Methods and compositions for targeted protein degradation

Abstract

Provided herein are compounds of Formula I and pharmaceutically acceptable salts and compositions thereof, which are useful in the treatment of cancer and related disorders.

Description

[0001] Related applications

[0002] This application claims priority to PCT / CN2020 / 120911, filed on October 14, 2020, the entire contents of which are incorporated herein by reference. Background Technology

[0003] Protein homeostasis (or proteostasis) refers to the ability of cells to regulate protein synthesis, folding, transport, and degradation. In particular, properly regulated protein degradation is essential for normal cellular function, including their proliferation, differentiation, and death, and is frequently dysregulated in cancer and other diseases (Van Die, Chin J Cancer, 2011, Vol. 30: pp. 124-137).

[0004] The ubiquitin-proteasome system (UPS) is one of the major pathways mediated by cells to process proteins and cycle metabolic processes (Yu and Matouschek, Annu Rev Biophys, 2017, Vol. 46: 149–173; Navon and Ciechanover, J Biol Chem, 2009, Vol. 284: 33713–33718). Ubiquitin is a widely expressed protein with 76 amino acid residues. Regarding the degradation of proteins by UPS, ubiquitination occurs when ubiquitin is linked to a lysine residue in the substrate protein, involving a series of enzymatic steps. First, ubiquitin is transferred to an E1 ubiquitin activator. Then, the activated ubiquitin is transferred from E1 to an E2 ubiquitin conjugase. Third, one of hundreds of different E3 ubiquitin ligases links ubiquitin to a lysine residue in the substrate protein. This enzymatic process is repeated, resulting in the substrate protein being labeled with a polyubiquitin chain. Such ubiquitin-tagged proteins can then be delivered to the proteasome, a large, multi-subunit complex that degrades proteins. The ability of some cell chaperone proteins and chaperone complexes to direct proteins to UPSs is enhanced by their direct interaction with E3 ubiquitin ligases (Amm et al., Biochim Biophys Acta, 2014, Vol. 1843: pp. 182–196; Taipale et al., Cell, 2012, Vol. 150: pp. 987–1001). In addition to protein degradation, protein ubiquitination can regulate other processes such as subcellular localization, activity, and protein-protein interactions.

[0005] Chemical-induced targeted protein degradation (TPD) has emerged as a new modality for small molecule drug development. Small molecules can be used to promote the interaction of one or more target proteins with one or more components of various cellular protein degradation pathways, thereby inducing the degradation of one or more target proteins as a means to treat disease.

[0006] In particular, proteolysis targeting chimeras (PROTACs) are an example of such small molecules that intentionally induce the proteolysis of specific proteins by sequestering the UPS (Burslem and Crews, Cell, 2020, vol. 181 : pp. 102-114; Pettersson and Crews, Drug Discov Today Technol, 2019, vol. 31 : pp. 15-27). PROTAC molecules are bifunctional small molecules that simultaneously bind one or more target proteins and an E3 ubiquitin ligase, thereby forming a ternary complex in the cell between the target protein, the PROTAC molecule, and the E3 ligase protein. The induced proximity of the target protein and the E3 ligase results in ubiquitination of the target protein, and subsequent proteasomal degradation of the target protein. While PROTACs incorporating target protein binders that promiscuously bind to multiple proteins can degrade multiple proteins, in some cases the protein-protein interactions between the individual target and E3 ligase can increase or decrease the observed potency and selectivity of degradation, for example by inhibiting the formation of some ternary complexes due to charge repulsion and steric clashes between a given target protein and E3 ligase pair (Pettersson and Crews, Drug Discov Today Technol, 2019, vol. 31 : pp. 15-27; Bondeson et al., Cell Chem Biol, 2018, vol. 25 : pp. 78-87; Gadd et al., Nat Chem Biol, 2017, vol. 13 : pp. 514-521; Zengerle et al., ACS Chem Biol, 2015, vol. 10 : pp. 1770-1777).

[0007] Other chemical-induced TPD methods have also been described, such as molecular glues (Che et al., Bioog Med Chem Lett, 2018, vol. 28 : pp. 2585-2592), AUTACs, ATTECs, and LYTACs (Ding et al., Trends Pharmacol Sci, 2020, vol. 41 : pp. 464-474). For example, the AUTAC technology follows a similar induced proximity principle, but targets proteins for degradation via autophagy (Daiki et al., Mol Cell, 2019, vol. 76 : pp. 797-810).

[0008] Overall, TPD technology has many advantages over conventional biochemical inhibitors (Pettersson and Crews, Drug Discov Today Technol, 2019, Vol. 31 : pp. 15-27; Ding et al., Trends Pharmacol Sci, 2020, Vol. 41 : pp. 464-474). For example, unlike conventional inhibitors, TPD agents act in substoichiometric fashion and can often mediate sequential degradation of multiple molecules of a target protein, often resulting in greater potency than isolated target-binding moieties and other biochemical inhibitors into which they are incorporated. Furthermore, because inhibition of target protein function by TPD agents is primarily due to degradation rather than simple biochemical inhibition, recovery of target protein function is often slower than observed with biochemical inhibitors. TPD agents can also have improved target selectivity compared to biochemical inhibitors. Finally, TPD agents can target proteins that are not affected by biochemical inhibition by interacting with binding pockets that do not affect the biochemical activity of the target but still allow for degradation of the target.

[0009] However, some drawbacks are associated with current TPD technology. These include promiscuous degradation of target proteins in many tissues and organs, not just those in which the target protein participates in disease processes, which is expected to result in adverse side effects of therapy. Furthermore, resistance to these technologies can develop through mutations or alterations in expression of UPS components such as E3 ligases (Ottis et al., ACS Chem Biol, 2019, Vol. 14: pp. 2215-2223; Zhang et al., Mol Cancer Ther, 2019, Vol. 18: pp. 1302-1311), resulting in loss of therapeutic efficacy. Thus, there is a need for improved / alternative methods and compositions for TPD.

[0010] It is also desirable to develop improved / alternative TPD agents that mediate the degradation of proteins associated with cancer and other diseases. Mitogen-activated protein kinases (MAPKs) regulate many different aspects of cellular function, including growth, survival, and death of cancer cells. In particular, one component of the MEK5 signaling pathway, MAPK7 (also known as ERK5), is believed to play an important role in a variety of different types of cancer (Hoang et al., Cancer Lett, 2017, 392:51-59; Stecca and Rovida, Int J Mol Sci, 2019, 20:1426; Pereira and Rodrigues, Trends Mol Med, 2020, 26:394-407; Tubita et al., Int J Mol Sci, 2020, 21:938). For example, in triple-negative breast cancer (TNBC), there is a correlation between high MAPK7 expression and poor prognosis (Ortiz-Ruiz et al., Oncotarget, 2014, 5:11308-11318). Likewise, in prostate cancer, strong nuclear MAPK7 localization is an independent prognostic factor for poor disease-specific survival (McCracken et al., Oncogene, 2008, 27:2978-2988). Importantly, many of the functions of MAPK7 are not affected by selective MAPK7 biochemical inhibitors, thus a TPD approach is needed to block its function in cancer cells (Lin et al., Proc Natl Acad Sci USA, 2016, 113:11865-11870). Thus, MAPK7 represents an attractive drug target, and it is desirable to develop agents that induce TPD of MAPK7. SUMMARY

[0011] The present disclosure provides tumor-targeting protein degradation chimeras, referred to as chaperone-mediated protein degraders (CHAMPs), that comprise a first moiety capable of binding to one or more target proteins (e.g., MAPK7) and a second moiety capable of binding to one or more chaperone proteins or protein components of a chaperone complex (e.g., HSP90). Such CHAMP compounds include compounds of Formula I:

[0012]

[0013] and pharmaceutically acceptable salts thereof, wherein W, D, L, A, R 10 , R 12 , R 16 , R 17 , R 18 , R19 , k and v are as defined herein.

[0014] Also provided are compositions comprising the disclosed compounds of Formula I and methods of making the same. In one aspect, the disclosed compounds induce targeted degradation of oncogenic proteins in a tumor-selective manner and are useful in the treatment of cancer and related disorders. DETAILED DESCRIPTION

[0015] 1. General Description of Compounds

[0016] Provided herein are CHAMP compounds of Formula I:

[0017]

[0018] or a pharmaceutically acceptable salt thereof, wherein,

[0019] A is a chemical moiety that binds to a HSP90 protein;

[0020] L is a linker;

[0021] W and D are each independently N or CR 9 ;

[0022] R 10 , R 16 , and R 19 are each independently selected from halo, (Ci-C6)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2-C6)alkynyl, -(Ci-C6)alkylOR c , -(Ci-C6)alkylN(R d )2, -(Ci-C6)alkylC(O)OR d , -(Ci-C6)alkylC(O)N(R d )2, -(Ci-C6)alkylO(Ci-C6)alkylN(R d )2, -(Ci-C6)alkylSOR d , -(Ci-C6)alkylS(O)2R d , -(Ci-C6)alkylSON(R d )2, -(Ci-C6)alkylSO2N(R d )2, -(Ci-C6)alkylcycloalkyl, -(Ci-C6)alkylheterocyclyl, -(Ci-C6)alkylheteroaryl, -(Ci-C6)alkylaryl, -(Ci-C6)alkoxy, halo(Ci-C6)alkoxy, CN, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -C(O)R d , -C(O)OR d , -C(O)N(R d )2, N(Rd )2, -C(O)NR d (C1-C6)alkylN(R d )2, -NR d (C1-C6)alkylN(R d )2, -NR d (C1-C6)alkylOR d , -SOR d , -S(O)2R d , -SON(R d )2, -SO2N(R d )2, and CN, wherein each aryl, cycloalkyl, heterocyclyl, and heteroaryl is optionally substituted, individually and in combination with -(C1-C6)alkylcycloalkyl, -(C1-C6)alkylheterocyclyl, -(C1-C6)alkylheteroaryl, -(C1-C6)alkylaryl, by from 1 to 3 groups selected from the group consisting of R e ;

[0023] M is O, S, or NR 11 ;

[0024] R 11 , R 17 , R 18 , and R 20 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, and S(O)2(C1-C6)alkyl (alternatively, R 17 or R 18 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, C3-C6cycloalkyl, and S(O)2(C1-C6)alkyl);

[0025] R 12 is hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylOR c , S(O)2(C1-C6)alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C(O)(C1-C6)alkyl, or -(C1-C6)alkylaryl, wherein each aryl, cycloalkyl, heterocyclyl, and heteroaryl is optionally substituted, individually and in combination with -(C1-C6)alkylaryl, by from 1 to 3 groups selected from the group consisting of R e ;

[0026] R c and R d are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, and halo(C1-C6)alkyl;

[0027] R e is selected from the group consisting of halo, oxo, CN, NO2, -N(R d )2, -OR d , -C(O)OR d, (C1-C6)alkyl, -(C1-C6)alkylOR c , halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, -(C1-C6)alkylC(O)OR d , -(C1-C6)alkylC(O)N(R d )2, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2-C6)alkynyl, -(C1-C6)alkylSR d , -(C1-C6)alkylOR c , -(C1-C6)alkylN(R d )2, -C(O)N(R d )2, -C(O)NR d C 1-6 alkylN(R d )2, -NR d C 1-6 alkylN(R d )2, -NR d C 1-6 alkylOR d , -SOR d , -S(O)2R d , -SON(R d )2, -SO2N(R d )2, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and

[0028] k and v are each independently 0, 1, 2, or 3.

[0029] 2. Definitions

[0030] As used herein, the articles “a” and “an” refer to one or more than one (i.e., to at least one) of the grammatical object of the article. When used in conjunction with the term “comprising” the use of the words “a” or “an” can mean “one,” but it is also consistent with the meaning of “one or more” “at least one,” and “one or more than one.”

[0031] As used herein, “about” and “approximately” generally mean an acceptable degree of error for the quantities given, such as within 20% (percent), typically within 10%, and more typically within 5% of a given value. The term “substantially” means more than 50%, preferably more than 80%, and most preferably more than 90% or 95%.

[0032] As used herein, the term “comprising” or “including,” or any variation thereof, is used in its inclusive sense and specifies the presence of the stated features but does not preclude the presence or addition of further features in various embodiments.

[0033] As used herein, the term "consisting essentially of means those elements required by a given embodiment. This term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristic of that embodiment of the disclosure.

[0034] The term "comprising," as used herein, means that the compositions, methods, and respective components thereof described herein can include, but are not limited to, those elements as enumerated.

[0035] As used herein, unless otherwise indicated, the term "alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms, e.g., (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 representative saturated branched alkyl groups include isopropyl, sec-butyl, isobutyl, t-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, and the like.

[0036] As used herein, unless otherwise indicated, the term "alkenyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms (e.g., (C2-C6)alkenyl or (C2-C4)alkenyl) and having at least one carbon-carbon double bond. Representative straight chain and branched (C2-C 10 )alkenyl groups include ethenyl, allyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, and the like.

[0037] As used herein, unless otherwise indicated, the term "alkynyl" refers to a saturated straight-chain or branched-chain acyclic hydrocarbon having 2 to 10 carbon atoms (e.g., (C2-C6)alkynyl or (C2-C4)alkynyl) and having at least one carbon-carbon triple bond. Representative straight-chain and branched-chain alkynyl groups include ethynyl, propynyl, 1 -butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl- 1 -butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonylnyl, 2-nonylnyl, 8-nonylnyl, 1-decynyl, 2-decynyl, 9-decynyl, and the like.

[0038] As used herein, the term "cycloalkyl" refers to a saturated monocyclic alkyl 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.

[0039] The term "oxo" refers to the group =0.

[0040] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more (including all) hydrogen groups are replaced by a halo group, wherein each halo group is independently selected from -F, -CI, -Br, and -I. Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.

[0041] As used herein, "alkoxy" is an alkyl group connected to another moiety via an oxygen linker.

[0042] As used herein, "haloalkoxy" is a haloalkyl group connected to another moiety via an oxygen linker.

[0043] As used herein, the term "alkylene" refers to an alkyl group having two points of attachment. Straight-chain alkylene groups are preferred. Non-limiting examples of alkylene groups include methylene ethylene, n-propylene, i-propylene, and the like. The alkylene group can optionally be substituted with one or more substituents.

[0044] As used herein, the term "heterocyclyl" refers to a monocyclic heterocyclic ring system that is a saturated ring or an unsaturated non-aromatic ring that contains up to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, as size and valency permit. The heterocycle can be attached via any heteroatom or carbon atom. Representative heterocycles include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydropyrimidyl, and the like.

[0045] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic heteroaromatic ring containing carbon atom ring members and one or more heteroatom ring members selected from nitrogen, oxygen, and sulfur, to the extent the size of the definition permits. Representative heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridinyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridinyl, quinazolinyl, purinyl, benzothiophenyl, and the like. The point of attachment of a heteroaromatic or heteroaryl ring to another group can be at a carbon atom or a heteroatom of the heteroaromatic ring.

[0046] As used herein, the term "halogen" or "halo" refers to F, CI, Br, or I.

[0047] When a heterocyclyl or heteroaryl group contains a nitrogen atom, it can be substituted or unsubstituted as valence permits.

[0048] The terms "linker" or "tether," used interchangeably, refer to a chemical moiety that connects two other moieties (e.g., a first binding moiety and a second binding moiety). The linker can covalently connect the first binding moiety and the second binding moiety. In one aspect, the linker is not cleavable in vivo. In another aspect, the linker comprises one or more cyclic ring systems. In another aspect, the linker comprises an alkyl chain that is optionally substituted and / or interrupted by one or more chemical groups. In one aspect, the linker comprises optimal spatial and chemical properties that achieve optimal therapeutic activity. In one aspect, the linker does not interfere with the ability of the first binding moiety and / or the second binding moiety to bind their respective targets (e.g., HSP90 and MAPK7). In one aspect, the linker alters the ability of the first binding moiety and / or the second binding moiety to bind their respective targets (e.g., HSP90 and MAPK7).

[0049] The term "MAPK7" refers to the protein product of the mitogen-activated protein kinase 7 gene, also known as extracellular signal-regulated kinase 5 or ERK5 gene.

[0050] The term "HSP90" refers to the collective term for the protein products of the heat shock protein 90 (90 kDa) gene family members, individually or in various combinations, including: HSP90AA1 (HSP90-alpha or HSP90a), HSP90AB1 (HSP90-beta or HSP90b), HSP90B1 (GRP94), and TRAP1.

[0051] When used to describe a chemical group that can have multiple points of attachment, the hyphen (-) designates the point of attachment of the group to the variable for which it is defined. For example, -NR a R b and -C(O)NR a (C 1-4 alkylene)NR a R indicates the point of attachment of these groups to the nitrogen and carbon atoms, respectively.

[0052] The hash key in indicates the point at which the described group is attached to the defined variable.

[0053] When a compound is named or depicted by structure to be stereochenically pure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight relative to all other stereoisomers. Weight percent purity relative to all other stereoisomers is the ratio of the weight of one stereoisomer to the weight of the other stereoisomers. For example, when a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure by weight. Weight percent optical purity is the ratio of the weight of an enantiomer to the weight of the enantiomer plus the weight of its optical isomer.

[0054] For pharmaceutical uses, pharmaceutically acceptable salts of the disclosed compounds refer to nontoxic “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, hydrobromic, phosphoric, nitric, and sulfuric acids, and salts of organic acids such as acetic, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids. Compounds of the present teachings having an acidic group, such as a carboxylic acid, 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 having a quaternary ammonium group also contain a counterion such as chloride, bromide, iodide, acetate, perchlorate, and the like. Other examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, benzoate, and salts with amino acids such as glutamic acid.

[0055] The term "pharmaceutically acceptable carrier" means a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles 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, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0056] Any of the compositions or methods provided herein can be combined with any of the other compositions and methods provided herein.

[0057] As used herein, the term "subject" refers to humans and non-human animals, including veterinary subjects. The term "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, mice, rabbits, sheep, dogs, cats, horses, cows, chickens, amphibians, and reptiles. In preferred embodiments, the subject is a human and can be referred to as a patient.

[0058] As used herein, the term "treat," "treating," or "treatment" refers to the act of obtaining beneficial or desired clinical results, including, but not limited to, alleviating or improving one or more signs or symptoms of a disease or condition, reducing the extent of a disease, stabilizing the state of a disease (i.e., not worsening), improving or remitting the state of a disease, decreasing the rate of progression or delaying the time of progression, and remission (whether partial or total, whether detectable or undetectable). "Treatment" can also mean prolonging survival as compared to expected survival if treatment were not present. Treatment does not necessarily mean cure.

[0059] A "therapeutically effective amount" is an amount sufficient to treat a disease in a subject. A therapeutically effective amount can be administered in one or more administrations. In one aspect, a therapeutically effective amount means a dosage of about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day.

[0060] The term "administer," "administering," or "administration" includes any method of delivering a pharmaceutical composition or agent to the body of a subject or to a particular region in the body or on the body surface of a subject. In certain embodiments of the application, the agent is administered intravenously, intramuscularly, subcutaneously, intradermally, intranasally, orally, transdermally, or mucosally. In a preferred embodiment, the agent is administered intravenously. In another preferred embodiment, the agent is administered orally. Administering an agent can be performed by a number of people working in concert. Administering an agent includes, for example, directly or through another person prescribing the agent to be administered to a subject and / or providing instructions for taking a particular agent, by self-delivery, such as by oral delivery, subcutaneous delivery, intravenous delivery through a central line, etc.; or by delivery by a trained professional, such as intravenous delivery, intramuscular delivery, intratumoral delivery, etc.

[0061] 3. A compound

[0062] In a first embodiment, there is provided a compound of Formula I:

[0063]

[0064] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above.

[0065] In a second embodiment, A is selected from

[0066]

[0067] wherein

[0068] Q and U are each independently selected from phenyl, heteroaryl, heterocyclyl, and cycloalkyl, each of which is optionally substituted with 1 to 3 groups selected from R 2 ;

[0069] R 13 and R 14 are each independently selected from hydrogen, halo, -CN, (Ci-C4)alkyl, halo(Ci-C4)alkyl, and -C(0)NR a R b ;

[0070] R 15 is hydrogen, (Ci-C4)alkyl, or halo(Ci-C4)alkyl;

[0071] W is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 groups selected from R 2 ;

[0072] V is phenyl or a 5- to 9-membered heteroaryl optionally substituted with 1 to 3 groups selected from R 3 ;

[0073] R 1 halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy or halo(Ci-C4)alkoxy;

[0074] R 2 (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2-C6)alkynyl, halo(C2-C6)alkynyl, CN, -C 1-4 alkylOR a , -OR a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -C(O)NR a (C 1-4 alkylene)OR a , -C(O)NR a (C 1-4 alkylene)NR a R b , -C(O)NR a (C 1-4 alkylene)OR, -NR a R b , -O(C 1-4 alkylene)NR a R b , -C 1-4 alkylNR a R b , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -SO2NR a R b , -NR a (C 1-4 alkyl)OR a , -SH, -S(C 1-4 alkyl), -NR a (C 1-4 alkyl)NR a R b , -C 1-6 alkylC(O)NR a R b , -O(C 1-4 alkenylene)NR a C(O)(C 1-4 alkylene)NRa R b , phenyl or 5- to 7-membered heteroaryl, wherein each of said phenyl and 5- to 7-membered heteroaryl is optionally and independently substituted with 1 to 3 groups selected from R 4 ;

[0075] R a and R b are each independently selected from hydrogen and (Ci-C4)alkyl, wherein said (Ci-C4)alkyl is optionally substituted with one or more halo or 3- to 7-membered heterocyclyl, or both (alternatively, the 3- to 7-membered heterocyclyl can be optionally substituted, for example, with 1 to 3 groups selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, and -OSO2(Ci-C3)alkyl); and

[0076] R 3 and R 4 are each independently halo, -NR a R b , (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy, wherein the remaining variables are as described for Formula I. Alternatively, as part of a second embodiment, A is selected from

[0077]

[0078]

[0079] wherein

[0080] Q and U are each independently selected from phenyl, heteroaryl, heterocyclyl, and cycloalkyl, each of which is optionally substituted with 1 to 3 groups selected from R 2 ;

[0081] R 13 and R 14 are each independently selected from hydrogen, halo, -CN, (Ci-C4)alkyl, halo(Ci-C4)alkyl, and -C(O)NR a R b ;

[0082] R 15 is hydrogen, (Ci-C4)alkyl, or halo(Ci-C4)alkyl;

[0083] W is 5- or 6-membered heteroaryl optionally substituted with 1 to 3 groups selected from R 2 ;

[0084] V is phenyl or 5- to 9-membered heteroaryl optionally substituted with 1 to 3 groups selected from R 3 ;

[0085] R 1 halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy or halo(Ci-C4)alkoxy;

[0086] R 2 (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2-C6)alkynyl, halo(C2-C6)alkynyl, CN, -C 1-4 alkylOR a , -OR a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -C(O)NR a (C 1-4 alkylene)OR a , -C(O)NR a (C 1-4 alkylene)NR a R b , -C(O)NR a (C 1-4 alkylene)OR, -NR a R b , -O(C 1-4 alkylene)NR a R b , -C 1-4 alkylNR a R b , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -SO2NR a R b , -NR a (C 1-4 alkyl)OR a , -SH, -S(C 1-4 alkyl), -NR a (C 1-4 alkyl)NR a R b , -C 1-6 alkylC(O)NR a R b , -O(C 1-4 alkenylene)NR a C(O)(C 1-4 alkylene)NRa R b , phenyl or 5- to 7-membered heteroaryl, wherein the phenyl and 5- to 7-membered heteroaryl are each optionally and independently substituted with 1 to 3 groups selected from R 4 ;

[0087] R a and R b are each independently selected from hydrogen and (Ci-C4)alkyl, wherein the (Ci-C4)alkyl is optionally substituted with one or more halo or 3- to 7-membered heterocyclyl, or both (alternatively, the 3- to 7-membered heterocyclyl can be optionally substituted, for example, with 1 to 3 groups selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, and -OSO2(Ci-C3)alkyl); and

[0088] R 3 and R 4 are each independently halo, -NR a R b , (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy, wherein the remaining variables are as described for Formula I.

[0089] In another alternative, as part of the second embodiment, A is wherein the remaining variables are as described above for Formula I. In another alternative, A is wherein the remaining variables are as described above for Formula I.

[0090]

[0091] In a third embodiment, the compound of Formula I has the formula:

[0092]

[0093] or a pharmaceutically acceptable salt thereof, wherein the variables are as described for Formula I or the second embodiment.

[0094] In a fourth embodiment, the compound of Formula I has the formula:

[0095]

[0096] or a pharmaceutically acceptable salt thereof, wherein the variables are as described for Formula I or the second embodiment.

[0097] In a fifth embodiment, k is 0, wherein the remaining variables are as described above for Formula I or the first, second, third, or fourth embodiments.

[0098] In a sixth embodiment, v is 0, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, or fifth embodiments.

[0099] In a seventh embodiment, R 11 is hydrogen, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, or sixth embodiments.

[0100] In an eighth embodiment, R 17 is (Ci-C6)alkyl, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, or seventh embodiments. Alternatively, as part of the eighth embodiment, R 17 is methyl, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, or seventh embodiments.

[0101] In a ninth embodiment, R 12 is (Ci-C6)alkyl, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiments. Alternatively, as part of the ninth embodiment, R 12 is ethyl, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiments.

[0102] In a tenth embodiment, R 18 is (Ci-C3)alkyl or S(O)2(Ci-C3)alkyl, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiments. Alternatively, as part of the tenth embodiment, R 18 is S(O)2Me, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiments.

[0103] In an eleventh embodiment, A is selected from and Z is N or CH, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiments. Alternatively, as part of the eleventh embodiment, A is selected from the above structures and Z is CH, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiments.

[0104] In a twelfth embodiment, R 3 is (Ci-C4)alkyl or halo, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiments.

[0105] In a thirteenth embodiment, A is selected from wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiments. Alternatively, as part of the thirteenth embodiment, A is selected from wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiments. In another alternative, as part of the thirteenth embodiment, A is selected from wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiments. In another alternative, as part of the thirteenth embodiment, A is wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiments.

[0106] In a fourteenth embodiment, R 1 is halo or (Ci-C4)alkyl, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiments. Alternatively, as part of the fourteenth embodiment, R 1 is chloro, isopropyl, methyl, propyl, or ethyl, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiments. In another alternative, as part of the fourteenth embodiment, R 1 is isopropyl or ethyl, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiments.

[0107] In a fifteenth embodiment, R 2 is -OR a , -SR a , -C(O)NR a R b , or -C(O)NR a (C 1-4 alkylene)NR a R b , wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiments.

[0108] In a sixteenth embodiment, R a and R beach is independently selected from hydrogen and (Ci-C4)alkyl, wherein said (Ci-C4)alkyl is optionally substituted with 1 to 3 halo or 6-membered heterocyclyl, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiments.

[0109] In a seventeenth embodiment, R 2 is OH, -C(0)NHCH2CF3, -C(0)NHCH2CH3, -C(0)NHCH(CH3)2, -C(0)NH(CH2CH3)2, -C(0)NHCH(CH3)CF3, -C(0)NHcyclopropyl, -C(0)NHmethylcyclopropyl, C(0)NH2, or -C(0)NH(CH2)2piperidinyl, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiments. Alternatively, as part of the seventeenth embodiment, R 2 is -C(0)NHCH2CF3or OH, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiments. In another alternative, as part of the seventeenth embodiment, R 2 is OH, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiments.

[0110] In an eighteenth embodiment, L is selected from -Het 1 - X 1 -, -Het 1 -, -Het 1 - Het 2 - X 1 -, -Het1 -Het 2 -、-NR d -(CH2) m -X 3 -NR c -(CH2) m -Het 1 -X 1 -Het 2 -X 2 -、-NR c -(CH2) m -Het 1 -X 1 -Het 2 -X 2 -、-Het 1 -X 1 -Het 2 -X 2 -、O-(CH2) m -NR c -X 1 -(CH2) m -NR d -、-X 1 -NR c -X 2 -O-(CH2) m -NR d -、-X 1 -Het 1 -X 2 -Het 2 -(CH2) m O-、O-Het 1 -、O-Het 1 -X 1 -、-X 1 (OCH2CH2) n -NR c -、-(CH2) m NR c -、-(CH2) m -、-O-、X 1 NR c -、-NR c -(CH2) m -X 1 -Het 1 -X 2 -、-NR d -(CH2) m -X 3 -NR c -(CH2) m -Het 1 -X1 -Het 2 -X 2 -, O-Het 1 -X 1 -(CH2) m -NR d -, -X 1 -NR c -X 2 -(CH2) m -NR d -, X 1 -Het 1 -X 2 -NR c -X 3 -Het 2 -(OCH2CH2) n -(CH2) m -NR d -(CH2) m -, -NR d -(CH2) m -X 1 -NR c -(CH2CH2O) n -, -NR c -(CH2) m -X 1 -NR c -(CH2) p -, X 1 -Het 1 -X 2 -NR c -X 3 -Het 2 -(OCH2CH2) n -NR d -(CH2) m -, -NR c -(CH2) m -X 1 -Het 1 -X 2 -Het 2 -X 3 -, O-X 1 -Het 1 -, -O(CH2) m -X 1 -Het 1 -X 2 -Het 2 -X 3 -, -O(CH2) m -X 1 -NRc -(CH2) p -Het 1 -X 2 -Het 2 -X 3 -, O-(CH2) m -NR c -, O-X 1 -Het 1 -X 2 -, -X 1 -NR c -(CH2) m -Het 1 -X 2 -Het 2 -X 3 -(CH2) p -NR d -(CH2) p -, -NR c -(CH2) m -X 1 -(CH)CH3-Het 1 -X 2 -Het 3 -X 3 -, -NR c -(CH2) m -X 1 -(CH2) p -Het 1 -X 2 -Het 2 -X 3 -, -NR c -(CH2) m -X 1 -NR d -(CH2) p -Het 1 -X 2 -Het 2 -X 3 -, -NR c -(CH2) m -NR d -X 1 -Het 1 -X 2 -, Het 1 -X 1 -Het 2 -X 2 -, -Het 1 -X 1 -Het 2 -X 2-O-, -0(CH2) m -Het 1 -(CH2) p -O(CH2) m -NR c -X 2 -, -0(CH2) m -Het 1 -(CH2) p -O(CH2) m -NR c -X 2 -, -Het 1 -O-(CH2) m -X 1 -Het 2 -X 2 -, -Het 1 -O-(CH2) m -X 1 -NR c -(CH2CH2O) n (CH2) m -Het 2 -X 2 -, -Het 1 -X 1 -NR c -(CH2) m -, -Het 1 -X 1 -Het 2 -Het 3 -X 2 -, -Het 1 -X 1 -NR c -(CH2CH2O) n (CH2) m -, -Het 1 -X 1 -NR c -(CH2CH2O) n Het 2 -(CH2) m -X 2 -, -Het 1 -X 1 -NR c -(CH2CH2O) n -, -Het 1 -X 1 -NR c -(CH2) m -Het 2 -X 2 -Het3 -(CH2) m -, -Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -X 2 -, -Het 1 -X 1 -Het 2 -, -Het 1 -X 1 -NR c -, -Het 1 -X 1 -NR c -(CH2) m -Phe-X 2 -Het 2 -(CH2) m -, -Het 1 -X 1 -Het 2 -Het 3 -, -Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -X 2 -(CH2) p -NR c -(CH2) m -, -Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -(CH2) m -O-, -Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -(CH2) p -NR c -(CH2) m -, -Het 1 -X 1 -Het 2 -(CH2CH2O) n -, -Het 1 -X 1 -(CH2) m -Het 2 -X 2 -, -(CH2CH2O)o -(CH2) p -Het 1 -X 1 -Het 2 -(CH2CH2O) n -(CH2CH2O) n -(CH2) m -Het 1 -X 1 -Het 2 -X 2 -Het 1 -X 1 -Phe-X 2 -NR c -X 3 -(CH2CH2O) o -(CH2) p -Het 1 -X 1 -Phe-X 2 -NR c -(CH2CH2O) n -(CH2CH2O) n -(CH2) m -NR c -Phe-X 1 -(CH2CH2O) o -(CH2) p -NR c -Phe-(CH2CH2O) n -(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m -(CH2CH2O) n -(CH2) m -NR c -(CH2CH2O) n -(CH2) m -C(O)-NR d -(CH2CH2O) o -(CH2) p -(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m -Het 1 -X 1 -Het2 -X 2 -, -(CH2CH20) o -(CH2) p -NR c -(CH2CH20) n -(CH2) m -Het 1 -X 1 -Het 2 -X 2 -(CH2CH20) o , -NR c -(CH2CH20) n -(CH2) m -Phe-NH-X 1 -Het 1 -X 2 , -NR c -(CH2CH20) n -(CH2) m -Phe-NH-X 1 -Het 1 -X 2 -(CH2CH20) o , -(CH2CH20) o -(CH2) p -NR c -(CH2CH20) n -(CH2) m -Phe-X 1 -NR c -(CH2CH20) o -(CH2) p -, -(CH2CH20) o -(CH2) p -NR c -(CH2CH20) n -(CH2) m -Het 1 -X 1 -, -(CH2CH20) o -(CH2) p -NR c -(CH2CH20) n -(CH2) m -Het 1 -X 1 -(CH2CH20) n -, -(CH2CH20) n -(CH2) m -NR c -(CH2)m -C(O)-NR d -Het 1 -X 1 -Het 2 -(CH2CH2O) o -(CH2) p or -NR c -(CH2) m -C(O)-NR d -(CH2) m -Het 1 -X 1 -Het 2 -X 2 -, C(O)O-X 1 -Het 1 -(CH2CH2O) o -(CH2) m -NR c -, -Het 1 -(CH2) m -Het 2 -, -Het 1 -X 1 -Het 2 -(CH2) p -O-(CH2) m -, O(CH2) m C(O), -OC(O)-NR c -(CH2) m -NR d -, -OC(O)-NR c -(CH2) m -O-(CH2) m -NR d -, OC(O)Het 1 , -OC(O)-NR c -(CH2CH2O) o -NR d -, OC(O)Het 1 -Het 2 -, -OC(O)-NR c -(CH2) m C(O)-Het 1 -X 1 -Het 2 -, O-(CH2) m -Het 1 - and O-(CH2) m -Het 1 -X 1 -Het 2 ;

[0111] Het 1 , Het 2 , and Het 3 are each independently phenyl, 4- to 6-membered heterocyclyl, 5- to 7-membered heteroaryl, or 4- to 6-membered cycloalkyl, each of which is optionally substituted with (Ci-C4)alkyl;

