Methods and compositions for targeting protein degradation

Abstract

Provided herein are chaperone retention effect drug conjugates (CREDCs) comprising an etiotecan-like moiety, a linker, and a chemical moiety that binds to the HSP90 protein. Also provided herein are pharmaceutical compositions comprising the disclosed CREDCs and their use for the treatment of cancer and related conditions.

Description

Related Applications

[0001] This application claims priority to International Application No. PCT / CN2023 / 085328, filed March 31, 2023, the entire contents of which are incorporated herein by reference. BACKGROUND

[0002] Despite advances, treatment of cancer with chemotherapeutic agents remains disappointing. Patients receiving treatment for cancer with chemotherapeutic agents suffer debilitating treatment regimens and often have poor prognoses. This is because the effectiveness and / or application of chemotherapeutic agents containing toxic moieties can be reduced by off-target or unwanted side effects caused by systemic toxicity. The ability to concentrate chemotherapeutic agents in tumor tissue while reducing exposure to normal tissue can greatly reduce off-target toxicity and improve overall clinical outcomes.

[0003] Cancer is characterized by aberrant protein expression and activation. HSP90 (heat shock protein 90 kDa) is a chaperone that facilitates the three-dimensional folding and maintenance of important components of cell growth signaling proteins including many oncogenes (Trepel J. et al., Nat Rev Cancer. 2010, 10:537-49; Birbo B. et al., Int J Mol Sci., 2021, 22:10317). Cancer cells exist in a tumor microenvironment characterized by reduced blood flow, high interstitial pressure, hypoxia, and acidosis. To alleviate these conditions that negatively impact overall protein stability, cancer cells overexpress HSP90 and even secrete it extracellularly (Lang BJ et al., Int J Mol Sci. 2019, 20:4507; Taha EA et al., Int J Mol Sci. 2019, 20:4588). Additionally, HSP90 chaperone activity is greatly enhanced in cancer cells due to the abundance of mutant or misfolded proteins (Lacey T, Lacey H, Cancer Treat Res Commun. 2021, 28:100400). Cancer-specific post-translational modifications and protein-protein interaction states also affect HSP90 chaperone activity (Backe SJ et al., J Biol Chem. 2020, 295:11099-11117). In cancer cells, this elevated expression and enhanced chaperone activity results in increased binding of HSP90 to small molecule drugs that target its N-terminal ATP binding. This is in contrast to normal non-proliferating cells that do not have elevated levels of HSP90 expression or activity (Kamal A et al., Nature. 2003 425:407-10; Moulick K et al., Nat Chem Biol. 2011, 7:818-26). Due to these differences, HSP90 drugs exhibit a chaperone retention effect by concentrating in tumor tissue while being cleared from normal tissue.

[0004] Camptothecin analogues such as irinotecan, eczetidine, and SN-38 are antitumor agents that inhibit DNA topoisomerase I (Topo I) activity and prevent the relaxation of supercoiled DNA during DNA replication and RNA transcription (Pommier Y, Nat RevCancer. 2006, 6:789–802). These drugs are commonly used in chemotherapy regimens to treat colorectal cancer, pancreatic cancer, small cell lung cancer, gastric cancer, and pediatric sarcoma (Fujita K et al., World J Gastroenterol. 2015, 21:12234–12248; Rubinson DA et al., Hematol Oncol Clin North Am. 2015, 29:761–776; Levy B et al., JNCCN. 2013, 11:780–787; Mahipal A et al., JNCCN. 2015, 13:1281–1291; Yohe ME et al., Cancer Treat Res Commun. 2021, 28:100400). However, these drugs have issues with bioavailability and off-target toxicity (Venditto VJ, Simanek ES, Mol Pharm. 2010, 7:307-49). Therefore, there is a need for conjugate drug conjugates (CREDCs) that effectively target and concentrate antitumor agents (such as camptothecin analogues) into tumor tissue. Summary of the Invention

[0005] This article provides CREDC, which comprises an ixotecan-like moiety, a linker, and a chemical moiety that binds to the HSP90 protein. Such compounds include those having Formula I: (I); and its pharmaceutically acceptable salts, of which R Q R T X, L, and A are as defined herein. Compositions comprising the disclosed Formula I compounds are also provided, as well as methods for their preparation and their biochemical activities. Detailed Implementation

[0006] 1. General description of compounds This article provides CREDC compounds having Formula I: (I); Or its pharmaceutically acceptable salt, in which R Q and R T Each is independently selected from H, optionally substituted (C1-C4) alkyl, optionally substituted aryl and optionally substituted heteroaryl, or R. Qand R T Together with the carbon to which they are attached, they form optionally substituted cycloalkyl groups or optionally substituted heterocyclic groups; X does not exist or -NR W , where R W It is H or (C1-C4) alkyl; L is the connector; and A is the chemical part that binds to the HSP90 protein.

[0007] 2. Definition As used herein, the articles “a” and “an” refer to one or more of the grammatical objects of the article, such as at least one. When used in conjunction with the term “contains” in this article, the use of the words “a” or “a kind” can mean “one (kind),” but it is also consistent with the meanings of “one (kind) or more (kinds),” “at least one (kind),” and “one (kind) or more than one (kind).”

[0008] As used herein, “about” and “approximately” generally mean the acceptable degree of error of a measured quantity given the nature or precision of the measurement. Exemplary error levels are within 20 percent (%) of a given range of values, typically within 10 percent, and more typically within 5 percent. The term “substantially” means more than 50%, preferably more than 80%, and most preferably more than 90% or 95%.

[0009] As used herein, the terms “comprising” or “including” are used to refer to compositions, methods and their respective components present in a given embodiment, but may also include unspecified elements.

[0010] As used herein, unless otherwise stated, the term "alkyl" means a saturated straight-chain or branched acyclic hydrocarbon having 1 to 10 carbon atoms, such as (C1-C6)alkyl or (C1-C4)alkyl. Representative straight-chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl; while saturated branched alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4 4-Dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl, etc.

[0011] As used herein, the term "cycloalkyl" refers to a saturated monocycloalkyl group having, for example, 3 to 10 carbon atoms (e.g., 4 to 6 carbon atoms). Representative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

[0012] The term "oxo" refers to the =O group.

[0013] As used herein, the term "haloalkyl" means an alkyl group in which one or more (including all) hydrogen groups are replaced by a halogroup, wherein each halogroup is independently selected from -F, -Cl, -Br, and -I. Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, etc.

[0014] "Alkoxy" refers to an alkyl group attached to an oxygen-bonded atom, represented by –O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0015] "Haloalkoxy" is a haloalkyl group that is attached to another part by an oxygen atom, such as, for example, –OCHF2 or –OCF3.

[0016] As used herein, the term "heterocyclic group" refers to a 4- to 12-membered monocyclic or polycyclic saturated or partially unsaturated heterocyclic ring (e.g., a bridging bicyclic ring) containing 1 to 4 heteroatoms independently selected from N, O, and S. Heterocyclic rings can be attached by any heteroatom or carbon atom, provided the valence number allows. Representative heterocycles include morpholino, thiomorpholino, pyrrolidone, pyrrolylalkyl, piperidinyl, piperazine, oxacyclopropyl, dioxacyclohexyl, oxacyclobutyl, dihydrofuranyl, dihydropyranyl, isoindolinyl, dihydropyridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroazinel, tetrahydropyrimidinyl, diazabicyclooctyl, hexahydropyrrolizinyl, 2-azaspiro[3.3]heptyl, 2,7-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, 3,8-azabicyclo[3.2.1]octyl, 3 ,6-diazabicyclo[3.1.1]heptyl, octahydro-1H-pyrrolo[2,3-c]pyridyl, etc. As long as the valence number allows, optional substituents on the heterocyclic group may be present at any substituted position and include, for example, positions attached to the heterocyclic group.

[0017] As used herein, the term "heteroaryl" refers to a 5- to 12-membered aromatic group containing 1 to 4 heteroatoms selected from N, O, and S. Heteroaryl groups can be monocyclic or bicyclic. Provided the valence number allows, heteroaryl groups can be attached via any heteroatom or carbon atom. Representative heteroaryl groups include pyridinyl, furanyl, thiopheneyl, pyrroleyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazoleyl, benzoxazolyl, benzofuranyl, indolazilyl, imidazopyridyl, tetrazolyl, benzoimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indoleyl, tetrahydroindoleyl, azaindoleyl, imidazopyridyl, quinazolinyl, purinyl, benzothiapheneyl, etc. Optional substituents on the heteroaryl group can be present at any substituted position, including, for example, a position attached to a heteroaryl group, provided the valence number allows.

[0018] As used in this article, the term "halogen" or "halogenated" refers to F, Cl, Br, or I.

[0019] The terms "tether" or "anchor" are used interchangeably to refer to a chemical part that connects two other parts (e.g., a therapeutic part and a binding part). A tether can covalently link a therapeutic part (e.g., eczema) and a binding part (e.g., a chemical part that binds to the HSP90 protein). In one aspect, the tether is not cleavable in vivo. In another aspect, the tether comprises a ring system of one or more rings. In yet another aspect, the tether comprises an alkyl chain optionally substituted and / or interrupted by one or more chemical groups. In one aspect, the tether contains optimal spatial and chemical properties to achieve optimal therapeutic activity.

[0020] The term "HSP90" refers, collectively, individually, or in various combinations, to the protein products of members of the heat shock protein 90 (90 kDa) gene family, including: HSP90AA1 (HSP90-alpha or HSP90α), HSP90AB1 (HSP90-beta or HSP90β), HSP90B1 (GRP94), and TRAP1.

[0021] When used to describe chemical groups that may have multiple attachment points, the hyphen (-) indicates the attachment point of the group to the variable that defines it. For example, -NH(C1-C4)alkyl means that the attachment point of the group is located on a nitrogen atom.

[0022] Hyphens, such as in “ In the diagram, the point where the drawn group is attached to the defined variable is indicated.

[0023] The compounds described herein may have a chiral center and / or a geometric center (E and Z-isomers). It should be understood that this disclosure covers all stereoisomers and geometric isomers. Tautomeric forms of the compounds described herein are also part of this disclosure.

[0024] When the stereochemistry of a disclosed compound is named or described by structure, the named or described stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% (by weight) pure relative to all other stereoisomers. The weight percentage purity relative to all other stereoisomers is the ratio of the weight of one stereoisomer to the weight of the other stereoisomers.

[0025] Pharmaceutically acceptable salts of the disclosed compounds used in pharmaceuticals refer to non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include, for example, salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) and salts of organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid). Compounds of this teaching containing acidic groups (such as carboxylic acids) can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable basic salts include, for example, ammonium salts, alkali metal salts (such as sodium and potassium salts), and alkaline earth metal salts (such as magnesium and calcium salts). Compounds containing quaternary ammonium groups also contain counter anions such as chloride, bromide, iodide, acetate, perchlorate, etc. Other examples of such salts include hydrochlorides, hydrobromicates, sulfates, methanesulfonates, nitrates, benzoates, and salts formed with amino acids such as glutamic acid.

[0026] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or loading agent that does not impair the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, adjuvants, or loading agents that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0027] Any composition or method provided herein may be combined with any or more of the other compositions and methods provided herein.

[0028] As used herein, the term "subject" refers to humans and non-human animals, including veterinary subjects. The term "non-human animal" includes all vertebrates, such as mammals and non-mammals, including non-human primates, mice, rabbits, sheep, dogs, cats, horses, cattle, chickens, amphibians, and reptiles. In a preferred embodiment, the subject is a human and may be referred to as a patient.

[0029] As used herein, the term "treat," "treating," or "treatment" preferably refers to actions that achieve beneficial or desired clinical outcomes, including but not limited to reducing or improving one or more signs or symptoms of a disease or condition, reducing the severity of the disease, stabilizing the state of the disease (i.e., preventing it from worsening), improving or alleviating the state of the disease, slowing the rate of progression or delaying the time of progression, and achieving remission (whether partial or complete). "Treatment" may also mean prolonged survival compared to expected survival without treatment. Treatment is not necessarily a cure.

[0030] A "therapeutic effective dose" is an amount sufficient to treat the disease of the subject. A therapeutic effective dose can be administered once or multiple times. In one respect, a therapeutic effective dose refers to a dose of approximately 0.01 mg / kg body weight / day to approximately 100 mg / kg body weight / day.

[0031] The terms "administer," "administering," or "administration" encompass any method of delivering a pharmaceutical composition or agent to a subject's whole body or to a specific area inside or on the subject's body. In some embodiments of the invention, the agent is administered intravenously, intramuscularly, subcutaneously, intradermally, intranasally, or orally, percutaneously, or via a mucosal membrane. In a preferred embodiment, the agent is administered intravenously. In another preferred embodiment, the agent is administered orally. Administering an agent involves a number of people working together to perform the action. Administering an agent includes, for example, directly or through a third party prescribing the agent to be administered to the subject and / or providing instructions for taking the specific agent, by self-delivery, such as by oral delivery, subcutaneous delivery, intravenous delivery via the central line, etc.; or by delivery by a trained professional, such as intravenous delivery, intramuscular delivery, intratumoral delivery, etc.

