = O, C = S, C _3-5 Cycloalkyl or 3-7 membered heterocyclyl;

R ₃ is selected from C _1-4 Alkyl or C _1-4 A haloalkyl group;

R ₄ selected from H, -O-C _1-4 Alkyl or-O-C _1-4 A haloalkyl group.

In a more specific embodiment, the present invention provides a compound of formula (III), (III-1), or (III-2) as described above, or a pharmaceutically acceptable salt, isotopic variation, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,

ring A is selected from 3-7 membered heterocyclyl or 5-10 membered heteroaryl;

ring B is C _6-10 An aryl group;

ring C being C _6-10 An aryl group;

ring a, ring B, and ring C are optionally substituted with 1,2, or 3R #;

r # is selected from H, halogen, C _3-5 Cycloalkyl or 3-7 membered heterocyclyl; or two R # on the same carbon atom together form C = O, C = S, C _3-5 Cycloalkyl or 3-7 membered heterocyclyl;

R ₃ is selected from C _1-4 Alkyl orC _1-4 A haloalkyl group;

R ₄ selected from H, -O-C _1-2 Alkyl or-O-C _1-2 A haloalkyl group.

R _s Selected from H, C _1-2 Alkyl or O-C _1-2 A haloalkyl group;

ring A is selected from 5-6 membered heterocyclyl or 5-6 membered heteroaryl;

ring B is C _6-10 An aryl group;

ring C is C _6-10 An aryl group;

ring a, ring B, and ring C are optionally substituted with 1,2, or 3R #;

r # is selected from H, halogen or C _3-5 A cycloalkyl group; or two R # on the same carbon atom together form C = O or C _3-5 A cycloalkyl group;

R ₃ is selected from C _1-2 Alkyl or C _1-2 A haloalkyl group;

R ₄ selected from H or-O-C _1-2 An alkyl group.

R ₁ is selected from

R ₃ Is selected from-CF ₃ or-CH ₃ ；

R ₄ Is selected from H or-OCH ₃ 。

R ₃ is selected from C _1-4 Alkyl or C _1-4 A haloalkyl group;

R ₄ selected from H or-O-C _1-4 An alkyl group.

R ₁ is selected from C _3-10 A cycloalkyl group, a,

Preferably C _3-10 A cycloalkyl group, a,

ring A is selected from a 3-7 membered heterocyclic group (preferably a 3-7 membered heterocyclic group containing an oxygen atom) or a 5-10 membered heteroaryl group;

ring B is C _6-10 An aryl group;

ring C being C _6-10 An aryl group;

ring a, ring B, and ring C are optionally substituted with 1,2, or 3R #;

R ₃ is selected from C _1-4 Alkyl or C _1-4 A haloalkyl group;

R ₄ selected from H or-O-C _1-4 An alkyl group.

R ₁ is selected from C _5-10 A cycloalkyl group, a,

Preferably C _5-10 A cycloalkyl group, a,

R _s Selected from H, C _1-2 Alkyl or O-C _1-2 A haloalkyl group;

ring A is selected from a 5-6 membered heterocyclic group (preferably an oxygen atom containing 5-6 membered heterocyclic group) or a 5-6 membered heteroaryl group;

ring B is C _6-10 An aryl group;

ring C is C _6-10 An aryl group;

ring a, ring B, and ring C are optionally substituted with 1,2, or 3R #;

r # is selected from H, halogen, = O or C _3-5 A cycloalkyl group;

R ₃ is selected from C _1-2 Alkyl or C _1-2 A haloalkyl group;

R ₄ selected from H or-O-C _1-2 An alkyl group.

R ₁ is selected from

R ₃ Is selected from-CF ₃ or-CH ₃ ；

R ₄ Is selected from H or-OCH ₃ 。

R ₁ is selected from C _3-10 Cycloalkyl radicals or

Wherein ring A is an oxygen atom-containing 3-7-membered heterocyclic group or 5-10-membered heteroaryl group;

R ₃ is selected from C _1-4 Alkyl or C _1-4 A haloalkyl group;

R ₄ selected from H or-O-C _1-4 An alkyl group.

R ₁ is selected from C _5-10 Cycloalkyl radicals or

Wherein ring A is a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group containing an oxygen atom;

R ₃ is selected from C _1-2 Alkyl or C _1-2 A haloalkyl group;

R ₄ selected from H or-O-C _1-2 An alkyl group.

R ₁ is selected from

R ₃ Is selected from-CF ₃ or-CH ₃ ；

R ₄ Is selected from H or-OCH ₃ 。

In a more specific embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein the compound is selected from the group consisting of:

the compounds of the present invention may include one or more asymmetric centers, and thus may exist in a variety of stereoisomeric forms, e.g., 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. Isomers may be separated from mixtures by methods known to those skilled in the art, including: chiral High Pressure Liquid Chromatography (HPLC) and the formation and crystallization of chiral salts; alternatively, preferred isomers may be prepared by asymmetric synthesis.

The compounds of the invention may exist in tautomeric forms. Tautomers are functional isomers resulting from the rapid movement of an atom in a molecule at two positions, tautomers are specific functional isomers, and a pair of tautomers can be interconverted, but usually a relatively stable isomer is the main form of existence. The most prominent examples are enol and keto tautomers.