[0112] X 1 , X 2 , and X 3 are each independently C(O) or (CH2) r ; and

[0113] m, n, o, p, q, and r are each independently an integer selected from 0, 1, 2, 3, 4, 5, and 6, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiments. Alternatively, as part of an eighteenth embodiment, L is selected from 1 - X 1 -, Het 1 - X 1 - Het 2 - X 2 -, Het 1 - O-(CH2) m - X 1 - Het 2 - X 2 -, Het 1 - O-(CH2) m - X 1 - NR c - (CH2CH2O) n (CH2) m - Het 2 - X 2 -, Het 1 - X 1 - NR c - (CH2) m -, Het 1 - X 1 - Het 2 - Het 3 - X 2 -, Het 1 - X 1 - NR c - (CH2CH2O) n(CH2) m -, Het 1 -X 1 -NR c -(CH2CH2O) n Het 2 -(CH2) m -X 2 , Het 1 -X 1 -NR c -(CH2CH2O) n -, Het 1 -X 1 -NR c -(CH2) m -Het 2 -X 2 -Het 3 -(CH2) m -, Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -X 2 -, Het 1 -X 1 -Het 2 -, Het 1 -X 1 -NR c -, Het 1 -X 1 -NR c -(CH2) m -Phe-X 2 -Het 2 -(CH2) m -, Het 1 -X 1 -Het 2 -Het 3 -, Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -X 2 -(CH2) p -NR c -(CH2) m -, Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -(CH2) m-O-, Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -(CH2) p -NR c -(CH2) m -, Het 1 -X 1 -Het 2 -(CH2CH2O) n -, Het 1 -X 1 -(CH2) m -Het 2 -X 2 -, -(CH2CH2O) o -(CH2) p -Het 1 -X 1 -Het 2 -(CH2CH2O) n , -(CH2CH2O) n -(CH2) m -Het 1 -X 1 -Het 2 -X 2 , Het 1 -X 1 -Phe-X 2 -NR c -X 3 -, -(CH2CH2O) o -(CH2) p -Het 1 -X 1 -Phe-X 2 -NR c -(CH2CH2O) n -, -(CH2CH2O) n -(CH2) m -NR c -Phe-X 1 -, -(CH2CH2O) o -(CH2) p -NR c -Phe-(CH2CH2O) n -, -(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2)m -(CH2CH2O) n -(CH2) m -NR c -(CH2CH2O) n -(CH2) m -C(O)-NR d -(CH2CH2O) o -(CH2) p -,(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m -Het 1 -X 1 -Het 2 -X 2 -,(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m -Het 1 -X 1 -Het 2 -X 2 -(CH2CH2O) o ,NR c -(CH2CH2O) n -(CH2) m -Phe-NH-X 1 -Het 1 -X 2 ,NR c -(CH2CH2O) n -(CH2) m -Phe-NH-X 1 -Het 1 -X 2 -(CH2CH2O) o -,(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m -Phe-X 1 -NR c -(CH2CH2O) o -(CH2) p -,(CH2CH2O) o -(CH2) p-NR c -(CH2CH2O) n -(CH2) m -Het 1 -X 1 -、-(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m -Het 1 -X 1 -(CH2CH2O) n -、-(CH2CH2O) n -(CH2) m -NR c -(CH2) m -C(O)-NR d -Het 1 -X 1 -Het 2 -(CH2CH2O) o -(CH2) p and NR c -(CH2) m -C(O)-NR d -(CH2) m -Het 1 -X 1 -Het 2 -X 2 wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiments. Alternatively, as part of an eighteenth embodiment, L is Het 1 -X 1 -*, Het 1 -X 1 -Het 2 -X 2 -*, Het 1 -O-(CH2) m -X 1 -Het 2 -X 2 -*, Het 1 -O-(CH2) m -X 1 -NR c-(CH2CH2O) n (CH2) m -Het 2 -X 2 -*, Het 1 -X 1 -NR c -(CH2) m -*, Het 1 -X 1 -Het 2 -Het 3 -X 2 -*, Het 1 -X 1 -NR c -(CH2CH2O) n (CH2) m -*, Het 1 -X 1 -NR c -(CH2CH2O) n Het 2 -(CH2) m -X 2 *, Het 1 -X 1 -NR c -(CH2CH2O) n -*, Het 1 -X 1 -NR c -(CH2) m -Het 2 -X 2 -Het 3 -(CH2) m -*, Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -X 2 -*, Het 1 -X 1 -Het 2 -*, Het 1 -X 1 -NR c -*, Het 1 -X 1 -NR c -(CH2) m -Phe-X 2 -Het 2 -(CH2) m -*, Het 1 -X1 -Het 2 -Het 3 *, Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -X 2 -(CH2) p -NR c -(CH2) m *, Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -(CH2) m -O- *, Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -(CH2) p -NR c -(CH2) m *, Het 1 -X 1 -Het 2 -(CH2CH2O) n *, Het 1 -X 1 -(CH2) m -Het 2 -X 2 *, -(CH2CH2O) o -(CH2) p -Het 1 -X 1 -Het 2 -(CH2CH2O) n *, -(CH2CH2O) n -(CH2) m -Het 1 -X 1 -Het 2 -X 2 *, Het 1 -X 1 -Phe-X 2 -NR c -X 3 *, -(CH2CH2O) o -(CH2) p -Het 1 -X 1 -Phe-X2 -NR c -(CH2CH2O) n *, -(CH2CH2O) n -(CH2) m -NR c -Phe-X 1 *, -(CH2CH2O) o -(CH2) p -NR c -Phe-(CH2CH2O) n *, -(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m *, (CH2CH2O) n -(CH2) m -NR c -(CH2CH2O) n -(CH2) m -C(O)-NR d -(CH2CH2O) o -(CH2) p *, -(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m -Het 1 -X 1 -Het 2 -X 2 *, -(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m -Het 1 -X 1 -Het 2 -X 2 -(CH2CH2O) o *, NR c -(CH2CH2O) n -(CH2) m -Phe-NH-X 1 -Het 1 -X 2 *, NR c -(CH2CH2O) n-(CH2) m -Phe-NH-X 1 -Het 1 -X 2 -(CH2CH2O) o *-, -(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m -Phe-X 1 -NR c -(CH2CH2O) o -(CH2) p *-, -(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m -Het 1 -X 1 *-, -(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m -Het 1 -X 1 -(CH2CH2O) n *-, -(CH2CH2O) n -(CH2) m -NR c -(CH2) m -C(O)-NR d -Het 1 -X 1 -Het 2 -(CH2CH2O) o -(CH2) p *or NR c -(CH2) m -C(O)-NR d -(CH2) m -Het 1 -X 1 -Het 2 -X 2wherein * indicates the point of attachment to A and wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiments. Alternatively, as part of an eighteenth embodiment, Het 1 Het 2 and Het 3 are each independently phenyl, 7- to 9-membered heterocyclyl, 5- to 7-membered heteroaryl, or 4- to 6-membered cycloalkyl, each of which is optionally substituted with (Ci-C4)alkyl, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiments.

[0114] In a nineteenth embodiment, L is Het 1 -X 1 -Het 2 -X 2 -*, Het 1 -O-(CH2) m -X 1 -Het 2 -X 2 -*, Het 1 -O-(CH2) m -X 1 -NR c -(CH2CH2O) n (CH2) m -Het 2 -X 2 -*, Het 1 -X 1 -NR c -(CH2) m -*, Het 1 -X 1 -Het 2 -Het 3 -X 2 -*, Het 1 -X 1 -NR c -(CH2CH2O) n (CH2) m -*, Het1 -X 1 -NR c -(CH2CH2O) n Het 2 -(CH2) m -X 2 *, Het 1 -X 1 -NR c -(CH2CH2O) n *, Het 1 -X 1 -NR c -(CH2) m -Het 2 -X 2 -Het 3 -(CH2) m *, Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -X 2 *, Het 1 -X 1 -Het 2 *, Het 1 -X 1 -NR c *, Het 1 -X 1 -NR c -(CH2) m -Phe-X 2 -Het 2 -(CH2) m *, Het 1 -X 1 -Het 2 -Het 3 *, Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -X 2 -(CH2) p -NR c -(CH2) m *, Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -(CH2) m -O- *, Het 1-X 1 -Het 2 -(CH2) m -Het 3 -(CH2) p -NR c -(CH2) m -* or Het 1 -X 1 -Het 2 -(CH2CH2O) n -*, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment. Alternatively, as part of a nineteenth embodiment, L is Het 1 -X 1 -Het 2 -X 2 -*, Het 1 -X 1 -NR c -(CH2) m -*, Het 1 -X 1 -Het 2 -Het 3 -X 2 -* or Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -X 2 -*, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment. In another alternative, as part of a nineteenth embodiment, L is Het 1 -X 1 -NR c -(CH2) m -* or Het 1 -X 1 -Het 2 -(CH2) m-Het 3 -X 2 -*, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiments. In yet another alternative, as part of a nineteenth embodiment, L is 1 -X 1 -Het 2 -(CH2) m -Het 3 -X 2 -*, wherein the remaining variables are as described above for Formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiments.

[0115] In a twentieth embodiment, Het 1 and Het 2 are each independently phenyl or 4- to 6-membered heterocyclyl. Alternatively, as part of a twentieth embodiment, Het 1 and Het 2 are each independently piperidinyl, phenyl, pyridinyl, piperazinyl, or pyrrolidinyl.

[0116] In a twenty-first embodiment, m, n, o, p, q, and r, as described herein (e.g., as in the eighteenth or nineteenth embodiments, or as applied to the twentieth embodiment), are each independently an integer selected from 0, 1, 2, and 3.

[0117] In a twenty-second embodiment, L is selected from

[0118]

[0119] wherein the remaining variables are as described above for formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment. Alternatively, as part of a twenty-second embodiment, L is selected from

[0120] wherein the remaining variables are as described above for formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment. Alternatively, as part of a twenty-second embodiment, L is selected from wherein the remaining variables are as described above for formula I or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment.

[0121] Specific compounds are provided in the Examples section below and are included as part of the present application. Salts and free bases of these compounds are also included.

[0122] 4. Uses, Formulations, and Administration

[0123] The compounds and compositions described herein can be used generally as anti-cancer therapies. In one aspect, the disclosed compounds and compositions behave as tumor-targeting chaperone-mediated protein degradation agents (CHAMPs), where one portion of the compound is responsible for binding to MAPK7 and another portion is responsible for binding to a protein component of HSP90 or other chaperone protein or chaperone complex (e.g., a member of the HSP70 family). Their mechanism of action includes, but is not limited to, degrading MAPK7 and / or other related members of the mitogen-activated protein kinase (MAPK) protein family, thereby preventing downstream signals that can lead to inhibition of cancer cell growth and / or induction of cancer cell death or other MAPK7 or MAPK functions. In one aspect, the disclosed compounds effect degradation of MAPK7.

[0124] In one aspect, the disclosed compounds and compositions include chaperone or chaperone complex binders with a range of different binding affinities. In different embodiments, it can be desirable to use high-affinity binders, medium-affinity binders, or low-affinity binders. Because HSP90-binding moieties that interact with the N-terminal ATP-binding pocket of HSP90 can inhibit HSP90 activity and induce degradation of HSP90 client proteins (Schopf et al., Nat Rev Mol Cell Biol, 2017, vol. 18: pp. 345-360), some CHAMP molecules can induce degradation of not only the desired target protein(s), which can or can not be HSP90 client proteins, but also HSP90 client proteins. EGFR and ERBB2 (HER2) are two such HSP90 client proteins (Xu et al., J Biol Chem, 2001, vol. 276: pp. 3702-3708). This combination of degradation activities can increase the biological activity of CHAMP molecules compared to other TPD technologies against the same target, and can evade resistance mechanisms to MAPK7 inhibitors and degraders, such as those mediated by HSP90 client proteins.

[0125] In one aspect, the disclosed compounds and compositions behave as tumor-targeted CHAMPs, where one portion of the compound is responsible for binding to MAPK7 and another portion is responsible for binding to a protein component of HSP90 or other chaperone or chaperon complex (e.g., a member of the HSP70 family). In one aspect, the disclosed compounds and compositions have prolonged pharmacokinetic exposure in cancer cells and tumors relative to normal cells, tissues, and organs (Kamal et al., Nature, 2003, vol. 425: pgs. 407-410; Vilenchik et al., Chem Biol, 2004, vol. 11: pgs. 787-797). In one aspect, the disclosed compounds have an increased therapeutic index relative to other MAPK7 inhibitors.

[0126] Accordingly, provided herein are methods of treating a disorder responsive to degradation of MAPK7, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds or compositions described herein. Also provided is the use of one or more compounds or compositions described herein in the manufacture of a medicament for treating a disorder responsive to degradation of MAPK7. Also provided is the use of a compound or composition described herein for treating a disorder responsive to degradation of MAPK7.

[0127] In one aspect, the disorders treated by the compounds and compositions of the present application are cancer. The term "cancer" or "tumor" is well understood in the art and refers to, for example, the presence of cells in a subject that have the typical characteristics of cancerous cells, such as uncontrolled proliferation, immortalization, metastatic potential, rapid growth and proliferation rate, decreased cell death / apoptosis, and certain characteristic morphological features. Cancer cells typically exist in the form of a solid tumor. However, cancer also includes non-solid tumors, for example, blood tumors, such as leukemia, in which the cancer cells originate in the bone marrow. As used herein, the term "cancer" includes pre-cancerous cancers as well as malignant cancers. Cancer includes, but is not limited to, acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (myelocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, bone marrow myelocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, biliary duct cancer, bladder cancer, brain cancer, breast cancer, bronchus cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic granulocytic leukemia, colon cancer, large bowel cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, dysplastic changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's); malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaria, pancreas, prostate, skin and uterus; lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelodysplastic syndrome, myeloma, myxosarcoma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.Other cancers include primary cancer, metastatic cancer, oropharyngeal cancer, hypopharyngeal cancer, liver cancer, gallbladder cancer, bile duct cancer, small intestine cancer, urinary tract cancer, kidney cancer, urothelial cancer, female genital tract cancer, uterine cancer, gestational trophoblastic cancer disease, male genital tract cancer, seminal vesicle cancer, testicular cancer, germ cell tumors, endocrine gland tumors, thyroid cancer, adrenal cancer, pituitary gland cancer, hemangioma, bone and soft tissue sarcoma, Kaposi's sarcoma, neural cancer, eye cancer, meningeal cancer, glioblastoma, neuroma, neuroblastoma, schwannoma, solid tumors arising from hematopoietic malignancies such as leukemia, metastatic melanoma, recurrent or persistent ovarian epithelial cancer, fallopian tube cancer, primary peritoneal cancer, gastrointestinal stromal tumor, 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 cancer, refractory malignancies, triple negative breast cancer, HER2 amplified breast cancer, nasopharyngeal cancer, oral cancer, biliary tract cancer, hepatocellular carcinoma, squamous cell carcinoma of the head and neck (SCCHN), non-marrow thyroid cancer, recurrent glioblastoma multiforme, type 1 neurofibromatosis, CNS cancer, liposarcoma, leiomyosarcoma, salivary gland cancer, mucosal melanoma, acral / lentiginous melanoma, paraganglioma, pheochromocytoma, advanced metastatic cancer, solid tumors, triple negative breast cancer, colorectal cancer, sarcoma, melanoma, kidney cancer, endometrial cancer, thyroid cancer, rhabdomyosarcoma, multiple myeloma, ovarian cancer, glioblastoma, gastrointestinal stromal tumor, mantle cell lymphoma, and refractory malignancies.

[0128] As used herein, a "solid tumor" is understood to be any pathogenic tumor that can be palpated or detected as an abnormal growth of three dimensions using imaging methods. Solid tumors are distinct from blood tumors such as leukemia. However, the cells of blood tumors originate in the bone marrow; thus, the tissue from which the cancer cells arise is a solid tissue that can be hypoxic.

[0129] "Tumor tissue" or "tissue of a tumor" is understood to be the cells, extracellular matrix, and other naturally occurring components associated with a solid tumor.

[0130] The specific dose and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of the compound described in the composition will also depend on the particular compound in the composition.

[0131] Examples

[0132] Example 1: Synthesis of compound 043

[0133] A representative synthesis scheme for compound 043 is shown below. Specific synthesis routes for intermediates are also shown.

[0134]

[0135] Intermediate 2:

[0136] 4-(4-aminobenzyl)piperazine-1-carboxylic acid tert-butyl ester

[0137] To a solution of compound 1 (2.0 g, 15.6 mmol) in EtOH (15 mL) and H2O (5 mL) was added iron powder (1.72 g, 77.9 mmol) and NH4Cl (3.4 g, 105.5 mmol). The resulting mixture was heated to 80 °C for 2 h. The reaction solution was cooled to room temperature and filtered. The filtrate was poured into aqueous NaHCO3solution, extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4and concentrated to give intermediate 2 (1.81 g, yield 100%) as a white solid.

[0138] Intermediate 3:

[0139] 4-(4-(2,4-dihydroxy-5-isopropylphenylthioamino)benzyl)piperazine-1-carboxylic acid tert-butyl ester A solution of compound 2-1 (1.45 g, 6.30 mmol), ClCH2COONa (1.09 g, 9.53 mmol) and NaHCO3(1.60 g, 19.1 mmol) in DMF (10 mL) was stirred at 30 °C for 3 h. Compound 2 (1.85 g, 6.3 mmol) was added to the mixture. After the resulting mixture was heated at 80 °C for 4 h, the reaction mixture was poured into ice water and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated and purified by SGC eluting with DCM:MeOH = 20:1 to give intermediate 3 (2.1 g, yield 70%) as a yellow oil.

[0140] Intermediate 4:

[0141] 4-(4-(7-hydroxy-6-isopropyl-2-oxo-4-thioxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)benzyl)piperazine-1-carboxylic acid tert-butyl ester

[0142] A solution of intermediate 3 (2.1 g, 4.3 mmol) and CDI (1.40 g, 8.6 mmol) in THF (15 mL) was stirred at room temperature for 4 h. The reaction solution was poured into brine (25 mL) and extracted with EtOAc (25 mL x 2). The combined organic layers were washed with brine, dried over Na2S04and concentrated to give intermediate 4 (2.7 g, crude), which was used for further reaction without purification.

[0143] Intermediate 5:

[0144] 4-(4-(3-(2,4-Dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)piperazine-l- carboxylic acid tert-butyl ester

[0145] To a solution of intermediate 4 (2.7 g, crude) in EtOH (6 mL) was added NH2NH2-H20 (253 mg, 7.9 mmol). The resulting mixture was stirred at room temperature overnight. The precipitated solid was filtered to give intermediate 5 (1.3 g, yield 48.5%) as a white solid.

[0146] Intermediate 6:

[0147] 4-(5-Hydroxy-4-(4-(piperazin-l-ylmethyl)phenyl)-4H-l,2,4-triazol-3-yl)-6-isopropylphenyl-l,3- diol, hydrochloride A solution of intermediate 5 (1.3 g, 2.50 mmol) in HC1 / MeOH (3 N, 15 mL) was stirred at room temperature for 16 h. The reaction solution was concentrated to give intermediate 6 (1.02 g, yield 98%) as a white solid.

[0148] Intermediate 8:

[0149] 5-(Methylamino)pyrimidine-2,4(lH,3H)-dione

[0150] To a 500 mL three-necked round-bottom flask, equipped with a condenser, was added 5-bromopyrimidine-2,4(lH,3H)-dione (40 g, 0.2 mol) and methylamine (30% (w / v) aqueous solution, 400 mL). The reaction mixture was stirred and heated at 80 °C for 3.5 h. At 25 °C, the reaction mixture was acidified to pH ~ 4.5 with dilute aqueous HC1 solution. The resulting light yellow precipitate was filtered and washed with water, then dried in vacuum to provide intermediate 8 (25 g, yield 89%) as a light yellow solid.

[0151] Intermediate 9:

[0152] N-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)-N-methyl-2-nitrobenzamide was added to a solution of intermediate 8 (30 g, 0.21 mol) in tetrahydrofuran (THF) (300 mL) at 0 °C. 2-nitrobenzoyl chloride (61 g, 0.32 mol) was added slowly. The resulting clear brown solution was stirred at 0 °C for 40 min and then at room temperature for 4.5 h. The reaction mixture was acidified with dilute aqueous HC1. The resulting light yellow solid was filtered and the filter cake was washed with water and then dried in vacuo to provide intermediate 9 (32 g, 52% yield) as a light yellow solid.

[0153] Intermediate 10:

[0154] N-(2,4-dichloropyrimidin-5-yl)-N-methyl-2-nitrobenzamide

[0155] A solution of intermediate 9 (32 g, 0.11 mol) and N,N-dimethylaniline (12 g, 0.1 mol) in phosphorus oxychloride (205 mL) was heated at 100 °C overnight. The solvent was removed by a rotary evaporator and the residue was dried in vacuo to provide crude intermediate 10 which was used in the next reaction without further purification.

[0156] Intermediate 11:

[0157] 2-chloro-5-methyl-5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][l,4]diazon-6-one Crude intermediate 10 (36 g, 0.11 mol) was dissolved in acetic acid (400 mL) and then iron (37 g, 0.66 mol) was added at 25 °C under vigorous stirring. The mixture was heated at 60 °C for 5 h. Water (100 mL) and ethanol (10 mL) were added and the reaction mixture was stirred for 30 min. The precipitate was filtered and extracted between EtOAc and water. The combined EtOAc phase was dried over sodium sulfate and then concentrated to give crude intermediate 11 which was purified by SGC to give intermediate 11 (20 g, 70% yield over two steps) as a white solid.

[0158] Intermediate 12:

[0159] 2-chloro-5, 11-dimethyl-5, 11-dihydro-6H-benzo [e] pyrimidine [5, 4-b] [1, 4] diazepin-6-one Intermediate 11 (5 g, 19.18 mmol) was dissolved in DMF (50 mL) and then NaH (60% in mineral oil, 1.53 g, 38 mmol) was added at 0 °C under stirring. The mixture was stirred at room temperature for 2 h. Water was added and extracted with EtOAc (50 mL x 3). The combined EtOAc phase was dried over sodium sulfate and then concentrated to give crude intermediate 12 which was purified by SGC to give intermediate 12 as a white solid (4.8 g, yield 91%).

[0160] Intermediate 13:

[0161] 1-(4-((5, 11-dimethyl-6-oxo-6, 11-dihydro-5H-benzo [e] pyrimidine [5, 4-b] [1, 4] diazepin-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxylic acid methyl ester To a solution of intermediate 12 (5 g, 18.2 mmol) in dioxane (50 mL) was added 1-(4-amino-3-ethoxyphenyl)piperidine-4-carboxylic acid methyl ester (5.07 g, 18.2 mmol), K2CO3(7.55 g, 54.6 mmol), X-Phos (1.7 g) and Pd2(dba)3(1.6 g). The mixture was stirred under Ar atmosphere at reflux overnight. Water was added and extracted with EtOAc (50 mL x 3). The combined EtOAc phase was dried over sodium sulfate and then concentrated to give crude intermediate 13 which was purified by SGC to give intermediate 13 as a white solid (4.0 g, yield 43%).

[0162] Intermediate 14:

[0163] 1-(4-((5, 11-dimethyl-6-oxo-6, 11-dihydro-5H-benzo [e] pyrimidine [5, 4-b] [1, 4] diazepin-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxylic acid To a solution of intermediate 13 (2 g, 3.87 mmol) in H2O / MeOH / THF (10 mL / 5 mL / 5 mL) was added LiOH-H2O (0.42 g, 10 mmol). The mixture was stirred at room temperature overnight. Water was added and extracted with EtOAc (50 mL x 3). 1 N HCl was added and the pH was adjusted to 4. The precipitated solid was collected by filtration and dried to give compound intermediate 14 as a white solid (1.5 g, yield 87.7%).

[0164] Compound 043:

[0165] 2-((4-(4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4- yl)benzyl)piperazin-1 -carbonyl)piperidin-1 -yl)-2-ethoxyphenyl)amino)-5,11 -dimethyl- 5,11 -dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one, hydrochloride

[0166] To a solution of intermediate 6 (340 mg, 0.7 mmol), HATU (290 mg, 0.77 mmol) and DIEA (450 mg, 3.48 mmol) in DMF (8 mL) was added intermediate 14 (350 mg, 0.7 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was purified by preparative HPLC to give intermediate 15 (TFA salt) as a white solid. This was added to a solution of NaHC03and EtOAc was added, then extracted. The organic phase was dried and concentrated. H20 (10 mL) and CH3CN (1 mL) were added to the residue, followed by 3N HC1 (0.17 mL). This was lyophilized to give compound 043 as a yellow solid (230 mg).

[0167] 1 H NMR (400 MHz, DMSO-d6): d 13.02 (s, 1 H), 11.92 (m, 2H), 9.94-9.24 (m, 1 H), 8.49 (d, J = 28.4 Hz, 2H), 8.26 (d, J = 8.4 Hz, 1 H), 7.72-7.45 (m, 6H), 7.30-7.19 (m, 4H), 6.91 (s, 1 H), 6.36 (s, 1 H), 4.49-4.16 (m, 6H), 3.76-3.53 (m, 5H), 3.41 (s, 3H), 3.37 (s, 3H), 3.29 (d, J = 8.4 Hz, 2H), 3.23-3.12 (m, 2H), 3.10-2.89 (m, 3H), 2.29 (s, 2H), 1.94 (s, 2H), 1.40 (t, J = 7.2 Hz, 3H), 1.03 (d, J = 6.8 Hz, 6H). LCMS (ESI): R T = 1.080 min, m / z found 894.3 [M-HCI+H] + .

[0168] Example 2: synthesis of compound 065

[0169] A representative synthesis scheme for compound 065 is shown below. Specific synthesis routes for intermediates are also shown.

[0170]

[0171] Intermediate 3:

[0172] (E)-N'-(3,3-dimethyl-5-oxocyclohexylidene)-4-methylbenzenesulfonohydrazide

[0173] A mixture of 1 (200 g, 1426.72 mmol), 2 (265.71 g, 1426.7167 mmol) and p-toluenesulfonic acid (24.54 g, 142.67 mmol) in toluene (8 L) was heated to 120 °C. After 1 h, the mixture was cooled, followed by the addition of toluene (1.2 L). The mixture was then refluxed for 1 h. The reaction was cooled to ambient temperature. The precipitated solid was collected by filtration, washed with diethyl ether three times and dried under vacuum to give intermediate 3 (360 g, 1167.30 mmol, 81.82 %). LCMS: m / z 309 [M+H] + .

[0174] Intermediate 4:

[0175] 6,6-dimethyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indazol-4-one

[0176] To a suspension of 3 (360 g, 1167.30 mmol) and TEA (486.67 mL, 3501.33 mmol) in THF (3 L) was added trifluoroacetyl 2,2,2-trifluoroacetate (243.51 mL, 1750.67 mmol) at 0 °C. The resulting reaction was heated to 55 °C for 3 h, the reaction mixture was cooled to ambient temperature. To the mixture was added methanol (1.4 L) and 1 N NaOH (1.4 L). After stirring for 3 h, the reaction mixture was diluted with saturated ammonium chloride (3 L), extracted with ethyl acetate three times, the organic layers were combined, washed with brine, dried over sodium sulfate and concentrated in vacuum. The residue was purified by column chromatography to give intermediate 4 (160 g, 689.05 mmol, 59.04 %). LCMS: m / z 233 [M+H] + .

[0177] Intermediate 6:

[0178] 2-bromo-4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-lH-indazol-l- yl)benzonitrile NaH (15.50 g, 645.98 mmol) was added to a solution of 4 (150 g, 645.98 mmol) in DMSO (2 L) at room temperature. After 15 min, solid 2-bromo-4-fluorobenzonitrile (129.20 g, 645.98 mmol) was added. The reaction mixture was heated at 45 °C overnight. The mixture was cooled to room temperature and quenched with saturated aqueous NH4Cl solution. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give intermediate 6 (180 g, 436.67 mmol, 67.59 %). LCMS: m / z 412 [M+H] + .

[0179] Intermediate 8:

[0180] 2-((4-(benzyloxy)phenyl)amino)-4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7- tetrahydro-lH-indazol-l-yl)benzonitrile

[0181] To a solution of 6 (50 g, 121.30 mmol) in toluene (500 mL) was added 7 (24.17 g, 121.30 mmol) and Cs2CO3 (79.04 g, 242.59 mmol). Then BINAP (15.10 g, 24.26 mmol) and Pd(OAc)2 (2.74 g, 12.13 mmol) were added successively under nitrogen protection. The mixed reaction was heated to 120 °C for 3 h. After the mixed reaction was filtered, the filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography to give intermediate 8 (40 g, 75.39 mmol, 62.16 %). LCMS: m / z 531 [M+H] + .

[0182] Intermediate 9:

[0183] 2-((4-(benzyloxy)phenyl)amino)-4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7- tetrahydro-lH-indazol-l-yl)benzamide

[0184] At 0 °C, 1N NaOH (226.18 mL, 226.18 mmol) and H₂O₂ (25.63 g, 226.18 mmol) were added dropwise to a solution of 8 (40 g, 75.39 mmol) of EtOH (400 mL) and DMSO (100 mL). The mixture was then stirred at room temperature for 2 hours, diluted with water, extracted with EtOAc, washed with brine, and dried over sodium sulfate. The organic layer was concentrated under vacuum, and the residue was purified by silica gel column chromatography to give intermediate 9 (35 g, 63.80 mmol, 84.63%). LCMS: m / z 549 [M+H] + .

[0185] Intermediate 10:

[0186] 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-((4-hydroxyphenyl)amino)benzamide

[0187] Pd / C 10% (6.7 g, 6.38 mmol) was added to a solution of 9 (35 g, 63.80 mmol) in 400 mL of MeOH, and the mixture was stirred overnight at room temperature in the presence of H₂. After filtration, washing with EA, and then washing with DCM, the packing material was concentrated under vacuum to give intermediate 10 (26 g, 56.71 mmol, 88.89%) as a solid. LCMS: m / z 459 [M+H] + .

[0188] Intermediate 12:

[0189] 2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl methanesulfonate

[0190] TEA (2.03 mL, 14.62 mmol) was added to a THF (15 mL) solution of 11 (1 g, 4.87 mmol) at 0 °C, followed by the dropwise addition of MsCl (0.57 mL, 7.31 mmol) to the reaction mixture while maintaining the temperature below 5 °C. The mixture was then stirred at room temperature for 2 hours, followed by dilution with water. It was then extracted with EA, washed with saturated brine, dried over sodium sulfate, and concentrated under vacuum to give intermediate 12 (1.3 g, 4.59 mmol, 94.17%). LCMS: m / z 284 [M+H] + .

[0191] Intermediate 13:

[0192] tert-Butyl (2-(2-(4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-lH-indazol-l-yl)phenyl)amino)phenoxy)ethoxy)ethyl) carbamate To a solution of 12 (1.3 g, 4.59 mmol) in DMF (20 mL) was added 10 (1.89 g, 4.13 mmol) and K2CO3 (1.90 g, 13.76 mmol), the mixture was stirred at 90 °C overnight. Then water was added, which was extracted with EA, washed with saturated brine, dried over sodium sulfate and concentrated in vacuum, the residue was purified by silica gel column to give the intermediate as a solid (1.6 g, 2.48 mmol, 54.01%). LCMS: 646 [M+H] + .

[0193] Intermediate 14:

[0194] 2-((4-(2-(2-Aminoethoxy)ethoxy)phenyl)amino)-4-(6,6-dimethyl-4-oxo-3- (trifluoromethyl)-4,5,6,7-tetrahydro-lH-indazol-l-yl)benzamide

[0195] To a solution of 13 (1.6 g, 2.48 mmol) in acetonitrile (25 mL) was added TsOH (1.41 g, 7.43 mmol), the mixture was stirred at 50 °C for 2 hours, saturated NaHCO3 solution was added to pH 8-9, then it was extracted with EA, washed with saturated brine, dried over sodium sulfate, concentrated in vacuum to give the intermediate 14 as a yellow solid, which was used without further purification. LCMS: 546 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 10.08 (s, 1H), 8.16 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.01 (s, 1H), 6.94 (t, J = 9.6 Hz, 3H), 4.07 (t, J = 4.6 Hz, 2H), 3.70 (d, J = 9.0 Hz, 1H), 3.41 (t, J = 5.8 Hz, 3H), 2.89 (s, 2H), 2.65 (t, J = 5.8 Hz, 2H), 2.41 (s, 2H), 1.02 (s, 6H).

[0196] Compound 065:

[0197] N-(2-(2-(4-((2-carbamoyl-4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7- tetrahydro-lH-indazol-l-yl)phenyl)amino)phenoxy)ethoxy)ethyl)-l-(4-((5, 11- dimethyl-6-oxo-6, 11-dihydro-5H-benzo[e]pyrimido[5,4-b][l,4]diazepin-2- yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid.

[0198] To a solution of intermediate 14 (340 mg, 0.7 mmol), HATU (290 mg, 0.77 mmol) and DIEA (450 mg, 3.48 mmol) in DMF (8 mL) was added intermediate 15 (350 mg, 0.7 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was purified by preparative HPLC to give compound 067 (TFA salt) as a white solid. (230 mg) as a yellow solid. 1 HNMR (400 MHz, DMSO-d6): δ 10.12 (s, 1H), 8.37 (s, 1H), 8.20-8.05 (m, 3H), 7.90 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 7.6, 1.6 Hz, 1H), 7.64-7.47 (m, 2H), 7.26-7.16 (m, 4H), 7.03-6.93 (m, 5H), 4.55-4.28 m, 4H), 4.16-4.08 (m, 5H), 3.74 (t, J = 4.4 Hz, 2H), 3.64 (d, J = 12.2 Hz, 2H), 3.51 (t, J = 5.6 Hz, 2H), 3.39 (s, 3H), 3.32 (s, 3H), 3.26 (dd, J = 11.4, 5.8 Hz, 2H), 2.91 (s, 2H), 2.42 (s, 3H), 1.88 (s, 3H), 1.35 (t, J = 6.8 Hz, 3H), 1.03 (s, 6H). LCMS (ESI): R T = 1.500 min, m / z found 1030.4 [M-CF3COOH+H] + .

[0199] Example 3: Synthesis of compound 143

[0200] A representative synthesis scheme for compound 143 is shown below. Specific synthesis routes for intermediates are also shown.

[0201]

[0202] Intermediate 3:

[0203] To a solution of compound 1 (3.0 g, 16.20 mmol) and compound 2 (4.6 g, 17.82 mmol) in DMF (50 mL) was added DIEA (8.37 g, 64.79 mmol) followed by HATU (6.77 g, 17.82 mmol). The mixture was stirred at room temperature overnight. LC-MS indicated the reaction was complete. The reaction mixture was diluted with water (100 mL), extracted with EA (150 mL x 2). The combined organic layers were washed with saturated aqueous NaHC03solution, concentrated in vacuo, the crude product was purified by SGC eluted with DCM:MeOH = 50:1 to give compound 3 (2.7 g, yield 39%) as a brown solid.

[0204] Intermediate 5:

[0205] To a solution of compound 3 (200 mg, 0.47 mmol), compound 4 (189.2 mg, 0.94 mmol) and PPh3 (369.9 mg, 1.41 mmol) in anhydrous THF (9 mL) was added. The mixture was stirred at room temperature for 15 min under Ar atmosphere. DEAD (245.6 mg, 1.41 mmol) was added. Then the reaction mixture was heated to 65 °C and stirred at 65 °C overnight under Ar atmosphere. LC-MS indicated the reaction was complete. The reaction mixture was diluted with water (30 mL), extracted with EA (50 mL x 2). The combined organic layers were concentrated in vacuo, and purified by SGC eluted with PE:EA = 3:1 to give compound 5 (152 mg, yield 53%) as a yellow solid.

[0206] Intermediate 6:

[0207] To a solution of compound 3 (152 mg, 0.25 mmol) in MeOH (2 mL) was added HC1 / dioxane (2 mL). The mixture was stirred at room temperature for 1 h, LC-MS indicated the reaction was complete. The reaction mixture was concentrated in vacuo to give intermediate 6 (124 mg, yield 97%) as a yellow solid.