[0032] 3. Compounds In the first embodiment, the compound of formula I is a compound of formula II or III: (II) or (III); Or its pharmaceutically acceptable salt, wherein R Q R T X, L, and A are as described above for Equation I.

[0033] In the second embodiment, the compound of formula I is the compound of formula III: (III); Or its pharmaceutically acceptable salt, wherein R Q R TX, L, and A are as described above for Equation I.

[0034] In the third embodiment, X is absent or -NR in the compound of formula I, II, or III. W , where R W It is H or CH3, wherein the remaining variables are as described in Formula I above. Alternatively, as part of the third embodiment, X is absent or -NH in the compounds of Formula I, II, or III, wherein the remaining variables are as described in Formula I above.

[0035] In the fourth embodiment, R in the compound of formula I, II or III Q and R T Each is independently selected from H and (C1-C4) alkyl groups, wherein the remaining variables are as described in Formula I or the third embodiment above. Alternatively, as part of the fourth embodiment, R in the compounds of Formula I, II, or III... Q and R T Each is independently selected from H, CH(CH3)2, and CH3, wherein the remaining variables are as described in Formula I or the third embodiment above. In another alternative, as part of the fourth embodiment, R in the compound of Formula I, II, or III... Q It's H, and R T The components are selected from H, CH(CH3)2, and CH3, wherein the remaining variables are as described in Formula I or the third embodiment above. Alternatively, as part of the fourth embodiment, R in the compound of Formula I, II, or III... Q and R T Each is H, and the remaining variables are as described in Equation I or the third embodiment above.

[0036] In the fifth embodiment, A in the compound of formula I, II, or III is selected from... , , and ; Z and Z' are each independently selected from N or CH; R 1 R 1A and R 1AA Each is independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, (C1-C4)alkoxy and halo(C1-C4)alkoxy; R 3 R 3A and R 3AAEach is independently selected from hydrogen, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -(C0-C4)alkylheterocyclic and -(C0-C4)heteroaryl, wherein each of the heterocyclic and heteroaryl groups is optionally selected from 1 to 3 of R Z Substitution of groups; R Z Selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, (C1-C4)alkoxy and halo(C1-C4)alkoxy; R a and R b Each is independently selected from hydrogen, (C1-C4)alkyl, and halo(C1-C4)alkyl; R 4 It is a (C1-C4) alkyl group; R 5 and R 5A Each is independently a (C1-C4) alkyl group; R 6 and R 6A Each is independently hydrogen or (C1-C4) alkyl; R 7 It is halogen; and The wavy line indicates the attachment point with connector L, wherein the remaining variables are as described in Formula I or any of the third or fourth embodiments above. Alternatively, as part of a fifth embodiment, A in the compound of Formula I, II, or III is selected from... , , and The remaining variables are as described in Equation I above or in any of the third or fourth embodiments.

[0037] In the sixth embodiment, Z and Z' are each CH, and the remaining variables are as described in Equation I above or any of the third to fifth embodiments.

[0038] In the seventh embodiment, R 1 R 1A and R 1AA Each is a (C1-C4) alkyl group, wherein the remaining variables are as described in Formula I above or any of the third to sixth embodiments. Alternatively, as part of a seventh embodiment, R 1 R 1A and R 1AA Each is isopropyl, wherein the remaining variables are as described in Formula I above or any of the third to sixth embodiments.

[0039] In the eighth embodiment, R3 R 3A and R 3AA Each is independently selected from hydrogen, -(C1-C4)alkyl heterocyclic and heteroaryl, wherein each heterocyclic and heteroaryl is optionally composed of 1 to 3 groups selected from R Z The group substitution, wherein the remaining variables are as described in Formula I above or any of the third to seventh embodiments. Alternatively, as part of the eighth embodiment, R 3A It is hydrogen, wherein the remaining variables are as described in Formula I above or any of the third to seventh embodiments. In another alternative, as part of an eighth embodiment, R 3AA It is hydrogen, wherein the remaining variables are as described in Formula I above or any of the third to seventh embodiments. In another alternative, as part of an eighth embodiment, R 3 Selected from -(C1-C4)alkyl (5 to 6-membered) heterocyclic groups and fused 8- to 10-membered heteroaryl groups, each optionally surrounded by 1 to 3 groups selected from R Z The group is substituted, wherein the remaining variables are as described in Formula I above or any of the third to seventh embodiments. In another alternative, as part of the eighth embodiment, R 3 Selected from -(C1-C4)morpholinyl, indolyl, piperazineyl, wherein the morpholinyl, indolyl, and piperazineyl are each optionally composed of 1 to 3 elements selected from R Z The group substitutions, wherein the remaining variables are as described in Formula I above or any of the third to seventh embodiments.

[0040] In the ninth embodiment, R Z It is a (C1-C4) alkyl group, wherein the remaining variables are as described in Formula I above or any of the third to eighth embodiments.

[0041] In the tenth embodiment, R a It is hydrogen; and R b It is a haloalkyl (C1-C4) group, wherein the remaining variables are as described in Formula I above or any of the third to ninth embodiments. Alternatively, as part of the tenth embodiment, R a It is hydrogen; and R b It is CH2CF3, wherein the remaining variables are as described in Equation I above or any of the third to ninth embodiments.

[0042] In the eleventh embodiment, R 4 It is CH3, where the remaining variables are as described in Formula I above or any of the third to tenth embodiments.

[0043] In the twelfth embodiment, R 5and R 5A Each is CH3, and the remaining variables are as described in Equation I above or any of the third to eleventh embodiments.

[0044] In the thirteenth embodiment, R 6 and R 6A Each is hydrogen, and the remaining variables are as described in Formula I above or any of the third to twelfth embodiments.

[0045] In the fourteenth embodiment, R 7 It is chlorine, wherein the other variables are as described in Formula I above or any of the third to thirteenth embodiments.

[0046] In the fifteenth embodiment, L in the compound of formula I, II, or III is selected from -(CH2). r -HET 1 -X 1 -HET 2 -(CH2) s -OC(O)-, -(CH2) r -HET 1 -X 1 -(CH2) q -HET 2 -(CH2) s -OC(O)-, -(CH2) r -HET 1 -X 1 -HET 2 -(CH2) s -C(O)O-(CH2) m -X 2 -、-(CH2) r -HET 1 -HET 2 -(CH2) s -C(O)-(CH2) m -X 2 -、-(CH2) y OC(O)-、-(CH2) r -HET 1 -(CH2) w -SS-HET 2 -(CH2) s -OC(O)-, -(CH2) r -HET 1 -X 1 -(CH2) s -OC(O)-, -(CH2) r -HET 1 -X1 -IT 2 -(CH2) s -NHC(O)O-(CH2) m -X 2 -、-(CH2) r -IT 1 -C(O)O-(CH2) m -X 2 -、-(CH2) r NR f (CH2) v -IT 2 -X 1 -IT 1 -(CH2) s -OC(O)-、-(CH2) r NR f (CH2) v -IT 2 -X 1 -IT 1 -(CH2) s -C(O)O-(CH2) m -X 2 -、-(CH2) r NR f (CH2) v -IT 2 -(CH2) s -NHC(O)O-(CH2) m -X 2 -、-(CH2) r -IT 3 -OC(O)-、-(CH2) r -IT 2 -X 1 -IT 3 -OC(O)-、-(CH2) r -IT 3 -X 1 -(CH2) s -OC(O)-、-(CH2) r -IT 3 -X 1 -IT 2 -OC(O)-、-X 1 -IT 3 -OC(O)-、-X 1 -IT 3 -X 2 -(CH2) s -OC(O)-、-(CH2) r-IT 1 -IT 2 -(CH2) s -OC(O)-、-(CH2) r -IT 1 -(CH2) q -IT 2 -(CH2) s -OC(O)-、-(CH2) r -IT 1 -X 1 -(CH2) w -SS-THE 2 -(CH2) s -OC(O)-、-(CH2) r -IT 1 -IT 2 -(CH2) s -NHC(O)O-(CH2) m -X 2 -、-(CH2) r -IT 1 -NHC(O)O-(CH2) m -X 2 -、-(CH2) r NR f (CH2) v -IT 2 -X 1 -(CH2) q -IT 1 -(CH2) s -OC(O)-、-(CH2) r NR f (CH2) v -IT 2 -IT 1 -(CH2) s -C(O)O-(CH2) m -X 2 -、-(CH2) r NR f (CH2) v -OC(O)-、-(CH2) r NR f (CH2) v -IT 2 -(CH2) w -SS-THE 1 -(CH2) s -OC(O)-、-(CH2) r NR f(CH2) v -HET 2 -X 1 -(CH2) s -OC(O)-,-(CH2) r ARN f (CH2) v -HET 2 -X 1 -HET 1 -(CH2) s -NHC(O)O-(CH2) m -X 2 -、-(CH2) r ARN f (CH2) v -HET 2 -C(O)O-(CH2) m -X 2 -、-(CH2) r ARN f (CH2) v -HET 2 -X 1 -(CH2) s -OC(O)-,-(CH2) r ARN f (CH2) v -HET 2 -X 1 -(CH2) s -C(O)-(CH2) m -X 2 -、-(CH2) r ARN f (CH2) v -HET 2 -X 1 -(CH2) q -HET 1 -(CH2) s -NHC(O)O-(CH2) m -X 2 -、-(CH2) r ARN f (CH2) v -HET 2 -X 1 -(CH2) s -NHC(O)O-(CH2) m -X 2 -、-(CH2) r ARN f (CH2) v -HET2 -X 1 -IT 1 -(CH2) s -NHC(O)O-(CH2) m -X 2 -(CH2) m -X 2 -、-(CH2) r NR f (CH2) v -IT 2 -X 1 -(CH2) s -NHC(O)O-(CH2) m -X 2 -、-(CH2) r -IT 1 -X 1 -(CH2) q -IT 3 -(CH2) s -OC(O)-、-(CH2) r -IT 1 -X 1 -IT 3 -(CH2) s -C(O)O-(CH2) m -X 2 -、-(CH2) r -IT 1 -IT 3 -(CH2) s -C(O)-(CH2) m -X 2 -、-(CH2) r -IT 1 -(CH2) w -SS-THE 3 -(CH2) s -OC(O)-、-(CH2) r -IT 1 -X 1 -IT 3 -(CH2) s -NHC(O)O-(CH2) m -X 2 -、-(CH2) r -IT 3 -C(O)O-(CH2) m -X 2 -、-(CH2) r NR f (CH2)v -HET 2 -X 1 -HET 3 -(CH2) s -OC(O)-, -(CH2) r NR f (CH2) v -HET 3 -X 1 -HET 1 -(CH2) s -C(O)O-(CH2) m -X 2 -、-(CH2) r NR f (CH2) v -HET 3 -(CH2) s -NHC(O)O-(CH2) m -X 2 -, -C(O)NH-CRR'-C(O)NH-CRR'-C(O)NHCRR'C(O)NH(CH2) m -X 2 -, -C(O)NH-CRR'-C(O)NH-CRR'-C(O)NH-HET 2 -(CH2) s -OC(O)-, C(O), -C(O)-X 1 -HET 1 -X 2 -,-X 1 -HET 1 -X 2 -C(O)-HET 1 -X 1 -HET 2 -X 2 and C(O)-X 1 -O-; m, q, r, s, v, w, and y are each independently between 0 and 4; R f Selected from hydrogen and (C1-C4) alkyl groups; X 1 and X 2 Each is independently selected from CO and -CH2-; HET 1 HET 2 and HET 3 Each is independently selected from monocyclic heterocyclic groups, bicyclic heterocyclic groups, monocyclic cycloalkyl groups, and phenyl groups; and R' and R'' are each independently selected from hydrogen and (C1-C4)alkyl groups, wherein the (C1-C4)alkyl groups are optionally substituted with phenyl or NHC(O)NH2, and the remaining variables are as described in Formula I above or in any of the third to fourteenth embodiments. Alternatively, as part of the fifteenth embodiment, L is selected from C(O), -C(O)-X 1 -HET 1 -X 2 -,-X 1 -HET 1 -X 2 -C(O)-HET 1 -X 1 -HET 2 -X 2 and C(O)-X 1 -O-, where the remaining variables are as described in Equation I above or any of the third to fourteenth embodiments.

[0047] In the sixteenth embodiment, X 1 and X 2 Each is -CH2-, and the remaining variables are as described in Equation I above or any of the third to fifteenth embodiments.

[0048] In the seventeenth embodiment, HET 1 HET 2 and HET 3 Each is independently selected from monocyclic heterocyclic groups and monocyclic cycloalkyl groups, wherein the remaining variables are as described in Formula I above or any of the embodiments from the third to the sixteenth. Alternatively, as part of the seventeenth embodiment, HET 1 and HET 2 and HET 3 Each is independently selected from piperazine-yl and cyclohexyl, wherein the remaining variables are as described in Formula I above or any of the third to sixteenth embodiments. Alternatively, as part of the seventeenth embodiment, L is selected from C(O). , , and C(O)CH2O ,in The attachment point to A is indicated, wherein the remaining variables are as described in Equation I above or in any of the third to sixteenth embodiments.

[0049] Compounds having formulas I, II, and III are further disclosed in the examples and are included in this disclosure. These include pharmaceutically acceptable salts and neutral forms.