One skilled in the art will appreciate that the organic compound may form a complex with the solvent in 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 combined with 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, ether, and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "solvate" includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

The term "hydrationThe term "compound" means a compound which is bound to water. In general, 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, hydrates of the compounds can be used, for example, of the formula R.xH 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 hydrates (x is a number greater than 0 and less than 1), e.g., hemihydrate (R0.5H) 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 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 of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may result in a crystalline form being favored. Various polymorphs of a compound may be prepared by crystallization under different conditions.

The invention also includes isotopically-labeled compounds (isotopic variations) 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, such as 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 ³⁶ and (4) Cl. Compounds of the invention containing the aforementioned isotopes and/or other isotopes of other atoms, precursors thereofBoth the body drug and the pharmaceutically acceptable salts of said compound or said prodrug are within the scope of the present invention. Certain isotopically-labelled compounds of the invention, e.g. by incorporation of radioactive isotopes (e.g. by introducing ³ H and ¹⁴ c) Can be used in drug and/or substrate tissue distribution assays. Tritium, i.e. ³ H and carbon-14, i.e. ¹⁴ The C isotopes are particularly preferred because of their ease of preparation and detection. Further, by heavier isotopes, e.g. deuterium, i.e. ² H, may be preferred in some cases because of the higher metabolic stability that may provide therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of formula (a) of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the 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, for example in the blood, to its active form with a medicinal effect. Pharmaceutically acceptable Prodrugs are described in t.higuchi and v.stella, prodrugs as Novel Delivery Systems, vol.14 of a.c.s.symposium Series, edward b.roche, ed., bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press,1987, and d.fleisher, s.ramon and h.bra "Improved oral Delivery: the solubility limits of the overcom by the use of the drugs ", advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each of which is incorporated herein by reference.

A prodrug is any covalently bonded compound of the present invention that releases the parent compound in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a manner such that the modification is cleaved, either by routine manipulation or in vivo, to yield the parent compound. Prodrugs include, for example, compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amino, or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide, and benzoate/amide derivatives of the hydroxy, mercapto, and amino functional groups of the compounds of formula (a). In addition, in the case of carboxylic acid (-COOH), esters such as methyl ester, ethyl ester, and the like may be used. The ester itself 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 which readily break down 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 (a) 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 present invention.

Pharmaceutical composition and kit

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the 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 compounds formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

Suitable formulations for administration of the compounds of the present invention will be apparent to those of ordinary skill in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions (especially solutions for injection (subcutaneous, intravenous, intramuscular) and infusion (injectable)), elixirs, syrups, cachets, emulsions, inhalants or dispersible powders. The amount of the one or more pharmaceutically active compounds should be in the range of 0.1 to 90wt%, preferably 0.5 to 50wt% of the composition as a whole, i.e. in an amount sufficient to achieve the dosage ranges specified below. The prescribed dose may be administered several times per day, if necessary.

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

Administration of drugs

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

Typically, an effective amount of a compound provided herein is administered. The amount of compound actually administered can be determined by a physician, as the case may be, including the condition to be treated, the chosen route of administration, 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 condition described herein, a subject at risk of developing the condition is administered a compound provided herein, typically based on the recommendations of a physician and under the supervision of a physician, at a dosage level as described above. Subjects at risk of developing a particular disorder, typically include subjects with a family history of the disorder, or those determined to be particularly susceptible to developing the disorder by genetic testing or screening.

The pharmaceutical compositions provided herein may also be administered chronically ("chronic administration"). By long-term administration is meant administration of the compound or pharmaceutical composition thereof over a long period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration may continue 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 the 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. The bolus dose depends on the targeted systemic level of the active ingredient through the body, e.g., an intramuscular or subcutaneous bolus dose results in a slow release of the active ingredient, while a bolus delivered directly to the vein (e.g., by IV intravenous drip) can be delivered more rapidly, resulting in a rapid rise in the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV intravenous drip, to provide a steady state concentration of the active ingredient in the body of the subject. 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 generally, however, the compositions are provided in unit dosage form for convenient administration of the precise dosage. 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 the purpose of 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 the liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients and processing aids useful in forming the desired dosage form.

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

In order to provide blood levels similar to, or lower than, those used with the injected dose, transdermal doses are generally selected in amounts of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from 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 obtain sufficient steady state levels, a preload 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, as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like. Solid forms may include, for example, any of the following components, or compounds with similar properties: a binder, 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, e.g., colloidal silicon dioxide; sweetening agents, 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 injection, 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, with the remainder being injectable excipients and the like.

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

The compounds of the invention may also be administered by transdermal means. Thus, transdermal administration can be achieved using a reservoir (reservoir) or porous membrane type, or a patch of various solid matrices.

The above components of the compositions for oral, injection or topical administration are merely representative. Other materials and processing techniques are described in Remington's Pharmaceutical Sciences,17th edition,1985, mack Publishing company, easton, pennsylvania, section 8, which is 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, which optionally include 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 sulfoalkyl ether β -cyclodextrin, e.g., sulfobutyl ether β -cyclodextrin, also known as Captisol. See, e.g., U.S.5,376,645. In some embodiments, the formulation includes hexapropyl- β -cyclodextrin (e.g., 10-50% in water).