[0208] Compound 143:

[0209] N-(4'-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4- b][1,4]diazepin-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carbonyl)piperidin-4- yl)oxy)-[1,1 '-biphenyl]-4-yl)-3',6-dimethoxy-[1,1 '-biphenyl]-3-carboxamide, trifluoroacetic acid.

[0210] To a solution of compound 6 (35.79 mg, 0.066 mmol) and compound 7 (30 mg, 0.06 mmol) in DMF (2 mL) was added DIEA (30.86 mg, 0.239 mmol) followed by HATU (24.97 mg, 0.066 mmol). The mixture was stirred at room temperature for 1 h. LC-MS indicated the reaction was complete. The reaction mixture was purified by preparative HPLC (TFA) to give compound 143 (18.92 mg, 32% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 8.39 (s, 1H), 8.25-7.95 (m, 4H), 7.85 (d, J = 8.4 Hz, 2H), 7.73-7.49 (m, 6H), 7.40-6.95 (m, 11H), 4.75-4.66 (m, 2H), 4.19-4.11 (m, 2H), 3.94-3.78 (m, 8H), 3.71-3.63 (m, 2H), 3.54-3.45 (m, 1H), 3.40 (s, 4H), 3.33 (s, 4H), 3.09-2.95 (m, 1H), 2.10-1.85 (m, 6H), 1.74-1.50 (m, 2H), 1.37 (t, J = 6.8 Hz, 3H), 1.27-1.21 (m, 1H). LCMS (ESI): R T = 1.778 min, m / z found 993.1 [M-CF3COOH+H] + .

[0211] Additional compounds were prepared according to the general procedures and protocols described in the examples, including the following:

[0212] Compound 001

[0213]

[0214] 2-((4-(4-(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6(11H)-one, trifluoroacetic acid. 1H NMR (400 MHz, DMSO-d6): δ 11.98 (s, 1H), 9.63 (s, 1H), 9.36 (s, 1H), 8.20-8.19 (m, 1H), 7.66 (s, 1H), 7.51-7.50 (m, 2H), 7.23-7.21 (m, 5H), 6.88 (s, 1H), 6.63-6.62 (m, 2H), 6.25 (s, 1H), 5.33 (d, J = 4.7 Hz, 1H), 4.34 (s, 3H), 3.99 (s, 3H), 3.26-3.20 (m, 12H), 2.95-2.93 (m, 5H), 1.95-1.93 (m, 4H), 1.49-1.47 (m, 2H), 1.23-1.20 (m, 5H), 0.85 (d, J = 6.8 Hz, 6H). LCMS (ESI): R T = 1.047 min, m / z found 925.3 [M-CF3COOH+H] + .

[0215] Compound 002

[0216]

[0217] N-(2-(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)ethoxy)ethyl)-2-((1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-2-yl)amino)-3-ethoxyphenyl)piperidin-4-yl)oxy)acetamide, trifluoroacetic acid. 1 H NMR (400 MHz, DMSO-d6): δ 11.95 (s, 1H), 9.63 (s, 1H), 9.39 (s, 1H), 8.19 (s, 1H), 7.96 (s, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.48 (s, 1H), 7.38-7.10 (m, 6H), 6.87-6.60 (m, 3H), 6.26 (s, 1H), 5.32 (d, J = 4.7 Hz, 1H), 4.00 (s, 3H), 3.88-3.49 (m, 8H), 3.30 (m, 11H), 3.08-2.77 (m, 7H), 1.96 (m, 3H), 1.51 (d, J = 47.6 Hz, 3H), 1.19 (m, 7H), 0.97 (d, J = 6.8 Hz, 6H). LCMS (ESI): R T = 1.061 min, m / z found 1012.0 [M-CF3COOH+H]+ .

[0218] Compound 003

[0219]

[0220] N-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)- 1 -(3-ethoxy-4-((11 -methyl-6-oxo-6, 11 -dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2- yl)amino)phenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 H NMR (400 MHz, DMSO-d6): δ 11.90 (s, 1H), 9.58 (s, 1H), 9.37 (s, 1H), 8.53-8.43 (m, 2H), 8.11-8.00 (m, 2H), 7.77-7.43 (m, 2H), 7.19-7.11 (m, 6H), 6.86 (s, 1H), 6.24 (s, 1H), 4.28 (d, J = 5.3 Hz, 2H), 4.13 (d, J = 6.2 Hz, 2H), 3.67-3.50 (m, 5H), 3.39 (s, 3H), 3.32 (s, 3H), 3.00-2.95 (m, 1H), 1.92-1.80 (m, 3H), 1.36-1.34 (m, 3H), 1.19-1.15 (m, 2H), 1.01 (d, J = 6.9 Hz, 6H). LC-MS (ESI): R T = 1.161 min, m / z found 825.5 [M-CF3COOH+H] + .

[0221] Compound 004

[0222]

[0223] 2-((4-(4-(4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4- yl)benzyl)piperazin-1-yl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5H- benzo[e]pyrimido[5,4-b][1,4]diazepin-6(11H)-one, trifluoroacetic acid. 1H NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 9.41 (s, 1H), 8.31 (s, 1H), 7.87 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.20-7.11 (m, 7H), 6.77 (s, 1H), 6.61 (s, 1H), 6.49 (d, J = 9.5 Hz, 1H), 6.26 (s, 1H), 4.38-4.30 (m, 1H), 4.09-4.03 (m, 4H), 3.67-3.44 (m, 2H), 3.42-4.40 (m, 2H), 3.38-3.35 (m, 2H), 3.28-3.20 (m, 2H), 2.96-2.90 (m, 2H), 2.73-2.63 (m, 5H), 2.33 (s, 3H), 1.79-1.67 (m, 5H), 1.29 (t, J = 6.9 Hz, 5H), 1.25-1.17 (m, 2H), 0.94 (d, J = 6.9 Hz, 6H). LC-MS (ESI): R T = 1.154 min, m / z found 977.3 [M-CF3COOH+H] + .

[0224] Compound 005

[0225]

[0226] N-(2-((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)oxy)ethyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400 MHz, CD3OD): δ 8.54 (d, J = 8.7 Hz, 1H), 8.31 (s, 1H), 7.75 (d, J = 6.8 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.33-7.13 (m, 6H), 6.74 (s, 1H), 6.25 (s, 1H), 4.56 (s, 2H), 4.24 (d, J = 6.6 Hz, 2H), 3.81-3.53 (m, 6H), 3.46-3.44 (m, 8H), 3.01 (dt, J = 13.7, 6.8 Hz, 1H), 2.70-2.65 (m, 1H), 2.15-2.08 (m, 4H), 1.51 (t, J = 6.9 Hz, 3H), 0.92 (d, J = 6.9 Hz, 6H). LCMS (ESI): R T = 1.39 min, m / z found = 869.5 [M-CF3COOH+H] + .

[0227] Compound 006

[0228]

[0229] N-((2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4- yl)benzyl)piperidin-1-yl)ethoxy)methyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H- benzo[e]pyrimidine[5,4-b][1,4]diazepin-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 H NMR (400 MHz, DMSO-d6): δ 11.92 (s, 1H), 9.60 (s, 1H), 9.40 (s, 1H), 9.07 (s, 1H), 8.33 (s, 1H), 7.94-7.80 (m, 3H), 7.68 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 6.9 Hz, 1H), 7.16-7.09 (m, 6H), 6.75 (s, 1H), 6.26 (s, 1H), 4.08-4.07 (m, 3H), 3.69-3.56 (m, 5H), 3.40-3.35 (m, 5H), 3.26-3.20 (m, 9H), 2.98-2.87 (m, 4H), 1.75-1.72 (m, 8H), 1.42-1.40 (m, 2H), 1.30-1.28 (m, 4H), 0.92 (d, J = 6.9 Hz, 6H). LC-MS (ESI): R T= 1.148 min, m / z found 981.0 [M-CF3COOH+H] + .

[0230] Compound 007

[0231]

[0232] N-(2-(3-(((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4- yl)benzyl)(methyl)amino)methyl)phenoxy)ethyl)-1-(4-((5,11-dimethyl-6-oxo-6,11- dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-2-yl)amino)-3- ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 HNMR (400 MHz, DMSO-d6): δ 11.98 (s, 1H), 9.64-9.50 (m, 2H), 8.43-8.09 (m, 3H), 7.68 (d, J = 7.8 Hz, 1H), 7.62-7.47 (m, 3H), 7.38 (t, J = 7.8 Hz, 1H), 7.28-7.07 (m, 8H), 6.90 (s, 1H), 6.26 (s, 1H), 4.42-4.00 (m, 16H), 3.64-3.62 (m, 2H), 3.39-3.32 (m, 8H), 3.05-2.92 (m, 1H), 2.31-2.30 (m, 1H), 1.92-1.90 (m, 4H), 1.35-1.30 (m, 3H), 1.01 (d, J = 6.8 Hz, 6H). LCMS (ESI): R T = 1.333 min, m / z found 988.4 [M-CF3COOH+H] + .

[0233] Compound 008

[0234]

[0235] N-(2-(3-(((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4- yl)benzyl)(methyl)amino)methyl)phenoxy)ethyl)-1-(4-((5,11-dimethyl-6-oxo-6,11- dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-2-yl)amino)-3- ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.91(s,1H),9.60(s,1H),9.38(s,1H),8.38(s,1H),8.16-8.07(m, 2H),7.69(dd,J=7.7,1.4Hz,1H),7.51(t,J=7.0Hz,1H),7.26-7.09(m,7H),6.81(s,1H),6.26 (s,1H),4.16-4.12(m,2H),3.66-3.62(m,2H),3.32-3.26(m,9H),3.00-2.98(m,1H),2.74-2. 71(m,2H),2.50-2.40(m,2H),1.90-1.85(m,4H),1.36(t,J=6.8Hz,3H),0.98(d,J=6.9Hz,6H). LCMS(ESI):R T = 1.513 min, measured m / z value is 839.8 [M-CF3COOH+H] + .

[0236] Compound 009

[0237]

[0238] N-(2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)phenoxy)ethyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ11.85(s,1H),9.71-9.43(m,2H),8.35(s 1H),8.15-8.09(m,2H),7.70-7.67(m,1H),7.51-7.42(m,1H),7.30-7.06(m,5H ),6.94(d,J=8.9Hz,2H),6.82(s,1H),6.24(s,1H),4.13(q,J=6.8Hz,2H),4.03 -3.84(m,2H),3.65(d,J=11.6Hz,2H),3.52-3.18(m,10H),2.98-2.96(m,1H),2 .46-2.36(m,2H),1.89-1.80(m,3H),1.36-1.33(m,6H),0.98(d,J=6.9Hz,6H). LCMS(ESI):R T= 1.39 min, m / z found = 855.5 [M-CH3COOH+H] + .

[0239] Compound 010

[0240]

[0241] N-((1-(1-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperidine-4-carbonyl)pyrrolidin-3-yl)methyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 HNMR (400 MHz, DMSO-d6): δ 11.94 (s, 1H), 9.45 (s, 2H), 8.26-8.25 (m, 2H), 7.91-7.90 (m, 3H), 7.68 (s, 1H), 7.49 (s, 1H), 7.33-7.07 (m, 5H), 6.76 (s, 1H), 6.56-6.53 (m, 2H), 6.27 (s, 1H), 5.32 (s, 1H), 4.08 (s, 2H), 3.64 (s, 3H), 3.38 (s, 3H), 3.28 (s, 3H), 2.79 (s, 8H), 2.33 (s, 4H), 1.93 (s, 4H), 1.66-1.61 (m, 8H), 1.26-1.20 (m, 7H). LCMS (ESI): R T = 1.018 min, m / z found = 1019.3 [M-CF3COOH+H] + .

[0242] Compound 011

[0243]

[0244] 1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-2-yl)amino)-3-ethoxyphenyl)-N-((1-(1-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400 MHz, DMSO): δ 11.98 (s, 1H), 9.60 (s, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 8.06-8.05 (m, 2H), 7.69 (d, J = 7.1 Hz, 1H), 7.50-7.48 (m, 3H), 7.31-7.15 (m, 4H), 7.04-7.01 (m, 2H), 6.91 (s, 1H), 6.24 (s, 1H), 4.22-4.20 (m, 8H), 3.97 (s, 1H), 3.67 (d, J = 11.1 Hz, 2H), 3.40 (s, 3H), 3.33 (s, 3H), 3.20-3.18 (m, 2H), 2.97 (s, 6H), 2.38-2.36 (m, 2H), 1.98-1.58 (m, 12H), 1.36 (t, J = 6.9 Hz, 3H), 1.23 (s, 3H), 1.01 (t, J = 7.4 Hz, 3H). LCMS (ESI): R T = 1.005 min, m / z found 1019.3 [M-CF3COOH+H] + .

[0245] Compound 012

[0246]

[0247] 1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-2- yl)amino)-3-ethoxyphenyl)-N-((1-(1-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H- 1,2,4-triazol-4-yl)benzyl)piperidine-4-carbonyl)pyrrolidin-3-yl)methyl)piperidine-4- carboxamide, trifluoroacetic acid. 1H NMR (400 MHz, DMSO): δ 12.00 (s, 1H), 9.50 (m, 3H), 8.37 (s, 1H), 8.10 (m, 3H), 7.69 (dd, J = 7.7, 1.4 Hz, 1H), 7.50 (m, 3H), 7.30 - 7.13 (m, 4H), 6.96 (d, J = 41.6 Hz, 3H), 6.24 (s, 1H), 4.27 (s, 2H), 4.13 (d, J = 6.9 Hz, 2H), 3.36 (m, 10H), 3.20 - 2.85 (m, 8H), 2.67 (s, 1H), 2.35 - 2.32 (m, 4H), 2.04 - 1.75 (m, 9H), 1.35 (t, J = 6.8 Hz, 3H), 1.23 (s, 2H), 1.01 (dd, J = 8.3, 6.5 Hz, 3H). LCMS (ESI): R T = 0.999 min, m / z found 1005.3 [M-CH3COOH+H] + .

[0248] Compound 013

[0249]

[0250] 2-((2-Ethoxy-4-(4-(4-((4-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidin-1- yl)phenyl)amino)-5,11-dimethyl-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6(11H)-one, trifluoroacetic acid. 1H NMR (400 MHz, DMSO): δ 11.96 (s, 1H), 8.39 (s, 1H), 8.20 (m, 2H), 7.69 (dd, J = 7.7, 1.6 Hz, 1H), 7.52 (t, J = 7.0 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.29 - 7.14 (m, 5H), 7.03 (s, 1H), 6.89 (s, 1H), 6.25 (s, 1H), 4.40 (d, J = 12.7 Hz, 1H), 4.23 - 3.88 (m, 5H), 3.66 (d, J = 11.0 Hz, 2H), 3.40 (s, 3H), 3.34 (s, 3H), 3.01 (m, 9H), 2.62 - 2.53 (m, 1H), 2.37 (q, J = 7.4 Hz, 3H), 1.86 (m, 8H), 1.37 (t, J = 6.9 Hz, 3H), 1.27 - 1.11 (m, 2H), 1.00 (t, J = 7.5 Hz, 4H). LCMS (ESI): R T = 1.078 min, m / z found 977.3 [M-CF3COOH+H] + .

[0251] Compound 014

[0252]

[0253] 1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2- yl)amino)-3-ethoxyphenyl)-N-(2-(2-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H- 1,2,4-triazol-4-yl)phenoxy)ethoxy)ethyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400 MHz, DMSO-d6): δ 11.84 (s, 1H), 9.55 (s, 1H), 9.34 (s, 1H), 8.37 (s, 1H), 8.09-8.06 (m, 3H), 7.69 (dd, J = 7.8, 1.6 Hz, 1H), 7.54-7.48 (m, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 6.85 (s, 1H), 6.24 (s, 1H), 4.17-4.04 (m, 4H), 3.76-3.69 (m, 2H), 3.65 (d, J = 11.6 Hz, 2H), 3.49 (t, J = 5.7 Hz, 2H), 3.39 (s, 3H), 3.32 (s, 3H), 3.28-3.22 (m, 2H), 2.35 (m, 3H), 2.00-1.99 (m, 1H), 1.88 (s, 4H), 1.35 (t, J = 6.7 Hz, 3H), 1.23 (s, 3H), 0.99 (t, J = 7.5 Hz, 3H). LCMS (ESI): R T = 1.157 min, m / z found 885.2 [M-CF3COOH+H] + .

[0254] Compound 015

[0255]

[0256] N-(2-(2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)phenoxy)ethoxy)ethyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400 MHz, DMSO): δ 11.86 (s, 1H), 9.58 (s, 1H), 9.38 (s, 1H), 8.37 (s, 1H), 8.09 (m, 3H), 7.69 (dd, J = 7.7, 1.6 Hz, 1H), 7.50 (d, J = 6.9 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 7.18 (t, J = 7.3 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 6.81 (s, 1H), 6.25 (s, 1H), 4.10-4.08 (m, 5H), 3.72 (s, 2H), 3.65 (d, J = 11.2 Hz, 2H), 3.49 (t, J = 5.8 Hz, 2H), 3.39 (s, 3H), 3.32 (s, 3H), 3.25 (d, J = 5.8 Hz, 2H), 3.01-2.96 (m, 1H), 2.00 (d, J = 7.5 Hz, 1H), 1.87 (s, 4H), 1.35 (t, J = 6.9 Hz, 3H), 1.24 (s, 3H), 0.98 (d, J = 6.9 Hz, 6H). LCMS (ESI): R T = 1.192 min, m / z found 899.3 [M-CF3COOH+H] + .

[0257] Compound 016

[0258]

[0259] N-(2-(2-(2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400 MHz, DMSO-d6): δ 11.86 (s, 1H), 9.58 (s, 1H), 9.38 (s, 1H), 8.37 (s, 1H), 8.09-8.06 (m, 3H), 7.69 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 7.1 Hz, 1H), 7.28-7.15 (m, 3H), 7.09 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.81 (s, 1H), 6.25 (s, 1H), 4.10-4.09 (m, 4H), 3.63-3.61 (m, 9H), 3.42-3.40 (m, 5H), 3.32 (s, 3H), 3.23 (d, J = 5.5 Hz, 2H), 3.01-2.95 (m, 1H), 2.04-1.81 (m, 5H), 1.35 (t, J = 6.9 Hz, 3H), 1.24 (s, 2H), 0.98 (d, J = 6.9 Hz, 6H). LCMS (ESI): R T = 1.186 min, m / z found 943.2 [M-CF3COOH+H] + .

[0260] Compound 017

[0261]

[0262] 1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2- yl)amino)-3-ethoxyphenyl)-N-(2-(2-(2-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5- hydroxy-4H-1,2,4-triazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400 MHz, DMSO-d6): δ 11.83 (s, 1H), 9.54 (s, 1H), 9.33 (s, 1H), 8.37 (s, 1H), 8.01 (s, 2H), 7.69 (dd, J = 7.7, 1.6 Hz, 1H), 7.51 (t, J = 6.9 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 6.85 (s, 1H), 6.24 (s, 1H), 4.13 (d, J = 6.8 Hz, 2H), 4.08 - 4.04 (m, 2H), 3.75 - 3.52 (m, 9H), 3.45 - 3.38 (m, 5H), 3.32 (s, 3H), 3.22 (d, J = 5.7 Hz, 2H), 2.35 (q, J = 7.6 Hz, 2H), 2.02 - 1.84 (m, 4H), 1.38 - 1.22 (m, 8H), 0.99 (t, J = 7.5 Hz, 3H). LCMS (ESI): R T = 1.159 min, m / z found 929.2 [M-CF3COOH+H] + .

[0263] Compound 018

[0264]

[0265] 5-(2,4-Dihydroxy-5-methylphenyl)-4-(4-((4-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11- dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)-3-ethoxyphenyl)piperidin-4- yl)carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-N-(2,2,2-trifluoroethyl)-4H- 1,2,4-triazole-3-carboxamide, trifluoroacetic acid. 1H NMR (400 MHz, DMSO-d6): δ 9.71-9.63 (m, 3H), 8.36 (s, 1H), 8.09-8.01 (m, 2H), 7.69 (dd, J = 1.2 Hz, 1H), 7.53-7.16 (m, 8H), 6.72 (s, 2H), 6.29 (s, 1H), 4.42-4.39 (m, 1H), 4.13-4.11 (m, 3H), 4.01-3.92 (m, 6H), 3.68-3.65 (m, 2H), 3.39 (s, 4H), 3.31 (s, 4H), 3.10-2.86 (m, 7H), 2.67-2.50 (m, 2H), 2.05-1.96 (m, 2H), 1.87 (s, 3H), 1.78 (s, 6H), 1.34 (t, J = 6.8 Hz, 3H), 1.23 (s, 2H), 1.17-0.98 (m, 2H). LCMS (ESI): R T = 1.123 min, m / z found 1072.3 [M-CF3COOH+H] + .

[0266] Compound 019

[0267]

[0268] 2-((2-Ethoxy-4-(4-(4-((4-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-2-fluorobenzyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-6-one, trifluoroacetic acid. 1H NMR (400 MHz, DMSO-d6): δ 12.00 (s, 1H), 9.64-9.40 (m, 2H), 8.37 (s, 1H), 8.15-8.05 (m, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.53-7.49 (m, 1H), 7.44-7.40 (m, 1H), 7.26-6.94 (m, 6H), 6.26 (s, 1H), 4.57-4.37 (m, 5H), 4.16-4.11 (m, 3H), 4.01-3.98 (m, 1H), 3.76-3.64 (m, 3H), 3.39 (s, 4H), 3.32 (s, 4H), 3.07-2.94 (m, 7H), 2.42-2.33 (s, 4H), 2.02-1.77 (m, 8H), 1.37-1.33 (m, 3H), 1.23-1.08 (m, 2H), 1.05-1.01 (m, 4H). LCMS (ESI): R T = 1.033 min, m / z 995.3 [M-CF3COOH+H] + .

[0269] Compound 020

[0270]

[0271] 2-((4-(4-(4-((4-(4-(3-(2,4-dihydroxy-5-propylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-6-one, trifluoroacetic acid. 1H NMR (400 MHz, CD3OD): δ 8.23 (s, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.76-7.70 (m, 1H), 7.53-7.48 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.26-7.14 (m, 4H), 6.72-6.59 (m, 3H), 6.23 (s, 1H), 5.36-5.31 (m, 1H), 4.12 (m, 6.9 Hz, 2H), 3.65 (m, 4H), 3.47 (s, 3H), 3.41 (s, 3H), 3.13 (s, 1H), 2.81-2.58 (m, 10H), 2.32 (m, 6.9 Hz, 4H), 2.18 (d, J = 7.7 Hz, 1H), 2.03 (d, J = 5.9 Hz, 1H), 1.94-1.85 (m, 4H), 1.81 (d, J = 11.5 Hz, 2H), 1.60 (s, 2H), 1.45-1.37 (m, 6H), 0.90 (t, J = 6.7 Hz, 3H), 0.79 (t, J = 7.4 Hz, 3H). LCMS (ESI): R T = 1.033 min, m / z found 991.3 [M-CF3COOH+H] + .

[0272] Compound 021

[0273]

[0274] 2-((4-(4-(4-((4-(4-(3-(2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-6-one, trifluoroacetic acid. 1H NMR (400 MHz, CD3OD): δ 8.56 (d, J = 8.7 Hz, 1H), 8.33 (s, 1H), 7.76 (m, 1.5 Hz, 1H), 7.56-7.50 (m, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.30-7.19 (m, 6H), 7.03 (d, J = 8.5 Hz, 1H), 6.26 (m, 1H), 6.17 (d, J = 2.2 Hz, 1H), 4.57 (m, 1H), 4.25 (m, 6.8 Hz, 2H), 4.14 (m, 1H), 3.97 (s, 2H), 3.82-3.66 (m, 5H), 3.47 (m, 6H), 3.13 (m, 12H), 2.80 (m, 2H), 2.71 (m, 1H), 2.15 (m, 6H), 1.90 (m, 2H), 1.51 (t, J = 7.0 Hz, 3H). LCMS (ESI): R T = 0.973 min, m / z found = 949.2 [M-CF3COOH+H] + .

[0275] Compound 022

[0276]

[0277] 4-(4-((4-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4- b] [1,4]diazepin-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carbonyl)piperidin-4- yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-(2,2,2- trifluoroethyl)-4H-1,2,4-triazole-3-carboxamide, trifluoroacetic acid. 1H NMR (400 MHz, DMSO-d6): δ 9.67 (m, 2H), 8.37 (s, 1H), 8.09 (m, 2H), 7.69 (m, 1.5 Hz, 1H), 7.51 (m, 1H), 7.39 (m, 7.8 Hz, 4H), 7.27-7.14 (m, 2H), 6.98 (s, 1H), 6.68 (s, 1H), 6.31 (s, 1H), 4.40 (m, 1H), 4.13 (m, 2H), 4.05-3.88 (m, 4H), 3.66 (m, 2H), 3.39 (s, 3H), 3.32 (s, 3H), 3.14-2.72 (m, 9H), 2.58 (s, 1H), 2.34-2.22 (m, 3H), 1.90 (m, 9H), 1.35 (t, J = 6.9 Hz, 3H), 1.25-0.98 (m, 4H), 0.89 (m, 4H). LCMS (ESI): R T = 1.083 min, m / z found 1086.3 [M-CF3COOH+H] + .

[0278] Compound 023

[0279]

[0280] 2-((4-(4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)phenyl)piperazin-1- carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-6-one, trifluoroacetic acid. 1 H NMR (400 MHz, DMSO-d6): δ 11.92 (s, 1H), 9.66 (s, 1H), 9.51 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 7.76-7.74 (m, 1H), 7.60-7.55 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.27-7.22 (m, 1H), 7.13-7.01 (m, 5H), 6.85 (s, 1H), 6.33 (s, 1H), 4.24-4.18 (m, 2H), 3.85-3.68 (m, 9H), 3.46 (s, 4H), 3.39 (s, 4H), 3.32-3.27 (m, 4H), 3.09-3.02 (m, 2H), 1.97 (s, 3H), 1.42 (t, J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 6H). LCMS (ESI): R T= 1.268 min, m / z found 880.2 [M-CF3COOH+H] + .

[0281] Compound 024

[0282]

[0283] 2-((4-(4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4- yl)benzyl)piperazin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-6H- benzo[e]pyrimidine[5,4-b][1,4]diazepin-6-one, trifluoroacetic acid. 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 10.11 (s, 1H), 9.66 (s, 1H), 9.37 (s, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.69 (m, 1.5 Hz, 1H), 7.51 (t, J = 8.5 Hz, 3H), 7.33 - 7.13 (m, 4H), 6.89 (s, 1H), 6.76 (s, 1H), 6.26 (s, 1H), 4.34 (m, 3H), 4.11 (m, 6.7 Hz, 3H), 3.73 (s, 3H), 3.35 (m, 8H), 3.15 - 2.85 (m, 7H), 1.81 (s, 4H), 1.33 (t, J = 6.9 Hz, 3H), 1.02 (d, J = 6.9 Hz, 6H). LCMS (ESI): R T = 1.083 min, m / z found 894.2 [M-CF3COOH+H] + .

[0284] Compound 025

[0285]

[0286] 2-((4-(4-(4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4- yl)benzyl)piperidin-1-yl)methyl)piperazin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl- 5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-6-one, trifluoroacetic acid. 1H NMR (400 MHz, DMSO-d6): δ 11.92 (s, 1H), 9.62 (s, 1H), 9.41 (s, 1H), 8.87 (s, 1H), 8.35 (s, 1H), 8.16-7.85 (m, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.56-7.46 (m, 1H), 7.28-7.09 (m, 7H), 6.76 (s, 1H), 6.27 (s, 1H), 4.44-4.34 (m, 2H), 4.16-3.93 (m, 6H), 3.70-3.61 (m, 2H), 3.54-3.44 (m, 2H), 3.39 (s, 3H), 3.30 (s, 3H), 3.22-2.64 (m, 10H), 2.12-1.91 (m, 2H), 1.81-1.70 (m, 8H), 1.53-1.40 (m, 2H), 1.36-1.29 (m, 3H), 0.94 (d, J = 6.8 Hz, 6H). LCMS (ESI): R T = 1.009 min, m / z found 990.4 [M-CF3COOH+H] + .

[0287] Compound 026

[0288]

[0289] N-(4-(3-(2,4-dihydroxyphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-l-(4-((5, 11- dimethyl-6-oxo-6, 11 -dihydro-5H-benzo [e] pyrimido [5, 4-b] [l, 4] diazepin-2-yl)amino)-3- ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 H NMR (400 MHz, DMSO-d6): δ 11.89 (s, 1H), 9.59 (s, 2H), 8.49-8.37 (m, 2H), 8.13-8.02 (m, 2H), 7.69 (dd, J = 7.6, 1.3 Hz, 1H), 7.53-7.49 (m, 1H), 7.26-7.04 (m, 8H), 6.24-6.17 (m, 2H), 4.32 (s, 4H), 4.28 (d, J = 5.1 Hz, 2H), 4.13 (dd, J = 12.1, 8.6 Hz, 2H), 3.67 (d, J = 12.2 Hz, 2H), 3.39 (s, 3H), 3.32 (s, 3H), 1.93 (s, 4H), 1.35 (t, J = 6.8 Hz, 3H). LCMS (ESI): R T= 1.063 min, m / z found 783.3 [M-CF3COOH+H] + .

[0290] Compound 027

[0291]

[0292] N-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)-1 -(4- ((5,11 -dimethyl-6-oxo-6,11 -dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-2- yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 H NMR (400 MHz, DMSO-d6): δ 11.86 (s, 1H), 9.64-9.24 (m, 2H), 8.54-8.32 (m, 2H), 8.19-7.99 (m, 1H), 7.74-7.63 (m, 1H), 7.57-7.46 (m, 1H), 7.28-7.09 (m, 6H), 6.93 (s, 1H), 6.23 (s, 1H), 5.35-4.45 (m, 3H), 4.28 (d, J = 5.2 Hz, 2H), 4.19-4.09 (m, 2H), 3.71 -3.62 (m, 2H), 3.39 (s, 3H), 3.32 (s, 3H), 2.02-1.76 (m, 8H), 1.40-1.29 (m, 3H). LCMS (ESI): R T = 1.094 min, m / z found 797.4 [M-CF3COOH+H] + .

[0293] Compound 028

[0294]

[0295] 1 -(4-((5,11 -dimethyl-6-oxo-6,11 -dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-2- yl)amino)-3-ethoxyphenyl)-N-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4- triazol-4-yl)benzyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400 MHz, DMSO-d6): δ 11.96-11.84 (m, 1H), 9.58 (s, 1H), 9.39 (s, 1H), 8.51 (s, 1H), 8.43-7.32 (m, 1H), 8.13 (s, 2H), 7.72 (s, 1H), 7.53 (s, 1H), 7.36-7.08 (m, 7H), 6.97-6.87 (m, 1H), 6.31-6.21 (m, 1H), 4.32 (s, 3H), 4.15 (s, 3H), 3.69 (s, 2H), 3.48-3.27 (m, 7H), 2.44-2.33 (m, 3H), 1.93 (s, 4H), 1.37 (s, 3H), 1.12-0.96 (m, 3H). LCMS (ESI): R T = 1.137 min, m / z found 811.7 [M-CF3COOH+H] + .

[0296] Compound 029

[0297]

[0298] N-(4-(3-(2,4-dihydroxy-5-propylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2- yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 H NMR (400 MHz, DMSO-d6): δ 11.87 (s, 1H), 9.60-9.25 (m, 2H), 8.56-8.32 (m, 2H), 8.12 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.55-7.47 (m, 1H), 7.30-7.06 (m 7H), 6.86 (s, 1H), 6.24 (s, 1H), 4.92-4.35 (m, 5H), 4.28 (d, J = 5.2 Hz, 2H), 4.17-4.08 (m, 2H), 3.72-3.61 (m, 2H), 3.44-3.26 (m, 6H), 2.35-2.28 (m, 3H), 1.93 (s, 4H), 1.49-1.30 (m, 5H), 0.80 (t, J = 7.2 Hz, 3H). LCMS (ESI): R T = 1.174 min, m / z found 825.3 [M-CF3COOH+H] + .

[0299] Compound 030

[0300]

[0301] N-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-2- (trifluoromethyl)benzyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4- b] [1,4]diazepin-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide trifluoroacetic acid. 1 H NMR (400 MHz, DMSO-d6): δ 12.02 (s, 1H), 9.61-6.37 (m, 2H), 8.58 (s, 1H), 8.37 (s, 1H), 8.15-8.05 (m, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.51-7.46 (m, 4H), 7.26-7.16 (m, 2H), 6.99 (s, 2H), 6.24 (s, 1H), 5.04-4.51 (m, 4H), 4.44 (d, J = 4.4 Hz, 2H), 4.14 (dd, J = 11.9, 5.4 Hz, 2H), 3.68 (d, J = 11.2 Hz, 2H), 3.39 (s, 3H), 3.32 (s, 3H), 3.07-3.01 (m, 1H), 2.10-1.76 (m, 4H), 1.35 (t, J = 6.5 Hz, 3H), 1.06 (d, J = 6.8 Hz, 6H). LCMS (ESI): R T = 1.253 min, m / z found 893.7 [M-CF3COOH+H] + .

[0302] Compound 031

[0303]

[0304] 1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)- 3-ethoxyphenyl)-N-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-2- (trifluoromethyl)benzyl)piperidine-4-carboxamide trifluoroacetic acid. 1H NMR (400 MHz, DMSO-d6): δ 12.01 (s, 1H), 9.59 (s, 1H), 9.37 (s, 1H), 8.54 (s, 1H), 8.36 (s, 1H), 8.17-7.96 (m, 2H), 7.69 (d, J = 7.2 Hz, 1H), 7.54-7.43 (m, 4H), 7.26-7.16 (m, 2H), 7.01 (s, 1H), 6.24 (s, 1H), 4.71-4.27 (m, 6H), 4.12 (dd, J = 14.0, 6.7 Hz, 2H), 3.68 (d, J = 12.0 Hz, 2H), 3.35 (d, J = 30.0 Hz, 6H), 2.44-2.33 (m, 4H), 2.05-1.76 (m, 3H), 1.34 (t, J = 6.4 Hz, 3H), 1.26-1.14 (m, 1H), 1.05 (t, J = 7.6 Hz, 3H). LCMS (ESI): R T = 1.167 min, m / z found 879.7 [M-CF3COOH+H] + .

[0305] Compound 032

[0306]

[0307] 2-((4-(4-(4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diazepin-6-one, hydrochloride. 1H NMR (400MHz, DMSO-d6): δ11.95(s,1H),9.50(d,J=95.9Hz,2H),8.36(s,1H),8.20-7.94(m,2H),7.69(d,J=7.6Hz,1H),7.51- 7.38(m,3H),7.26-7.16(m,4H),7.10-6.87(m,1H),6.82(s,1H),6.26(s,1H),5.29-4.66(m,4H),4.39(d,J=12.0Hz,1H),4.13 (q,J=6.8Hz,2H),3.99(d,J=9.6Hz,1H),3.66(d,J=12.0Hz,2H),3.39(s,3H),3.32(s,4H),3.18-2.81(m,8H),2.45-2.30(m,2 H), 2.06-1.92 (m, 1H), 1.90-1.64 (m, 7H), 1.34 (t, J = 6.7Hz, 3H), 1.27-1.20 (m, 1H), 1.17-1.06 (m, 1H), 0.98 (d, J = 6.8Hz, 9H). LCMS(ESI):R T =1.060 min, measured m / z value is 991.4 [M-HCl+H] + .