[0050] 4. Uses, formulations, and application The compounds and compositions disclosed herein are commonly used in anticancer therapies. The terms “cancer” or “tumor” are well known in the art and refer to, for example, cells present in a subject that exhibit typical characteristics of cancerous cells, such as uncontrolled proliferation, immortalization, metastatic potential, rapid growth and proliferation rate, reduced cell death / apoptosis, and certain characteristic morphological features. Cancer cells typically exist in the form of solid tumors. However, cancer also includes non-solid tumors, such as hematologic malignancies like leukemia, where cancer cells originate in the bone marrow. As used herein, the term “cancer” includes both precancerous and malignant cancers. Cancers include, but are not limited to, acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocyte, myeloblast, adenocarcinoma, angiosarcoma, astrocytoma, bone marrow monocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic granulocytic leukemia, and other related diseases. Colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, Burkitt lymphoma, dysplastic changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocytosis, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, angioblastoma, hepatocellular carcinoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, etc. Slurosarcoma, liposarcoma, lung cancer, lymphangiosarcoma, lymphangiosarcoma, lymphocytic leukemia, lymphoma (Hodgkin's and non-Hodgkin's); malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus; T-cell or B-cell-derived lymphomas, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell lung cancer. Small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinoma and sarcoma), gastric cancer, squamous cell carcinoma, synovial tumor, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumors, uterine cancer, and nephroblastoma.Other cancers include primary cancers, metastatic cancers, oropharyngeal cancer, hypopharyngeal cancer, liver cancer, gallbladder cancer, bile duct cancer, small intestine cancer, urinary tract cancer, kidney cancer, urothelial carcinoma, female reproductive tract cancers, uterine cancer, gestational trophoblastic cancer, male reproductive tract cancers, seminal vesicle cancer, testicular cancer, germ cell tumors, endocrine gland tumors, thyroid cancer, adrenal cancer, pituitary adenocarcinoma, hemangioma, bone and soft tissue sarcoma, and Kaposi's sarcoma. Sarcoma, neurocarcinoma, eye cancer, meningeal carcinoma, glioblastoma, neuroma, neuroblastoma, schwannoma, solid tumors caused by hematopoietic system malignancies such as leukemia, metastatic melanoma, recurrent or persistent epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, gastrointestinal stromal tumors, colorectal cancer, gastric cancer, melanoma, glioblastoma multiforme, non-squamous non-small cell lung cancer, malignant glioma, epithelial ovarian cancer, primary peritoneal serous carcinoma, metastatic liver cancer, neuroendocrine carcinoma, refractory malignant tumors, triple-negative breast cancer, HER2-amplified breast cancer, nasopharyngeal carcinoma. Oral cancer, biliary tract cancer, hepatocellular carcinoma, squamous cell carcinoma of the head and neck (SCCHN), non-medullary thyroid carcinoma, recurrent glioblastoma multiforme, neurofibromatosis type 1, CNS cancer, liposarcoma, leiomyosarcoma, salivary gland cancer, mucosal melanoma, acral / lentiginesous melanoma, paraganglioma, pheochromocytoma, advanced metastatic cancer, solid tumors, triple-negative breast cancer, colorectal cancer, sarcoma, melanoma, renal cancer, endometrial cancer, thyroid cancer, rhabdomyosarcoma, multiple myeloma, ovarian cancer, glioblastoma, gastrointestinal stromal tumors, mantle cell lymphoma, and refractory malignancies.

[0051] As used in this article, "solid tumor" is understood to be any pathogenic tumor that can be palpated or detected using imaging methods and exhibits abnormal growth in three dimensions. Solid tumors differ from hematologic malignancies such as leukemia. However, the cells of hematologic malignancies originate from the bone marrow; therefore, the tissue that produces cancer cells is potentially hypoxic solid tissue.

[0052] "Tumor tissue" or "tissue of a tumor" is understood to include cells, extracellular matrix, and other naturally occurring components associated with solid tumors.

[0053] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, timing of administration, excretion rate, drug combination, as well as the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compounds described herein in the composition will also depend on the specific compounds in the composition.

[0054] Example Chemical synthesis The following representative embodiments are intended to help illustrate this disclosure and are not intended to, and should not be construed as limiting the scope of the invention. Unless otherwise stated, the starting materials are generally obtained from commercial sources or prepared in other embodiments.

[0055] Preparation of compounds The compound claimed in this document was prepared according to the procedure outlined in the following scheme.

[0056] Example 1: Synthesis of Compound 001 The representative synthetic scheme for compound 001 is shown below. The specific synthetic route for the intermediate is also shown.

[0057] Intermediate 2: ((1R,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-1-yl)(9H-fluorene-9-yl)methylcarbamate In 25 o At C, Fmoc-Osu (0.75 g, 2.26 mmol, 1.5 eq) was added to a solution of compound 1 (0.80 g, 1.51 mmol, 1.0 eq) and 0.75 M NaHCO3 (20.06 mL, 0.75 mol / L, 10.0 eq) in MeCN (40 mL). The reaction mixture was heated to 25 °C. o The mixture was stirred at C for 18 h. The reaction mixture was concentrated and purified by FC (DCM:MeOH=1:20) to obtain compound 2 as a yellow solid (0.95 g, yield 96%).

[0058] Intermediate 4: (1R,9S)-1-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12Hbenzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(tert-butoxycarbonyl)glycine ester In 0 o At C, compound 3 (0.48 g, 2.73 mmol, 2.0 eq) was added to a solution of DCM (40 mL) under stirring. oEDCI (0.53 g, 2.73 mmol, 2.0 eq) and DMAP (0.05 g, 0.41 mmol, 0.3 eq) were added at C for 4 min. Compound 2 (0.91 g, 1.37 mmol, 1.0 eq) was then added to the solution and incubated at 25 °C. o The mixture was stirred at C for 18 h. The reaction mixture was concentrated and purified by FC (DCM:MeOH=1:20) to obtain compound 4 (0.85 g, yield 72%) as a yellow solid.

[0059] Intermediate 5: (1R,9S)-1-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-ylglycine ester In 25 o At C, TFA (2.25 mL) was added to a solution of compound 4 (800 mg, 0.982 mmol, 1.0 eq) in DCM (11.25 mL). The mixture was then heated to 25 °C. o The mixture was stirred at C for 1 h. The mixture was then concentrated under reduced pressure to obtain the desired product (850 mg, crude product) as a yellow solid.

[0060] Intermediate 7: (1R,9S)-1-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carbonyl)glycine ester In 25 o Compound 5 (351 mg, 0.49 mmol, 1.0 eq) was added to a mixture of compound 6 (237 mg, 0.54 mmol, 1.1 eq), PyBop (383 mg, 0.736 mmol, 1.5 eq), and DIPEA (0.49 mL, 2.95 mmol, 6.0 eq) in DCM (20 mL) at C. The mixture was then incubated at 25 °C. o The mixture was stirred at C for 18 h. The mixture was concentrated and purified by preparative HPLC (TFA) to give compound 7 as a yellow solid (0.27 g, yield 48%).

[0061] Compound 001: (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carbonyl)glycine ester 2,2,2-trifluoroacetate In 0 o At C, piperidine (0.32 mL) was added to a solution of compound 4 (270 mg, 0.238 mmol, 1.0 eq) in DMF (12.92 mL). The mixture was then heated in 0°C. o The mixture was stirred at C for 10 min. The mixture was concentrated and purified by preparative HPLC (TFA) to obtain the desired product compound 001 (210.2 mg, TFA salt, yield 86%) as a yellow solid. 1 HNMR(400 MHz, DMSO) δ10.07-10.04 (m, 1H), 9.83 (s, 1H), 9.70 (s, 1H), 9.38-9.36 (m, 1H), 8.54-8.50 (m, 3H), 7.82-7.80 (m, 1H), 7.38-7.36 (m, 4H), 7.23-7.21 (m, 1H), 6.75 (s, 1H), 6.42 (s, 1H), 5.73-5.71 (m, 1H), 5.57-5.53 (m,2H), 5.46-5.44 (m, 1H), 5.14-5.12 (m, 1H), 4.29-4.25 (m, 4H), 3.94-3.92 (m,2H), 3.66-3.62 (m, 3H), 3.17-3.07 (m, 3H), 2.99-2.95 (m, 2H), 2.46-2.40 (m,3H), 2.19-2.11 (m, 4H), 0.92-0.89 (m, 9H). LCMS: m / z (ES+) (M+H) + = 913.2, Rt = 0.879 min.

[0062] Following the general procedure described above, the following other compounds were prepared using appropriate starting materials: Compound 001 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carbonyl)glycine ester 2,2,2-trifluoroacetate. 1 H NMR(400 MHz, DMSO) δ10.07-10.04 (m, 1H), 9.83 (s, 1H), 9.70 (s, 1H), 9.38-9.36(m, 1H), 8.54-8.50 (m, 3H), 7.82-7.80 (m, 1H), 7.38-7.36 (m, 4H), 7.23-7.21(m, 1H), 6.75 (s, 1H), 6.42 (s, 1H), 5.73-5.71 (m, 1H), 5.57-5.53 (m, 2H),5.46-5.44 (m, 1H), 5.14-5.12 (m, 1H), 4.29-4.25 (m, 4H), 3.94-3.92 (m, 2H), 3.66-3.62 (m, 3H), 3.17-3.07 (m, 3H), 2.99-2.95 (m, 2H), 2.46-2.40 (m, 3H), 2.19-2.11 (m, 4H), 0.92-0.89 (m, 9H). LCMS (ESI): R T = 0.879 min, m / z measured value 913.2 [M+H] + .

[0063] Compound 002 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carbonyl)glycine ester 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) δ9.96 (s, 1H), 9.82 (s, 1H), 9.68 (s, 1H), 9.39-9.37 (m, 1H), 8.51-8.48 (m, 3H), 7.83-7.80 (m, 1H), 7.38-7.34 (m, 4H), 7.22-7.18 (m, 1H), 6.75 (s, 1H), 6.42 (s, 1H), 5.74-5.68 (m, 1H), 5.56-5.52 (m, 2H), 5.46-5.42(m, 1H), 5.13-5.11 (m, 1H), 4.28-4.22 (m, 4H), 3.94-3.92 (m, 2H), 3.60-3.56(m, 2H), 3.24-2.91 (m, 6H), 2.54-2.52 (m, 1H), 2.44-2.40 (m, 3H), 2.23-2.10(m, 3H), 0.94-0.90 (m, 9H). LCMS (ESI): R T = 0.844 min, m / z measured value 913.3 [M+H] + .

[0064] Compound 003 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)acetyl)glycine ester 2,2,2-trifluoroacetate. 1 H NMR (400 MHz, DMSO) δ10.15 (s, 1H),9.75 (s, 1H), 9.63 (t, J = 6.4 Hz, 1H), 8.60-8.52 (m, 3H), 7.84 (d, J= 10.8 Hz,1H), 7.48-7.39 (m, 4H), 7.17 (s, 1H), 6.67 (s, 1H), 6.30 (s, 1H), 5.74-5.65(m, 1H), 5.53-5.41 (m, 3H), 5.12 (s, 1H), 4.30-4.24 (m, 1H), 4.14-4.08 (m,2H), 3.99-3.91 (m, 3H), 3.38-3.28 (m, 6H), 3.17-3.08 (m, 4H), 2.96-2.86 (m,4H), 2.43 (s, 3H), 2.22-2.10 (m, 4H), 0.91 (t, J = 7.6 Hz, 3H), 0.85 (d, J = 6.8Hz, 6H). LCMS (ESI): R T = 0.829 min, m / z measured value 1051.4 [M+H] + .

[0065] Compound 004 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)acetyl)glycine ester 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) δ10.12 (s,1H), 9.73 (s, 1H), 9.63 (t, J = 6.4 Hz, 1H), 8.47 (s, 3H), 7.85 (d, J = 10.8Hz, 1H), 7.48-7.39(m, 4H), 7.17 (s, 1H), 6.66 (s, 1H), 6.29 (s, 1H), 5.71 (d,J = 19.2 Hz, 1H), 5.58-5.42(m, 3H), 5.10 (s, 1H), 4.29-3.94(m, 6H), 3.29-2.90(m, 14H), 2.43 (s, 4H), 2.20-2.15(m, 3H), 0.92 (t, J = 7.2 Hz, 3H), 0.84 (d,J = 6.8 Hz, 6H). LCMS (ESI): R T = 0.797 min, m / z measured value 1051.4 [M+H] + .

[0066] Compound 005 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl 2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)acetate 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) δ9.87 (s, 1H), 9.76 (s,1H), 9.65 (t, J = 6.4 Hz, 1H), 8.55 (s, 3H), 7.84 (d, J = 10.8 Hz, 1H), 7.54-7.52 (m, 2H), 7.45-7.43 (m, 2H), 7.11 (s, 1H), 6.70 (s, 1H), 6.31 (s, 1H), 5.73 (d, J = 19.2 Hz, 1H), 5.55 (s, 2H), 5.45 (d, J = 19.2 Hz, 1H), 5.13 (s,1H), 4.36 (s, 2H), 3.98-3.94 (m, 3H), 3.40–3.01 (m, 9H), 2.95-2.91 (m, 2H), 2.72-2.68 (m, 2H), 2.43 (s, 3H), 2.22–2.12 (m, 3H), 0.94 (t, J = 7.4 Hz, 3H),0.88 (d, J = 6.8 Hz, 6H). LCMS (ESI): R T = 0.947 min, m / z measured value 821.2 [M+H] + .

