Heterobifunctional compounds and methods of treating disease

Abstract

This invention provides heterobifunctional compounds, pharmaceutical compositions, and their use in treating diseases such as cancer.

Description

[0001] Cross-citation of related applications

[0002] This application claims the benefit and priority of Chinese Patent Application Serial No. 202411404732.7, filed October 9, 2024; U.S. Provisional Patent Application Serial No. 63 / 563,000, filed March 8, 2024; U.S. Provisional Patent Application Serial No. 63 / 618,075, filed January 5, 2024; and U.S. Provisional Patent Application Serial No. 63 / 544,710, filed October 18, 2023; the contents of each of these patent applications are incorporated herein by reference in their entirety. Technical Field

[0003] This invention provides heterobifunctional compounds, pharmaceutical compositions, and their use in treating diseases such as cancer. Background Technology

[0004] Despite extensive research and scientific advancements reported in the literature on cancer treatment, the disease remains a significant health concern. Solid tumors, including prostate, breast, and lung cancer, remain highly prevalent in the world's population. The incidence of prostate cancer increases with age, and the number of patients diagnosed continues to rise with increasing life expectancy. Breast cancer is one of the most common cancers in women and a leading cause of death for women aged 50-55. Lung cancer is a leading cause of cancer death, with over 85% of lung cancers being non-small cell lung cancer (NSCLC). Many lung cancers are attributed to smoking. Current treatment options for these cancers are not effective for all patients and / or may have substantial adverse side effects.

[0005] New therapies are needed to address this unmet need in cancer treatment. Specifically, new therapies are required that achieve anti-cancer effects through mechanisms different from commonly used treatments. Exemplary mechanisms of common anti-cancer therapies include (a) DNA alkylation, which restricts cell proliferation; (b) topoisomerase inhibition, where the therapeutic agent inhibits the activity of topoisomerases, thereby restricting DNA strand separation; and (c) mitosis inhibition, where the therapeutic agent reduces the cell's ability to divide. New therapies that achieve anti-cancer effects through different mechanisms offer the opportunity to treat cancer more effectively and / or cancers that have become resistant to currently available drugs.

[0006] This invention addresses the aforementioned needs and provides other related advantages. Summary of the Invention

[0007] This invention provides heterobifunctional compounds, pharmaceutical compositions, and their use in treating diseases such as cancer. Specifically, one aspect of the invention provides a series of heterobifunctional compounds, such as compounds represented by formula I:

[0008]

[0009] Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the embodiments. Further description of a range of additional heterobifunctional compounds is provided in the detailed description of the invention. This compound may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0010] Another aspect of the present invention provides a crystalline compound of formula II-5:

[0011]

[0012] This compound may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0013] Another aspect of the invention provides a method for treating cancer. The method includes administering a therapeutically effective amount of a compound described herein, such as a compound of formula I, to a patient in need to treat cancer.

[0014] Another aspect of the invention provides a method for inducing cancer cell death. The method includes contacting cancer cells with an effective amount of a compound described herein, such as a compound of formula I, to induce cancer cell death.

[0015] [Brief explanation of the attached image]

[0016] Figure 1 A graph showing the formation of the ternary complex detected between the test compound, androgen receptor, and BRD4 protein is further described in Example 67.

[0017] Figure 2 A diagram showing the formation of the ternary complex detected between compound II-5, the androgen receptor, and the BRD4 protein is further described in Example 68.

[0018] Figure 3 A graph showing cell viability as a function of the dose of compound II-5 is further described in Example 69.

[0019] Figure 4 A graph showing the formation of relative ternary complexes in samples collected at the end of the PK / PD castration VCaP tumor xenograft model study, after treatment with different doses of compound II-5, is further described in Example 70.

[0020] Figure 5 To demonstrate the effects of different doses of compound II-5, in PK / PD Ar amp V7 + A graph showing the relative total amount of cMYC mRNA present in the tumor collected at the end of the castration VcaP model, as further described in Example 70.

[0021] Figure 6 To show the effect of different doses of compound II-5 on PK / PD Ar amp V7 + A graph showing the relative total amount of HEXIM1 mRNA present in the tumor collected at the end of the castration VcaP model, as further described in Example 70.

[0022] Figure 7 To show the effect of different doses of compound II-5 on PK / PD Ar amp V7 + A graph showing the relative total amount of TXNIP mRNA present in the tumor collected at the end of the castration VcaP model, as further described in Example 70.

[0023] Figure 8 A graph showing tumor growth in mice treated with compound II-5, compound A, or a causative agent is further described in Example 70.

[0024] Figure 9 A waterfall plot showing the change in tumor size relative to baseline at the end of the study in mice treated with compound II-5, compound A, or the causative agent is further described in Example 70.

[0025] Figure 10 A graph showing the plasma PSA levels determined at the end of the study in mice treated with compound II-5, compound A, or the causative agent is further described in Example 70.

[0026] Figure 11 A graph showing tumor volume in mice treated with: (i) the mediator, (ii) compound II-5 according to a first dosing regimen, wherein the dosing frequency is the same as that used for the mediator and for compound A, (iii) compound II-5 according to a second dosing regimen, wherein the dosing frequency is twice that used for the mediator and for compound A, or (iv) compound A, as further described in Example 71.

[0027] Figure 12 A waterfall plot showing the change in tumor size relative to baseline at the end of the study in mice treated with: (i) the mediator, (ii) compound II-5 according to the first dosing regimen, wherein the dosing frequency is the same as that used for the mediator and for compound A, (iii) compound II-5 according to the second dosing regimen, wherein the dosing frequency is twice that used for the mediator and for compound A, or (iv) compound A, as further described in Example 71.

[0028] Figure 13A graph showing the plasma PSA levels determined at the end of the study in mice treated with: (i) the mediator, (ii) compound II-5 according to the first dosing regimen, wherein the dosing frequency is the same as that used for the mediator and for compound A, (iii) compound II-5 according to the second dosing regimen, wherein the dosing frequency is twice that used for the mediator and for compound A, or (iv) compound A, as further described in Example 71.

[0029] Figure 14 An X-ray powder diffraction pattern of compound II-5 in crystalline form A is depicted, as further described in Example 59.

[0030] Figure 15 Differential scanning calorimetry (DSC) plots of compound II-5 in crystalline form A are further described in Example 59.

[0031] Figure 16 Thermogravimetric analysis curves of compound II-5 in crystalline form A are plotted, as further described in Example 59.

[0032] Figure 17 An X-ray powder diffraction pattern depicting compound II-5 in crystalline form B is shown, as further described in Example 61.

[0033] Figure 18 Differential scanning calorimetry (DSC) curves of compound II-5 in crystalline form B are depicted, as further described in Example 61.

[0034] Figure 19 Thermogravimetric analysis curves of compound II-5 in crystalline form B are plotted, as further described in Example 61.

[0035] Figure 20 To illustrate the formation of relative ternary complexes in samples collected at the end of the PK / PD castration VCaP tumor xenograft model study for mice treated with compound II-5, compound B, or the mediator, a diagram is further described in Example 72.

[0036] Figure 21 To show the results for each of compounds II-5 and B in PK / PD Ar amp V7 + A graph showing the relative total amount of cMYC mRNA present in the tumor collected at the end of the castration VcaP model, as further described in Example 72.

[0037] Figure 22 To show the results for each of compounds II-5 and B in PK / PD Ar amp V7 +A graph showing the relative total amount of HEXIM1 mRNA present in the tumor collected at the end of the castration VcaP model, as further described in Example 72.

[0038] Figure 23 A graph showing tumor volume in mice treated with (i) the mordant, (ii) compound II-5, or (iii) compound B is further described in Example 73.

[0039] Figure 24 A graph showing the normalized BRET signal for compounds II-5 and B versus compound concentrations in a BRD4 cell TE assay using inducible androgen receptor (AR) is provided, as further described in Example 74. Invention Details

[0041] This invention provides heterobifunctional compounds, pharmaceutical compositions, and their use in treating diseases such as cancer. Unless otherwise indicated, the invention is practiced using conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as “Comprehensive Organic Synthesis” (edited by BM Trost and I. Fleming, 1991–1992); “Handbook of Experimental Immunology” (edited by DM Weir and CC Blackwell); “Current Protocols in Molecular Biology” (edited by FM Ausubel et al., 1987, and periodically updated); and “Current Protocols in Immunology” (edited by JE Coligan et al., 1991), each incorporated herein by reference in its entirety.

[0042] Various aspects of the invention are set forth in the following sections; however, the aspects of the invention described in a particular section are not limited to any particular section. Furthermore, when a variable is not defined, its prior definition shall prevail.

[0043] definition

[0044] The compounds of this invention include those generally described herein, and are further described by the classes, subclasses and species disclosed herein. Unless otherwise indicated, the following definitions shall apply as used herein. Unless otherwise indicated, these definitions apply whether the terms are used alone or in combination with other terms. Thus, the definition of "alkyl" applies to "alkyl" and the "alkyl" portion of "-O-alkyl," etc. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. Furthermore, the general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th edition, Smith, MB and March, J. eds., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0045] As used herein, the term "aliphatic" or "aliphatic group" means a straight (i.e., unbranched) or branched chain, substituted or unsubstituted, hydrocarbon chain that is fully saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as "cycloaliphatic"), and has a single connection point with the rest of the molecule. Unless otherwise stated, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms, and in other embodiments, the aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" refers to a fully saturated or containing one or more unsaturated units, but is not aromatic, and has a single connection point with the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched chains, substituted or unsubstituted alkyl, alkenyl, alkynyl and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0046] As used herein, the term "bicyclic" or "bicyclic system" refers to any bicyclic system, i.e., a carbon ring or heterocyclic ring, saturated or having one or more unsaturated units, with one or more shared atoms between the two rings of the ring system. Therefore, the term includes any permissible ring fusion, such as orthocyclic or spirocyclic. As used herein, the term "heterobicyclic" is a subgroup of "bicyclic" systems requiring one or more heteroatoms to be present in one or both rings of the bicyclic ring. Such heteroatoms may be present at the ring junctions and optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic system, i.e., a carbon ring or heterocyclic ring, saturated or partially unsaturated, with at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain or atom or valence bond connecting two bridgeheads, wherein a “bridgehead” is any skeletal atom of a ring system bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below, wherein each group is connected to the remainder of the molecule at any substituted carbon or nitrogen atom. Unless otherwise stated, the bridged bicyclic group is optionally substituted with one or more substituents as set forth with respect to aliphatic groups. Additionally or alternatively, any substituted nitrogen atom in the bridged bicyclic group is optionally substituted. Exemplary bicycles include:

[0047]

[0048] An exemplary bridging dual ring includes:

[0049]

[0050] .

[0051] The term "lower alkyl" refers to C 1-4 Straight-chain or branched-chain alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0052] The term "lower haloalkyl" refers to a C-aryl group that has been substituted with one or more halogen atoms. 1-4 Straight-chain or branched-chain alkyl groups.

[0053] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of basic nitrogen; or a substituted nitrogen of a heterocycle, such as N (e.g., in 3,4-dihydro-2-) H-pyrrole group), NH (as in pyrroleyl group) or NR + (e.g., in N-substituted pyrroleyl groups).

[0054] As used in this article, the term "unsaturated" means that a part has one or more unsaturated units.

[0055] As used in this article, the term "divalent C" 1-8 (or C) 1-6 "Saturated or unsaturated, straight or branched hydrocarbon chains" refers to divalent alkylene, alkenyl, and ynylene chains as defined herein.

[0056] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2). n - where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The substituted alkylene chain is a polymethylene in which one or more methylene hydrogen atoms are substituted by a substituent. Suitable substituents include those described below with respect to the substituted aliphatic group.

[0057] The term "-(C0 alkylene)-" refers to a bond. Therefore, the term "-(C0 alkylene)-" refers to a bond. 0-3 alkylene)-” encompasses both the bond (i.e., C0) and -(C 1-3 (alkylene) group.

[0058] The term "alkenyl" refers to a divalent alkenyl group. The substituted alkenyl chain is a polymethylene containing at least one double bond, wherein one or more hydrogen atoms are substituted by a substituent. Suitable substituents include those described below with respect to the substituted aliphatic group.

[0059] The term "halogen" refers to F, Cl, Br, or I.

[0060] The term "aryl," used alone or as part of a larger portion of "aralkyl," "aralkyloxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" is used interchangeably with the term "aryl ring." In some embodiments of the invention, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, anthracene, and similar groups, which may have one or more substituents. As used herein, the scope of the term "aryl" also includes groups in which an aromatic ring is fused with one or more non-aromatic rings, such as dihydroindenyl, phthalimide, naphthylimide, phenanthridine, or tetrahydronaphthyl, and similar groups. The term "haloaryl" refers to an aryl group substituted with at least one halogen. Exemplary haloaryl groups include chlorophenyl (e.g., 3-chlorophenyl, 4-chlorophenyl), fluorophenyl, and similar groups. The term "phenylene" refers to a divalent phenyl group.

[0061] The terms "heteroaryl" and "heteroary-" used alone or as part of a larger portion (e.g., "heteroarylalkyl" or "heteroarylalkoxy") refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in the ring array; and having one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrazinyl, indazinyl, purinyl, naphthidyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroary-" also include groups in which a heteroaryl ring is fused with one or more aryl, cycloaliphatic, or heterocyclic rings, unless otherwise stated, wherein the linking group or linking point is on the heteroaryl ring or on a ring fused with the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothiopheneyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, terpineyl, quinazolinyl, quinoxalinyl, 4 H- Quinazinyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. The heteroaryl group can be monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl," or "heteroarylene," any of which includes optionally substituted rings. The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are optionally substituted independently. The term "haloheteroaryl" refers to a heteroaryl group substituted with at least one halogen. Exemplary haloheteroaryl groups include chloropyridine, fluopyridine, chloropyrazole, fluopyrazole, and similar groups. The term "heteroarylide" refers to a divalent heteroaryl group. Similarly, the terms "pyrazolylide," "imidazolyl," and "pyrrolidinylide" refer to divalent pyrazolyl, imidazolyl, and pyrrolidinyl, respectively. Similarly, the terms "pyridazinyl", "pyrimidinyl", "pyrazinyl", and "pyridinyl" refer to divalent pyridazinyl, pyrimidinyl, pyrazinyl, and pyridinyl, respectively.

[0062] As used herein, the terms “heterocyclic,” “heterocyclic group,” “heterocyclic ring,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above, in addition to a carbon atom. When used to refer to the ring atom of a heterocycle, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (e.g., in 3,4-dihydro-2-oxohydrogen ions). H -pyrrole group), NH (as in pyrroleyl group) or + NR (as in) N -In substituted pyrrolidinyl groups).

[0063] Heterocycles may be attached to their side groups at any heteroatom or carbon atom that produces a stable structure, and any of the ring atoms may optionally be substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazine, dioxane, dioxazopenyl, diazinopinyl, oxazinopinyl, thioazinopinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quininecycloyl. The terms “heterocycle,” “heterocyclic group,” “heterocyclic ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic group” are used interchangeably herein and also include groups in which the heterocyclic ring is fused with one or more aryl, heteroaryl, or cycloaliphatic rings, such as indololinyl, 3 H-Indolyl, chromoalkyl, phenanthridineyl, or tetrahydroquinolinyl. The heterocyclic group can be monocyclic or bicyclic. The term "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic group, wherein the alkyl and heterocyclic portions are optionally substituted independently. The term "hemiecyclic" refers to a divalent heterocyclic group. The terms "piperidinyl," "piperazinyl," and "aziridineyl" refer to divalent piperidinyl, piperazinyl, and aziridineyl, respectively.

[0064] As used herein, the term "heterocyclic alkyl" refers to a saturated heterocyclic group. The term "hemiecyclic alkylene" refers to a divalent heterocyclic alkyl group.

[0065] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double bond or parabond. The term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, but not to include aryl or heteroaryl moiety as defined herein.

[0066] As described herein, the compounds of the present invention may contain a “optionally substituted” portion. Generally, the term “substituted” means, regardless of whether it is preceded by the term “optionally,” that one or more hydrogens of the specified portion are substituted with suitable substituents. Unless otherwise indicated, the “optionally substituted” group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure can be substituted with more than one substituent selected from the specified group. The combinations of substituents contemplated in this invention are preferably those that form stable or chemically viable compounds. As used herein, the term “stable” means a compound that remains substantially unchanged when subjected to conditions permissible for its production, detection, and, in some embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0067] Each optional substituent on the substituted carbon is independently selected from the following monovalent substituents: halogen; -(CH2). 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R°;-O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0- 4SR°;-(CH2) 0-4 Ph, which can be replaced by R°; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be substituted by R°; -CH=CHPh, which can be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 -Pyridyl group, which can be substituted with R°; -NO2; -CN; -N3; ​​-(CH2) 0-4N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR-; SC(S)SR°; -(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°;-(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)₂OR°;-(CH₂) 0-4 OS(O)2R°;-S(O)2NR°2;-S(O)(NR°)R°;-S(O)2N=C(NR°2)2;-(CH2) 0-4 S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; SiR°3; -(C 1-4 (linear or branched alkylene)ON(R°)2; or -(C 1-4 (Straight-chain or branched-chain alkylene)C(O)ON(R°)2.

[0068] Each R° is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, -CH2- (5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the foregoing definition, two independently occurring R° together with intercalation atoms form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted on the saturated carbon atom of R° with a divalent substituent selected from =O and =S; or each R° may optionally be substituted independently with a monovalent substituent selected from: halogen, -(CH2) 0-2 R ● -(halogenated R) ● -(CH2) 0-2 OH, -(CH2) 0-2 OR ● -(CH2) 0-2 CH(OR ● 2. -O(halogenated R) ● -CN, -N3, -(CH2) 0-2 C(O)R ● -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● -(CH2) 0-2 SR ● -(CH2) 0-2 SH, -(CH2) 0-2 NH2、-(CH2) 0-2 NHR ● -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● -(C 1-4 (straight-chain or branched-chain alkylene)C(O)OR ● or -SSR ● .

[0069] Each R ● It is independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each R ● It is either unsubstituted or substituted with one or more halogens when preceded by a halogen group; or the substituents optionally present on the saturated carbon are independently selected from =O, =S, =NN. 2. =NNHC(O) =NNHC(O)O =NNHS(O)2 =N =NO -O(C( 2)) 2-3 O- or -S(C( 2)) 2-3 The divalent substituent of S-, or the divalent substituent bonded to the ortho-substituted carbon of the "optionally substituted" group, is -O(C). 2) 2-3 O-, where each appears independently It is selected from hydrogen, C 1-6 Aliphatic or unsubstituted 5-6 member saturated, partially unsaturated or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0070] when C 1-6 When aliphatic, Optional halogen, -R ● -(halogenated R) ● -OH, -OR ● -O(halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2 substitution, where each R ● It is independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each R ● It is either not substituted or, if preceded by a halogen group, is substituted by one or more halogens.

[0071] The optional substituents that can replace nitrogen are independently -R † -NR † 2. -C(O)R † -C(O)OR † -C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R) † )S(O)2R †; where each R † Independently hydrogen, C 1-6 Aliphatic, unsubstituted -OPh or unsubstituted 5-6 member saturated, partially unsaturated or aryl rings having 0-4 independent heteroatoms selected from nitrogen, oxygen or sulfur, or two independently occurring R... † Together with intercalated atoms, they form unsubstituted 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic rings with 0-4 independently selected heteroatoms from nitrogen, oxygen, or sulfur; wherein when R † C 1-6 When aliphatic, R † Optional halogen, -R ● -(halogenated R) ● -OH, -OR ● -O(halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2 substitution, where each R ● It is independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each R ● It is either not substituted or, if preceded by a halogen group, is substituted by one or more halogens.

[0072] As used herein, the term "pharmaceutically acceptable salt" means that salts suitable for contact with human and lower animal tissues within the bounds of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or similar reactions, and which are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with an amino group and inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed using other methods (such as ion exchange) employed in the art. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioate, glucono-heptate, glycerophosphate, gluconate, hemisulfate, heptaate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and similar salts.

[0073] Furthermore, acids generally considered suitable for forming pharmaceutically usable salts from basic pharmaceutical compounds are, for example, discussed in: P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International Journal of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book(Food & Drug Administration, Washington, DC, on its website). This publicly available information is incorporated herein by reference.

[0074] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and similar salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using relative ions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate ions.

[0075] Unless otherwise specified, the structures described herein are intended to include all isomers (e.g., enantiomers, diastereomers, and geometric (or configurational) forms of the structures; for example, R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E configurational isomers. Therefore, individual stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric (or configurational) forms, are within the scope of the present invention. Unless otherwise specified, all tautomers of the compounds of the present invention are within the scope of the present invention. The present invention includes compounds differing only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention and comprising hydrogen substituted with deuterium or tritium, or carbon substituted with deuterium or tritium... 13 C or 14 Compounds enriched with carbon-substituted carbon are within the scope of this invention. Such compounds can be used, for example, as analytical tools, probes in bioassays, or therapeutic agents according to the invention.

[0076] A mixture of diastereomers can be separated into their individual diastereomers based on their physicochemical differences using methods known to those skilled in the art, such as chromatography and / or fractional crystallization. The diastereomers can be separated by reacting the enantiomeric mixture with a suitable optically active compound (e.g., a volatile auxiliary, such as a volatile alcohol or Mosher's acid chloride), converting it into a diastereomeric mixture, and then converting (e.g., hydrolyzing) the individual diastereomers to their respective pure enantiomers. Alternatively, specific enantiomers of the compounds of the present invention can be prepared by asymmetric synthesis. Furthermore, in the case where the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxylic acid group), a diastereomeric salt can be formed with a suitable optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatography known in this art, and then recovery of the pure enantiomers.

[0077] Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers, or may, for example, be mixed as racemates or mixed with all other or other selected stereoisomers. The palmate center in the compounds of the present invention may have, for example, […]. IUPAC The 1974 Recommendations defined S or R Configuration. Furthermore, with regard to the fact that the compounds described herein may exist as transisomers (e.g., substituted biaryl compounds), all such transisomers are considered part of the invention.

[0078] Chemical names, common names, and chemical structures are used interchangeably to describe the same structure. If both chemical structure and chemical name are used to refer to a chemical compound and there is ambiguity between the two, the structure shall prevail. It should also be noted that any carbon atoms and heteroatoms in the text, flowcharts, examples, and tables of this document that do not meet the required valence are assumed to have a sufficient number of hydrogen atoms to meet the required valence.

[0079] Unless the context is inappropriate, as used herein, the terms “a” and “an” mean “one or more (kinds)” and include the plural.

[0080] The term "alkyl" refers to a saturated straight-chain or branched hydrocarbon, such as a straight-chain or branched group with 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C1, respectively. 12 Alkyl, C1-C 10 Alkyl and C1-C6 alkyl groups. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0081] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group with 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein as "C3-C6 cycloalkyl" for example, derived from cycloalkanes. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term "cycloalkylene" refers to a divalent cycloalkyl group.

[0082] The term "haloalkyl" refers to an alkyl group substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and similar groups. The term "chloroalkyl" refers to an alkyl group substituted with at least one chlorine. The term "bromoalkyl" refers to an alkyl group substituted with at least one bromine. The term "haloalkylene" refers to a divalent haloalkyl group.

[0083] The term "hydroxyalkyl" refers to an alkyl group that is substituted with at least one hydroxyl group. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and similar groups.

[0084] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are substituted with heteroatoms (e.g., N, O, or S). Exemplary heteroalkyl groups include -OCH3, -CH2OCH3, -CH2CH2N(CH3)2, and -CH2CH2OH. Heteroalkyl groups may contain, for example, 2-4, 2-6, or 2-8 atoms selected from groups of carbon atoms and heteroatoms (e.g., N, O, or S). The phrase 3-8-membered heteroalkyl refers to a heteroalkyl group having 3 to 8 atoms selected from groups of carbon atoms and heteroatoms. The term "heteroalkylene" refers to a divalent heteroalkyl group.

[0085] The terms "alkenyl" and "alkynyl" are technically accepted and refer to unsaturated aliphatic groups that are similar in length and possible substitutions to the alkyl groups described above, but each contains at least one double or triple bond. The term "haloalkenyl" refers to an alkenyl group substituted with at least one halogen. The term "fluoroalkenyl" refers to an alkenyl group substituted with at least one fluorine. The term "nitroalkenyl" refers to an alkenyl group substituted with at least one nitro group.

[0086] The term "subcarbonyl group" refers to a divalent cyclic aliphatic group.

[0087] The term "alkoxyl" or "alkoxy" is technically recognized and refers to an alkyl group as defined above having an oxygen group attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and similar groups. The term "haloalkoxy" refers to an alkoxy group substituted with at least one halogen. Exemplary haloalkoxy groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and similar groups.

[0088] The term "oxo" is technically accepted and refers to the "=O" substituent. For example, cyclopentane substituted with oxo is cyclopentanone.

[0089] The term "amino" is technically accepted and refers to both unsubstituted and substituted amines, for example, portions that can be represented by the following general formula:

[0090]

[0091] Where R 50 R 51 R 52 and R 53 Each can independently represent hydrogen, alkyl, alkenyl, or -(CH2). m -R 61 , or R 50 and R 51 Together with the N atom it is attached to, it forms a heterocycle with 4 to 8 atoms in the ring structure; R 61 It represents aryl, 3-7 membered cycloalkyl, 4-7 membered cycloalkenyl, 5-10 membered heteroaryl or 3-10 membered heterocyclic; and m is 0 or an integer in the range of 1 to 8.

[0092] The term "amide" is technically recognized and refers to both unsubstituted and substituted amides, for example, portions that can be represented by the following general formula:

[0093]

[0094] Where R 50 and R 51 Each can independently represent hydrogen, alkyl, alkenyl, or -(CH2). m -R 61 , or R 50 and R 51 Together with the N atom it is attached to, it forms a heterocycle with 4 to 8 atoms in the ring structure; R 61 Represents aryl, 3-7 membered cycloalkyl, 4-7 membered cycloalkenyl, 5-10 membered heteroaryl, or 3-10 membered heterocyclic; and m is 0 or an integer in the range of 1 to 8; and R 52 It can be alkyl, alkenyl, or -(CH2). m -R 61 .

[0095] symbol" "Indicates the connection point."

[0096] Unless otherwise indicated, when any substituent or variable appears more than once in any ingredient or compound of the present invention, its definition at each occurrence is independent of its definition at each other occurrence.

[0097] One or more compounds of the present invention may exist in both unsolvated and solvated forms with pharmaceutically acceptable solvents (such as water, ethanol, and the like), and the present invention is intended to cover both solvated and unsolvated forms. "Solvate" means the physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate will be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution phases and separable solvates. Non-limiting examples suitable for solvates include ethoxides, methanols, and the like. "Hydrate" is a solvate in which the solvent molecule is H₂O.

[0098] As used herein, the terms "individual" and "patient" are used interchangeably and refer to an organism to be treated by the method of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., rats, monkeys, horses, cattle, pigs, dogs, cats, and similar animals), and most preferably include humans.

[0099] The term "IC" 50 "The technically recognized concentration of the compound required to achieve 50% inhibition of the target" is defined as the concentration of the compound that is technically recognized as the concentration required to achieve 50% inhibition of the target.

[0100] As used herein, the term "effective amount" means an amount of compound sufficient to achieve a beneficial or desired outcome (e.g., therapeutic, ameliorative, inhibitory, or preventative outcome). An effective amount may be administered once or multiple times by application, dosing, or dose and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treatment" includes any effect that improves a disease, ailment, condition, or similar symptom, such as alleviating, reducing, moderating, improving, or eliminating, or improving its symptoms.

[0101] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent and an inert or active carrier, making the composition particularly suitable for in vivo or in vitro diagnostic or therapeutic uses.

[0102] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as phosphate-buffered saline solutions, water, emulsions (such as oil / water or water / oil emulsions), and various types of wetting agents. Compositions may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th edition, Mack Publ. Co., Easton, PA

[1975] .

[0103] For therapeutic use, salts of the compounds of the present invention are intended to be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases may also be used, for example, to prepare or purify pharmaceutically acceptable compounds.

[0104] Furthermore, when the compounds of the present invention contain a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, carboxylic acids), zwitterions (“internal salts”) can be formed. Such acidic and basic salts used within the scope of the present invention are pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts. Such salts of the compounds of the present invention can be formed, for example, by reacting the compounds of the present invention with a certain amount (such as equivalents) of an acid or base in a medium (such as a medium in which salts precipitate) or in an aqueous medium, followed by lyophilization.

[0105] Throughout the description, where compositions are described as having, including, or containing specific components, or processes and methods are described as having, including, or containing specific steps, it is also contemplated that the compositions of the present invention are substantially composed of or comprised of the described components, and that the processes and methods according to the present invention are substantially composed of or comprised of the described processing steps.

[0106] Generally, unless otherwise specified, the percentages of the composition are by weight.

[0107] I. Heterofunctional compounds

[0108] One aspect of the present invention provides heterobifunctional compounds. These compounds can be used in the pharmaceutical compositions and treatment methods described herein. Exemplary compounds, together with exemplary procedures for preparing these compounds, are described in the following sections. Without being limited by theory, these compounds can enhance therapeutic effects by binding to androgen receptors and BRD4 (bromine-containing domain protein 4).

[0109] Part A: Compound of Formula I

[0110] One aspect of the present invention provides a compound represented by formula I:

[0111]

[0112] Or its pharmaceutically acceptable salt; wherein:

[0113] R 1 The phenyl group is substituted with the following: (i) cyano group and R appearing m times. 4 , and (ii) C 1-4 Alkoxy or C 1-4 Haloalkoxy;

[0114] R 2 C is represented independently each time it appears. 1-4 alkyl;

[0115] R 3 It is hydrogen or C 1-4 alkyl;

[0116] R 4 C 1-4 alkyl;

[0117] R 5 C is represented independently each time it appears. 1-4 Alkyl or halogen;

[0118] A 1 It is pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, or phenylene, each of which is represented by R n times. 5 replace;

[0119] L is a connector; and

[0120] A 2 One of the following:

[0121] or ;

[0122] B 1 For (i) R that appears 1, 2, 3 or 4 times 2 The substituted cyclobutylene, or (ii) R appearing 0, 1 or 2 times. 2 Substituted cyclohexyl groups;

[0123] R 1A C 1-4 Alkyl or C 3-4 cycloalkyl;

[0124] R 2A C is represented independently each time it appears. 1-4 Alkyl or C 3-4 cycloalkyl;

[0125] R 3A Hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated or C 1-4 Alkoxy;

[0126] R 4A For -(C 0-6 Alkylene)-(containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroaryl), -(C 1-6 alkylene)-C(O)N(R 5A (R) 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A -(C 1-6 (alkylene)-CO2R 7A -(C 1-6Alkylene)-OC(O)R 7A -(C 1-6 alkylene)-cyano, -(C 1-6 alkylene)-O-(C 1-6 Alkyl), C 1-6 Alkyl, C 3-6 cycloalkyl or hydrogen; or R 4A and R 10A Together with the carbon atom it is attached to, they form C 3-5 Saturated carbon rings;

[0127] R 5A and R 6A Independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; or R 5A and R 6A Together with the nitrogen atom it is attached to, it forms a 3-7 membered ring containing one nitrogen atom;

[0128] R 7A C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or C 3-6 cycloalkyl;

[0129] R 10A It is hydrogen or C 1-4 Alkyl; and

[0130] m, n, and p are independently 0, 1, or 2.

[0131] The definition of the variable in Formula I above includes multiple chemical groups. This application covers embodiments such as i) the variable is defined as a single chemical group selected from those chemical groups described above, ii) the variable is defined as a set of two or more of those chemical groups described above, and iii) the compound is defined by a combination of variables defined by (i) or (ii).

[0132] In some embodiments, the compound is a compound of formula I.

[0133] As defined above, R 1 The phenyl group is substituted with the following: (i) cyano group and R appearing m times. 4 , and (ii) C 1-4 Alkoxy or C 1-4 Haloalkoxy. In some embodiments, R 1 The phenyl group is substituted with the following: (i) cyano group and R appearing m times. 4 , and (ii) C 1-4 Alkyl group. In some embodiments, R 1For cyano and C 1-4 Alkoxy-substituted phenyl. In some embodiments, R 1 It is a phenyl group substituted with cyano and methoxy groups. In some embodiments, R 1 for In some implementations, R 1 The phenyl group is substituted with the following: (i) cyano group and R appearing m times. 4 , and (ii) C 1-4 Haloalkoxy. In some embodiments, R 1 For cyano and C 1-4 Haloalkoxy-substituted phenyl groups. In some embodiments, R 1 For cyano and C 1-4 A fluoroalkoxy-substituted phenyl group. In some embodiments, R 1 It is a phenyl group substituted with cyano and trifluoromethoxy groups. In some embodiments, R 1 for .

