KRAS-degrading PROTAC based on cerebellar protein and related uses thereof

Abstract

Provided herein are compounds that target KRas and are therefore useful in the treatment of cancer.

Description

[0001] Citations of relevant applications

[0002] This application claims priority to U.S. Provisional Application Serial No. 63 / 592,814, filed October 24, 2023; U.S. Provisional Application Serial No. 63 / 486,528, filed February 23, 2023; and U.S. Provisional Application Serial No. 63 / 481,672, filed January 26, 2023, all of which are hereby incorporated herein by reference in their entirety. Background Technology

[0003] E3 ubiquitin ligases (such as cerebellum) confer substrate specificity for ubiquitination, and due to the specificity of these ubiquitin ligases for certain protein substrates, they are more attractive therapeutic agents than general proteasome inhibitors. Bifunctional compounds (such as those described in U.S. Patent Application Publications 2015 / 0291562 and 2014 / 0356322, both incorporated herein by reference) are used to recruit endogenous proteins to E3 ubiquitin ligases for ubiquitination and degradation. Specifically, these publications describe bifunctional or proteolytically targeted chimeric compounds (…). These bifunctional compounds are suitable as regulators of targeted ubiquitination of various peptides and proteins, which are then degraded via the proteasome system. They are used to recruit endogenous proteins to E3 ubiquitin ligases for degradation. Specifically, the publications provide bifunctional or proteolytically targeted chimeric (PROTAC) compounds suitable as regulators of targeted ubiquitination of various peptides and other proteins, which are degraded and / or otherwise inhibited by the bifunctional compounds after targeted ubiquitination.

[0004] The Kirsten rat sarcoma (KRAS) gene is an oncogene encoding KRas, a small GTPase signaling protein. Ras proteins associate with the plasma membrane and act as a switch in the transduction of extracellular signals to intracellular responses, thereby regulating, for example, cell division. Numerous activating or gain-of-function mutations of the KRas gene are known, and in fact, KRas is one of the most frequently mutated genes in cancer. Gain-of-function KRas mutations are found in approximately 30% of all human cancers, including, for example, pancreatic cancer (>80%), colon cancer (approximately 40-50%), lung cancer (approximately 30-50%), non-small cell lung cancer, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, and breast cancer. These activating mutations impair the ability of KRas to switch between active and inactive states. The crucial role of mutant KRas in the initiation, maintenance, progression, and metastasis of various cancers has been identified, and mutations are frequently associated with poor prognosis and increased resistance to chemotherapy and biological therapies, including those targeting the epidermal growth factor receptor, for example. However, despite its critical role and high incidence in cancer, the lack of effective therapies that directly target this oncogene has led to it being considered "drugless."

[0005] Therefore, there has always been a need in the field for effective treatments for diseases associated with KRas overexpression, aggregation, and / or overactivation. Summary of the Invention

[0006] This article provides compounds that target KRas and are therefore useful for treating cancer.

[0007] This article provides compounds of any of formulas I-IV:

[0008]

[0009]

[0010] Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. Compounds of formulas V and VI are also provided herein:

[0011]

[0012] Or its pharmaceutically acceptable salt.

[0013] On the one hand, this paper provides compounds of the formula AI or AIV:

[0014]

[0015]

[0016] Or its pharmaceutically acceptable salt.

[0017] On the other hand, this paper provides a compound of formula VII:

[0018] Or its pharmaceutically acceptable salt.

[0019] In the embodiments, the compound of formula I has the structure of formula IA:

[0020]

[0021] Or its pharmaceutically acceptable salt.

[0022] In the embodiments, the compound of formula I has the structure of formula IB:

[0023]

[0024] Or its pharmaceutically acceptable salt.

[0025] In the embodiments, the compound of formula I has the structure of formula IB-i:

[0026] Or its pharmaceutically acceptable salt.

[0027] In the embodiments, the compound of formula II has the structure of formula IIA:

[0028]

[0029] Or its pharmaceutically acceptable salt.

[0030] In the embodiments, the compound of formula II has the structure of formula IIB:

[0031]

[0032] Or its pharmaceutically acceptable salt.

[0033] In the embodiments, the compound of formula III has the structure of formula IIIA:

[0034]

[0035] (IIIA)

[0036] Or its pharmaceutically acceptable salt.

[0037] In the embodiments, the compound of formula IV has the structure of formula IVA:

[0038]

[0039] Or its pharmaceutically acceptable salt.