[0067] Compound 006 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)acetate 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) δ10.11 (s, 1H), 9.75 (s,1H), 9.63 (t, J = 6.4 Hz, 1H), 8.55 (s, 3H), 7.84 (d, J = 10.8 Hz, 1H), 7.50(d, J = 8.4z Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.11 (s, 1H), 6.65 (s, 1H), 6.30 (s, 1H), 5.72 (d, J = 19.2 Hz, 1H), 5.59-5.43 (m, 3H), 5.11 (s, 1H),4.33 (s, 2H), 3.96-3.92 (m, 2H), 3.77-3.65(m, 3H), 3.31-3.07 (m, 10H), 2.82-79 (m, 1H), 2.41 (s, 3H), 2.21-2.15(m, 3H), 0.93 (t, J = 7.6 Hz, 3H), 0.80 (d, J = 7.2 Hz, 6H). LCMS (ESI): R T = 1.565 min, m / z measured value 821.2 [M+H] + .

[0068] Compound 007 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindololine-5-yl)methyl)piperazin-1-yl)acetate 2,2,2-trifluoroacetate. 1HNMR (400 MHz, DMSO) δ10.02 (s, 1H), 9.69-9.65 (m, 2H), 8.54 (s, 3H), 7.83 (d,J = 10.8 Hz, 1H), 7.41-7.38 (m, 3H), 7.09 (s, 1H), 7.03 (s, 1H), 6.41 (s,1H), 5.75-5.73 (m, 1H), 5.54 (s, 2H), 5.46-5.42 (m, 1H), 5.13 (s, 1H), 4.83-4.79 (m, 4H), 4.32 (s, 2H), 3.77-3.59 (m, 3H), 3.34-2.95 (m, 10H), 2.45-2.41(m, 3H), 2.21-2.15 (m, 3H), 1.14 (d, J = 6.8 Hz, 6H), 0.92 (t, J = 7.2 Hz, 3H). LCMS (ESI): R T = 1.255 min, m / z measured value 871.7 [M+H] + .

[0069] Compound 008 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindololine-5-yl)methyl)piperazin-1-yl)acetate 2,2,2-trifluoroacetate. 1HNMR (400 MHz, DMSO) δ10.04 (s, 1H), 9.68 (s, 1H), 8.53 (s, 3H), 7.82 (d, J =10.8 Hz, 1H), 7.48-7.34(m, 3H), 7.08 (s, 1H), 7.01 (s, 1H), 6.39 (s, 1H),5.73-5.67 (m, 1H), 5.57-5.4 (m, 3H), 5.09 (s, 1H), 4.89-4.64 (m, 4H), 4.27(s, 2H), 3.72-3.53 (m, 3H), 3.26-2.97 (m, 11H), 2.40 (s, 3H), 2.20-2.12(m ,3H), 1.11 (d, J = 6.8 Hz, 6H), 0.91 (t, J = 7.2 Hz, 3H). LCMS (ESI): R T = 1.109 min, m / z measured value 871.7 [M+H] + .

[0070] Compound 009 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolline-5-carbonyl)glycine ester 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) δ10.15 – 10.00 (m, 1H), 9.63 (s, 1H), 9.10 (s, 1H), 8.43 (s, 3H), 7.86 – 7.80(m, 3H), 7.46 – 7.38 (m, 1H), 7.26 (s, 1H), 7.03 (s, 1H), 6.39 (s, 1H), 5.71(d, J = 19.2 Hz, 1H), 5.53 (s, 2H), 5.43 (d, J = 19.2 Hz, 1H), 5.12 (s, 1H),4.82 – 4.74 (m, 4H), 4.38 – 4.32 (m, 1H), 4.18 – 4.12 (m, 1H), 3.12 – 3.05 (m, 3H), 2.34 – 2.13 (m, 4H), 1.13 (d, J = 6.8 Hz, 6H), 0.91 (t, J = 7.2 Hz, 3H). LCMS (ESI): R T = 1.238 min, m / z measured value 816.2 [M+H] + .

[0071] Compound 010 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolline-5-carbonyl)glycine ester 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) δ10.09 (s, 1H), 9.72 (s, 1H), 9.08 (s, 1H), 8.48 (s, 3H), 7.82-7.77(m, 3H),7.43-7.27(m, 2H), 7.02 (s, 1H), 6.38 (s, 1H), 5.72-5.65 (m, 1H), 5.51 (s,2H), 5.07 (s, 1H), 4.87-4.73 (m, 4H), 4.34-4.28 (m, 1H), 4.17-4.13 (m, 1H),3.09-3.05 (m, 2H), 2.42 (s, 3H), 2.21-2.14(m, 3H), 2.02-1.96 (m, 1H), 1.22(s, 2H), 1.11 (d, J = 6.8 Hz, 6H), 0.91 (t, J = 7.2 Hz, 3H). LCMS (ESI): R T =0.998 min, m / z measured value 816.2 [M+H] + .

[0072] Compound 011 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-phenylisoxazole-3-carbonyl)glycine ester 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) δ9.76 (s, 1H), 9.64 (s, 1H), 9.40 (t, J = 6.0 Hz, 1H), 8.46-8.42 (m, 3H), 7.78 (d, J = 10.8 Hz, 1H), 7.29-2.25 (m, 2H), 7.23-7.17 (m, 4H), 6.76 (s,1H), 6.42 (s, 1H), 5.72 (d, J = 19.2 Hz, 1H), 5.54 (s, 2H), 5.43 (d, J = 19.2Hz, 1H), 5.15-5.11 (m, 1H), 4.34-4.28 (m, 1H), 4.18-4.12 (m, 1H), 3.33-3.29(m, 1H), 3.15-3.11 (m, 1H), 2.99-2.95 (m, 1H), 2.55-2.51 (m, 1H), 2.43 (s,3H), 2.21-2.17 (m, 1H), 2.13-2.09 (m, 2H), 0.93-0.87 (m, 9H). LCMS (ESI): R T =1.129 min, m / z measured value 813.9 [M+H] + .

[0073] Compound 012 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-phenylisoxazole-3-carbonyl)glycine ester 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO)δ9.76 (s, 1H), 9.63 (s, 1H), 9.40 (t, J = 6.0 Hz, 1H), 8.45 (s, 3H), 7.76 (d,J = 10.8 Hz, 1H), 7.25-7.22(m, 3H), 7.17-7.12(m, 3H), 6.75 (s, 1H), 6.41 (s,1H), 5.71 (d, J = 19.2 Hz, 1H), 5.55 (s, 2H), 5.47-5.43(m, 1H), 5.12 (s, 1H),4.33-4.27 (m, 1H), 4.19-4.13 (m, 1H), 3.27-3.10(m, 2H), 2.99-2.95 (m, 1H), 2.43 (s, 3H), 2.24-2.19(m, 1H), 2.15-2.11(m, 2H), 0.93-0.89(m, 9H). LCMS(ESI): R T = 1.419 min, m / z measured value 814.2 [M+H] + .

[0074] Compound 013 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-((1r,4S)-4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)cyclohexane-1-carbonyl)glycine ester 2,2,2-trifluoroacetate. 1H NMR (400MHz, DMSO) δ9.76 (s, 1H), 9.62 (m, 1H), 9.10 (s, 1H), 8.50 (s, 3H), 8.35-8.31(m, 1H), 7.85-7.82 (m, 1H), 7.40-7.37 (m, 4H), 7.16 (s, 1H), 6.65 (s, 1H), 6.33 (s, 1H), 5.74-5.70 (m, 1H), 5.53 (s, 2H), 5.46-5.42 (m, 1H), 5.12 (s,1H), 4.16-4.12 (m, 5.8 Hz, 1H), 4.02-3.98 (m, 1H), 3.96-3.91 (m, 2H), 3.38-3.29 (m, 6H), 3.10-3.02 (m, 2H), 2.96–2.88 (m, 4H), 2.76-2.74 (m, 1H), 2.52-2.48 (m, 3H), 2.43 (s, 3H), 2.23-2.11 (m, 4H), 1.82-1.80 (m, 5H), 1.47-1.35(m, 2H), 0.93-0.90 (m, 5H), 0.84 (d, J = 6.8 Hz, 6H). LCMS (ESI): R T = 0.996 min, m / z measured value 1133.9 [M+H] + .

[0075] Compound 014 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-((1r,4S)-4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)cyclohexane-1-carbonyl)glycine ester 2,2,2-trifluoroacetate. 1H NMR (400MHz, DMSO) δ9.93 (s, 1H), 9.62-9.60 (m, 1H), 8.58 (s, 3H), 8.32-8.30 (m, 1H), 7.84-7.82 (m, 1H), 7.44-7.40 (m, 4H), 7.19-7.16 (m, 1H), 6.66 (s, 1H), 6.33(s, 1H), 5.72-5.70 (m, 1H), 5.56-5.54 (m, 2H), 5.45-5.43 (m, 1H), 5.11 (s,1H), 4.15-3.97 (m, 4H), 3.32-3.28 (m, 2H), 3.21-3.03 (m, 4H), 2.97-2.79 (m,6H), 2.77-2.75 (m, 1H), 2.57-2.51 (m, 3H), 2.42 (s, 3H), 2.22-2.07 (m, 4H),1.84-1.64 (m, 5H), 1.44-1.32 (m, 2H), 0.94-0.90 (m, 5H), 0.85 (d, J = 6.8 Hz, 6H). LCMS (ESI): R T = 0.952 min, m / z measured value 1133.9 [M+H] + .

[0076] Compound 015 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl1H-indol-6-yl)isoxazole-3-carbonyl)glycine ester 2,2,2-trifluoroacetate. 1H NMR(400 MHz, DMSO) δ9.70 (s, 1H), 9.56 (s, 1H), 9.38-9.35 (m, 1H), 8.39-8.36 (m,3H), 7.77 (d, J = 10.8 Hz, 1H), 7.37-7.32 (m, 2H), 7.25 (d, J = 3.2 Hz, 1H), 7.20 (s, 1H), 6.88-6.82 (m, 1H), 6.81 (s, 1H), 6.39 (s, 1H), 6.31 (d, J = 3.2Hz, 1H), 5.69 (d, J = 19.2 Hz, 1H), 5.53 (s, 2H), 5.41 (d, J = 19.2 Hz, 1H),5.12-5.07 (m, 1H), 4.38-4.32 (m, 1H), 4.21-4.15 (m, 1H), 3.59 (s, 3H), 2.97-2.93 (m, 2H), 2.42 (s, 3H), 2.18-2.08 (m, 4H), 1.66-1.62 (m, 1H), 0.89-0.84 (m, 9H). LCMS (ESI): R T = 0.947 min, m / z measured value 821.2 [M+H] + .

[0077] Compound 016 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-(2-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindololine-5-yl)oxy)acetyl)glycine ester 2,2,2-trifluoroacetate. 1H NMR (400MHz, DMSO) δ10.03 (s, 1H), 9.60 (s, 1H), 8.67 – 8.60 (m, 1H), 8.48 – 8.30 (m,2H), 7.81 (d, J = 10.8 Hz, 1H), 7.21 – 7.14 (m, 2H), 7.01 (s, 1H), 6.95 –6.85 (m, 2H), 6.38 (s, 1H), 5.70 (d, J = 19.2 Hz, 1H), 5.52 (s, 2H), 5.44 (d,J = 19.2 Hz, 1H), 5.08 (s, 1H), 4.65 (s, 4H), 4.51 (s, 2H), 4.25 – 4.19 (m,1H), 4.09 – 4.03 (m, 1H), 3.11 – 3.05 (m, 2H), 2.42 – 2.37 (m, 5H), 2.20 –2.10 (m, 4H), 1.12 (d, J = 6.8 Hz, 6H), 0.90 (t, J = 7.2 Hz, 3H). LCMS(ESI):R T = 1.354 min, m / z measured value 846.4 [M+H] + .

[0078] Compound 017 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzoyl)glycine ester 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) δ9.99 (s, 1H), 9.71 (s, 1H), 9.64(t, J = 6.4 Hz, 1H), 9.22 (t, J = 5.6 Hz, 1H), 8.45 (s, 3H), 7.90 (d, J = 8.8Hz, 2H), 7.85 (d, J = 10.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.26 (s, 1H), 6.74 (s, 1H), 6.27 (s, 1H), 5.71 (d, J = 19.6 Hz, 1H), 5.53 (s, 2H), 5.43 (d,J = 19.6 Hz, 1H), 5.11 (s, 1H), 4.36-4.18 (m, 1H), 4.17-4.14 (m, 1H), 3.96-3.92 (m, 2H), 3.30 (s, 2H), 3.16-3.11 (m, 1H), 2.94-2.91(m, 1H), 2.43 (s,3H), 2.19-2.14(m, 3H), 0.92-0.88 (m, 9H). LCMS (ESI): R T = 1.380 min, m / z measured value 939.2 [M+H] + .