[0134] In some implementations, R 1 It is a group selected from the compounds described in Table 1 or Table 2 below.

[0135] As defined above, R 2 C is represented independently each time it appears. 1-4 Alkyl group. In some embodiments, R 2 It is methyl. In some embodiments, R 2 It is a group selected from the compounds described in Table 1 or Table 2 below.

[0136] As defined above, R 3 It is hydrogen or C 1-4 Alkyl group. In some embodiments, R 3 It is hydrogen. In some implementations, R 3 C 1-4 Alkyl group. In some embodiments, R 3 It is a group selected from the compounds described in Table 1 or Table 2 below.

[0137] As defined above, A 1 It is pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, or phenylene, each of which is represented by R n times. 5 Replacement. In some implementations, A 1 R appears n times 5 Substituted pyridazine group. In some embodiments, A 1 for In some implementations, A 1 R appears n times 5Substituted pyrimidine group. In some embodiments, A 1 for ,in For the connection point with L. In some implementations, A 1 for ,in For the connection point with L. In some implementations, A 1 R appears n times 5 Substituted pyrazine group. In some embodiments, A 1 for In some implementations, A 1 R appears n times 5 Substituted pyridyl group. In some embodiments, A 1 for ,in For the connection point with L. In some implementations, A 1 R appears n times 5 Substituted phenylene. In some embodiments, A 1 for In some implementations, A 1 R appears 0 times 5 Substituted pyridazine group. In some embodiments, A 1 R appears 0 times 5 Substituted pyrimidine group. In some embodiments, A 1 R appears 0 times 5 Substituted pyrazine group. In some embodiments, A 1 R appears 0 times 5 Substituted pyridyl group. In some embodiments, A 1 R appears 0 times 5 Substituted phenylene. In some embodiments, A 1 It is a group selected from the compounds described in Table 1 or Table 2 below.

[0138] As defined above, A 2 for or In some implementations, A 2 for In some implementations, A 2 for .

[0139] In some implementations, A 2 for In some implementations, A 2 for In some implementations, A 2for In some implementations, A 2 for or In some implementations, A 2 for or .

[0140] In some implementations, A 2 for , , or In some implementations, A 2 for , , or In some implementations, A 2 for , , or .

[0141] In some implementations, A 2 for , , , , or .

[0142] In some implementations, A 2 for or , , , , or In some implementations, A 2 for , , , , , or .

[0143] In some implementations, A 2 One of the following: In some implementations, A 2 One of the following: .

[0144] In some implementations, A 2 for or In some implementations, A 2 for , or .

[0145] In some implementations, A 2 for In some implementations, A 2 for In some implementations, A 2 for .

[0146] In some implementations, A 2 It is a group selected from the compounds described in Table 1 or Table 2 below.

[0147] As defined above, B 1 For (i) R that appears 1, 2, 3 or 4 times 2 The substituted cyclobutylene, or (ii) R appearing 0, 1 or 2 times. 2 Replaced cyclohexylene. In some embodiments, B 1 R appears 1, 2, 3 or 4 times 2 Replaced cyclobutylene. In some embodiments, B 1 R appears 4 times 2 Replaced cyclobutylene. In some embodiments, B 1 R appears 0, 1, or 2 times. 2 Replaced cyclohexylene. In some embodiments, B 1 R appears 0 times 2 Substituted cyclohexyl (i.e., B) 1 (For cyclohexylene). In some implementations, B 1 It is a group selected from the compounds described in Table 1 or Table 2 below.

[0148] As defined above, R 1A C 1-4 Alkyl or C 3-4 Cycloalkyl. In some embodiments, R 1A C 1-4 Alkyl group. In some embodiments, R 1A It is methyl. In some embodiments, R 1A C 3-4 Cycloalkyl. In some embodiments, R 1A It is a group selected from the compounds described in Table 1 or Table 2 below.

[0149] As defined above, R 2A C is represented independently each time it appears.1-4 Alkyl or C 3-4 Cycloalkyl. In some embodiments, R 2A C 1-4 Alkyl group. In some embodiments, R 2A It is methyl. In some embodiments, R 2A C 3-4 Cycloalkyl. In some embodiments, R 2A It is a group selected from the compounds described in Table 1 or Table 2 below.

[0150] As defined above, R 3A Hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated or C 1-4 Alkyl group. In some embodiments, R 3A For hydrogen, C 1-4 Alkyl or C 1-4 Alkyl group. In some embodiments, R 3A It is hydrogen. In some implementations, R 3A It is a halogen group. In some embodiments, R 3A It is fluorine. In some embodiments, R 3A It is chlorine. In some implementations, R 3A C 1-4 Alkyl group. In some embodiments, R 3A It is methyl. In some embodiments, R 3A C 1-4 Alkyl group. In some embodiments, R 3A It is methoxylated. In some embodiments, R 3A C 1-4 Halogenated groups. In some embodiments, R 3A It is trifluoromethyl. In some embodiments, R 3A Halogenated, C 1-4 Alkyl or C 1-4 Alkyl group. In some embodiments, R 3A It is a group selected from the compounds described in Table 1 or Table 2 below.

[0151] As defined above, R 4A For -(C 0-6 Alkylene)-(containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroaryl), -(C 1-6 alkylene)-C(O)N(R 5A (R) 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A -(C1-6 (alkylene)-CO2R 7A -(C 1-6 Alkylene)-OC(O)R 7A -(C 1-6 alkylene)-cyano, -(C 1-6 alkylene)-O-(C 1-6 Alkyl), C 1-6 Alkyl, C 3-6 cycloalkyl or hydrogen; or R 4A and R 10A Together with the carbon atom it is attached to, they form C 3-5 Saturated carbon ring. In some embodiments, R 4A For -(C 1-6 alkylene)-C(O)N(R 5A (R) 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A -(C 1-6 (alkylene)-CO2R 7A -(C 1-6 Alkylene)-OC(O)R 7A or -(C 0-6 Alkylene group (containing one, two, or three 5-6 heteroaryl groups independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4A For -(C 1-6 alkylene)-C(O)N(R 5A (R) 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A -(C 1-6 (alkylene)-CO2R 7A or -(C 1-6 Alkylene)-OC(O)R 7A In some implementations, R 4A It is hydrogen. In some implementations, R 4A For -(C 1-6 (alkylene)-cyano. In some embodiments, R 4A C 1-6 Alkyl group. In some embodiments, R 4A It is methyl. In some embodiments, R 4A For -(C 1-6 alkylene)-C(O)N(R 5A (R) 6A In some implementations, R 4A For -(C 1-6(alkylene)-CO2R 7A In some implementations, R 4A For -(C 1-6 alkylene)-N(R 5A )C(O)R 7A In some implementations, R 4A For -(C 1-6 Alkylene)-OC(O)R 7A .

[0152] In some implementations, R 4A For -(C 0-6 Alkylene group (containing one, two, or three 5-6 heteroaryl groups independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4A For -(C 0-6 Alkylene group (containing one, two, or three 5-6 heteroaryl groups independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4A For -(C 1-2 Alkylene group (containing one, two, or three 5-6 heteroaryl groups independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4A For -(C 1-2 Alkylene group (containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur) - (a five-membered heteroaryl group). In some embodiments, R 4A For -(C 1-2 (alkylene)-(oxazolyl).

[0153] In some implementations, R 4A For -(C 1-6 alkylene)-O-(C 1-6 Alkyl). In some embodiments, R 4A For -(C 1-2 alkylene)-O-(C 1-2 alkyl).

[0154] In some implementations, R 4A and R 10A Together with the carbon atom it is attached to, they form C 3-5 Saturated carbon rings.

[0155] In some implementations, R 4A It is a group selected from the compounds described in Table 1 or Table 2 below.

[0156] As defined above, R 5A and R 6A Independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; or R 5A and R6A Together with the nitrogen atom it is attached to, it forms a 3-7 membered ring containing one nitrogen atom. In some embodiments, R 5A and R 6A Independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 5A It is hydrogen. In some implementations, R 5A C 1-6 Alkyl group. In some embodiments, R 5A C 3-6 Cycloalkyl. In some embodiments, R 6A It is hydrogen. In some implementations, R 6A C 1-6 Alkyl group. In some embodiments, R 6A C 3-6 Cycloalkyl. In some embodiments, R 5A and R 6A Together with the nitrogen atom it is attached to, it forms a 3-7 membered ring containing one nitrogen atom. In some embodiments, R 5A and R 6A Together with the nitrogen atom it is attached to, it forms a three-membered ring containing one nitrogen atom. In some embodiments, R 5A and R 6A Together with the nitrogen atom it is attached to, it forms a four-membered ring containing one nitrogen atom. In some embodiments, R 5A and R 6A Together with the nitrogen atom it is attached to, it forms a 5-membered ring containing one nitrogen atom. In some embodiments, R 5A and R 6A Together with the nitrogen atom it is attached to, it forms a six-membered ring containing one nitrogen atom. In some embodiments, R 5A and R 6A Together with the nitrogen atom it is attached to, it forms a 7-membered ring containing one nitrogen atom. In some embodiments, R 5A It is a group selected from the compounds depicted in Table 1 or Table 2 below. In some embodiments, R 6A It is a group selected from the compounds described in Table 1 or Table 2 below.

[0157] As defined above, R 7A C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or C 3-6 Cycloalkyl. In some embodiments, R 7A C 1-6 Alkyl group. In some embodiments, R 7A For -(C1-6 alkylene)-(C 3-6 (Cycloalkyl). In some embodiments, R 7A C 3-6 Cycloalkyl. In some embodiments, R 7A It is a group selected from the compounds described in Table 1 or Table 2 below.

[0158] As defined above, R 10A It is hydrogen or C 1-4 Alkyl group. In some embodiments, R 10A It is hydrogen. In some implementations, R 10A C 1-4 Alkyl group. In some embodiments, R 10A It is methyl. In some embodiments, R 10A It is a group selected from the compounds described in Table 1 or Table 2 below.

[0159] As generally defined above, m, n, and p are independently 0, 1, or 2. In some embodiments, p is 2. In some embodiments, p is 1. In some embodiments, p is 0. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, p is a corresponding value among the groups depicted in the compounds described in Table 1 or Table 2 below. In some embodiments, m is a corresponding value among the groups depicted in the compounds described in Table 1 or Table 2 below. In some embodiments, n is a corresponding value among the groups depicted in the compounds described in Table 1 or Table 2 below.

[0160] In some embodiments, the compound of formula I is further defined by formula Ia or a pharmaceutically acceptable salt thereof:

[0161]

[0162] In some implementations, variable R 1 R 2 R 3 A 1 and A 2 The definition is one of the implementation schemes described in Formula I above.

[0163] In some embodiments, the compound of formula I is further defined by formula Ib or formula Ic or a pharmaceutically acceptable salt thereof:

[0164]

[0165] In some implementations, variable R1 R 2 R 3 A 1 and A 2 The definition is one of the embodiments described above in conjunction with Formula I. In some embodiments, the compound is a compound of Formula Ib or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula Ic or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the compound of formula I is further defined by formula Id or a pharmaceutically acceptable salt thereof:

[0167]

[0168] In some implementations, variable A 1 and A 2 The definition is one of the implementation schemes described in Formula I above.

[0169] In some embodiments, the compound of formula I is further defined by formula Ie or a pharmaceutically acceptable salt thereof:

[0170]

[0171] In some implementations, variable A 1 and A 2 The definition is one of the implementation schemes described in Formula I above.

[0172] In some embodiments, the compound of formula I is further defined by formula If or a pharmaceutically acceptable salt thereof:

[0173]

[0174] In some implementations, variable A 1 and A 2 The definition is one of the implementation schemes described in Formula I above.

[0175] In some embodiments, the compound of formula I is further defined by formula Ig or a pharmaceutically acceptable salt thereof:

[0176]

[0177] (Ig).

[0178] In some implementations, variable A 1 and A 2 The definition is one of the implementation schemes described in Formula I above.

[0179] In some embodiments, the compound of formula I is further defined by formula Ih or a pharmaceutically acceptable salt thereof:

[0180]

[0181] (Ih).

[0182] In some implementations, variable A 1 and A 2 The definition is one of the implementation schemes described in Formula I above.

[0183] In some embodiments, the compound of formula I is further defined by formula Ii or a pharmaceutically acceptable salt thereof:

[0184]

[0185] In some implementations, variable A 1 and A 2 The definition is one of the implementation schemes described in Formula I above.

[0186] In some embodiments, the compound of formula I is further defined by formula Ij or a pharmaceutically acceptable salt thereof:

[0187]

[0188] In some implementations, variable A 1 and A 2 The definition is one of the implementation schemes described in Formula I above. In some implementation schemes, the variable R... 1 R 2 and R 3 The definition is one of the implementation schemes described in Formula I above.

[0189] In some embodiments, the compound of formula I is further defined by formula Ik or a pharmaceutically acceptable salt thereof:

[0190]

[0191] In some implementations, variable A 1 and A 2 The definition is one of the implementation schemes described in Formula I above. In some implementation schemes, the variable R... 1 and R 3 The definition is one of the implementation schemes described in Formula I above.

[0192] In some embodiments, the compound of formula I is further defined by formula Il or formula Im or a pharmaceutically acceptable salt thereof:

[0193]

[0194] In some implementations, variable A 1 and A 2The definition is one of the implementation schemes described in Formula I above. In some implementation schemes, the variable R... 1 and R 3 The definition is one of the embodiments described above in conjunction with Formula I. In some embodiments, the compound is a compound of Formula Il or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula Im or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, the compound of formula I is further defined by formula In or a pharmaceutically acceptable salt thereof:

[0196]

[0197] In some implementations, variable A 1 and A 2 The definition is one of the implementation schemes described in Formula I above.

[0198] In some embodiments, the compound of formula I is further defined by formula Io or formula Ip or a pharmaceutically acceptable salt thereof:

[0199]

[0200]

[0201] In some implementations, variable A 1 and A 2 The definition is one of the implementation schemes described in Formula I above. In some implementation schemes, the variable R... 3 The definition is one of the embodiments described above in conjunction with Formula I. In some embodiments, the compound is a compound of Formula Io or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula Ip or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, the compound of formula I is further defined by formula Iq or a pharmaceutically acceptable salt thereof:

[0203]

[0204] In some implementations, variable A 1 and A 2 The definition is one of the implementation schemes described in Formula I above.

[0205] In some embodiments, the compound of formula I is further defined by formula Ir or formula Is or a pharmaceutically acceptable salt thereof:

[0206]

[0207] In some implementations, variable A 1 and A2 The definition is one of the implementation schemes described in Formula I above. In some implementation schemes, the variable R... 3 The definition is one of the embodiments described above in conjunction with Formula I. In some embodiments, the compound is a compound of Formula Ir or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula Is or a pharmaceutically acceptable salt thereof.

[0208] Another aspect of the present invention provides a compound or a pharmaceutically acceptable salt thereof represented by the formula It, Iu, Iv or Iw:

[0209]

[0210]

[0211] in

[0212] L is one of the following:

[0213] (i) -(a 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen) -O- ,in This is the connection point with the phenylene in the formula;

[0214] (ii) A 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing one, two, or three heteroatoms independently selected from nitrogen and oxygen; or

[0215] (iii) -(7-11 membered spirocyclic saturated heterocycles containing one or two heteroatoms selected from nitrogen)-(C 2-4 (ethynyl)- ,in The connection point with the phenylene in the formula; and

[0216] t is 0 or 1.

[0217] In some implementations, t is 0. In some implementations, t is 1.

[0218] Another aspect of the present invention provides a compound or a pharmaceutically acceptable salt thereof represented by formula Ix, Iy, Iz or Iaa:

[0219]

[0220]

[0221] in:

[0222] R 20 It can be methyl, ethyl, -CH2-O-CH3 or -(CH2)2-O-CH3;

[0223] L is one of the following:

[0224] (i) -(a 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen) -O- ,in This is the connection point with the phenylene in the formula;

[0225] (ii) A 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing one, two, or three heteroatoms independently selected from nitrogen and oxygen; or

[0226] (iii) -(7-11 membered spirocyclic saturated heterocycles containing one or two heteroatoms selected from nitrogen)-(C 2-4 (ethynyl)- ,in The connection point with the phenylene in the formula; and

[0227] t is 0 or 1.

[0228] In some implementations, t is 0. In some implementations, t is 1. In some implementations, R 20 It is methyl or ethyl. In some embodiments, R 20 It is -CH2-O-CH3 or -(CH2)2-O-CH3.

[0229] In some embodiments, L is -(a 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-O- ,in The connection point is the phenylene group in the formula. In some embodiments, L is a 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing one, two, or three heteroatoms independently selected from nitrogen and oxygen. In some embodiments, L is -(a 7-11 membered spirocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(C 2-4 (ethynyl)- ,in For the connection point with the phenylene in the formula. In some embodiments, L is one of the following:

[0230]

[0231] in This is the connection point with the phenylene in the formula.

[0232] In some implementations, L is ,in L represents the connection point with the phenylene group in the formula. In some embodiments, L is... ,in This is the connection point with the phenylene in the formula.

[0233] The compound may be further characterized by, for example, the identity of L, which is an exemplary further embodiment of L provided in part C below.

[0234] In some embodiments, the compound is represented by formula Iab or a pharmaceutically acceptable salt thereof:

[0235]

[0236] In some embodiments, the compound is represented by formula Iac or a pharmaceutically acceptable salt thereof:

[0237]

[0238] In some embodiments, the compound is represented by formula Iad or a pharmaceutically acceptable salt thereof:

[0239]

[0240] In some embodiments, the compound is represented by formula Iae or a pharmaceutically acceptable salt thereof:

[0241]

[0242] In some embodiments, the compound is represented by formula Iaf or a pharmaceutically acceptable salt thereof:

[0243]

[0244] (Iaf).

[0245] In some embodiments, the compound is represented by formula Iag or a pharmaceutically acceptable salt thereof:

[0246]

[0247] (Iag).

[0248] In some embodiments, the compound is represented by formula Iah or a pharmaceutically acceptable salt thereof:

[0249]

[0250] (Iah).

[0251] Part B: Compounds of Formula II

[0252] Another aspect of the present invention provides a compound represented by Formula II:

[0253]

[0254] (II)

[0255] Or its pharmaceutically acceptable salt; wherein:

[0256] TPL is a group defined by formula II-1, which is represented by R appearing once. II-1A The substitution is given by the following:

[0257]

[0258] (II-1)

[0259] Or its pharmaceutically acceptable salt; wherein:

[0260] R II-1A For the bond with L;

[0261] R 1 The phenyl group is substituted with the following: (i) cyano group and R appearing m times. 4 , and (ii) C 1-4 Alkoxy or C 1-4 Haloalkoxy;

[0262] R 2 C is represented independently each time it appears. 1-4 alkyl;

[0263] R 3 It is hydrogen or C 1-4 alkyl;

[0264] R 4 C 1-4 alkyl;

[0265] R 5 C is represented independently each time it appears. 1-4 Alkyl or halogen;

[0266] A 1 It is pyridazinyl, pyrimidinyl, pyrazinyl, pyridinyl, or phenyl, each of which is represented by R n times. 5 replace;

[0267] B 1 For (i) R that appears 1, 2, 3 or 4 times 2 The substituted cyclobutylene, or (ii) R appearing 0, 1 or 2 times. 2 Substituted cyclohexyl groups;

[0268] L is a connector;

[0269] EPL is the part that combines with BRD4; and

[0270] m and n are independently 0, 1 or 2.

[0271] The definition of the variable in Formula II above includes multiple chemical groups. This application covers embodiments such as i) the variable is defined as a single chemical group selected from those chemical groups described above, ii) the variable is defined as a set of two or more of those chemical groups described above, and iii) the compound is defined by a combination of variables defined by (i) or (ii).

[0272] In some embodiments, the compound is a compound of formula II.

[0273] As defined above, R 1 The phenyl group is substituted with the following: (i) cyano group and R appearing m times. 4 , and (ii) C 1-4 Alkoxy or C 1-4 Haloalkoxy. In some embodiments, R 1 The phenyl group is substituted with the following: (i) cyano group and R appearing m times. 4 , and (ii) C 1-4 Alkyl group. In some embodiments, R 1 For cyano and C 1-4 Alkoxy-substituted phenyl. In some embodiments, R 1 It is a phenyl group substituted with cyano and methoxy groups. In some embodiments, R 1 for In some implementations, R 1 The phenyl group is substituted with the following: (i) cyano group and R appearing m times. 4 , and (ii) C 1-4 Haloalkoxy. In some embodiments, R 1 For cyano and C 1-4 Haloalkoxy-substituted phenyl groups. In some embodiments, R 1 For cyano and C 1-4 A fluoroalkoxy-substituted phenyl group. In some embodiments, R 1 It is a phenyl group substituted with cyano and trifluoromethoxy groups. In some embodiments, R 1 for .

[0274] In some implementations, R 1 It is a group selected from the compounds described in Table 1 or Table 2 below.

[0275] As defined above, R 2 C is represented independently each time it appears. 1-4 Alkyl group. In some embodiments, R 2 It is methyl. In some embodiments, R 2It is a group selected from the compounds described in Table 1 or Table 2 below.

[0276] As defined above, R 3 It is hydrogen or C 1-4 Alkyl group. In some embodiments, R 3 It is hydrogen. In some implementations, R 3 C 1-4 Alkyl group. In some embodiments, R 3 It is a group selected from the compounds described in Table 1 or Table 2 below.

[0277] As defined above, A 1 It is pyridazinyl, pyrimidinyl, pyrazinyl, pyridinyl, or phenyl, each of which is represented by R n times. 5 Replacement. In some implementations, A 1 R appears n times 5 Substituted pyridazinyl group. In some embodiments, A 1 R appears n times 5 Substituted pyrimidinyl group. In some embodiments, A 1 R appears n times 5 Substituted pyrazinyl group. In some embodiments, A 1 R appears n times 5 Substituted pyridinyl group. In some embodiments, A 1 R appears n times 5 Substituted phenyl groups. In some embodiments, A 1 It is a group selected from the compounds described in Table 1 or Table 2 below.

[0278] As defined above, B 1 For (i) R that appears 1, 2, 3 or 4 times 2 The substituted cyclobutylene, or (ii) R appearing 0, 1 or 2 times. 2 Replaced cyclohexylene. In some embodiments, B 1 R appears 1, 2, 3 or 4 times 2 Replaced cyclobutylene. In some embodiments, B 1 R appears 4 times 2 Replaced cyclobutylene. In some embodiments, B 1 R appears 0, 1, or 2 times. 2 Replaced cyclohexylene. In some embodiments, B 1 R appears 0 times 2 Substituted cyclohexyl (i.e., B) 1 (For cyclohexylene). In some implementations, B 1 It is a group selected from the compounds described in Table 1 or Table 2 below.

[0279] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, m is a corresponding value selected from the groups depicted in the compounds described in Table 1 or Table 2 below. In some embodiments, n is a corresponding value selected from the groups depicted in the compounds described in Table 1 or Table 2 below.

[0280] In some implementations, TPL is the R that appears once. II-1A Replacement In some implementations, TPL is the R that appears once. II-1A Replacement In some implementations, TPL is... In some implementations, TPL is... .

[0281] In some implementations, TPL is the R that appears once. II-1A Replacement In some implementations, TPL is the R that appears once. II-1A Replacement In some implementations, TPL is... In some implementations, TPL is... .

[0282] In some implementations, EPL is defined by Equation II-2, which is determined by the first occurrence of R. II-2A The substitution is given by the following:

[0283] or ;

[0284] in

[0285] R II-2A For the bond with L;

[0286] R 1A C 1-4 Alkyl or C 3-4 cycloalkyl;

[0287] R 2A C is represented independently each time it appears. 1-4 Alkyl or C 3-4 cycloalkyl;

[0288] R 3A Hydrogen, halogen, C 1-4 Alkyl or C 1-4 Alkoxy;

[0289] R 4A For -(C 0-6 Alkylene)-(containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroaryl), -(C 1-6 alkylene)-C(O)N(R 5A (R) 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A -(C 1-6 (alkylene)-CO2R 7A -(C 1-6 Alkylene)-OC(O)R 7A -(C 1-6 alkylene)-cyano, -(C 1-6 alkylene)-O-(C 1-6 Alkyl), C 1-6 Alkyl, C 3-6 cycloalkyl or hydrogen; or R 4A and R 10A Together with the carbon atom it is attached to, they form C 3-5 Saturated carbon rings;

[0290] R 5A and R 6A Independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; or R 5A and R 6A Together with the nitrogen atom it is attached to, it forms a 3-7 membered ring containing one nitrogen atom;

[0291] R 7A C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or C 3-6 cycloalkyl;

[0292] R 10A It is hydrogen or C 1-4 Alkyl; and

[0293] m, n, and p are independently 0, 1, or 2.

[0294] In some implementations, EPL is defined by Equation II-2, which is determined by the first occurrence of R. II-2A The substitution is given by the following: In some implementations, EPL is... .

[0295] In some implementations, EPL is In some implementations, EPL is... In some implementations, EPL is... In some implementations, EPL is... or In some implementations, EPL is... or .

[0296] In some implementations, EPL is , , or In some implementations, EPL is... , , or In some implementations, EPL is... , , or .

[0297] In some implementations, EPL is , , , , or .

[0298] In some implementations, EPL is or , , , , , or In some implementations, EPL is... , , , , , , or .

[0299] In some implementations, EPL is one of the following: In some implementations, EPL is one of the following: .

[0300] In some implementations, EPL is or In some implementations, EPL is... , or .

[0301] In some implementations, EPL is In some implementations, EPL is... In some implementations, EPL is... .

[0302] In some embodiments, EPL is a group selected from the compounds depicted in Table 1 or Table 2 below.

[0303] As defined above, R 1A C 1-4 Alkyl or C 3-4 Cycloalkyl. In some embodiments, R 1A C 1-4 Alkyl group. In some embodiments, R 1A It is methyl. In some embodiments, R 1A C 3-4 Cycloalkyl. In some embodiments, R 1A It is a group selected from the compounds described in Table 1 or Table 2 below.

[0304] As defined above, R 2A C is represented independently each time it appears. 1-4 Alkyl or C 3-4 Cycloalkyl. In some embodiments, R 2A C 1-4 Alkyl group. In some embodiments, R 2A It is methyl. In some embodiments, R 2A C 3-4 Cycloalkyl. In some embodiments, R 2A It is a group selected from the compounds described in Table 1 or Table 2 below.

[0305] As defined above, R 3A Hydrogen, halogen, C 1-4 Alkyl or C 1-4 Alkyl group. In some embodiments, R 3A It is hydrogen. In some implementations, R 3A It is a halogen group. In some embodiments, R 3A It is fluorine. In some embodiments, R 3A It is chlorine. In some implementations, R 3A C 1-4 Alkyl group. In some embodiments, R 3A It is methyl. In some embodiments, R 3A C 1-4 Alkyl group. In some embodiments, R 3A It is methoxylated. In some embodiments, R 3A Halogenated, C1-4 Alkyl or C 1-4 Alkyl group. In some embodiments, R 3A It is a group selected from the compounds described in Table 1 or Table 2 below.

[0306] As defined above, R 4A For -(C 0-6 Alkylene)-(containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroaryl), -(C 1-6 alkylene)-C(O)N(R 5A (R) 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A -(C 1-6 (alkylene)-CO2R 7A -(C 1-6 Alkylene)-OC(O)R 7A -(C 1-6 alkylene)-cyano, -(C 1-6 alkylene)-O-(C 1-6 Alkyl), C 1-6 Alkyl, C 3-6 cycloalkyl or hydrogen; or R 4A and R 10A Together with the carbon atom it is attached to, they form C 3-5 Saturated carbon ring. In some embodiments, R 4A For -(C 1-6 alkylene)-C(O)N(R 5A (R) 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A -(C 1-6 (alkylene)-CO2R 7A -(C 1-6 Alkylene)-OC(O)R 7A or -(C 0-6 Alkylene group (containing one, two, or three 5-6 heteroaryl groups independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4A For -(C 1-6 alkylene)-C(O)N(R 5A (R) 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A -(C 1-6 (alkylene)-CO2R 7A or -(C1-6 Alkylene)-OC(O)R 7A In some implementations, R 4A It is hydrogen. In some implementations, R 4A For -(C 1-6 (alkylene)-cyano. In some embodiments, R 4A C 1-6 Alkyl group. In some embodiments, R 4A It is methyl. In some embodiments, R 4A For -(C 1-6 alkylene)-C(O)N(R 5A (R) 6A In some implementations, R 4A For -(C 1-6 (alkylene)-CO2R 7A In some implementations, R 4A For -(C 1-6 alkylene)-N(R 5A )C(O)R 7A In some implementations, R 4A For -(C 1-6 Alkylene)-OC(O)R 7A .

[0307] In some implementations, R 4A For -(C 0-6 Alkylene group (containing one, two, or three 5-6 heteroaryl groups independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4A For -(C 0-6 Alkylene group (containing one, two, or three 5-6 heteroaryl groups independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4A For -(C 1-2 Alkylene group (containing one, two, or three 5-6 heteroaryl groups independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4A For -(C 1-2 Alkylene group (containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur) - (a five-membered heteroaryl group). In some embodiments, R 4A For -(C 1-2 (alkylene)-(oxazolyl).

[0308] In some implementations, R 4A For -(C 1-6 alkylene)-O-(C 1-6 Alkyl). In some embodiments, R 4A For -(C 1-2 alkylene)-O-(C1-2 alkyl).

[0309] In some implementations, R 4A and R 10A Together with the carbon atom it is attached to, they form C 3-5 Saturated carbon rings.

[0310] In some implementations, R 4A It is a group selected from the compounds described in Table 1 or Table 2 below.

[0311] As defined above, R 5A and R 6A Independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; or R 5A and R 6A Together with the nitrogen atom it is attached to, it forms a 3-7 membered ring containing one nitrogen atom. In some embodiments, R 5A and R 6A Independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 5A It is hydrogen. In some implementations, R 5A C 1-6 Alkyl group. In some embodiments, R 5A C 3-6 Cycloalkyl. In some embodiments, R 6A It is hydrogen. In some implementations, R 6A C 1-6 Alkyl group. In some embodiments, R 6A C 3-6 Cycloalkyl. In some embodiments, R 5A and R 6A Together with the nitrogen atom it is attached to, it forms a 3-7 membered ring containing one nitrogen atom. In some embodiments, R 5A and R 6A Together with the nitrogen atom it is attached to, it forms a three-membered ring containing one nitrogen atom. In some embodiments, R 5A and R 6A Together with the nitrogen atom it is attached to, it forms a four-membered ring containing one nitrogen atom. In some embodiments, R 5A and R 6A Together with the nitrogen atom it is attached to, it forms a 5-membered ring containing one nitrogen atom. In some embodiments, R 5A and R 6A Together with the nitrogen atom it is attached to, it forms a six-membered ring containing one nitrogen atom. In some embodiments, R 5A and R 6ATogether with the nitrogen atom it is attached to, it forms a 7-membered ring containing one nitrogen atom. In some embodiments, R 5A It is a group selected from the compounds depicted in Table 1 or Table 2 below. In some embodiments, R 6A It is a group selected from the compounds described in Table 1 or Table 2 below.

[0312] As defined above, R 7A C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or C 3-6 Cycloalkyl. In some embodiments, R 7A C 1-6 Alkyl group. In some embodiments, R 7A For -(C 1-6 alkylene)-(C 3-6 (Cycloalkyl). In some embodiments, R 7A C 3-6 Cycloalkyl. In some embodiments, R 7A It is a group selected from the compounds described in Table 1 or Table 2 below.

[0313] As defined above, R 10A It is hydrogen or C 1-4 Alkyl group. In some embodiments, R 10A It is hydrogen. In some implementations, R 10A C 1-4 Alkyl group. In some embodiments, R 10A It is methyl. In some embodiments, R 10A It is a group selected from the compounds described in Table 1 or Table 2 below.