[0040] In the embodiments, the compound of formula V has the structure of formula VA:

[0041]

[0042] Or its pharmaceutically acceptable salt.

[0043] In the embodiments, the compound of formula VI has the structure of formula VIA:

[0044]

[0045] Or its pharmaceutically acceptable salt.

[0046] On the other hand, this paper provides a compound of formula IVB:

[0047]

[0048] Or its pharmaceutically acceptable salt.

[0049] This article also provides methods for treating or improving disease states or symptoms that are regulated by or causally related to target proteins (e.g., KRas).

[0050] Additionally, this document provides a method for treating a disease or condition in a subject, the method comprising administering to the subject an effective amount of the compound disclosed herein or a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0051] In this embodiment, the disease or condition is cancer.

[0052] This document also provides methods for modulating KRas protein activity, the methods comprising administering to a subject an effective amount of any compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any compound disclosed herein and a pharmaceutically acceptable carrier.

[0053] This article also provides methods for modulating cerebellar protein activity, the methods comprising administering to a subject an effective amount of any compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any compound disclosed herein and a pharmaceutically acceptable carrier.

[0054] This document also provides a method for degrading target proteins in cells, the method comprising contacting the cells with an effective amount of any compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any compound disclosed herein and a pharmaceutically acceptable carrier. Attached Figure Description

[0055] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the present disclosure and, together with this specification, help to explain the principles of the disclosure. The drawings are for illustrative purposes only and should not be construed as limiting the scope of the disclosure. Further objects, features, and advantages of the disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings, which illustrate illustrative embodiments of the disclosure.

[0056] Figure 1 The degradation of HiBiT in various KRAS cells treated with compound 69 was demonstrated.

[0057] Figure 2 Cell-free ubiquitination of KRAS G12D treated with compounds according to one or more embodiments of this disclosure is demonstrated.

[0058] Figure 3A and 3B (A) Proliferation in AsPC-1 cells treated with G12D compound 69, E3-inactive compound 69, and control. (B) Proliferation in various cell types treated with active compound 69.

[0059] Figure 4A and 4B (A) pERK in AsPC-1 spheroids treated with G12D compound 69 was inhibited over time. (B) pERK in AsPC-1 spheroids treated with E3 inactive compound 69 was inhibited over time.

[0060] Figure 5 The activity of caspase 3 / 7 in GP2d globules treated with G12D compound 69, E3-inactive compound 69 and KRAS-inactive compound 69 after 16 hours was demonstrated.

[0061] Figure 6A and 6B (A) KRAS levels and cPARP induction in GP2d tumors treated with a single dose of compound G12D 69. (B) Tumor concentration and KRAS levels in GP2d tumors treated with a single dose of compound G12D 69.

[0062] Figure 7A and 7B (A) is a graph showing the growth volume of GP2d tumors after treatment with mordant or compound 69. (B) XB is a graph showing the growth volume of GP2d tumors after treatment with mordant or compound 102.

[0063] Figure 8 This is a graph showing the growth volume of LS180 tumors after treatment with a catalyst or compound 102.

[0064] Figure 9A and Figure 9B (A) is a graph showing the growth volume of AsPC-1 tumors after treatment with mordant or compound 69. (B) is a graph showing the growth volume of AsPC-1 tumors after treatment with mordant or compound 102.

[0065] Figure 10A and 10B (A) is a graph showing the growth volume of SW1990 tumors after treatment with mordant or compound 69. (B) is a graph showing the growth volume of SW1990 tumors after treatment with mordant or compound 102.

[0066] Figure 11 This is a graph showing the growth volume of HPAC tumors after treatment with a catalyst or compound 69.

[0067] Figure 12 This is a graph showing the growth volume of the Panc04.03 tumor after treatment with the catalyst or compound 69. Detailed Implementation

[0068] definition

[0069] The following lists definitions of various terms used to describe the compounds and compositions disclosed herein. These definitions apply to the terminology used throughout this specification and claims, unless otherwise limited, either individually or as part of a larger group, in specific instances.

[0070] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Typically, the nomenclature used herein, as well as laboratory procedures for cell culture, molecular genetics, organic chemistry, and peptide chemistry, are those well-known and commonly used in the art.

[0071] The specific compounds of this invention can be identified in this specification by their chemical names and / or chemical structures. If there is any direct conflict between the chemical name and the chemical structure, the chemical structure shall prevail.