[0079] Compound 018 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-(5-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pent-4-ynyl)glycine ester 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) δ8.56 (t, J = 6.0 Hz, 1H), 8.42 –8.39 (m, 3H), 8.04 (s, 1H), 7.86 (d, J = 10.8 Hz, 1H), 7.21 (s, 1H), 7.18 (s,1H), 6.67 (s, 2H), 5.76 – 5.68 (m, 1H), 5.51 (s, 2H), 5.47 – 5.40 (m, 1H), 5.25 (s, 2H), 5.14 – 5.11 (m, 1H), 4.21 – 4.15 (m, 1H), 4.00 – 3.94 (m, 1H),3.74 – 3.71 (m, 4H), 2.45 – 2.39 (m, 6H), 2.25 – 2.21 (m, 6H), 2.19 – 2.14(m, 6H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): R T =0.649 min, m / z measured value 444.6 [1 / 2M+H] + .

[0080] Compound 019 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carbonyl)-L-valine ester 2,2,2-trifluoroacetate. 1HNMR (400 MHz, DMSO) δ 9.83 (s, 1H), 9.69 (s, 1H), 9.34 (s, 1H), 8.43 (s, 3H), 7.65 (d, J = 10.8 Hz, 1H), 7.38-7.36 (m, 3H), 7.18 (s, 1H), 6.81 (s, 1H), 6.46 (s, 1H), 5.71 (d, J = 19.2 Hz, 1H), 5.54 (s, 2H), 5.45 (d, J = 19.2 Hz, 1H), 5.10 (s, 1H), 4.43-4.39 (m, 4H), 3.96-3.92 (m, 4H), 3.14-3.10 (m, 4H), 3.09-3.01 (m, 3H), 2.21-2.17 (m, 5H), 1.67-1.63 (m, 1H), 1.21-1.19 (m, 2H), 0.95-0.91 (m, 15H). LCMS (ESI): R T = 1.683 min, m / z measured value 956.4 [M+H] + .

[0081] Compound 020 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carbonyl)-D-valine ester 2,2,2-trifluoroacetate. 1HNMR(400 MHz, DMSO) δ 9.83 (s, 1H), 9.69 (s, 1H), 9.35 (d, J = 10.8 Hz, 1H), 8.40(s, 2H), 7.68 (d, J = 10.8 Hz, 1H), 7.44-7.40 (m, 4H), 7.17 (s, 1H), 6.82 (s,1H), 6.46 (s, 1H), 5.71 (d, J = 19.2 Hz, 1H), 5.54 (s, 2H), 5.43 (d, J = 19.2Hz, 1H), 5.11 (s, 1H), 4.44-4.38 (m, 2H), 3.96 (s, 1H), 3.59-3.51 (m, 5H),3.13-3.07 (m, 4H), 3.05–2.95 (m, 3H), 2.19-2.15 (m, 5H), 1.66-1.64 (m, 1H),1.21-1.17 (m, 2H), 0.97-0.91 (m, 15H). LCMS (ESI): R T = 1.703 min, m / z measured value 956.4 [M+H] + .

[0082] Compound 021 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-methylpiperazin-1-yl)methyl)phenyl)isoxazole-3-carbonyl)glycine ester 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) δ9.79 (s, 1H), 9.68 (s, 1H), 9.35 (t, J = 6 Hz,1H), 8.47 (s, 3H), 7.80 (d, J = 10.8 Hz, 1H), 7.24 (m, 5H), 6.70 (s, 1H),6.43 (s, 1H), 5.71 (d, J = 19.2 Hz, 1H), 5.54 (s, 2H), 5.43 (d, J = 19.2 Hz,1H), 5.12 (s, 1H), 4.24 (m, 2H), 3.53 (s, 2H), 3.30 – 3.25 (m, 2H), 3.11 (s,1H), 2.96 (m, 4H), 2.76 (s, 3H), 2.68 – 2.66 (m, 1H), 2.42 (s, 3H), 2.35 –2.30 (m, 2H), 2.21 – 2.07 (m, 3H), 0.92 (d, J = 7.2 Hz, 3H), 0.88 (d, J = 6.8Hz, 6H). LCMS (ESI): R T = 0.721 min, m / z measured value 463.8 [1 / 2M+H] + .

[0083] Compound 022 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-((1r,4s)-4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)cyclohexane-1-carbonyl)-L-alanine ester formate. 1H NMR (400 MHz, DMSO) δ10.51 (s, 1H), 9.60 (s, 1H), 8.38 (d, J = 6.8 Hz, 1H), 7.61 (d, J = 10.8 Hz, 1H), 7.36 (dd, J = 20.4, 8.4 Hz, 4H), 7.06 (s, 1H), 6.62 (s, 1H), 6.36 (s,1H), 5.66 – 5.39 (m, 4H), 4.36 (m, 2H), 4.02 – 3.94 (m, 2H), 3.50 (s, 2H), 3.09 (s, 2H), 2.90 – 2.86 (m, 1H), 2.69 (d, J = 1.8 Hz, 3H), 2.38 (s, 5H), 2.35 (s, 4H), 2.13 (dd, J = 14.9, 7.3 Hz, 6H), 1.79 (d, J = 37.3 Hz, 5H), 1.52 (s, 3H), 1.40 (d, J = 7.3 Hz, 3H), 1.26 (s, 2H), 0.91 (m, 5H), 0.80 (m, 6H). LCMS (ESI): R T = 0.658 min, m / z measured value 574.4 [1 / 2M+H] + .

[0084] Compound 023 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-((1r,4s)-4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)cyclohexane-1-carbonyl)-L-valine ester formate. 1H NMR (400 MHz, DMSO)δ 10.50 (s, 1H), 9.61 (t, J = 6.4 Hz, 1H), 8.30 – 8.21 (m, 1H), 7.56 (d, J =10.8 Hz, 1H), 7.37 – 7.31 (m, 4H), 7.08 – 7.05 (m, 1H), 6.62 – 6.60 (m, 1H), 6.34 (s, 1H), 5.66 – 5.58 (m, 1H), 5.53 – 5.44 (m, 2H), 5.42 – 5.34 (m, 1H), 4.39 – 4.36 (m, 1H), 4.14 – 4.09 (m, 1H), 4.00 – 3.91 (m, 2H), 3.51 – 3.44(m, 2H), 3.07 – 2.84 (m, 4H), 2.67 (s, 3H), 2.42 – 2.33 (m, 13H), 2.19 – 2.04(m, 8H), 1.84 – 1.70 (m, 4H), 1.57 – 1.34 (m, 4H), 0.97 – 0.88 (m, 9H), 0.83 – 0.76 (m, 6H). LCMS (ESI): R T = 0.670 min, m / z measured value 588.3 [1 / 2M+H] + .

[0085] Compound 024 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-N-((1r,4s)-4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)cyclohexane-1-carbonyl)-N-methylglycine ester formate. 1H NMR (400 MHz, DMSO) (400 MHz, DMSO) δ 10.46 (s, 1H), 9.58 (s, 1H), 7.64 (t, J = 10.4 Hz, 1H), 7.40 – 7.26 (m, 4H), 7.12 (d, J = 14.4 Hz, 1H), 6.62 (d, J = 4.4 Hz, 1H), 6.34 (d, J = 3.6 Hz, 1H), 5.63 (d, J = 18.8 Hz, 1H), 5.51 (d, J = 6.4Hz, 2H), 5.41 – 5.31 (m, 1H), 4.48 – 4.13 (m, 2H), 3.96 (s, 2H), 3.09 (s,2H), 2.78 (s, 1H), 2.08 - 1.90 (m, 11H), 1.83 - 1.00 (m, 11H), 0.91 (t, J =6.4 Hz, 4H), 0.80 (t, J = 9.2 Hz, 6H). LCMS (ESI): R T = 1.380 min, m / z measured value 574.2 [1 / 2M+H] + .

[0086] Compound 025 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-((1r,4s)-4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)cyclohexane-1-carbonyl)-L-alanine ester formate. 1H NMR (400 MHz, DMSO)δ 10.50 (s, 1H), 9.58 (s, 1H), 8.36 (d, J = 6.8 Hz, 1H), 7.59 (d, J = 10.8Hz, 1H), 7.34 (m, 4H), 7.04 (s, 1H), 6.60 (s, 1H), 6.34 (s, 1H), 5.70 – 5.26(m, 4H), 4.32 (m, 2H), 4.03 – 3.85 (m, 2H), 3.48 (s, 2H), 3.06 (s, 2H), 2.89– 2.83 (m, 1H), 2.68 – 2.66 (m, 3H), 2.36 (s, 5H), 2.34 – 2.32 (m, 4H), 2.16– 2.04 (m, 6H), 1.78 (d, J = 40.8 Hz, 5H), 1.50 (s, 3H), 1.37 (d, J = 7.2 Hz,3H), 1.23 (s, 2H), 0.89 (m, 5H), 0.78 (d, J = 7.0 Hz, 6H). LCMS (ESI): R T =0.647 min, m / z measured value 574.4 [1 / 2M+H] + .

[0087] Compound 026 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl((1r,4s)-4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)cyclohexane-1-carbonyl)-L-valine ester formate. 1H NMR (400 MHz, DMSO) δ10.45 (s, 1H), 9.52 (t, J = 6.4 Hz, 1H), 8.22-8.20 (m, 1H), 8.11-8.07 (m,1H), 7.51-7.47 (m, 1H), 7.30-7.26 (m, 4H), 7.03-6.97 (m, 1H), 6.56-6.52 (m,1H), 6.28 (s, 1H), 5.56-5.52 (m, 1H), 5.42 (s, 2H), 5.35-5.23 (m, 1H), 4.35(s, 1H), 4.09-4.01 (m, 2H), 3.91-3.79 (m, 4H), 3.18-3.14 (m, 4H), 2.98-2.90(m, 3H), 2.82-2.70 (m, 3H), 2.29-2.24 (m, 5H), 2.07-2.01 (m, 8H), 1.83-1.62(m, 5H), 1.44-1.38 (m, 4H), 1.21-1.15 (m, 2H), 0.94-0.86 (m, 3H), 0.84-0.76 (m, 6H), 0.74-0.66 (m, 6H). LCMS (ESI): R T = 1.445 min, m / z measured value 1176.4 [M+H] + .

[0088] Compound 027 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl((1r,4S)-4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)cyclohexane-1-carbonyl)-L-histidine-L-valine ester. LCMS (ESI): R T =5.088 min, m / z measured value 1312.6 [M+H] + .

[0089] Compound 028 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl((1r,4S)-4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)cyclohexane-1-carbonyl)-L-histidine-D-valine ester. LCMS (ESI): R T =5.176 min, m / z measured value 1312.6 [M+H] + .

[0090] Compound 029 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl((1r,4S)-4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)cyclohexane-1-carbonyl)-L-histidine-L-valine ester. 1 H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 10.47 (s, 1H), 9.60 (s, 2H), 8.39 (d, J = 7.6 Hz, 1H),7.91 (s, 1H), 7.71 – 7.47 (m, 2H), 7.31 – 7.38 (m, 3H), 7.06 (d, J= 12.4 Hz,1H), 6.64 (s, 1H), 6.36 (s, 1H), 5.70 – 5.37 (m, 4H), 4.69 (s, 1H), 4.38 –4.29 (m, 2H), 4.03 – 3.92 (m, 2H), 3.49 (s, 2H), 3.30 – 2.86 (m, 6H), 2.69 (s, 1H), 2.46 – 1.96 (m, 17H), 1.66 – 1.73 (m, 4H), 1.25 – 1.39 (m, 4H), 1.06 – 0.66 (m, 16H). LCMS (ESI): R T = 0.909 min, m / z measured value 656.8 [M / 2+H] + .

[0091] Compound 30 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl((1r,4S)-4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)cyclohexane-1-carbonyl)-L-histidine-L-valine ester 2,2,2-trifluoroacetate. 1 HNMR (400 MHz, DMSO) δ 14.25 (s, 1H), 10.37 (s, 1H), 9.78 – 9.65 (m, 2H), 8.93 (s, 2H), 8.49 – 8.29 (m, 4H), 7.74 (d, J = 10.8 Hz, 1H), 7.39 (d, J = 7.6 Hz,4H), 7.23 – 7.10 (m, 2H), 6.65 (s, 1H), 6.35 (s, 1H), 5.73 (d, 1H), 5.55 (s,2H), 5.45 (s, 1H), 5.14 (s, 1H), 4.84 (s, 1H), 4.41 (d, J= 6.4 Hz, 1H), 4.03 –3.93 (m, 2H), 3.62 (s, 3H), 2.93-3.02 (m, 13H), 2.69 (s, 1H), 2.44 (s, 3H), 2.15-2.30 (m, 6H), 1.66-1.82 (m, 4H), 1.25-1.36 (m, 3H), 0.85-0.98 (m, 16H). LCMS (ESI): R T = 0.906 min, m / z measured value 656.8 [M / 2+H] + .