[0308] Compound 033

[0309]

[0310] 2-((4-(4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-2-fluorobenzyl)piperazin-1-yl)piperidine-1-carbonyl)piperidine-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.99(s,1H),9.64(s,1H),9.39(s,1H),8.36(s,1H),8.09(s,3H),7.69 (d,J=7.5Hz,1H),7.54-7.48(m,1H),7.47-7.39(m,1H),7.28-7.09(m,4H),7.01(d,J=9.1Hz,1H), 6.91(s,1H),6.26(s,1H),4.52(s,1H),4.12(d,J=6.3Hz,4H),3.67(m,6H),3.39(s,6H),3.31(s,3 H), 3.16-2.92 (m, 8H), 2.08 (m, 2H), 1.80 (s, 4H), 1.51 (s, 2H), 1.34 (m, 4H), 1.02 (d, J = 6.8Hz, 6H). LCMS(ESI):R T =1.180 min, measured m / z value is 996.0 [M-CF3COOH+H] + .

[0311] Compound 034

[0312]

[0313] 4-(4-((4-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.64(s,1H),8.36-8.32(m,2H),8.09-8.08(m,2H),7.68-7.73(m,2H), 7.53-7.16(m,8H),6.91-6.75(m,1H),6.62(s,1H),6.31(s,1H),4.39-4.38(m,1H),4.15-4.10(m ,2H),4.05-3.95(m,1H),3.68-3.65(m,2H),3.39(s,4H),3.32(s,4H),3.11-2.89(m,6H),2.53- 2.35(m,5H),2.41-2.22(m,3H),1.80-1.73(m,8H),1.34(m,4H),1.02(m,2H),0.85-0.84(m,4H). LCMS(ESI):R T =1.060 min, measured m / z value is 1004.4 [M-CF3COOH+H] + .

[0314] Compound 035

[0315]

[0316] N-(4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)methyl)phenethyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.78(s,1H),9.61(m,1H),8.33(s,1H),7.95(s,3H),7.68-7.67(d,J= 7.5Hz,1H),7.50-7.17(m,13H),6.59(s,1H),6.34(s,1H),4.24-4.23(m,2H),4.11-4.07(m,4H) ,3.99-3.90(m,4H),3.65-3.62(m,3H),3.38-3.29(m,9H),2.91-2.74(m,5H),2.55-2.54(m,1H ), 2.33 (m, 1H), 2.01 (m, 1H), 1.77-1.70 (m, 5H), 1.33-1.24 (m, 5H), 0.82-0.81 (d, J = 6.8Hz, 6H). LCMS(ESI):R T =1.230 min, measured m / z value is 1135.3 [M-CF3COOH+H] + .

[0317] Compound 036

[0318]

[0319] N-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-2-fluorobenzyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ11.96(s,1H),9.61(s,1H),9.42(s,1H),8.49(s,1H),8.37(s,1H), 8.28-7.99(m,2H),7.70-7.67(m,1H),7.53-7.49(m,1H),7.29-6.93(m,9H),6.25(s,1H),4. 31(d,J=4.4Hz,2H),4.16-4.11(m,2H),3.67(d,J=12Hz,2H),3.39(s,3H),3.32(s,3H),3.04 -3.00(m,2H),1.99-1.78(m,4H),1.35(t,J=7.2Hz,3H),1.24(s,2H),1.04(d,J=7.2Hz,6H). LCMS(ESI):R T=1.366 min, measured m / z value is 843.8 [M-CF3COOH+H] + .

[0320] Compound 037

[0321]

[0322] 1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)-N-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-2-fluorobenzyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ11.95(s,1H),9.59(s,1H),9.42(s,1H),8.47(s,1H),8.37(s,1H), 8.20-8.01(m,2H),7.70-7.67(m,1H),7.53-7.49(m,1H),7.27-6.95(m,8H),6.25(s,1H),4. 30(d,J=5.2Hz,2H),4.16-4.11(m,2H),3.67(d,J=12Hz,2H),3.39(s,3H),3.32(s,3H),2.43 -2.37(m,3H),1.96-1.73(m,4H),1.35(t,J=6.8Hz,3H),1.24(s,2H),1.04(d,J=7.6Hz,4H). LCMS(ESI):R T =1.327 min, measured m / z value is 829.8 [M-CF3COOH+H] + .

[0323] Compound 038

[0324]

[0325] 2-((4-(4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-2-(trifluoromethyl)benzyl)piperazin-1-yl)piperidin-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ12.02(s,1H),9.60(s,1H),9.36(s,1H),8.31(s,1H),7.86-7.65(m,5H),7.49-7.42( m,3H),7.24-7.14(m,2H),6.90(s,1H),6.61(d,J=2.8Hz,1H),6.51-6.47(m,1H),6.25(s,1H),4.42-4.38(m,1H ),4.08-3.98(m,3H),3.67-3.55(m,5H),3.78(s,3H),3.26(s,3H),3.03-2.99(m,2H),2.73-2.54(m,4H),2.51 (s,2H),2.39-2.35(m,4H),1.85-1.62(m,6H),1.29(t,J=6.8Hz,4H),1.24-1.15(m,3H),1.01(d,J=7.2Hz,6H). LCMS(ESI):R T =1.367 min, measured m / z value is 1046.0 [M-CF3COOH+H] + .

[0326] Compound 039

[0327]

[0328] N-(4-(3-(2,4-dihydroxy-5-propylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ11.87(s,1H),9.58-9.26(m,2H),8.56-8.34(m,2H),8.30-7 .95(m,2H),7.69(dd,J=7.6Hz,1.2Hz,1H),7.55-7.47(m,1H),7.28-7.08(m,7H),6.8 6(s,1H),6.24(s,1H),4.31-4.24(m,4H),4.18-4.11(m,4H),3.71-3.61(m,2H),3.44 -3.26(m,7H),2.37-2.29(m,2H),1.97(s,4H),1.48-1.32(m,5H),0.83-0.77(m,3H). LCMS(ESI):R T=1.240 min, measured m / z value is 825.3 [M-CF3COOH+H] + .

[0329] Compound 040

[0330]

[0331] 2-((4-(4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)phenyl)piperazin-1-yl)piperidine-1-carbonyl)piperidine-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ11.87(s,1H),9.74-9.36(m,3H),8.35(s,1H),8.14-7.84(m,2H),7.68(dd,J=7.6 Hz,1.6Hz,1H),7.54-7.47(m,1H),7.26-7.00(m,6H),6.90-6.65(m,2H),6.27(s,1H),4.67-4.47(m,3H),4 .24-4.08(m,4H),3.94-3.84(m,2H),3.74-3.50(m,6H),3.39(s,3H),3.31(s,3H),3.23-3.09(m,3H),3.02 -2.91(m,4H),2.22-2.08(m,2H),1.79(s,4H),1.66-1.43(m,2H),1.37-1.30(m,3H),0.96(d,J=6.8Hz,6H). LCMS(ESI):R T =1.206 min, measured m / z value is 964.0 [M-CF3COOH+H] + .

[0332] Compound 041

[0333]

[0334] N-((1-(1-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperidine-4-carbonyl)piperidine-4-yl)methyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid.1 H NMR (400MHz, DMSO-d6): δ11.91(s,1H),9.59(s,1H),9.41(s,1H),8.31(s,1H),7.89-7.77(m,3H),7.70-7.64(m,1H),7.54-7.45(m,1H) ,7.29(d,J=8.0Hz,2H),7.23(d,J=8.4Hz,1H),7.19-7.10(m,3H),6.75(s,1H),6.63-6.59(m,1H),6.52-6.47(m,1H),6.26(s,1H),4.41- 4.32(m,1H),4.12-4.02(m,2H),3.96-3.85(m,1H),3.71-3.60(m,2H),3.42(s,2H),3.38(s,3H),3.28(s,3H),3.02-2.89(m,4H),2.84- 2.74(m,2H),2.71-2.56(m,3H),2.29-2.21(m,1H),2.03-1.93(m,2H),1.85-1.41(m,14H),1.29(t,J=6.8Hz,3H),0.93(d,J=6.8Hz,6H). LCMS(ESI):R T =1.035 min, measured m / z value is 1033.4 [M-CF3COOH+H] + .

[0335] Compound 042

[0336]

[0337] 2-((4-(4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)piperidine-1-carbonyl)piperidine-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6(11H)-one, hydrochloride. 1H NMR (400MHz, DMSO-d6): δ11.98(s,1H),9.70(s,1H),9.29(s,1H),8.44(s,1H),8.36(s,1H),8.26(s,1H),7.74-7.58(m,4 H),7.55-7.49(m,1H),7.44(s,1H),7.31-7.17(m,4H),6.93(s,1H),6.34(s,1H),4.59-4.53(m,1H),4.45-4.33(m,2H),4. 23-4.12(m,3H),3.80-3.45(m,12H),3.40(s,3H),3.36(s,3H),3.20-3.08(m,2H),3.05-2.99(m,1H),2.70-2.54(m,2H), 2.35-2.10(m,4H),1.98-1.82(m,2H),1.76-1.64(m,1H),1.61-1.49(m,1H),1.40(t,J=6.8Hz,3H),1.04(d,J=6.8Hz,6H). LC-MS(ESI):R T = 1.031 min, measured m / z value is 977.3 [M-HCl+H] + .

[0338] Compound 043

[0339]

[0340] 2-((4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazine-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, hydrochloride. 1H NMR (400MHz, DMSO-d6): δ13.02 (s, 1H), 11.92 (d, J = 50.0Hz, 2H), 9.94-9.24 (m, 1H), 8.49 (d, J = 28. 4Hz,2H),8.26(d,J=8.4Hz,1H),7.72-7.45(m,6H),7.30-7.19(m,4H),6.91(s,1H),6.36(s,1H),4 .49-4.16(m,6H),3.76-3.53(m,5H),3.41(s,3H),3.37(s,3H),3.29(d,J=8.4Hz,2H),3.23-3.12( m,2H),3.10-2.89(m,3H),2.29(s,2H),1.94(s,2H),1.40(t,J=7.2Hz,3H),1.03(d,J=6.8Hz,6H). LCMS(ESI):R T =1.080 min, measured m / z value is 894.3 [M-HCl+H] + .

[0341] Compound 044

[0342]

[0343] 2-((4-(4-((4-((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, hydrochloride. 1H NMR (400MHz, DMSO-d6): δ11.93(s,1H),9.64(m,3H),8.42(s,1H),8.28(s,2H),7.70(d,J=7.7Hz,1H),7.52(t,J=7.5Hz,2H),7.2 7(d,J=8.3Hz,1H),7.19(t,J=7.8Hz,3H),7.12(d,J=8.3Hz,2H),6.77(d,J=4.5Hz,1H),6.31(s,1H),4.37(s,2H),4.21-4.15(m, 4H),3.99(s,1H),3.59(s,3H),3.45(s,2H),3.40(s,3H),3.35(s,3H),3.10(s,3H),3.01-2.89(m,3H),2.81(s,2H),2.68-2.54( m,3H),2.10(s,2H),1.87(m,3H),1.69(s,3H),1.39(t,J=6.8Hz,3H),1.24(s,1H),1.17(s,1H),1.04(s,1H),0.97-0.93(m,6H). LCMS(ESI):R T =1.100 min, measured m / z value is 990.4 [M-HCl+H] + .

[0344] Compound 045

[0345]

[0346] (R)-N-(1-(4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)methyl)phenyl)ethyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carboxamide, trifluoroacetic acid. 1HNMR (400MHz, DMSO-d6): δ11.92(s,1H),9.62(s,1H),9.39(s,1H),8.42-8.35(m,2H),8.07-7.95(m, 2H),7.68(dd,J=8.0,1.2Hz,1H),7.55-7.34(m,5H),7.25-7.09(m,6H),6.92-6.67(m,2H),6.26(d,J =3.6Hz,1H),4.97-4.93(m,1H),4.37-4.08(m,4H),3.70-3.65(m,2H),3.39(s,3H),3.35-3.31(m,5H ),3.14-2.66(m,4H),2.48-2.30(s,4H),2.02-1.63(m,7H),1.41-1.24(m,9H),0.94(d,J=6.8Hz,6H). LCMS(ESI):R T =1.345 min, measured m / z value is 1027.0 [M-CF3COOH+H] + .

[0347] Compound 046

[0348]

[0349] 2-((4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-2-(trifluoromethyl)benzyl)piperazine-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ12.07(s,1H),9.65(s,1H),9.38(s,1H),8.36(s,1H),8.23-7.95 (m,2H),7.85(d,J=7.6Hz,1H),7.71-7.49(m,4H),7.26-7.16(m,2H),7.01-6.89(m,2H),6 .25(s,1H),4.72-4.54(m,4H),4.13(q,J=6.8Hz,4H),3.67(d,J=10.8Hz,4H),3.36(d,J=2 9.2Hz, 8H), 3.12-2.81 (m, 4H), 1.85 (s, 4H), 1.35 (t, J = 6.8Hz, 3H), 1.04 (d, J = 6.8Hz, 7H). LCMS(ESI):R T=1.320 min, measured m / z value is 962.3 [M-CF3COOH+H] + .

[0350] Compound 047

[0351]

[0352] 2-((4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazine-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)(methyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1 H NMR (400MHz, CD3OD): δ7.96(s,1H),7.79-7.76(m,2H),7.60-7.55(m,3H),7.40( d,J=8.4Hz,2H),7.26-7.21(m,4H),6.89-6.76(m,3H),6.22(s,1H),4.39(m,3H) ,4.08-4.03(m,3H),3.96-3.80(m,4H),3.49-3.43(m,9H),3.11-3.05(m,4H),1. 99-1.91(s,4H),1.32-1.41(m,5H),1.21(t,J=7.6Hz,3H),1.02(d,J=7.6Hz,6H). LCMS(ESI):R T =1.043 min, measured m / z value is 908.5 [M-CF3COOH+H] + .

[0353] Compound 048

[0354]

[0355] 2-((4-(4-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazine-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.89(s,1H),9.57(s,1H),9.32(s,1H),8.31(s,1H),7.86(s,1H),7.78(d,J=8.8H z,1H),7.68-7.65(m,1H),7.51-7.46(m,1H),7.30-7.11(m,6H),6.90(s,1H),6.61(d,J=2.0Hz,1H),6.50-6 .47(m,1H),6.23(s,1H),4.09-4.03(m,2H),3.67-3.64(m,2H),3.53-3.47(m,6H),3.38(s,3H),3.31(s,1H) ,3.28(s,3H),2.73-2.67(m,3H),2.37-2.28(m,4H),1.95(s,3H),1.67-1.71(m,4H),1.29(t,J=7.2Hz,3H). LCMS(ESI):R T = 1.041 min, measured m / z value is 866.3 [M-CF3COOH+H] + .

[0356] Compound 049

[0357]

[0358] 2-((2-ethoxy-4-(4-(4-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazine-1-carbonyl)piperidin-1-yl)phenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.98(s,1H),10.05(s,1H),9.62(d,J=3.2Hz,1H),9.34(d,J=4.0Hz,1H),8. 35(s,1H),8.10-8.18(m,2H),7.70-7.67(m,1H),7.53-7.47(m,3H),7.29-7.10(m,5H),6.98-6.68(m,3 H),6.24(s,1H),4.34(s,1H),4.30(s,2H),4.14-4.08(m,3H),3.70-3.66(m,2H),3.39(s,4H),3.31(s ,4H),3.13-2.90(m,5H),2.45-2.33(m,2H),1.82(s,5H),1.33(t,J=7.6Hz,3H),1.02(t,J=7.8Hz,4H). LCMS(ESI):R T =1.076 min, measured m / z value is 880.3 [M-CF3COOH+H] + .

[0359] Compound 050

[0360]

[0361] 2-((4-(4-(4-(3-(2,4-dihydroxy-5-propylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazine-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.89(s,1H),9.52(s,1H),9.35(s,1H),8.31(s,1H),7.86(s,1H),7.79(d,J=8.8Hz,1H),7. 67(dd,J=7.6,1.6Hz,1H),7.52-7.46(m,1H),7.31-7.10(m,6H),6.79(s,1H),6.61(d,J=2.0Hz,1H),6.49(dd,J=8.8,2 .0Hz,1H),6.25(s,1H),4.11-4.03(m,2H),3.70-3.62(m,2H),3.53(s,2H),3.47(s,3H),3.38(s,3H),3.31-3.25(m,4 H),2.79-2.62(m,3H),2.41-2.25(m,7H),1.72-1.63(m,4H),1.44-1.35(m,2H),1.32-1.26(m,3H),0.80-0.74(m,3H). LCMS(ESI):R T =1.198 min, measured m / z value is 894.9 [M-CF3COOH+H] + .

[0362] Compound 051

[0363]

[0364] (R)-2-((4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)-3-methylpiperazine-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.98(s,1H),9.62(s,1H),9.34(s,1H),8.33(s,1H),8 .05-7.82(m,1H),7.71-7.65(m,1H),7.59-7.43(m,3H),7.33-6.85(m,6H),6.78 -6.54(m,1H),6.25(s,1H),4.13-4.05(m,5H),3.73-3.63(m,4H),3.41-3.27(m, 9H),3.10-2.75(m,7H),1.83-1.66(m,4H),1.52-1.28(m,7H),1.06-0.97(m,7H). LCMS(ESI):R T = 1.042 min, measured m / z value is 908.3 [M-CF3COOH+H] + .

[0365] Compound 052

[0366]

[0367] 2-((2-ethoxy-4-(4-(4-((4-(4-(3-hydroxy-5-(4-hydroxy-5-isopropyl-2-methoxyphenyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)phenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, CD3OD): δ8.23(s,1H),8.10(d,J=8.8Hz,1H),7.75-7.71(m,1H),7.53-7.47(m,1H),7.35(d,J=8.0Hz,2 H),7.25-7.11(m,5H),6.69-6.59(m,2H),6.24(s,1H),5.36-5.31(m,1H),4.60(s,3H),4.57-4.50(m,1H),4.16-4.04 (m,3H),3.67-3.56(m,4H),3.47(s,3H),3.40(s,3H),3.21-3.11(m,3H),2.83-2.72(m,3H),2.63-2.48(m,7H),2.33 -2.26(m,2H),2.21-2.15(m,1H),2.06-1.99(m,1H),1.82-1.78(m,7H),1.43(t,J=6.8Hz,3H),1.16(d,J=6.8Hz,6H). LCMS(ESI):R T = 1.163 min, measured m / z value is 1005.4 [M-CF3COOH+H] + .

[0368] Compound 053

[0369]

[0370] N-(2-((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)oxy)ethyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, hydrochloride. 1H NMR (400MHz, DMSO): δ11.92(s,1H),9.60(s,1H),9.36(d,J=2.4Hz,1H),8.41(d,J=4.8Hz,1H),8.20- 8.13(m,2H),7.70-7.68(m,1H),7.52-7.50(m,1H),7.34-7.14(m,7H),6.85(s,1H),6.25(s,1H),4.4 7(d,J=6.0Hz,2H),4.18-4.13(m,2H),3.64-3.55(m,8H),3.54-3.45(m,3H),3.43(s,3H),3.40(s,3H ),3.31-3.27(m,2H),3.01-2.97(m,1H),2.04-1.92(m,2H),1.38-1.33(m,4H),0.98(d,J=7.6Hz,6H). LCMS(ESI):R T = 1.341 min, measured m / z value is 870.0 [M-HCl+H] + .

[0371] Compound 054

[0372]

[0373] 2-((4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazine-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)(methyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, hydrochloride. 1 H NMR (400MHz, DMSO-d6): δ11.98(s,1H),11.33-10.48(m,1H),9.64(s,1H),9.41(s,1H) ),8.20(s,1H),7.68-7.47(m,5H),7.28-7.14(m,6H),6.89(s,2H),6.28(s,1H),4.48- 4.46(m,1H),4.33-4.30(m,2H),4.20(d,J=3.2Hz,1H),4.06-3.91(m,4H),3.64-3.48 (m,3H),3.34-3.31(m,9H),3.23-2.85(m,5H),1.88-1.80(m,4H),1.09-0.97(m,10H). LCMS(ESI):R T= 1.084 min, measured m / z value is 908.4 [M-HCl+H] + .

[0374] Compound 055

[0375]

[0376] (S)-2-((4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)-3-methylpiperazine-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ11.93(s,1H),9.60(s,1H),9.41(s,1H),8.31(s,1H),7.87-7.13(m,1 1H),6.78-6.48(m,3H),6.27(s,1H),4.07(q,J=6.8Hz,2H),3.92-3.62(m,5H),3.38(s,3H),3.3 3(s,3H),3.28(s,1H),3.10-2.91(m,2H),2.87-2.61(m,3H),2.45-2.32(m,1H),2.15-1.94(m, 1H), 1.77-1.59 (m, 4H), 1.31-1.23 (m, 5H), 1.07 (dd, J = 31.7, 5.4Hz, 2H), 0.95 (d, J = 6.0Hz, 6H). LCMS(ESI):R T =1.060 min, measured m / z value is 908.4 [M-CF3COOH+H] + .

[0377] Compound 056

[0378]

[0379] N-(4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(isopropylcarbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)methyl)benzyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.62(d,J=24Hz,1H),9.79(d,J=15.6Hz,1H),8.76(d,J=8.8Hz,1H),8.40-8.32(m,2H),7.87(s,1H),7.80(d,J=8. 8Hz,1H),7.67(dd,J=7.7,1.6Hz,1H),7.51-7.4(m,1H),7.35-7.14(m,10H),6.63-6.37(m,2H),6.51(dd,J=8.8,1.9Hz,1H),6.35(s,1H),4. 27-4.05(m,5H),3.95-3.86(m,1H),3.68(d,J=12.0Hz,2H),3.38(s,3 H),3.28(s,3H),2.96-2.72(m,3H),2.70-2.59(m,2H),2.58-2.52(m,2 H),2.39-2.27(m,2H),2.04-1.92(m,1H),1.85-1.66(m,5H),1.65-1.5 2(m,3H),1.31-1.23(m,6H),1.11-1.06(m,5H),0.80(d,J=6.9Hz,6H). LCMS(ESI):R T =1.330 min, measured m / z value is 1082.2 [M-CF3COOH+H] + .

[0380] Compound 057

[0381]

[0382] 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((((6-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)pyridin-3-yl)methyl)(methyl)amino)methyl)phenyl)-N-(2,2,2-trifluoroethyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.03(s,1H),9.87-9.64(m,2H),8.64(s,1H),8.36(s,1H),8.12-7.87(m,3H),7.6(dd,J=7.8,1.5H z,1H),7.67-7.40(m,7H),7.27-7.16(m,2H),6.99-6.76(m,2H),6.29(s,1H),4.56-4.36(m,6H),4.12(dd,J=13.7,6.0Hz,3H) ,4.01-3.92(m,4H),3.66(d,J=11.2Hz,2H),3.39(s,3H),3.31(s,3H),3.09-2.86(m,3H),2.81-2.86(m,2H),2.57-2.51(m,3 H),2.11-1.97(m,1H),1.94-1.80(m,4H),1.72-1.55(m,2H),1.34(t,J=6.4Hz,3H),1.26-1.01(m,2H),0.91(d,J=6.6Hz,6H). LCMS(ESI):R T =1.140 min, measured m / z value is 1136.4 [M-CF3COOH+H] + .

[0383] Compound 058

[0384]

[0385] 4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-(2,2,2-trifluoroethyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.67-9.63(m,2H),8.85(s,1H),8.64(s,1H),7.76-7.74(d,J=7.7Hz,1H), 7.60-7.59(d,J=6.9Hz,2H),7.48-7.34(m,6H),6.87-6.68(m,3H),6.31(s,1H),4.42-4.27(m,3H), 4.14-4.10(m,8H),3.69(m,6H),3.46(s,3H),3.09-2.86(m,9H),2.57-2.47(m,2H),2.30-2.24(m,2 H), 2.01 (s, 1H), 1.77-1.71 (m, 6H), 1.19 (t, J = 6.9Hz, 3H), 1.18-0.90 (m, 2H), 0.89 (t, J = 7.4Hz, 3H). LCMS(ESI):R T =1.200 min, measured m / z value is 1149.9 [M-CF3COOH+H] + .

[0386] Compound 059

[0387]

[0388] 2-((4-(4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-2-fluorobenzyl)piperazin-1-yl)piperidine-1-carbonyl)piperidine-1-yl)-2-ethoxyphenyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ12.00(s,1H),9.70(s,1H),9.14(s,1H),8.84(s,1H),8.63(s,1H),7.76- 7.74(m,1H),7.60(m,2H),7.59-7.40(m,3H),7.14-7.11(m,1H),7.02-6.99(m,1H),6.91(s,1H),6. 26(s,1H),4.55-4.52(m,2H),4.05-4.02(m,3H),3.69-3.60(m,8H),3.46-3.41(m,3H),3.16-2.84 (m,9H),2.06(m,2H),1.74(s,3H),1.28-1.17(m,8H),1.20(t,J=6.4Hz,3H),1.01(d,J=6.9Hz,6H). LCMS(ESI):R T =1.210 min, measured m / z value is 1058.9 [M-CF3COOH+H] + .

[0389] Compound 060

[0390]

[0391] 2-((4-(4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-phenyl)piperazin-1-yl)piperidine-1-carbonyl)piperidine-1-yl)-2-ethoxyphenyl)amino)-5-methyl-11-(methanesulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ11.88(s,1H),9.62(m,2H),9.43(s,1H),8.82(s,1H),8.62(s, 1H),7.76-7.74(m,1H),7.59-7.58(m,2H),7.47-7.45(m,2H),7.10-7.00(m,4H),6.78- 6.52(m,2H),6.27(s,1H),4.60-4.50(m,1H),4.25-3.54(m,15H),3.46(s,3H),3.21-2. 75(m,8H),2.15(m,2H),1.73-1.45(m,6H),1.19(t,J=6.4Hz,3H),0.94(d,J=6.9Hz,6H). LCMS(ESI):R T=1.150 min, measured m / z value is 1028.1 [M-CF3COOH+H] + .

[0392] Compound 061

[0393]

[0394] 2-((4-(4-((4-((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ11.97(s,1H),9.62(s,1H),9.43(s,1H),8.88(s,1H),8.64(s, 1H),7.76(d,J=7.8Hz,1H),7.60-7.20(m,8H),6.78-6.68(m,3H),6.26(s,1H),4.43-4. 31(m,1H),4.07-3.99(m,4H),3.90-3.80(s,3H),3.70(s,8H),3.46(s,4H),3.06-2.81( m,11H),2.02-1.90(m,1H),1.88-1.72(m,6H),1.23-1.18(m,4H),0.98(d,J=7.6Hz,7H). LCMS(ESI):R T = 1.043 min, measured m / z value is 1054.9 [M-CF3COOH+H] + .

[0395] Compound 062

[0396]

[0397] N-(2-(2-(2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)-1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.88(s,1H),9.66(s,1H),9.43(s,1H),8.88(s,1H),8.65(s,1H),8.01-7. 96(m,1H),7.76(d,J=7.8Hz,1H),7.60(d,J=3.6Hz,2H),7.48-7.45(m,2H),7.09(d,J=9.2Hz,1H),6. 95-6.72(m,5H),6.26(s,1H),4.08-4.03(m,4H),3.74-3.66(m,9H),3.47-3.40(m,10H),3.23-3.17( m,4H),3.00-2.96(m,2H),2.42-2.33(m,1H),1.82(s,4H),1.23-1.18(m,4H),0.98(d,J=6.8Hz,7H). LCMS(ESI):R T = 1.253 min, measured m / z value is 1006.9 [M-CF3COOH+H] + .

[0398] Compound 063

[0399]

[0400] 4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.39(s,1H),9.71(s,1H),8.76(s,1H),8.60(s,1H),8.28(s,1H),7.74(d,J=7.2Hz ,2H),7.59-7.57(m,2H),7.47-7.43(m,1H),7.35-7.25(m,5H),6.59-6.47(m,3H),6.32(s,1H),4.41-4.37(m, 1H),4.03-3.96(m,3H),3.72-3.63(m,5H),3.49-3.45(m,6H),3.03-2.94(m,1H),2.77-2.70(m,4H),2.39-2. 27(m,7H),2.24-2.08(m,5H),1.78-1.67(m,7H),1.17-1.13(m,3H),1.03-0.95(m,1H),0.83(t,J=7.2Hz,4H). LCMS(ESI):R T = 1.118 min, measured m / z value is 1069.2 [M-CF3COOH+H] + .

[0401] Compound 064

[0402]

[0403] 2-((4-(4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)piperidine-1-carbonyl)piperidine-1-yl)-2-ethoxyphenyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.93(s,1H),9.60(s,1H),9.41(s,1H),8.76(s,1H),8.60(s,1H),7.74(d,J=7.2Hz,1H),7. 64-7.55(m,2H),7.47-7.43(m,1H),7.29-7.24(m,3H),7.12(d,J=8.4Hz,2H),6.77(s,1H),6.59-6.47(m,2H),6.26(s ,1H),4.39(d,J=12.8Hz,1H),4.06-3.97(m,3H),3.70(d,J=11.6Hz,5H),3.44(d,J=12.4Hz,6H),3.34-3.30(m,4H),3 .05-2.93(m,2H),2.82-2.66(m,4H),2.46-2.23(m,4H),1.86-1.58(m,6H),1.38-1.13(m,5H),0.94(d,J=6.8Hz,6H). LCMS(ESI):R T =1.150 min, measured m / z value is 1042.2 [M-CF3COOH+H] + .

[0404] Compound 065

[0405]

[0406] N-(2-(2-(4-((2-carbamoyl-4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)phenoxy)ethoxy)ethyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.12(s,1H),8.37(s,1H),8.20-8.05(m,3H),7.90(d,J=8.4Hz,1H),7.69(dd, J=7.6,1.6Hz,1H),7.64-7.47(m,2H),7.26-7.16(m,4H),7.03-6.93(m,5H),4.55-4.28m,4H),4.16-4.08 (m,5H),3.74(t,J=4.4Hz,2H),3.64(d,J=12.2Hz,2H),3.51(t,J=5.6Hz,2H),3.39(s,3H),3.32(s,3H), 3.26(dd,J=11.4,5.8Hz,2H),2.91(s,2H),2.42(s,3H),1.88(s,3H),1.35(t,J=6.8Hz,3H),1.03(s,6H). LCMS(ESI):R T =1.500 min, measured m / z value is 1030.4 [M-CF3COOH+H] + .

[0407] Compound 066

[0408]

[0409] 5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-((4-(3-(4-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)propoxy)phenyl)amino)benzamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.13(s,1H),8.36(s,1H),8.21(s,1H),8.16-8.07(m,1H),7.91( d,J=8.4Hz,1H),7.70-7.49(m,3H),7.26-7.16(m,4H),7.04-6.94(m,5H),4.41(d,J=16.4Hz ,2H),4.22-3.83(m,18H),3.67(d,J=10.4Hz,3H),3.39(s,3H),3.32(s,3H),2.92(s,3H),2 .43(s,3H),2.15-2.04(m,2H),1.97-1.67(m,8H),1.34(t,J=6.9Hz,3H),1.13-0.93(m,9H). LCMS(ESI):R T =1.180 min, measured m / z value is 1166.5 [M-CF3COOH+H] + .

[0410] Compound 067

[0411]

[0412] N-(2-(2-(4-((2-carbamoyl-4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)phenoxy)ethoxy)ethyl)-1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ11.12(s,1H),8.85(s,1H),8.64(s,1H),8.19(s,1H),8.01(s,1H ),7.91-7.89(m,1H),7.76-7.74(m,1H),7.59-7.58(m,3H),7.49-7.44(m,2H),7.25-7.22( m,2H),7.03-6.93(m,5H),4.10-3.96(m,5H),3.75-3.65(m,8H),3.51-3.46(m,6H),3.28- 3.23(m,2H),2.91(s,3H),2.43(s,3H),1.85-1.72(m,4H),1.21-1.18(m,3H),1.03(s,6H). LCMS(ESI):R T=1.500 min, measured m / z value is 1094.3 [M-CF3COOH+H] + .

[0413] Compound 068

[0414]

[0415] 5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-((4-(3-(4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carbonyl)piperidine-4-yl)methyl)piperazin-1-yl)propoxy)phenyl)amino)benzamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ10.13(s,1H),8.85(s,1H),8.63(s,1H),8.21(s,1H),7.91(d,J=8.5Hz,1H),7 .75(d,J=7.8Hz,1H),7.59(d,J=3.8Hz,3H),7.50-7.43(m,1H),7.25(d,J=8.9Hz,2H),7.04(d,J=2.0Hz ,1H),7.00-6.91(m,3H),4.41(m,2H),4.11-3.95(m,13H),3.70(s,6H),3.46(s,3H),3.11(m,8H),2.92 (s,3H),2.89-2.79(m,2H),2.43(s,2H),2.00(m,4H),1.76(s,6H),1.19(t,J=6.7Hz,3H),1.04(s,6H). LCMS(ESI):R T =1.160 min, measured m / z value is 616.1 [1 / 2M-CF3COOH+H] + .

[0416] Compound 069

[0417]

[0418] 2-((4-(4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-2-(trifluoromethyl)benzyl)piperazin-1-yl)piperidin-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ12.04(s,1H),9.69-9.35(m,3H),8.84(s,1H),8.63(s ,1H),7.75(d,J=7.5Hz,2H),7.62-7.43(m,5H),6.93(s,1H),6.72(m,2H),6.25 (s,1H),4.55(m,1H),4.14-4.02(m,8H),3.70(s,6H),3.46(s,6H),3.15-2.83( m, 9H), 2.10 (s, 2H), 1.76 (s, 4H), 1.19 (t, J = 6.7Hz, 3H), 1.02 (d, J = 6.9Hz, 6H). LCMS(ESI):R T =1.100 min, measured m / z value is 1109.3 [M-CF3COOH+H] + .

[0419] Compound 070

[0420]

[0421] 2-((2-ethoxy-4-(4-(4-((4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)phenyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.94(s,1H),9.62-9.33(m,2H),8.85(s,1H),8.64(s,1H),7.75(d,J =7.6Hz,1H),7.60-7.20(m,8H),6.87(d,J=4.4Hz,1H),6.86-6.64(m,1H),6.24(s,1H),4.44-4. 34(m,4H),4.13-3.98(m,5H),3.72-3.65(m,6H),3.46-3.42(m,5H),3.16-2.81(m,8H),2.43-2 .31(m,4H),1.97-1.93(m,1H),1.78-1.68(m,6H),1.19(d,J=6.8Hz,4H),0.98(d,J=7.6Hz,5H). LCMS(ESI):R T =1.004 min, measured m / z value is 1041.4 [M-CF3COOH+H] + .