[0314] As generally defined above, m, n, and p are independently 0, 1, or 2. In some embodiments, p is 2. In some embodiments, p is 1. In some embodiments, p is 0. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, p is a corresponding value among the groups depicted in the compounds described in Table 1 or Table 2 below. In some embodiments, m is a corresponding value among the groups depicted in the compounds described in Table 1 or Table 2 below. In some embodiments, n is a corresponding value among the groups depicted in the compounds described in Table 1 or Table 2 below.

[0315] In some implementations, EPL is determined by the variable A described in Formula I above. 2To define. In some implementations, EPL is defined by the variable A described in Associative Formula I. 2 Defined by one or more implementation schemes.

[0316] The compound may be further characterized, for example, by the identity of L. Exemplary further embodiments of L are provided in section C below.

[0317] Part C: Exemplary further description of the connector (L) component of compounds of formula I and II

[0318] Compounds of Formula I and II may be further characterized, for example, by the identity of the linker (L) component. Various linkers are known to those skilled in the art and can be used in the heterobifunctional compounds described herein. For example, in some embodiments, L comprises one or more optionally substituted groups selected from amino acids, polyether chains, aliphatic groups, and any combination thereof. In some embodiments, L consists of one or more optionally substituted groups selected from amino acids, polyether chains, aliphatic groups, and any combination thereof. In some embodiments, L consists of one or more groups selected from amino acids, polyether chains, aliphatic groups, and any combination thereof.

[0319] In some implementations, L is symmetric. In some implementations, L is asymmetric. In some implementations, L is a bond.

[0320] In some implementations, L is a covalent bond or a divalent C. 1-30 A saturated or unsaturated, straight or branched hydrocarbon chain, wherein 1-15 methylene units of L are optionally and independently substituted with: cyclopropylene, -N(H)-, -N(C)-. 1-4 alkyl)-, -N(C 3-5 Cycloalkyl)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(H)-, -S(O)2N(C 1-4 alkyl)-、-S(O)2N(C 3-5 cycloalkyl)-, -N(H)C(O)-, -N(C 1-4 Alkyl)C(O)-, -N(C 3-5 Cycloalkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-4 alkyl)-、-C(O)N(C 3-5Cycloalkyl), phenylene, 8-10 membered bicyclic aryl, 4-7 membered saturated or partially unsaturated carbocyclic, 8-10 membered bicyclic saturated or partially unsaturated carbocyclic, 3-7 membered saturated or partially unsaturated heterocyclic with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic saturated or partially unsaturated heterocyclic with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heterocyclic with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heterocyclic with 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0321] In some implementations, L is a divalent, saturated or unsaturated, straight or branched chain C. 1-60 A hydrocarbon chain in which 0-20 methylene units are independently substituted with: -O-, -S-, -N(R) )-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R S(O)2-、-S(O)2N(R) )-、-N(R )C(O)-、-C(O)N(R )-、-OC(O)N(R )-、-N(R C(O)O-, optionally substituted 3- to 10-membered carbocyclic groups, or optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R Each time it appears, it independently represents hydrogen and C. 1-6 Alkyl or C 3-6 Cycloalkyl.

[0322] In some implementations, L is a divalent, saturated or unsaturated, straight or branched chain C. 1-60 A hydrocarbon chain in which 0-20 methylene units are independently substituted with the following: -O-, -S-, -N(H)-, -N(C)-. 1-6 Alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C 1-6 Alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C 1-6 Alkyl)-, -N(H)C(O)-, -N(C 1-6 Alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 Alkyl)-, -OC(O)N(H)-, -OC(O)N(C 1-6 Alkyl)-, -N(H)C(O)O-, -N(C1-6 Alkyl)C(O)O-, optionally substituted 3- to 10-membered carbon cycloalkanes, or optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0323] In some implementations, L is a divalent, saturated, straight-chain, or branched chain C. 3-30 A hydrocarbon chain in which 0-15 methylene units are independently substituted with: -O-, -N(H)-, -N(C)-, ... 1-6 Alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 Alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 Alkyl group, 3-10 membered carbon cycloyl group, or 3-10 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0324] In some implementations, L is a divalent, saturated, straight-chain, or branched chain C. 3-30 A hydrocarbon chain in which 0-15 methylene units are independently substituted with: -O-, -N(H)-, -N(C)-, ... 1-6 Alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 Alkyl)C(O)-, -C(O)N(H)- or -C(O)N(C 1-6 alkyl)-.

[0325] In other embodiments, L comprises a polyethylene glycol chain ranging in size from about 1 to about 12 ethylene glycol units, from about 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to about 5 ethylene glycol units, or from about 2 to about 4 ethylene glycol units. In other embodiments, L is a polyethylene glycol chain bimolecular unit ranging in size from about 1 to about 12 ethylene glycol units, from about 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to about 5 ethylene glycol units, or from about 2 to about 4 ethylene glycol units.

[0326] In some embodiments, L is a heteroalkylene group having 4 to 30 atoms selected from carbon, oxygen, nitrogen, and sulfur. In some embodiments, L is a heteroalkylene group having 4 to 20 atoms selected from carbon, oxygen, nitrogen, and sulfur. In some embodiments, L is a heteroalkylene group having 4 to 10 atoms selected from carbon, oxygen, nitrogen, and sulfur. In some embodiments, L is a heteroalkylene group having 4 to 30 atoms selected from carbon, oxygen, and nitrogen. In some embodiments, L is a heteroalkylene group having 4 to 20 atoms selected from carbon, oxygen, and nitrogen. In some embodiments, L is a heteroalkylene group having 4 to 10 atoms selected from carbon, oxygen, and nitrogen. In some embodiments, L is a heteroalkylene group having 4 to 30 atoms selected from carbon and oxygen. In some embodiments, L is a heteroalkylene group having 4 to 20 atoms selected from carbon and oxygen. In some embodiments, L is a heteroalkylene group having 4 to 10 atoms selected from carbon and oxygen.

[0327] In additional embodiments, L is an optionally substituted (poly)ethylene glycol having 1 to about 100 ethylene glycol units, about 1 to about 50 ethylene glycol units, about 1 to about 25 ethylene glycol units, about 1 to about 10 ethylene glycol units, about 1 to about 8 ethylene glycol units, about 1 to about 6 ethylene glycol units, 2 to about 4 ethylene glycol units, or optionally substituted alkyl groups interspersed with optionally substituted O, N, S, P, or Si atoms. In some embodiments, L is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic group.

[0328] In some implementations, L is a divalent, saturated or unsaturated, straight or branched chain C. 1-45 A hydrocarbon chain in which 0-10 methylene units are independently substituted with: -O-, -S-, -N(R) )-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R S(O)2-、-S(O)2N(R) )-、-N(R )C(O)-、-C(O)N(R )-、-OC(O)N(R )-、-N(R )C(O)O-, optionally substituted carbocyclic group or optionally substituted heterocyclic group, wherein R Each time it appears, it independently represents hydrogen and C. 1-6 Alkyl or C 3-6 Cycloalkyl.

[0329] In some implementations, L is a divalent, saturated or unsaturated, straight or branched chain C. 1-45A hydrocarbon chain in which 0-10 methylene units are independently substituted with: -O-, -S-, -N(R) )-, -OC(O)-, -C(O)O, -S(O)-, -S(O)2-, -N(R S(O)2-、-S(O)2N(R) )-、-N(R )C(O)-、-C(O)N(R )-、-OC(O)N(R )-、-N(R C(O)O-, optionally substituted 3- to 10-membered carbocyclic groups, or optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein R Each time it appears, it independently represents hydrogen and C. 1-6 Alkyl or C 3-6 Cycloalkyl.

[0330] In some embodiments, L has the formula -N(R)- (optionally substituted 3-20-membered heteroalkylene groups). p -CH2-C(O)-, where R is hydrogen or optionally substituted C1-C6 alkyl, and p is 0 or 1.

[0331] In some embodiments, L has the formula -N(R)-(3-20-membered heteroalkylene). p -CH2-C(O)-; wherein the 3-20 heteroalkyl group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from halogens, C1-C6 haloalkyls, C3-C6 cycloalkyls, hydroxyl groups and cyano groups; R is hydrogen or optionally substituted C1-C6 alkyl; and p is 0 or 1.

[0332] In some embodiments, L has the formula -N(R)-(3-20-membered heteroalkylene). p -CH2-C(O)-; wherein the 3-20 heteroalkyl group is optionally substituted by 1, 2 or 3 substituents independently selected from halogens and C1-C6 haloalkyl groups; R is hydrogen or C1-C6 alkyl; and p is 0 or 1.

[0333] In some implementations, L is a divalent, saturated or unsaturated, straight or branched chain C. 1-60 A hydrocarbon chain in which 0-20 methylene units are independently substituted with the following: -O-, -S-, -N(H)-, -N(C)-. 1-6 Alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C 1-6 Alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C1-6 Alkyl)-, -N(H)C(O)-, -N(C 1-6 Alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 Alkyl)-, -OC(O)N(H)-, -OC(O)N(C 1-6 Alkyl)-, -N(H)C(O)O-, -N(C 1-6 Alkyl)C(O)O-, optionally substituted 3- to 10-membered carbon cycloalkanes, or optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0334] In some implementations, L is a divalent, saturated, straight-chain, or branched chain C. 3-30 A hydrocarbon chain in which 0-15 methylene units are independently substituted with: -O-, -N(H)-, -N(C)-, ... 1-6 Alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 Alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 Alkyl group, 3-10 membered carbon cycloyl group, or 3-10 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0335] In some implementations, L is a divalent, saturated, straight-chain, or branched chain C. 3-30 A hydrocarbon chain in which 0-15 methylene units are independently substituted with: -O-, -N(H)-, -N(C)-, ... 1-6 Alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 Alkyl)C(O)-, -C(O)N(H)- or -C(O)N(C 1-6 alkyl)-.

[0336] In some implementations, L is a divalent, saturated or unsaturated, straight or branched chain C. 5-40 A hydrocarbon chain in which 1-20 methylene units of the hydrocarbon are independently substituted with: -O-, -N(H)-, -N(C)-, ... 1-6 Alkyl)-, -N(H)C(O)-, -N(C 1-6 Alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 Alkyl group, optionally substituted 3- to 10-membered carbon cycloalkanes, or optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0337] In some embodiments, L is -(a 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen)-X 1 - , where X 1 C 0-4 Alkylene, C 2-4 alkyne or O, where To be with A 2 The connection point.

[0338] In some embodiments, L is -(an 8-10 membered spirocyclic or fused bicyclic saturated heterocycle containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocycle is separated by 0, 1, or 2 occurrences of C). 1-4 (alkyl or halogenated)-X 1 - , where X 1 C 0-4 Alkylene, C 2-4 alkyne or O, where To be with A 2 The connection point.

[0339] In some embodiments, L is -(a 10-13 membered spirocyclic saturated heterocycle containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen)-X 1 - , where X 1 C 0-4 Alkylene, C 2-4 alkyne or O, where To be with A 2 The connection point.

[0340] In some implementations, X 1 C 1-4 Alkylene. In some embodiments, X 1 C 2-4 Ethyne group. In some embodiments, X 1 For -C≡C-. In some implementations, X 1 It is O.

[0341] In some embodiments, L is -(an 8-10 membered spirocyclic or bicyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen and oxygen)-O- ,in To be with A 2 The connection point.

[0342] In some embodiments, L is a 7-11 membered spirocyclic or fused bicyclic saturated heterocyclic containing one, two or three heteroatoms selected from nitrogen and oxygen.

[0343] In some embodiments, L is -(an 8-10 member fused bicyclic saturated heterocycle containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocycle is separated by 0, 1, or 2 occurrences of C). 1-4 Alkyl substitution)-.

[0344] In some embodiments, L is -(a 9-13 membered tricyclic saturated heterocycle containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen)-(C 0-4 (alkylene)- ,in To be with A 2 The connection point.

[0345] In some embodiments, L is an 8-10 member fused aromatic or partially unsaturated ring containing one, two, or three heteroatoms selected from nitrogen and oxygen.

[0346] In some embodiments, L is a 7-8 membered spirocyclic ring or a fused bicyclic saturated heterocyclic ring containing two heteroatoms selected from nitrogen.

[0347] In some embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-X 3 -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-, where X 3 C 1-10 Alkylene, -O-, -N(H)-, -N(C)- 1-4 Alkyl group or bond.

[0348] In some embodiments, L is -(piperidine)-(C 1-5 alkylene)-(piperazinyl)- ,in To be with A 2 The connection point. In some embodiments, L is -(piperazinyl)-(azapyridine)- or (azapyrocyclobutane)-(piperazinyl)- ,in To be with A 2 The connection point.

[0349] In some embodiments, L is -(a 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-O- ,in This is the connection point with the phenylene in the formula.

[0350] In some embodiments, L is a 7-11 membered spirocyclic or fused bicyclic saturated heterocyclic containing one, two or three heteroatoms independently selected from nitrogen and oxygen.

[0351] In some embodiments, L is -(a 7-11 membered spirocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(C 2-4 (ethynyl)- ,in This is the connection point with the phenylene in the formula.

[0352] In some implementations, L is one of the following:

[0353]

[0354]

[0355] in To be with A 2 The connection point.

[0356] In some implementations, L is one of the following:

[0357]

[0358]

[0359] in To be with A 2 The connection point.

[0360] In some implementations, L is ,in To be with A 2 The connection point. In some implementations, L is... ,in To be with A 2 The connection point.

[0361] Additional exemplary implementations of L

[0362] In some embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(OCH2CH2). 1-15 -O- ,in To be with A 2 The connection point.

[0363] In some embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(OCH2CH2). 1-5 -O- ,in To be with A 2 The connection point.

[0364] In some embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(OCH2CH2). 6-10 -O- ,in To be with A 2 The connection point.

[0365] In some embodiments, L is -piperidinyl-(OCH2CH2) 1-15 -O- ,in To be with A 2 The connection point.

[0366] In some implementations, L is ,in To be with A 2 The connection point. In some implementations, L is... ,in To be with A 2 The connection point. In some implementations, L is... ,in To be with A 2 The connection point.

[0367] In some embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(OCH2CH2). 1-15 -N(H)C(O)-C 1-10 alkylene- -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -N(C 1-4 Alkyl)C(O)-C 1-10 alkylene- -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -C(O)N(H)-C 1-10 alkylene- Or -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -C(O)N(C 1-4 alkyl)-C 1-10 alkylene- ,in To be with A 2 The connection point.

[0368] In some embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(OCH2CH2). 1-10-N(H)C(O)-C 1-5 alkylene- -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(OCH2CH2) 1-10 -N(C 1-4 Alkyl)C(O)-C 1-5 alkylene- -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(OCH2CH2) 1-10 -C(O)N(H)-C 1-5 alkylene- Or -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(OCH2CH2) 1-10 -C(O)N(C 1-4 alkyl)-C 1-5 alkylene- ,in To be with A 2 The connection point.

[0369] In some embodiments, L is -piperidinyl-(OCH2CH2) 1-5 -N(H)C(O)-C 1-5 alkylene- -piperidinyl-(OCH2CH2) 1-5 -N(C 1-4 Alkyl)C(O)-C 1-5 alkylene- -piperidinyl-(OCH2CH2) 1-5 -C(O)N(H)-C 1-5 alkylene- or -piperidinyl-(OCH2CH2) 1-5 -C(O)N(C 1-4 alkyl)-C 1-5 alkylene- ,in To be with A 2 The connection point.

[0370] In some embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(OCH2CH2). 1-10 - -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(C 0-10 (alkylene)-O- or - (a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen) -C 1-10 Alkylene, wherein To be with A2 The connection point.

[0371] In some embodiments, L is -piperidinyl-(OCH2CH2) 1-5 - ,-piperidinyl-(C 0-5 (alkylene)-O- or -piperidinyl-(C 1-5 (alkylene)- ,in To be with A 2 The connection point.

[0372] In some embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-X 1 - ,in To be with A 2 The connection point of X, and X 1 For (i) C 1-10 Alkylene, wherein one or two methylene groups are optionally surrounded by -O-, -N(H)- or -N(C)-. 1-4 (ii) alkyl-substituted, containing one or two heteroatoms selected from nitrogen, or (iii) -(containing one or two heteroatoms selected from nitrogen, a 3-7 membered monocyclic saturated heterocycle)-(C 1-10 Alkylene)-.

[0373] In some embodiments, L is -(piperidine)-X 1 - ,in To be with A 2 The connection point of X, and X 1 For (i) C 1-5 Alkylene, wherein one or two methylene groups are optionally surrounded by -O-, -N(H)- or -N(C)-. 1-4 (ii) alkyl-substituted, or (iii) a 3- or 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen, or (iv) -(a 3- or 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen)-(C 1-5 Alkylene)-.

[0374] In some implementations, L is ,in To be with A 2 The connection point of X, and X 1 For (i) C 1-10 Alkylene, wherein one or two methylene groups are optionally surrounded by -O-, -N(H)- or -N(C)-. 1-4(ii) alkyl-substituted, containing one or two heteroatoms selected from nitrogen, or (iii) -(containing one or two heteroatoms selected from nitrogen, a 3-7 membered monocyclic saturated heterocycle)-(C 1-10 Alkylene)-.

[0375] In some embodiments, L is -(piperazinyl)-X 1 - ,in To be with A 2 The connection point of X, and X 1 For (i) C 1-5 Alkylene, wherein one or two methylene groups are optionally substituted with -O-, (ii) a 3- or 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen, or (iii) -(a 3- or 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen)-(C 1-5 Alkylene)-.

[0376] In some implementations, L is ,in To be with A 2 The connection point of X, and X 1 For (i) C 1-10 Alkylene, wherein one or two methylene groups are optionally substituted with -O-, (ii) a 3- to 7-membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen, or (iii) -(a 3- to 7-membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(C 1-10 Alkylene)-.

[0377] In some embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-X 2 -(C 1-10 (alkylene)- ,in To be with A 2 The connection point of X, and X 2 -O-, -N(H)-, or -N(C)- 1-6 Alkyl group). In some embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-X 2 -(C 1-10 (alkylene)- ,in To be with A 2 The connection point of X, and X 2 It is -O-.

[0378] In some embodiments, L is -(piperidine)-X 2 -(C 1-10 (alkylene)- ,in To be with A 2 The connection point of X, and X 2 -O-, -N(H)-, or -N(C)- 1-6 Alkyl group. In some embodiments, L is -(piperidine)-X. 2 -(C 1-10 (alkylene)- ,in To be with A 2 The connection point of X, and X 2 It is -O-.

[0379] In some embodiments, L is -(piperidine)-X 2 -(A 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)- ,in To be with A 2 The connection point of X, and X 2 -O-, -N(H)-, or -N(C)- 1-6 Alkyl group. In some embodiments, L is -(piperidine)-X. 2 -(A 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)- ,in To be with A 2 The connection point of X, and X 2 It is -O-.

[0380] In some implementations, L is ,in To be with A 2 The connection point of X, and X 2 -O-, -N(H)-, or -N(C)- 1-6 Alkyl group. In some embodiments, L is... ,in To be with A 2 The connection point of X, and X 2 It is -O-.

[0381] In some implementations, L is ,in To be with A 2 The connection point of X, and X 2 -O-, -N(H)-, or -N(C)- 1-6 Alkyl group. In some embodiments, L is... ,in To be with A 2 The connection point of X, and X 2 It is -O-.

[0382] In some embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-X 1 - ,in To be with A 2 The connection point of X, and X 1 -(OCH2CH2) 1-10 One of the CH2 groups is optionally surrounded by -C(H)(C 3-6 (Cycloalkyl)-substituted.

[0383] In some embodiments, L is a 7-11 membered spirocyclic or fused bicyclic saturated heterocyclic containing one, two, or three heteroatoms selected from nitrogen and oxygen. In some embodiments, L is a 7-8 membered spirocyclic or fused bicyclic saturated heterocyclic containing two heteroatoms selected from nitrogen.

[0384] In some embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-X 3 -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-, where X 3 C 1-10 Alkylene, -O-, -N(H)-, -N(C)- 1-4 Alkyl group or bond.

[0385] In some embodiments, L is -(piperidine)-(C 1-5 alkylene)-(piperazinyl)- ,in To be with A 2 The connection point.

[0386] In some embodiments, L is -(piperazinyl)-(azapyridine)- or (azapyrocyclobutane)-(piperazinyl)- ,in To be with A 2 The connection point.

[0387] In some embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-X 3 -(C 3-6 (cycloalkylene)-O- -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-X 3 -(C 3-6 cycloalkylene)-N(H)- Or - (a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen) -X 3 -(C 3-6 cycloalkylene)-N(C1-4 alkyl)- ,in To be with A 2 The connection point of X, and X 3 C 1-10 Alkylene, -O-, -N(H)-, -N(C)- 1-4 Alkyl group or bond.

[0388] In some embodiments, L is -(piperidine)-X 3 -(C 3-6 (cycloalkylene)-O- -(piperidine)-X 3 -(C 3-6 cycloalkylene)-N(H)- or -(piperidinyl)-X 3 -(C 3-6 (cycloalkylene)- ,in To be with A 2 The connection point of X, and X 3 C 1-10 Alkylene, -O-, -N(H)-, -N(C)- 1-4 Alkyl group or bond.

[0389] In some implementations, L has the formula -(C 0-12 alkylene)-(optionally substituted 3-40-membered heteroalkylene)-(C 0-12 Alkylene)-.

[0390] In some implementations, L is , , , , , , or ,in To be with A 2 The connection point.

[0391] In some implementations, L is , , , , , , , , , or ,in To be with A 2 The connection point.

[0392] In some implementations, L is or ,in To be with A 2 The connection point.

[0393] In some implementations, L is ,in To be with A 2 The connection point.

[0394] In some embodiments, L is -(an 8-12 membered spirocyclic heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 3-4 (cycloalkylene)- -(an 8-12 membered spirocyclic heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 (alkylene)- -(an 8-12 membered spirocyclic heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-C(O)-(C 1-4 (alkylene)- - (containing one or two independently selected heteroatoms of nitrogen and oxygen, comprising a 5-6 member saturated monocyclic heterocyclic group) - (containing one or two independently selected heteroatoms of nitrogen and oxygen, comprising a 3-5 member saturated monocyclic heterocyclic group) - - (containing one or two 5- or 6-membered saturated monocyclic heterocyclic groups independently selected from nitrogen and oxygen) -O- -(containing one or two 5- or 6-membered saturated monocyclic heterocyclic groups independently selected from nitrogen and oxygen)-(C 0-4 (alkylene)- -(5-6 membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms)-(C 0-4 (alkylene)-O- - (an 8-12 membered spirocyclic heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen) -C(O)- -(an 8-12 membered spirocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-O-(C 0-6 (alkylene)- -(an 8-12 membered spirocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-(C 1-6 alkylene)-O-(C 0-6 (alkylene)- -(5-6 membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms)-C(O)N(H)-(C 0-6 (alkylene)- 、-(N(C 1-6 alkyl)-(C 0-6 alkylene)-C(O)N(H)-(C0-6 (alkylene)- -(an 8-12 membered spirocyclic heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 2-4 (ethynyl)- -(containing one or two 5- or 6-membered saturated monocyclic heterocyclic groups independently selected from nitrogen and oxygen)-(C 1-6 Alkyl group - (containing one or two independent heteroatoms selected from nitrogen and oxygen, 3-5 membered saturated monocyclic heterocyclic groups) - -(a 5-6 membered saturated monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-C(O)N(H)-(C 0-6 alkylene)-N(H))- -(C(O)N(H)-(C 0-6 Alkylene group (5-6 membered saturated monocyclic heterocyclic group containing 1 or 2 heteroatoms) - - (containing one or two 5- or 6-membered saturated monocyclic heterocyclic groups independently selected from nitrogen and oxygen) -N(C 1-6 Alkyl group - (containing one or two 5- or 6-membered saturated monocyclic heterocyclic groups independently selected from nitrogen and oxygen) -O- -C(O)- (containing one or two 5- or 6-membered saturated monocyclic heterocyclic groups selected from nitrogen) -C(O)- -(C 0-6 alkylene group - (a 5-6 member saturated monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen) -C(O)- -(a 5-6 member saturated monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-C(O)-(C 0-6 Alkylene) -C(O)-(a 5-6 member saturated monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-(C 1-6 (alkylene)- -(C(O)N(H)-(C 1-6 alkylene)-C(O)N(H)-(C 0-6 (alkylene)- Or -(containing 1, 2, or 3 independently selected heteroatoms of nitrogen and oxygen, 8-11 membered fused bicyclic heterocyclic groups)-(C 1-4 (alkylene)- ,in To be with A 2 The connection point.

[0395] In some implementations, L is -N(C 1-6 alkyl)-(a 5-6 member saturated monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-C(O)-(C 0-6(alkylene)- - (containing one or two 5- or 6-membered saturated monocyclic heterocyclic groups selected from nitrogen) - (containing one or two 5- or 6-membered saturated monocyclic heterocyclic groups selected from nitrogen) - (C 0-4 (alkylene)-O- -(C 0-6 alkylene)-N(H)C(O)N(H)-(C 0-6 (alkylene)- -N(H)-(C 0-6 alkylene)-(a 5-6 member saturated monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-(C 0-6 (alkylene)- -(C 0-6 alkylene)-C(O)-(a 5-6 member saturated monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-(C 0-6 (alkylene)- -(C 0-6 alkylene group - (a 5-6 member saturated monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen) -C(O)N(C 1-6 alkyl)-(C 0-6 (alkylene)- -(C 0-6 alkylene)-(a 5-6 member saturated monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-(C 0-6 alkylene)-N(C 1-6 Alkyl group - (containing one or two heteroatoms selected from nitrogen, 3-6 membered saturated monocyclic heterocyclic groups) - -(a 4-6 membered monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-(C 0-6 alkylene)-O- (containing one or two 5- or 6-membered heteroaryl groups selected from nitrogen)-O- -(a 4-6 membered monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-(C 0-6 (alkylene)-(containing one or two 5-6-membered heteroaryl groups selected from nitrogen)-O- -(a 4-6 membered monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-(C 0-6 Alkylene group (containing one or two 5-6 heteroaryl groups selected from nitrogen) - -(an 8-12 membered spirocyclic heterocyclic group substituted with 1 or 2 fluorine atoms and containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 1-4 (alkylene)- -(a 5-6 membered saturated monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-(C 0-4 alkylene)-(C3-6 (Cycloalkylene)-(C 0-4 (alkylene)-O- -(a 5-6 membered saturated monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-(C 0-4 alkylene)-(C 3-6 (Cycloalkylene)-(C 0-4 (alkylene)- -(C 0-4 Alkylene group (containing 1, 2, or 3 independently selected heteroatoms of nitrogen and oxygen, 8-12 membered spirocyclic heterocyclic groups) -(C 0-4 alkylene)-(C 3-6 (Cycloalkylene)-(C 2-4 (ethynyl)- -(C 0-4 alkylene)-(an 8-10 member fused bicyclic heterocyclic group substituted with 1 or 2 fluorine atoms and containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 (alkylene)- - (an 8-12 membered spirocyclic heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen) -O- -(an 8-12 membered spirocyclic heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 Alkylene group (containing one or two 5- or 6-membered saturated monocyclic heterocyclic groups selected from nitrogen) - -(C 0-4 alkylene)-(a 4-6 membered saturated heterocyclic group containing one or two heteroatoms selected from nitrogen)-(phenylene substituted with trifluoromethyl)-(C 0-4 alkylene)-N(H)- Or, it could be -(a 5-6 member saturated monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-C(O)-(a 5-6 member saturated monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-(C 0-6 (alkylene)- -(C 3-6 cycloalkylene)-C(O)N(C 1-6 Alkyl)(C 0-6 (alkylene)- - (a 5-6 membered saturated monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen) - (a phenylene group substituted with a methyl or halide group appearing 0 or 1 times) - (C 0-6 (alkylene)- -(a 5-6 membered saturated monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen)-(C 0-6 alkylene)-(a 5-6 member saturated monocyclic heterocyclic group containing one or two heteroatoms selected from nitrogen, substituted with oxygen)-(C0-6 (alkylene)- - (an 8-12 membered spirocyclic ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen is capped by C 1-4 alkyl-substituted heterocyclic group)-(C 0-6 Alkylene)-(O) 0-1 -(C 2-4 (-(acetylenyl)-(an 8-12 membered spirocyclic heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 (alkylene)- -(C 0-4 alkylene)-(C 3-7 (Cycloalkylene)-(C 2-4 (ethynyl)- -(C 1-4 Alkylene)-(containing 1, 2 or 3 independently selected heteroatoms of nitrogen and oxygen, 8-12 membered spirocyclic heterocyclic groups)-(C 0-4 (alkylene)- -(C 1-4 Alkylene)-(containing 1, 2 or 3 independently selected heteroatoms of nitrogen and oxygen, 5-7 membered saturated heterocyclic groups)-(C 0-4 (alkylene)- -(C 0-4 alkylene)-(containing one or two 5-7 membered saturated heterocyclic groups independently selected from nitrogen and oxygen)-(C 2-4 (alkenyl)- or -(C 0-4 alkylene)-(a 6-8 membered saturated heterocyclic group substituted with 1 or 2 fluorine atoms and containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 (alkylene)- ,in To be with A 2 The connection point.

[0396] In some implementations, L is -N(H)-(C 2-9 alkylene)-O-(C 1-6 alkylene)-C(O)- -N(H)-(C 10-20 alkylene)-O-(C 1-6 alkylene)-C(O)- -N(H)-[(C 2-4 [alkylene]-O-] 2-6 -(C 1-6 alkylene)-C(O)- -N(H)-[(C 2-4 [alkylene]-O-] 7-15 -(C1-6 alkylene)-C(O)- -N(H)-(C 1-6 alkylene)-C(O)- -N(H)-(C 7-15 alkylene)-C(O)- -N(H)-[(C 2-4 [alkylene]-O-] 2-6 -(C 1-6 (alkylene)- -N(H)-[(C 2-4 [alkylene]-O-] 7-15 -(C 1-6 (alkylene)- -N(H)-(C 2-9 alkylene)-O-(C 1-6 alkylene)-C(O)N(C 1-6 alkyl)-(C 1-6 (alkylene)- -N(H)-(C 2-9 alkylene)-O-(C 1-6 alkylene)-C(O)N(H)-(C 1-6 (alkylene)- -N(H)-[(C 2-4 [alkylene]-O-] 2-6 -(C 1-6 alkylene)-N(H)-(C 1-6 (alkylene)- -N(H)-[(C 2-4 [alkylene]-O-] 7-15 -(C 1-6 alkylene)-N(H)-(C 1-6 (alkylene)- -N(H)-[(C 2-4 [alkylene]-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 (alkylene)- or -N(H)-[(C 2-4 [alkylene]-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 (alkylene)- ,in To be with A 2 The connection point.

[0397] In some implementations, L is -N(H)-(C2-9 alkylene)-O-(C 1-6 alkylene)-C(O)- -N(H)-(C 10-20 alkylene)-O-(C 1-6 alkylene)-C(O)- -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-C(O)- -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-C(O)- -N(H)-(C 1-6 alkylene)-C(O)- -N(H)-(C 7-15 alkylene)-C(O)- -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 (alkylene)- -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 (alkylene)- -N(H)-(C 2-9 alkylene)-O-(C 1-6 alkylene)-C(O)N(C 1-6 alkyl)-(C 1-6 (alkylene)- -N(H)-(C 2-9 alkylene)-O-(C 1-6 alkylene)-C(O)N(H)-(C 1-6 (alkylene)- -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(H)-(C 1-6 (alkylene)- -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(H)-(C 1-6 (alkylene)- -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 (alkylene)- Or -N(H)-[CH2CH2-O-] 7-15 -(C1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 (alkylene)- ,in To be with A 2 The connection point.

[0398] In some implementations, L is -N(H)-[(C 2-4 [alkylene]-O-] 2-6 -(C 1-6 alkylene)-C(O)- -N(H)-[(C 2-4 [alkylene]-O-] 7-15 -(C 1-6 alkylene)-C(O)- -N(H)-(C 1-6 alkylene)-N(C 1-6 alkyl)C(O)-(C 1-6 Alkylene) -N(H)-(C 1-6 alkylene)-N(H)C(O)-(C 1-6 Alkylene) -N(H)-(C 2-6 (alkylene)- -N(H)-(C 7-15 (alkylene)- -N(C 1-6 alkyl)-(C 2-6 (alkylene)- -N(C 1-6 alkyl)-(C 7-15 (alkylene)- -N(H)-[(C 2-4 [alkylene]-O-] 2-6 -(C 1-6 (alkylene)- -N(H)-[(C 2-4 [alkylene]-O-] 7-15 -(C 1-6 (alkylene)- -N(H)-(C 1-6 (alkylene)-(3-6 membered heterocyclic alkylene)-(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 (alkylene)- -N(H)-(C 1-6 (alkylene)-(3-6 membered heterocyclic alkylene)-(C 1-6 alkylene)-N(H)-(C 1-6 (alkylene)- -N(H)-(C 2-6 alkylene)-N(H)-(C 1-6 (alkylene)- or -N(H)-(C 2-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 (alkylene)- ,in To be with A 2 The connection point.