[0092] Compound 31 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl((1r,4S)-4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((1,1,1-trifluoro-3-morpholinopropane-2-yl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)cyclohexane-1-carbonyl)glycine ester. 1 H NMR (400 MHz, DMSO)δ 10.29 (s, 1H), 9.58 (d, J = 9.6 Hz, 1H), 8.33 (s, 1H), 7.70 (d, J = 10.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.12 (s, 1H), 6.66 (s,1H), 6.35 (s, 1H), 5.65 (d, J = 19.2 Hz, 1H), 5.51 (s, 2H), 5.39 (d, J = 19.2 Hz,2H), 4.72 (s, 2H), 4.58 (s, 1H), 4.40 (s, 2H), 4.10 (d, J = 17.6 Hz, 2H), 3.95(d, J= 12.0 Hz, 2H), 3.12 – 2.96 (m, 3H), 2.94 – 2.86 (m, 3H), 2.69 (s, 3H), 2.61 (d, J = 8.8 Hz, 3H), 2.37 (d, J = 14.4 Hz, 10H), 2.22 – 1.96 (m, 10H), 1.93(s, 1H), 1.82 – 1.70 (m, 4H), 1.50 – 1.34 (m, 4H), 1.26 (s, 5H), 0.95 – 0.80(m, 14H). LCMS (ESI): R T = 0.606 min, m / z measured value 616.7 [M / 2+H] + .

[0093] Compound 32 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)acetyl)-L-histidine-D-valine ester. LCMS (ESI): R T = 2.071 min, m / z measured value 561.4 [M / 2+H] + .

[0094] Compound 33 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)acetyl)-L-histidine-L-valine ester. LCMS (ESI): R T = 2.004 min, m / z measured value 561.4 [M / 2+H] + .

[0095] Compound 34 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-1-((1r,4S)-4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)cyclohexane-1-carboxamide)cyclopropane-1-carboxylate 2,2,2-trifluoroacetate. 1 H NMR (400 MHz, DMSO) δ 9.78 – 9.65 (m, 1H), 8.65 (s, 1H), 8.53 – 8.47 (m, 1H), 7.84 (d, J = 10.8 Hz, 1H), 7.41 – 7.37 (m, 4H), 7.25 (s, 1H), 6.66 (s, 1H), 6.35 (s, 1H), 5.75 – 5.70 (m, 1H), 5.52 (s, 2H), 5.46 – 5.41 (m, 1H), 5.14(s, 1H), 3.99 – 3.93 (m, 3H), 3.63 – 3.59 (m, 2H), 3.09 – 2.90 (m, 8H), 2.25– 2.06 (m, 8H), 1.93 – 1.76 (m, 8H), 1.54 – 1.41 (m, 6H), 1.26 – 1.17 (m,2H), 1.08 – 0.99 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H), 0.85 (d, J = 6.4 Hz, 6H). LCMS(ESI): R T = 0.995 min, m / z measured value 580.2 [M / 2+H] + .

[0096] Compound 35 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(1-(2-(6-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-1H-indol-1-yl)ethyl)piperidin-4-carbonyl)-L-histidine-L-valine ester 2,2,2-trifluoroacetate. 1 H NMR (400 MHz, DMSO-d6): δ 11.25 (s,1H), 9.65 (s, 1H), 9.35 (s, 1H), 8.83 (s, 1H), 8.46 – 8.40 (m, 2H), 7.71 (d, J = 10.8 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.43 – 7.38 (m, 1H), 7.26 (t, J = 9.2Hz, 2H), 7.06 (s, 1H), 6.83 (s, 1H), 6.82 – 6.77 (m, 1H), 6.44 (d, J = 2.0 Hz,1H), 6.23 (s, 1H), 5.77 – 5.67 (m, 1H), 5.46 – 5.41 (m, 1H), 5.12 (s, 1H),4.82 – 4.87 (m, 1H), 4.41 – 4.37 (m, 1H), 4.24 (s, 2H), 3.71 (s, 2H), 3.52(s, 3H), 3.22 – 3.17 (m, 8H), 2.68 – 2.66 (m, 1H), 2.52 (d, J = 1.6 Hz, 2H), 2.41 (s, 3H), 2.35 – 2.28 (m, 2H), 2.21 – 2.12 (m, 3H), 1.99 – 1.64 (m, 5H),0.97 (d, J = 6.8 Hz, 3H), 0.93 – 0.86 (m, 12H). LCMS (ESI): R T = 0.852 min, m / z measured value 580.2 [M / 2+H] + .

[0097] Compound 36 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)benzoyl)-L-histidine-L-valine ester 2,2,2-trifluoroacetate. 1 H NMR (400 MHz, DMSO-d6): δ 9.77 (s, 1H), 9.65 (s, 1H), 8.51-8.41 (m, 4H), 7.89 (s, 2H), 7.70(d, J = 10.8 Hz, 1H), 7.39 (d, J = 13.6 Hz, 6H), 7.10 (d, J = 7.2 Hz, 1H), 6.67 (s,1H), 6.32 (s, 1H), 5.72 (d, J = 19.2 Hz, 1H), 5.54 (s, 2H), 5.44 (d, J = 20 Hz,1H), 5.12 (s, 1H), 5.04 (d, J = 5.6 Hz, 1H), 4.43-4.39 (m, 2H), 4.00 – 3.92 (m,2H), 3.45 – 3.11(m, 15H), 2.73 – 2.61 (m, 2H), 2.52 (s, 2H), 2.41 (s, 3H),2.36 – 2.27 (m, 3H), 2.16 (d, J = 7.4 Hz, 3H), 0.97-0.85 (m, 15H). LCMS(ESI):R T = 0.870 min, m / z measured value 653.8 [M / 2+H] + .

[0098] Compound 37 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)acetyl)-L-histidine-L-valine ester. 1 H NMR (400 MHz, DMSO) δ 11.82 (s, 1H),10.52 – 10.38 (m, 1H), 9.58 (s, 2H), 8.60 (s, 1H), 7.94 (s, 1H), 7.68 (d, J =11.2 Hz, 2H), 7.56 (s, 2H), 7.30 (s, 12H), 7.02 (s, 2H), 6.84 (s, 2H), 6.60(s, 3H), 6.34 (s, 3H), 5.96 – 5.82 (m, 2H), 5.60 (s, 1H), 5.50 (s, 4H), 5.38(s, 2H), 4.75 (s, 2H), 4.56 (s, 1H), 4.34 (s, 3H), 4.24 (s, 2H), 3.96 (s,7H), 3.08 (s, 9H), 3.02 – 2.94 (m, 5H), 2.86 (s, 8H), 1.24 (s, 6H), 1.15 (s,5H), 0.96 (s, 5H), 0.94 (d, J = 4.4 Hz, 8H), 0.92 (s, 8H), 0.90 (s, 7H), 0.88(s, 3H), 0.82 (s, 8H), 0.80 (s, 10H), 0.78 (s, 7H). LCMS (ESI): R T = 0.702 min, m / z measured value 615.8 [M / 2+H] + .

[0099] Compound 38 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)benzoyl)-L-histidine-L-valine ester 2,2,2-trifluoroacetate. 1 H NMR (400 MHz, DMSO) δ 9.77 (s, 1H), 9.65 (s, 1H), 8.51-8.41 (m, 6H), 7.89 (s, 2H), 7.70-7.54 (m, 1H), 7.39-7.20 (m, 7H), 7.10-7.04 (m, 1H), 6.67 (s, 1H), 6.32 (s,1H), 5.72-5.64 (m, 1H), 5.54 (s, 2H), 5.44-5.32 (m, 1H), 5.12 (s, 1H), 5.04-4.90 (m, 1H), 4.43-4.39 (m, 2H), 4.00–3.92 (m, 2H), 3.45–3.11(m, 13H), 2.52-2.40 (m, 5H), 2.41-2.31 (m, 3H), 2.36–2.27 (m, 4H), 1.16-1.04 (m, 3H), 0.97-0.85 (m, 12H). LCMS (ESI): R T = 0.924 min, m / z measured value 653.8 [M / 2+H] + .

[0100] Compound 39 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(1-(2,4-dihydroxy-5-isopropylphenyl)-5-(4-(morpholinomethyl)phenyl)-1H-1,2,3-triazol-4-carbonyl)glycine ester 2,2,2-trifluoroacetate. 1HNMR (400 MHz, DMSO) δ 9.73 – 9.71 (m, 1H), 9.02 (t, J = 6.0 Hz, 1H), 8.52 –8.39 (m, 2H), 7.90 – 7.82 (m, 1H), 7.42 – 7.21 (m, 5H), 7.03 – 6.70 (m, 2H), 6.38 – 6.37 (m, 1H), 5.92 – 5.86 (m, 1H), 5.76 – 5.68 (m, 1H), 5.52 (s, 2H),5.48 – 5.40 (m, 1H), 5.11 (s, 1H), 4.31 – 4.20 (m, 3H), 4.00 – 3.89 (m, 1H),3.56 – 3.49 (m, 3H), 3.14 – 3.01 (m, 6H), 2.26 – 2.24 (m, 3H), 2.18 – 2.14(m, 4H), 1.24 (s, 1H), 1.15 (s, 1H), 1.00 (d, J = 6.4 Hz, 6H), 0.89 (t, J = 7.2Hz, 3H). LCMS (ESI): R T = 0.582 min, m / z measured value 913.0 [M+H] + .

[0101] Compound 40 (1R,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl((1r,4S)-4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)cyclohexane-1-carbonyl)glycine ester. 1 H NMR (400 MHz, DMSO-d6): δ 10.46(s, 1H), 9.59 - 9.56 (m, 1H), 8.31 (s, 1H), 7.66 (d, J= 10.8 Hz, 1H), 7.36 -7.10 (m, 4H), 7.10 (s, 1H), 6.61 (s, 1H), 6.34 (s, 1H), 5.62 (d, J = 19.4 Hz,1H), 5.50 (s, 2H), 5.32 (d, J = 19.2 Hz, 1H), 4.36 (s, 1H), 4.36 - 4.08 (m,1H), 3.99 - 3.91 (m, 3H), 3.05 - 3.02 (m, 2H), 2.91 - 2.86 (m, 1H), 2.39 -2.02 (m, 18H), 1.91 (s, 2H), 1.78 - 1.68 (m, 5H), 1.46 - 1.21 (m, 4H), 0.93 -0.89 (m, 3H), 0.81 - 0.79 (m, 9H). LCMS (ESI): R T = 0.999 min, m / z measured value 567.4 [M / 2+H] + .

[0102] Compound 41 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)acetyl)-L-prolyl-L-valine ester 2,2,2-trifluoroacetate. 1 H NMR (400 MHz, DMSO) δ9.76 (s, 1H), 9.62 (t, J= 6.4 Hz, 1H), 8.51 – 8.44 (m, 4H), 7.84 – 7.71 (m,1H), 7.45 – 7.36 (m, 4H), 7.11 – 7.06 (m, 1H), 6.64 (s, 1H), 6.33 – 6.31 (m,1H), 5.75 – 5.70 (m, 1H), 5.57 – 5.42 (m, 3H), 5.10 (s, 1H), 4.66 – 4.60 (m,1H), 4.31 – 4.26 (m, 2H), 4.00 – 3.91 (m, 3H), 3.33 – 3.22 (m, 6H), 3.11 –2.87 (m, 8H), 2.42 (s, 3H), 2.27 – 2.14 (m, 6H), 2.05 – 1.78 (m, 4H), 1.00–1.09 (m, 9H), 0.84 (d, J = 6.8 Hz, 6H). LCMS (ESI): R T = 0.804 min, m / z measured value 595.8 [M / 2+H] + .

[0103] Compound 42 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)acetyl)-L-alanyl-L-prolyl-L-valine ester.

[0104] 1H NMR (400 MHz, DMSO) δ 9.78 (s, 1H), 9.65 – 9.62 (m, 1H), 8.79 – 8.35 (m, 5H), 7.77 – 7.71 (m, 1H), 7.49 – 7.39 (m, 4H), 7.13 – 7.07 (m, 1H), 6.68 (s, 1H), 6.32 (s, 1H), 5.74 – 5.62 (m, 1H), 5.58 – 5.43 (m, 3H), 5.11 (s, 1H), 4.75 – 4.47 (m, 2H), 4.38 – 4.16 (m, 2H), 4.01 – 3.92 (m, 4H), 3.33– 3.23 (m, 4H), 3.17 – 3.09 (m, 4H), 3.01 – 2.90 (m, 6H), 2.43 (s, 3H), 2.21– 2.17 (m, 6H), 2.03 – 1.89 (m, 3H), 1.29 – 1.23 (m, 3H), 1.01 – 0.91 (m, 9H), 0.87 (d, J = 6.4 Hz, 6H). LCMS (ESI): R T = 0.422 min, m / z measured value 1261.4 [M+H] + .

[0105] Compound 43 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(1-((1-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-4-yl)methyl)piperidin-4-carbonyl)glycine ester 2,2,2-trifluoroacetate. 1 H NMR (400 MHz, DMSO) δ10.10 (s, 1H), 9.77 – 9.75 (m, 1H), 9.67 – 9.64 (m, 1H), 9.25 – 9.05 (m, 1H),8.52 – 8.50 (m, 2H), 7.84 (d, J= 10.8 Hz, 1H), 7.56 – 7.46 (m, 5H), 7.17 –7.15 (m, 1H), 6.69 (s, 1H), 6.32 (s, 1H), 5.74 – 5.69 (m, 1H), 5.58 – 5.42(m, 4H), 5.11 (s, 1H), 4.40 – 3.93 (m, 8H), 3.18 – 3.05 (m, 4H), 2.97 – 2.90(m, 8H), 2.43 (s, 3H), 2.17 – 2.15 (m, 2H), 1.95 – 1.80 (m, 7H), 1.43 – 1.34(m, 2H), 1.03 – 0.92 (m, 3H), 0.87 (d, J = 6.8 Hz, 6H). LCMS (ESI): R T = 1.196 min, m / z measured value 567.4 [M / 2+H] + .