Drug combination

Many chemotherapeutic agents currently known in the art may be used in combination with the compounds of the present invention.

The pharmacologically active substance to be used together/in combination with the compounds of formula (I) of the present invention (including all individual embodiments or a general subset of compound (I)) or in the medical use, treatment and/or prevention method as defined herein (above and below) may be selected from any one or more of the following (preferably only one further pharmacologically active substance is used in all these embodiments):

inhibitors of EGFR and/or mutants thereof

a. For example, afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, oxitinib, EGF-816;

b. preferred are afatinib, oxitinib and cetuximab;

c. most preferred is afatinib;

inhibitors of ErbB2 (Her 2) and/or mutants thereof

a. For example, afatinib, lapatinib, trastuzumab, pertuzumab;

b. preferred are afatinib and trastuzumab;

c. most preferred is trastuzumab;

inhibitors of ALK and/or mutants thereof

a. For example, crizotinib, aratinib, entretinib, bugatitinib;

b. preferred are crizotinib and azitinib;

c. most preferred is crizotinib;

inhibitors of MEK and/or mutants thereof

a. For example, trametinib, cobicistinib, bimetinib (binimetinib), semetinib, remimetinib (refametinib);

b. preferred are trametinib and cobitinib;

c. most preferred is trametinib;

inhibitors of KRAS G12C

a. For example ARS-853 (Compound V-64 in WO 2014/152588), example I-272 in WO 2016/044772;

inhibitors of BCR-ABL and/or mutants thereof

a. For example, imatinib, dasatinib, nilotinib;

b. preferred are imatinib and nilotinib;

c. most preferred is imatinib;

inhibitors of FGFR1 and/or FGFR2 and/or FGFR3 and/or mutants thereof

a. For example, nintedanib;

inhibitors of ROS1 and/or mutants thereof

a. For example, crizotinib, entritinib, loratinib, ceritinib (ceritinib), meritinib (mertinib);

b. preferred are crizotinib and emtrictinib;

c. most preferred is crizotinib;

inhibitors of c-MET and/or mutants thereof

Inhibitors of AXL and/or mutants thereof

Inhibitors of NTRK1 and/or mutants thereof

Inhibitors of RET and/or mutants thereof

13. Taxane derivatives

a. For example, paclitaxel, albumin-bound paclitaxel (nab-paclitaxel), docetaxel;

b. preferred is paclitaxel;

14. platinum-containing compounds

a. For example, cisplatin, carboplatin, oxaliplatin;

15. antimetabolites

a. For example, a combination of 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, trifluridine, and tipiracil (= TAS 102);

b. preferably gemcitabine;

16. mitotic kinase inhibitors

a. For example, CDK4/6 inhibitors

i. For example, palbociclib, rebciclib, aberra (abemaciclib);

preferred are palbociclib and abbeli;

most preferred is abelian;

17. immunotherapeutic agent

a. For example, immune checkpoint inhibitors

i. For example, anti-CTLA 4mAb, anti-PD 1mAb, anti-PD-L2 mAb, anti-LAG 3mAb, anti-TIM 3mAb;

preferred is an anti-PD 1mAb;

for example, YIPLUMAMMA, navizumab, pembrolizumab, ATTRIBUMBLE, avelumab (Avelumab), DOVALUMAb, PIDIlizumab (pidilizumab), PDR-001 (BAP 049-clone-E disclosed and used in WO 2017/019896);

preferred are nivolumab, pembrolizumab and PDR-001;

most preferred is pembrolizumab;

18. anti-angiogenic agents

a. For example, bevacizumab, nintedanib;

b. most preferred is bevacizumab;

19. topoisomerase inhibitors

a. For example, irinotecan, liposomal irinotecan, topotecan;

b. most preferred is irinotecan;

inhibitors of A-Raf and/or B-Raf and/or C-Raf and/or mutants thereof

a. For example, RAF-709 (= example 131 in WO 2014/151616), LY-3009120 (= example 1 in WO 2013/134243);

inhibitors of erk and/or mutants thereof

a. For example, ulitinib (ulixertinib);

22. modulators of apoptosis

a. For example, inhibitors of the interaction between p53 (preferably functional p53, most preferably wt p 53) and MDM2 ("MDM 2 inhibitors");

i. for example, HDM-201, NVP-CGM097, RG-7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115;

preferred are HDM-201, RG-7388 and AMG-232

b. For example, PARP inhibitors;

c. for example, MCL-1 inhibitors;

mTOR inhibitors

a. For example, rapamycin, temsirolimus, everolimus, ridaforolimus;

24. epigenetic modulators

a. For example, BET inhibitors

i. For example, JQ-1, GSK 525762, OTX 015 (= MK 8628), CPI 0610, TEN-010 (= RO 6870810);

b. for example, CDK9 inhibitors;

inhibitors of IGF1/2 and/or IGF1-R

a. For example, pertuzumab (xentuzumab) (antibody 60833 in WO 2010/066868), MEDI-573 (= dostuzumab (dusigizumab)).