[0422] Compound 071

[0423]

[0424] 1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)-N-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.89(s,1H),9.55(s,1H),9.35(d,J=2.4Hz,1H),8.85(s,1H),8.64(s,1H),8.4 5(s,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H),7.48-7.43(m,2H),7.22-7.10(m,4H),6.90(s,1H) ,7.84-6.70(m,1H),6.23(s,1H),4.27(d,J=5.6Hz,2H),4.07-4.00(m,2H),3.84-5.54(m,7H),3.46(s,3H ),3.05-3.78(m,2H),2.45-2.34(m,3H),1.87-1.79(m,4H),1.19(d,J=6.4Hz,3H),1.01(d,J=7.2Hz,3H). LCMS(ESI):R T =1.205 min, measured m / z value is 875.2 [M-CF3COOH+H] + .

[0425] Compound 072

[0426]

[0427] 2-((4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-2-(trifluoromethyl)benzyl)piperazine-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ12.08(s,1H),9.66(s,1H),9.39(s,1H),8.85(s,1H ),8.63(s,1H),7.86-7.74(m,2H),7.60-7.44(s,6H),6.97(s,1H),6.78-6.63 (m,2H),6.25(s,1H),4.08-4.00(m,2H),3.73-3.65(m,7H),3.46-3.36(m,10 H), 3.07-2.73 (m, 5H), 1.76 (s, 4H), 1.23-1.16 (m, 4H), 1.04 (d, J = 7.2Hz, 6H). LCMS(ESI):R T= 1.314 min, measured m / z value is 1025.9 [M-CF3COOH+H] + .

[0428] Compound 073

[0429]

[0430] N-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)-1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ11.87(s,1H),9.57(s,1H),9.33(s,1H),8.84(s,1H),8.63(s,1H),8.48-8 .40(m,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=4.0Hz,2H),7.52-7.39(m,2H),7.23-7.09(m,4H),6.94 (s,1H),6.85-6.60m,2H),6.23(s,1H),4.30-4.24(m,2H),4.10-3.99(m,2H),3.75-3.64(m,6H),3. 46(s,3H),3.02-2.82(m,2H),2.44-2.38(m,1H),1.97(s,3H),1.92-1.74(m,4H),1.22-1.15(m,3H). LCMS(ESI):R T =1.063 min, measured m / z value is 861.7 [M-CF3COOH+H] + .

[0431] Compound 074

[0432]

[0433] N-(4-(3-(2,4-dihydroxy-5-propylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)-1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.88(s,1H),9.60-9.30(m,2H),8.84(s,1H),8.64(s,1H),8.48-8.39 (m,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H),7.50-7.39(m,2H),7.25-7.07(m,5H),6.8 9-6.61(m,3H),6.23(s,1H),4.27(d,J=5.7Hz,2H),4.10-4.00(m,2H),3.70(s,5H),3.46(s,4H) ,2.36-2.29(m,2H),2.04-1.76(m,5H),1.47-1.38(m,2H),1.24-1.16(m,6H),0.82-0.77(m,3H). LCMS(ESI):R T =1.157 min, measured m / z value is 889.6 [M-CF3COOH+H] + .

[0434] Compound 075

[0435]

[0436] N-Cyclopropyl-4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.72(s,1H),9.07(d,J=4.8Hz,1H),8.86(s,1H),8.64(s,1H),7.75(d,J=7.6Hz,1H), 7.62-7.56(m,3H),7.50-7.30(m,6H),6.92-6.60(m,3H),6.30(s,1H),4.44-4.36(m,3H),4.09-3.97(m,7H),3. 73-3.64(m,7H),3.46(s,5H),3.04-2.88(m,6H),2.77-2.65(m,3H),2.61-2.54(m,2H),2.30-2.23(m,2H),2.0 6-1.94(m,1H),1.84-1.69(m,7H),1.26-1.16(m,4H),1.14-0.96(m,2H),0.91-0.85(m,3H),0.67-0.55(m,4H). LCMS(ESI):R T =1.032 min, measured m / z value is 1108.3 [M-CF3COOH+H] + .

[0437] Compound 076

[0438]

[0439] 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)benzyl)(methyl)amino)methyl)phenyl)-N-(2,2,2-trifluoroethyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.03-9.65(m,4H),8.83(s,1H),8.63(s,1H),7.75(d,J=7.2Hz,1H) ,7.64-7.26(m,13H),6.84-6.54(m,3H),6.30(s,1H),4.53-4.44(m,1H),4.38(d,J=14.1Hz,2 H),4.27-4.16(m,3H),4.00-3.94(m,6H),3.69(s,6H),3.46(s,3H),3.03-2.83(m,4H),2.59- 2.55(m,2H),1.83-1.64(m,6H),1.23-1.16(m,5H),1.05-0.97(m,1H),0.91(d,J=6.4Hz,6H). LCMS(ESI):R T =1.200 min, measured m / z value is 600.5 [M / 2-CF3COOH+H] + .

[0440] Compound 077

[0441]

[0442] (R)-N-(1-(4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)methyl)phenyl)ethyl)-1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.92(s,1H),9.61(s,1H),9.47-9.30(m,2H),8.81(s,1H),8.62(s,1H),8.37(d,J=7.6Hz,1H), 7.75(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H),7.48-7.37(m,7H),7.24-7.09(m,4H),6.84-6.51(m,3H),6.26(d,J=3.2Hz,1 H),4.98-4.91(m,1H),4.22(d,J=2.9Hz,2H),4.05-4.01(m,2H),3.71-3.67(m,6H),3.46(s,3H),3.33(d,J=13.3Hz,1H), 3.18-3.07(m,1H),3.00-2.79(m,4H),1.81-1.67(m,8H),1.42-1.34(m,5H),1.17(t,J=6.8Hz,3H),0.94(d,J=6.8Hz,6H). LCMS(ESI):R T =1.140 min, measured m / z value is 1089.8 [M-CF3COOH+H] + .

[0443] Compound 078

[0444]

[0445] 4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-(1,1,1-trifluoroprop-2-yl)-4H-1,2,4-triazol-3-carboxamide, hydrochloride. 1H NMR (400MHz, DMSO-d6): δ9.73-9.61(m,2H),8.85(s,1H),8.64(s,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H ),7.49-7.32(m,6H),6.84-6.63(m,2H),6.30(s,1H),4.68-4.60(m,1H),4.44-4.36(m,2H),4.33-4.14(m,6H),4.0 8-.399(m,4H),3.69(s,5H),3.46(s,3H),3.20-2.77(m,10H),2.61-2.56(m,1H),2.28(q,J=7.6Hz,2H),2.08-1.95 (m,1H),1.85-1.67(m,6H),1.34(d,J=7.0Hz,3H),1.19(t,J=6.8Hz,3H),1.14-0.98(m,2H),0.90(t,J=7.5Hz,3H). LCMS(ESI):R T =1.100 min, measured m / z value is 1164.3 [M-HCl+H] + .

[0446] Compound 079

[0447]

[0448] 1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)-N-((1-(1-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperidine-4-carbonyl)piperidine-4-yl)methyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.97(s,1H),9.60(s,1H),9.46(s,1H),9.32(s,1H),8.80(s,1H),8.6 2(s,1H),7.89(s,1H),7.75(d,J=8.0Hz,1H),7.60-7.44(m,4H),7.38-7.16(m,3H),6.91(s,1H), 6.67(s,2H),6.23(s,1H),4.30(m,3H),4.07-4.00(m,2H),3.70(m,7H),3.46(s,3H),3.28(m,4H) ,2.93(s,7H),2.37(m,7.3Hz,3H),1.87-1.56(m,10H),1.29-1.08(m,5H),1.01(t,J=7.5Hz,3H). LCMS(ESI):R T =1.000 min, measured m / z value is 1083.3 [M-CF3COOH+H] + .

[0449] Compound 080

[0450]

[0451] N-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)-1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ11.90(s,1H),9.58-9.36(m,2H),8.86(s,1H),8.64(s,1H),8.46 (s,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H),7.48-7.44(m,2H),7.24-7.11(m,4H ),6.88-6.69(m,3H),6.24(s,1H),4.28(d,J=5.6Hz,2H),4.23-3.97(m,5H),3.70(s,4H), 3.46(s,3H),3.03-2.96(m,2H),1.88(s,4H),1.20(t,J=6.8Hz,3H),1.01(d,J=6.8Hz,7H). LCMS(ESI):R T=1.225 min, measured m / z value is 889.2 [M-CF3COOH+H] + .

[0452] Compound 081

[0453]

[0454] 5-(2,4-dihydroxy-5-methylphenyl)-4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-N-(2,2,2-trifluoroethyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ9.93-9.50(m,3H),8.86(s,1H),8.64(s,1H),7.76(d,J=7.6Hz,1 H),7.59(d,J=3.6Hz,2H),7.52-7.32(m,6H),6.97-6.59(m,3H),6.29(s,1H),4.49-4.36( m,6H),4.05-3.93(m,6H),3.70(s,5H),3.46(s,3H),3.14-2.83(m,8H),2.06-1.96(m,1H) ,1.87(s,3H),1.84-1.71(m,6H),1.25-1.10(m,6H),1.05-0.95(m,1H),0.85-0.71(m,1H). LCMS(ESI):R T =1.060 min, measured m / z value is 1136.3 [M-CF3COOH+H] + .

[0455] Compound 082

[0456]

[0457] 2-((2-ethoxy-4-(4-(4-((4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-2-fluorobenzyl)piperazin-1-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)phenyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1HNMR (400MHz, DMSO-d6): δ11.96(s,1H),9.59(s,1H),9.37(s,1H),8.74(s,1H),8.60(s,1H),7.74(d,J=7.2Hz,1H),7 .58(d,J=3.2Hz,2H),7.47-7.25(s,3H),7.05-6.89(m,3H),6.59-6.47(m,2H),6.25(s,1H),4.38-4.29(m,1H),4.03- 3.96(m,3H),3.68-3.65(m,5H),3.47-3.45(m,6H),3.08-2.96(m,1H),2.81-2.66(m,3H),2.65-2.55(m,3H),2.40-2. 32(m,8H),2.10(d,J=6.8Hz,2H),1.75-1.66(m,7H),1.15(t,J=7.2Hz,3H),1.01(t,J=7.6Hz,4H),0.96-0.85(m,1H). LCMS(ESI):R T =1.000 min, measured m / z value is 1059.3 [M-CF3COOH+H] + .

[0458] Compound 083

[0459]

[0460] 4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carbonyl)piperidine-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.72(s,1H),9.14(s,1H),8.83(s,1H),8.63(s,1H),7.75(d,J=8.0Hz,2H),7.62- 7.30(m,10H),6.81-6.62(m,3H),6.30(s,1H),4.47-4.45(m,2H),4.13-4.01(m,5H),3.69(s,7H),3.50-3. 42(m,7H),3.14-3.06(m,3H),2.96-2.80(m,2H),2.29-2.23(s,2H),2.11-1.98(m,1H),1.85-1.70(m,8H), 1.25-1.23(m,3H),1.19-1.13(m,3H),1.03-0.98(m,1H),0.87(t,J=7.2Hz,4H),0.67(s,2H),0.53(s,2H). LCMS(ESI):R T =1.058 min, measured m / z value is 1122.3 [M-CF3COOH+H] + .

[0461] Compound 084

[0462]

[0463] 4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-(pent-3-yl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.72(s,1H),8.85(s,1H),8.66-8.63(m,2H),7.75(d,J=8.0Hz,1H),7.59(d,J=3.6Hz,2 H),7.48-7.31(m,6H),6.81-6.55(m,3H),6.31(s,1H),4.42-4.40(m,2H),4.33-4.25(m,4H),4.17-4.00(m,6H),3 .69(s,5H),3.57-3.55(m,1H),3.46(s,5H),3.06-2.87(m,9H),2.30-2.24(m,2H),2.05-1.96(m,1H),1.88-1.76( m,6H),1.46-1.40(m,4H),1.21(t,J=6.8Hz,3H),1.15-0.97(m,2H),0.90(t,J=7.6Hz,3H),0.79(t,J=6.8Hz,6H). LCMS(ESI):R T =1.099 min, measured m / z value is 1138.4 [M-CF3COOH+H] + .

[0464] Compound 085

[0465]

[0466] 2-((4-(4-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazine-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.96(s,1H),9.94(s,1H),9.61(s,1H),9.30(s,1H),8.78(s,1H),8 .61(s,1H),7.75(d,J=7.6Hz,1H),7.61-7.43(m,5H),7.37-7.25(m,3H),6.97(s,1H),6.71-6. 51(m,2H),6.23(s,1H),4.54-4.19(m,4H),4.10-3.97(m,4H),3.74-3.66(m,7H),3.46(s,4H) ,3.37-3.26(m,2H),3.12-2.78(m,5H),1.98(s,3H),1.80-1.65(m,4H),1.17(t,J=6.8Hz,3H). LCMS(ESI):R T =1.000min, measured m / z value is 930.3[M-CF3COOH+H] + .

[0467] Compound 086

[0468]

[0469] 2-((2-ethoxy-4-(4-(4-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazine-1-carbonyl)piperidin-1-yl)phenyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ11.90(s,1H),9.55(s,1H),9.35(s,1H),8.74(s,1H),8.60(s,1H), 7.74(d,J=7.6Hz,1H),7.62-7.54(m,2H),7.48-7.41(m,1H),7.33-7.11(m,5H),6.83(s,1H), 6.62-6.45(m,2H),6.25(s,1H),4.08-3.95(m,2H),3.74-3.62(m,5H),3.56-3.44(m,9H),2. 82-2.68(m,3H),2.41-2.27(m,6H),1.72-1.63(m,4H),1.17-1.12(m,3H),1.00-0.94(m,3H). LCMS(ESI):R T=1.036 min, measured m / z value is 944.2 [M-CF3COOH+H] + .

[0470] Compound 087

[0471]

[0472] 2-((4-(4-(4-(3-(2,4-dihydroxy-5-propylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazine-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ11.89(s,1H),9.54-9.33(m,2H),8.76-8.58(m,2H),7.74(d,J=7. 6Hz,1H),7.61-7.42(m,3H),7.31-7.10(m,5H),6.79(s,1H),6.62-6.46(m,2H),6.25(s,1H ),4.08-3.96(m,2H),3.75-3.64(m,5H),3.57-3.44(m,9H),2.82-2.66(m,3H),2.42-2.27( m, 6H), 1.73-1.62 (m, 4H), 1.43-1.33 (m, 2H), 1.15 (t, J = 6.8Hz, 3H), 0.77 (t, J = 7.2Hz, 3H). LCMS(ESI):R T =1.069 min, measured m / z value is 958.3 [M-CF3COOH+H] + .

[0473] Compound 088

[0474]

[0475] 1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)-N-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-2-fluorobenzyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.96(s,1H),9.59(s,1H),9.39(s,1H),8.85(s,1H),8.64(s,1H),8.44(s,1H),7.75 (d,J=7.6Hz,1H),7.59(d,J=4.0Hz,2H),7.48-7.44(m,2H),7.25(t,J=8.4Hz,1H),7.06(dd,J=10.8,1.5Hz,1H) ,6.99-6.92(m,2H),6.91-6.66(m,2H),6.25(s,1H),4.30(d,J=5.4Hz,2H),4.09-4.01(m,3H),3.70(s,4H),3. 46(s,3H),2.97(s,2H),2.40(q,J=7.6Hz,3H),1.94-1.74(m,4H),1.20(t,J=6.7Hz,3H),1.04(t,J=7.6Hz,3H). LCMS(ESI):R T =1.290 min, measured m / z value is 892.8 [M-CF3COOH+H] + .

[0476] Compound 089

[0477]

[0478] 1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)-N-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ12.02(s,1H),9.60(s,1H),9.38(s,1H),8.86(s,1H),8.64(s,1H) ,8.54(s,1H),7.76(d,J=7.6Hz,1H),7.63-7.39(m,7H),7.01(s,1H),6.96-6.64(m,2H),6.2 4(s,1H),4.44(d,J=5.2Hz,2H),4.08-4.03(m,3H),3.70(s,5H),3.47(s,3H),3.17-2.85(m, 2H), 2.41 (q, J = 7.6Hz, 2H), 2.00-1.75 (m, 4H), 1.20 (t, J = 6.8Hz, 3H), 1.05 (t, J = 7.6Hz, 3H). LCMS(ESI):R T =1.370 min, measured m / z value is 942.7 [M-CF3COOH+H] + .

[0479] Compound 090

[0480]

[0481] 2-((4-(4-((4-((4-(3-(2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.89(s,1H),9.59(d,J=24.4Hz,2H),8.67(d,J=56.0Hz,2H),7.74(d,J=7.6Hz,1H),7.63-7 .54(m,2H),7.50-7.41(m,1H),7.32-7.18(m,3H),7.15-6.97(m,3H),6.64-6.43(m,2H),6.30-6.11(m,2H),4.37(d,J= 12.7Hz,1H),4.08-3.92(m,3H),3.80-3.59(m,5H),3.43(d,J=14.0Hz,5H),3.37-3.34(m,2H),3.11-2.94(m,1H),2.8 4-2.64(m,3H),2.44-2.24(m,7H),2.11(d,J=6.8Hz,2H),1.82-1.57(m,7H),1.15(t,J=6.8Hz,3H),1.06-0.79(m,2H). LCMS(ESI):R T =1.040 min, measured m / z value is 1012.8 [M-CF3COOH+H] + .

[0482] Compound 091

[0483]

[0484] 1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)-N-(2-(2-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)phenoxy)ethoxy)ethyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.84(s,1H),9.57-9.33(m,2H),8.85(s,1H),8.64(s,1H),7.98(s,1H) ,7.75(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H),7.48-7.44(m,2H),7.08(d,J=7.2Hz,2H),6.93-6. 68(m,5H),6.25(s,1H),4.16-3.99(m,5H),3.77-3.66(m,7H),3.50-3.41(m,5H),3.25-3.22(m,2 H),3.04-2.88(m,2H),2.38-2.32(m,3H),1.78(s,4H),1.24-1.17(m,3H),1.00(d,J=7.2Hz,3H). LCMS(ESI):R T =1.223 min, measured m / z value is 948.8 [M-CF3COOH+H] + .

[0485] Compound 092

[0486]

[0487] N-(4-(3-(2,4-dihydroxyphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)-1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ11.89(s,1H),9.62-9.58(m,2H),8.83(d,J=4.8Hz,1H),8.63(s,1H) ,8.42(d,J=3.6Hz,1H),7.75(d,J=8.0Hz,1H),7.59(d,J=4.0Hz,2H),7.48-7.43(m,2H),7.21 -7.03(m,5H),6.87-6.55(m,1H),6.24-6.16(m,2H),4.27(d,J=6.0Hz,2H),4.08-4.00(m,2H) ,3.95-3.55(m,8H),3.46(s,3H),3.12-2.64(m,2H),1.86-1.77(m,4H),1.19(d,J=6.8Hz,3H). LCMS(ESI):R T=1.108 min, measured m / z value is 847.2 [M-CF3COOH+H] + .

[0488] Compound 093

[0489]

[0490] 5-(2,4-dihydroxy-5-propylphenyl)-4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-N-(2-(piperidin-1-yl)ethyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ9.25(s,1H),9.28-9.21(m,1H),9.08(s,1H),8.84(s,1H),8.63(s,1H),7.75(d,J=7.6Hz, 1H),7.59(d,J=4.0Hz,2H),7.47-7.30(m,6H),6.72-6.65(m,2H),6.30(s,1H),4.44-4.33(m,3H),4.07-4.02(m,4H) ,3.69(s,6H),3.56-3.49(m,5H),3.46(s,4H),3.20(d,J=5.2Hz,2H),3.06-2.83(m,12H),2.61-2.53(m,1H),2.24(t ,J=7.2Hz,2H),2.11-1.92(m,1H),1.83-1.55(m,12H),1.35-1.29(m,1H),1.20-0.99(m,5H),0.74(t,J=7.2Hz,6H). LCMS(ESI):R T =0.936 min, measured m / z value is 597.6 [M / 2-CF3COOH+H] + .

[0491] Compound 094

[0492]

[0493] 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-((4-(2-(4-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carbonyl)piperazin-1-yl)ethoxy)phenyl)amino)benzamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ10.16(s,2H),8.82(s,1H),8.63(s,1H),8.21(s,1H),7.91(d,J=8.4Hz,1H),7.75(d,J=7.6Hz ,1H),7.65-7.56(m,3H),7.51-7.36(m,2H),7.29(d,J=8.8Hz,2H),7.09-7.02(m,3H),6.99-6.94(m,1H),6.80-6.56(m 2H),4.58-4.43(m,1H),4.41-4.34(m,2H),4.09-4.02(m,5H),3.75-3.67(m,6H),3.64-3.56(m,4H), 3.46(s,4H),2.98-2.86(m,5H),2.43(s,2H),1.84-1.70(m,4H),1.19(t,J=6.8Hz,3H),1.04(s,6H). LCMS(ESI):R T = 1.276 min, measured m / z value is 1118.8 [M-CF3COOH+H] + .

[0494] Compound 095

[0495]

[0496] (1R,4R)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl(3-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbamate)propyl)carbamate, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ8.85(s,1H),8.64(s,1H),8.43(s,1H),7.99(s,1H),7.86(s,1H),7 .81-7.73(m,2H),7.59(d,J=4.0Hz,2H),7.50-7.35(m,2H),7.10-6.70(m,5H),4.57-4.48(m ,1H),4.09-4.02(m,3H),3.73-3.63(m,7H),3.49-3.42(m,4H),3.09-3.03(m,2H),3.00-2.9 5(m,4H),2.45(s,2H),2.36-2.31(m,1H),2.06-1.78(m,8H),1.54-1.19(m,9H),1.03(s,6H). LCMS(ESI):R T =1.509 min, measured m / z value is 1112.9 [M-CF3COOH+H] + .

[0497] Compound 096

[0498]

[0499] 4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-N-ethyl-5-(5-ethyl-2,4-dihydroxyphenyl)-4H-1,2,4-triazol-3-carboxamide, hydrochloride. 1H NMR (400MHz, DMSO-d6): δ10.39(s,1H),9.73(s,1H),8.99-8.93(m,1H),8.75(s,1H),8.60(s,1H),7.74(d,J=7.6Hz,1H),7 .58(d,J=3.6Hz,2H),7.45-7.25(m,8H),6.60-6.47(m,3H),6.32(s,1H),5.05-5.01(m,1H),4.42-4.33(m,1H),4.05-3.96 (m,3H),3.71-3.60(m,6H),3.49(s,2H),3.45(s,3H),3.19-3.15(m,2H),3.05-2.99(m,1H),2.79-2.71(m,3H),2.42-2.31 (m,7H),2.24-2.11(m,4H),2.03-1.95(m,1H),1.77-1.66(m,6H),1.28-1.14(m,8H),1.07-1.01(m,4H),0.86-0.81(m,4H). LCMS(ESI):R T = 1.134 min, measured m / z value is 1095.8 [M-HCl+H] + .

[0500] Compound 097

[0501]

[0502] 4-(4-(((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)benzyl)(methyl)amino)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-(2,2,2-trifluoroethyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.03-9.65(m,3H),8.88(s,1H),8.65(s,1H),7.76(d,J=7.6Hz ,1H),7.76-7.29(m,12H),6.96-6.72(m,3H),6.29(s,1H),4.52-4.18(m,5H),4.11-3.92 (m,5H),3.76-3.67(m,5H),3.47(s,4H),3.16-2.79(m,4H),2.61-2.55(m,4H),2.29(q,J =7.4Hz,2H),1.91-1.71(m,5H),1.70-1.53(m,2H),1.32-1.08(m,5H),1.04-0.90(m,4H). LCMS(ESI):R T =1.255 min, measured m / z value is 1184.7 [M-CF3COOH+H] + .

[0503] Compound 098

[0504]

[0505] 4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-isopropyl-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.34(d,J=20.0Hz,1H),9.73(s,1H),8.77(d,J=11.6Hz,2H),8.60(s,1H),7.74(d,J=8.0Hz, 1H),7.59-7.24(m,8H),6.59-6.47(m,3H),6.32(s,1H),4.38(d,J=12.0Hz,1H),4.19(q,J=6.8Hz,1H),4.07-3.87(m,4H ),3.69(d,J=10.0Hz,5H),3.53-3.47(m,2H),3.45(s,4H),3.10-2.95(m,1H),2.81-2.68(m,3H),2.43-2.28(m,6H),2.2 2(q,J=7.4Hz,2H),2.12(d,J=6.8Hz,2H),2.04-1.94(m,1H),1.81-1.62(m,7H),1.23-1.07(m,10H),0.89-0.80(m,4H). LCMS(ESI):R T =1.155 min, measured m / z value is 1109.8 [M-CF3COOH+H] + .

[0506] Compound 099

[0507]

[0508] 2-((4-(4-((4-((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)(ethyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.95(s,1H),9.62(s,1H),9.38(s,1H),8.79-8.37(m,1H),7.20(s,1H),7.5 6-7.35(m,4H),7.21(d,J=8.8Hz,2H),7.13-6.97(m,1H),6.82(s,1H),6.73-6.47(m,2H),6.26(s,1H) ,4.43-4.36(m,1H),4.09-3.93(m,12H),3.68-3.64(m,3H),3.44(s,4H),3.21(s,3H),3.09-2.83(m,9 H), 2.63-2.54 (m, 2H), 2.06-1.89 (m, 1H), 1.82-1.61 (m, 6H), 1.19-1.04 (m, 6H), 0.98 (d, J = 6.8Hz, 7H). LCMS(ESI):R T = 5.067 min, measured m / z value is 1083.3 [M-CF3COOH+H] + .

[0509] Compound 100

[0510]

[0511] 5-(2,4-dihydroxy-5-methylphenyl)-4-(4-(((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)benzyl)(methyl)amino)methyl)phenyl)-N-(2,2,2-trifluoroethyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.04(s,1H),9.70-9.58(m,2H),8.74(s,1H),8.60(s,1H),7.74(d,J=7.6 Hz,1H),7.59-7.13(m,13H),6.65-6.46(m,3H),6.30(s,1H),5.45-5.11(m,1H),4.46-4.36(m,1H), 4.00-3.93(m,5H),3.71-3.61(m,4H),3.68(s,2H),3.51-3.45(m,4H),2.99-2.92(m,1H),2.75-2.6 7(m,3H),2.07-1.97(m,4H),1.80-1.52(m,10H),1.24(s,3H),1.19-1.13(m,3H),0.97-0.83(m,2H). LCMS(ESI):R T =1.245 min, measured m / z value is 1172.1 [M-CF3COOH+H] + .

[0512] Compound 101

[0513]

[0514] 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-((4-(2-(4-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carbonyl)piperazin-1-yl)ethoxy)phenyl)amino)benzamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ10.16(s,1H),8.38(s,1H),8.27-8.20(m,2H),8.12-8.04(m,1 H),7.92(d,J=8.8Hz,1H),7.71-7.50(m,3H),7.31-6.96(m,10H),4.37(s,2H),4.17-4. 11(m,3H),3.86-3.76(m,7H),3.65-3.55(m,6H),3.40(s,3H),3.33(s,3H),3.22-3.11( m,2H),3.00-2.94(m,3H),2.43(s,2H),1.89(s,3H),1.35(t,J=6.8Hz,3H),1.04(s,6H). LCMS(ESI):RT = 1.302 min, measured m / z value is 1154.8 [M-CF3COOH+H] + .

[0515] Compound 102

[0516]

[0517] (1R,4R)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl(3-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbamate)propyl)carbamate, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ8.39(s,2H),8.22-7.96(m,4H),7.81-7.68(m,2H),7.54-7. 50(m,1H),7.37-7.07(m,6H),6.90(s,1H),6.75-6.72(m,1H),4.53(s,1H),4.18-4.1 2(m,2H),3.69-3.65(m,3H),3.58-3.40(m,5H),3.34-3.24(m,5H),3.11-2.98(m,6H) ,2.45(s,3H),2.06-1.93(m,7H),1.57-1.48(m,4H),1.38-1.23(m,5H),1.04(s,6H). LCMS(ESI):R T = 1.519 min, measured m / z value is 1048.9 [M-CF3COOH+H] + .

[0518] Compound 103

[0519]

[0520] (1R,4R)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl(2-(2-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbamate)ethoxy)ethyl)carbamate, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ8.54-8.33(m,2H),8.24-7.96(m,4H),7.83-7.67(m,2H),7. 55-6.87(m,8H),6.76-6.69(m,1H),4.59-4.49(m,1H),4.18-4.09(m,2H),3.67(s,3H ),3.44-3.38(m,8H),3.32(s,3H),3.27-3.20(m,3H),3.17-3.09(m,3H),2.97(s,2H) ,2.44(s,3H),2.08-1.87(m,8H),1.56-1.43(m,2H),1.38-1.21(m,7H),1.03(s,6H). LCMS(ESI):R T =1.506 min, measured m / z value is 1078.8 [M-CF3COOH+H] + .

[0521] Compound 104

[0522]

[0523] (1R,4R)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl4-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carbonyl)piperazine-1-carboxylic acid ester, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ8.36-8.34(m,2H),8.29-7.96(m,3H),7.85-7.67(m,2H),7. 56-7.48(m,1H),7.37(s,1H),7.29-7.17(m,2H),7.15-6.95(m,2H),6.89(d,J=2.0Hz 1H),6.74(dd,J=8.4,1.6Hz,1H),4.68-4.58(m,1H),4.20-4.12(m,2H),3.68(s,4H),3.52-3.48(m,5H),3.46-3.43(m,2H),3. 41-3.37(m,5H),3.33(s,4H),2.99(s,3H),2.45(s,2H),2.06-1.88(m,8H),1.61-1.51(m,2H),1.42-1.33(m,5H),1.04(s,6H). LCMS(ESI):R T =1.594 min, measured m / z value is 1060.9 [M-CF3COOH+H] + .

[0524] Compound 105

[0525]

[0526] (1R,4R)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl(2-(2-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carbamate)ethoxy)ethyl)carbamate, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ8.83(s,1H),8.64(s,1H),8.43(s,1H),8.05-7.89(m,2H),7.82- 7.72(m,2H),7.59(d,J=3.6Hz,2H),7.52-7.31(m,3H),7.11-7.04(m,1H),6.95-6.67(m,4H ),4.58-4.49(m,1H),4.10-4.01(m,3H),3.72-3.65(m,6H),3.48-3.37(m,9H),3.25-3.09( m,4H),3.03-2.85(m,4H),2.44(s,3H),2.08-1.79(m,8H),1.55-1.17(m,8H),1.03(s,6H). LCMS(ESI):R T =1.508 min, measured m / z value is 1142.9 [M-CF3COOH+H] + .

[0527] Compound 106

[0528]

[0529] (1R,4R)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl4-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carbonyl)piperazine-1-carboxylic acid ester, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ8.89(s,1H),8.66(s,1H),8.49(s,1H),8.00(s,1H),7.81-7.75(m,2H) ,7.60-7.31(m,5H),6.95-6.73(m,4H),4.65-4.60(m,1H),4.10-4.04(m,3H),3.69(d,J=8.8Hz,4 H),3.60-3.33(m,13H),3.25-3.09(m,1H),3.02-2.87(m,3H),2.45(s,2H),2.07-1.78(m,8H),1 .56(dd,J=20.6,10.3Hz,2H), 1.37(dd,J=21.2,10.7Hz,2H), 1.22(t,J=6.8Hz,3H), 1.04(s,6H). LCMS(ESI):R T =1.590 min, measured m / z value is 1124.9 [M-CF3COOH+H] + .

[0530] Compound 107

[0531]

[0532] 4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-(1,1,1-trifluoroprop-2-yl)-4H-1,2,4-triazol-3-carboxamide, hydrochloride. 1 H NMR (400MHz, DMSO-d6): δ11.58(s,1H),9.80(s,1H),9.66(d,J=9.0Hz,1H),9.09(s,1H ),8.72(s,1H),7.99-7.27(m,12H),6.80(s,1H),6.37(s,1H),4.66(m,1H),4.40(m,2H ),4.17-4.12(m,4H),3.72(s,7H),3.60(s,4H),3.48(s,5H),3.11(s,4H),2.61(t,J=1 1.6Hz,1H),2.20(m,10H),1.40-1.24(m,6H),1.22-1.03(m,2H),0.95(t,J=7.5Hz,3H). LCMS(ESI):RT =1.140 min, measured m / z value is 1164.3 [M-HCl+H] + .

[0533] Compound 108

[0534]

[0535] 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-((4-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperidin-4-yl)methoxy)phenyl)amino)benzamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ10.10(s,1H),8.40(s,1H),8.30-8.11(m,3H),7.91(d,J=8.4Hz,1H),7.71-7.5 0(m,3H),7.27-6.93(m,10H),4.47(d,J=12.4Hz,1H),4.17(q,J=6.8Hz,2H),4.04(d,J=12.4Hz,1H),3.8 6(d,J=6.0Hz,2H),3.70-3.64(m,2H),3.40(s,3H),3.34(s,3H),3.16-2.02(m,2H),2.91(s,2H),2.69-2 .56(m,1H),2.52-2.43(m,4H),2.08-1.79(m,7H),1.38(t,J=6.8Hz,3H),1.29-1.14(m,2H),1.04(s,6H). LCMS(ESI):R T =1.493 min, measured m / z value is 1040.5 [M-CF3COOH+H] + .

[0536] Compound 109

[0537]

[0538] (1R,4R)-4-((2-cyano-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl(2-(2-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbamate)ethoxy)ethyl)carbamate, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ8.37(s,1H),8.17-8.01(m,3H),7.69(dd,J=7.9,2.0Hz,2H),7.54-7.49(m,1 H),7.26-6.86(m,7H),6.18(d,J=7.6Hz,1H),4.52-4.43(m,1H),4.14(q,J=6.8Hz,2H),3.67-3.64(m, 3H),3.42-3.39(m,6H),3.33(s,3H),3.23(dd,J=11.2,5.6Hz,3H),3.14(dd,J=11.6,6.0Hz,2H),2.98 (s,2H),2.55-2.38(m,5H),2.08-1.80(m,8H),1.59-1.41(m,4H),1.35(t,J=6.8Hz,3H),1.03(s,6H). LCMS(ESI):R T =1.458 min, measured m / z value is 1061.5 [M-CF3COOH+H] + .

[0539] Compound 110

[0540]

[0541] 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carbonyl)piperidine-4-yl)methoxy)phenyl)amino)benzamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.09(s,1H),8.92(s,1H),8.67(s,1H),8.20(s,1H),7.90(d,J=8.4Hz,1 H),7.76(d,J=7.6Hz,1H),7.61-7.45(m,5H),7.23(d,J=8.8Hz,2H),7.03-6.83(m,6H),4.48-4.44 (m,1H),4.12-4.01(m,3H),3.86(d,J=6.0Hz,2H),3.71-3.64(m,5H),3.30-3.08(m,2H),2.96-2.9 0(m,3H),2.64-2.57(m,1H),2.51-2.43(m,5H),2.08-1.84(m,8H),1.27-1.15(m,6H),1.03(s,6H). LCMS(ESI):R T =1.497 min, measured m / z value is 1104.4 [M-CF3COOH+H] + .

[0542] Compound 111

[0543]

[0544] (1R,4R)-4-((2-((l2-azine)-l3-methyl)-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl(2-(2-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbamate)ethoxy)ethyl)carbamate, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ8.86 (s, 1H), 8.64 (s, 1H), 7.97 (d, J = 5.2Hz, 1H), 7.77-7.44 (m,6H),7.10-6.86(m,5H),6.18(s,1H),4.47(s,1H),4.08-4.01(m,2H),3.70-3.63(m ,6H),3.41-3.40(m,4H),3.29-3.20(m,2H),3.15-3.11(m,2H),3.02-2.98(m,4H),2.5 1-2.34(m,6H),2.08-1.83(m,8H),1.52-1.43(m,4H),1.24-1.18(m,4H),1.03(s,6H). LCMS(ESI):R T =1.492 min, measured m / z value is 1125.5 [M-CF3COOH+H] + .