[0106] Compound 44 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl((1r,4S)-4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindololine-5-yl)methyl)piperazin-1-yl)methyl)cyclohexane-1-carbonyl)glycine ester 2,2,2-trifluoroacetate. 1 H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 9.64 (s,1H), 8.46 (s, 3H), 8.29 (s, 1H), 7.84 (d, J= 10.4 Hz, 1H), 7.28 (s, 3H), 7.16(s, 1H), 7.04 (s, 1H), 6.40 (s, 1H), 5.79 – 5.64 (m, 1H), 5.60 – 5.34 (m, 3H), 5.12 (s, 1H), 4.78 (s, 4H), 4.16 – 3.97 (m, 2H), 3.11 – 2.94 (m, 13H), 2.43 (s, 4H), 2.20 – 2.11 (m, 5H), 1.75 (s, 4H), 1.30 (m, 3H), 1.14 (d, J = 6.8Hz, 6H), 0.91 (t, J = 7.2 Hz, 5H). LCMS (ESI): R T = 0.610 min, m / z measured value 1010.2 [M+H] + .

[0107] Compound 45 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl((S)-2-(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)acetamide)valbuyl)-L-prolyl-L-valine ester 2,2,2-trifluoroacetate. 1 H NMR (400 MHz, DMSO-d6): δ 9.76 (s, 1H), 9.64 (s, 1H), 8.46 (s, 3H), 8.38 - 8.36 (m, 1H), 7.72 (d, J= 10.4 Hz, 1H), 7.40 (s, 4H), 7.23 - 7.07 (m, 1H), 6.67 (s,1H), 6.32 - 6.30 (m, 1H), 5.72 -5.68 (m, 1H), 5.59 - 5.40 (m, 3H), 5.11 (s,1H), 4.57 (s, 2H), 4.28 – 4.21 (m, 1H), 4.06 – 3.87 (m, 3H), 3.71- 3.63 (m,3H), 3.22 – 2.84 (m, 11H), 2.68 (s, 1H), 2.43 (s, 3H), 2.19 - 2.17 (m, 5H), 2.09 – 1.83 (m, 4H), 1.66 – 1.25 (m, 5H), 1.02 – 0.94 (m, 10H), 0.89 – 0.79 (m, 9H). LCMS (ESI): R T = 0.814 min, m / z measured value 645.3 [M / 2+H] + .

[0108] Compound 46 (S)-4-((S)-2-(((S)-1-(((1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)oxy)-3-methyl 1-Oxobutane-2-yl)carbamoyl)pyrrolidine-1-yl)-3-(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)acetamide)-4-oxobutyric acid-2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO-d6): δ 9.75 (s, 1H), 9.64 (s, 1H), 8.45 (s, 3H), 8.23 ​​- 8.21 (m, 1H), 7.73 - 7.70 (m, 1H), 7.41 (s, 4H), 7.14 (s, 1H), 6.68 (s, 1H), 6.32 (s, 1H), 5.72 - 5.67 (m, 1H), 5.52 - 5.51 (m, 2H), 5.47 - 5.42 (m, 1H), 5.10 (s, 1H), 4.93 (s, 1H), 4.21 -4.19 (m, 1H), 4.13 - 4.04 (m, 1H), 3.98 - 3.96 (m, 2H), 3.69 (s, 2H), 3.17 -3.07 (m, 8H), 2.68 (s, 2H), 2.43 (s, 4H), 2.33 (s, 1H), 2.20 - 2.07 (m, 4H),1.97 - 1.90 (m, 4H), 1.63 - 1.52 (m, 2H), 1.24 - 1.15 (m, 2H), 1.03 (s, 1H), 1.00 - 0.74 (m, 18H). LCMS (ESI): R T = 0.767 min, m / z measured value 653.2 [M / 2+H] + .

[0109] Compound 47 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)acetyl)-L-histyl-L-valine ester 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) δ11.82 (s, 1H), 10.52 – 10.38 (m, 1H), 9.58 (s, 2H), 8.60 (s, 1H), 7.94 (s,1H), 7.68 (d, J = 11.2 Hz, 2H), 7.56 (s, 2H), 7.30 (s, 12H), 7.02 (s, 2H),6.84 (s, 2H), 6.60 (s, 3H), 6.34 (s, 3H), 5.96 – 5.82 (m, 2H), 5.60 (s, 1H),5.50 (s, 4H), 5.38 (s, 2H), 4.75 (s, 2H), 4.56 (s, 1H), 4.34 (s, 3H), 4.24(s, 2H), 3.96 (s, 7H), 3.08 (s, 9H), 3.02 – 2.94 (m, 5H), 2.86 (s, 8H), 1.24(s, 6H), 1.15 (s, 5H), 0.96 (s, 5H), 0.94 (d, J = 4.4 Hz, 8H), 0.92 (s, 8H), 0.90 (s, 7H), 0.88 (s, 3H), 0.82 (s, 8H), 0.80 (s, 10H), 0.78 (s, 7H). LCMS(ESI): R T = 1.265 min, m / z measured value 1230.8 [M+H] + .

[0110] Compound 48 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)acetyl)-L-histyl-L-prolyl-L-valine ester 2,2,2-trifluoroacetate. 1 H NMR (400MHz, DMSO) δ 14.12 (s, 1H), 10.20 (s, 1H), 9.78 (s, 1H), 9.65 (t, J= 6.0 Hz,1H), 8.90 (s, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.47 (s, 3H), 7.67 (d, J = 10.8 Hz,1H), 7.47 – 7.39 (m, 5H), 7.09 (s, 1H), 6.67 (s, 1H), 6.32 (s, 1H), 5.76 –5.69 (m, 1H), 5.59 – 5.42 (m, 3H), 5.10 (s, 1H), 4.94 – 4.89 (m, 1H), 4.60 –4.58 (m, 1H), 4.39 – 4.35 (m, 1H), 4.01 – 3.92 (m, 2H), 3.78 – 3.73 (m, 1H), 3.64 – 3.60 (m, 1H), 3.15 – 3.06 (m, 7H), 3.01 – 2.90 (m, 6H), 2.42 (s, 3H), 2.34 – 2.28 (m, 2H), 2.26 – 2.15 (m, 5H), 2.01 – 1.90 (m, 4H), 1.00 – 0.92(m, 12H), 0.87 (d, J = 6.4 Hz, 6H). LCMS (ESI): R T = 0.602 min, m / z measured value 664.5 [M / 2+H] + .

[0111] Compound 49 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl((1r,4S)-4-((4-(4-(3-carbamoyl-5-(2,4-dihydroxy-5-isopropylphenyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)cyclohexane-1-carbonyl)glycine ester 2,2,2-trifluoroacetate. 1 H NMR (400 MHz, DMSO) δ 9.76 (s,1H), 8.47 (s, 2H), 8.33 – 8.25 (m, 2H), 7.84 (d, J= 10.8 Hz, 1H), 7.71 (s,1H), 7.42 – 7.33 (m, 4H), 7.16 (s, 1H), 6.59 (s, 1H), 6.33 (s, 1H), 5.75–5.68(m, 1H), 5.52 (d, J = 3.6 Hz, 2H), 5.68–5.28 (m, 1H), 5.11 (s, 1H), 4.17 – 4.12(m, 1H), 4.02 – 3.97 (m, 1H), 3.31 – 3.23 (m, 5H), 2.95 – 2.87 (m, 5H), 2.73(s, 1H), 2.69 – 2.65 (m, 1H), 2.53 (s, 3H), 2.42 (s, 4H), 2.35 – 2.31 (m,1H), 2.20 – 2.06 (m, 5H), 1.76 (s, 6H), 1.40 – 1.34 (m, 3H), 0.91 (t, J = 7.2Hz, 3H), 0.82 (d, J = 6.8 Hz, 6H). LCMS (ESI): R T = 1.236 min, m / z measured value 526.4 [M / 2+H] + .

[0112] Compound 50 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindololine-5-yl)methyl)piperazin-1-yl)acetyl)-L-histidine-L-valine ester 2,2,2-trifluoroacetate. 1 H NMR (400 MHz, DMSO) δ 14.19 (s, 1H), 10.04 (s, 1H), 9.68 (s, 1H), 8.83 (s, 1H), 8.65 – 8.51 (m, 4H), 7.65 (d, J= 10.4 Hz, 1H),7.44 – 7.29 (m, 3H), 7.17 – 7.03 (m, 3H), 6.41 (s, 1H), 5.73 – 5.65 (m, 1H),5.59 – 5.41 (m, 3H), 5.09 (s, 1H), 4.86 – 4.80 (m, 5H), 4.39 (t, J = 7.2 Hz,1H), 4.27 – 4.00 (m, 2H), 3.32 – 3.24 (m, 5H), 3.17 – 3.06 (m, 6H), 2.99 –2.93 (m, 4H), 2.41 (s, 3H), 2.33 – 2.29 (m, 2H), 2.23 – 2.19 (m, 4H), 1.13(d, J = 6.4 Hz, 6H), 0.98 – 0.92 (m, 3H), 0.89 (d, J = 6.8 Hz, 6H). LCMS (ESI): R T = 0.563 min, m / z measured value 554.3 [M / 2+H] + .

[0113] Compound 51 (1S,9S)-1-amino-9-ethyl-5-fluoro-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl((1r,4S)-4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)cyclohexane-1-carbonyl)glycine ester formate. 1H NMR (400 MHz, DMSO-d6) δ10.45 (s, 1H), 9.60 - 9.56 (m, 1H), 8.31 -8.30 (m, 1H), 7.70 -7.68 (m, 1H),7.36 -7.29 (m, 4H), 7.11 (s, 1H), 6.61 (s, 1H), 6.34 (s, 1H), 5.65 – 5.37 (m,4H), 4.39 (s, 1H), 4.11 – 4.10 (m, 1H), 3.99 – 3.91 (m, 3H), 3.07 (s, 2H),2.92 – 2.86 (m, 1H), 2.75 – 2.58 (m, 1H), 2.41 – 2.24 (m, 12H), 2.17 – 2.01(m, 8H), 1.86 – 1.56 (m, 5H), 1.40 – 1.31 (m, 4H), 0.92 –0.88 (m, 3H), 0.81 –0.80(m, 8H). LCMS (ESI): R T = 1.188 min, m / z measured value 1134.6 [M+H] + .

[0114] Biological blood assay cell lines The following cancer cell lines were used: MV4-11 human biphenotype B-myeloid monocytic leukemia (ATCC, #CRL-9591); HCT-116 human colon cancer (ATCC, #CRL-247). Cell lines were cultured primarily according to ATCC recommendations.

[0115] HSP90α binding fluorescence polarization (FP) assay Unless otherwise specified, the binding of the test compound to the HSP90α (HSP90AA1) protein was measured by fluorescence polarization (FP) using the HSP90α (N-terminal) Assay Kit (BPSBioscience, #50298) according to the manufacturer's instructions. A fluorescently labeled HSP90 binding compound, FITC-galdromycin (final concentration 5 nM), was provided and used. Each test compound was serially diluted 2.5-fold from 20 μM to 5.2 nM to determine its binding to HSP90α. After the final step of adding HSP90α protein to each well, the plate was mixed with brief shaking, incubated at 25°C for 120 min, and fluorescence was measured using a PerkinElmer EnVision Plate Reader. The mP value after background subtraction was calculated from the raw data, and the IC50 value (the concentration at which 50% maximum inhibition is achieved) was calculated using a four-parameter log[inhibitor] vs. response curve fitting and GraphPad Prism 7 software. The results are shown in Table 1.

[0116] Table 1

[0117] CellTiter-Glo® Reagent for Cancer Cell Line Proliferation Assay Cells were seeded at 4,000 cells / well in 96-well tissue culture plates and incubated in 100 μl of medium at 37°C / 5% CO2 for 24–48 hr. Serial dilutions of each test compound were prepared, ranging from 20 μM to 1.02 nM. MV4-11 cells (human biphenotype B-myeloid monocytic leukemia) and HCT116 cells (human colorectal cancer cell line) were then treated with various concentrations of the test compound, resulting in a final concentration of 0.5% DMSO / well, followed by incubation at 37°C / 5% CO2 for 24 hr. 100 μl of CellTiter-Glo® reagent (Promega Corporation, Madison, WI) was added to each well, and treatment was performed according to the manufacturer's instructions. Results were analyzed using GraphPad 7 software, and IC50 values ​​were calculated. The results are shown in Table 2. IC50<100 nM; B. IC50=100-1000 nM; C. IC50>1000 nM.