[0399] In some implementations, L is -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-C(O)- -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-C(O)- -N(H)-(C 1-6 alkylene)-N(C 1-6 alkyl)C(O)-(C 1-6 Alkylene) -N(H)-(C 1-6 alkylene)-N(H)C(O)-(C 1-6 Alkylene) -N(H)-(C 2-6 (alkylene)- -N(H)-(C 7-15 (alkylene)- -N(C 1-6 alkyl)-(C 2-6 (alkylene)- -N(C 1-6 alkyl)-(C 7-15 (alkylene)- -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 (alkylene)- -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 (alkylene)- -N(H)-(C 1-6 (alkylene)-(3-6 heteroalkylene)-(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 (alkylene)- -N(H)-(C 1-6 (alkylene)-(3-6 heteroalkylene)-(C1-6 alkylene)-N(H)-(C 1-6 (alkylene)- -N(H)-(C 2-6 alkylene)-N(H)-(C 1-6 (alkylene)- or -N(H)-(C 2-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 (alkylene)- ,in To be with A 2 The connection point.

[0400] In some implementations, L is -[(C 2-4 [alkylene]-O-] 2-6 -(C 1-6 (alkylene)- 、-[(C 2-4 [alkylene]-O-] 7-15 -(C 1-6 (alkylene)- 、-[(C 2-4 [alkylene]-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 (alkylene)- 、-[(C 2-4 [alkylene]-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 (alkylene)- 、-[(C 2-4 [alkylene]-O-] 2-6 -(C 1-6 alkylene)-N(H)(C 1-6 (alkylene)- 、-[(C 2-4 [alkylene]-O-] 7-15 -(C 1-6 alkylene)-N(H)(C 1-6 (alkylene)- -(C 1-9 alkylene)-C(O)N(H)-(C 1-6 (alkylene)- -(C 1-9 alkylene)-N(H)C(O)-(C 1-6 (alkylene)- -(C 1-9 alkylene)-C(O)N(H)-[(C2-4 [alkylene]-O-] 2-6 -(C 1-6 (alkylene)- -(C 1-9 alkylene)-N(H)C(O)-[(C 2-4 [alkylene]-O-] 2-6 -(C 1-6 (alkylene)- -(C 1-9 alkylene)-C(O)N(H)-[(C 2-4 [alkylene]-O-] 7-15 -(C 1-6 (alkylene)- -(C 1-9 alkylene)-N(H)C(O)-[(C 2-4 [alkylene]-O-] 7-15 -(C 1-6 (alkylene)- -(C 1-9 alkylene)-C(O)N(H)-[(C 2-4 [alkylene]-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 (alkylene)- -(C 1-9 alkylene)-N(H)C(O)-[(C 2-4 [alkylene]-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 (alkylene)- -(C 1-9 alkylene)-C(O)N(H)-[(C 2-4 [alkylene]-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 (alkylene)- or -(C 1-9 alkylene)-N(H)C(O)-[(C 2-4 [alkylene]-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 (alkylene)- ,in To be with A 2 The connection point.

[0401] In some implementations, L is -[CH2CH2-O-] 2-6 -(C 1-6 (alkylene)- -[CH2CH2-O-] 7-15 -(C 1-6 (alkylene)- -[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 (alkylene)- -[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 (alkylene)- -[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(H)(C 1-6 (alkylene)- -[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(H)(C 1-6 (alkylene)- -(C 1-9 alkylene)-C(O)N(H)-(C 1-6 (alkylene)- -(C 1-9 alkylene)-N(H)C(O)-(C 1-6 (alkylene)- -(C 1-9 Alkylene)-C(O)N(H)-[CH2CH2-O-] 2-6 -(C 1-6 (alkylene)- -(C 1-9 Alkylene)-N(H)C(O)-[CH2CH2-O-] 2-6 -(C 1-6 (alkylene)- -(C 1-9 Alkylene)-C(O)N(H)-[CH2CH2-O-] 7-15 -(C 1-6 (alkylene)- -(C 1-9 Alkylene)-N(H)C(O)-[CH2CH2-O-] 7-15 -(C 1-6 (alkylene)- -(C 1-9Alkylene)-C(O)N(H)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 (alkylene)- -(C 1-9 Alkylene)-N(H)C(O)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 (alkylene)- -(C 1-9 Alkylene)-C(O)N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 (alkylene)- or -(C 1-9 Alkylene)-N(H)C(O)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 (alkylene)- ,in To be with A 2 The connection point.

[0402] In some implementations, L is -N(H)-[(C 2-4 [alkylene]-O-] 2-6 -(C 1-6 alkylene)-N(H)- -N(H)-[(C 2-4 [alkylene]-O-] 7-15 -(C 1-6 alkylene)-N(H)- -N(C 1-6 alkyl)-[(C 2-4 [alkylene]-O-] 2-6 -(C 1-6 alkylene)-N(H)- -N(C 1-6 alkyl)-[(C 2-4 [alkylene]-O-] 7-15 -(C 1-6 alkylene)-N(H)- -N(C 1-6 alkyl)-[(C 2-4 [alkylene]-O-] 2-6 -(C1-6 alkylene)-N(C 1-6 alkyl)- or -N(C 1-6 alkyl)-[(C 2-4 [alkylene]-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)- ,in To be with A 2 The connection point.

[0403] In some implementations, L is -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(H)- -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(H)- -N(C 1-6 Alkyl group - [CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(H)- -N(C 1-6 Alkyl group - [CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(H)- -N(C 1-6 Alkyl group - [CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)- or -N(C 1-6 Alkyl group - [CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)- ,in To be with A 2 The connection point.

[0404] In some implementations, L is one of the following:

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416] The dummy key indicates the connection point.

[0417] In some implementations, L is -C(H)(R 100 )-、-C(R 100 )2-、O、-N(R 101 -, -S(O)2-, and optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 The cycloene group or optionally substituted 3- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 Cycloalkyl, and R 101 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 100 Each occurrence independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 101 It can be hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0418] In some implementations, L is -CH2-Y 20 -、-C(H)(R 100 )-Y 20 -、-C(R 100 )2-Y 20 -、-OY 20 -、-N(R 101 )-Y 20 -、-S(O)2-Y 20 -、-C(O)-Y 20 -、-(C can be arbitrarily replaced) 3-7 (cycloalkylene)-Y 20-、-(C can be arbitrarily replaced) 4-7 (cyclohexene)-Y 20 -, - (optionally substituted 3-7 membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur) -Y 20 -、-Y 20 -CH2-、-Y 20 -C(H)(R 100 )-、-Y 20 -C(R 100 )2-、-Y 20 -O-、-Y 20 -N(R 101 )-、-Y 20 -S(O)2-、-Y 20 -C(O)-、-Y 20 -(C, which can be arbitrarily replaced) 3-7 (cycloalkylene)-, -Y 20 -(C, which can be arbitrarily replaced) 4-7 (cycloene group)- or -Y 20 -(optionally substituted 3-7 membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur)-; wherein R 100 Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 Cycloalkyl, and R 101 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 100 Each occurrence independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 101 It can be hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0419] In some implementations, L is one of the following:

[0420]

[0421]

[0422]

[0423]

[0424] Where X 20 Y 20 and Z 20 Independently -CH2-, -C(H)(R 100 )-、-C(R 100 )2-、O、-N(R101 -, -S(O)2-, -C(O)-, and optionally substituted C 3-7 Cycloalkyl or optionally substituted C 4-7 cyclohexene group; wherein R 100 Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 Cycloalkyl, and R 101 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 100 Each occurrence independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 101 It can be hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0425] In some implementations, L is one of the following:

[0426]

[0427] Where X 20 Y 20 and Z 20 Independently for -C(R) 100 )- or -N-; where R 100 Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 100 Each time it appears, it independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0428] In some implementations, L is -X 20 -Y 20 -Z 20 -, where X 20 Y 20 and Z 20 Independently -CH2-, -C(H)(R 100 )-、-C(R 100 )2-、O、-N(R 101 -, -S(O)2-, -C(O)-, and optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 The cycloene group or optionally substituted 3- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 Cycloalkyl, and R101 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 100 Each occurrence independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 101 It can be hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0429] In some implementations, L is -X 20 =Y 20 -Z 21 -, where X 20 and Y 20 Independently for -C(R) 100 )- or -N-, and Z 21 -CH2-, -C(H)(R 100 )-、-C(R 100 )2-、O、-N(R 101 -, -S(O)2-, -C(O)-, and optionally substituted C 3-7 Cycloalkyl or optionally substituted C 4-7 cyclohexene group; wherein R 100 Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 Cycloalkyl, and R 101 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 100 Each occurrence independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 101 It can be hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0430] In some implementations, L is -C≡CZ 20 -, where Z 20 -CH2-, -C(H)(R 100 )-、-C(R 100 )2-、O、-N(R 101 -, -S(O)2-, -C(O)-, and optionally substituted C 3-7 Cycloalkyl or optionally substituted C 4-7 cyclohexene group; wherein R 100 Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 Cycloalkyl, and R 101 For hydrogen, C 1-6 Alkyl or C3-6 Cycloalkyl. In some embodiments, R 100 Each occurrence independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 101 It can be hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0431] In some implementations, L is one of the following:

[0432]

[0433]

[0434]

[0435]

[0436] Where X 20 Y 20 and Z 20 Independently -CH2-, -C(H)(R 100 )-、-C(R 100 )2-、O、-N(R 101 -, -S(O)2-, -C(O)-, and optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 The cycloene group or optionally substituted 3- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 Cycloalkyl, and R 101 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 100 Each occurrence independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 101 It can be hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0437] In some implementations, L is one of the following:

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448] Where V 20 W 20 X 20 Y 20 and Z 20 Independently -CH2-, -C(H)(R 100 )-、-C(R 100 )2-、O、-N(R 101 -, -S(O)2-, -C(O)-, and optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 The cycloene group or optionally substituted 3- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 Cycloalkyl, and R 101 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 100 Each occurrence independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 101 It can be hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0449] In some implementations, L is one of the following:

[0450]

[0451]

[0452] Among them W 20 X 20 Y 20 and Z 20 Independently for -C(R) 100 )- or -N-; where R 100Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 100 Each time it appears, it independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0453] In some implementations, L is one of the following:

[0454]

[0455] Among them W 20 X 20 Y 20 and Z 20 Independently for -C(R) 100 )- or -N-; where R 100 Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 100 Each time it appears, it independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0456] In some implementations, L is one of the following:

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468] Where U, V, W, X, Y, and Z are independently -CH2-, -C(H)(R 100 )-、-C(R 100 )2-、O、-N(R101 -, -S(O)2-, -C(O)-, and optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 The cycloene group or optionally substituted 3- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 cycloalkyl; R 101 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; and dummy bonds indicate connection points. In some embodiments, R 100 Each occurrence independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 101 It can be hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0469] In some implementations, L is one of the following:

[0470]

[0471]

[0472] Where X, Y, and Z are independently -C(R) 100 - or -N-; V and W are independently -CH2-, -C(H)(R 100 )-、-C(R 100 )2-、O、-N(R 101 -, -S(O)2-, -C(O)-, and optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 The cycloene group or optionally substituted 3- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 cycloalkyl; R 101 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; and dummy bonds indicate connection points. In some embodiments, R 100 Each occurrence independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 101 It can be hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0473] In some implementations, L is one of the following:

[0474]

[0475]

[0476] Where W, X, Y, and Z are independently -C(R) 100 - or -N-; V is -CH2-, -C(H)(R 100 )-、-C(R 100 )2-、O、-N(R 101 -, -S(O)2-, -C(O)-, and optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 The cycloene group or optionally substituted 3- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 cycloalkyl; R 101 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; and dummy bonds indicate connection points. In some embodiments, R 100 Each occurrence independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 101 It can be hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0477] In some implementations, L is one of the following:

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491] Where T, U, V, W, X, Y, and Z are independently -CH2-, -C(H)(R 100 )-、-C(R 100 )2-、O、-N(R 101 -, -S(O)2-, -C(O)-, and optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 The cycloene group or optionally substituted 3- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 cycloalkyl; R 101 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; and dummy bonds indicate connection points. In some embodiments, R 100 Each occurrence independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 101 It can be hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0492] In some implementations, L is one of the following:

[0493]

[0494]

[0495] Where W, X, Y, and Z are independently -C(R) 100 - or -N-; U and V are independently -CH2-, -C(H)(R 100 )-、-C(R 100 )2-、O、-N(R 101 -, -S(O)2-, -C(O)-, and optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 A cycloene group or optionally substituted 3- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; R 100 Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 cycloalkyl; R 101For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; and dummy bonds indicate connection points. In some embodiments, R 100 Each occurrence independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 101 It can be hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0496] In some implementations, L is one of the following:

[0497]

[0498]

[0499] Where X, Y, and Z are independently -C(R) 100 - or -N-; U, V, and W are independently -CH2-, -C(H)(R 100 )-、-C(R 100 )2-、O、-N(R 101 -, -S(O)2-, -C(O)-, and optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 The cycloene group or optionally substituted 3- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 Each time it appears, it independently represents hydrogen, halogen, and carbon. 1-6 Alkyl or C 3-6 cycloalkyl; R 101 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; and dummy bonds indicate connection points. In some embodiments, R 100 Each occurrence independently represents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 101 It can be hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0500] In some implementations, L is one of the following:

[0501]

[0502]

[0503] The variables m, n, o, p, and q are independent and can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0504] In some implementations, L is one of the following:

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512] Where any m or n is independently 0, 1, 2, 3, 4, 5 or 6; and any X is H or F.

[0513] In some implementations, L is one of the following:

[0514]

[0515]

[0516]

[0517]

[0518] Each of m or n is independently 0, 1, 2, 3, 4, 5, or 6.

[0519] In some implementations, L is one of the following:

[0520]

[0521]

[0522] Each of m or n is independently 0, 1, 2, 3, 4, 5, or 6.

[0523] In some implementations, L is one of the following:

[0524]

[0525]

[0526]

[0527]

[0528]

[0529] In some implementations, L is one of the following:

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536] In some implementations, L has the formula -(C 0-12 alkylene)-(optionally substituted 3-40-membered heteroalkylene)-(C 0-12 Alkylene). In some embodiments, L is C 4-14 Alkylene. In some embodiments, L is -(CH2). 6-10 -

[0537] In some implementations, L is -CH2CH2(OCH2CH2)- -CH2CH2(OCH2CH2)2- -CH2CH2(OCH2CH2)3- -CH2CH2(OCH2CH2)4- -CH2CH2(OCH2CH2)5- -CH2CH2(OCH2CH2)6- -CH2CH2(OCH2CH2)7- -CH2CH2(OCH2CH2)8- -CH2CH2(OCH2CH2)9- -CH2CH2(OCH2CH2) 10 - -CH2CH2(OCH2CH2) 11 - -CH2CH2(OCH2CH2) 12 - -CH2CH2(OCH2CH2) 13 - -CH2CH2(OCH2CH2) 14 - -CH2CH2(OCH2CH2) 15 - Or -CH2CH2(OCH2CH2) 16-20 - ,in To be with A 2 The connection point.

[0538] In some implementations, L is -(C 2-20 (alkylene)-(OCH2CH2) 2-4 -(C 0-4 (alkylene)- -(C 2-20 (alkylene)-(OCH2CH2) 5-7 -(C 0-4 (alkylene)- -(C 2-20 (alkylene)-(OCH2CH2) 8-10 -(C 0-4 (alkylene)- -(C 2-20 (alkylene)-(OCH2CH2) 11-13 -(C 0-4 (alkylene)- -(C 2-20 (alkylene)-(OCH2CH2) 14-16 -(C 0-4 (alkylene)- -(C 2-20 (alkylene)-(OCH2CH2) 17-20 -(C 0-4 (alkylene)- -(C 1-20 (alkylene)-(OCH2CH2) 1-10 -(C 0-4 alkylene)-C(O)- or -(C 1-20 (alkylene)-(OCH2CH2) 11-20 -(C 0-4 alkylene)-C(O)- ,in To be with A 2 The connection point.

[0539] In some implementations, L is -O(CH2CH2O). 2-4 -(C 0-4 (alkylene)- -O(CH2CH2O) 5-7 -(C0-4 (alkylene)- -O(CH2CH2O) 8-10 -(C 0-4 (alkylene)- -O(CH2CH2O) 11-13 -(C 0-4 (alkylene)- -O(CH2CH2O) 14-16 -(C 0-4 (alkylene)- -O(CH2CH2O) 16-20 -(C 0-4 (alkylene)- -O(CH2CH2O) 2-10 -(C 0-4 Alkylene C(O)- Or -O(CH2CH2O) 11-20 -(C 0-4 Alkylene C(O)- ,in To be with A 2 The connection point.

[0540] In some implementations, L is -(C 0-20 (alkylene)-(OCH2CH2) 1-10 -(N(C 1-4 alkyl))- -(C 0-20 (alkylene)-(OCH2CH2) 11-20 -(N(C 1-4 alkyl))- -(C 0-20 (alkylene)-(CH2CH2O) 1-10 -(C 2-10 alkylene)-(N(C) 1-4 alkyl))-(C 0-10 (alkylene)- or -(C 0-20 (alkylene)-(CH2CH2O) 11-20 -(C 2-10 alkylene)-(N(C) 1-4 alkyl))-(C 0-10 (alkylene)- ,in To be with A 2 The connection point.

[0541] In some embodiments, L is selected from those compounds described in Table 1 below.

[0542] Exemplary specific compounds

[0543] In some embodiments, the compound is a compound from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound from Table 1 or Table 2. In some embodiments, the compound is a compound from Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound from Table 1. In some embodiments, the compound is any one of compounds I-1 to I-124 from Table 1 or any one of compounds II-1 to II-12 from Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is any one of compounds I-1 to I-124 from Table 1 or any one of compounds II-1 to II-12 from Table 2. In some embodiments, the compound is any one of compounds I-1 to I-124 from Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is any one of compounds I-1 to I-124 from Table 1. In some embodiments, the compound is any one of compounds II-1 to II-12 from Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is any one of compounds II-1 to II-12 in Table 2. In some embodiments, the compound is any one of compounds I-1 to I-137 in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is any one of compounds I-1 to I-137 in Table 1. In some embodiments, the compound is a compound in Table 3, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound in Table 3.

[0544] Table 1.

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566] Table 2.

[0567]

[0568]

[0569]

[0570] Table 3.

[0571]

[0572] Synthesis method

[0573] The following synthetic procedures illustrate methods for preparing the compounds described herein. These procedures are provided for illustrative purposes and are not intended to limit the scope or spirit of the invention. The starting materials shown in the procedures may be obtained from commercial sources or may be prepared based on procedures described in the literature.

[0574] In the process, those skilled in organic synthesis will understand that the functional groups present on various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be obvious to those skilled in the art and thus indicate alternative methods (e.g., the use of protecting groups or alternative reactions). Protecting group chemistry and strategies are well known, such as those described in "Protecting Groups in Organic Synthesis," TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, the entire contents of which are hereby incorporated by reference.

[0575] The synthetic route described in Procedure 1 is a general method for preparing compound F. The reaction of chloride A with compound B (where X is a borate ester) under palladium coupling conditions yields compound C. Removal of the protecting group (Pg) from compound C yields compound D. Pg can be, for example, a Boc protecting group, which can be removed by treatment of the compound with trifluoroacetic acid. Coupling of compound D with compound E (such as a nucleophilic aromatic substitution reaction when the leaving group in compound E is chlorine) yields the final compound F.

[0576]

[0577] The modular synthetic route described in Procedure 1 can be easily modified to provide additional compounds by performing functional group conversions on intermediate and / or final compounds. Such functional group conversions are well known in this art, for example, as... Comprehensive Organic Synthesis (B.M. Trost and I. Fleming, eds., 1991-1992); Organic Synthesis , 3rd edition (Michael B. Smith, Wavefunction, Inc., Irvine: 2010); Modern Methods of Organic Synthesis , 4th edition (William Carruthers and Iain Coldham, Cambridge University Press, Cambridge: 2004); March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure , 8th edition, (Michael B. Smith, John Wiley & Sons, New York: 2020); and Comprehensive Organic Transformations: A Guide to Functional Group PreparationsAs described in the 3rd edition (edited by Richard C. Larock, John Wiley & Sons, New York: 2018). Protecting group strategies can be employed where appropriate to accommodate different functional groups in the molecules used in the synthetic pathway. Protecting group chemistry and strategies are described, for example, in... Protecting Groups in Organic Synthesis, 3rd edition TW Greene and PGM Wuts, John Wiley & Sons, 1999 and Greene's Protective Groups in Organic Synthesis, 5th Edition , (Peter GM Wuts, John Wiley & Sons: 2014).

[0578] Part D: Crystalline form of compound II-5

[0579] Another aspect of the present invention provides a crystalline compound of formula II-5:

[0580]

[0581] The crystalline form of a compound of formula II-5 can provide properties that make the compound more suitable for manufacture. For example, crystalline form A of a compound of formula II-5 has been identified as having particularly good properties. One advantage of crystalline form A is that it exhibits superior stability compared to crystalline form B.

[0582] Crystal form A

[0583] One aspect of the present invention provides a crystalline compound of formula II-5 having a crystalline form A. Crystalline form A can be characterized by X-ray powder diffraction, differential scanning calorimetry, and / or purity.

[0584] In some embodiments, the compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 13.1 ± 0.2, 17.6 ± 0.2, 18.3 ± 0.2, 18.7 ± 0.2, 19.5 ± 0.2, 23.8 ± 0.2, and 25.6 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 8.1 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 9.9 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 10.5 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 15.8 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 19.8 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 25.3 ± 0.2.

[0585] In some embodiments, the compound exhibits an X-ray powder diffraction pattern containing at least one peak from the following diffraction angles (2θ): 13.1 ± 0.2, 17.6 ± 0.2, 18.3 ± 0.2, 18.7 ± 0.2, 19.5 ± 0.2, 23.8 ± 0.2, and 25.6 ± 0.2. In some embodiments, the compound exhibits an X-ray powder diffraction pattern containing at least two, three, or four peaks from the following diffraction angles (2θ): 13.1 ± 0.2, 17.6 ± 0.2, 18.3 ± 0.2, 18.7 ± 0.2, 19.5 ± 0.2, 23.8 ± 0.2, and 25.6 ± 0.2. In some embodiments, the compound exhibits an X-ray powder diffraction pattern containing at least five peaks from the following diffraction angles (2θ): 13.1 ± 0.2, 17.6 ± 0.2, 18.3 ± 0.2, 18.7 ± 0.2, 19.5 ± 0.2, 23.8 ± 0.2, and 25.6 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 8.1 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 9.9 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 10.5 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 15.8 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 19.8 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 25.3 ± 0.2.

[0586] In some embodiments, the relative intensity of the peaks at these diffraction angles (2θ) is at least 20%. In some embodiments, the relative intensity of the peaks at these diffraction angles (2θ) is at least 30%.

[0587] In some embodiments, the compound is characterized by the following X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, interplanar distance d, and relative intensity (expressed as a percentage relative to the strongest peak):

[0588] .

[0589] In some embodiments, the compound has substantially the following properties: Figure 14 The X-ray powder diffraction pattern shown is shown.

[0590] In some embodiments, as determined by differential scanning calorimetry, the compound has an initial melting point in the range of about 180°C to about 200°C. In some embodiments, as determined by differential scanning calorimetry, the compound has an initial melting point of about 192°C. In some embodiments, as determined by differential scanning calorimetry, the compound has an initial melting point of 192°C. In some embodiments, the compound has a melting point substantially similar to... Figure 15 The same differential scanning calorimetry curves are shown in the figure.

[0591] In some embodiments, the compound has a purity greater than 98% by weight. In some embodiments, the compound has a purity greater than 99% by weight. In some embodiments, the compound has a purity greater than 99.5% by weight. In some embodiments, the purity of the compound is determined by high-performance liquid chromatography (HPLC).

[0592] Crystal form B

[0593] Another aspect of the present invention provides a crystalline compound of formula II-5 having a crystalline form B. Crystalline form B can be characterized by X-ray powder diffraction, differential scanning calorimetry, and / or purity.

[0594] In some embodiments, the compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 9.4 ± 0.2, 12.8 ± 0.2, 15.4 ± 0.2, 18.2 ± 0.2, 18.7 ± 0.2, 20.2 ± 0.2, and 24.6 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes peaks at one or more of the following diffraction angles (2θ): 8.5 ± 0.2, 11.7 ± 0.2, 12.5 ± 0.2, 17.6 ± 0.2, 19.6 ± 0.2, 21.9 ± 0.2, and 23.5 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 8.5 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 11.7 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 12.5 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 17.6 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 19.6 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 21.9 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 23.5 ± 0.2.

[0595] In some embodiments, the compound exhibits an X-ray powder diffraction pattern containing at least one peak from the following diffraction angles (2θ): 9.4 ± 0.2, 12.8 ± 0.2, 15.4 ± 0.2, 18.2 ± 0.2, 18.7 ± 0.2, 20.2 ± 0.2, and 24.6 ± 0.2. In some embodiments, the compound exhibits an X-ray powder diffraction pattern containing at least two, three, or four peaks from the following diffraction angles (2θ): 9.4 ± 0.2, 12.8 ± 0.2, 15.4 ± 0.2, 18.2 ± 0.2, 18.7 ± 0.2, 20.2 ± 0.2, and 24.6 ± 0.2. In some embodiments, the compound exhibits an X-ray powder diffraction pattern comprising at least five peaks from the following diffraction angles (2θ): 9.4 ± 0.2, 12.8 ± 0.2, 15.4 ± 0.2, 18.2 ± 0.2, 18.7 ± 0.2, 20.2 ± 0.2, and 24.6 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further comprises peaks at one or more of the following diffraction angles (2θ): 8.5 ± 0.2, 11.7 ± 0.2, 12.5 ± 0.2, 17.6 ± 0.2, 19.6 ± 0.2, 21.9 ± 0.2, and 23.5 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2θ): 8.5 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 11.7 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 12.5 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 17.6 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 19.6 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 21.9 ± 0.2. In some embodiments, the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 23.5 ± 0.2.

[0596] In some embodiments, the relative intensity of the peaks at these diffraction angles (2θ) is at least 20%. In some embodiments, the relative intensity of the peaks at these diffraction angles (2θ) is at least 30%.

[0597] In some embodiments, the compound is characterized by the following X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, interplanar distance d, and relative intensity (expressed as a percentage relative to the strongest peak):

[0598] .

[0599] In some embodiments, the compound has substantially the following properties: Figure 17 The X-ray powder diffraction pattern shown is shown.

[0600] In some embodiments, as determined by differential scanning calorimetry, the compound has an initial melting point in the range of about 180°C to about 200°C. In some embodiments, as determined by differential scanning calorimetry, the compound has an initial melting point of about 192°C. In some embodiments, as determined by differential scanning calorimetry, the compound has an initial melting point of 192°C. In some embodiments, the compound has a melting point substantially similar to... Figure 18 The same differential scanning calorimetry curves are shown in the figure.

[0601] In some embodiments, the compound has a purity greater than 98% by weight. In some embodiments, the compound has a purity greater than 99% by weight. In some embodiments, the compound has a purity greater than 99.5% by weight. In some embodiments, the purity of the compound is determined by high-performance liquid chromatography (HPLC).

[0602] The foregoing description describes several embodiments relating to the crystalline form of the compound of formula II-5. This patent application specifically covers all combinations of embodiments.

[0603] II. Therapeutic Applications

[0604] The heterobifunctional compounds described herein, such as compounds of Formula I, Formula II, or other compounds in Section I, provide therapeutic benefits to patients suffering from cancer. Therefore, one aspect of the invention provides a method of treating cancer. The method comprises administering a therapeutically effective amount of the compounds described herein, such as compounds of Formula I, Formula II, or other compounds in Section I, to a patient in need to treat cancer. In some embodiments, the compound is a compound of Formula I. In some embodiments, a specific compound of Formula I is a compound defined by one of the embodiments described above.

[0605] cancer

[0606] In some implementations, the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland cancer, bile duct cancer and gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia. In some implementations, the cancer is prostate cancer.

[0607] In some implementation schemes, cancers include squamous cell carcinoma, lung cancer (including small cell lung cancer and non-small cell lung cancer), vulvar cancer, thyroid cancer, lung adenocarcinoma and lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, liver cancer, anal cancer, penile cancer, and head and neck cancer. In some implementations, cancer is selected from at least one of the following groups: ALL, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-BALL, pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, lymphoma, leukemia, multiple myeloma, myeloproliferative disorders, large B-cell lymphoma, or B-cell lymphoma.

[0608] In some implementations, the cancer is a solid tumor or leukemia. In some other implementations, the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterine cancer, esophageal cancer, liver cancer, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma. In some other implementations, the cancer is small cell lung cancer, non-small cell lung cancer, melanoma, central nervous system tissue cancer, brain cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, or diffuse large B-cell lymphoma. In some other embodiments, the cancer is breast cancer, colon cancer, small cell lung cancer, non-small cell lung cancer, prostate cancer, kidney cancer, ovarian cancer, leukemia, melanoma, or cancer of the central nervous system.

[0609] In some implementations, the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, or hemangioblastoma.

[0610] In some implementation schemes, the cancer is neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, glioblastoma, brainstem glioma, malignant brain tumors with poor prognosis, malignant glioma, degenerative astrocytoma, degenerative oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C and D stage colorectal cancer, unresectable colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma. Sarcoma), nuclear type acute myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, low-grade follicular lymphoma, metastatic melanoma, localized melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, progressive ossifying fibrous dysplasia, hormone-refractory prostate cancer, resectable high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waidenstrom's macroglobulinemia. Macroglobulinemia, smoking myeloma, indolent myeloma, fallopian tube cancer, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, castration-resistant prostate cancer, castration-resistant metastatic prostate cancer, papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or leiomyoma.

[0611] In some implementations, the cancers include bone cancer, pancreatic cancer, skin cancer, head or neck cancer, melanoma of the skin or eye, ovarian cancer, colon cancer, rectal cancer, anal cancer, stomach cancer, gastrointestinal cancer (stomach, colon, rectum, and duodenum), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, and Hodgkin's disease. Disease), esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, non-Hodgkin's lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or one or more combinations of the aforementioned cancers.

[0612] In some implementations, the cancer is hepatocellular carcinoma, ovarian cancer, ovarian epithelial carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatobiliary ductal carcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; degenerative thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / stomach (GIST) cancer; lymphoma; head and neck squamous cell carcinoma (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibromatosis-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenström's macroglobulinemia; or medulloblastoma.

[0613] In some implementation schemes, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, degenerative thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic duct carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1-related malignant peripheral nerve sheath tumor (MPNST), Waldenström's macroglobulinemia, or medulloblastoma.

[0614] In some implementations, the cancer is a solid tumor, such as sarcoma, carcinoma, or lymphoma. In some implementations, the cancer is kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma or liver cancer; melanoma; breast cancer; colorectal carcinoma or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; liver cancer. Cholangiocarcinoma; soft tissue and synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; degenerative thyroid carcinoma; adrenocortical carcinoma; pancreatic cancer; pancreatic duct carcinoma or pancreatic adenocarcinoma; gastrointestinal / stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland carcinoma; glioma or brain cancer; neurofibromatosis-1-related malignant peripheral nerve sheath tumor (MPNST); Waldenström's macroglobulinemia; or medulloblastoma.

[0615] In some implementations, the cancer is renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial carcinoma, ovarian tumor, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, degenerative thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic duct carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1-related malignant peripheral nerve sheath tumor (MPNST), Waldenström's macroglobulinemia, or medulloblastoma.

[0616] In some implementations, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial carcinoma, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, degenerative thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic duct carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1-related malignant peripheral nerve sheath tumor (MPNST), Waldenström's macroglobulinemia, or medulloblastoma.