[0072] As used herein, the articles “a” and “an” refer to one or more (i.e., at least one) of the grammatical objects of an item. For example, “an element” means one or more elements. Furthermore, the use of the term “including” and other forms such as “include,” “includes,” and “included” is not restrictive.

[0073] As used herein, the term “about” will be understood by one of ordinary skill in the art and will vary to some extent in the context of its use. As used herein, when referring to measurable values ​​such as quantity, duration of time, etc., the term “about” means to cover a variation of ±20% or ±10% (inclusive) relative to a specified value, as such variation is suitable for performing the disclosed methods.

[0074] As used herein, the term "administration" refers to the provision of a therapeutic agent to a subject. Various techniques for administering therapeutic agents available in the art include, but are not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0075] The terms "treat," "treated," "treating," or "treatment" include reducing or alleviating at least one symptom related to or caused by the state, condition, or disease being treated. In some embodiments, treatment includes alleviating symptoms of cancer.

[0076] As used herein, the terms “prevent” or “prevention” mean that if the condition or disease does not occur, it will not develop, or if the condition or disease has already occurred, it will not further develop. The ability to prevent some or all of the symptoms associated with the condition or disease is also considered.

[0077] As used herein, the term "cell" is intended to refer to cells in vitro, ex vivo, or in vivo. In embodiments, ex vivo cells may be a portion of a tissue sample excised from an organism such as a mammal. In embodiments, in vitro cells may be cells in a cell culture. In embodiments, in vivo cells may be cells living in an organism such as a mammal.

[0078] As used herein, the term "subject" refers to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets such as sheep, cattle, pigs, dogs, cats, and rodents. Preferably, the subject is a human.

[0079] As used herein, the terms “effective amount,” “pharmaceutical effective amount,” and “therapeutic effective amount” refer to a non-toxic but sufficient amount of a drug to provide the desired biological outcome. This outcome may be a reduction or relief of signs, symptoms, or causes of disease, or any other desired alteration of a biological system. In any individual case, the appropriate therapeutic amount can be determined by a person skilled in the art using routine laboratory methods.

[0080] As used herein, the term “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not eliminate the biological activity or properties of a compound and is relatively non-toxic; that is, the material can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any component of the composition containing it.

[0081] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to: mineral salts or organic acid salts of basic residues such as amines; basic salts or organic salts of acidic residues such as carboxylic acids; and so on. Pharmaceutically acceptable salts of this disclosure include, for example, conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of this disclosure can be synthesized by conventional chemical methods from parent compounds containing a basic or acidic moiety. Typically, these salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both; typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The phrase "pharmaceutically acceptable salt" is not limited to a single salt or a 1:1 salt. For example, "pharmaceutically acceptable salt" also includes disalts, such as dihydrochlorides. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0082] As used herein, the terms "composition" or "pharmaceutical composition" refer to a mixture of at least one compound that can be used in this disclosure with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates the administration of the compound to a subject. Various techniques for administering compounds available in the art include, but are not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0083] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, relating to the delivery or transport of a compound useful in this disclosure to or to a subject, such that the compound can perform its intended function. Typically, such constructs carry or transport from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense that it is compatible with other components of formulations containing compounds useful in this disclosure and is harmless to the subject. Examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic compatible substances used in pharmaceutical formulations.

[0084] As used herein, "pharmaceuticalally acceptable carrier" also includes any and all coating agents, antibacterial and antifungal agents, and absorption delay agents that are compatible with the activity of compounds useful in this disclosure and physiologically acceptable to a subject. Supplemental active compounds may also be incorporated into the composition. "Pharmaceuticalally acceptable carrier" may further include pharmaceutically acceptable salts of the compounds disclosed herein. Additional ingredients that may be included in the pharmaceutical composition are known in the art and described in references such as Remington's Pharmaceutical Sciences (edited by Genaro, Mark Publishing Co., Easton, PA, 1985), which is incorporated herein by reference.

[0085] Unless otherwise stated, as used herein, the term "alkyl" on its own or as part of another substituent means a straight-chain or branched hydrocarbon having a specified number of carbon atoms (i.e., C64 ... 1-6 Alkyl groups (meaning alkyl groups having one to six carbon atoms) include both straight-chain and branched groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. 1-6 Other examples of alkyl groups include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0086] The term "alkenyl," used alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. Formally, an alkenyl group corresponds to an alkene in which one of the CH bonds is replaced by the alkenyl group at the junction with the rest of the compound. The term "C..." n-m "Alkenyl" refers to an alkenyl group having n to m carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc.