[0118] Table 2

[0119] plasma stability The test compound was prepared at 1 mM in DMSO, and a 1 mM working solution of propantheline or mevinolin was prepared in acetonitrile. Propantheline was used as a positive control in human, canine, and mouse plasma, while mevinolin was used as a positive control in rat plasma. The assay plate was preheated at 37°C for 15 minutes, and then 398 µL of plasma was added. Then, 2 µL of the 1 mM test compound and 2 µL of the 1 mM control compound were added to the 398 µL of plasma to achieve a final concentration of 5 µM for both the test and control compounds. The final concentration of the organic solvent was 0.5%. Each assay was performed in duplicate.

[0120] Plasma samples were incubated at 37°C. Then, 50 µL aliquots of each plasma sample were taken at 0, 1, 2, 4, 8, and 24 hours (Cpd 1–Cpd 10) or at 0, 15, 30, 60, and 120 min (Cpd 11–Cpd 26). The reaction was terminated by adding 450 µL of cold formaldehyde containing 5% formic acid and an internal standard. All samples were vortexed for 10 min and then centrifuged at 3,220 g for 30 min to precipitate proteins. For each sample, 100 μL of the supernatant was transferred to a new plate. The sample supernatant was diluted with ultrapure water and loaded onto a liquid chromatography-mass spectrometer. The samples were analyzed by LC-MS / MS. All calculations were performed using Microsoft Excel. Peak area ratios were determined based on the extracted ion chromatograms.

[0121] The percentage of remaining compound at each time point was calculated using the following equation: Remaining percentage at t min (%) = Peak area ratio at t min / Peak area ratio at 0 min × 100. Where the peak area ratio at t min is the peak area ratio of the control and test compounds at t min; the peak area ratio at 0 min is the peak area ratio of the control and test compounds at time 0. The slope value k was determined by linear regression of the natural logarithm of the remaining percentage of parent drug versus incubation time curve. The in vivo half-life (in vivo t1 / 2) was determined from the slope value: in vivo t 1 / 2 = -(0.693 / k). The results are shown in Table 3.

[0122] Table 3

[0123] Note: Cpd 1-Cpd 10 were incubated at 0, 1, 2, 4, 8 and 24 hours, and Cpd 11-Cpd 26 were incubated at 0, 15, 30, 60 and 120 minutes.

[0124] Modifications and variations of the methods and compositions described in this disclosure will be readily apparent to those skilled in the art without departing from the scope and spirit of this disclosure. Although this disclosure has been described in conjunction with specific embodiments, it should be understood that the claimed disclosure should not be unduly limited to such specific embodiments. In fact, various modifications to the modes of performing this disclosure are intended and will be understood by those skilled in the art to be within the scope of this disclosure as expressed in the appended claims.

[0125] Incorporated by reference All patents and publications mentioned in this specification are incorporated herein by reference as if each individual patent and publication were expressly and individually indicated to be incorporated by reference.

Claims

1. A compound of formula I: (I)； Or its pharmaceutically acceptable salt, in which R Q and R T Each is independently selected from H, optionally substituted (C1-C4) alkyl, optionally substituted aryl and optionally substituted heteroaryl, or R. Q and R T Together with the carbon to which they are attached, they form optionally substituted cycloalkyl groups or optionally substituted heterocyclic groups; X does not exist or -NR W , where R W It is H or (C1-C4) alkyl; L is the connector; and A is the chemical part that binds to the HSP90 protein.

2. The compound according to claim 1, wherein the compound is a compound of formula II or III: (II) or (III); Or its pharmaceutically acceptable salt.

3. The compound according to claim 1 or 2, wherein the compound is a compound of formula III: (III); Or its pharmaceutically acceptable salt.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein X is absent or -NR. W , where R W It is H or CH3.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein X is absent or is NH.

6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R Q and R T Each is independently selected from H and (C1-C4) alkyl groups.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R Q and R T Each is independently selected from H, CH(CH3)2 and CH3.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R Q It's H, and R T Selected from H, CH(CH3)2 and CH3.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R Q and R T Each is H.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein A is selected from... , , and ; Z and Z' are each independently selected from N or CH; R 1 R 1A and R 1AA Each is independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, (C1-C4)alkoxy and halo(C1-C4)alkoxy; R 3 R 3A and R 3AA Each is independently selected from hydrogen, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -(C0-C4)alkylheterocyclic and -(C0-C4)heteroaryl, wherein each of the heterocyclic and heteroaryl groups is optionally selected from 1 to 3 of R Z Substitution of groups; R Z Selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, (C1-C4)alkoxy and halo(C1-C4)alkoxy; R a and R b Each is independently selected from hydrogen, (C1-C4)alkyl, and halo(C1-C4)alkyl; R 4 It is a (C1-C4) alkyl group; R 5 and R 5A Each is independently a (C1-C4) alkyl group; R 6 and R 6A Each is independently hydrogen or (C1-C4) alkyl; R 7 It is halogen; and The wavy line indicates the attachment point with connector L.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein A is selected from... , , and .

12. The compound of claim 10 or claim 11, or a pharmaceutically acceptable salt thereof, wherein Z and Z' are each CH.

13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 12, wherein R 1 R 1A and R 1AA Each is an (C1-C4) alkyl group.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 13, wherein R 1 R 1A and R 1AA Each is isopropyl.

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 14, wherein R 3 R 3A and R 3AA Each is independently selected from hydrogen, -(C1-C4)alkyl heterocyclic and heteroaryl, wherein each heterocyclic and heteroaryl is optionally composed of 1 to 3 groups selected from R Z The group is substituted.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 15, wherein R 3A It is hydrogen.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 16, wherein R 3AA It is hydrogen.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 17, wherein R 3 Selected from -(C1-C4)alkyl (5 to 6-membered) heterocyclic groups and fused 8- to 10-membered heteroaryl groups, each optionally surrounded by 1 to 3 groups selected from R Z The group is substituted.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 18, wherein R 3 Selected from -(C1-C4)morpholinyl, indolyl, piperazineyl, wherein the morpholinyl, indolyl, and piperazineyl are each optionally composed of 1 to 3 elements selected from R Z The group is substituted.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 19, wherein R Z It is a (C1-C4) alkyl group.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 20, wherein R a It is hydrogen; and R b It is a halogenated (C1-C4) alkyl group.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 21, wherein R a It is hydrogen; and R b It is CH2CF3.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 22, wherein R 4 It is CH3.

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 23, wherein R 5 and R 5A Each is CH3.

25. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 24, wherein R 6 and R 6A Each is hydrogen.

26. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 25, wherein R 7 It is chlorine.

27. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, wherein... L is selected from -(CH2) r -HET 1 -X 1 -HET 2 -(CH2) s -OC(O)-, -(CH2) r -HET 1 -X 1 -(CH2) q -HET 2 -(CH2) s -OC(O)-, -(CH2) r -HET 1 -X 1 -HET 2 -(CH2) s -C(O)O-(CH2) m -X 2 -, -(CH2) r -HET 1 -HET 2 -(CH2) s -C(O)-(CH2) m -X 2 -, -(CH2) y OC(O)-, -(CH2) r -HET 1 -(CH2) w -S-S-HET 2 -(CH2) s -OC(O)-, -(CH2) r -HET 1 -X 1 -(CH2) s -OC(O)-, -(CH2) r -HET 1 -X 1 -HET 2 -(CH2) s -NHC(O)O-(CH2) m -X 2 -, -(CH2) r -HET 1 -C(O)O-(CH2) m -X 2 -, -(CH2) r NR f (CH2) v -HET 2 -X 1 -HET 1 -(CH2) s -OC(O)-、-(CH2) r NR f (CH2) v -IT 2 -X 1 -IT 1 -(CH2) s -C(O)O-(CH2) m -X 2 -、-(CH2) r NR f (CH2) v -IT 2 -(CH2) s -NHC(O)O-(CH2) m -X 2 -、-(CH2) r -IT 3 -OC(O)-、-(CH2) r -IT 2 -X 1 -IT 3 -OC(O)-、-(CH2) r -IT 3 -X 1 -(CH2) s -OC(O)-、-(CH2) r -IT 3 -X 1 -IT 2 -OC(O)-、-X 1 -IT 3 -OC(O)-、-X 1 -IT 3 -X 2 -(CH2) s -OC(O)-、-(CH2) r -IT 1 -IT 2 -(CH2) s -OC(O)-、-(CH2) r -IT 1 -(CH2) q -IT 2 -(CH2) s -OC(O)-、-(CH2) r -IT 1 -X 1 -(CH2) w -SS-THE 2 -(CH2) s -OC(O)-、-(CH2) r -IT 1 -IT 2 -(CH2) s -NHC(O)O-(CH2) m -X 2 -、-(CH2) r -IT 1 -NHC(O)O-(CH2) m -X 2 -、-(CH2) r NR f (CH2) v -IT 2 -X 1 -(CH2) q -IT 1 -(CH2) s -OC(O)-、-(CH2) r NR f (CH2) v -IT 2 -IT 1 -(CH2) s -C(O)O-(CH2) m -X 2 -、-(CH2) r NR f (CH2) v -OC(O)-、-(CH2) r NR f (CH2) v -IT 2 -(CH2) w -SS-THE 1 -(CH2) s -OC(O)-、-(CH2) r NR f (CH2) v -IT 2 -X 1 -(CH2) s -OC(O)-、-(CH2) r NR f (CH2) v -IT 2 -X 1 -IT 1 -(CH2) s -NHC(O)O-(CH2) m -X 2 -、-(CH2) r NR f (CH2) v -HET 2 -C(O)O-(CH2) m -X 2 -、-(CH2) r ARN f (CH2) v -HET 2 -X 1 -(CH2) s -OC(O)-,-(CH2) r ARN f (CH2) v -HET 2 -X 1 -(CH2) s -C(O)-(CH2) m -X 2 -、-(CH2) r ARN f (CH2) v -HET 2 -X 1 -(CH2) q -HET 1 -(CH2) s -NHC(O)O-(CH2) m -X 2 -、-(CH2) r ARN f (CH2) v -HET 2 -X 1 -(CH2) s -NHC(O)O-(CH2) m -X 2 -、-(CH2) r ARN f (CH2) v -HET 2 -X 1 -HET 1 -(CH2) s -NHC(O)O-(CH2) m -X 2 -(CH2) m -X 2 -、-(CH2) r ARN f (CH2) v -HET 2 -X 1 -(CH2) s -NHC(O)O-(CH2) m -X 2 -、-(CH2) r -IT 1 -X 1 -(CH2) q -IT 3 -(CH2) s -OC(O)-、-(CH2) r -IT 1 -X 1 -IT 3 -(CH2) s -C(O)O-(CH2) m -X 2 -、-(CH2) r -IT 1 -IT 3 -(CH2) s -C(O)-(CH2) m -X 2 -、-(CH2) r -IT 1 -(CH2) w -SS-THE 3 -(CH2) s -OC(O)-、-(CH2) r -IT 1 -X 1 -IT 3 -(CH2) s -NHC(O)O-(CH2) m -X 2 -、-(CH2) r -IT 3 -C(O)O-(CH2) m -X 2 -、-(CH2) r NR f (CH2) v -IT 2 -X 1 -IT 3 -(CH2) s -OC(O)-、-(CH2) r NR f (CH2) v -IT 3 -X 1 -IT 1 -(CH2) s -C(O)O-(CH2) m -X 2 -、-(CH2) r NR f (CH2) v -HET 3 -(CH2) s -NHC(O)O-(CH2) m -X 2 -、-C(O)NH-CRR’-C(O)NH-CRR’-C(O)NHCRR’C(O)NH(CH2) m -X 2 -、-C(O)NH-CRR’-C(O)NH-CRR’-C(O)NH-HET 2 -(CH2) s -OC(O)-、C(O)、-C(O)-X 1 -HET 1 -X 2 -,-X 1 -HET 1 -X 2 、-C(O)-HET 1 -X 1 -HET 2 -X 2 and C(O)-X 1 -O-; m, q, r, s, v, w, and y are each independently between 0 and 4; R f Selected from hydrogen and (C1-C4) alkyl groups; X 1 and X 2 Each is independently selected from CO and -CH2-; HET 1 HET 2 and HET 3 Each is independently selected from monocyclic heterocyclic groups, bicyclic heterocyclic groups, monocyclic cycloalkyl groups, and phenyl groups; and R' and R'' are each independently selected from hydrogen and (C1-C4) alkyl, wherein the (C1-C4) alkyl is optionally substituted with phenyl or NHC(O)NH2.

28. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27, wherein L is selected from C(O), -C(O)-X 1 -HET 1 -X 2 -、-X 1 -HET 1 -X 2 -C(O)-HET 1 -X 1 -HET 2 -X 2 and C(O)-X 1 -O-.

29. The compound of claim 27 or 28, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 Each is -CH2-.

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 27 to 29, wherein HET 1 HET 2 and HET 3 Each is independently selected from monocyclic heterocyclic groups and monocyclic cycloalkyl groups.

31. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 27 to 30, wherein HET 1 and HET 2 and HET 3 Each is independently selected from piperazine and cyclohexyl groups.

32. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 27 to 30, wherein L is selected from C(O), , , and C(O)CH2O ,in This indicates the attachment point to A.

33. The compound of claim 1, wherein the compound is selected from... 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ;as well as Or a pharmaceutically acceptable salt of any of the foregoing.

34. A pharmaceutical composition comprising the compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

35. A method of treating cancer, comprising administering to a subject a therapeutically effective amount of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, or the composition of claim 34.

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