In the present invention, it is understood that the combinations, compositions, kits, methods, uses or compounds for use according to the invention can envisage the simultaneous, concurrent, sequential, alternating or separate administration of the active ingredients or components. It is to be understood that the SOS1 inhibitor compound (e.g., a compound of formula (I)) and the at least one other pharmacologically active agent can be formulated for administration dependently or independently, e.g., such that the SOS1 inhibitor compound (e.g., a compound of formula (I)) and the at least one other pharmacologically active agent can be administered as part of the same pharmaceutical composition/dosage form or, preferably, in separate pharmaceutical compositions/dosage forms.

Examples

The reagents used in the present invention are commercially available reagents directly or synthesized by conventional methods well known in the art.

The following illustrative specific reaction schemes or procedures are used in the present invention, and are specifically as follows:

example 1

Preparation of key intermediates

Synthesis of intermediate a1

4-bromophenol a1-1 (4.5g, 26.0 mmol) and 3-bromo-2-methylpropan-1-ene a1-2 (2.9mL, 28.6 mmol) were dissolved in 100mL of acetone, and potassium carbonate (18.0 g, 260.1mmol) was added to the reaction solution and stirred at 75 ℃ for 12 hours, and the reaction was stopped by TLC detection. Filtration, concentration of the filtrate under reduced pressure, addition of water (50 mL), extraction with ethyl acetate, drying over anhydrous sodium sulfate, concentration to give a colorless oil a1-3 (5.8 g), LC-MS: [ M + H ]] ⁺ ＝227。

The intermediates a1 to 3 (3.75g, 16.5 mmol) from the above step were dissolved in 50mL of N, N-diethylaniline and stirred at 190 ℃ for 12 hours. The reaction was stopped, 1N hydrochloric acid was slowly added to the system to adjust pH to about 7, ether extraction, washing with saturated brine, drying over anhydrous sodium sulfate, concentration, column chromatography separation (PE/EA = 20/1) gave colorless oil a1-4 (1.2 g), yield: 32%, LC-MS: [ M + H ]] ⁺ ＝227。

The intermediate a1-4 (1.2g, 5.3 mmol) obtained above was dissolved in 50mL of dichloromethane, and elemental iodine (270mg, 1.1 mmol) was added to the solution to carry out a reaction at room temperature for 12 hours, followed by stopping the reaction. Adding saturated sodium thiosulfate aqueous solution into the reaction solution to adjust the reaction solution to be colorless, extracting the mixture by dichloromethane, and washing an organic phase by saturated salt waterWashing, drying over anhydrous sodium sulfate, and concentration gave a colorless oil a1 (1.0 g), yield: 83%, LC-MS M + H ⁺ ＝227。

Synthesis of intermediate a2

Under the protection of nitrogen, concentrated sulfuric acid (3.8g, 38mmol) is dropwise added into the raw material a2-1 (22.0g, 117mmol), the temperature is raised to 40 ℃, then the raw material a2-2 (10.75mL, 110mmol) is dropwise and slowly added, the reaction is continued for 2 hours, and then the reaction is stopped. The reaction solution was slowly poured into 50mL of ice water, extracted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, concentrated, washed with n-heptane, and suction-filtered to give a white solid a2-3 (15 g), yield: 46 percent.

Intermediate a2-3 (6.3g, 23mmol) and pyridine hydrochloride (12.8g, 103mmol) from the previous step were dissolved in quinoline (11.5g, 88mmol) under nitrogen, slowly warmed to 175 ℃ and stirred for 16 h. After cooling to room temperature, 6N hydrochloric acid (120 mL) was slowly added to the reaction solution, ether was extracted, the organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated to give intermediate a2 (4.0 g) as a colorless oil, yield: 77 percent.

Synthesis of intermediate a3

Lithium aluminum hydride (1.35g, 35.68mmol) was dissolved in 200mL of diethyl ether under ice-cooling, and a solution of a3-1 (8.0 g,29.7 mmol) in diethyl ether (100 mL) prepared in advance was slowly added dropwise thereto, followed by stirring for 1 hour. To the reaction solution, 20mL of ice water and 2.5M aqueous sodium hydroxide solution (4 mL) were added to quench the reaction, the solvent was distilled off under reduced pressure, 30mL of ice water was added to the system, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give a3-2 (6.5 g) as a white solid in yield: 96%, LC-MS: [ M + H ]] ⁺ ＝227。

The intermediate a3-2 (6.0 g,26.6 mmol) and DIEA (3.45g, 26.6 mmol) were dissolved in 120mL of vinegar under ice-bath conditionsThionyl chloride (3.78g, 31.9 mmol) was slowly added dropwise to isopropyl ester, and the reaction was continued for 1 hour after completion of the dropwise addition. To the reaction mixture was added 100mL of ice water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate to obtain a3-3 (6.0 g) as a white solid, yield: 93%, LC-MS: [ M + H] ⁺ ＝245。