[0617] In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer or ovarian tumor. In some embodiments, the cancer is epithelial ovarian cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is papillary serous uterine carcinoma (UPSC). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is degenerative thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer or pancreatic duct carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumor (MPNST). In some embodiments, the cancer is neurofibromatosis-1-associated MPNST. In some embodiments, the cancer is Waldenström's macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[0618] Causes cancer cell death

[0619] Another aspect of the invention provides a method for inducing cancer cell death. The method comprises contacting cancer cells with an effective amount of a compound described herein, such as a compound of formula I or II, or other compounds in section I, to induce cancer cell death. In some embodiments, the specific compound of formula I or II is a compound defined by one of the embodiments described above.

[0620] In some embodiments, the cancer cells are selected from ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland cancer, bile duct cancer and gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia. In some embodiments, the cancer cells are one or more of the cancers described in the section titled "Cancer" above. In some embodiments, the cancer cells are prostate cancer cells.

[0621] Exemplary bioactivity assay

[0622] The assays described herein can be used to assess the biological activity of the compounds described herein.

[0623] A. Determination of binding affinity to androgen receptors

[0624] The following procedure can be used to test the ability of a compound to bind to the androgen receptor. In a buffer containing 25 mM Hepes-Tris (pH 7.4), 1 mM EDTA, 10 mM Na2MoO4, 2 mM DTT, 5 μM triamcinolone acetonide, and 10% glycerol, with or without the test compound, fractions of cytosol (10⁶ cells / spot) are mixed with 1 nM […]. 3 [H]methyltrienolone was incubated together at 4°C for 24 hours. Non-specific binding could be determined in the presence of 1 μM testosterone. After incubation, the sample was rapidly filtered under vacuum through a glass fiber filter (GF / B, Packard) pre-soaked in 0.3% PEI, and washed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell collector (Unifilter, Packard). The filter was dried, and radioactivity was counted using a scintillation mixture (Microscint O, Packard) in a scintillation counter (Topcount, Packard). Results are expressed as the percentage of inhibition of specific binding of the control radioligand. Testosterone was used as a standard reference compound, and competition curves were obtained by testing at several concentrations in each experiment, from which IC50 was calculated. 50 .

[0625] B. Determination of binding affinity with BRD4-BD1

[0626] The following experimental procedure can be used to test the ability of the compound to bind to BRD4-BD1. The compound can be tested using the bromoKdELECT assay. A T7 phage strain displaying the bromine domain is grown in parallel in 24-well blocks of *E. coli* host derived from strain BL21. *E. coli* is grown to the logarithmic phase and infected with T7 phage from a frozen stock solution (multiple of infection = 0.4), and incubated with shaking at 32°C until lysis (90–150 min). The lysate is centrifuged (5,000 × g) and filtered (0.2 μm) to remove cell debris. Magnetic beads coated with streptavidin are treated with biotinylated small molecules or acetylated peptide ligands for 30 min at room temperature to produce an affinity resin for the bromine domain assay. Ligand beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligands and reduce nonspecific phage binding. The binding reaction was assembled by combining the bromine domain, ligand affinity beads, and test compound in 1x binding buffer (17% SeaBlock, 0.33x PBS, 0.04% Tween 20, 0.02% BSA, 0.004% sodium azide, 7.4 mM DTT). The test compound was prepared as a 1000X stock solution in 100% DMSO. Kd was determined using an 11-point 3-fold compound dilution series and a DMSO control point. All compounds used for Kd measurement were distributed in 100% DMSO via acoustic transfer (non-contact dispensing). The compounds were then directly diluted to the assay to a final DMSO concentration of 0.09%. All reactions can be performed in a polypropylene 384-well plate. The final volume for each reaction is 0.02 ml. The plate is incubated with shaking for 1 hour at room temperature, and the affinity beads are washed with wash buffer (1x PBS, 0.05% Tween 20). The beads are then resuspended in wash buffer (1x PBS, 0.05% Tween 20, 2 μM non-biotinylated affinity ligand) and incubated with shaking for 30 minutes at room temperature. The concentration of bromine domains in the elution buffer can be measured by qPCR.

[0627] C. Determination of binding affinity with BRD4-BD2

[0628] The following experimental procedure can be used to test the ability of the compound to bind to BRD4-BD2. The compound can be tested using the bromoKdELECT assay. A T7 phage strain displaying the bromine domain is grown in parallel in 24-well blocks of *E. coli* host derived from strain BL21. *E. coli* is grown to the logarithmic phase and infected with T7 phage from a frozen stock solution (multiple of infection = 0.4), and incubated with shaking at 32°C until lysis (90–150 min). The lysate is centrifuged (5,000 × g) and filtered (0.2 μm) to remove cell debris. Magnetic beads coated with streptavidin are treated with biotinylated small molecules or acetylated peptide ligands for 30 min at room temperature to produce an affinity resin for the bromine domain assay. Ligand beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligands and reduce nonspecific phage binding. The binding reaction was assembled by combining the bromine domain, ligand affinity beads, and test compound in 1x binding buffer (17% SeaBlock, 0.33x PBS, 0.04% Tween 20, 0.02% BSA, 0.004% sodium azide, 7.4 mM DTT). The test compound was prepared as a 1000X stock solution in 100% DMSO. Kd was determined using an 11-point 3-fold compound dilution series and a DMSO control point. All compounds used for Kd measurement were distributed in 100% DMSO via acoustic transfer (non-contact dispensing). The compounds were then directly diluted to the assay to a final DMSO concentration of 0.09%. The reaction can be performed in a polypropylene 384-well plate. The final volume for each well is 0.02 ml. The plate is incubated with shaking for 1 hour at room temperature, and the affinity beads are washed with wash buffer (1x PBS, 0.05% Tween 20). The beads are then resuspended in wash buffer (1x PBS, 0.05% Tween 20, 2 μM non-biotinylated affinity ligand) and incubated with shaking for 30 minutes at room temperature. The concentration of bromine domains in the elution buffer can be measured by qPCR.

[0629] Combination therapy

[0630] Compounds that can be used in the methods of this invention may be used in combination with one or more additional therapeutic agents that can be used to treat any disease contemplated herein. These additional therapeutic agents may include commercially available or synthetically available compounds that are skilled in the art. These additional therapeutic agents are known to treat, prevent, or alleviate the symptoms of any disease or condition contemplated herein.

[0631] Therefore, in some embodiments, the method further includes administering an additional therapeutic agent to the individual to treat the disease intended herein.

[0632] In some embodiments, administering the compounds of the present invention to an individual allows for the administration of a lower dose of additional therapeutic agent compared to the dose of a separate additional therapeutic agent required to achieve similar results in treating the diseases contemplated herein. For example, in some embodiments, the compounds of the present invention enhance the therapeutic activity of the additional therapeutic compound, thereby allowing a lower dose of the additional therapeutic compound to provide the same effect.

[0633] Synergistic effects can be calculated, for example, using suitable methods such as Sigmoid-E. max The equations mentioned above (Holford and Scheiner, 1981, Clin. Pharmacokinet. 6:429-453), the Loewe summation equation (Loewe and Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313-326), and the intermediate-effect equation (Chou and Talalay, 1984, Adv. Enzyme Regul. 22:27-55) can be applied to experimental data to generate corresponding graphs to help evaluate the effects of drug combinations. The corresponding graphs associated with these equations are concentration-response curves, equivalence curves, and combination index curves.

[0634] In some embodiments, the compounds and therapeutic agents of the present invention are co-administered to individuals. In other embodiments, the compounds and therapeutic agents of the present invention are co-formulated and co-administered to individuals.

[0635] In some embodiments, the compound is administered in combination with a second therapeutic agent having anticancer activity. In some embodiments, the second therapeutic agent is mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, or letrozole. (letrozole), raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptiniumAcetate, Ketanserin, Doxifluridine, Etretinate, Isotretinoin, Streptozocin, Nimustine, Vindesine, Flutamide, Drogenil, Butocin, Carmofur, Razoxane, Sizofilan, Carboplatin, Mitolactalol, Tegafur, Ifosfamide, Prednisolone Nimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, formestane, interferon-α, interferon-2α, interferon-β, interferon-γ, community-stimulating factor-1, community-stimulating factor-2, denileukin diftitox, interleukin-2, and luteinizing hormone-releasing factor.

[0636] In some embodiments, the second therapeutic agent is an mTOR inhibitor that inhibits cell proliferation, angiogenesis, and glucose uptake. Approved mTOR inhibitors for use in this invention include everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer).

[0637] In some embodiments, the second therapeutic agent is a poly-ADP-ribose polymerase (PARP) inhibitor. Approved PARP inhibitors for use in this invention include olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); and niraparib (Zejula®, Tesaro). Other investigational PARP inhibitors for use in this invention include talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

[0638] In some embodiments, the second therapeutic agent is a phosphatidylinositol 3-kinase (PI3K) inhibitor. Approved PI3K inhibitors for use in this invention include idelalisib (Zydelig®, Gilead). Other investigational PI3K inhibitors for use in this invention include alpelisib (BYL719, Novartis); taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

[0639] In some embodiments, the second therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors for use in this invention include bortezomib (Velcade®, Takeda); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda).

[0640] In some embodiments, the second therapeutic agent is a histone deacetylase (HDAC) inhibitor. Approved HDAC inhibitors for use in this invention include vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); and belinostat (Beleodaq®, Spectrum Pharmaceuticals). Other investigational HDAC inhibitors for use in this invention include entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China).

[0641] In some embodiments, the second therapeutic agent is a CDK inhibitor, such as a CDK 4 / 6 inhibitor. Approved CDK 4 / 6 inhibitors for use in this invention include palbociclib (Ibrance®, Pfizer); and ribociclib (Kisqali®, Novartis). Other investigational CDK 4 / 6 inhibitors for use in this invention include abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[0642] In some embodiments, the second therapeutic agent is an indoleamine (2,3)-dioxygenase (IDO) inhibitor. Investigative IDO inhibitors that may be used in this invention include epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); and an enzyme that breaks down kynurenine (Kyn Therapeutics).

[0643] In some embodiments, the second therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) or its receptor (EGFR). PDGF antagonists approved for use in this invention include olaaratumab (Lartruvo®; Eli Lilly). EGFR antagonists approved for use in this invention include cetuximab (Erbitux®; Eli Lilly); necitumumab (Portrazza®; Eli Lilly); panitumumab (Vectibix®; Amgen); and osimertinib (targeting activated EGFR; Tagrisso®; AstraZeneca).

[0644] In some embodiments, the second therapeutic agent is an aromatase inhibitor. Approved aromatase inhibitors for use in this invention include exemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca); and letrozole (Femara®, Novartis).

[0645] In some embodiments, the second therapeutic agent is a hedgehog protein pathway antagonist. Approved hedgehog protein pathway inhibitors for use in this invention include sonidegib (Odomzo®, Sun Pharmaceuticals) and vismodegib (Erivedge®, Genentech), both used to treat basal cell carcinoma.

[0646] In some embodiments, the second therapeutic agent is a folic acid inhibitor. Folic acid inhibitors approved for use in this invention include pemetrexed (Alimta®, Eli Lilly).

[0647] In some embodiments, the second therapeutic agent is a CCR4 inhibitor. Investigative CCR4 inhibitors that may be used in this invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).

[0648] In some embodiments, the second therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor. Investigative IDH inhibitors that may be used in this invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); and IDH305 (Novartis, NCT02987010).

[0649] In some embodiments, the second therapeutic agent is an arginase inhibitor. Investigative arginase inhibitors that may be used in this invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being investigated in a Phase 1 clinical trial for acute myeloid leukemia and myelomectomy syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[0650] In some embodiments, the second therapeutic agent is a glutaminase inhibitor. Among the glutaminase inhibitors under investigation that may be used in this invention is CB-839 (Calithera Biosciences).

[0651] In some implementations, the second therapeutic agent is an antibody that binds to a tumor antigen, that is, a protein expressed on the cell surface of tumor cells. Approved antibodies binding to tumor antigens for use in this invention include rituximab (Rituxan®, Genentech / BiogenIdec); ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech); ibritumomab (anti-CD20 and yttrium-90, Zevalin®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech); dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics); and trastuzumab. (Anti-HER2, Herceptin®, Genentech); ado-trastuzumab (anti-HER2, fused with emtansine, Kadcyla®, Genentech); pertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

[0652] In some embodiments, the second therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors for use in this invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals) and topotecan (Hycamtin®, GlaxoSmithKline). Investigative topoisomerase inhibitors for use in this invention include pixantrone (Pixuvri®, CTIBiopharma).

[0653] In some implementations, the second therapeutic agent is a nucleoside inhibitor or another therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibits rapidly proliferating cells. Nucleoside inhibitors or other therapeutic agents of this class include trabectedin (guanidine alkylating agent, Yondelis®, Janssen Oncology); mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (alkylating agent, 5-(3-methyltriazene-1-yl)-imidazol-4-carboxamide (MTIC), a prodrug of Temodar®, Merck); cytarabine injection (ara-C, an antimetabolite cytarabine analog, Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb; Glaostine®, NextSource Biotechnology); and azacitidine. (Cytidine pyrimidine nucleoside analogues, Vidaza®, Celgene); Omacetaxine mepesuccinate (cephalotaxine ester) (protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); Erwinia chrysanthemi (asparagine-consuming enzyme, Elspar®, Lundbeck; Erwinaze®, EUSAPharma); Eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic agent, Halaven®, Eisai); Cabazitaxel (microtubule inhibitor, tubulin-based antimitotic agent, Jevtana®, Sanofi-Aventis); Capacetrine (thymidine synthase inhibitor, Xeloda®, Genentech); Bendamustine (Bifunctional nitrogen mustard derivative, believed to form interstrand DNA crosslinks, Treanda®, Cephalon / Teva);Ixabepilone (a semi-synthetic analog of epothilone B, a microtubule inhibitor, a tubulin-based antimitotic agent, Ixempra®, Bristol-Myers Squibb); nelarabine (a prodrug of a deoxyguanosine analog, a nucleoside metabolism inhibitor, Arranon®, Novartis); colafabine (a prodrug of a ribonucleotide reductase inhibitor, a competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); and trifluridine and tipiracil (nucleoside analogs and thymidine phosphorylase inhibitors based on thymidine, Lonsurf®, Taiho Oncology).

[0654] In some embodiments, the second therapeutic agent is a platinum-based therapeutic agent, also known as a platinum class. Platinum classes cause DNA cross-linking, thereby inhibiting DNA repair and / or DNA synthesis, primarily in rapidly proliferating cells, such as cancer cells. Approved platinum-based therapeutic agents for use in this invention include cisplatin (Platinol®, Bristol-Myers Squibb); carboplatin (Paraplatin®, Bristol-Myers Squibb; also Teva; Pfizer); oxaliplatin (Eloxitin® Sanofi-Aventis); and nedaplatin (Aqupla®, Shionogi). Other clinically tested platinum-based therapeutic agents for use in this invention include picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agenix).

[0655] In some embodiments, the second therapeutic agent is a taxane compound that induces microtubule disruption essential for cell division. Approved taxane compounds for use in this invention include paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis; Docefraz®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis / Celgene), and cabazitaxel (Jevtana®, Sanofi-Aventis). Other clinically tested taxane compounds suitable for use in this invention include SID530 (SK Chemicals, Co.) (NCT00931008).

[0656] In some embodiments, the second therapeutic agent is an inhibitor of an anti-apoptotic protein, such as BCL-2. Approved anti-apoptotic agents for use in this invention include venetoclax (Venclexta®, AbbVie / Genentech) and blinatumomab (Blincyto®, Amgen). Other clinically tested therapeutic agents targeting apoptotic proteins for use in this invention include navitoclax (ABT-263, Abbott) and BCL-2 inhibitors (NCT02079740).

[0657] In some embodiments, the second therapeutic agent is a selective estrogen receptor modulator (SERM) that interferes with the synthesis or activity of estrogen. SERMs approved for use in this invention include raloxifene (Evista®, Eli Lilly).

[0658] In some embodiments, the second therapeutic agent is an inhibitor of the interaction between two major p53 repressor proteins, MDMX and MDM2. Inhibitors of the p53 repressor proteins under investigation that can be used in this invention include ALRN-6924 (Aileron), a stapling peptide that equivalently binds to and disrupts the interaction between MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelomectomy syndrome (MDS), and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

[0659] In some embodiments, the second therapeutic agent is an inhibitor of transforming growth factor-β (TGF-β or TGFβ). Investigative TGF-β protein inhibitors that may be used in this invention include NIS793 (Novartis), an anti-TGF-β antibody currently being tested in clinical trials for the treatment of various cancers, including breast cancer, lung cancer, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, prostate cancer, and kidney cancer (NCT02947165). In some embodiments, the TGF-β protein inhibitor is fresolimumab (GC1008; Sanofi-Genzyme), which is being investigated for melanoma (NCT00923169), renal cell carcinoma (NCT00356460), and non-small cell lung cancer (NCT02581787). Additionally, in some implementations, the additional therapeutic agent is a TGF-β scavenger, as described in Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978. One therapeutic compound currently in clinical trials for the treatment of solid tumors is M7824 (Merck KgaA - formerly MSB0011459X), a bispecific anti-PD-L1 / TGFβ scavenger compound (NCT02699515); and (NCT02517398). M7824 consists of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-β receptor II, which can act as a TGFβ “scavenger.”

[0660] In some implementations, the second therapeutic agent is a cancer vaccine. In some implementations, the cancer vaccine is selected from sipuleucel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or mildly symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (Imlygic®, BioVex / Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodular lesions of melanoma.In some implementations, the additional therapeutic agent is selected from oncolytic virus therapies, such as pexastimogenedevacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), an engineered thymidine kinase (TK)-deficient vaccinia virus expressing GM-CSF targeting hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (Reolysin®, Oncolytics) Biotech, a variant of respiratory enteric orphan virus (ROV) that cannot replicate in non-RAS-activated cells in various cancers, including colorectal cancer (NCT01622543), prostate cancer (NCT01619813), head and neck squamous cell carcinoma (NCT01166542), pancreatic adenocarcinoma (NCT00998322), and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAd1), an engineered drug for use in ovarian cancer (NCT02028117), metastatic or advanced epithelial tumors (such as colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer). (NCT02636036) is an adenovirus expressing full-length CD80 and T-cell receptor CD3 protein-specific antibody fragments; ONCOS-102 (Targovax / formerly Oncos) is an engineered adenovirus expressing GM-CSF in melanoma (NCT03003676) and peritoneal diseases, colorectal cancer, or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux GmbH) is a vaccinia virus engineered to express β-galactosidase (β-gal) / β-glucuronidase or β-gal / human sodium iodide cotransporter (hNIS) in peritoneal metastases (NCT01443260), fallopian tube cancer, and ovarian cancer (NCT02759588); or CG0070 (Cold Genesys is an adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818).

[0661] In some embodiments, the second therapeutic agent is an immune checkpoint inhibitor selected from PD-1 antagonists, PD-L1 antagonists, or CTLA-4 antagonists. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are administered in combination with the following: nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck); ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); or atezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech). Other immune checkpoint inhibitors applicable to this invention include REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636), NSCLC (NCT03088540), squamous cell carcinoma of the skin (NCT02760498), lymphoma (NCT02651662), and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody binding to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; and avelumab (Bavencio®, Pfizer / Merck KGaA, also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, in clinical trials for non-small cell lung cancer and Merkel cell carcinoma. Clinical trials are underway for PD-1 inhibitors including carcinoma, mesothelioma, solid tumors, kidney cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; and PDR001 (Novartis), an inhibitory antibody that binds to PD-1, is in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors.tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody targeting CTLA-4, and it is being investigated in clinical trials for multiple indications, including: mesothelioma, colorectal cancer, renal cell carcinoma, breast cancer, lung and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell carcinoma, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, endometrial cancer, liver metastases, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic degenerative thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody currently being investigated in a phase 1 clinical trial for advanced solid tumors (NCT02694822).

[0662] Another aspect of the invention provides the use of the compounds described herein (such as compounds of formula I, formula II, or other compounds in section I) in the manufacture of pharmaceutical agents. In some embodiments, the pharmaceutical agent is used to treat diseases described herein, such as cancer.

[0663] Another aspect of the invention provides the use of compounds described herein (such as compounds of formula I, formula II, or other compounds in section I) for the treatment of medical diseases, such as those described herein (e.g., cancer).

[0664] Another aspect of the invention provides compounds described herein (such as compounds of formula I, formula II, or other compounds in section I) for treating medical conditions such as those described herein, such as cancer.

[0665] Evaluation of cell growth inhibition in HEK293 and HeLa cells

[0666] The ability of the compound to inhibit the proliferation of HEK293 or HeLa cells was evaluated according to the following procedure. HEK293 and HeLa cells were cultured in DMEM medium supplemented with 10% fetal bovine serum and 1% Penn / Strep. Cells were seeded at 500 cells / well in 25 μL of complete medium in white 384-well plates. After seeding, the plates were rotated at 300 × g for three minutes and cultured in a humidified tissue culture incubator at 37°C and 5% CO2. After 24 hours, the compound was titrated in 100% DMSO and diluted in complete cell culture medium. 25 μL aliquots of the compound / medium mixture were added to the cells to bring the total volume in the wells to 50 μL. DMSO was used alone as a negative control. The plates were then rotated at 300 × g for three minutes and stored at 37°C and 5% CO2 for three days. Cell viability was quantified using CellTiter-Glo 2.0 reagent (Promega) on days 0 and 3 of compound treatment. After equilibrating the microplates at room temperature for 30 minutes, 25 μL of CellTiter-Glo 2.0 reagent was dispensed into each well to bring the total volume to 75 μL. The plates were mixed at 500 rpm for 2 minutes on a shaker, followed by incubation at room temperature for 10 minutes. After rapid rotation, luminescence readings were measured using an EnVision plate reader. The data were normalized for readings on day 0 and day 3 of DMSO treatment. Four-parameter nonlinear regression curve fitting was applied to the dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (MCIC) of each compound. 50 ).

[0667] III. Pharmaceutical Composition and Dosage Considerations

[0668] As indicated above, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions may be specifically formulated for administration in solid or liquid form, including those suitable for: (1) oral administration, e.g., enemas (aqueous or non-aqueous solutions or suspensions), lozenges (e.g., those intended for buccal, sublingual, and systemic absorption), pills, powders, granules, pastes for tongue application; (2) non-enteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, as, for example, a sterile solution or suspension or a sustained-release formulation; (3) topical application, e.g., as a cream, ointment, or controlled-release patch or spray for skin application; (4) intravaginal or rectal administration, e.g., as a pessary, cream, or foam; (5) sublingual; (6) ocular; (7) transdermal; or (8) nasal. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula I) and a pharmaceutically acceptable carrier.

[0669] As used herein, the phrase “therapeutic effective amount” means the amount of a compound, material, or composition comprising the compounds of the present invention that effectively produces a desired therapeutic effect in at least a subpopulation of animals, given a reasonable benefit / risk ratio applicable to any medical treatment.

[0670] The phrase “pharmaceutically acceptable” in this article refers to compounds, materials, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for use in human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and whose benefits / risks are commensurate with a reasonable ratio.

[0671] Wetting agents, emulsifiers and lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as colorants, releasing agents, coating agents, sweeteners, flavoring agents and aroma agents, preservatives and antioxidants may also be present in the composition.

[0672] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol and the like; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

[0673] The formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or non-intestinal administration. The formulations can be conveniently presented in unit dosage forms and can be prepared by any method well known in pharmaceutical technology. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific administration method. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount by which the compound produces a therapeutic effect. Generally, this amount, on a 100% basis, will be in the range of about 0.1% to about 99% of the active ingredient, preferably about 5% to about 70%, more preferably about 10% to about 30%.

[0674] In some embodiments, the formulations of the present invention comprise excipients selected from the group consisting of cyclodextrins, cellulose, liposomes, microcell forming agents (e.g., bile acids), and polymerization carriers (e.g., polyesters and polyanhydrides); and the compounds of the present invention. In some embodiments, the aforementioned formulations facilitate the oral bioavailability of the compounds of the present invention.

[0675] Methods for preparing these formulations or compositions include the step of associating the compounds of the present invention with a carrier and optionally one or more auxiliary components. Generally, formulations are prepared by uniformly and tightly associating the compounds of the present invention with a liquid carrier or a finely powdered solid carrier, or both, followed by shaping the product if necessary.

[0676] The formulations of the present invention suitable for oral administration may be in the form of capsules, flat capsules, pills, lozenges (using a flavoring base, typically sucrose and gum arabic or tragacanth), powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil emulsions, or as elixirs or syrups, or as soft lozenges (using an inert base, such as gelatin and glycerin, or sucrose and gum arabic) and / or as mouthwashes and similar forms, each containing a predetermined amount of the compound of the present invention as an active ingredient. The compounds of the present invention may also be administered as large pills, licks, or pastes.

[0677] In the solid dosage forms of the present invention (e.g., capsules, tablets, pills, sugar-coated tablets, powders, granules, throat lozenges and similar forms) intended for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers (such as sodium citrate or dicalcium phosphate) and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silica; (2) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates and Sodium carbonate; (5) solution blocking agents, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds, and surfactants, such as poloxamer and sodium lauryl sulfate; (7) humectants, such as cetyl alcohol, glyceryl monostearate, and nonionic surfactants; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) colorants; and (11) controlled-release agents, such as crospovidone or ethyl cellulose. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffers. Similar types of solid compositions may also be used as fillers in soft-shell and hard-shell gelatin capsules, using excipients such as lactose or toffee and high molecular weight polyethylene glycol and the like.

[0678] Tablets can be made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be made by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0679] The pharmaceutical compositions of the present invention, in tablet and other solid dosage forms, such as sugar-coated tablets, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings known in pharmaceutical formulation techniques. These dosage forms may also be formulated using, for example, different proportions of hydroxypropyl methylcellulose to provide a slow or controlled release of the active ingredient therein, thereby providing the desired release profile, other polymer matrices, liposomes, and / or microspheres. These dosage forms may be formulated for rapid release, for example, by freeze-drying. These dosage forms may be sterilized, for example, by filtration through a bacterial trap filter, or by incorporation of a sterilizing agent in the form of a sterile solid composition, which may be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain a light-blocking agent and may have a composition that optionally releases the active ingredient in a delayed manner only or preferably in specific portions of the gastrointestinal tract. Examples of encapsulation compositions that may be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, where appropriate, together with one or more of the above-described excipients.

[0680] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may also contain inert diluents commonly used in this art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranol, polyethylene glycol, and sorbitol fatty acid esters and mixtures thereof.

[0681] In addition to inert diluents, oral compositions may also contain adjuvants such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aroma agents and preservatives.

[0682] In addition to active compounds, suspensions may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum and mixtures thereof.

[0683] Formulations of the pharmaceutical compositions of the present invention for rectal or vaginal administration may be presented in suppository form, which may be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates, and are solid at room temperature but liquid at body temperature, thus melting in the rectal or vaginal cavity and releasing the active compound.

[0684] The formulations of the present invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or sprays containing suitable carriers known in the art.

[0685] Dosage forms for topical or transdermal administration of the compounds of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active compounds may be mixed under sterile conditions with pharmaceutically acceptable carriers and any preservatives, buffers, or propellants that may be required.

[0686] In addition to the active compounds of the present invention, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, tragacanth gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0687] In addition to the compounds of this invention, the powders and sprays may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders or mixtures thereof. Furthermore, the sprays may contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0688] Transdermal patches offer the additional advantage of providing controlled delivery of the compounds of the present invention into the body. Such dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flux of the compounds across the skin. The rate of this flux can be controlled by providing a rate-controlled membrane or by dispersing the compounds in a polymer matrix or gel.

[0689] Ophthalmic formulations, ointments, powders, solutions, and similar forms are also expected to be within the scope of this invention.

[0690] The pharmaceutical compositions of the present invention suitable for non-enteral administration comprise one or more compounds of the present invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, emulsions, or sterile powders, which may be reconstituted into sterile injectable solutions or dispersions prior to use, and may contain sugars, alcohols, antioxidants, buffers, antibacterial agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0691] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Suitable flowability can be maintained, for example, by using a coating material (such as lecithin) in the case of a dispersion, by maintaining the desired particle size, and by using a surfactant.

[0692] These compositions may also contain adjuvants, such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action on the subject compound can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, such as sugars, sodium chloride, and the like, may also be required in the composition. Additionally, absorption in injectable pharmaceutical forms can be prolonged by including delayed absorption agents, such as aluminum monostearate and gelatin.

[0693] In some cases, to prolong the action of a drug, it is necessary to slow the absorption of subcutaneously or intramuscularly injected drugs. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of the drug depends on its dissolution rate, which may depend on the crystal size and crystal form. Alternatively, delayed absorption of non-enteral drug forms can be achieved by dissolving or suspending the drug in an oil-based medium.

[0694] Injectable accumulation formulations are prepared by forming microcapsule matrices of the subject compound in biodegradable polymers, such as polylactide-polyglycolic acid. The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Accumulated injectable formulations are also prepared by encapsulating the drug in liposomes or microemulsions compatible with body tissues.

[0695] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they may be administered either alone or as a pharmaceutical composition comprising, for example, 0.1% to 99% (more preferably 10% to 30%) of the active ingredient and a pharmaceutically acceptable carrier.

[0696] The formulations of the present invention can be administered orally, non-enterally, topically, or rectally. Of course, these formulations are administered in a form suitable for each route of administration. For example, these formulations are administered in the form of tablets or capsules; by injection, inhalation, eye wash, ointment, suppository, etc.; by injection, infusion, or inhalation; topically by lotion or ointment; and rectally by suppository. Oral administration is preferred.

[0697] As used in this article, the phrases “non-enteric administration” and “non-enteric delivery” refer to drug delivery methods other than enteric and local administration, usually by injection, including but not limited to intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intra-bursal, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0698] As used in this article, the phrases “systemic administration,” “systemic delivery,” “peripheral delivery,” and “peripheral delivery” refer to the administration of compounds, drugs, or other materials into the patient’s system in a manner other than direct delivery to the central nervous system, thereby allowing them to undergo metabolism and other similar processes, such as subcutaneous delivery.

[0699] These compounds can be administered to humans and other animals for therapeutic purposes via any suitable route of administration, including oral, nasal (e.g., via spray), rectal, vaginal, non-intestinal, intracerebrospinal, and topical (e.g., via powder, ointment, or drops), including buccal and sublingual administration.

[0700] Regardless of the chosen route of administration, the compounds of the present invention and / or the pharmaceutical compositions of the present invention, which can be used in a suitable hydrated form, are formulated into pharmaceutically acceptable dosage forms using conventional methods known to those skilled in the art.

[0701] The actual dose level of the active ingredient in the pharmaceutical composition of the present invention can be varied to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response for a specific patient, composition and administration mode, while being non-toxic to the patient.

[0702] The selected dosage level will depend on a variety of factors, including the activity of the specific compound of the present invention or its ester, salt or amide, the route of administration, the timing of administration, the rate of excretion or metabolism of the specific compound, the rate and extent of absorption, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific compound, the age, sex, weight, disease, general health and medical history of the patient being treated, and similar factors known in medical technology.

[0703] Physicians or veterinarians familiar with this technique can easily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start with a dose of the compound of the present invention used in the pharmaceutical composition at a level below that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0704] Generally, the suitable daily dose of the compounds of the present invention will be the minimum dose at which the compounds effectively produce a therapeutic effect. This effective dose will generally depend on the factors described above. The compounds are preferably administered at a dose of about 0.01 mg / kg to about 200 mg / kg, more preferably about 0.1 mg / kg to about 100 mg / kg, and even more preferably about 0.5 mg / kg to about 50 mg / kg. When the compounds described herein are co-administered with another agent (e.g., as a sensitizer), the effective amount may be lower than when the agent is used alone.

[0705] If necessary, the effective daily dose of the active compound may be administered individually as two, three, four, five, six or more fractions at appropriate time intervals throughout the day, optionally in unit dosage form. Once-daily administration is preferred.

[0706] The present invention further provides a unit dosage form (such as a tablet or capsule) comprising a therapeutically effective amount of the difunctionally substituted phenylpyrimidinone or related compound described herein for the treatment of the medical conditions described herein.