[0545] Compound 112

[0546]

[0547] 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-((4-((1-(1-(3-ethoxy-4-(ethyl(5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carbonyl)piperidine-4-yl)methoxy)phenyl)amino)benzamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ10.10(s,1H),8.86(s,1H),8.19(s,1H),7.90(d,J=8.4Hz,1H),7.71 -7.41(m,5H),7.23(d,J=8.8Hz,2H),7.03-6.93(m,5H),6.62-6.45(m,2H),4.44(s,1H),4.06- 3.74(m,11H),3.45-3.40(m,3H),3.22(s,2H),3.12-3.00(m,1H),2.90-2.73(m,5H),2.59-2. 50(m,1H),2.43(s,2H),2.03-1.95(m,1H),1.86-1.68(m,6H),1.23-1.10(m,8H),1.08(s,6H). LCMS(ESI):R T= 1.907 min, measured m / z value is 1132.3 [M-CF3COOH+H] + .

[0548] Compound 113

[0549]

[0550] (1R,4R)-4-((2-((l2-azine)-l3-methyl)-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl(2-(2-(1-(3-ethoxy-4-(ethyl(5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbamate)ethoxy)ethyl)carbamate, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ8.65(s,1H),8.45(s,1H),7.88-7.87(m,1H),7.71-7.68(m,3H),7 .48-7.42(m,3H),7.08-6.87(m,4H),6.62-6.60(m,2H),6.19-6.17(m,1H),4.48-4.46(m,1 H),4.00-3.71(m,6H),3.53-3.38(m,8H),3.22-2.98(m,8H),2.72-2.70(m,2H),2.44(s,2H ),2.33-2.32(m,1H),1.96-1.95(m,4H),1.71-1.44(m,9H),1.23-1.08(m,5H),1.02(s,6H). LCMS(ESI):R T =1.860 min, measured m / z value is 1153.3 [M-CF3COOH+H] + .

[0551] Compound 114

[0552]

[0553] 4-(4-((4-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-(1,1,1-trifluoroprop-2-yl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ10.21(s,1H),9.70(s,1H),9.58-9.56(m,1H),8.31(s,1H),7.86(s,1H),7.80-7.78(m,1H),7.68- 7.66(m,1H),7.51-7.47(m,1H),7.34-7.14(m,6H),6.61(s,2H),6.51-6.48(m,1H),6.31(s,1H),4.66-4.64(m,1H),4.39-4. 36(m,1H),4.10-3.95(m,3H),3.67-3.64(m,2H),3.48(s,2H),3.38(s,3H),3.30-3.28(m,5H),3.02-2.98(m,1H),2.87-2.6 8(m,3H),2.38-2.33(m,6H),2.25-2.21(m,2H),2.12-2.11(m,2H),1.77-1.68(m,7H),1.33-1.28(m,7H),0.88-0.84(m,5H). LCMS(ESI):R T =1.140 min, measured m / z value is 1100.3 [M-CF3COOH+H] + .

[0554] Compound 115

[0555]

[0556] 4-(4-((4-((1-(1-(3-ethoxy-4-(ethyl(5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-(1,1,1-trifluoroprop-2-yl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.20(s,1H),9.70(s,1H),9.58-9.56(m,1H),8.66(s,1H),7.72-7.68(m,2H),7 .49-7.41(m,3H),7.32-7.25(m,4H),7.05-6.98(m,1H),6.62-6.59(m,3H),6.31(s,1H),4.66-4.64(m,1H) ,4.37-4.36(m,1H),3.97-3.75(m,9H),3.48-3.41(m,6H),3.30-3.22(m,2H),3.05-2.95(m,1H),2.82-2. 76(m,3H),2.45-2.38(m,5H),2.27-2.21(m,5H),1.77-1.71(m,8H),1.14-1.07(m,5H),0.88-0.73(m,5H). LCMS(ESI):R T =1.229 min, measured m / z value is 1190.1 [M-CF3COOH-H] - .

[0557] Compound 116

[0558]

[0559] (1R,4R)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl(2-(2-(2-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carbamate)ethoxy)ethoxy)ethyl)carbamate, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ8.76(s,1H),8.60(s,1H),8.43(d,J=7.2Hz,1H),8.07-7.70(m,4H),7.62-7.54(m,2H),7.48-7.22(m,3H),7.13-7.06(m ,1H),6.89(d,J=1.6Hz,1H),6.73(dd,J=8.4,1.6Hz,1H),6.59(d,J=2.0H z,1H),6.51-6.45(m,1H),4.58-4.48(m,1H),4.07-3.94(m,2H),3.75-3. 63(m,5H),3.50(s,4H),3.45(s,3H),3.42-3.38(m,4H),3.32-3.30(m,1 H),3.25-3.17(m,2H),3.14-3.08(m,2H),2.98(s,2H),2.69-2.59(m,2H) ,2.44(s,2H),2.34-2.22(m,1H),2.07-1.87(m,4H),1.78-1.60(m,4H),1 .54-1.43(m,2H),1.38-1.25(m,2H),1.15(t,J=6.8Hz,3H),1.03(s,6H). LCMS(ESI):R T =1.415 min, measured m / z value is 1187.0 [M-CF3COOH+H] + .

[0560] Compound 117

[0561]

[0562] (1R,4R)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carbonyl)piperidine-4-yl)methyl)piperazine-1-carboxylic acid ester, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.47(s,1H),8.85(s,1H),8.63(s,1H),8.50(s,1H),8.03(s,1H),7.83-7.73(m,2H),7.59(d,J=3 .6Hz,2H),7.51-7.30(m,3H),6.89(d,J=1.6Hz,1H),6.78-6.62(m,2H),4.68-4.60(m,1H),4.45-4.37(m,1H),4.07-4.00( m,6H),3.74-3.66(m,6H),3.54-3.44(m,7H),3.30-3.18(m,2H),3.06-2.97(m,6H),2.93-2.81(m,2H),2.64-2.54(m,1H), 2.45(s,2H),2.08-1.91(m,5H),1.82-1.68(m,6H),1.61-1.51(m,2H),1.44-1.33(m,2H),1.21-1.15(m,3H),1.04(s,6H). LCMS(ESI):R T =1.345 min, measured m / z value is 1222.6 [M-CF3COOH+H] + .

[0563] Compound 118

[0564]

[0565] (1R,4R)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl4-(1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carbonyl)piperidine-4-yl)piperazine-1-carboxylic acid ester, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ8.76(s,1H),8.60(s,1H),8.48(d,J=7.6Hz,1H),8.00(s,1H),7.82-7.72(m,2H),7.617-.54(m,2H),7.5 0-7.23(m,3H),6.88(d,J=2.0Hz,1H),6.73(dd,J=8.4,1.6Hz,1H),6.59(d,J=1.6Hz,1H),6.48(dd,J=8.8,2.0Hz,1H),4.63-4.53( m,1H),4.46-4.37(m,1H),4.09-3.96(m,3H),3.75-3.63(m,5H),3.45(s,4H),3.33-3.31(m,6H),3.08-2.92(m,3H),2.84-2.68(m, 3H), 2.45 (s, 7H), 2.06-1.88 (m, 4H), 1.84-1.62 (m, 6H), 1.57-1.47 (m, 2H), 1.40-1.28 (m, 3H), 1.15 (t, J = 6.8Hz, 3H), 1.03 (s, 6H). LCMS(ESI):R T = 1.318 min, measured m / z value is 1208.6 [M-CF3COOH+H] + .

[0566] Compound 119

[0567]

[0568] (1R,4R)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl(2-(4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)carbamate, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ8.70(s,1H),8.60(s,1H),8.42(d,J=7.6Hz,1H),7.97(s,1H),7.82-7.72(m,2H),7.58(d,J=4.0Hz,2H),7.48-7.42(m,1H) ,7.36-7.22(m,2H),7.03-6.96(m,1H),6.89(s,1H),6.72(d,J=8.0Hz,1H) ,6.59(s,1H),6.49(d,J=8.4Hz,1H),4.58-4.50(m,1H),4.43-4.33(m,1H) ,4.07-3.94(m,3H),3.85-3.78(m,2H),3.73-3.62(m,5H),3.50-3.36(m, 8H),3.08-2.94(m,3H),2.82-2.68(m,3H),2.59-2.52(m,1H),2.45(s,2H) ,2.38-2.26(m,4H),2.17-1.90(m,6H),1.81-1.64(m,7H),1.56-1.46(m,2 H),1.39-1.29(m,2H),1.18-1.13(m,3H),1.04(s,6H),0.98-0.80(m,2H). LCMS(ESI):R T =1.298 min, measured m / z value is 1279.6 [M-CF3COOH+H] + .

[0569] Compound 120

[0570]

[0571] (1R,4R)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl(2-(2-(2-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carbamoyl)ethoxy)ethoxy)ethyl)carbamate, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ8.42(d,J=7.2Hz,1H),8.30(s,1H),7.97(s,1H),7.85-7.66(m,4H),7.67(d,J=8.6Hz,1H),7.48(t,J=8.4Hz,1H),7 .31(s,1H),7.23-7.13(m,2H),7.04(t,J=6.0Hz,1H),6.88(s,1H),6.75-6.69(m,1H),6.61(d,J=2.0Hz,1H),6.53-6.46(m,1H),4.53(s,1H) ,4.07(q,J=7.2Hz,2H),3.69-3.60(m,2H),3.50(s,4H),3.44-3.36(m ,8H),3.28(s,3H),3.23-3.18(m,2H),3.15-3.09(m,2H),2.97(s,2H), 2.68-2.57(m,2H),2.44(s,2H),2.30-2.21(m,1H),2.09-1.88(m,4H), 1.80-1.62(m,4H),1.54-1.42(m,2H),1.36-1.27(m,5H),1.03(s,6H). LCMS(ESI):R T =1.450 min, measured m / z value is 1123.4 [M-CF3COOH+H] + .

[0572] Compound 121

[0573]

[0574] (1R,4R)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl4-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carbonyl)piperidine-4-yl)methyl)piperazine-1-carboxylic acid ester, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.44(s,1H),8.49(s,1H),8.35(s,1H),8.02(d,J=30.8Hz,3H),7.80(d,J=8.4Hz,1H),7.69(d, J=8.8Hz,1H),7.54-7.48(m,1H),7.34(s,1H),7.25-7.16(m,2H),6.92-6.71(m,3H),4.64(s,1H),4.41(d,J=12.8Hz,1H) ,4.14-4.09(m,2H),4.05-4.00(m,2H),3.70-3.67(m,3H),3.49(s,3H),3.39(s,3H),3.31-3.20(m,6H),3.15-2.88(m,1 0H),2.65-2.55(m,1H),2.45(s,2H),2.16-1.93(m,6H),1.79(s,6H),1.62-1.53(m,2H),1.43-1.24(m,5H),1.04(s,6H). LCMS(ESI):R T =1.250 min, measured m / z value is 1158.3 [M-CF3COOH+H] + .

[0575] Compound 122

[0576]

[0577] (1R,4R)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl(2-(4-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)carbamate, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ8.43(d,J=7.2Hz,1H),8.32(s,1H),8.00(s,1H),7. 86(s,1H),7.79(d,J=8.4Hz,2H),7.67(dd,J=7.7,1.6Hz,1H),7.51-7.45(m, 1H),7.35(s,1H),7.24-7.14(m,2H),7.04(t,J=5.6Hz,1H),6.90(s,1H),6.7 3(dd,J=9.2,1.6Hz,1H),6.61(d,J=2.2Hz,1H),6.50(dd,J=8.8,2.4Hz,1H), 4.59-4.48(m,1H),4.39(d,J=13.6Hz,1H),4.10-3.94(m,3H),3.81(d,J=5.2 Hz,2H),3.66(d,J=12.0Hz,2H),3.47-3.38(m,8H),3.28(s,4H),3.07-2.96( m,3H),2.79-2.67(m,3H),2.45(s,2H),2.31(d,J=16.4Hz,4H),2.17-1.90(m ,6H),1.82-1.63(m,8H),1.57-1.47(m,2H),1.37-1.28(m,5H),1.04(s,7H). LCMS(ESI):R T =1.330 min, measured m / z value is 1215.7 [M-CF3COOH+H] + .

[0578] Compound 123

[0579]

[0580] (R)-4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-(1,1,1-trifluoroprop-2-yl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.73-9.61(m,2H),8.85(s,1H),8.64(s,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H ),7.49-7.32(m,6H),6.84-6.63(m,2H),6.30(s,1H),4.68-4.60(m,1H),4.44-4.36(m,2H),4.33-4.14(m,6H),4.0 8-.399(m,4H),3.69(s,5H),3.46(s,3H),3.20-2.77(m,10H),2.61-2.56(m,1H),2.28(q,J=7.6Hz,2H),2.08-1.95 (m,1H),1.85-1.67(m,6H),1.34(d,J=7.0Hz,3H),1.19(t,J=6.8Hz,3H),1.14-0.98(m,2H),0.90(t,J=7.5Hz,3H). LCMS(ESI):R T =1.100 min, measured m / z value is 1164.3 [M-CF3COOH+H] + .

[0581] Compound 124

[0582]

[0583] (S)-4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-(1,1,1-trifluoroprop-2-yl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.73-9.61(m,2H),8.85(s,1H),8.64(s,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H ),7.49-7.32(m,6H),6.84-6.63(m,2H),6.30(s,1H),4.68-4.60(m,1H),4.44-4.36(m,2H),4.33-4.14(m,6H),4.0 8-.399(m,4H),3.69(s,5H),3.46(s,3H),3.20-2.77(m,10H),2.61-2.56(m,1H),2.28(q,J=7.6Hz,2H),2.08-1.95 (m,1H),1.85-1.67(m,6H),1.34(d,J=7.0Hz,3H),1.19(t,J=6.8Hz,3H),1.14-0.98(m,2H),0.90(t,J=7.5Hz,3H). LCMS(ESI):R T =1.100 min, measured m / z value is 1164.3 [M-CF3COOH+H] + .

[0584] Compound 125

[0585]

[0586] (1R,4R)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl4-(1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carbonyl)piperidine-4-yl)piperazine-1-carboxylic acid ester, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ8.48(d,J=8.0Hz,1H),8.32(s,1H),8.00(s,1H),7.87-7.77(m,3H),7.67(dd,J=7.8,2.0Hz,1H),7.51-7.47m,1H), 7.35(s,1H),7.24-7.14(m,2H),6.88(d,J=1.6Hz,1H),6.73(dd,J=8.4,1.6Hz,1H),6.61(d,J=2.4Hz,1H),6.49(dd,J=8.8,2.0Hz,1H),4.58 (s,1H),4.42(d,J=13.0Hz,1H),4.13-3.99(m,3H),3.66(d,J=12.4Hz,2H),3.52-3.43(m,1H),3.38(s,4H),3.30(s,2H),3.28(s,4H),3.03- 2.93(m,3H),2.81-2.65(m,3H),2.45(s,7H),2.02-1.87(m,4H),1.84 -1.62(m,6H),1.58-1.47(m,2H),1.38-1.18(m,7H),1.03(s,6H),0.98 -0.91(m,1H). LCMS(ESI):R T =1.180 min, measured m / z value is 1144.4 [M-CF3COOH+H] + .

[0587] Compound 126

[0588]

[0589] 2-((4-(4-((4-((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzoyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)piperidine-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.97(s,1H),9.60(s,1H),9.37(s,1H),8.31(s,1H),7.86-7.78(m,2H),7.78-7.66 (m,1H),7.49-7.38(m,3H),7.24-7.14(m,4H),6.88(s,1H),6.61-6.60(m,1H),6.50-6.48(m,1H),6.26(s,1H) ,4.40-4.37(m,1H),4.08-4.05(m,3H),3.67-3.61(m,4H),3.28(m,4H),3.02-2.99(m,2H),2.74-2.70(m,3H) ,2.51-2.31(m,4H),2.16(m,2H),1.79-1.64(m,7H),1.31-1.24(m,4H),1.01-1.00(m,7H),0.98-0.85(m,1H). LCMS(ESI):R T =1.040 min, measured m / z value is 1005.3 [M-CF3COOH+H] + .

[0590] Compound 127

[0591]

[0592] 2-((4-(4-((4-((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzoyl)piperazin-1-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.97(s,1H),9.60(s,1H),9.37(s,1H),8.74(s,1H),8.60(s,1H),7.74(d,J=7.7Hz,1H ),7.58(d,J=3.5Hz,2H),7.49-7.33(m,3H),7.24(m,8.7Hz,3H),6.87(s,1H),6.59(s,1H),6.48(d,J=8.6Hz,1H), 6.25(s,1H),4.37(s,1H),4.07-3.92(m,3H),3.68(s,7H),3.45(s,3H),3.31-3.23(m,3H),3.07-2.96(m,2H),2.7 5(s,3H),2.33(s,4H),2.16(s,2H),1.71(m,7H),1.15(t,J=6.9Hz,3H),1.00(d,J=6.9Hz,6H),0.96-0.78(m,2H). LCMS(ESI):R T =1.020 min, measured m / z value is 1069.3 [M-CF3COOH+H] + .

[0593] Compound 128

[0594]

[0595] 2-((2-ethoxy-4-(4-(4-((4-(4-(3-hydroxy-5-(4-hydroxy-5-isopropyl-2-methoxyphenyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)phenyl)amino)-5-methyl-11-(methanesulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.95(s,1H),9.83(s,1H),8.82(s,1H),8.63(s,1H),7.75(d, J=7.8Hz,1H),7.59(d,J=3.7Hz,2H),7.51-7.31(m,4H),7.11(d,J=6.1Hz,3H),6.69(m,2 H),6.30(s,1H),4.39(d,J=12.4Hz,1H),4.10-4.00(m,8H),3.69(s,7H),3.46(s,3H),3 .21(s,3H),3.12-2.84(m,10H),1.95(s,1H),1.74(d,J=8.7Hz,6H),1.28-1.03(m,12H). LCMS(ESI):R T =1.040 min, measured m / z value is 1069.3 [M-CF3COOH+H] + .

[0596] Compound 129

[0597]

[0598] 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-((4-((1-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carbonyl)piperidine-4-yl)methyl)piperidine-4-yl)methoxy)phenyl)amino)benzamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.11(s,1H),9.02(s,1H),8.37(s,1H),8.21-8.02(m,3H),7.91(d,J=8.8Hz,1H),7.7 0-7.49(m,3H),7.26-7.16(m,4H),7.03-6.93(m,5H),4.52-4.36(m,2H),4.16-4.10(m,3H),4.05-3.97(m,2H),3 .87(d,J=5.2Hz,2H),3.69-3.56(m,4H),3.39-3.32(m,7H),3.15-3.03(m,2H),3.01-2.87(m,6H),2.61-2.53(m ,1H),2.43(s,2H),2.17-1.95(m,3H),1.94-1.70(m,6H),1.68-1.57(m,2H),1.35(t,J=6.8Hz,3H),1.03(s,8H). LCMS(ESI):R T =1.176 min, measured m / z value is 1137.3 [M-CF3COOH+H] + .

[0599] Compound 130

[0600]

[0601] 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-((4-(2-(4-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)ethoxy)phenyl)amino)benzamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.14(s,1H),8.37(s,1H),8.25-8.00(m,3H),7.91(d,J=8.8Hz,1H),7.70-7 .49(m,3H),7.28-7.16(m,4H),7.06-6.94(m,7H),4.82-4.51(m,5H),4.42-4.39(m,2H),4.25(s,2H),4 .16-4.11(m,2H),3.99(d,J=2.0Hz,1H),3.68-3.64(m,2H),3.40-3.32(m,10H),3.24-3.03(m,3H),2.9 7-2.89(m,4H),2.61-2.54(m,1H),2.43(s,3H),2.02-1.63(m,8H),1.35(t,J=6.8Hz,3H),1.04(s,7H). LCMS(ESI):R T =1.151 min, measured m / z value is 1152.3 [M-CF3COOH+H] + .

[0602] Compound 131

[0603]

[0604] N-(2-(2-(2-(4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)phenoxy)ethoxy)ethoxy)ethyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ10.12(s,1H),8.38(s,1H),8.20-8.06(m,4H),7.90(d,J=8.4Hz,1H),7.70-7.49(m,3H),7.26-6.93(m,10H), 4.16-4.07(m,4H),3.76-3.55(m,8H),3.46-3.22(m,12H),2.90(s,2H),2.42(s,3H),1.91(s,4H),1.35(t,J=6.8Hz,3H),1.03(s,7H). LCMS(ESI):R T =1.443 min, measured m / z value is 1074.3 [M-CF3COOH+H]+ .

[0605] Compound 132

[0606]

[0607] N-(2-(2-(2-(4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ10.12(s,1H),8.37(s,1H),8.20-8.05(m,4H),7.90(d,J=8.4Hz,1H),7.70-7.49(m,3H),7.26-6.93(m,10H), 4.16-4.08(m,4H),3.75-3.53(m,12H),3.44-3.21(m,12H),2.90(s,2H),2.42(s,3H),1.91(s,4H),1.35(t,J=6.8Hz,3H),1.03(s,7H). LCMS(ESI):R T = 1.443 min, measured m / z value is 1118.3 [M-CF3COOH+H] + .

[0608] Compound 133

[0609]

[0610] 2-((4-(4-((4-((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)(ethyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ8.12(s,1H),7.65(d,J=6.8Hz,1H),7.48(s,1H),7.36-7.24(m,3H),7. 19-7.09(m,4H),6.93(s,1H),6.69-6.55(m,2H),6.48(s,1H),6.25(s,1H),4.42-4.34(m,1H),4. 05-3.86(m,5H),3.78-3.68(m,3H),3.48-3.39(m,7H),3.08-2.88(m,2H),2.82-2.70(m,4H),2. 44-2.25(m,7H),2.16-2.07(m,2H),1.82-1.60(m,8H),1.23-0.96(m,8H),0.87(d,J=6.8Hz,8H). LCMS(ESI):R T = 1.266 min, measured m / z value is 1019.9 [M-CF3COOH+H] + .

[0611] Compound 134

[0612]

[0613] 4-(4-((4-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-N-ethyl-5-(5-ethyl-2,4-dihydroxyphenyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1HNMR (400MHz, DMSO-d6): δ10.38(s,1H),9.70(s,1H),8.99-8.92(m,1H),8.31( s,1H),7.86(s,1H),7.79(d,J=8.8Hz,1H),7.67(dd,J=8.0,1.6Hz,1H),7.53-7 .46(m,1H),7.34(d,J=8.0Hz,2H),7.29-7.21(m,3H),7.19-7.12(m,1H),6.61( d,J=2.4Hz,1H),6.54(s,1H),6.52-6.47(m,1H),6.32(s,1H),4.42-4.34(m,1H) ,4.11-4.04(m,2H),4.01-3.93(m,1H),3.70-3.61(m,2H),3.49(s,2H),3.38(s ,3H),3.30-3.25(m,5H),3.21-3.13(m,2H),3.08-2.95(m,1H),2.78-2.65(m,3H ),2.59-2.51(m,2H),2.44-2.29(m,7H),2.24-2.18(m,2H),2.16-2.09(m,2H), 1.80-1.64(m,7H),1.32-1.27(m,3H),1.04(t,J=7.2Hz,3H),0.85-0.81(m,3H). LCMS(ESI):R T = 1.051 min, measured m / z value is 1032.3 [M-CF3COOH+H] + .

[0614] Compound 135

[0615]

[0616] 4-(4-((4-((1-(1-(3-ethoxy-4-(ethyl(5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-N-ethyl-5-(5-ethyl-2,4-dihydroxyphenyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.71(s,1H),9.04-8.96(m,1H),8.74-8.44(m,1H),7.72(s,1H),7 .65-7.20(m,8H),7.16-6.94(m,1H),6.72-6.52(m,3H),6.31(s,1H),4.42-4.38(m,1H),4.0 2-3.74(m,10H),3.44(s,5H),3.24-3.13(m,5H),3.12-2.76(m,11H),2.63-2.53(m,2H),2.2 9-2.22(m,2H),2.11-1.91(m,1H),1.82-1.62(m,7H),1.14-1.03(m,9H),0.90-0.84(m,3H). LCMS(ESI):R T =1.138 min, measured m / z value is 1124.3 [M-CF3COOH+H] + .

[0617] Compound 136

[0618]

[0619] 4-(4-((4-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)(ethyl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-N-ethyl-5-(5-ethyl-2,4-dihydroxyphenyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.73(s,1H),9.00(t,J=5.6Hz,1H),8.17(s,1H),7.67(d,J=7.2Hz,1H),7.59 -7.33(m,6H),7.27-7.13(m,2H),7.06(d,J=7.2Hz,1H),6.74(s,1H),6.63(s,2H),6.31(s,1H),4.40(d ,J=13.6Hz,1H),4.13-3.66(m,11H),3.34(s,5H),3.21-3.14(m,3H),3.12-2.80(m,12H),2.63-2.54(m ,2H),2.26(q,J=7.4Hz,2H),2.00(s,1H),1.85-1.68(m,7H),1.18-1.04(m,9H),0.87(t,J=7.4Hz,3H). LCMS(ESI):R T =1.160 min, measured m / z value is 1060.4 [M-CF3COOH+H] + .

[0620] Compound 137

[0621]

[0622] 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-((4-((1-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carbonyl)piperidine-4-yl)methyl)piperidine-4-yl)methoxy)phenyl)amino)benzamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.12(s,1H),9.01(s,1H),8.85(s,1H),8.64(s,1H),8.21(s,1H),7.91(d,J=8.4Hz,1H),7.76(d,J=7.8Hz, 1H),7.65-7.53(m,3H),7.51-7.38(m,2H),7.25(d,J=8.8Hz,2H),7.05-6.93(m,4H),6.83-6.59(m,2H),4.42(d,J=14.0Hz,1H),4.09- 3.99(m,4H),3.87(d,J=5.6Hz,2H),3.70(s,4H),3.57(s,2H),3.46(s,3H),3.32-3.21(m,1H),3.16-3.03(m,2H),3.04-2.96(m,3H),2 .92(s,3H),2.68-2.55(m,1H),2.43(s,4H),2.15-1.94(m,4H),1.86-1.70(m,5H),1.67-1.56(m,2H),1.23-1.13(m,4H),1.03(s,6H). LCMS(ESI):R T =1.300 min, measured m / z value is 1201.6 [M-CF3COOH+H] + .

[0623] Compound 138

[0624]

[0625] 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-((4-(2-(4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carbonyl)piperidine-4-yl)methyl)piperazin-1-yl)ethoxy)phenyl)amino)benzamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.15(s,1H),8.90(s,1H),8.65(s,1H),8.22(s,1H),7.91(d,J=8.5Hz,1H ),7.76(d,J=7.7Hz,1H),7.69-7.39(m,5H),7.27(d,J=8.8Hz,2H),7.08-6.72(m,6H),4.41(d,J=12 .6Hz,1H),4.26(s,2H),4.05(m,4H),3.70(s,5H),3.47(s,3H),3.34(s,5H),3.09(m,5H),2.93(s,7 H), 2.57 (t, J = 12.3Hz, 1H), 2.43 (s, 2H), 1.99 (s, 1H), 1.79 (s, 6H), 1.26-1.09 (m, 4H), 1.04 (s, 7H). LCMS(ESI):R T =1.270 min, measured m / z value is 1216.6 [M-CF3COOH+H] + .

[0626] Compound 139

[0627]

[0628] N-(2-(2-(2-(4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)phenoxy)ethoxy)ethoxy)ethyl)-1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.11(s,1H),8.86(s,1H),8.64(s,1H),8.20(s,1H),7.99(s,1H),7.90( d,J=8.5Hz,1H),7.76(d,J=7.7Hz,1H),7.59(d,J=3.8Hz,3H),7.47(m,1H),7.23(d,J=8.8Hz,2H),7 .05-6.92(m,4H),6.86-6.71(m,1H),4.11-4.00(m,7H),3.79-3.63(m,8H),3.62-3.53(m,4H),3.48 -3.40(m,5H),3.26-3.20(m,2H),2.90(s,2H),2.42(s,3H),1.83(s,4H),1.21(m,3H),1.03(s,6H). LCMS(ESI):R T =1.555 min, measured m / z value is 1138.6 [M-CF3COOH+H] + .

[0629] Compound 140

[0630]

[0631] N-(2-(2-(2-(4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)-1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidine[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.11(s,1H),8.88(s,1H),8.65(s,1H),8.20(s,1H),7.99(s,1H) ,7.90(d,J=8.5Hz,1H),7.76(d,J=7.7Hz,1H),7.68-7.40(m,5H),7.23(d,J=8.8Hz,2H),7. 05-6.69(m,6H),4.11-4.03(m,4H),3.79-3.64(m,7H),3.62-3.37(m,14H),3.29-3.19(m,2 H), 3.02 (s, 1H), 2.91 (s, 2H), 2.42 (s, 3H), 1.83 (s, 4H), 1.20 (t, J = 6.7Hz, 3H), 1.03 (s, 6H). LCMS(ESI):R T =1.555 min, measured m / z value is 1182.5 [M-CF3COOH+H] + .

[0632] Compound 141

[0633]

[0634] 2-((2-ethoxy-4-(4-(4-((4-(4-(3-hydroxy-5-(4-hydroxy-5-isopropyl-2-methoxyphenyl)-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)piperidine-1-yl)phenyl)(ethyl)amino)-5,11-dimethyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1HNMR (400MHz, DMSO-d6): δ11.90(s,1H),9.76(s,1H),8.08(s,1H),7.65(d,J=7.6Hz,1H),7.52-7.39(m ,1H),7.26-6.89(m,8H),6.57-6.46(m,2H),6.28(s,1H),4.39-4.35(m,1H),4.01-3.71(m,6H),3.41(s ,2H),3.32-3.23(m,5H),3.17(s,3H),3.11-2.97(m,2H),2.82-2.76(m,4H),2.67-2.51(m,4H),2.33(s ,7H),2.25-2.10(m,2H),2.02-1.92(m,1H),1.75-1.67(m,7H),1.09-1.00(m,10H),0.98-0.87(m,3H). LCMS(ESI):R T = 5.062 min, measured m / z value is 1033.3 [M-CF3COOH+H] + .

[0635] Compound 142

[0636]

[0637] 4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-4-hydroxy-2-methoxyphenyl)-N-(1,1,1-trifluoroprop-2-yl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.87(s,1H),9.64(d,J=8.8Hz,1H),8.86(s,1H),8.64(s,1H),7.75(d,J=7.6Hz,1H ),7.60(d,J=3.6Hz,2H),7.47-7.45(m,2H),7.35(s,2H),7.20-7.00(m,4H),6.82-6.68(m,1H),6.31(s,1H), 4.62-4.55(m,2H),4.38-4.26(m,2H),4.06-3.96(m,3H),3.70(s,6H),3.46(s,3H),3.30(s,3H),3.21-2.58 (m,11H),2.45-2.41(m,5H),2.11-1.52(m,8H),1.35(d,J=7.2Hz,3H),1.21-1.17(m,5H),1.08-1.04(m,3H). LCMS(ESI):R T =1.085 min, measured m / z value is 1178.3 [M-CF3COOH+H] + .

[0638] Compound 143

[0639]

[0640] N-(4'-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)-3',6-dimethoxy-[1,1'-biphenyl]-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.22(s,1H),8.39(s,1H),8.25-7.95(m,4H),7.85(d,J=8.4Hz ,2H),7.73-7.49(m,6H),7.40-6.95(m,11H),4.75-4.66(m,2H),4.19-4.11(m,2H),3.94 -3.78(m,8H),3.71-3.63(m,2H),3.54-3.45(m,1H),3.40(s,4H),3.33(s,4H),3.09-2.9 5(m,1H),2.10-1.85(m,6H),1.74-1.50(m,2H),1.37(t,J=6.8Hz,3H),1.27-1.21(m,1H). LCMS(ESI):R T =1.778 min, measured m / z value is 993.1 [M-CF3COOH+H] + .

[0641] Compound 144

[0642]

[0643] N-(4'-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)-3',6-dimethoxy-[1,1'-biphenyl]-3-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ10.21(s,1H),8.88(s,1H),8.65(s,1H),8.05-7.96(m ,2H),7.88-7.73(m,3H),7.65-7.58(m,6H),7.49-6.94(m,9H),4.74-4.66(m,1 H),4.08-4.03(m,2H),3.91-3.78(m,14H),3.73-3.67(m,5H),3.52-3.43(m,4H ),3.34-3.26(m,1H),2.98-2.88(m,1H),2.10-1.51(m,8H),1.25-1.15(m,3H). LCMS(ESI):R T =1.752 min, measured m / z value is 1057.1 [M-CF3COOH+H] + .

[0644] Compound 145

[0645]

[0646] N-(4'-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperidin-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)-3',6-dimethoxy-[1,1'-biphenyl]-3-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ10.21(s,1H),8.37(s,1H),8.14(s,1H),8.04-7.97(m,2H),7.84(d,J=8.8Hz ,2H),7.70-7.49(m,6H),7.42-6.90(m,11H),4.51-4.43(m,1H),4.20-4.10(m,4H),4.10-4.00(m,3H), 3.94-3.89(m,3H),3.87(s,3H),3.80(s,3H),3.71-3.63(m,3H),3.39(s,3H),3.32(s,3H),3.16-2.95( m,2H),2.68-2.57(m,1H),2.12-2.00(m,1H),1.96-1.76(m,5H),1.40-1.32(m,3H),1.27-1.13(m,2H). LCMS(ESI):R T =1.858 min, measured m / z value is 1008.1 [M-CF3COOH+H] + .

[0647] Compound 146

[0648]

[0649] N-(4'-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)-3',6-dimethoxy-[1,1'-biphenyl]-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ10.21(s,1H),8.89(s,1H),8.65(s,1H),8.06-7.97(m,2H),7.87-7 .74(m,3H),7.64-7.57(m,6H),7.53-6.88(m,10H),4.52-4.44(m,1H),4.11-4.03(m,3H),3. 93-3.89(m,2H),3.87(s,4H),3.80(s,5H),3.71(s,5H),3.47(s,3H),3.17-3.07(m,1H),2.9 6-2.89(m,1H),2.65-2.57(m,1H),2.11-2.02(m,1H),1.93-1.74(m,6H),1.27-1.14(m,6H). LCMS(ESI):R T = 1.763 min, measured m / z value is 1071.2 [M-CF3COOH+H] + .

[0650] Compound 147

[0651]

[0652] N-(3-((4'-(3',6-dimethoxy-[1,1'-biphenyl]-3-carbamate)-[1,1'-biphenyl]-4-yl)oxy)propyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carbamate, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6) δ10.21(s,1H),8.37(s,1H),8.23-7.92(m,5H),7.84(d,J=8.6Hz,2H),7.68(d,J=7.8Hz ,1H),7.61(d,J=8.6Hz,4H),7.51(t,J=7.7Hz,1H),7.37(t,J=7.9Hz,1H),7.26(dd,J=8.6,5.0Hz,2H),7.21-7. 05(m,4H),7.04-6.91(m,4H),5.17-4.24(m,3H),4.18-4.07(m,2H),4.07-3.98(m,2H),3.83(d,J=24.8Hz,6H), 3.67(d,J=11.7Hz,2H),3.39(s,3H),3.32(s,3H),3.29-3.20(m,3H),1.98-1.77(m,6H),1.35(t,J=6.8Hz,3H). LCMS(ESI):R T =1.637 min, measured m / z value is 967.2 [M-CF3COOH+H] + .