Chromium chloride (3.1g, 20mmol) was dissolved in 40mL of anhydrous tetrahydrofuran under protection of nitrogen in an ice bath, a tetrahydrofuran solution of lithium aluminum hydride (10.1 mL) was slowly added dropwise, and after stirring for 15 minutes, DMF (50 mL) and isopropanol (3 mL) were added. A DMF solution (50 mL) of intermediate a3-3 (1.98g, 8.1mmol) obtained in the above step was added to the system, and the reaction mixture was allowed to stand at room temperature for 12 hours. The reaction was stopped, water (300 mL) was added to the reaction mixture, n-hexane was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE/EA = 21/1) to obtain a white solid a3-4 (800 mg), yield: 47%, LC-MS: [ M + H ]] ⁺ ＝211。

After dissolving the intermediate a3-4 (800mg, 3.8mmol) obtained in the above step in 15mL of dichloroethane with ice bath and under nitrogen protection, diethylzinc toluene solution (9.5 mL) was added dropwise, and after completion of the dropwise addition, chloroiodomethane (1.4 mL, 19mmol) was added, and stirring was continued for 1 hour, followed by heating to 65 ℃ for reaction for 3 hours. After cooling to room temperature, 50mL of a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE/EA = 100/1) to obtain a colorless oil a3 (280 mg) in yield: 33%, LC-MS: [ M + H ]] ⁺ ＝225。

Example 2

Preparation of target molecules P1-P8

Under nitrogen protection, starting material P1-1 (2.13g, 9mmol) was added to a 100mL three-necked reaction flask and dissolved in 10mL anhydrous tetrahydrofuran at-78 ℃. N-butyllithium (4.5mL, 3.6 mmol) was slowly added dropwise to the reaction solution, and stirring was continued for 30 minutes after completion of the dropwise addition. A solution of the starting material P1-2 (645mg, 3.0 mmol) in THF (10 mL) was slowly added dropwise to the reaction, followed by dropwise additionAfter the reaction is finished, slowly raising the temperature to room temperature for continuing the reaction for 2 hours, monitoring the completion of the reaction by LC-MS, and stopping the reaction. The reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine. After drying over anhydrous sodium sulfate, column chromatography separation (eluent PE/EA = 3/1) gave P1-3 (384 mg) as a pale yellow solid in 34% yield LC-MS: [ M + H ]] ⁺ ＝374。

The intermediates P1-3 (384mg 1.04mmol), P-toluenesulfonic acid monohydrate (1.5g, 7.76mmol) and phenol (487mg, 5.18mmol) in the above step were dissolved in 10mL of dichloroethane under nitrogen protection, and the reaction was refluxed at 90 ℃ for 2 hours. The reaction was stopped, cooled to room temperature, filtered to remove P-toluenesulfonate, concentrated, and separated by column chromatography (eluent PE/EA = 3/1) to give P1 (300 mg, yield 65%, LC-MS: [ M + H ]: as a pale yellow solid] ⁺ ＝374。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.34(s,1H),9.63(s,1H),7.60(d,J＝7.9Hz,1H),7.47(d,J＝7.4Hz,1H),7.39(dd,J＝8.1,1.0Hz,1H),7.22(td,J＝7.9,3.3Hz,2H),7.09–7.02(m,2H),6.83(dd,J＝8.2,0.9Hz,1H),6.81–6.74(m,2H).

Referring to the synthetic route of the compound P1, the following target molecules are synthesized by using similar framework structures.

Example 2

Preparation of target molecule P9

The starting material P9-1 (1.0 g, 7.29mmol), the starting material P9-2 (1.23g, 7.44mmol) and hydroxylamine hydrochloride (1.55g, 22.3mmol) were dissolved in 40mL of water and 2mL of hydrochloric acid (concentration 2M), and anhydrous sodium sulfate (7.0 g) was added. The temperature was raised to 55 ℃ and the reaction was allowed to proceed for 3 hours, and LC-MS monitored the completion of the reaction. Stopping the reaction, cooling to room temperature, extracting with ethyl acetate, drying with anhydrous sodium sulfate, and concentrating to obtain crude product P9-3.LC-MS: [ M + H] ⁺ ＝209.3。

In ice bath, the crude product obtained in the previous step is dissolved in 10mL of concentrated sulfuric acid, and the temperature is raised to 85 ℃ for reaction for 30 minutes. Monitoring the reaction completion by LC-MS, slowly pouring the reaction solution into 50mL of ice water, stirring for 20 minutes, then performing suction filtration, washing a filter cake with water, and drying to obtain yellow solid P9-4 (450 mg) with two-step yield: 42%, LC-MS: [ M + H ]] ⁺ ＝192.2。

Preparing a Grignard reagent: bromocycloheptane (1.0 g, 5.6 mmol) was dissolved in 10mL anhydrous tetrahydrofuran; separately, one of magnesium chips (0.41g, 16.8mmol) and iodine particles was charged into a reaction flask. Slowly adding the prepared bromocycloheptane solution into a reaction bottle, and quickly heating to 60 ℃ to initiate the reaction. Continuously dropwise adding a bromocycloheptane diluent, and stirring at room temperature for 1 hour after dropwise adding. The concentration of the Grignard reagent was 0.56mmol/mL.