[0087] The term "alkynyl" (used alone or in combination with other terms) refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. Formally, an alkynyl corresponds to an alkyne in which one of the CH bonds is replaced by an alkyl group at the junction with the remainder of the compound. The term "C..." n-m "Alynyl" refers to an alkynyl group having n to m carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-yl, prop-2-yl, etc. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0088] As used herein, the term "haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halosubstituents, wherein the alkyl group and the halo group are as defined herein. For example, haloalkyl groups include chloromethyl, trifluoromethyl, bromoethyl, chlorofluoroethyl, etc.

[0089] Unless otherwise stated, the terms “halogenated” or “halogen” as used herein, alone or as part of another substituent, refer to a fluorine, chlorine, bromine or iodine atom, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

[0090] As used herein, the term "cycloalkyl" means a fully saturated non-aromatic carbocyclic system having one, two, or three rings, wherein such rings may be fused. The term "fused" means that the second ring exists (i.e., is connected or formed) by sharing (i.e., co-occurring) two adjacent atoms with the first ring. Cycloalkyl also includes bicyclic structures that may be inherently bridged or spirocyclic, wherein each individual ring in the bicyclic has 3-8 distinct atoms. The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptyl, and bicyclo[1.1.1]pentyl. In the examples, cycloalkyl refers to C 3-10 Cycloalkyl. In another embodiment, cycloalkyl refers to C10. 3-6 Cycloalkyl.

[0091] As used herein, the term "heterocyclic alkyl" means a non-aromatic carbocyclic system containing one, two, three, or four heteroatoms independently selected from N, O, and S and having one, two, or three rings, wherein such rings may be fused, where fusion is as defined above. The term "heterocyclic alkyl" includes unsaturated compounds such as dihydropyridyl, dihydropyridazinyl, dihydropyrimidinyl, and dihydropyrazinyl. Heterocyclic alkyl also includes bicyclic structures that may be inherently bridged or spirocyclic, wherein each individual ring in the bicyclic has 3-8 distinct atoms and contains 0, 1, or 2 N, O, or S atoms. The term "heterocyclic alkyl" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), and specifically includes, but is not limited to, epoxy groups, oxacyclobutyl groups, tetrahydrofuranyl groups, tetrahydropyranyl groups (i.e., oxacyclohexyl groups), pyranyl groups, dioxacycloalkyl groups, aziridinyl groups, aziridine groups, pyrrolidinyl groups, 2,5-dihydro-1H-pyrrolidinyl groups, oxazolyl groups, thiazolyl groups, piperidinyl groups, morpholinyl groups, piperazinyl groups, thiomorpholinyl groups, 1,3-oxazinyl groups, 1,3-thiazolyl groups, 2-azabicyclo[2.1.1]hexyl groups, 5-azabicyclo[2.1.1]hexyl groups, 6-azabicyclo[3.1.1]heptyl groups, 2-azabicyclo[2.2.1]heptyl groups, 3-azabicyclo[3.1.1]heptyl groups, and 2-azabicyclo[2.1.1]heptyl groups. [3.1.1]Heptyl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 3-oxa-7-azabicyclo[3.3.1]nonyl, 3-oxa-9-azabicyclo[3.3.1]nonyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, 2-oxaspiro[3.5]nonyl, 3-oxaspiro[5.3]nonyl and 8-oxabicyclo[3.2.1]octyl. In the embodiments, heterocyclic alkyl refers to a 3-12 membered heterocyclic alkyl group. In the embodiments, heterocyclic alkyl refers to a 6-12 membered heterocyclic alkyl group. In the embodiments, heterocyclic alkyl refers to a 3-10 membered heterocyclic alkyl group. In the embodiments, heterocyclic alkyl refers to a 6-8 membered heterocyclic alkyl group. In the embodiments, heterocyclic alkyl refers to a 6-membered heterocyclic alkyl group. In the embodiments, heterocyclic alkyl refers to a 7-membered heterocyclic alkyl group. In the embodiments, heterocyclic alkyl refers to a 9-membered heterocyclic alkyl group. In the embodiments, heterocyclic alkyl refers to a 9-membered heterocyclic alkyl group.