[0707] IV. Medical reagent kits

[0708] Another aspect of the invention is a kit comprising (i) the compounds described herein, such as compounds of formula I, formula II or other compounds in section I, and (ii) instructions for use, such as for treating cancer.

[0709] Example

[0710] The present invention, as generally described therein, will be more readily understood by reference to the following examples, which are intended to illustrate certain aspects and embodiments of the invention only and are not intended to limit the invention.

[0711] General methods

[0712] All reactions were carried out under a dry nitrogen or argon atmosphere. Glassware was dried before use. Unless otherwise instructed, commonly used reagents or materials were obtained from commercial sources and used without further purification. Anhydrous reagents were obtained by distillation with potassium hydroxide. N , N -Diisopropylethylamine (DIPEA). Produced by PureSolv TM The solvent drying system dries tetrahydrofuran (THF), dichloromethane (CH2Cl2), and dimethylformamide (DMF). PTLC refers to preparative thin-layer chromatography. Abbreviations: HFIP (hexafluoroisopropanol), HEPES (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid). Rapid column chromatography is performed using silica gel 60 (230-400 mesh). Analytical thin-layer chromatography (TLC) is performed on Merck silica gel plates equipped with QF-254 indicator and visualized by UV or KMnO4.

[0713] At room temperature, Agilent DD2 500 (500 MHz) 1 H; 125 MHz 13 C) or Agilent DD2 600 (600 MHz) 1 H; 150 MHz 13 C) or Agilent DD2 400 (400 MHz) 1H; 100 MHz 13 C) Recording on the spectrometer 1 H and 13 C10 NMR spectrum. Relative to residual CDCl3 (δ 7.26 ppm) 1 H; δ 77.0 ppm 13 C) CD3OD (δ 3.31 ppm) 1 H; δ 49.00 ppm 13 C) or d 6 -DMSO (δ 2.50 ppm 1 H; δ 39.52 ppm 13 C) Chemical shifts are reported in ppm. NMR chemical shifts relative to internal solvent peaks are expressed in ppm, and coupling constants are measured in Hz (bs = broad signal). In most cases, only the peaks of the major rotational isomers are reported.

[0714] Mass spectra were obtained using an Agilent 1100 series LC / MSD spectrometer. Analytical HPLC analysis was performed on a 250 × 4.6 mm C-18 column using gradient conditions (10–100% B, flow rate = 1.0 mL / min, 20 min) or as described in the LC-MS method table.

[0715] Unless otherwise instructed, preparative HPLC is performed on a 250 × 21.2 mm C-18 column using gradient conditions (10–100% B, flow rate = 10.0 mL / min, 20 min). The eluents used are solvent A (H₂O containing 0.1% TFA) and solvent B (CH₃CN containing 0.1% TFA). The final product is typically purified by reversed-phase HPLC, PTLC, or rapid column chromatography.

[0716]

[0717]

[0718]

[0719]

[0720]

[0721] The following abbreviations are used in this article: ACN or MeCN: acetonitrile; AcO: acetate; AcOH: acetic acid; B2pin2: bis(pinacolyl)diboron; BINAP: 2,2'-bis(diphenyl-phosphino)-1,1'-binaphthyl; Bn: benzyl; Boc: tert-butoxycarbonyl; BPD: bis(pinacolyl)diboron; BrettPhos Pd G3: [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate; DavePhos PdG3: [[2-(dicyclohexylphosphino)-2-(N,N-dimethylamino)-1,1-biphenyl]-2-(2-amino-1,1-biphenyl)]palladium(II)methanesulfonate; DCM: dichloromethane; DIAD: diisopropyl azodicarbonate; DIEA: diisopropylethylamine; DMAC: dimethylacetamide; DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; EtOH: ethanol; EA or EtOAc: ethyl acetate; equiv or eq Mole equivalent; FA: formic acid; Fmoc: fumonisylmethoxycarbonyl; h: hour; HATU: 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b Pyridinium 3-oxide hexafluorophosphate; HPLC: high-performance liquid chromatography; IPA or i -PrOH: Isopropanol; JQ1: 2-[(9 S )-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Decadecyl-2(6),4,7,10,12-pentene-9-yl]acetic acid; LCMS or LC-MS: liquid chromatography-mass spectrometry; MeOH: methanol; min: minutes; MS: mass spectrometry; n -BuLi: n-Butyllithium; NMM: N-Methylmorpholine; NMP: N-methylpyrrolidone; NMR: Nuclear magnetic resonance; PCy3: Tricyclohexylphosphine; Pd(dba)2: Bis(diphenylmethylene-acetone)palladium(0); Pd2(dba)3: Tris(diphenylmethylene-acetone)dipalladium(0); Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); PE: Petroleum ether; PPA: Polyphosphoric acid; psi: pounds per square inch; rt: room temperature; SFC: Supercritical fluid chromatography; SPhos Pd G3: (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium methanesulfonate(II); tBuXPhos Pd G3: Methanesulfonate-(2-di-tert-butylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); tert -BuO: tert-butanol salt; tert -BuOH: tert-butanol; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TMP: tetramethylpiperidine; TMS: trimethylsilyl; Tos or Ts: p-toluenesulfonyl; T4P: dihydrophosphoric acid 3-{2,6,8-trioxo-9-[(2 R ,3 R 4 R [-2,3,4,5-tetrahydroxypentyl]-1,2,3,6,8,9-hexahydro-7 H 9,9-dimethyl-9-propane; XANTPHOS: (9,9-dimethyl-9-propane) H -Dibenzopiperan-4,5-diyl)bis(diphenylphosphine); and XPhos: dicyclohexyl[2',4',6'-tris(prop-2-yl)[1,1'-biphenyl]-2-yl]phosphine.

[0722] Example 1 - Synthesis N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]-6-[6-[2-[4-[(9 S )-9-ethyl-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]hept-2-yl]pyridazine-3-carboxamide (I-6).

[0723]

[0724]

[0725] Step 1: Preparation ((1) r 4 r4-(4-cyano-3-(trifluoromethoxy)phenoxy)cyclohexyl)tert-butyl carbamate. At 0°C, it is directed towards ((1 r 4 r 3.15 g (14.63 mmol, 1.5 equivalents) of tert-butyl 4-hydroxycyclohexylcarbamate was added to a solution of DMF (20 mL) and THF (20 mL) with NaH (585 mg, 14.63 mmol, 60% purity, 1.5 equivalents). The mixture was stirred at 25 °C for 0.5 h. Then, 2 g (9.75 mmol, 1.0 equivalents) of 4-fluoro-2-(trifluoromethoxy)benzonitrile was added. The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with NH4Cl (20 mL) at 0 °C, followed by extraction with EtOAc (50 mL × 3). The combined organic layers were washed with H2O (100 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 5 / 1). Obtain a white solid ((1) r 4 r 4-(4-cyano-3-(trifluoromethoxy)phenoxy)cyclohexyl)tert-butyl carbamate (3.15 g, 7.87 mmol, 81% yield).

[0726] Step 2: Preparation of 4-(((1) r 4 r )-4-aminocyclohexyl)oxy)-2-(trifluoromethoxy)benzonitrile. At 25°C, ((1 r 4 r A solution of tert-butyl 4-(4-cyano-3-(trifluoromethoxy)phenoxy)cyclohexyl)carbamate (3.14 g, 7.84 mmol, 1.0 equivalent) in DCM (20 mL) and TFA (10 mL) was stirred for 1 hour. The reaction mixture was concentrated to give a colorless oily 4-(((1) r 4 r )-4-aminocyclohexyl)oxy)-2-(trifluoromethoxy)benzonitrile (3.25 g, 7.84 mmol, TFA salt).

[0727] Step 3: Preparation of 6-chloro- N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]pyridazine-3-carboxamide. To 4-(((1 r 4 rA solution of 3-4-aminocyclohexyl)oxy)-2-(trifluoromethoxy)benzonitrile (3.25 g, 7.84 mmol, 1.0 equivalent, TFA salt) and 6-chloropyridazine-3-carboxylic acid (1.24 g, 7.84 mmol, 1.0 equivalent) in DMF (20 mL) was mixed with DIEA (3.04 g, 23.53 mmol, 4.10 mL, 3.0 equivalent) and HATU (4.47 g, 11.77 mmol, 1.5 equivalent). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was added to ice water (200 mL) and filtered to give 6-chloro-3-carboxylic acid as a white solid. N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]pyridazine-3-carboxamide (3.34 g, 7.58 mmol, 97% yield).

[0728] Step 4: Prepare 6-[2-[4-[(9 S )-9-ethyl-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester. To (9 S )-7-(4-chlorophenyl)-9-ethyl-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 DavePhos Pd G3 (82 mg, 0.11 mmol, 0.1 equivalent) was added to a solution of tridecano-2(6),4,7,10,12-pentaene (400 mg, 1.08 mmol, 1.0 equivalent), 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (597 mg, 2.70 mmol, 2.5 equivalent) and Cs2CO3 (597 mg, 2.70 mmol, 2.5 equivalent) in MeCN (8 mL). The mixture was stirred at 90 °C under a N2 atmosphere for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to give the crude product. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 mm × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 70%-90% B for 10 min) to obtain a white solid 6-[2-[4-[(9 S )-9-ethyl-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6[Tweldecarbo-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (400 mg, 720 μmol, 67% yield).

[0729] Step 5: Preparation (9 S )-7-[4-[2-(2-azaspiro[3.3]hept-6-yl)ethynyl]phenyl]-9-ethyl-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaene. To 6-[2-[4-[(9 S )-9-ethyl-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [100 mg, 180 μmol, 1.0 equivalent]tetane-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (TFA) was added to a solution of DCM (1 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated and alkalized with saturated NaHCO3 at 0 °C. The mixture was extracted with DCM / MeOH (10:1, 20 mL × 2), dried over Na2SO4, filtered, and concentrated to give a yellow oil (9 S )-7-[4-[2-(2-azaspiro[3.3]hept-6-yl)ethynyl]phenyl]-9-ethyl-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Decadecyl-2(6),4,7,10,12-pentane (82 mg)]

[0730] Step 6: Preparation N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]-6-[6-[2-[4-[(9 S )-9-ethyl-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]hept-2-yl]pyridazine-3-carboxamide (I-6). To (9 S )-7-[4-[2-(2-azaspiro[3.3]hept-6-yl)ethynyl]phenyl]-9-ethyl-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6[Decadecyl-2(6),4,7,10,12-pentaene (82 mg, 0.18 mmol, 1.0 equivalent) and 6-chloro- N DIEA (70 mg, 0.54 mmol, 3.0 equivalents) was added to a solution of 4-[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]pyridazine-3-carboxamide (95 mg, 0.22 mmol, 1.2 equivalents) in NMP (0.5 mL). The mixture was stirred at 65 °C for 12 h. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 µm; mobile phase: [water (FA)-ACN]; gradient: 70%-90% B over 10 min) to obtain a white solid. N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]-6-[6-[2-[4-[(9 S )-9-ethyl-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Decadecyl-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]hept-2-yl]pyridazine-3-carboxamide (53 mg, 60 μmol, 33% yield). 1 H NMR (400 MHz, CD3OD) 7.91 (d, J = 9.4 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.47 -7.40 (m, 4H), 7.13 (d, J = 8.6 Hz, 1H), 7.06 (s, 1H), 6.87 (d, J = 9.2 Hz,1H), 4.61 - 4.44 (m, 1H), 4.25 (d, J = 6.0 Hz, 4H), 4.03 - 3.91 (m, 2H), 3.25(t, J = 7.8 Hz, 1H), 2.77 - 2.68 (m, 5H), 2.52 - 2.43 (m, 7H), 2.21 (s, 2H), 2.09 (d, J = 3.6 Hz, 2H), 1.70 (s, 3H), 1.65 (t, J = 9.8 Hz, 4H), 1.23 (t, J= 7.4 Hz, 3H). LC-MS: MS (ES + ): RT = 2.416 min, m / z = 860.5 [M+H] + .

[0731] Example 2 - Synthesis N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]-6-[6-[2-[4-(4,5,13-trimethylspiro[3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentane-9,1'-cyclopropane]-7-yl)phenyl]ethynyl]-2-azaspiro[3.3]hept-2-yl]pyridazine-3-carboxamide (I-7).

[0732]

[0733] Step 1: Preparation N -[1-[[3-(4-chlorobenzoyl)-4,5-dimethyl-2-thienyl]carbamoyl]cyclopropyl]tert-butyl carbamate. T4P (211.5 g, 293.5 mmol, 3.0 equivalent) was added to a solution of (2-amino-4,5-dimethyl-3-thienyl)-(4-chlorophenyl) ketone (26 g, 97.8 mmol, 1.0 equivalent), 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid (59 g, 293.5 mmol, 3.0 equivalent) and pyridine (38.7 g, 489 mmol, 39.5 mL, 5.0 equivalent) in EtOAc (50 mL). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with NaHCO3 (100 mL) and extracted with ethyl acetate (250 mL × 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was wet-milled with petroleum ether / ethyl acetate (3:1, 200 mL) to give a yellow solid. N -[1-[[3-(4-chlorobenzoyl)-4,5-dimethyl-2-thienyl]carbamoyl]cyclopropyl]tert-butyl carbamate (48 g, crude material).

[0734] Step 2: Preparation of 1-amino- N -[3-(4-chlorobenzoyl)-4,5-dimethyl-2-thienyl]cyclopropaneformamide. N1-[[3-(4-chlorobenzoyl)-4,5-dimethyl-2-thienyl]carbamoyl]cyclopropyl]tert-butyl carbamate (43 g, 95.8 mmol, 1.0 equivalent) was added to a solution of TFA (218 g, 1.9 mol, 142 mL, 20.0 equivalent) in DCM (140 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with NaHCO3 (200 mL) and extracted with ethyl acetate (250 mL × 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1-amino- N -[3-(4-chlorobenzoyl)-4,5-dimethyl-2-thienyl]cyclopropaneformamide (27 g, 80% yield).

[0735] Step 3: Preparation of 5-(4-chlorophenyl)-6,7-dimethyl-spiro[1] H -thiophene[2,3- e [1,4]diazapine-3,1'-cyclopropane]-2-one. Towards 1-amino- N 5-(4-chlorobenzoyl)-4,5-dimethyl-2-thienyl]cyclopropaneformamide (27 g, 77.4 mmol, 1.0 equivalent) was added to a solution of IPA (270 mL) with AcOH (23.2 g, 387 mmol, 22 mL, 5.0 equivalent). The mixture was stirred at 90 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was wet-milled with ethyl acetate (200 mL) to give 5-(4-chlorophenyl)-6,7-dimethyl-spiro[1] as a yellow solid. H -thiophene[2,3- e [1,4]diazapine-3,1'-cyclopropane]-2-one (22.6 g, 88% yield).

[0736] Step 4: Preparation of 7-(4-chlorophenyl)-4,5,13-trimethyl-spiro[3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentane-9,1'-cyclopropane]. The mixture was heated at -78°C. Tert -BuOK (1M, 6.7 mL, 1.1 equivalents) was added to 5-(4-chlorophenyl)-6,7-dimethyl-spiro[1] H -thiophene[2,3- e[1,4]diazapine-3,1'-cyclopropane]-2-one (2 g, 6 mmol, 1.0 equivalent) was added to a solution of THF (25 mL). The reaction mixture was heated to -10 °C and stirred at 25 °C for 0.5 h. The reaction mixture was then cooled to -78 °C. [chloro(phenoxy)phosphoryl]oxybenzene (1.95 g, 7.3 mmol, 1.5 mL, 1.2 equivalent) was added to the reaction mixture. The resulting mixture was heated to -10 °C for 0.75 h. Then, acetylhydrazine (672 mg, 9 mmol, 1.5 equivalent) was added to the reaction mixture. The reaction mixture was stirred at 25 °C. After 1 hour, tert -BuOH (30 mL) was added to the reaction mixture, and the mixture was heated at 90 °C for 1 hour. The mixture was poured into water (100 mL) and extracted with DCM (200 mL × 2). The combined organic layers were washed with brine (200 mL) and dried over Na2SO4. The mixture was concentrated, and the residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 40 mm × 15 µm; mobile phase: [water (FA)-ACN]; gradient: 37%-67% B for 15 min) to give 7-(4-chlorophenyl)-4,5,13-trimethyl-spiro[3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadeca-2(6),4,7,10,12-pentane-9,1'-cyclopropane] (600 mg, 26% yield) as a white solid.

[0737] Step 5: Preparation of tert-butyl 6-[2-[4-(4,5,13-trimethylspiro[3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadeca-2(6),4,7,10,12-pentaen-9,1'-cyclopropane]-7-yl)phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid. To 7-(4-chlorophenyl)-4,5,13-trimethyl-spiro[3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]... 2,6[Decadecyl-2(6),4,7,10,12-pentane-9,1'-cyclopropane] (400 mg, 1.08 mmol, 1.0 equivalent) and 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (599 mg, 2.71 mmol, 2.5 equivalent) were added to a solution of ACN (8 mL) with DavePhos Pd G3 (82.7 mg, 108 μmol, 0.1 equivalent) and Cs2CO3 (706 mg, 2.17 mmol, 2.0 equivalent). The mixture was stirred at 90 °C for 2 hours. The reaction mixture was filtered and concentrated to give the crude product. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 40 mm × 15 µm; mobile phase: [water (FA)-ACN]; gradient: 55%-85% B for 15 min) to obtain a yellow solid, 6-[2-[4-(4,5,13-trimethylspiro[3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0]). 2,6 [Tweldecarbon-2(6),4,7,10,12-pentene-9,1'-cyclopropane]-7-yl)phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (360 mg, 650 μmol, 60% yield).

[0738] Step 6: Preparation of 7-[4-[2-(2-azaspiro[3.3]hept-6-yl)ethynyl]phenyl]-4,5,13-trimethyl-spiro[3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadeca-2(6),4,7,10,12-pentaene-9,1'-cyclopropane]. To 6-[2-[4-(4,5,13-trimethylspiro[3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadeca-2(6),4,7,10,12-pentaene-9,1'-cyclopropane]. 2,6 [180 mg, 325 μmol, 1.0 equivalent]tetane-2(6),4,7,10,12-pentane-9,1'-cyclopropane]-7-yl)phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (2 mL) was added to a solution of TFA (1 mL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated, alkalized with aqueous NaHCO3 solution, and extracted with DCM / MeOH (10:1, 30 mL × 2). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a yellow oily 7-[4-[2-(2-azaspiro[3.3]hept-6-yl)ethynyl]phenyl]-4,5,13-trimethyl-spiro[3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0]2,6 [[Decadecane-2(6),4,7,10,12-pentane-9,1'-cyclopropane](146 mg, 321 μmol, crude material), which was used directly in the next step without purification.

[0739] Step 7: Preparation N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]-6-[6-[2-[4-(4,5,13-trimethylspiro[3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadeca-2(6),4,7,10,12-pentaen-9,1'-cyclopropane]-7-yl)phenyl]ethynyl]-2-azaspiro[3.3]hept-2-yl]pyridazine-3-carboxamide (I-7). To 7-[4-[2-(2-azaspiro[3.3]hept-6-yl)ethynyl]phenyl]-4,5,13-trimethyl-spiro[3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadeca-2(6),4,7,10,12-pentaen-9,1'-cyclopropane]-7-yl)phenyl]-4,5,13-trimethyl-spiro[3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6] 2,6 [Decadecano-2(6),4,7,10,12-pentane-9,1'-cyclopropane] (73.0 mg, 160 μmol, 1.0 equivalent) was added to a solution of NMP (1 mL) with DIEA (62.4 mg, 482 μmol, 84.1 μL, 3.0 equivalent) and 6-chloro- N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]pyridazine-3-carboxamide (70.9 mg, 160 μmol, 1.0 equivalent). The mixture was stirred at 65 °C for 12 hours. The residue was purified by preparative HPLC (column: Waters xbridge 150 × 25 mm 10 µm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 60%-80% B for 8 min) to obtain a white solid. N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]-6-[6-[2-[4-(4,5,13-trimethyl-spiro[3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Deca-2(6),4,7,10,12-pentene-9,1'-cyclopropane]-7-yl)phenyl]ethynyl]-2-azaspiro[3.3]hept-2-yl]pyridazine-3-carboxamide (34.4 mg, 40.1 μmol, 25% yield). 1 H NMR (400 MHz, CD3OD) δ 7.91 (d, J = 9.3 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.47 - 7.40 (m, 4H), 7.13 (dd, J = 2.3, 8.8 Hz, 1H), 7.06 (s,1H), 6.85 (d, J = 9.4 Hz, 1H), 4.56 - 4.51 (m, 1H), 4.24 (d, J = 5.9 Hz, 4H),4.02 - 3.92 (m, 1H), 3.25 (t, J = 8.0 Hz, 1H), 2.79 - 2.68 (m, 5H), 2.51 -2.42 (m, 5H), 2.22 (br d, J = 4.2 Hz, 2H), 2.10 (br s, 2H), 1.96 - 1.86 (m,1H), 1.70 - 1.60 (m, 7H), 1.54 (dt, J = 6.5, 8.5 Hz, 1H), 0.90 (br t, J = 8.7Hz, 2H). LC-MS: MS (ES) + ): RT = 2.376 min, m / z = 858.5 [M+H] + .

[0740] Example 3 - Composition N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]-6-[6-[2-[4-[(9 R )-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]hept-2-yl]pyridazine-3-carboxamide (I-8).

[0741]

[0742] Step 1: Preparation of tert-butyl (1-((3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)amino)-3-methoxy-1-oxopropyl-2-yl)carbamate. To (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl) methyl ketone (10.0 g, 37.6 mmol, 1.0 equivalent) and N-(tert-butoxycarbonyl)-O-methyl-L-serine (16.5 g, 75.26 mmol, 2.0 equivalents) was added to a solution in e (25 mL) along with pyridine (17.8 g, 225.7 mmol, 18.2 mL, 6.0 equivalents) and T4P (81.3 g, 112.8 mmol, 50% purity, 3.0 equivalents). The mixture was stirred at 25 °C for 12 hours. Ice water (200 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (2 × 200 mL). The combined organic phases were washed with 0.5 M HCl (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give tert-butyl 1-((3-(4-chlorobenzoyl)-4,5-dimethylthiophene-2-yl)amino)-3-methoxy-1-oxopropyl-2-yl)carbamate (17.0 g, crude material) as a yellow solid.

[0743] Step 2: Preparation of 2-amino- N -(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methoxypropionamide. TFA (20 mL) was added to a solution of tert-butyl (17.0 g, 36.4 mmol, 1.0 equivalent) in DCM (20 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. DCM (100 mL) was added to the residue, and the pH was adjusted to 7 by adding NaHCO3 (250 mL). The mixture was extracted with dichloromethane:methanol (10:1, 3 × 750 mL). The combined organic phases were washed with brine (250 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give crude 2-amino- N -(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methoxypropionamide (13 g, crude material) was used directly in the next step without purification.

[0744] Step 3: Preparation of 5-(4-chlorophenyl)-3-(methoxymethyl)-6,7-dimethyl-1,3-dihydro-2 H -thiophene[2,3- e [1,4]diazapine-2-one. Towards 2-amino- N12.0 g (32.7 mmol, 1.0 equivalent) of 3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methoxypropionamide (12.0 g, 32.7 mmol, 1.0 equivalent) was added to a solution of EtOH (60 mL) with AcOH (10.4 g, 174.6 mmol, 10 mL, 5.3 equivalent). The mixture was stirred at 40 °C for 12 h. Water (250 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane:methanol (10:1, 200 mL). The organic phase was washed with brine (250 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1). 5-(4-chlorophenyl)-3-(methoxymethyl)-6,7-dimethyl-1,3-dihydro-2-dimethylpropionamide was given as a yellow solid. H -thiophene[2,3- e [1,4]diazapine-2-one (9.0 g, 25.8 mmol, 78% yield).

[0745] Step 4: Preparation (9 R )-7-(4-chlorophenyl)-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Tweldecarbon-2(6),4,7,10,12-pentane. Potassium tert-butoxide (1.0 M, 15.7 mL, 1.1 equivalents) was added to 5-(4-chlorophenyl)-3-(methoxymethyl)-6,7-dimethyl-1,3-dihydro-2- H -thiophene[2,3- e[1,4]diazepine-2-one (5.0 g, 14.3 mmol, 1.0 equivalent) was added to a solution of THF (50 mL). The reaction mixture was heated to 25 °C and stirred at 25 °C for 30 min. The reaction mixture was cooled to -78 °C. Diphenyl chlorophosphate (4.6 g, 17.2 mmol, 3.5 mL, 1.2 equivalent) was added to the reaction mixture. The resulting mixture was heated to 25 °C for 30 min. Acetylhydrazine (1.59 g, 21.5 mmol, 1.5 equivalent) was added to the reaction mixture at 25 °C. Then, n-butanol (50 mL) was immediately added to the reaction mixture with stirring, and the mixture was heated to 90 °C for 1 h. The reaction mixture was quenched with H2O (100 mL) at 0 °C, followed by extraction with EtOAc (2 × 100 mL). The combined organic layers were washed with H2O (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250 × 80 mm × 10 µm; mobile phase: [water (TFA)-ACN]; gradient: 45%-75% B for 20 min) to obtain a yellow solid (9... R )-7-(4-chlorophenyl)-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Decadecyl-2(6),4,7,10,12-pentaene (8.0 g, 7.75 mmol, 54% yield).]

[0746] Step 5: Preparation of tert-butyl 6-[2-[4-[9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadecan-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid. To (9 R )-7-(4-chlorophenyl)-9-(methoxy-methyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6A solution of tridecano-2(6),4,7,10,12-pentaene (400 mg, 1.03 mmol, 1.0 equivalent) and 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (572 mg, 2.58 mmol, 2.5 equivalent) in MeCN (5 mL) was mixed with DavePhos Pd G3 (79 mg, 103 μmol, 0.1 equivalent) and Cs2CO3 (674 mg, 2.07 mmol, 2.0 equivalent). The mixture was stirred at 90 °C for 2 hours. The mixture was filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 µm; mobile phase: [water (FA)-ACN]; gradient: 56%-86% B for 10 min) to obtain a colorless oily 6-[2-[4-[9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0]). 2,6 [Tweldecarbo-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (450 mg, 787 μmol, 76% yield).

[0747] Step 6: Prepare 6-[2-[4-[(9 R )-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester. 6-[2-[4-[9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0]] was purified by preparative SFC (column: DAICL CHIRALPAK AS (250 mm × 30 mm, 10 µm); mobile phase: [CO2-EtOH]; B%: 40%, isocratic elution mode) and preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 µm; mobile phase: [water (FA)-ACN]; gradient: 58%-88% B for 10 min). 2,6 [Tweldecarbon-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was obtained as a colorless oil, yielding 6-[2-[4-[(9 R)-9-(methoxy-methyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclic[8.3.0.0] 2,6 [Tweldecarbon-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (200 mg, 350 μmol, 44% yield).

[0748] Step 7: Preparation (9 R )-7-[4-[2-(2-azaspiro[3.3]hept-6-yl)ethynyl]phenyl]-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaene. To 6-[2-[4-[(9 R )-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [190 mg, 332 μmol, 1.0 equivalent]tetane-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (2 mL) was added to a solution of DCM (2 mL) with TFA (1 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated and alkalized with saturated NaHCO3 at 0 °C. The mixture was extracted with DCM / MeOH (10:1, 50 mL × 2), dried over Na2SO4, filtered, and concentrated to give a colorless oil (9) R )-7-[4-[2-(2-azaspiro[3.3]hept-6-yl)ethynyl]phenyl]-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Decadecyl-2(6),4,7,10,12-pentane (157 mg, crude material).]

[0749] Step 8: Preparation N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]-6-[6-[2-[4-[(9 R )-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]hept-2-yl]pyridazine-3-carboxamide (I-8). To (9 R)-7-[4-[2-(2-azaspiro[3.3]hept-6-yl)ethynyl]phenyl]-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Decadecyl-2(6),4,7,10,12-pentaene (78 mg, 165 μmol, 1.0 equivalent) and 6-chloro-] N DIEA (64 mg, 496 μmol, 86 μL, 3.0 equivalents) was added to a solution of 3-[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]pyridazine-3-carboxamide (80 mg, 182 μmol, 1.1 equivalents) in NMP (1 mL). The mixture was stirred at 65 °C for 12 h. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 µm; mobile phase: [water (FA)-ACN]; gradient: 58%-88% B over 10 min) to give a white solid compound. N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]-6-[6-[2-[4-[(9 R )-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Decadecyl-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]hept-2-yl]pyridazine-3-carboxamide (23 mg, 26 μmol, 16% yield). 1H NMR (400 MHz, CD3OD) 7.93 (s, 1H), 7.80 - 7.77 (m,1H), 7.50 - 7.42 (m, 4H), 7.17 - 7.14 (m, 1H), 7.08 (s, 1H), 6.93 - 6.88 (m,1H), 4.60 - 4.49 (m, 1H), 4.48 - 4.42 (m, 1H), 4.42 - 4.37 (m, 2H), 4.31 -4.26 (m, 4H), 4.05 - 3.93 (m, 1H), 3.57 (s, 3H), 3.25 (s, 1H), 2.81 - 2.73(m, 2H), 2.72 (s, 3H), 2.53 - 2.48 (m, 2H), 2.47 (s, 3H), 2.27 - 2.18 (m,2H), 2.16 - 2.05 (m, 2H), 1.72 (s, 3H), 1.70 - 1.63 (m, 4H), -2.51 - -2.53(m, 1H). LC-MS: MS (ES + ): RT = 2.341 min, m / z = 876.5 [M+H] + LCMS method: 25.

[0750] Example 4 - Synthesis N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]-6-[6-[2-[4-[(9 S )-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]hept-2-yl]pyridazine-3-carboxamide (I-9).

[0751]

[0752]

[0753] Step 1: Preparation of tert-butyl 6-[2-[4-[9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadecan-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid. To (9 S)-7-(4-chlorophenyl)-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 DavePhos PdG3 (47 mg, 62 µmol, 0.1 equivalent) was added to a solution of tridecano-2(6),4,7,10,12-pentaene (250 mg, 624 µmol, 1.0 equivalent), 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (345 mg, 1.56 mmol, 2.5 equivalent) and Cs2CO3 (406 mg, 1.25 mmol, 2.0 equivalent) in MeCN (5 mL). The mixture was stirred at 90 °C under a N2 atmosphere for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to give the crude product. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 µm; mobile phase: [water (FA)-ACN]; gradient: 68%-88% B for 10 min) to obtain a white solid 6-[2-[4-[9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0]). 2,6 [Tweldecarbon-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (240 mg, 410 μmol, 66% yield).

[0754] Step 2: Prepare 6-[2-[4-[(9 S )-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester. Prepared by a preparative SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 µm); mobile phase: [CO2-ACN / i -PrOH (0.1% NH3.H2O)]; B%: 45%, isocratic elution mode) purification of 6-[2-[4-[9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Tweldecarbon-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was obtained as a white solid 6-[2-[4-[(9 S)-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Tweldecarbon-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (200 mg, 341 μmol, 83% yield).

[0755] Step 3: Preparation (9 S )-7-[4-[2-(2-azaspiro[3.3]hept-6-yl)ethynyl]phenyl]-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaene. To 6-[2-[4-[(9 S )-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [100 mg, 171 μmol, 1.0 equivalent]tetane-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (TFA) was added to a solution of DCM (1 mL) with TFA (0.5 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated and alkalized with saturated NaHCO3 at 0 °C. The mixture was extracted with DCM / MeOH (10:1, 2 × 20 mL), dried over Na2SO4, filtered, and concentrated to give a yellow oil (9 S )-7-[4-[2-(2-azaspiro[3.3]hept-6-yl)ethynyl]phenyl]-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Decadecyl-2(6),4,7,10,12-pentane (83 mg).]