Intermediate P9-4 (100mg.0.35mmol) was dissolved in 5mL of anhydrous tetrahydrofuran at-50 deg.C, new formulation of Grignard reagent (1.87 mL) was added slowly, warmed to room temperature, and reaction was continued for 2 hours. Monitoring the reaction completion by LC-MS, adding 30mL of saturated ammonium chloride aqueous solution into the system to quench the reaction, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain an intermediate P9-5 (50 mg) with yield: 33%, LC-MS: [ M + H ]] ⁺ ＝287.4。

Intermediate P9-5 (50mg, 0.17mmol) from the above step, P-toluenesulfonic acid (88mg, 0.51mmol) and phenol (32mg, 0.34mmol) were dissolved in 8mL of dichloroethane and reacted at 60 ℃ for 1 hour. Monitoring the reaction completion by LC-MS, adding 30mL of water into the system, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain a target product P9 (18 mg), yield: 28%, LC-MS: [ M + H ]] ⁺ ＝366。

¹ H NMR(400MHz,CDCl ₃ )δ7.66(s,1H),7.27(s,1H),7.25(s,1H),7.09(d,J＝8.3Hz,1H),6.72(d,J＝8.1Hz,2H),6.57(d,J＝8.3Hz,1H),3.86(s,3H),2.62(t,J＝9.8Hz,1H),2.10(s,3H),1.78–1.45(m,12H).

Example 3

Preparation of target molecules P2a and P2b

And (3) carrying out SFC chiral resolution on the compound P2 to obtain compounds P2a and P2b.

Example 4

Preparation of target molecules P10-P11

The starting material P10-1 (547mg, 2.8 mmol) was dissolved in 20mL of anhydrous tetrahydrofuran at-78 ℃, and 1.6M n-butyllithium (1.74mL, 2.8 mmol) was slowly added dropwise thereto, followed by stirring for 1 hour. The reaction mixture was added with the starting material P1-2 (300mg, 1.39mmol), and the mixture was allowed to warm to room temperature for 1 hour. Adding 30mL of saturated ammonium chloride solution to quench the reaction, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, separating by column chromatography to obtain a mixture (180 mg) of intermediate P10-2 and P11-1 with a yield of 39%, and LC-MS: [ M + H ]] ⁺ ＝334。

The mixture obtained in the above step (180mg, 0.54mmol), phenol (77mg, 1.1mmol) and p-toluenesulfonic acid (308mg, 1.6mmol) were dissolved in 8mL of dichloroethane, and the reaction was carried out at 60 ℃ for 1 hour. Monitoring reaction completion by LC-MS, stopping reaction, filtering, concentrating filtrate, and separating by HPLC chromatography to obtain compounds P10 (9.5 mg) and P11 (12 mg), LC-MS: [ M + H ]] ⁺ ＝410。

P10: ¹ H NMR(400MHz,DMSO-d ₆ )δ11.18(s,1H),9.50(s,1H),7.98(d,J＝2.2Hz,1H),7.55(d,J＝8.3Hz,3H),7.38(d,J＝2.0Hz,1H),7.20(t,J＝7.8Hz,1H),7.09(dd,J＝8.7,2.1Hz,1H),7.03–6.96(m,2H),6.95–6.89(m,1H),6.78–6.65(m,2H).

P11: ¹ H NMR(400MHz,DMSO-d ₆ )δ11.22(s,1H),9.65(s,1H),7.59(dd,J＝6.6,2.1Hz,1H),7.53(d,J＝8.1Hz,1H),7.51–7.45(m,3H),7.35(d,J＝7.5Hz,1H),7.30(tt,J＝7.4,5.8Hz,2H),7.10(t,J＝7.7Hz,1H),6.95–6.90(m,2H),5.26(s,1H).

Example 5

Preparation of target molecule P12

Under the protection of nitrogen, raw material P1-2 (991mg, 4.61mmol) and magnesium chips (142mg, 5.8mmol) are dissolved in 20mL of anhydrous tetrahydrofuran, an iodine simple substance is added, the temperature is rapidly raised to 50 ℃ to initiate the reaction, and the reaction is stirred for 1 hour. The starting material P12-1 (500mg 2.32mmol) was slowly added thereto at room temperature, and the mixture was reacted at room temperature for 1 hour. The completion of the reaction was monitored by LC-MS, quenched with 40mL of saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give intermediate P12-2 (300 mg), yield: 37% LC-MS: M + H ⁺ ＝350。

Intermediate P12-2 (300mg, 0.86mmol), phenol (121mg, 1.72mmol) and P-toluenesulfonic acid (491mg, 2.58mmol) were dissolved in 8mL of dichloromethane and reacted at 60 ℃ for 1 hour. The reaction was stopped, cooled to room temperature, filtered, the filtrate was concentrated, and column chromatography was performed to give compound P12 (80 mg), yield: 22%, LC-MS: [ M + H ]] ⁺ ＝426。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.20(s,1H),9.50(s,1H),7.95(d,J＝8.5Hz,1H),7.75(d,J＝5.4Hz,1H),7.61(d,J＝1.6Hz,1H),7.56(dd,J＝7.7,4.1Hz,2H),7.44(d,J＝5.4Hz,1H),7.21(t,J＝7.7Hz,1H),7.15(dd,J＝8.6,1.7Hz,1H),7.00(d,J＝8.7Hz,2H),6.73(d,J＝8.7Hz,2H).