[0653] Compound 148

[0654]

[0655] N-(3-((4'-(3',6-dimethoxy-[1,1'-biphenyl]-3-carbamate)-[1,1'-biphenyl]-4-yl)oxy)propyl)-1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carbamate, trifluoroacetic acid. 1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),8.92(s,1H),8.66(s,1H),8.11-7.96(m,3H),7.84(d, J=8.6Hz,2H),7.76(d,J=7.9Hz,1H),7.61(d,J=8.4Hz,7H),7.54-7.41(m,2H),7.37(t,J=8. 1Hz,1H),7.26(d,J=8.5Hz,1H),7.16-6.92(m,6H),4.18-4.01(m,9H),3.83(d,J=24.8Hz,6H ),3.73-3.66(m,4H),3.47(s,3H),3.29-3.23(m,2H),1.99-1.77(m,6H),1.27-1.17(m,3H). LCMS(ESI):R T =1.750 min, measured m / z value is 1032.0 [M-CF3COOH+H] + .

[0656] Compound 149

[0657]

[0658] N-(4'-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperidin-4-yl)oxy)-2'-(3-(dimethylamino)propoxy)-[1,1'-biphenyl]-4-yl)-3',6-dimethoxy-[1,1'-biphenyl]-3-carboxamide, trifluoroacetic acid. 1HNMR (400MHz, DMSO-d6) δ10.21(s,1H),9.40(s,1H),8.36(s,1H),8.17-7.94(m,4H),7.80(d,J=7.9Hz,2H),7.69(d,J= 7.6Hz,1H),7.55-7.09(m,11H),6.97(d,J=8.7Hz,1H),6.78-6.67(m,2H),4.71(s,1H),4.16-4.03(m,7H),3.84(d,J=25 .2Hz,9H),3.71-3.65(m,2H),3.53-3.45(m,1H),3.39(s,3H),3.31(s,4H),3.15-3.09(m,2H),2.99-2.90(m,1H),2.77( d,J=4.1Hz,6H),2.11-2.01(m,3H),1.98-1.92(m,1H),1.83(s,3H),1.72-1.63(m,1H),1.56(s,1H),1.39-1.31(m,3H). LCMS(ESI):R T =1.390 min, measured m / z value is 1095.1 [M-CF3COOH+H] + .

[0659] Compound 150

[0660]

[0661] N-(2'-(3-(dimethylamino)propoxy)-4'-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)-3',6-dimethoxy-[1,1'-biphenyl]-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6) δ10.21(s,1H),9.43(s,1H),8.85(s,1H),8.63(s,1H),8.05-7.94(m,2H),7.78(dd,J=18.6,7.7Hz,3H) ,7.60(s,2H),7.46(d,J=8.2Hz,3H),7.38(t,J=7.7Hz,2H),7.29-7.24(m,2H),7.14-7.08(m,2H),6.96(d,J=8.4Hz,1H),6.80- 6.59(m,4H),4.71(s,1H),4.09-3.99(m,5H),3.84(d,J=25.2Hz,8H),3.75-3.64(m,6H),3.46(s,4H),3.31(s,1H),3.16-3.07( m,2H),2.91(s,1H),2.77(d,J=4.3Hz,6H),2.09-1.91(m,5H),1.78(s,4H),1.70-1.63(m,1H),1.56(s,1H),1.22-1.15(m,3H). LCMS(ESI):R T =1.390 min, measured m / z value is 1158.8 [M-CF3COOH+H] + .

[0662] Compound 151

[0663]

[0664] N-(4'-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperidin-4-yl)methoxy)-2'-(3-(dimethylamino)propoxy)-[1,1'-biphenyl]-4-yl)-3',6-dimethoxy-[1,1'-biphenyl]-3-carboxamide, trifluoroacetic acid. 1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),9.44(s,1H),8.38(s,1H),8.19(s,2H),8. 02(dd,J=8.6,2.2Hz,1H),7.97(d,J=2.3Hz,1H),7.80(d,J=8.7Hz,2H),7.69(dd, J=7.8,1.6Hz,1H),7.55-7.49(m,1H),7.45(d,J=8.6Hz,2H),7.38(t,J=7.9Hz,1H ),7.29-7.23(m,3H),7.19(t,J=7.4Hz,1H),7.15-7.06(m,3H),6.98-6.94(m,1H) ,6.69-6.62(m,2H),4.48(d,J=12.7Hz,1H),4.15(q,J=6.9Hz,2H),4.05(t,J=5.8 Hz,3H),3.91(d,J=6.1Hz,2H),3.87(s,3H),3.81(s,3H),3.67(d,J=10.7Hz,2H), 3.40(s,3H),3.33(s,3H),3.16-3.07(m,3H),3.00(s,1H),2.77(d,J=4.9Hz,6H), 2.63(t,J=12.8Hz,1H),2.11-2.01(m,3H),1.95-1.78(m,6H),1.42-1.05(m,7H). LCMS(ESI):R T =1.280 min, measured m / z value is 1108.4 [M-CF3COOH+H] + .

[0665] Compound 152

[0666]

[0667] N-(3-((4'-(3',6-dimethoxy-[1,1'-biphenyl]-3-carbamate)-2-(3-(dimethylamino)propoxy)-[1,1'-biphenyl]-4-yl)oxy)propyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carbamate, trifluoroacetic acid. 1HNMR(400MHz,DMSO-d6)δ10.21(s,1H),9.44(s,1H),8.37(s,1H),8.21-7.93(m,5H),7.80(d,J=8.7Hz,2H ),7.69(dd,J=7.7,1.6Hz,1H),7.54-7.08(m,11H),7.02-6.82(m,2H),6.69-6.61(m,2H),4.17-4.00(m,6H ), 3.84 (d, J = 25.1 Hz, 6H), 3.67 (d, J = 11.7 Hz, 2H), 3.39 (s, 3H), 3.32 (s, 3H), 3.28-3.24 (m, 2H), 3.17-3.03 (m, 3H), 2.76 (d, J = 4.8 Hz, 6H), 2.43-2.35 (m, 1H), 2.10-2.02 (m, 2H), 1.95-1.79 (m, 6H), 1.38-1.21 (m, 4H). LCMS (ESI): RT = 1.240 min, measured m / z value is 1068.4 [M + CF3COOH + H] + .

[0668] Compound 153

[0669]

[0670] N-(4'-((1-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-2'-(3-(dimethylamino)propoxy)-[1,1'-biphenyl]-4-yl)-3',6-dimethoxy-[1,1'-biphenyl]-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6) δ10.74(s,1H),10.23(s,1H),9.57(s,1H),8.92(s,1H),8.35(s,1H),8.07-7.95(m,3H),7.82(d,J=8.7Hz,2H) ,7.68(dd,J=7.7,1.6Hz,1H),7.54-7.34(m,5H),7.29-7.07(m,5H),6.96(dd,J=8.2,2.0Hz,1H),6.85-6.64(m,2H),5.76(s,1H),5.2 1-5.12 (m, 2H), 4.43-4.26 (m, 5H), 4.13-4.00 (m, 7H), 3.86 (s, 3H), 3.80 (s, 3H), 3.70-3.60 (m, 2H), 3.39 (s, 3H), 3.30 (s, 3H), 3.19-3.02 (m, 7H), 2.95-2.85 (m, 1H), 2.78 (d, J = 4.7 Hz, 6H), 2.66-2.50 (m, 2H), 2.22-2.02 (m, 3H), 1.94-1.68 (m, 6H), 1.32 (t, J = 6.8 Hz, 3H). LCMS (ESI): RT = 1.330 min, measured m / z value is 1192.2 [M + CF3COOH + H] + .

[0671] Compound 154

[0672]

[0673] N-(4'-((1-((1-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)-3',6-dimethoxy-[1,1'-biphenyl]-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, CD3OD) δ8.56 (d, J=8.8Hz, 1H), 8.33 (s, 1H), 8.03-7.91 (m, 2H), 7.76 (d, J= 8.1Hz,3H),7.63-7.48(m,6H),7.37-7.04(m,12H),6.91(d,J=9.2Hz,1H),4.62(d,J=12 0.9Hz, 1H), 4.30-4.16(m, 3H), 3.90(s, 3H), 3.83(s, 4H), 3.78-3.66(m, 5H), 3.52-3.31(m, 8H), 3.25-3.09(m, 6H), 2.80-2.69(m, 1H), 2.31-1.90(m, 13H), 1.52(t, J = 6.8Hz, 3H). LCMS (ESI): RT = 1.340 min, measured m / z value is 1090.4 [M + CF3COOH + H] + .

[0674] Compound 155

[0675]

[0676] N-(2'-(3-(dimethylamino)propoxy)-4'-((1-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)-3',6-dimethoxy-[1,1'-biphenyl]-3-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, CD3OD) δ8.56 (d, J=8.8Hz, 1H), 8.33 (s, 1H), 8.03-7.91 (m, 2H), 7.76 (d, J= 8.1Hz,3H),7.63-7.48(m,6H),7.37-7.04(m,12H),6.91(d,J=9.2Hz,1H),4.62(d,J=12 0.9Hz, 1H), 4.30-4.16(m, 3H), 3.90(s, 3H), 3.83(s, 4H), 3.78-3.66(m, 5H), 3.52-3.31(m, 8H), 3.25-3.09(m, 6H), 2.80-2.69(m, 1H), 2.31-1.90(m, 13H), 1.52(t, J = 6.8Hz, 3H). LCMS(ESI): RT = 1.304 min, measured m / z value is 1254.0 [M + CF3COOH + H]+ .

[0677] Compound 156

[0678]

[0679] N-(4'-((1-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-[1,1'-biphenyl]-4-yl)-3',6-dimethoxy-[1,1'-biphenyl]-3-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),10.22(s,1H),9.57(s,1H),8.86(d,J=40.0Hz,2H),8.62(s,1H),8.05-7.95(m,2H),7.83-7.74(m,3H),7.60 -7.24(m,9H),7.15-7.07(m,2H),6.97-6.05(m,1H),6.71-6.56(m,2H),5.76( s,1H),5.21-5.12(m,2H),4.45-4.29(m,4H),4.06-3.99(m,7H),3.86(s,3H),3 .80(s,3H),3.69(s,4H),3.46(s,3H),3.19-3.01(m,7H),2.88-2.74(m,9H),2 .62-2.50(m,2H),2.20-2.04(m,3H),1.95-1.67(m,6H),1.17(t,J=6.8Hz,3H). LCMS (ESI): RT = 1.285 min, measured m / z value is 1256.5 [M + CF3COOH + H] + .

[0680] Compound 157

[0681]

[0682] N-(3-((4'-(3',6-dimethoxy-[1,1'-biphenyl]-3-carbamate)-2-(3-(dimethylamino)propoxy)-[1,1'-biphenyl]-4-yl)oxy)propyl)-1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carbamate, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ10.20(s,1H),9.42(s,1H),8.79(s,1H),8.62(s,1H),8.04-7.94(m,3H),7.83-7.72(m,3H), 7.58(d,J=3.4Hz,2H),7.45(d,J=8.8Hz,3H),7.25(t,J=7.6Hz,7H),7.19-7.15(m,6H),7.00-6.94(m,1H),6.70-6.63( m,3H),4.09-3.99(m,6H),3.87(s,3H),3.80(s,3H),3.72-3.66(m,5H),3.27-3.22(m,2H),3.14-3.06(m,2H),2.76(d ,J=4.7Hz,6H),2.30(s,6H),2.12-2.04(m,2H),1.92-1.85(m,2H),1.81-1.75(m,2H),1.23(s,1H),1.20-1.12(m,3H). LCMS(ESI):R T =1.350 min, measured m / z value is 1132.7 [M-CF3COOH+H] + .

[0683] Compound 158

[0684]

[0685] N-(2'-(3-(dimethylamino)propoxy)-4'-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)-3',6-dimethoxy-[1,1'-biphenyl]-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, CD3OD) δ8.68(s,1H),8.37(d,J=8.7Hz,1H),7.98(dd,J=8.6,2.3Hz,1H),7.93(d,J=2.3Hz,1H),7.85(d, J=6.5Hz,1H),7.75(d,J=8.6Hz,2H),7.66-7.55(m,6H),7.50(t,J=7.5Hz,1H),7.35-7.02(m,8H),6.92(d,J=1.7Hz,1 H),4.61(d,J=13.8Hz,1H),4.27-4.13(m,3H),3.90(s,3H),3.83(s,3H),3.80-3.62(m,5H),3.61-3.50(m,7H),3.44- 3.33(m,2H),3.25-3.10(m,4H),2.74(t,J=11.9Hz,1H),2.45-1.84(m,12H),1.47(t,J=7.0Hz,3H),1.38-1.18(m,4H). LCMS(ESI):R T =1.420 min, measured m / z value is 1171.2 [M-CF3COOH+H] + .

[0686] Compound 159

[0687]

[0688] 2-((4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazine-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR(400MHz,CD3OD)δ8.53(s,1H),7.81(dd,1H),7.67-7.56(m,2H),7.54-7.37(m,4H),7. 25(d,J=8.3Hz,2H),6.74(s,1H),6.65(d,J=2.2Hz,1H),6.58(dd,J=8.7,2.4Hz,1H),6.27( s,1H),4.13-3.97(m,2H),3.73-3.54(m,13H),3.09-2.98(m,1H),2.86-2.74(m,3H),2.58 -2.39(m,4H),2.25-2.12(m,1H),1.92-1.74(m,4H),1.33-1.28(m,7H),0.98-0.89(m,6H). LCMS(ESI):R T =1.160 min, measured m / z value is 958.5 [M-CF3COOH+H] + .

[0689] Compound 160

[0690]

[0691] 2-((4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazine-1-carbonyl)piperidin-1-yl)-2-ethoxyphenyl)(ethyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1 H NMR(400MHz,CD3OD)δ8.53(s,1H),7.81(dd,1H),7.67-7.56(m,2H),7.54-7.37(m,4H),7. 25(d,J=8.3Hz,2H),6.74(s,1H),6.65(d,J=2.2Hz,1H),6.58(dd,J=8.7,2.4Hz,1H),6.27( s,1H),4.13-3.97(m,2H),3.73-3.54(m,13H),3.09-2.98(m,1H),2.86-2.74(m,3H),2.58 -2.39(m,4H),2.25-2.12(m,1H),1.92-1.74(m,4H),1.33-1.28(m,7H),0.98-0.89(m,6H). LCMS(ESI):R T =1.160 min, measured m / z value is 985.5 [M-CF3COOH+H]+ .

[0692] Compound 161

[0693]

[0694] 4-(4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-((1,1,1-trifluoroprop-2-yl)carbamoyl)-4H-1,2,4-triazol-3-yl)-2-ethyl-5-hydroxyphenyl isobutyl ester, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ8.68(s,1H),8.34(d,J=8.2Hz,1H),7.86(d,J=6.4Hz,1H),7.65-7.60(m,1H),7.56(d,J=7.3Hz,1H),7.52-7.45 (m,3H),7.36(d,J=8.3Hz,2H),7.19(s,1H),7.14(d,J=8.5Hz,1H),7.08(s,1H),6.46(s,1H),4.73-4.63(m,1H),4.58(d,J=12.4Hz,1H),4 .32-4.03(m,4H),3.92(s,2H),3.76(s,3H),3.59(d,J=13.9Hz,9H),3.20(d,J=14.0Hz,5H),2.96(s,4H),2.86-2.80(m,3H),2.71(t,J=1 1.8Hz, 2H), 2.34 (q, J = 7.5Hz, 2H), 2.14-2.10 (M, 6H), 2.01-1.80 (m, 3H), 1.47-1.41 (m, 6H), 1.28 (d, J = 7.0Hz, 6H), 0.99 (t, J = 7.5Hz, 3H). LCMS (ESI): RT = 1.360 min, measured m / z value is 618.3 [M / 2-CF3COOH+H] + .

[0695] Compound 162

[0696]

[0697] 2-(4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-((1,1,1-trifluoroprop-2-yl)carbamoyl)-4H-1,2,4-triazol-3-yl)-4-ethyl-5-hydroxyphenyl isobutyl ester, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ8.68(s,1H),8.34(d,J=8.2Hz,1H),7.86(d,J=6.4Hz,1H),7.65-7.60(m,1H),7.56(d,J=7.3Hz,1H),7.52-7.45 (m,3H),7.36(d,J=8.3Hz,2H),7.19(s,1H),7.14(d,J=8.5Hz,1H),7.08(s,1H),6.46(s,1H),4.73-4.63(m,1H),4.58(d,J=12.4Hz,1H),4 .32-4.03(m,4H),3.92(s,2H),3.76(s,3H),3.59(d,J=13.9Hz,9H),3.20(d,J=14.0Hz,5H),2.96(s,4H),2.86-2.80(m,3H),2.71(t,J=1 1.8Hz, 2H), 2.34 (q, J = 7.5Hz, 2H), 2.14-2.10 (M, 6H), 2.01-1.80 (m, 3H), 1.47-1.41 (m, 6H), 1.28 (d, J = 7.0Hz, 6H), 0.99 (t, J = 7.5Hz, 3H). LCMS (ESI): RT = 1.360 min, measured m / z value is 618.3 [M / 2-CF3COOH+H] + .

[0698] Compound 163

[0699]

[0700] N-(2-(diethylamino)ethyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperazin-1-yl)methyl)phenyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.77(s,1H),9.24(t,J=6.0Hz,2H),8.34(s,1H),8.03(s,1H),7.92-7.90(m,1H),7.68(dd,J=8. 0,4.0Hz,1H),7.54-7.47(m,3H),7.44(d,J=8.0Hz,2H),7.24(d,J=8.0Hz,1H),7.18(t,J=6.0Hz,1H),6.80(s,1H),6.73( s,1H),6.31(s,1H),4.35(s,1H),4.10(q,J=16.0Hz,1H),3.70-3.67(m,8H),3.56-3.52(m,4H),3.39(s,3H),3.30(s,3H) ,3.22-3.17(m,8H),3.00–2.85(m,5H),1.79(s,4H),1.32(t,J=6.0Hz,3H),1.19(t,J=6.0Hz,6H),0.92(d,J=8.0Hz,6H). LCMS(ESI):R T =1.120 min, measured m / z value is 1021.2 [M-CF3COOH+H] + .

[0701] Compound 164

[0702]

[0703] N-(2-(diethylamino)ethyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carbonyl)piperazin-1-yl)methyl)phenyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.78(s,1H),9.24(t,J=5.9Hz,2H),8.78(s,1H),8.62(s,1H),7.75(d,J=8.0Hz,1H),7.5 9(d,J=4.0Hz,2H),7.52(d,J=8.3Hz,2H),7.45-7.43(m,2H),7.33(d,J=8.0Hz,1H),6.73(s,1H),6.67(s,1H),6.56 (d,J=8.0Hz,1H),6.31(s,1H),4.34(s,1H),4.07-3.99(m,1H),3.73-3.68(m,6H),3.54(s,6H),3.49(s,3H),3.46 (s,3H),3.24-3.16(m,8H),3.00-2.93(m,1H),2.84(s,4H),1.74(s,4H),1.22–1.14(m,9H),0.92(d,J=8.0Hz,6H). LCMS(ESI):R T =1.090 min, measured m / z value is 1085.3 [M-CF3COOH+H] + .

[0704] Compound 165

[0705]

[0706] N-(4-(((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)(ethyl)amino)methyl)benzyl)-1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6) δ12.00(s,1H),9.83(s,1H),9.67(s,1H),9.37(s,1H),8.56(t,J=5.8Hz,1H),8.37(s,1H),8.15(s,1H),8.02( s,1H),7.69(dd,J=7.7,1.6Hz,1H),7.53-7.49(m,3H),7.45(d,J=8.1Hz,2H),7.34(d,J=8.1Hz,2H),7.27-7.24(m,3H),7.18(t,J=7.5 Hz,1H),7.03-6.96(m,1H),6.90(s,2H),6.25(s,1H),4.31(dd,J=20.5,8.4Hz,6H),4.14-4.12(m,3H),3.68(d,J=12.0Hz,2H),3.39( s,3H),3.32(s,3H),3.13(s,1H),3.04-2.91(m,3H),1.94(s,4H),1.35(t,J=6.9Hz,3H),1.25(t,J=7.1Hz,4H),1.01(d,J=6.9Hz,6H). LCMS(ESI):R T =1.250 min, measured m / z value is 972.5 [M-CF3COOH+H] + .

[0707] Compound 166

[0708]

[0709] N-(4-(((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)(ethyl)amino)methyl)benzyl)-1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6) δ12.00(s,1H),9.70(d,J=39.7Hz,2H),9.36(s,1H),8.84(s,1H),8.63(s,1H),8.50(t,J=6.0H z,1H),7.75(d,J=7.8Hz,1H),7.59(d,J=3.7Hz,2H),7.52-7.42(m,5H),7.33(d,J=8.0Hz,2H),7.26(d,J=8.2Hz,2H),6 .90(s,1H),6.83-6.57(m,2H),6.24(s,1H),4.34-4.26(m,5H),4.06-4.02(m,2H),3.74-3.68(m,5H),3.46(s,3H),3.0 3-2.84(m,5H),2.45-2.39(m,1H),1.90-1.75(m,4H),1.26-1.23(m,4H),1.18(t,J=6.7Hz,3H),1.01(d,J=6.8Hz,6H). LCMS(ESI):R T =1.240 min, measured m / z value is 1036.4 [M-CF3COOH+H] + .

[0710] Compound 167

[0711]

[0712] 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperazin-1-yl)methyl)phenyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6) δ9.79(s,1H),8.99-8.96(m,1H),8.34(s,1H),8.06(s,1H),7.93(d,J=8.6Hz,1H),7.69(dd,J=7 .8,1.6Hz,1H),7.59-7.47(m,4H),7.44(d,J=8.4Hz,2H),7.24(d,J=8.1Hz,1H),7.18(t,J=7.4Hz,1H),6.84(s,1H),6. 76-6.71(m,1H),6.69(s,1H),6.32(s,1H),4.37(s,2H),4.14-4.08(m,3H),3.70-3.67(m,8H),3.40-3.34(m,11H),3.3 1(s,5H),2.99-2.92(m,4H),2.78(s,3H),2.75-2.67(m,3H),1.81(s,4H),1.33(t,J=6.9Hz,3H),0.90(d,J=6.9Hz,6H). LCMS(ESI):R T =1.240 min, measured m / z value is 1048.2 [M-CF3COOH+H] + .

[0713] Compound 168

[0714]

[0715] 2-((4-(4-(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6(11H)-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.86 (s, 1H), 9.07-9.04 (m, 1H), 8.88 (s, 1H), 8.69 (s, 1H), 7.82 (d, J = 8.0Hz, 1H), 7.66-7. 60(m,4H),7.55-7.49(m,3H),7.44(d,J=12.0Hz,1H),6.79-6.76(m,2H),6.68(d,J=8.0Hz,1H),6.38(s,1H),4.44(s ,2H),4.13-4.08(m,2H),3.80-3.75(m,8H),3.52(s,3H),3.46-3.42(m,4H),3.30-3.21(m,4H),3.05-3.01(m,1H), 3.00-2.92(m,4H),2.85(s,3H),2.80-2.72(m,3H),1.83-1.80(m,4H),1.25(t,J=6.0Hz,3H),0.97(d,J=8.0Hz,6H). LCMS(ESI):R T =1.135 min, measured m / z value is 1112.2 [M-CF3COOH+H] + .

[0716] Compound 169

[0717]

[0718] 2-((4-(4-(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6(11H)-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.98(s,1H),9.93(s,1H),9.63(s,1H),9.34(s,1H),8.53(s,1H),8.36(s,1H),8.05(d,J=45.0Hz ,2H),7.68(d,J=7.7Hz,1H),7.48(dd,J=22.0,8.1Hz,5H),7.34(d,J=8.0Hz,2H),7.26(t,J=8.8Hz,3H),7.18(t,J=7.5Hz,1H ), 6.90(s,2H), 6.24(s,1H), 4.73-4.52(m,3H), 4.37(dd,J=23.7,9.2Hz,6H), 4.15(dd,J=19.2,12.3Hz,5H), 3.68(d,J=11.8Hz,2H), 3.39(s,3H), 3.32(s,3H), 3.01(dd,J=13.8,6.9Hz,1H), 1.91(s,4H), 1.34(t,J=6.9Hz,3H), 1.01(d,J=6.8Hz,6H). LCMS(ESI):RT=1.420min, measured m / z value is 958.6[M-CF3COOH+H] + .

[0719] Compound 170

[0720]

[0721] N-(4-(((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)(methyl)amino)methyl)benzyl)-1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carboxamide, trifluoroacetic acid. 1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),9.88-9.73(m,1H),9.61(s,1H),9.32(s,1H),8.79(s,1H),8.62(s,1H),8.54-8.38 (m,1H),7.75(d,J=7.8Hz,1H),7.58(d,J=3.9Hz,2H),7.52-7.43(m,5H),7.30(dd,J=27.8,8.2Hz,5H),6.90(s,1H),6.72- 6.53(m,2H),6.24(s,1H),4.46-4.30(m,5H),4.26-4.13(m,4H),4.07-3.98(m,3H),3.71(d,J=17.5Hz,5H),3.46(s,3H), 3.06-2.95(m,1H),2.84-2.71(m,1H),2.43-2.35(m,1H),1.88-1.72(m,4H),1.17(t,J=6.9Hz,3H),1.01(d,J=6.9Hz,6H). LCMS(ESI):R T =1.040 min, measured m / z value is 1022.3 [M-CF3COOH+H] + .

[0722] Compound 171

[0723]

[0724] 4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-N-ethyl-5-(5-ethyl-4-hydroxy-2-methoxyphenyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),9.07-9.00(m,1H),8.82(s,1H),8.62(s,1H),7.75(d,J=7.8Hz,1 H),7.59(d,J=4.0Hz,2H),7.51-7.44(m,2H),7.33(s,3H),7.22-7.06(m,3H),6.77-6.51m,1H),6.28(s ,1H),4.44-4.37(m,2H),4.10-3.97(m,6H),3.74-3.64(m,6H),3.46(s,3H),3.30(s,3H),3.23-3.14( m,3H),3.11-2.77(m,9H),2.44-2.33(m,4H),1.82-1.63(m,7H),1.21-1.14(m,3H),1.08-1.03(m,8H). LCMS(ESI):R T =1.040 min, measured m / z value is 1110.3 [M-CF3COOH+H] + .

[0725] Compound 172

[0726]

[0727] 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperazin-1-yl)methyl)phenyl)-N-(2-(4-methylsulfonyl)piperazin-1-yl)ethyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR(400MHz,DMSO-d6)δ10.72-10.22(m,1H),9.79(s,1H),9.37-9.23(m,1H),8.36(s,1H),8.11(s,1H ),8.03-7.90(m,1H),7.69(dd,J=7.7,1.7Hz,1H),7.57-7.42(m,5H),7.28-7.14(m,2H),7.00-6.74(m ,2H),6.72(s,1H),6.32(s,1H),4.53-4.28(m,3H),4.12(q,J=6.9Hz,2H),3.85-3.44(m,9H),3.39(s, 4H), 3.36-3.07 (m, 13H), 3.06-2.88 (m, 8H), 1.83 (s, 4H), 1.34 (t, J = 6.9Hz, 3H), 0.92 (d, J = 6.9Hz, 6H). LCMS(ESI):R T =1.000min, measured m / z value is 1111.2[M-CF3COOH+H] + .

[0728] Compound 173

[0729]

[0730] 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperazin-1-yl)methyl)phenyl)-N-(2,2,3,3,3-pentafluoropropyl-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid). 1HNMR (400MHz, DMSO-d6) δ10.43-9.99(m,1H),9.76(s,1H),9.66(t,J=6.5Hz,1H),8.36(s,1H),8.12( s,1H),7.97(s,1H),7.69(dd,J=7.7,1.6Hz,1H),7.59-7.43(m,5H),7.28-7.14(m,2H),7.04-6.68(m, 3H),6.31(s,1H),4.57-4.32(m,3H),4.29-3.94(m,5H),3.69(d,J=11.7Hz,2H),3.55-3.43(m,1H),3. 39(s,3H),3.31(s,5H),3.20-2.85(m,7H),1.83(s,4H),1.34(t,J=6.9Hz,3H),0.92(d,J=6.9Hz,6H). LCMS(ESI):R T =1.260 min, measured m / z value is 1053.2 [M-CF3COOH+H] + .

[0731] Compound 174

[0732]

[0733] 5-(2,4-Dihydroxy-5-isopropylphenyl)-4-(4-((4-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperazin-1-yl)methyl)phenyl)-N-(2-(4-methylsulfonyl)piperazin-1-yl)ethyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.77(s,1H),9.28(s,1H),8.81(s,1H),8.62(s,1H),7.75(d, J=7.9Hz,1H),7.51(m,8H),7.36(s,1H),6.65-6.63(m,3H),6.31(s,1H),4.38(s,4H), 4.11-3.95(m,3H),3.69(s,7H),3.55(s,3H),3.46(s,4H),3.20(d,J=66.1Hz,8H),3.0 3(s,4H),2.98-2.87(m,6H),1.75(s,4H),1.18(t,J=6.8Hz,3H),0.92(d,J=6.9Hz,6H). LCMS(ESI):R T =1.033 min, measured m / z value is 1175.2 [M-CF3COOH+H] + .

[0734] Compound 175

[0735]

[0736] 5-(2,4-Dihydroxy-5-isopropylphenyl)-4-(4-((4-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidine-4-carbonyl)piperazin-1-yl)methyl)phenyl)-N-(2,2,3,3,3-pentafluoropropyl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6): δ10.13(s,1H),9.76-9.65(m,2H),8.83(s,1H),8.63(s,1H),7.75(d,J =7.7Hz,1H),7.57(dd,J=17.9,6.0Hz,4H),7.44(dd,J=19.4,14.1Hz,4H),6.69-6.66(m,3H),6. 31(s,1H),4.39(s,3H),4.31-4.17(m,1H),4.02-3.98(m,4H),3.69(s,5H),3.39(d,J=56.6Hz, 6H), 3.13 (s, 1H), 3.06–2.79 (m, 6H), 1.77 (s, 4H), 1.19 (t, J = 6.8Hz, 3H), 0.92 (d, J = 6.9Hz, 6H). LCMS(ESI):R T=1.260 min, measured m / z value is 1117.1 [M-CF3COOH+H] + .

[0737] Compound 176

[0738]

[0739] (R)-4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-(1,1,1-trifluoroprop-2-yl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6) δ9.83-9.54(m,2H),8.86(s,1H),8.65(s,1H),7.76(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H),7.55 -7.38(m,4H),7.34(d,J=8.2Hz,2H),6.88(s,1H),6.76(s,1H),6.69(s,1H),6.31(s,1H),4.69-4.59(m,2H),4.40(d,J= 13.2Hz,1H),4.13-3.80(m,5H),3.69(s,5H),3.47(s,3H),3.23-2.74(m,11H),2.63-2.50(m,4H),2.28(q,J=7.5Hz,2H) ,2.01(s,1H),1.90-1.71(m,6H),1.34(d,J=7.0Hz,3H),1.21(t,J=6.9Hz,3H),1.17-0.97(m,2H),0.90(t,J=7.5Hz,3H). LCMS(ESI):R T =1.180 min, measured m / z value is 1164.3 [M-CF3COOH+H] + .

[0740] Compound 177

[0741]

[0742] (S)-4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-(1,1,1-trifluoroprop-2-yl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6) δ9.93 (s, 1H), 9.60 (d, J = 9.1Hz, 1H), 8.98 (s, 1H), 8.70 (s, 1H), 7.78-7.74 (m, 1H), 7.74 -7.29(m,10H),6.77(s,1H),6.47(s,1H),4.71-4.61(m,2H),4.38(d,J=12.0Hz,2H),4.14-4.07(m,4H),3.71( s,5H),3.65-3.55(m,4H),3.48(s,4H),3.45-3.25(m,5H),3.16-3.02(m,3H),2.71-2.55(m,2H),2.32(q,J=7. 4Hz,2H),2.17-1.98(m,3H),1.95-1.79(m,3H),1.39-1.19(m,10H),1.11-1.01(m,1H),0.95(t,J=7.5Hz,3H). LCMS(ESI):R T =1.180 min, measured m / z value is 1164.3 [M-CF3COOH+H] + .

[0743] Compound 178

[0744]

[0745] 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-((1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-N-(2,2,2-trifluoroethyl)-4H-1,2,4-triazol-3-carboxamide. 1H NMR (400MHz, DMSO-d6): δ9.57(s,1H),8.72(s,1H),8.60(s,1H),7.74(d,J=7.3Hz,1H),7.61-7.53(m,2H),7. 49-7.17(m,7H),6.63-6.44(m,3H),6.24(s,1H),4.04-3.91(m,4H),3.66(d,J=19.0Hz,4H),3.48(d,J=19.5H z,6H),2.95-2.89(m,1H),2.68-2.60(m,2H),2.41(s,5H),2.17(d,J=7.1Hz,2H),2.05-1.94(m,1H),1.78(d, J=11.7Hz,2H),1.65(s,1H),1.24(s,4H),1.15(t,J=6.9Hz,4H),0.93(d,J=6.7Hz,1H),0.79(d,J=6.8Hz,6H). LCMS(ESI):R T = 1.210 min, measured m / z value is 1053.5 [M+H] + .

[0746] Compound 179

[0747]

[0748] 4-(4-((4-((1-((1-((3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-(1,1,1-trifluoroprop-2-yl)-4H-1,2,4-triazol-3-carboxamide 2,2,2-trifluoroacetic acid ester, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.80-9.56(m,2H),9.19(s,1H),8.79(s,1H),8.62(s,1H),7.75(d,J=7.7Hz,1 H),7.64-7.28(m,9H),6.64(d,J=32.5Hz,3H),6.31(s,1H),4.63(dd,J=15.6,7.5Hz,1H),4.11-3.94(m, 3H),3.69(s,6H),3.57(s,2H),3.46(s,3H),3.17(s,2H),3.02(s,4H),2.94-2.62(m,8H),2.28(q,J=7.4 Hz,3H),1.89(dd,J=27.5,12.1Hz,7H),1.40-1.31(m,8H),1.18(t,J=6.8Hz,3H),0.89(t,J=7.5Hz,3H). LCMS(ESI):R T =1.090 min, measured m / z value is 1150.6 [M-CF3COOH+H] + .

[0749] Compound 180

[0750]

[0751] 4-(4-(4-((4-(1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-carbonyl)piperazin-1-yl)methyl)phenyl)-5-hydroxy-4H-1,2,4-triazol-3-yl)-5-hydroxy-2-isopropylphenyl phosphate dihydrogen ester. 1H NMR (400MHz, DMSO-d6): δ8.53(s,1H),8.33(s,1H),7.75(d,J=7.9Hz,1H),7.55-7.41 (m,3H),7.31-7.24(m,3H),7.22-7.13(m,4H),6.86(s,1H),4.34(s,2H),4.26(d,J=7. 0Hz, 2H), 3.70(s, 2H), 3.63-3.56(m, 2H), 3.52-3.44(m, 8H), 3.21-3.16(m, 2H), 3.13-3.11(m, 1H), 2.98(s, 2H), 2.05(s, 5H), 1.52(t, J = 6.9Hz, 3H), 1.16(d, J = 6.9Hz, 6H). LCMS(ESI): RT = 1.040 min, measured m / z value is 974.2[M+H]+.