[0756] Step 4: Preparation N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]-6-[6-[2-[4-[(9 S )-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]hept-2-yl]pyridazine-3-carboxamide (I-9). To (9 S)-7-[4-[2-(2-azaspiro[3.3]hept-6-yl)ethynyl]phenyl]-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Decadecyl-2(6),4,7,10,12-pentaene (83 mg, 0.17 mmol, 1.0 equivalent) and 6-chloro- N DIEA (66 mg, 0.51 mmol, 3.0 equivalents) was added to a solution of 4-[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]pyridazine-3-carboxamide (90 mg, 0.21 mmol, 1.2 equivalents) in NMP (0.5 mL). The mixture was stirred at 65 °C for 12 h. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 µm; mobile phase: [water (FA)-ACN]; gradient: 66%-86% B over 10 min) to obtain a white solid. N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]-6-[6-[2-[4-[(9 S )-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Deca-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]hept-2-yl]pyridazine-3-carboxamide (20 mg, 22 μmol, 13% yield). 1 H NMR (400 MHz, CD3OD) 7.93 (d, J = 9.2 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.47 - 7.40 (m, 4H), 7.13 (d, J = 8.8 Hz, 1H), 7.05 (s,1H), 6.89 (d, J = 9.4 Hz, 1H), 4.60 - 4.48 (m, 1H), 4.29 - 4.23 (m, 5H), 4.03- 3.92 (m, 1H), 3.87 - 3.73 (m, 2H), 3.35 (s, 3H), 3.28 - 3.23 (m, 1H), 2.77- 2.69 (m, 7H), 2.51 - 2.44 (m, 5H), 2.21 (d, J= 6.4 Hz, 2H), 2.10 (d, J =3.8 Hz, 2H), 1.70 (s, 3H), 1.68 - 1.61 (m, 4H).

[0757] Example 5 - Synthesis N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]-6-[6-[2-[4-[(9 S )-4,5,9,13-Tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]hept-2-yl]pyridazine-3-carboxamide(I-12)

[0758]

[0759] Step 1: Prepare 6-[2-[4-[(9 S )-4,5,9,13-Tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester. Under N2, towards (9 S )-7-(4-chlorophenyl)-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 A solution of tridecano-2(6),4,7,10,12-pentaene (400 mg, 1.12 mmol, 1.0 equivalent) and 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (620 mg, 2.80 mmol, 2.5 equivalent) in ACN (5.0 mL) was supplemented with DavePhos Pd G3 (86.0 mg, 112 μmol, 0.1 equivalent) and Cs2CO3 (730 mg, 2.24 mmol, 2.0 equivalent). The suspension was degassed under vacuum and purged three times with N2. The mixture was stirred at 90 °C under N2 for 2 hours. The reaction mixture was filtered and concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 40 mm × 15 µm; mobile phase: [water (FA)-ACN]; gradient: 57%–87% B over 15 min). The compound 6-[2-[4-[(9)] was obtained as a brown oil. S )-4,5,9,13-Tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0]2,6 [Tweldecarbon-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (380 mg, 701 μmol, 63% yield).

[0760] Step 2: Preparation (9 S )-7-[4-[2-(2-azaspiro[3.3]hept-6-yl)ethynyl]phenyl]-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaene. To 6-[2-[4-[(9 S )-4,5,9,13-Tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [100 mg, 185 μmol, 1.0 equivalent]tetane-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (TFA) was added to a solution of DCM (2.0 mL). The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated and alkalized with aqueous NaHCO3 solution and extracted with DCM / MeOH (10:1, 20 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a colorless oil (9 S )-7-[4-[2-(2-azaspiro[3.3]hept-6-yl)ethynyl]phenyl]-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Decadecyl-2(6),4,7,10,12-pentaene (82.0 mg, 185 μmol, 100% yield).]

[0761] Step 3: Preparation N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]-6-[6-[2-[4-[(9 S )-4,5,9,13-Tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]hept-2-yl]pyridazine-3-carboxamide (I-12). To 6-chloro- N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazine-3-carboxamide (83.0 mg, 212 μmol, 1.3 equivalents) was added to a solution of DIEA (63.0 mg, 490 μmol, 85 μL, 3.0 equivalents) and 6-chloro- N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]pyridazine-3-carboxamide (89.0 mg, 203 μmol, 1.1 equivalents). The mixture was stirred at 65 °C for 12 hours. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 µm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 53%-73% B over several minutes) to obtain a grayish-white solid. N -[4-[4-cyano-3-(trifluoromethoxy)phenoxy]cyclohexyl]-6-[6-[2-[4-[(9 S )-4,5,9,13-Tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Decadecyl-2(6),4,7,10,12-pentene-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]hept-2-yl]pyridazine-3-carboxamide (54.68 mg, 64.64 μmol, 35% yield). 1 H NMR (400 MHz, CD3OD) δ 7.91 (d, J = 9.3 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.46 -7.40 (m, 4H), 7.15 - 7.11 (m, 1H), 7.05 (s, 1H), 6.86 (d, J = 9.4 Hz, 1H), 4.53 (br s, 1H), 4.33 - 4.22 (m, 5H), 3.98 (br d, J = 3.5 Hz, 1H), 3.64 -3.58 (m, 1H), 3.29 - 3.21 (m, 1H), 2.76 - 2.72 (m, 1H), 2.70 (s, 3H), 2.49(br d, J = 7.8 Hz, 2H), 2.44 (s, 3H), 2.21 (br s, 2H), 2.09 (br s, 2H), 2.-0(d, J= 6.7 Hz, 3H), 1.71 - 1.62 (m, 6H). LC-MS: MS (ES + ): RT = 2.416 min, m / z =860.5 [M+H] + LCMS method: 25.

[0762] Example 6 - Synthesis N -((1 r 4 r )-4-(4-cyano-3-(trifluoromethoxy)phenoxy)cyclohexyl)-6-(8-(4-( S )-6-ethyl-2,3,9-trimethyl-6 H -Thiophene[3,2- f [1,2,4]triazolo[4,3- a [1,4]diazapine-4-yl)phenyl)-2-azaspiro[4.5]dec-2-yl)pyridazine-3-carboxamide (I-13)

[0763] Step 1: Preparation N -[(1 S )-1-[[3-(4-chlorobenzoyl)-4,5-dimethyl-2-thienyl]carbamoyl]propyl]tert-butyl carbamate. At 0°C, it is directed towards (2 S 2-(tert-butoxycarbonylamino)butyric acid (4.6 g, 22.6 mmol, 3.0 equivalent) was added to a solution of DCM (30 mL) containing NMM (4.6 g, 45 mmol, 5.0 mL, 6.0 equivalent) and isobutyl chloroformate (4.6 g, 33 mmol, 4.4 mL, 4.5 equivalent). The mixture was stirred at 25 °C for 1 hour. Immediately afterwards, (2-amino-4,5-dimethyl-3-thienyl)-(4-chlorophenyl)methyl ketone (2 g, 7.5 mmol, 1.0 equivalent) was added, and the mixture was stirred again at 25 °C for 11 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 40 mm × 15 µm; mobile phase: [water (FA)-ACN]; gradient: 62%-92% B for 15 min) to obtain N -[(1 S )-1-[[3-(4-chlorobenzoyl)-4,5-dimethyl-2-thienyl]carbamoyl]propyl]tert-butyl carbamate (1 g, 29% yield).

[0764] Step 2: Preparation (2 S )-2-amino- N -[3-(4-chlorobenzoyl)-4,5-dimethyl-2-thienyl]butyramide. To N -[(1 S 1-[[3-(4-chlorobenzoyl)-4,5-dimethyl-2-thienyl]carbamoyl]propyl]tert-butyl carbamate (500 mg, 1.1 mmol, 1.0 equivalent) was added to a solution of DCM (5 mL) with TFA (1.3 g, 11.1 mmol, 823 μL, 10.0 equivalent). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and the filtrate was concentrated. Product (2) S )-2-amino- N -[3-(4-chlorobenzoyl)-4,5-dimethyl-2-thienyl]butyramide was used directly in the next step without purification.

[0765] Step 3: Preparation (3 S )-5-(4-chlorophenyl)-3-ethyl-6,7-dimethyl-1,3-dihydrothiopheno[2,3- e [1,4]diazapine-2-one. To (2 S )-2-amino- N -[3-(4-chlorobenzoyl)-4,5-dimethyl-2-thienyl]butyramide (380 mg, 1.1 mmol, 1.0 equivalent) in i AcOH (325 mg, 5.4 mmol, 310 μL, 5.0 equivalent) was added to a solution of -PrOH (5 mL). The mixture was stirred at 90 °C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give (3 S )-5-(4-chlorophenyl)-3-ethyl-6,7-dimethyl-1,3-dihydrothiopheno[2,3- e [1,4]Diazapine-2-one (220 mg, 61% yield).

[0766] Step 4: Preparation (9 S )-7-(4-chlorophenyl)-9-ethyl-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentane. Potassium tert-butoxide (1 M, 859 μL, 1.3 equivalents) was added at -78 °C to a concentration containing (3 S )-5-(4-chlorophenyl)-3-ethyl-6,7-dimethyl-1,3-dihydrothiopheno[2,3-e [1,4]diazapine-2-one (220 mg, 660 μmol, 1.0 equivalent) was added to THF (5 mL). The reaction mixture was heated to -10 °C over 0.5 h and stirred at 25 °C for another 0.5 h. The reaction mixture was cooled to -78 °C. [chloro(phenoxy)phosphoryl]oxybenzene (230 mg, 859 μmol, 178 μL, 1.3 equivalent) was added to the reaction mixture. The resulting mixture was heated to -10 °C over 0.75 h. Then, acetylhydrazine (73 mg, 991 μmol, 1.5 equivalent) was added to the reaction mixture. The reaction mixture was stirred at 25 °C. After 1 hour, tert -BuOH (5 mL) was added to the reaction mixture, and the mixture was heated to 90 °C for 1 hour. The reaction mixture was concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150 × 25 mm × 10 µm; mobile phase: [water (FA)-ACN]; gradient: 47%-77% B over 10 min) to obtain (9 S )-7-(4-chlorophenyl)-9-ethyl-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Decadecyl-2(6),4,7,10,12-pentaene (100 mg, 41% yield).]

[0767] Step 5: Prepare 8-(4-(( S )-6-ethyl-2,3,9-trimethyl-6 H -Thiophene[3,2- f [1,2,4]triazolo[4,3- a [1,4]diazapine-4-yl)phenyl)-2-azaspiro[4.5]dec-7-en-2-carboxylic acid tert-butyl ester. 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-2-azaspiro[4.5]dec-7-en-2-carboxylic acid tert-butyl ester (636 mg, 1.75 mmol, 1.0 equivalent), (9) S )-7-(4-chlorophenyl)-9-ethyl-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6A mixture of tridecano-2(6),4,7,10,12-pentaene (650 mg, 1.75 mmol, 1.0 equivalent), Xphos Pd G4 (150 mg, 175 μmol, 0.1 equivalent) and K3PO4 (1.12 g, 5.26 mmol, 3.0 equivalent) in H2O (1 mL) and THF (4 mL) was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:1 to 0:1) to give a yellow solid 8-(4-( S )-6-ethyl-2,3,9-trimethyl-6 H -Thiophene[3,2- f [1,2,4]triazolo[4,3- a [1,4]diazapine-4-yl)phenyl)-2-azaspiro[4.5]dec-7-ene-2-carboxylic acid tert-butyl ester (1.3 g, crude material).

[0768] Step 6: Preparation ( S )-8-(4-(6-ethyl-2,3,9-trimethyl-6 H -Thiophene[3,2- f [1,2,4]triazolo[4,3- a [1,4]diazapine-4-yl)phenyl)-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester. To 8-(4-(( S )-6-ethyl-2,3,9-trimethyl-6 H -Thiophene[3,2- f [1,2,4]triazolo[4,3- a [1,4]diazapine-4-yl)phenyl)-2-azaspiro[4.5]dec-7-ene-2-carboxylic acid tert-butyl ester (1.3 mg, 2.3 mmol, 1.0 equivalent) was added to a solution of Pd / C (940 mg, 10% purity) in TFE (4 mL). The mixture was stirred at 20 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 40 mm × 15 µm; mobile phase: [water (TFA)-ACN]; gradient: 45%-75% B over 10 min) to give a yellow solid. S )-8-(4-(6-ethyl-2,3,9-trimethyl-6 H -Thiophene[3,2- f [1,2,4]triazolo[4,3- a[1,4]diazapine-4-yl)phenyl)-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (600 mg, 1.05 mmol, 46% yield).

[0769] Step 7: Preparation ( S )-8-(4-(6-ethyl-2,3,9-trimethyl-6 H -Thiophene[3,2- f [1,2,4]triazolo[4,3- a [1,4]diazapine-4-yl)phenyl)-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester. Separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 µm); mobile phase: [CO2-EtOH (0.1% NH3.H2O)]; B%: 50%, isocratic elution mode) S )-8-(4-(6-ethyl-2,3,9-trimethyl-6 H -Thiophene[3,2- f [1,2,4]triazolo[4,3- a [1,4]diazapine-4-yl)phenyl)-2-azaspiro[4,5]decane-2-carboxylic acid tert-butyl ester (600 mg, 1.05 mmol) was given to ( S )-8-(4-(6-ethyl-2,3,9-trimethyl-6 H -Thiophene[3,2- f [1,2,4]triazolo[4,3- a [1,4]diazapine-4-yl)phenyl)-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (350 mg, 609 μmol).

[0770] Step 8: Preparation ( S )-4-(4-(2-azaspiro[4.5]dec-8-yl)phenyl)-6-ethyl-2,3,9-trimethyl-6 H -Thiophene[3,2- f [1,2,4]triazolo[4,3- a [1,4] Diazapine. To ( S )-8-(4-(6-ethyl-2,3,9-trimethyl-6 H -Thiophene[3,2- f [1,2,4]triazolo[4,3- a[1,4]diazapine-4-yl)phenyl)-2-azaspiro[4,5]decane-2-carboxylic acid tert-butyl ester (300 mg, 575 μmol, 1.0 equivalent) was added to a solution of DCM (2 mL) with TFA (1 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated and alkalized with an aqueous solution of NaHCO3. After extraction with DCM / MeOH (10:1, 10 mL × 2), the organic phase was concentrated to give the crude product ( S )-4-(4-(2-azaspiro[4.5]dec-8-yl)phenyl)-6-ethyl-2,3,9-trimethyl-6 H -Thiophene[3,2- f [1,2,4]triazolo[4,3- a [1,4] Diazapine (270 mg, crude) was used directly in the next step without purification.

[0771] Step 9: Preparation N -((1 r 4 r )-4-(4-cyano-3-(trifluoromethoxy)phenoxy)cyclohexyl)-6-(8-(4-( S )-6-ethyl-2,3,9-trimethyl-6 H -Thiophene[3,2- f [1,2,4]triazolo[4,3- a [1,4]diazapine-4-yl)phenyl)-2-azaspiro[4.5]dec-2-yl)pyridazine-3-carboxamide (I-13). To ( S )-4-(4-(2-azaspiro[4.5]dec-8-yl)phenyl)-6-ethyl-2,3,9-trimethyl-6 H -Thiophene[3,2- f [1,2,4]triazolo[4,3- a [1,4] Diazapine (130 mg, 274 μmol, 1.0 equivalent) was added to a solution of NMP (0.5 mL) with DIEA (106 mg, 823 µmol, 143 μL, 3.0 equivalent) and 6-chloro- N -((1 r 4 r4-(4-cyano-3-(trifluoromethoxy)phenoxy)cyclohexyl)pyridazine-3-carboxamide (157 mg, 356 μmol, 1.3 equivalents). The mixture was stirred at 65 °C for 12 hours. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 50 mm × 10 µm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 60%-90% B for 10 min) to obtain a white solid. N -((1 r 4 r )-4-(4-cyano-3-(trifluoromethoxy)phenoxy)cyclohexyl)-6-(8-(4-( S )-6-ethyl-2,3,9-trimethyl-6 H -Thiophene[3,2- f [1,2,4]triazolo[4,3- a [1,4]diazapine-4-yl)phenyl)-2-azaspiro[4.5]dec-2-yl)pyridazine-3-carboxamide (177 mg, 199 μmol, 73% yield). 1 H NMR (400 MHz, CD3OD): δ 7.92 (d, J = 9.5 Hz, 1H), 7.76(d, J = 8.8 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.37 - 7.29 (m, 2H), 7.14 (dd, J =2.3, 8.8 Hz, 1H), 7.09 - 7.01 (m, 2H), 4.57 - 4.47 (m, 1H), 4.05 - 3.90 (m,2H), 3.77 - 3.50 (m, 4H), 2.70 (s, 3H), 2.68 - 2.59 (m, 1H), 2.57 - 2.46 (m,2H), 2.44 (s, 3H), 2.29 - 2.18 (m, 2H), 2.15 - 2.04 (m, 2H), 1.96 (br t, J =7.0 Hz, 2H), 1.91 - 1.76 (m, 4H), 1.74 - 1.56 (m, 11H), 1.23 (t, J = 7.3 Hz, 3H). LC-MS: MS (ES) + ): RT = 2.306 min, m / z = 878.6 [M+H]+ LCMS method: 25.

[0772] Example 7 - Composition N -[(1 r 4 r )-4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]-6-[8-[4-[(9 S )-4,5,9,13-Tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [1-Deca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2-azaspiro[4,5]dec-2-yl]pyridazine-3-carboxamide (I-19)

[0773]

[0774]

[0775]

[0776]

[0777]

[0778] Step 1: Preparation ((1) r 4 r 4-(4-cyano-3-methoxyphenoxy)cyclohexyl)carbamate tert-butyl ester. At 0°C under a N2 atmosphere, tert-butyl ester was added to a solution of NaH (1.25 g, 31.21 mmol, 60% purity, 1.2 equivalents) in DMF (60 mL). r 4 r 4-Hydroxycyclohexyl)carbamate tert-butyl ester (5.6 g, 26.01 mmol, 1.0 equivalent). After 30 minutes, 4-fluoro-2-methoxybenzonitrile (3.93 g, 26.01 mmol, 1.0 equivalent) was added. The reaction mixture was slowly heated to 25 °C and stirred for 12 hours. The reaction mixture was quenched at 0 °C with saturated NH4Cl aqueous solution (100 mL). The resulting mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 0:1 to 3:1) to give a white solid ((1 r 4 r 4-(4-cyano-3-methoxyphenoxy)cyclohexyl)tert-butyl carbamate (4.8 g, 13.86 mmol, 53% yield).

[0779] Step 2: Preparation of 4-(((1) r 4 r )-4-aminocyclohexyl)oxy)-2-methoxy-benzonitrile. To ((1 r 4 r TFA (1 mL) was added to a solution of 4-(4-cyano-3-methoxyphenoxy)cyclohexyl)carbamate (0.5 g, 1.44 mmol, 1.0 equivalent) in DCM (2 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, giving a yellow oily 4-(((1) r 4 r )-4-aminocyclohexyl)oxy)-2-methoxybenzonitrile (520 mg, 1.44 mmol, 99.99% yield, TFA salt).

[0780] Step 3: Preparation of 6-chloro- N -[(1 r 4 r )-4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]pyridazine-3-carboxamide. To 4-(((1 r 4 r HATU (823 mg, 2.16 mmol, 1.5 equivalent) and DIEA (560 mg, 4.33 mmol, 754 μL, 3.0 equivalent) were added to a solution of 4-aminocyclohexyl)oxy)-2-methoxybenzonitrile (520 mg, 1.44 mmol, 1.0 equivalent) and 6-chloropyridazine-3-carboxylic acid (229 mg, 1.44 mmol, 1.0 equivalent) in DMF (2 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (column: Waters xbridge 150 × 25 mm × 10 µm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 49%-69% B for 8 min) to give 6-chloro- N -[(1 r 4 r )-4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]pyridazine-3-carboxamide (337 mg, 871 μmol, 60% yield).

[0781] Step 4: Preparation of tert-butyl 8-hydroxy-2-azaspiro[4.5]decane-2-carboxylate. NaBH4 (400 mg, 10 mmol, 1.3 equivalents) was added to a solution of tert-butyl 8-oxo-2-azaspiro[4.5]decane-2-carboxylate (2 g, 7.8 mmol, 1 equivalent) in DCM (20 mL). The mixture was stirred at 20 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain crude tert-butyl 8-hydroxy-2-azaspiro[4.5]decane-2-carboxylate, which was used directly in the next step without purification.

[0782] Step 5: Preparation of tert-butyl 8-iodo-2-azaspiro[4.5]decane-2-carboxylate. PPh3 (2.8 g, 10 mmol, 1.4 equivalent), imidazole (1.6 g, 23 mmol, 3 equivalent), and I2 (2.9 g, 11 mmol, 2 mL, 1.5 equivalent) were added to a solution of tert-butyl 8-hydroxy-2-azaspiro[4.5]decane-2-carboxylate (2 g, 7.8 mmol, 1 equivalent) in DCM (20 mL). The mixture was stirred at 40 °C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO2, EA:PE = 5:1) to give tert-butyl 8-iodo-2-azaspiro[4.5]decane-2-carboxylate (2 g, 69% yield) as a white oil.

[0783] Step 6: Preparation of (2-tert-butoxycarbonyl-2-azaspiro[4.5]dec-8-yl)-iodine-zinc. At 40°C, a stirred solution of Zn (830 mg, 12 mmol, 5.8 equivalents) in DMAC (2 mL) was added to a DMAC solution containing TMSCl (88 mg, 810 μmol, 102 μL, 0.37 equivalents) and 1,2-dibromoethane (152 mg, 810 μmol, 61 μL, 0.37 equivalents). After stirring for 30 minutes, tert-butyl 8-iodine-2-azaspiro[4.5]decane-2-carboxylate (800 mg, 2 mmol, 1 equivalent) was added. The mixture was stirred again at 40°C for 1 hour and then filtered. After filtration, the filtrate was concentrated to obtain crude substance (2-tert-butoxycarbonyl-2-azaspiro[4.5]dec-8-yl)-iodine-zinc, which was used directly in the next step without purification.

[0784] Step 7: Prepare 8-[4-[(9 S )-4,5,9,13-Tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6[Tweldecarbon-2(6),4,7,10,12-pentene-7-yl]phenyl]-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester. To (2-tert-butoxycarbonyl-2-azaspiro[4.5]dec-8-yl)-iodine-zinc (940 mg, 2 mmol, 3.8 equivalents) and (9 S )-7-(4-chlorophenyl)-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 A solution of tridecano-2(6),4,7,10,12-pentaene (200 mg, 560 μmol, 1 equivalent) in THF (1 mL) was supplemented with dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphine; methanesulfonate; (2-phenylphenylamino)palladium (1... + (87 mg, 112 μmol, 0.2 equivalents). The mixture was stirred at 70 °C for 12 hours. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 µm; mobile phase: [water (FA)-ACN]; gradient: 65%-95% B over 9 min) to give 8-[4-[(9 S )-4,5,9,13-Tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Tetrate-2(6),4,7,10,12-pentene-7-yl]phenyl]-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (250 mg, 79% yield).

[0785] Step 8: Preparation (9 S )-7-[4-(2-azaspiro[4.5]dec-8-yl)phenyl]-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Deca-2(6),4,7,10,12-pentane. To 8-[4-[(9 S )-4,5,9,13-Tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6[Tetrate-2(6),4,7,10,12-pentene-7-yl]phenyl]-2-azaspiro[4,5]decane-2-carboxylic acid tert-butyl ester (830 mg, 1 mmol, 1 equivalent) was added to a solution of TFA (1 g, 13 mmol, 1 mL, 9 equivalents) in DCM (3 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered, diluted with H2O (20 mL), and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (50 mL), filtered, and concentrated under reduced pressure to give (9... S )-7-[4-(2-azaspiro[4.5]dec-8-yl)phenyl]-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Decadecyl-2(6),4,7,10,12-pentane. The residue was used directly in the next step without purification.]

[0786] Step 9: Preparation N -[(1 r 4 r )-4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]-6-[8-[4-[(9 S )-4,5,9,13-Tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Decadecyl-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2-azaspiro[4,5]decyl-2-yl]pyridazine-3-carboxamide. To (9 S )-7-[4-(2-azaspiro[4.5]dec-8-yl)phenyl]-4,5,9,13-tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 A solution of tridecano-2(6),4,7,10,12-pentaene (0.15 g, 326 μmol, 1 equivalent) in NMP (1 mL) was supplemented with DIEA (371 mg, 2 mmol, 0.5 mL, 8 equivalents) and 6-chloro- N -[(1 r 4 r[4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]pyridazine-3-carboxamide (138 mg, 358 μmol, 1.1 equivalents). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was filtered, diluted with H₂O (20 mL), and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (50 mL), filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO₂, dichloromethane:methanol = 10:1) to give a white solid. N -[(1 r 4 r )-4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]-6-[8-[4-[(9 S )-4,5,9,13-Tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Decadecyl-2(6),4,7,10,12-pentene-7-yl]phenyl]-2-azaspiro[4,5]decyl-2-yl]pyridazine-3-carboxamide (0.17 g, 195 μmol, 59% yield, 93% purity).

[0787] Step 10: Preparation N -[(1 r 4 r )-4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]-6-[8-[4-[(9 S )-4,5,9,13-Tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [1-Deca-2(6),4,7,10,12-pentene-7-yl]phenyl]-2-azaspiro[4,5]dec-2-yl]pyridazine-3-carboxamide (I-19). Purified by preparative SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm × 10 µm); mobile phase: [CO2-ACN / MeOH (0.1% NH3.H2O)]; B%: 65%, isocratic elution mode). N -[(1 r 4 r )-4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]-6-[8-[4-[(9 S )-4,5,9,13-Tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [170 mg]tetane-2(6),4,7,10,12-pentene-7-yl]phenyl]-2-azaspiro[4,5]dec-2-yl]pyridazine-3-carboxamide was obtained as a white solid.N -[(1 r 4 r )-4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]-6-[8-[4-[(9 S )-4,5,9,13-Tetramethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [Decadec-2(6),4,7,10,12-pentene-7-yl]phenyl]-2-azaspiro[4,5]dec-2-yl]pyridazine-3-carboxamide (53 mg, 33%). 1 H NMR: (400 MHz, MeOD) δ = 7.94 (d, J = 9.5 Hz, 1H), 7.52 (d, J = 9.4 Hz, 1H), 7.46- 7.40 (m, 2H), 7.38 - 7.32 (m, 2H), 7.06 (d, J = 9.5 Hz, 1H), 6.72 - 6.64(m, 2H), 4.58 (s, 1H), 4.55 - 4.46 (m, 1H), 4.34 - 4.24 (m, 1H), 4.05 - 3.96(m, 1H), 3.94 (s, 3H), 3.74 - 3.52 (m, 4H), 2.72 (s, 3H), 2.44 (s, 3H), 2.24(s, 2H), 2.16 - 2.08 (m, 2H), 2.04 - 1.94 (m, 5H), 1.92 - 1.82 (m, 4H), 1.72- 1.62 (m, 10H). QCMS: MS (ES + ): RT = 1.977 min, m / z = 810 [M+1]; LCMS method: 25.

[0788] Example 8 - Composition N -[4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]-6-[2-[[4-[(9 S )-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-7-azaspiro[3.5]non-7-yl]pyridazine-3-carboxamide (I-25)

[0789]

[0790] Step 1: Preparation of tert-butyl 2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)methylene]-7-azaspiro[3.5]nonane-7-carboxylate. The tert-butyl ester was added dropwise to a solution of TMP (18.50 g, 131.00 mmol, 22.24 mL, 2.09 equivalents) in THF (150 mL) at -30 °C. n -BuLi (2.5 M, 52.40 mL, 2.09 equivalents). After addition, the mixture was stirred at -30°C for 1 hour, followed by dropwise addition of THF (40 mL) containing 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)methyl]-1,3,2-dioxaborhexacyclopentanane (25.53 g, 95.27 mmol, 1.52 equivalents) at -78°C. The resulting mixture was stirred at -78°C for 1 hour. Immediately thereafter, THF (40 mL) containing tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (15 g, 62.68 mmol, 1 equivalent) was added at -78°C. The mixture was stirred at -78°C for 1 hour, followed by stirring at 25°C for another 10 hours. The reaction mixture was quenched with 150 mL of aqueous NH4Cl solution. The aqueous phase was extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the residue. The residue was then analyzed by rapid silica gel chromatography (ISCO). ® 80 g SepaFlash ® The residue was purified using a silica rapid column and an eluent gradient of 0-10% ethyl acetate / petroleum ether at 100 mL / min. The compound 2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)methylene]-7-azaspiro[3,5]nonane-7-carboxylic acid tert-butyl ester (16 g, 44.04 mmol, 70.26% yield) was obtained as a yellow oil.

[0791] Step 2: Prepare 2-[[4-[(9 S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentene-7-yl]phenyl]methylene]-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester. 2-[(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)methylene]-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (1.29 g, 3.55 mmol, 1.51 equivalents), 2-[[(9 S The mixture of 7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadeca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (1 g, 2.36 mmol, 1 equivalent), Xphos Pd G4 (203 mg, 235.92 μmol, 0.1 equivalent) and K3PO4 (1.00 g, 4.72 mmol, 2 equivalent) in THF (10 mL) and H2O (1 mL) was degassed and purged three times with N2. The mixture was stirred at 60 °C under N2 atmosphere for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. The residue was analyzed by rapid silica gel chromatography (ISCO). ® 40 g SepaFlash ® The residue was purified using a rapid silica column (elution buffer 0-9% DCM / MeOH, 30 mL / min). A yellow solid, 2-[[4-[(9]...], was obtained. S )-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentene-7-yl]phenyl]methylene]-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (1.85 g, crude material).

[0792] Step 3: Prepare 2-[[4-[(9 S )-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentene-7-yl]phenyl]methyl]-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester. Under N2 atmosphere, towards 2-[[4-[(9 S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentene-7-yl]phenyl]methylene]-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (850 mg, 1.36 mmol, 1 equivalent) was added to a solution of MeOH (10 mL) with Pd / C (300 mg, 281.90 μmol, 10% purity, 2.07 × 10⁻⁶). -1 (Equivalent). The suspension was degassed and purged three times with H2. The mixture was stirred at 50°C under H2 (50 psi) for 24 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. Compound 2-[[4-[(9) was given as a yellow solid. S )-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentene-7-yl]phenyl]methyl]-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (720 mg, crude material).

[0793] Step 4: Prepare 2-[[(9 S )-7-[4-(7-azaspiro[3.5]non-2-ylmethyl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentane-9-yl]methyl]oxazole. To 2-[[4-[(9 S 4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadeca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (720 mg, 1.15 mmol, 1 equivalent) was added to a solution of DCM (8 mL) with TFA (2.30 g, 20.19 mmol, 1.5 mL, 17.58 equivalent). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with an aqueous solution of NaHCO3 (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. Compound 2-[[(9) was obtained as a grayish-white solid. S)-7-[4-(7-azaspiro[3.5]non-2-ylmethyl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentane-9-yl]methyl]oxazole (540 mg, crude).

[0794] Step 5: Preparation N -[4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]-6-[2-[[4-[(9 S )-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentene-7-yl]phenyl]methyl]-7-azaspiro[3.5]non-7-yl]pyridazine-3-carboxamide (I-25). To 2-[[(9 S )-7-[4-(7-azaspiro[3.5]non-2-ylmethyl)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadeca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (160 mg, 304 μmol, 1.0 equivalent) was added to a solution of NMP (0.5 mL) with DIEA (118 mg, 911 μmol, 159 μL, 3.0 equivalent) and 6-chloro- N -[4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]pyridazine-3-carboxamide (153 mg, 395 μmol, 1.3 equivalents). The mixture was stirred at 65 °C for 12 h. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 µm; mobile phase: [water (FA)-ACN]; gradient: 64%-94% B for 10 min) to give the compound as a grayish-white solid. N -[4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]-6-[2-[[4-[(9 S )-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentene-7-yl]phenyl]methyl]-7-azaspiro[3.5]non-7-yl]pyridazine-3-carboxamide (178 mg, 200 μmol, 66% yield). 1H NMR (400 MHz, CD3OD) 7.93 - 7.79 (m, 2H), 7.49 (d, J =9.3 Hz, 1H), 7.35 - 7.24 (m, 3H), 7.22 - 7.15 (m, 2H), 7.14 - 7.08 (m, 1H), 6.71 - 6.57 (m, 2H), 4.82 - 4.69 (m, 1H), 4.58 - 4.34 (m, 1H), 3.93 (br s,3H), 3.92 - 3.88 (m, 3H), 3.73 - 3.57 (m, 4H), 2.84 - 2.72 (m, 2H), 2.71 -2.66 (m, 3H), 2.63 - 2.51 (m, 1H), 2.47 - 2.35 (m, 3H), 2.25 - 2.04 (m, 4H), 2.02 - 1.93 (m, 2H), 1.76 - 1.49 (m, 13H). LC-MS: MS (ES + ): RT = 2.426 min, m / z = 877.4 [M+H] + LCMS method: 25.