Example 6

Preparation of target molecule P13

Under nitrogen protection, at-50 ℃, the starting material P13-1 (1.14g, 4.0mmol) was dissolved in 20mL of anhydrous tetrahydrofuran, and 2 was slowly added dropwise.N-butyllithium (1.6mL, 4.0 mmol) at a concentration of 5M, and stirred at-50 ℃ for 1 hour after dropwise addition; 7- (trifluoromethyl) indoline-2, 3-dione P1-2 (430mg, 2.0 mmol) was dissolved in 4mL of anhydrous tetrahydrofuran, and was slowly added to the reaction solution, and after completion of dropping, the reaction was allowed to warm to room temperature for 2 hours. The reaction was quenched by adding 40mL of a saturated aqueous ammonium chloride solution to the system, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give P13-2 (500 mg) as a pale yellow solid, yield: 59%, LC-MS: [ M + H ]] ⁺ ＝424。

Dissolving the intermediate P13-2 (423mg, 1.0mmol) in the previous step in 15mL of dichloroethane under the protection of nitrogen, adding benzofuran-2 (3H) -ketone P13-3 (200mg, 1.5mmol) and P-toluenesulfonic acid (571mg, 3.0mmol), heating to 70 ℃, reacting for 30 minutes, filtering, concentrating the filtrate, and carrying out column chromatography separation (PE/EA = 5/1) to obtain a white solid P13 (24 mg), 20 percent and LC-MS (M + H + MS)] ⁺ ＝426。

¹ H NMR(400MHz,CDCl ₃ )δ7.99(s,1H),7.49(d,J＝8.0Hz,1H),7.36(d,J＝7.5Hz,1H),7.20(d,J＝7.0Hz,2H),7.15(dd,J＝8.5,2.1Hz,1H),7.13–7.08(m,2H),7.03(d,J＝8.4Hz,1H),6.81–6.74(m,2H),5.17(s,1H),3.69(s,2H).

Example 7

Preparation of target molecule H1

Under the protection of nitrogen, raw material H1-1 (7.3 g, 30mmol) is dissolved in 24mL of anhydrous tetrahydrofuran at-78 ℃, 2.5M n-butyllithium (14.4 mL, 36mmol) is slowly dropped, stirring is continued for 30 minutes, then a prepared solution of P1-2 (2.15g, 10mmol) in tetrahydrofuran (20 mL) is slowly dropped, the reaction is continued for 2 hours after the dropping is finished, and the temperature is raised to room temperature, and the reaction is stopped. The reaction mixture was quenched by adding 30mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE/EA = 3/1) to obtain a yellow oil H1-2 (2.3 g), yield: 62% LC-MS: [ M + H ]] ⁺ ＝378。

The intermediate H1-2 (2.3 g, 6.10mmol) obtained in the above step, p-toluenesulfonic acid monohydrate (8.12g, 42.7mmol) and phenol (2.87g, 30.5mmol) were dissolved in 50mL of dichloroethane under nitrogen protection, and the reaction was refluxed at 90 ℃ for 2 hours. The reaction was stopped, cooled to room temperature, filtered to remove p-toluenesulfonate, concentrated, and column chromatographed (PE/EA = 3/1) to give H1-3 (2.0 g) as a pale yellow solid in yield: 72%, LC-MS: [ M + H ]] ⁺ ＝454。

The above H1-3 (50mg, 0.11mmol) was dissolved in 5mL of anhydrous tetrahydrofuran, borane dimethylsulfide (0.2mL, 0.4mmol) was added, and the reaction was carried out at 50 ℃ for 10 hours. After cooling to room temperature, the reaction mixture was quenched by adding 2mL of methanol, concentrated, and separated by column chromatography (PE/EA = 4/1) to obtain compound H1 (20 mg) in yield: 41%, LC-MS: [ M + H ]] ⁺ ＝440。

¹ H NMR(400MHz,DMSO-d ₆ )δ9.35(s,1H),7.29–7.16(m,6H),6.95(d,J＝8.7Hz,2H),6.74–6.61(m,3H),6.23(s,1H),3.99(s,2H).

Referring to the synthetic route of compound H1, the following target molecules were synthesized using a similar backbone structure.

Example 8

The compounds were tested for inhibition of breast cancer cell proliferation specifically as follows:

MCF-7 (estrogen receptor positive, cultured in MEM medium containing 10% fetal bovine serum and 1% streptomycin) and MDA-MB-231 (estrogen receptor negative, cultured in L-15 medium containing 10% fetal bovine serum and 1% streptomycin) breast cancer cells were used to examine the proliferation inhibitory effect of compounds on breast cancer cells.