[0752] Compound 181

[0753]

[0754] 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-((1-((1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-N-(1,1,1-trifluoropropyl-2-yl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1 H NMR(400MHz,DMSO-d6)δ9.77(s,1H),9.61(d,J=8.9Hz,1H),9.20-9.05(m,1H),8.77(s,1H),8.61(s,1H),7 .75(d,J=7.8Hz,1H),7.58(s,2H),7.48-7.32(m,5H),6.66(d,J=6.4Hz,2H),6.56(d,J=7.8Hz,1H),6.33(s ,1H),5.32(t,J=4.6Hz,1H),4.70-4.59(m,1H),4.11-3.98(m,4H),3.68(s,8H),3.46(s,4H),3.07-2.73(m ,12H),2.02-1.81(m,7H),1.34(d,J=7.0Hz,4H),1.24(s,5H),1.18(t,J=6.7Hz,3H),0.87(d,J=6.0Hz,6H). LCMS(ESI):RT =1.105 min, measured m / z value is 1164.7 [M-CF3COOH+H] + .

[0755] Compound 182

[0756]

[0757] 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-((1-(1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-N-(1,1,1-trifluoropropyl-2-yl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1 H NMR (400MHz, DMSO-d6) δ9.77(s,1H),9.62(s,1H),9.59(s,1H),8.83(s,1H),8.63(s,1H),7.75(d,J=7 .8Hz,1H),7.59(d,J=3.7Hz,3H),7.54-7.32(m,8H),6.83-6.60(m,3H),6.33(s,1H),4.68-4.59(m,1H ),4.40(d,J=11.9Hz,1H),4.11-3.93(m,4H),3.69(s,7H),3.46(s,5H),2.96-2.88(m,4H),2.04-1.92 (m,2H),1.75(s,8H),1.34(d,J=7.0Hz,4H),1.24(s,3H),1.19(t,J=6.7Hz,5H),0.87(d,J=6.8Hz,6H). LCMS(ESI):R T =1.210 min, measured m / z value is 1178.7 [M-CF3COOH+H] + .

[0758] Compound 183

[0759]

[0760] 2-((4-(4-((7-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1 HNMR(400MHz,DMSO-d6)δ11.98(s,1H),10.03(s,1H),9.80-9.60(m,2H),9.37(s,1H),8.74(s,1H),8.60(s,1H),7.75(d,J=8.2Hz,1 H),7.58(s,2H),7.47(d,J=8.0Hz,2H),7.29(t,J=9.6Hz,2H),6.84(s,1H),6.62(s,1H),6.52(d,J=8.3Hz,1H),6.26(s,1H),4.24(s, 1H),4.15(s,1H),4.09–3.89(m,5H),3.68(s,3H),3.46(s,3H),3.29-3.17(m,4H),3.07-2.85(m,3H),2.65(d,J=11.1Hz,2H),2.35-2 .16(m,3H),2.09-1.94(m,1H),1.80(dd,J=42.0,11.6Hz,4H),1.37-1.21(m,4H),1.17(t,J=6.9Hz,3H),1.00(dd,J=6.6,3.6Hz,6H). LCMS(ESI):R T =0.940 min, measured m / z value is 984.3 [M-CF3COOH+H] + .

[0761] Compound 184

[0762]

[0763] 2-((4-(4-((2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1HNMR(400MHz,CD3OD)δ8.61(s,1H),7.96(d,J=8.8Hz,1H),7.84(dd,J=7.7,1.5Hz,1H),7.64-7 .45(m,6H),7.38(d,J=8.4Hz,2H),6.89(d,J=4.9Hz,2H),6.83(d,J=8.2Hz,1H),6.21(s,1H),4. 46(s,2H),4.17-4.07(m,5H),3.74-3.67(m,2H),3.56(d,J=4.3Hz,6H),3.14-3.06(m,5H),2.2 4-2.14(m,3H),2.06-1.98(m,3H),1.67-1.57(m,2H),1.40-1.27(m,9H),1.03(d,J=6.9Hz,6H). LCMS(ESI):R T =1.150 min, measured m / z value is 984.5 [M-CF3COOH+H] + .

[0764] Compound 185

[0765]

[0766] 4-(4-((4-((1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-(1,1,1-trifluoroprop-2-yl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6) δ9.70 (s, 1H), 9.60 (d, J = 9.0Hz, 1H), 8.77 (s, 1H), 8.62 (s, 1H), 7.75 (d, J = 7.4Hz, 1H),7.60-7.57(m,2H),7.49-7.29(m,7H),6.68(s,2H),6.59(s,1H),6.31(s,1H),4.67-4.61(m,1H),4. 07-3.99(m,4H),3.68(s,5H),3.46(s,3H),2.99(s,4H),2.77(s,2H),2.34-2.24(m,3H),2.03-1.97(m,1 H), 1.84 (d, J = 12.5Hz, 2H), 1.34 (d, J = 7.0Hz, 5H), 1.24 (s, 3H), 1.18 (t, J = 6.9Hz, 4H), 0.92-0.84 (m, 4H). LCMS(ESI):R T =1.210 min, measured m / z value is 1053.3 [M-CF3COOH+H] + .

[0767] Compound 186

[0768]

[0769] 4-(4-((4-((1-(4-((11-cyclopentyl-5-methyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-5-(5-ethyl-2,4-dihydroxyphenyl)-N-(1,1,1-trifluoroprop-2-yl)-4H-1,2,4-triazol-3-carboxamide, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ9.69(s,1H),9.60(d,J=9.2Hz,1H),8.35(s,1H),7.93(s,1H),7.8 7-7.73(m,1H),7.57(d,J=7.7Hz,1H),7.48-7.24(m,7H),7.16(t,J=7.2Hz,1H),6.68(s,3H ), 6.31(s,1H), 4.63(s,2H), 4.07(d,J=7.5Hz,3H), 3.41(s,6H), 3.07(s,8H), 2.28(d,J=7.6Hz,5H), 2.06(s,2H), 1.84(s,2H), 1.57(s,6H), 1.36-1.26(m,9H), 0.89(t,J=7.5Hz,4H). LCMS(ESI): RT=1.330min, measured m / z value is 1043.3[M-CF3COOH+H]+.

[0770] Compound 187

[0771]

[0772] 2-((4-(4-((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-ethoxyphenyl)amino)-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one. 1H NMR (400MHz, DMSO-d6): δ11.92(s,1H),9.60(s,1H),9.41(s,1H),8.72(s,1H),8.60(s,1H),7.74(d,J=7.5Hz,1H),7.58(d,J=3.7Hz,2H ),7.48-7.41(m,1H),7.27(dd,J=16.9,8.5Hz,3H),7.13(d,J=8.3Hz,2H),6.76(s,1H),6.57(s,1H),6.47(d,J=8.7Hz,1H),6.27(s,1H) 4.07-3.91(m,3H), 3.65(d,J=20.0Hz,5H), 3.45(d,J=4.4Hz,6H), 3.03-2.90(m,1H), 2.63(t,J=11.4Hz,2H), 2.37(s,6H), 2.16(d,J=6.4Hz,2H), 2.03-1.95(m,1H), 1.76(d,J=11.0Hz,2H), 1.62(s,1H), 1.32(d,J=15.0Hz,2H), 1.15(t,J=6.9Hz,3H), 0.94(d,J=6.9Hz,6H). LCMS(ESI): RT=1.150min, measured m / z value is 944.3[M+H]. + .

[0773] Compound 188

[0774]

[0775] 11-Cyclopentyl-2-((4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)-2-ethoxyphenyl)amino)-5-methyl-5,11-dihydro-6H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6): δ11.93(s,1H),9.62(s,1H),8.47(s,1H),8.33(s,1H),7.85(s,1H),7.75(d,J=8.9H z,1H),7.56(d,J=6.0Hz,1H),7.43(d,J=7.4Hz,1H),7.34(d,J=8.0Hz,1H),7.26(d,J=8.6Hz,1H),7.15(d,J =7.8Hz, 3H), 6.78(s, 1H), 6.60(s, 1H), 6.49(s, 1H), 6.27(s, 1H), 4.05(d, J = 5.6Hz, 2H), 3.52(s, 2H), 3.40(s, 3H), 2.33(s, 1H), 2.08(s, 4H), 1.56(s, 5H), 1.29-1.23(m, 8H), 1.17-1.09(m, 3H), 0.96(d, J = 6.8Hz, 6H). LCMS(ESI): RT = 1.117 min, measured m / z value is 837.5 [M-CF3COOH+H] + .

[0776] Compound 189

[0777]

[0778] 2-((4-(4-(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)-2-oxoethoxy)piperidin-1-yl)-2-ethoxyphenyl)amino)-5,11-dimethyl-5H-benzo[e]pyrimidine[5,4-b][1,4]diaza-6(11H)-one, trifluoroacetic acid. 1H NMR (400MHz, DMSO-d6) δ11.92(s,1H),9.59(s,1H),9.40(s,1H),8.32(s,1H),7.93(s,1H),7.69(d,J=8.8Hz, 1H),7.55(dd,J=7.7,1.6Hz,1H),7.43(ddd,J=12.2,4.9Hz,1H),7.34(d,J=8.3Hz,2H),7.26(d,J=8.3Hz,1H) ,7.15(t,J=7.6Hz,3H),6.78(s,1H),6.61(d,J=2.2Hz,1H),6.51-6.45(m,1H),6.28(s,1H),3.78(s,3H),3.5 2(s,2H),3.40(s,3H),3.12(s,4H),2.99-2.95(m,1H),1.56(s,5H),1.28-1.17(m,8H),0.96(d,J=6.9Hz,6H). LCMS(ESI):R T =1.097 min, measured m / z value is 823.4 [M-CF3COOH+H] + .

[0779] Compound 190

[0780]

[0781] 4-(4-((4-((11-cyclopentyl-5-methyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)-3-ethoxyphenyl)piperazin-1-yl)methyl)phenyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4H-1,2,4-triazol-3-carboxamide. 1H NMR (400MHz, DMSO-d6) δ8.95(t,J=5.8Hz,1H),8.34(s,1H),7.86(s,1H),7.76(d,J=8.7Hz,1H),7.56(dd,J=7.7,1.6Hz,1H),7.44(d d,J=13.4,5.0Hz,3H),7.29(dd,J=24.1,8.3Hz,3H),7.15(t,J=7.5Hz,1H),6.65-6.57(m,2H),6.50(dd,J=8.8,2.2Hz,1H),6.33(s,1 H),4.65-4.54(m,1H),4.12-4.00(m,2H),3.58(s,2H),3.40(s,4H),3.23-3.08(m,7H),3.00-2.87(m,1H),2.56(s,4H),2.32-2.22( m,1H),2.12-2.00(m,1H),1.65-1.46(m,5H),1.44-1.33(m,1H),1.27(t,J=6.9Hz,3H),1.05(t,J=7.2Hz,3H),0.83(d,J=6.9Hz,6H). LCMS(ESI):R T = 1.437 min, measured m / z value is 892.5 [M+H] + .

[0782] Compound 191

[0783]

[0784] 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-((1-(3-ethoxy-4-((5-methyl-11-(methanesulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimidin[5,4-b][1,4]diaza-2-yl)amino)benzyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-N-(2,2,2-trifluoroethyl)-4H-1,2,4-triazol-3-carboxamide. 1H NMR (400MHz, DMSO-d6): δ10.45(s,1H),9.83(s,1H),9.68-9.54(m,1H),8.9 2(s,1H),8.69(s,1H),7.76(d,J=7.5Hz,2H),7.70-7.55(m,3H),7.53-7.25( m,6H),6.61(s,1H),6.38(s,1H),4.22-3.89(m,6H),3.70(s,4H),3.48(s,7H ), 2.98-2.81 (m, 2H), 2.45-2.06 (m, 9H), 1.24 (s, 8H), 0.82 (d, J = 6.8Hz, 7H). LCMS(ESI):R T = 1.367 min, measured m / z value is 1067.5 [M+H] + .

[0785] Example 2: Testing various CHAMP molecules

[0786] Materials and methods

[0787] cell lines

[0788] The following cancer cell lines were used: A549 human lung cancer (ATCC, #CCL-185); BT-474 human breast cancer (ATCC, #HTB-20); MDA-MB-231 human breast adenocarcinoma (ATCC, #CRM-HTB-26); MDA-MB-468 human breast adenocarcinoma (ATCC, #HTB-132); MV-4-11 human acute myeloid leukemia (ATCC, #CRL-9591); and U-87MG human glioblastoma (ATCC, #HTB-14). The cell lines were cultured primarily according to ATCC recommendations.

[0789] HSP90α binding fluorescence polarization (FP) assay

[0790] Unless otherwise specified, use the HSP90α (N-terminus) Assay Kit (BPS Bioscience, #50298) to measure the binding of the test compound to the HSP90α protein by fluorescence polarization (FP) following the manufacturer's instructions. Use a fluorescently labeled HSP90-binding compound (i.e., the provided FITC-geldmycin) (5 nM final concentration) or RNK04010 (a triazolone-based HSP90-binding small molecule) labeled with a piperazine-phenyl linker (5 nM final concentration) using a BODIPY label. Assay 2.5-fold serial dilutions (range 20 μM to 5.2 nM) of each test compound for HSP90α binding. After the final step of adding the HSP90α protein to each well, mix the plate by brief shaking, incubate the FITC-geldmycin at 25 °C for 120 min or the RNK04010 for 300 min, and measure fluorescence using a PerkinElmer EnVision plate reader. The mP value after background subtraction was calculated from the raw data, and a four-parameter "log[inhibitor] vs. response" curve was fitted. The IC50 value (the concentration at which 50% of the maximum inhibition occurs) was calculated using GraphPadPrism 7 software.

[0791] MAPK7 kinase assay

[0792] Unless otherwise specified, follow the manufacturer's instructions to measure the inhibition of MAPK7 kinase activity by the ADP-Glo ​​kinase assay (Promega, #V6930). Prepare 3-fold serial dilutions of each test compound in the range of 50 μM to 2.54 nM. Additionally, as a positive control, prepare 4-fold serial dilutions of the MAPK7 inhibitor XMD17-109 (MedChemExpress, #HY-15665) in the range of 10 μM to 0.04 nM. Briefly, in 384-well plates, add the test compound to a kinase reaction mixture containing recombinant MAPK7 protein (Carna Biosciences, #04-146; 20 nM final concentration), myelin basic protein (SignalChem Biotech, #M42-54G; 0.1 mg / mL final concentration), and ATP (340 μM final concentration), mix by shaking, and incubate with the ADP-Glo ​​reagent and kinase assay reagent. Emissions were measured on a BioTek plate reader. The inhibition percentage was calculated and plotted using the following equation, and the IC50 value (the concentration at which 50% of maximum inhibition occurs) was calculated using GraphPad Prism7 software:

[0793]

[0794] The average ratio of the 10-well positive control (10μM XMD17-109) on the entire plate.

[0795] The average ratio of the 10-well negative control (0.5% DMSO) on the entire plate.

[0796] MAPK7 protein blot protein degradation assay

[0797] U-87MG human glioblastoma cells were seeded in 6-well or 12-well tissue culture plates. After 1 hour, various concentrations of test compounds were added and the cells were incubated at 37°C / 5% CO2 for 48 hours. Cells were then washed with cold PBS, aspirated, and lysed with cold RIPA buffer containing a mixture of protease / phosphatase inhibitors. After centrifugation, the total protein concentration of the cell lysates was determined using the BCA protein assay. Samples were normalized to equivalent protein concentrations, and 5X SDS-PAGE loading buffer was added, followed by denaturation at 100°C for 10 minutes. 20 μL of each sample / well was loaded onto an SDS-PAGE gel and electrophoresed at 80 V for 20 minutes, followed by electrophoresis at 120 V for 1.5 hours. The gel was then wet-blown onto a nitrocellulose membrane at 250 mA for 2.5 hours. The membrane was incubated with blocking buffer for 1 hour and washed three times with TBST for 5 minutes each. Then, following the manufacturer's recommendations, the membrane was incubated overnight at 4°C with anti-MAPK7 (anti-ERK5; Cell Signaling Technology, #12950) and anti-β-actin (Cell Signaling Technology, #3700) monoclonal antibodies diluted in blocking buffer. After three washes, the blot was incubated with appropriately labeled secondary antibody at room temperature for 1 hour, followed by another wash. Fluorescence imaging and quantification were performed using LI-COR Odyssey. Results were analyzed using GraphPad Prism 7 software. ERBB2 (HER2) flow cytometry protein degradation assay.

[0798] BT-474 human breast cancer cells were seeded at a density of 250,000 cells / well in 24-well tissue culture plates and incubated at 37°C / 5% CO2 for 24 hours. Cells were then treated with various concentrations of test compounds and incubated at 37°C / 5% CO2 for 24 hours. To analyze total ERBB2 expression by flow cytometry, cells were isolated with trypsin, washed, counted, and treated with 10 μL / 10... 6Cells were treated with a PE-conjugated anti-ERBB2 monoclonal antibody (R&D Systems, #FAB1129P) in the dark at 25°C for 30 min. Cells were then washed, resuspended in 200 μL of 1% paraformaldehyde, and analyzed by flow cytometry. Compound inhibition was determined using the following equation, and the DC50 value (the concentration at which 50% of the maximum degradation of ERBB2 occurs) was calculated using GraphPad Prism 7 software:

[0799] Inhibition % = 100 - (DB) / (SB) * 100%.

[0800] S: Fluorescence intensity of cells and antibodies

[0801] D: Fluorescence intensity of cells and antibodies treated with the compound.

[0802] B: Fluorescence intensity of cells without antibodies

[0803] Cancer cell line proliferation (CCK-8 assay)

[0804] Cells were seeded at a density of 4,000 cells / well in 96-well tissue culture plates and incubated at 37°C / 5% CO2 for 24 hours. Serial dilutions of each test compound in the range of 20 μM to 1.02 nM were prepared in triplicate. Cells were then treated with various concentrations of the test compound, with a final concentration of 0.5% DMSO / well, followed by incubation at 37°C / 5% CO2 for 72 hours. 10 μL of cell proliferation assay reagent CCK-8 (Dojindo Molecular Technologies, #CK04) was added to each well and incubated at 37°C / 5% CO2 for 3–4 hours, with absorbance measured at 450 nm using a Perkin Elmer EnVision plate reader. Compound inhibition was determined using the following equation, and the EC50 value (concentration at which 50% maximum inhibition occurs) was calculated using GraphPad Prism 7 software:

[0805] Inhibition % = 100 - (DB) / (SB) * 100%.

[0806] S: Absorbance of cells treated with DMSO

[0807] D: Absorbance of cells treated with the compound

[0808] B: Absorbance of a culture medium containing DMSO but without cells.

[0809] result

[0810] Numerous synthetic protocols have been developed to construct various CHAMP molecules (referred to as MAPK7-CHAMP molecules) designed for the degradation of MAPK7. Representative examples are shown, each consisting of an HSP90 binder linked to a MAPK7 binder. Similar chemical reactions can be applied to other CHAMP molecules, not limited to these specific HSP90-binding and MAPK7-binding moieties.

[0811] Competition with fluorescently labeled HSP90 binders, FITC-geldmycin, or RNK04010 (BODIPY label) was measured using HSP90α-binding fluorescence polarization (FP) assays to evaluate the binding affinity of CHAMP molecules to HSP90. As shown in Table 1, the CHAMP molecules containing the HSP90 binding moiety described in the literature generally conform to the published structure-activity relationship (SAR).

[0812] In this assay, incorporating MAPK7 binders with similar molecular weights to the HSP90 binders into CHAMP generally had little effect on the binding of CHAMP molecules to HSP90α (Table 1). There are several reasons for this: first, the co-crystal structures of these moieties and their corresponding proteins are available, allowing for precise structure-based molecular design; second, the linkers are constructed to provide rigidity with appropriate lengths.

[0813] In the biochemical kinase assay, the binding of various CHAMP molecules to MAPK7 was evaluated by measuring the inhibition of MAPK7 phosphorylation activity, as shown in Table 1. The CHAMP molecules containing the MAPK7 binding moiety described in the literature are largely consistent with the published SAR.

[0814] The incorporation of chaperone-binding moieties (such as the HSP90 chaperone) typically has little effect on the binding of CHAMP molecules to MAPK7, as measured by this assay. There are several reasons for this: first, the co-crystal structures of these moieties and their corresponding proteins are available, allowing for precise structure-based molecular design; second, the chaperones are constructed to provide rigidity with appropriate lengths.

[0815] Heterobifunctional CHAMP molecules, possessing both MAPK7-binding and HSP90-binding moieties, were designed to induce targeted protein degradation (TPD) of MAPK7. As shown in Table 2, U-87MG human glioblastoma cells expressing MAPK7 were treated with various concentrations of CHAMP compounds for 48 hours, and the degradation of MAPK7 was observed by Western blotting.

[0816] CHAMP molecules may include chaperone or chaperone complex binders with a range of different binding affinities. In different embodiments, high-affinity, medium-affinity, or low-affinity binders are desired. Since the HSP90 binding moiety interacting with the N-terminal ATP-binding pocket of HSP90 may inhibit HSP90 activity and induce degradation of HSP90 client proteins, some CHAMP molecules may induce degradation not only of one or more desired target proteins (which may or may not be HSP90 client proteins) but also that of the HSP90 client protein. As shown in Table 1, CHAMP compounds also exhibit varying degrees of degradation of the HSP90 client protein ERBB2, as assessed by flow cytometry in BT-474 human breast cancer cells expressing ERBB2.

[0817] As shown in Table 1, various MAPK7 CHAMP molecules also inhibited the growth and / or survival of a group of cancer cell lines, as measured by the CCK-8 cell line proliferation assay.

[0818] Table 1: Biochemical and cell-based assays of compounds

[0819]

[0820]

[0821]

[0822]

[0823] 1 HSP90α binding FP (BODIPY) determination: A. IC50 < 100 nM; B. IC50 = 100 nM to 1000 nM; C. IC50 > 1000 nM;

[0824] 2 HSP90α binding FP (FITC) determination: A. IC50 < 100 nM; B. IC50 = 100 nM to 1000 nM; C. IC50 > 1000 nM;

[0825] 3 MAPK7 kinase assay: A. IC50 < 100 nM; B. IC50 = 100 nM to 1000 nM; C. IC50 > 1000 nM; 4 Flow cytometry assay of ERBB2 protein degradation in BT-474 cells: A. DC50 < 100 nM; B. DC50 = 100 nM to 1000 nM; C.

[0826] DC50 > 1000nM;5 A549 CCK-8 proliferation assay: A. EC50 < 100 nM; B. EC50 = 100 nM to 1000 nM; C.

[0827] EC50 > 1000 nM; 6 MDA-MB-231CCK-8 proliferation assay: A. EC50 < 100 nM; B. EC50 = 100 nM to 1000 nM; C.

[0828] EC50 > 1000 nM; 7 MDA-MB-468CCK-8 proliferation assay: A. EC50 < 100 nM; B. EC50 = 100 nM to 1000 nM; C.

[0829] EC50 > 1000 nM; 8 MV-4-11CCK-8 proliferation assay: A. EC50 < 100 nM; B. EC50 = 100 nM to 1000 nM; C.

[0830] EC50 > 1000 nM; 9 U87 MG CCK-8 proliferation assay: A. EC50 < 100 nM; B. EC50 = 100 nM to 1000 nM; C.

[0831] EC50>1000nM

[0832] Table 2: MAPK7 degradation of the compounds

[0833]

[0834]

[0835] -1 Western blot assay of MAPK7 protein degradation in U-87MG cells:

[0836] A. >66% degradation; B. 33%-66% degradation; C. <33% degradation

[0837] 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.

[0838] Incorporate by reference

[0839] 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: or a pharmaceutically acceptable salt thereof, wherein A is selected from: wherein , , , and ; Z is N or CH; Q is independently selected from phenyl and saturated monocyclic alkyl of 4-6 carbon atoms and U is independently selected from phenyl, and each of Q and U is optionally substituted with 1 to 3 groups selected from R 2 ; R 13 and R 14 are each independently selected from the group consisting of hydrogen, halo, -CN, (Ci-C4)alkyl, halo(Ci-C4)alkyl, and -C(O)NR a R b ; R 1 halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, or halo(C1-C4)alkoxy; R 2 (C1-C4)alkyl, halo(C1-C4)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2-C6)alkynyl, halo(C2-C6)alkynyl, CN, -C 1-4 alkylOR a , -OR a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -C(O)NR a (C 1-4 alkylene)OR a , -C(O)NR a (C 1-4 alkylene)NR a R b , -C(O)NR a (C 1-4 alkylene)OR, -NR a R b , -O(C 1-4 alkylene)NR a R b , -C 1-4 alkylNR a R b , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -SO2NR a R b , -NR a (C 1-4 alkyl)OR a , -SH, -S(C 1-4 alkyl), -NR a (C 1-4 alkyl)NR a R b , -C 1-6 alkylC(O)NR a R b , -O(C 1-4 alkenylene)NR a C(O)(C 1-4 alkylene)NR a R b , phenyl or 5- to 7-membered heteroaryl, wherein the phenyl and 5- to 7-membered heteroaryl are each optionally and independently substituted with 1 to 3 groups selected from R 4 ; R a and R b are each independently selected from the group consisting of hydrogen and (Ci-C4)alkyl, wherein the (Ci-C4)alkyl is optionally substituted with one or more halo or 3- to 7-membered heterocyclyl, or both; and R 3 and R 4 each independently halo, -NR a R b , (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy; m, n, o, p, q, and r are each independently an integer selected from 0, 1, 2, 3, 4, 5, and 6; L is Het 1 -X 1 , Het 1 -X 1 -Het 2 -X 2 , Het 1 -O-(CH2) m -X 1 -Het 2 -X 2 , Het 1 -O-(CH2) m -X 1 -NR c -(CH2CH2O) n (CH2) m -Het 2 -X 2 , Het 1 -X 1 -NR c -(CH2) m , Het 1 -X 1 -Het 2 -Het 3 -X 2 , Het 1 -X 1 -NR c -(CH2CH2O) n (CH2) m , Het 1 -X 1 -NR c -(CH2CH2O) n Het 2 -(CH2) m -X 2 , Het 1 -X 1 -NR c -(CH2CH2O) n , Het 1 -X 1 -NR c -(CH2) m -Het 2 -X 2 -Het 3 -(CH2) m , Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -X 2 , Het 1 -X 1 -Het 2 , Het 1 -X 1 -NR c , Het 1 -X 1 -NR c -(CH2) m -Phe-X 2 -Het 2 -(CH2) m , Het 1 -X 1 -Het 2 -Het 3 , Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -X 2 -(CH2) p -NR c -(CH2) m , Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -(CH2) m -O , Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -(CH2) p -NR c -(CH2) m , Het 1 -X 1 -Het 2 -(CH2CH2O) n , Het 1 -X 1 -(CH2) m -Het 2 -X 2 , -(CH2CH2O) o -(CH2) p -Het 1 -X 1 -Het 2 -(CH2CH2O) n , -(CH2CH2O) n -(CH2) m -Het 1 -X 1 -Het 2 -X 2 , Het 1 -X 1 -Phe-X 2 -NR c -X 3 , -(CH2CH2O) o -(CH2) p -Het 1 -X 1 -Phe-X 2 -NR c -(CH2CH2O) n , -(CH2CH2O) n -(CH2) m -NR c -Phe-X 1 , -(CH2CH2O) o -(CH2) p -NR c -Phe-(CH2CH2O) n , -(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m , (CH2CH2O) n -(CH2) m -NR c -(CH2CH2O) n -(CH2) m -C(O)-NR d -(CH2CH2O) o -(CH2) p -(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m -Het 1 -X 1 -Het 2 -X 2 -(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m -Het 1 -X 1 -Het 2 -X 2 -(CH2CH2O) o NR c -(CH2CH2O) n -(CH2) m -Phe-NH-X 1 -Het 1 -X 2 NR c -(CH2CH2O) n -(CH2) m -Phe-NH-X 1 -Het 1 -X 2 -(CH2CH2O) o -(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m -Phe-X 1 -NR c -(CH2CH2O) o -(CH2) p -(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m -Het 1 -X 1 -(CH2CH2O) o -(CH2) p -NR c -(CH2CH2O) n -(CH2) m -Het 1 -X 1 -(CH2CH2O) n -(CH2CH2O) n -(CH2) m -NR c -(CH2) m -C(O)-NR d -Het 1 -X 1 -Het 2 -(CH2CH2O) o -(CH2) p or NR c -(CH2) m -C(O)-NR d -(CH2) m -Het 1 -X 1 -Het 2 -X 2 , represents the point of attachment to A; Het 1 , Het 2 , and Het 3 each independently is piperidinyl, phenyl, pyridinyl, piperazinyl, or pyrrolidinyl; X 1 , X 2 , and X 3 are each independently C(O) or (CH2) r ; and k and v are each independently 0, 1, 2, or 3. R 10 and R 16 are each independently selected from the group consisting of halo, (Ci-C6)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2-C6)alkynyl, -(Ci-C6)alkylOR c , -(Ci-C6)alkylN(R d )2, -(Ci-C6)alkylC(O)OR d , -(Ci-C6)alkylC(O)N(R d )2, -(Ci-C6)alkylO(Ci-C6)alkylN(R d )2, -(Ci-C6)alkylSOR d , -(Ci-C6)alkylS(O)2R d , -(Ci-C6)alkylSON(R d )2, -(Ci-C6)alkylSO2N(R d )2, -(Ci-C6)alkoxy, halo(Ci-C6)alkoxy, CN, -C(O)R d , -C(O)OR d , -C(O)N(R d )2, N(R d )2, -C(O)NR d (Ci-C6)alkylN(R d )2, -NR d (Ci-C6)alkylN(R d )2, -NR d (Ci-C6)alkylOR d , -SOR d , -S(O)2R d , -SON(R d )2, -SO2N(R d )2, and CN; R 19 independently selected from the group consisting of hydrogen, halo, (Ci-C6)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2-C6)alkynyl, -(Ci-C6)alkylOR c , -(Ci-C6)alkylN(R d )2, -(Ci-C6)alkylC(O)OR d , -(Ci-C6)alkylC(O)N(R d )2, -(Ci-C6)alkylO(Ci-C6)alkylN(R d )2, -(Ci-C6)alkylSOR d , -(Ci-C6)alkylS(O)2R d , -(Ci-C6)alkylSON(R d )2, -(Ci-C6)alkylSO2N(R d )2, -(Ci-C6)alkoxy, halo(Ci-C6)alkoxy, CN, -C(O)R d , -C(O)OR d , -C(O)N(R d )2, N(R d )2, -C(O)NR d (Ci-C6)alkylN(R d )2, -NR d (Ci-C6)alkylN(R d )2, -NR d (Ci-C6)alkylOR d , -SOR d , -S(O)2R d , -SON(R d )2, -SO2N(R d )2, and CN; R 11 , R 17 , R 18 and R 20 are each independently selected from the group consisting of hydrogen, (Ci-C6)alkyl and S(O)2(Ci-C6)alkyl; R 12 is hydrogen, (Ci-C6)alkyl, halo(Ci-C6)alkyl, -(Ci-C6)alkylOR c , S(O)2(Ci-C6)alkyl or C(O)(Ci-C6)alkyl; R c and R d are each independently selected from the group consisting of hydrogen, (Ci-C6)alkyl, and halo(Ci-C6)alkyl; and 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein k is 0. 。 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein v is 0.

12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is CH.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 11 is hydrogen.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 17 is (Ci-C6)alkyl.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 17 is methyl.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 12 is (Ci-C6)alkyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 12 is ethyl.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 18 is (Ci-C3)alkyl or S(0)2(Ci-C3)alkyl.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 18 is S(O)2Me.

14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is 13. The compound of claim 1, wherein each R 3 is (Ci-C4)alkyl or halo.

15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is or .

16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is , or .

29. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein m, n, o, p, q, and r are each independently an integer selected from 0, 1, 2, and 3. 。 17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is halo or (Ci-C4)alkyl.

18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is chloro, isopropyl, methyl, propyl, or ethyl.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is isopropyl or ethyl.

20. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is -OR a , -SR a , -C(O)NR a R b or -C(O)NR a (C 1-4 alkylene)NR a R b .

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R a and R b are each independently selected from hydrogen and (Ci-C4)alkyl, wherein the (Ci-C4)alkyl is optionally substituted with 1 to 3 halo groups or 6-membered heterocyclyl.

22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is OH, -C(O)NHCH2CF3, -C(O)NHCH2CH3, -C(O)NHCH(CH3)2, -C(O)NH(CH2CH3)2, -C(O)NHCH(CH3)CF3, -C(O)NHcyclopropyl, -C(O)NHmethylcyclopropyl, C(O)NH2, or -C(O)NH(CH2)2piperidinyl.

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is -C(O)NHCH2CF3 or OH.

24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is OH.

25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is Het 1 - X 1 - Het 2 - X 2 , Het 1 - O-(CH2) m - X 1 - Het 2 - X 2 , Het 1 - O-(CH2) m - X 1 - NR c - (CH2CH2O) n (CH2) m - Het 2 - X 2 , Het 1 - X 1 - NR c - (CH2) m , Het 1 - X 1 - Het 2 - Het 3 - X 2 , Het 1 - X 1 - NR c - (CH2CH2O) n (CH2) m , Het 1 - X 1 - NR c - (CH2CH2O) n Het 2 - (CH2) m - X 2 , Het 1 - X 1 - NR c - (CH2CH2O) n , Het 1 - X 1 - NR c - (CH2) m - Het 2 - X 2 - Het 3 - (CH2) m , Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -X 2 , Het 1 -X 1 -Het 2 , Het 1 -X 1 -NR c , Het 1 -X 1 -NR c -(CH2) m -Phe-X 2 -Het 2 -(CH2) m , Het 1 -X 1 -Het 2 -Het 3 , Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -X 2 -(CH2) p -NR c -(CH2) m , Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -(CH2) m -O , Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -(CH2) p -NR c -(CH2) m or Het 1 -X 1 -Het 2 -(CH2CH2O) n .

26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is Het 1 -X 1 -Het 2 -X 2 , Het 1 -X 1 -NR c -(CH2) m , Het 1 -X 1 -Het 2 -Het 3 -X 2 or Het 1 -X 1 -Het 2 -(CH2) m -Het 3 -X 2 .

27. The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein L is Het 1 - X 1 - N c - (CH2) m or Het 1 - X 1 - Het 2 - (CH2) m - Het 3 - X 2 .

28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is Het 1 - X 1 - Het 2 - (CH2) m - Het 3 - X 2 .

30. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L is selected from 31. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and .

32. The compound according to claim 1, wherein the compound is selected from the following structural formulas: , and . and 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 33. The compound according to claim 1, wherein the compound is selected from the following structural formulas: , or a pharmaceutically acceptable salt of any of the foregoing compounds.

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

35. Use of a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34, in the manufacture of a medicament for the treatment of cancer. ​

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