[0795] Example 9 - Composition N -[4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]-6-[8-[4-[(9 R )-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadeca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2-azaspiro[4.5]dec-2-yl]pyridazine-3-carboxamide (I-27)

[0796]

[0797]

[0798] Step 1: Preparation of tert-butyl 8-hydroxy-2-azaspiro[4.5]decane-2-carboxylate. NaBH4 (400 mg, 10 mmol, 1.3 equivalents) was added to a solution of tert-butyl 8-oxo-2-azaspiro[4.5]decane-2-carboxylate (2 g, 7.8 mmol, 1 equivalent) in DCM (20 mL). The mixture was stirred at 20 °C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain crude tert-butyl 8-hydroxy-2-azaspiro[4.5]decane-2-carboxylate, which was used directly in the next step without purification.

[0799] Step 2: Preparation of tert-butyl 8-iodo-2-azaspiro[4.5]decane-2-carboxylate. PPh3 (2.8 g, 10 mmol, 1.4 equivalent), imidazole (1.6 g, 23 mmol, 3 equivalent), and I2 (2.9 g, 11 mmol, 2 mL, 1.5 equivalent) were added to a solution of tert-butyl 8-hydroxy-2-azaspiro[4.5]decane-2-carboxylate (2 g, 7.8 mmol, 1 equivalent) in DCM (20 mL). The mixture was stirred at 40 °C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC (SiO2, ethyl acetate:petroleum ether = 5:1) to give tert-butyl 8-iodo-2-azaspiro[4.5]decane-2-carboxylate (2 g, 69% yield) as a white oil.

[0800] Step 3: Preparation of (2-tert-butoxycarbonyl-2-azaspiro[4.5]dec-8-yl)-iodine-zinc. At 40°C, a stirred solution of Zn (830 mg, 12 mmol, 5.8 equivalents) in DMAC (2 mL) was added to a DMAC solution containing TMSCl (88 mg, 810 μmol, 102 μL, 0.37 equivalents) and 1,2-dibromoethane (152 mg, 810 μmol, 61 μL, 0.37 equivalents). After stirring for 30 minutes, tert-butyl 8-iodide-2-azaspiro[4.5]decane-2-carboxylate (800 mg, 2 mmol, 1 equivalent) was added. The mixture was stirred at 40°C for another hour, followed by filtration. The filtrate was concentrated to obtain the crude product (2-tert-butoxycarbonyl-2-azaspiro[4.5]dec-8-yl)-iodine-zinc.

[0801] Step 4: Prepare 8-[4-[(9 R )-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadecan-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester. To (9R )-7-(4-chlorophenyl)-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 A solution of tridecano-2(6),4,7,10,12-pentaene (202 mg, 522 μmol, 1 equivalent) and (2-tert-butoxycarbonyl-2-azaspiro[4.5]dec-8-yl)iodine-zinc (900 mg, 2.09 mmol, 4 equivalents) in THF (2 mL) was supplemented with Sphos Pd G3 (81 mg, 104 μmol, 0.2 equivalents). The mixture was stirred at 70 °C for 12 hours. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (FA conditions; column: Phenomenex luna C18 150 × 25 mm × 10 µm; mobile phase: [water (FA)-ACN]; gradient: 66%-96% B for 10 min) to obtain 8-[4-[(9 R )-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0] 2,6 [120 mg, 39% yield] tert-butyl decane-2(6),4,7,10,12-pentene-7-yl]phenyl]-2-azaspiro[4.5]decane-2-carboxylate (tert-butyl ester).

[0802] Step 5: Preparation (9 R )-7-[4-(2-azaspiro[4.5]dec-8-yl)phenyl]-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaene. To 8-[4-[(9 R9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadeca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (70 mg, 118 μmol, 1.0 equivalent) was added to a solution of DCM (1 mL) with TFA (0.5 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated, alkalized with aqueous NaHCO3 solution, and extracted with DCM / MeOH (10:1, 10 mL × 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give a yellow solid (9- R )-7-[4-(2-azaspiro[4.5]dec-8-yl)phenyl]-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaene (110 mg, 224 μmol).

[0803] Step 6: Preparation N -[4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]-6-[8-[4-[(9 R )-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2-azaspiro[4.5]dec-2-yl]pyridazine-3-carboxamide (I-27). To (9 R )-7-[4-(2-azaspiro[4.5]dec-8-yl)phenyl]-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaene (55 mg, 112 μmol, 1.0 equivalent) and 6-chloro- N -[4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]pyridazine-3-carboxamide (56 mg, 146 μmol, 1.3 equivalents) was added to a solution of NMP (0.5 mL) with DIEA (45 mg, 336 μmol, 0.1 mL, 3.0 equivalents). The mixture was stirred at 65 °C for 8 hours. The residue was purified by preparative HPLC (column: Waters xbridge 150 × 25 mm 10 µm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 60%-80% B for 8 min) to obtain a white solid. N-[4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]-6-[8-[4-[(9 R )-9-(methoxymethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentene-7-yl]phenyl]-2-azaspiro[4.5]dec-2-yl]pyridazine-3-carboxamide (38.17 mg, 44.31 μmol, 39.45% yield, 97.51% purity). 1 HNMR (400 MHz, CD3OD) δ 7.94 (d, J = 9.4 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H),7.48 - 7.41 (m, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.07 (br d, J = 9.1 Hz, 1H),6.72 - 6.62 (m, 2H), 4.47 - 4.32 (m, 3H), 4.05 - 3.96 (m, 1H), 3.94 (s, 3H),3.74 - 3.53 (m, 7H), 2.77 - 2.61 (m, 4H), 2.46 (s, 3H), 2.29 - 2.18 (m, 2H), 2.13 (br d, J = 4.0 Hz, 2H), 1.98 (t, J = 7.1 Hz, 2H), 1.86 - 1.86 (m, 1H), 1.92 - 1.80 (m, 4H), 1.74 - 1.59 (m, 11H). LC-MS: MS (ES + ): RT = 2.115 min, m / z = 840.1 [M+H] + LCMS method: 25.

[0804] Example 10 - Composition N -[4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]-6-[8-[4-[(9 S)-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadeca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2-azaspiro[4.5]dec-2-yl]pyridazine-3-carboxamide (I-29)

[0805]

[0806]

[0807] Step 1: Preparation of (2-tert-butoxycarbonyl-2-azaspiro[4.5]dec-8-yl)-iodine-zinc. At 40 °C, a stirred solution of Zn (1.4 g, 22 mmol, 10 equivalents) in DMAC (2 mL) containing TMSCl (88 mg, 810 μmol, 102 μL, 0.37 equivalents) and 1,2-dibromoethane (152 mg, 810 μmol, 61 μL, 0.37 equivalents) was added. After stirring for 30 minutes, tert-butyl 8-iodine-2-azaspiro[4.5]decane-2-carboxylate (800 mg, 2 mmol, 1 equivalent) was added. The mixture was stirred again at 40 °C for 1 hour and then filtered. The filtrate was concentrated to obtain crude material (2-tert-butoxy-carbonyl-2-azaspiro[4.5]dec-8-yl)-iodine-zinc, which was used directly in the next step without purification.

[0808] Step 2: Preparation of 8-[4-[(9 S )-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadeca-2(6),4,7,10,12-pentene-7-yl]phenyl]-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester. To (2-tert-butoxycarbonyl-2-azaspiro[4.5]dec-8-yl)-iodine-zinc (940 mg, 2 mmol, 4 equivalents) and (9 SSphos Pd G3 (77 mg, 99 μmol, 0.2 equivalents) was added to a solution of 200 mg, 498 μmol, 1 equivalent of 7-(4-chlorophenyl)-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tridecane-2(6),4,7,10,12-pentaene (100 mg, 498 μmol, 1 equivalent) in THF (1 mL). The mixture was stirred at 70 °C for 12 h. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 µm; mobile phase: [water(FA)-ACN]; gradient: 68%-98% B for 10 min) to give 8-[4-[(9 S 9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentane-7-yl]phenyl]-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (110 mg, 182 μmol, 36% yield).

[0809] Step 3: Preparation (9 S )-7-[4-(2-azaspiro[4.5]dec-8-yl)phenyl]-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]deca-2(6),4,7,10,12-pentaene. To 8-[4-[(9 S 9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetadeca-2(6),4,7,10,12-pentene-7-yl]phenyl]-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (75 mg, 124 μmol, 1.0 equivalent) was added to a solution of DCM (1 mL) with TFA (0.5 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated, alkalized with aqueous NaHCO3 solution, and extracted with DCM / MeOH (10:1, 10 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated to give a yellow solid (9 S )-7-[4-(2-azaspiro[4.5]dec-8-yl)phenyl]-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaene (120 mg, 238 μmol).

[0810] Step 4: Preparation N -[4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]-6-[8-[4-[(9 S )-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2-azaspiro[4.5]dec-2-yl]pyridazine-3-carboxamide (I-29). To (9 S )-7-[4-(2-azaspiro[4.5]dec-8-yl)phenyl]-9-(2-methoxyethyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]tetane-2(6),4,7,10,12-pentaene (60 mg, 120 μmol, 1.0 equivalent) and 6-chloro- N -[4-(4-cyano-3-methoxy-phenoxy)cyclohexyl]pyridazine-3-carboxamide (60 mg, 155 μmol, 1.3 equivalents) was added to a solution of NMP (0.5 mL) with DIEA (50 mg...

Claims

1. A compound represented by formula I, (I) Or its pharmaceutically acceptable salt; wherein: R 1 The phenyl group is substituted with the following: (i) cyano group and R appearing m times. 4 , and (ii) C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups; R 2 C is represented independently each time it appears. 1-4 alkyl; R 3 It is hydrogen or C 1-4 alkyl; R 4 C 1-4 alkyl; R 5 C is represented independently each time it appears. 1-4 Alkyl or halogen; A 1 It is pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, or phenylene, each of which is represented by R n times. 5 replace; L is a connector; and A 2 One of the following: or ; B 1 For (i) R that appears 1, 2, 3 or 4 times 2 The substituted cyclobutylene, or (ii) the R group appearing 0, 1 or 2 times. 2 Substituted cyclohexyl groups; R 1A C 1-4 Alkyl or C 3-4 cycloalkyl; R 2A C is represented independently each time it appears. 1-4 Alkyl or C 3-4 cycloalkyl; R 3A Hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated or C 1-4 Alkoxy; R 4A For -(C 0-6 Alkylene)-(containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroaryl), -(C 1-6 alkylene)-C(O)N(R 5A (R) 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A -(C 1-6 (alkylene)-CO2R 7A -(C 1-6 Alkylene)-OC(O)R 7A -(C 1-6 alkylene)-cyano, -(C 1-6 alkylene)-O-(C 1-6 Alkyl), C 1-6 Alkyl, C 3-6 cycloalkyl or hydrogen; or R 4A and R 10A Together with the carbon atom it is attached to, they form C 3-5 Saturated carbon rings; R 5A and R 6A Independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; or R 5A and R 6A Together with the nitrogen atom it is attached to, it forms a 3-7 membered ring containing one nitrogen atom; R 7A C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or C 3-6 cycloalkyl; R 10A It is hydrogen or C 1-4 Alkyl; and m, n, and p are independently 0, 1, or 2.

2. The compound of claim 1, wherein R 1 The phenyl group is substituted with the following: (i) cyano group and R appearing m times. 4 , and (ii)C 1-4 Alkyl group.

3. The compound of claim 1, wherein R 1 The phenyl group is substituted with the following: (i) cyano group and R appearing m times. 4 , and (ii)C 1-4 Halogenated alkoxy groups.

4. The compound of claim 1, wherein R 1 for .

5. The compound of claim 1, wherein R 1 for .

6. The compound according to any one of claims 1 to 3, wherein m is 0.

7. The compound according to any one of claims 1 to 6, wherein R 2 C 1-4 alkyl.

8. The compound according to any one of claims 1 to 6, wherein R 2 It is a methyl group.

9. The compound according to any one of claims 1 to 8, wherein R 3 It is hydrogen.

10. The compound according to any one of claims 1 to 9, wherein B 1 R appears 1, 2, 3 or 4 times 2 Substituted cyclobutylene.

11. The compound according to any one of claims 1 to 9, wherein B 1 R appears 4 times 2 Substituted cyclobutylene.

12. The compound according to any one of claims 1 to 9, wherein B 1 R appears 0, 1, or 2 times. 2 Substituted cyclohexylene.

13. The compound according to any one of claims 1 to 9, wherein B 1 It is a subcyclohexyl group.

14. The compound of any one of claims 1 to 13, wherein the compound is a compound of formula I.

15. The compound of any one of claims 1 to 9, wherein the compound is a compound of formula Ia or a pharmaceutically acceptable salt thereof: (It)。 16. The compound of any one of claims 1 to 9, wherein the compound is a compound of formula Ib or Ic or a pharmaceutically acceptable salt thereof: (Ib)(Ic).

17. The compound of claim 1, wherein the compound is a compound of formula Id or a pharmaceutically acceptable salt thereof: (Id)。 18. The compound of claim 1, wherein the compound is a compound of formula Ie or a pharmaceutically acceptable salt thereof: (Ie)。 19. The compound of claim 1, wherein the compound is a compound of formula If or a pharmaceutically acceptable salt thereof: (If)。 20. The compound of claim 1, wherein the compound is a compound of formula Ig or a pharmaceutically acceptable salt thereof: (Ig)。 21. The compound of claim 1, wherein the compound is a compound of formula Ih or a pharmaceutically acceptable salt thereof: (Them).

22. The compound of claim 1, wherein the compound is a compound of formula Ii or a pharmaceutically acceptable salt thereof: (Ii)。 23. The compound of any one of claims 1 to 9, wherein the compound is a compound of formula Ij or a pharmaceutically acceptable salt thereof: (Ij)。 24. The compound of any one of claims 1 to 6, wherein the compound is a compound of formula Ik or a pharmaceutically acceptable salt thereof: (I).

25. The compound of any one of claims 1 to 6, wherein the compound is a compound of formula I1 or formula Im or a pharmaceutically acceptable salt thereof: (Il)(Im).

26. The compound of claim 1, wherein the compound is a compound of formula In or a pharmaceutically acceptable salt thereof: (In)。 27. The compound of claim 1, wherein the compound is a compound of formula Io or formula Ip or a pharmaceutically acceptable salt thereof: (Io) (Ip).

28. The compound of claim 1, wherein the compound is a compound of formula Iq or a pharmaceutically acceptable salt thereof: (Iq)。 29. The compound of claim 1, wherein the compound is a compound of formula Ir or formula Is or a pharmaceutically acceptable salt thereof: (Ir) (Is).

30. The compound according to any one of claims 1 to 29, wherein A 1 R appears n times 5 Substituted pyridazinyl group.

31. The compound according to any one of claims 1 to 29, wherein A 1 for .

32. The compound according to any one of claims 1 to 29, wherein A 1 R appears n times 5 Substituted pyrimidine group.

33. The compound according to any one of claims 1 to 29, wherein A 1 for ,in This is the connection point with L.

34. The compound according to any one of claims 1 to 29, wherein A 1 for ,in This is the connection point with L.

35. The compound according to any one of claims 1 to 29, wherein A 1 R appears n times 5 Substituted pyrazine group.

36. The compound according to any one of claims 1 to 29, wherein A 1 for .

37. The compound according to any one of claims 1 to 29, wherein A 1 R appears n times 5 Substituted pyridyl group.

38. The compound of any one of claims 1 to 29, wherein A 1 for ,in This is the connection point with L.

39. The compound according to any one of claims 1 to 29, wherein A 1 R appears n times 5 Substituted phenylene.

40. The compound according to any one of claims 1 to 29, wherein A 1 for .

41. The compound of any one of claims 1 to 30, 32, 35, 37 or 39, wherein n is 0.

42. The compound according to any one of claims 1 to 41, wherein R 3A Halogenated, C 1-4 Alkyl or C 1-4 Alkyl group.

43. The compound according to any one of claims 1 to 42, wherein A 2 for .

44. The compound according to any one of claims 1 to 41, wherein A 2 for .

45. The compound according to any one of claims 1 to 43, wherein R 4A and R 10A Together with the carbon atom it is attached to, they form C 3-5 Saturated carbon rings.

46. ​​The compound according to any one of claims 1 to 44, wherein R 4A For -(C 0-6 Alkylene group (containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur) - (5-6 membered heteroaryl groups).

47. The compound of any one of claims 1 to 44, wherein R 4A For -(C 1-2 Alkylene group (containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur) - (5-6 membered heteroaryl groups).

48. The compound of any one of claims 1 to 44, wherein R 4A For -(C 1-2 Alkylene group (containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur) - (a 5-membered heteroaryl group).

49. The compound according to any one of claims 1 to 44, wherein R 4A For -(C 1-2 (alkylene)-(oxazolyl).

50. The compound of any one of claims 1 to 44, wherein R 4A For -(C 1-6 alkylene)-O-(C 1-6 alkyl).

51. The compound according to any one of claims 1 to 44, wherein R 4A For -(C 1-2 alkylene)-O-(C 1-2 alkyl).

52. The compound of any one of claims 1 to 44, wherein R 4A C 1-6 alkyl.

53. The compound according to any one of claims 1 to 44, wherein R 4A It is a methyl group.

54. The compound according to any one of claims 1 to 53, wherein R 1A C 1-4 alkyl.

55. The compound according to any one of claims 1 to 53, wherein R 1A It is a methyl group.

56. The compound according to any one of claims 1 to 55, wherein R 2A C 1-4 alkyl.

57. The compound of any one of claims 1 to 55, wherein R 2A It is a methyl group.

58. The compound of any one of claims 1 to 57, wherein p is 2.

59. The compound according to any one of claims 1 to 41, wherein A 2 for .

60. The compound according to any one of claims 1 to 41, wherein A 2 for .

61. The compound according to any one of claims 1 to 41, wherein A 2 for .

62. The compound according to any one of claims 1 to 41, wherein A 2 for or .

63. The compound according to any one of claims 1 to 41, wherein A 2 for or 。 64. The compound according to any one of claims 1 to 41, wherein A 2 for , , or .

65. The compound according to any one of claims 1 to 41, wherein A 2 for , , or .

66. The compound according to any one of claims 1 to 41, wherein A 2 for , , or .

67. The compound according to any one of claims 1 to 41, wherein A 2 for , , , , or .

68. The compound according to any one of claims 1 to 41, wherein A 2 for or , , , , , or .

69. The compound according to any one of claims 1 to 41, wherein A 2 for , , , , , or .

70. The compound according to any one of claims 1 to 41, wherein A 2 One of the following: 。 71. The compound according to any one of claims 1 to 41, wherein A 2 One of the following: 。 72. The compound according to any one of claims 1 to 71, wherein L is divalent, saturated or unsaturated, straight-chain or branched-chain C. 1-60 A hydrocarbon chain in which 0-20 methylene units are independently substituted with the following: -O-, -S-, -N(H)-, -N(C)-. 1-6 Alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C 1-6 Alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C 1-6 Alkyl)-, -N(H)C(O)-, -N(C 1-6 Alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 Alkyl)-, -OC(O)N(H)-, -OC(O)N(C 1-6 Alkyl)-, -N(H)C(O)O-, -N(C 1-6 Alkyl)C(O)O-, -N (optionally substituted 3-10-membered carbon cycloyl)-, optionally substituted 3-10-membered carbon cycloyl, or optionally substituted 3-10-membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

73. The compound of any one of claims 1 to 71, wherein L is a divalent, saturated, straight-chain or branched C. 3-30 A hydrocarbon chain in which 0-15 methylene units are independently substituted with: -O-, -N(H)-, -N(C)-, ... 1-6 Alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 Alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 Alkyl group, 3-10 membered carbon cyclic group, or 3-10 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

74. The compound of any one of claims 1 to 71, wherein L is a divalent, saturated, straight-chain or branched C. 3-30 A hydrocarbon chain in which 0-15 methylene units are independently substituted with: -O-, -N(H)-, -N(C)-, ... 1-6 Alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 Alkyl)C(O)-, -C(O)N(H)- or -C(O)N(C 1-6 alkyl)-.

75. The compound of any one of claims 1 to 71, wherein L is divalent, saturated or unsaturated, straight-chain or branched-chain C. 5-40 A hydrocarbon chain in which 1-20 methylene units of the hydrocarbon are independently substituted with: -O-, -N(H)-, -N(C)-, -O-, -N(H)-, -N(C)-, -N(H ... 1-6 Alkyl)-, -N(H)C(O)-, -N(C 1-6 Alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 Alkyl group, optionally substituted 3- to 10-membered carbon cycloalkanes, or optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

76. The compound according to any one of claims 1 to 71, wherein L is -(a 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen)-X 1 - , where X 1 C 0-4 Alkylene, C 2-4 alkyne or O, where To be with A 2 The connection point.

77. The compound of any one of claims 1 to 71, wherein L is -(an 8-10 membered spirocyclic or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocycle is separated by 0, 1 or 2 occurrences of C 1-4 (alkyl or halogenated)-X 1 - , where X 1 C 0-4 Alkylene, C 2-4 alkyne or O, where To be with A 2 The connection point.

78. The compound of any one of claims 1 to 71, wherein L is -(a 10-13 membered spirocyclic saturated heterocycle containing one, two, or three heteroatoms selected from nitrogen and oxygen)-X 1 - , where X 1 C 0-4 Alkylene, C 2-4 alkyne or O, where To be with A 2 The connection point.

79. The compound of any one of claims 76 to 78, wherein X 1 C 1-4 Alkylene.

80. The compound of any one of claims 76 to 78, wherein X 1 C 2-4 Alynyl group.

81. The compound of any one of claims 76 to 78, wherein X 1 It is -C≡C-.

82. The compound of any one of claims 76 to 78, wherein X 1 It is O.

83. The compound according to any one of claims 1 to 71, wherein L is -(an 8-10 membered spirocyclic or bicyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen and oxygen)-O- ,in To be with A 2 The connection point.

84. The compound of any one of claims 1 to 71, wherein L is a 7-11 membered spirocyclic or fused bicyclic saturated heterocyclic containing one, two or three heteroatoms selected from nitrogen and oxygen.

85. The compound of any one of claims 1 to 71, wherein L is -(an 8-10 member fused bicyclic saturated heterocycle containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocycle is separated by 0, 1, or 2 occurrences of C 1-4 Alkyl substitution)-.

86. The compound according to any one of claims 1 to 71, wherein L is -(a 9-13 membered tricyclic saturated heterocycle containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen)-(C 0-4 (alkylene)- ,in To be with A 2 The connection point.

87. The compound of any one of claims 1 to 71, wherein L is an 8- to 10-membered fused aromatic or partially unsaturated ring containing one, two, or three heteroatoms selected from nitrogen and oxygen.

88. The compound of any one of claims 1 to 71, wherein L is a 7-8 membered spirocyclic ring or a fused bicyclic saturated heterocyclic ring containing two heteroatoms selected from nitrogen.

89. The compound according to any one of claims 1 to 71, wherein L is -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-X 3 -(a 3-7 membered monocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-, where X 3 C 1-10 Alkylene, -O-, -N(H)-, -N(C)- 1-4 Alkyl group or bond.

90. The compound of any one of claims 1 to 71, wherein L is -(piperidine)-(C 1-5 alkylene)-(piperazinyl)- ,in To be with A 2 The connection point.

91. The compound according to any one of claims 1 to 71, wherein L is -(piperazinyl)-(azacyclobutane)- or -(aza-butane)-(piperazinyl)- ,in To be with A 2 The connection point.

92. The compound according to any one of claims 1 to 71, wherein L is one of the following: ， in To be with A 2 The connection point.

93. The compound according to any one of claims 1 to 71, wherein L is one of the following: ,in To be with A 2 The connection point.

94. A compound or a pharmaceutically acceptable salt thereof represented by the formula It, Iu, Iv or Iw. (It) (Iu) (Iv) (Iw) in L is one of the following: (i) -(a 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen) -O- ,in This is the connection point with the phenylene in the formula; (ii) A 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing one, two, or three heteroatoms independently selected from nitrogen and oxygen; or (iii) -(7-11 membered spirocyclic saturated heterocycles containing one or two heteroatoms selected from nitrogen)-(C 2-4 (ethynyl)- ,in The connection point with the phenylene in the formula; and t is 0 or 1.

95. The compound of claim 94, wherein t is 0.

96. A compound represented by formula Ix, Iy, Iz or Iaa, or a pharmaceutically acceptable salt thereof. (Ix) (Iy) (Iz) (Iaa) in: R 20 It can be methyl, ethyl, -CH2-O-CH3 or -(CH2)2-O-CH3; L is one of the following: (i) -(a 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen) -O- ,in This is the connection point with the phenylene in the formula; (ii) A 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing one, two, or three heteroatoms independently selected from nitrogen and oxygen; or (iii) -(7-11 membered spirocyclic saturated heterocycles containing one or two heteroatoms selected from nitrogen)-(C 2-4 (ethynyl)- ,in The connection point with the phenylene in the formula; and t is 0 or 1.

97. The compound of claim 96, wherein t is 0.

98. The compound of claim 96 or 97, wherein R 20 It can be methyl or ethyl.

99. The compound of claim 96 or 97, wherein R 20 It is -CH2-O-CH3 or -(CH2)2-O-CH3.

100. The compound of any one of claims 94 to 99, wherein L is -(a 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing one, two, or three heteroatoms independently selected from nitrogen and oxygen)-O- ,in This is the connection point with the phenylene group in the formula.

101. The compound of any one of claims 94 to 99, wherein L is a 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing one, two or three heteroatoms independently selected from nitrogen and oxygen.

102. The compound according to any one of claims 94 to 99, wherein L is -(a 7-11 membered spirocyclic saturated heterocycle containing one or two heteroatoms selected from nitrogen)-(C 2-4 (ethynyl)- ,in This is the connection point with the phenylene group in the formula.

103. The compound according to any one of claims 94 to 99, wherein L is one of the following: in This is the connection point with the phenylene group in the formula.

104. The compound according to any one of claims 1 to 71 or 94 to 99, wherein L is ,in This is the connection point with the phenylene group in the formula.

105. The compound according to any one of claims 1 to 71 or 94 to 99, wherein L is ,in This is the connection point with the phenylene group in the formula.

106. The compound of claim 94, wherein the compound is represented by formula Iab or a pharmaceutically acceptable salt thereof: (Iab).

107. The compound of claim 94, wherein the compound is represented by formula Iac or a pharmaceutically acceptable salt thereof: (Iac)。 108. The compound of claim 94, wherein the compound is represented by formula Iad or a pharmaceutically acceptable salt thereof: (Them)。 109. The compound of claim 94, wherein the compound is represented by formula Iae or a pharmaceutically acceptable salt thereof: (Yes).

110. The compound of claim 94, wherein the compound is represented by formula Iaf or a pharmaceutically acceptable salt thereof: (Iaf)。 111. The compound of claim 1, wherein the compound is represented by formula Iag or a pharmaceutically acceptable salt thereof: (Iag)。 112. The compound of claim 1, wherein the compound is represented by formula Iah or a pharmaceutically acceptable salt thereof: (Iah)。 113. A compound listed in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

114. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 113 and a pharmaceutically acceptable carrier.

115. A method of treating cancer, the method comprising administering to a patient in need a therapeutically effective amount of a compound as claimed in any one of claims 1 to 113 to treat the cancer.

116. The method of claim 115, wherein the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, gastric cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland cancer, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia.

117. The method of claim 115, wherein the cancer is prostate cancer.

118. The method of any one of claims 115 to 117, wherein the patient is a human.

119. A method for causing cancer cell death, the method comprising contacting cancer cells with an effective amount of a compound as claimed in any one of claims 1 to 113 to cause the cancer cells to die.

120. The method of claim 119, wherein the cancer cells are selected from ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, gastric cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland cancer, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia cells.

121. The method of claim 119, wherein the cancer cell is a prostate cancer cell.

122. A crystalline compound of formula II-5, (II-5) 123. The compound of claim 122, wherein the compound displays an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 13.1 ± 0.2, 17.6 ± 0.2, 18.3 ± 0.2, 18.7 ± 0.2, 19.5 ± 0.2, 23.8 ± 0.2, and 25.6 ± 0.

2.

124. The compound of claim 123, wherein the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 8.1 ± 0.

2.

125. The compound of claim 123 or 124, wherein the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 9.9 ± 0.

2.

126. The compound of any one of claims 123 to 125, wherein the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 10.5 ± 0.

2.

127. The compound of any one of claims 123 to 126, wherein the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 15.8 ± 0.

2.

128. The compound of any one of claims 123 to 127, wherein the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 19.8 ± 0.

2.

129. The compound of any one of claims 123 to 128, wherein the X-ray powder diffraction pattern further includes a peak at the following diffraction angle (2θ): 25.3 ± 0.

2.

130. The compound of any one of claims 123 to 129, wherein the relative intensity of the peak at the diffraction angle (2θ) is at least 20%.

131. The compound of any one of claims 123 to 129, wherein the relative intensity of the peak at the diffraction angle (2θ) is at least 30%.

132. The compound of claim 122, characterized in that... The following X-ray powder diffraction patterns are expressed based on the diffraction angle 2θ, the interplanar distance d, and the relative intensity (expressed as a percentage relative to the strongest peak): 。 133. The compound of claim 122, wherein the compound has a substantially X-ray powder diffraction pattern as shown in FIG1.

134. The compound of any one of claims 122 to 133, wherein, as determined by differential scanning calorimetry, the compound has an initial melting point in the range of about 180°C to about 200°C.

135. The compound of any one of claims 122 to 133, wherein the compound has an initial melting point of about 192°C, as determined by differential scanning calorimetry.

136. The compound of any one of claims 122 to 133, wherein the compound has a differential scanning calorimetry profile substantially the same as that shown in FIG2.

137. The compound of claim 122, wherein the compound displays an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 9.4 ± 0.2, 12.8 ± 0.2, 15.4 ± 0.2, 18.2 ± 0.2, 18.7 ± 0.2, 20.2 ± 0.2, and 24.6 ± 0.

2.

138. The compound of claim 137, wherein the X-ray powder diffraction pattern further includes peaks at one or more of the following diffraction angles (2θ): 8.5 ± 0.2, 11.7 ± 0.2, 12.5 ± 0.2, 17.6 ± 0.2, 19.6 ± 0.2, 21.9 ± 0.2, and 23.5 ± 0.

2.

139. The compound of claim 137 or 138, wherein the relative intensity of the peak at the diffraction angle (2θ) is at least 20%.

140. The compound of claim 137 or 138, wherein the relative intensity of the peak at the diffraction angle (2θ) is at least 30%.

141. The compound of claim 122, characterized in that... The following X-ray powder diffraction patterns are expressed based on the diffraction angle 2θ, the interplanar distance d, and the relative intensity (expressed as a percentage relative to the strongest peak): 。 142. The compound of claim 122, wherein the compound has a substantially X-ray powder diffraction pattern as shown in FIG4.

143. The compound of any one of claims 137 to 142, wherein, as determined by differential scanning calorimetry, the compound has an initial melting point in the range of about 180°C to about 200°C.

144. The compound of any one of claims 137 to 142, wherein the compound has an initial melting point of about 192°C, as determined by differential scanning calorimetry.

145. The compound of any one of claims 137 to 142, wherein the compound has a differential scanning calorimetry profile substantially the same as that shown in FIG5.

146. The compound of any one of claims 122 to 145, wherein the compound has a purity of more than 98% by weight.

147. The compound of any one of claims 122 to 145, wherein the compound has a purity of more than 99% by weight.

148. The compound of any one of claims 122 to 145, wherein the compound has a purity of more than 99.5% by weight.

149. A compound listed in Table 3 or a pharmaceutically acceptable salt thereof.

150. A pharmaceutical composition comprising a compound as claimed in any one of claims 122 to 149 and a pharmaceutically acceptable carrier.

151. A method of treating cancer, the method comprising administering to a patient in need a therapeutically effective amount of a compound as claimed in any one of claims 122 to 149 to treat the cancer.

152. The method of claim 151, wherein the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, gastric cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland cancer, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia.

153. The method of claim 151, wherein the cancer is prostate cancer.

154. The method of any one of claims 151 to 153, wherein the patient is a human.

155. A method for causing cancer cell death, the method comprising contacting cancer cells with an effective amount of a compound as claimed in any one of claims 122 to 149 to cause the cancer cells to die.

156. The method of claim 155, wherein the cancer cells are selected from ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, gastric cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland cancer, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia cells.

157. The method of claim 155, wherein the cancer cell is a prostate cancer cell.

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