MCF-7 and MDA-MB-231 cells were seeded in 384-well microplates (600/30. Mu.L) and incubated overnight at 37 ℃ under 5% carbon dioxide. Adding 30nL of different concentrations of compounds to each well using Echo 655 (Labcyte, model: 655) and 5% CO at 37% ₂ Incubate in incubator for 3 days. Then, 30. Mu.L of the kit was added to each wellThe prepared CTG reagent (Promega, cat. No.: G7573) was shaken and incubated at 25 ℃ in the dark for 30 minutes, and the plate was scanned and the signal values recorded using an Envision instrument (Perkinelmer, model: envision 2105).

The inhibition (%) was calculated using the following formula:

％Inhibition＝100-(Signal _cmpd -Signal _{Ave_BL} )/(Signal _{Ave_VC} -Signal _{Ave_BL} )×100

Signal _{ave_pc} ：The average signal for the positive controls across the plate。

Signal _{ave_vc} ：The average signal for negative controls across the plate。

IC was calculated using GraphPad8.0 as a non-linear regression equation ₅₀ ：

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)×HillSlope))

X is Log logarithm of inhibitor concentration; y is the inhibition rate%.

Antiproliferative assay of Compounds on MCF-7 cells

Table 1: antiproliferative effect of compounds on half the effective concentration of MCF-7 cells

Compound (I)	MCF-7/IC ₅₀ /nM	Compound (I)	MCF-7/IC ₅₀ /nM
				P1	269*	P2	19
P2a	20	P2b	>500
				P3	77	P4	207
P5	>500	P6	>500
				P7	38	P8	142
P9	7	P10	47
				P11	>500	P12	18
P13	>500	P14	121
				H1	719*	H2	>500
H3	>500	H4	>500

* : results representing 7 days incubation of the compounds with cells

The above results show that: the invention has good inhibition effect on ER + positive breast cancer.

Antiproliferative assay of Compounds on non-ER-Positive MDA-MB-231 cells

The above results show that: the invention has no inhibitory activity on ER-negative breast cancer, and embodies the high-selectivity inhibition on estrogen receptor positive breast cancer.

Example 10

Mouse pharmacokinetic evaluation experiment

CD1 female mice were used as test animals and administered orally/intravenously (10 mg/kg for oral administration and 2mg/kg for intravenous administration).

The experimental scheme is as follows: oral groups were 3 per group and intravenous groups were three per group. Oral administration: plasma samples were collected before (0 h) and after (0.25, 0.5,1,2,4,8, 24h) administration; vein: plasma samples were collected before (0 h) and after (0.083, 0.25,0.5,1,2,4,8, 24h) administration; the blood concentration of the plasma of the mice after oral administration and intravenous administration is respectively measured by an LC/MS/MS method, collected data are calculated by AB Sciex QTRAP 6500 software, and the experimental results are as follows:

the experimental results show that the compound has good oral absorption effect.

Claims

1. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a compound of formula (I-1) or (I-2):

R ₁ is selected from C _3-10 Cycloalkyl radical, C _5-12 And a cycloalkylalkyl group or a 5-to 10-membered heteroaryl group; optionally substituted with 1,2 or 3R #;

R ₃ selected from H, halogen, C _1-6 Alkyl or C _1-6 A haloalkyl group;

R ₄ selected from H, halogen, -O-C _1-6 Alkyl or-O-C _1-6 A haloalkyl group;

R ₅ is H or halogen;

R ₆ is H or halogen;

R ₇ is-OH, -CN or-NH ₂ 。

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,

R ₁ is selected from

R ₃ is selected from-CF ₃ or-CH ₃ ；

R ₄ Is selected from H or-OCH ₃ ；

R ₅ Is H;

R ₆ is H;

R ₇ is-OH.

3. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a compound of formula (III), (III-1), or (III-2):

wherein the content of the first and second substances,

R ₃ is selected from C _1-4 Alkyl or C _1-4 Alkyl halidesA group;

R ₄ selected from H, -O-C _1-4 Alkyl or-O-C _1-4 A haloalkyl group.

4. The compound of claim 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,

Rs is selected from H and C _1-4 Alkyl radical, C _1-4 Haloalkyl, O-C _1-4 Alkyl or O-C _1-4 A haloalkyl group;

ring A is selected from 3-7 membered heterocyclyl or 5-10 membered heteroaryl;

ring B is C _6-10 An aryl group;

ring C being C _6-10 An aryl group;

ring a, ring B, and ring C are optionally substituted with 1,2, or 3R #;

R ₃ is selected from C _1-4 Alkyl or C _1-4 A haloalkyl group;

R ₄ selected from H, -O-C _1-2 Alkyl or-O-C _1-2 A haloalkyl group.

5. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,

R ₁ is selected from

R ₃ Is selected from-CF ₃ or-CH ₃ ；

R ₄ Is selected from H or-OCH ₃ 。

6. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein the compound is selected from the group consisting of:

7. a pharmaceutical composition comprising a compound of any one of claims 1-6, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, optionally other therapeutic agent.

8. Use of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, in the manufacture of a medicament for the treatment or prevention of cancer.

9. A compound of any one of claims 1-6, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutical composition of claim 7, for use in the treatment or prevention of cancer.

10. The use of claim 8 or the use of a compound or pharmaceutical composition of claim 9, wherein the cancer is breast cancer, ovarian cancer, uterine cancer, cervical cancer or endometrial cancer.