[0092] A 6-membered heterocyclic alkyl ring is a heteroaryl group having six ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 6-membered heterocyclic alkyl rings include piperidinyl, piperazine, dioxane, thiaalkyl, dithiaalkyl, morpholinyl, thiomorpholinyl, and dihydropyridinyl.

[0093] A 7-membered heterocyclic alkyl ring is a heteroaryl group having seven ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 7-membered heterocyclic alkyl groups include azepinel, oxacycloheptyl, thionylheptyl, oxathionylheptyl, diazaspiro[3.3]heptyl, and azespiro[3.3]heptyl.

[0094] A 9-membered heterocyclic alkyl ring is a heterocyclic alkyl ring having nine ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 9-membered heterocyclic alkyl rings are 2-azaspiro[3.5]nonyl and 2,7-diazaspiro[3.5]nonyl.

[0095] An 11-membered heterocyclic alkyl ring is a heteroaryl group having eleven ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 11-membered heterocyclic alkyl groups include 3,9-diazaspiro[5.5]undecyl and 3-azaspiro[5.5]undecyl.

[0096] As used herein, the term "aromatic" refers to a carbon ring or heterocycle having one or more polyunsaturated rings and exhibiting aromatic characteristics (i.e., having (4n+2) delocalized π(pi) electrons, where n is an integer).

[0097] As used herein, the term "aryl" refers to an aromatic carbocyclic system containing one, two, or three rings, wherein such rings may be fused, as defined above. If the rings are fused, one of the rings must be completely unsaturated, and the fused rings may be completely saturated, partially unsaturated, or completely unsaturated. The term "aryl" includes, but is not limited to, phenyl, naphthyl, indenyl, and 1,2,3,4-ttetrahydronaphthyl. In some embodiments, the aryl group has six carbon atoms. In some embodiments, the aryl group has six to ten carbon atoms. In some embodiments, the aryl group has six to sixteen carbon atoms. In some embodiments, the aryl group has six to ten carbon atoms.

[0098] As used herein, the term “heteroaryl” means an aromatic carbocyclic system containing one, two, three, or four heteroatoms independently selected from N, O, and S and having one, two, or three rings, wherein such rings may be fused, where fusion is as defined above. The term "heteroaryl" includes, but is not limited to, furanyl, thiophene, oxazolyl, thiazolyl, imidazole, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridinyl, pyrazinyl, imidazole[1,2-a]pyridinyl, pyrazazole[1,5-a]pyridinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenten[b]pyridinyl, 6,7-dihydro-5H-cyclopenten-[c]pyridinyl, 1,4, 5,6-Tetrahydrocyclopenteno[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenteno[c]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridyl, 4,5,6,7-tetrahydro-1H-indazoleyl, and 4,5,6,7-tetrahydro-2H-indazoleyl. In the examples, the heteroaryl group is a 5-10-membered heteroaryl group. In the examples, the heteroaryl group is a 5-7-membered heteroaryl group. In the examples, the heteroaryl group is a 6-membered heteroaryl group.

[0099] A 5-membered heteroaryl ring is a heteroaryl group having five ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 5-membered heteroaryl rings include thiophene, furanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0100] A 6-membered heteroaryl ring is a heteroaryl group having six ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 6-membered heteroaryl rings are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

[0101] It should be understood that if an aryl, heteroaryl, cycloalkyl, or heterocyclic moiety can be bonded to or otherwise connected to a specified moiety via different ring atoms (i.e., shown or described without specifying a particular connection point), then all possible points are intended to be connected, whether via a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridinyl" means 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, and the term "thiophene" means 2-thiophene or 3-thiophene, and so on.

[0102] The term "independently chosen" is used in this document to indicate that, for variables appearing in more than one position in a genus, the identity of the variable is determined separately in each case. For example, if R x R appears as a substituent on two different atoms. x Two instances can be the same part or different parts. If a single atom is R x The same applies when more than one instance replaces it. In each case, R x Their identity is determined independently of other identities.

[0103] compound

[0104] This article provides compounds that target Kras and are therefore useful for treating cancer.

[0105] Specifically, this article provides compounds of any one of formulas I-IV:

[0106]

[0107]

[0108] Or its pharmaceutically acceptable salt.

[0109] in:

[0110] Q 1 Selected from C(R) 14 2. C(O) and NR 14 ;

[0111] Q 2 It is CR 14 Or N;

[0112] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0113] R 3Selected from H, halogenated, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0114] R 4 Selected from C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups, of which C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups are optionally R 4a replace;

[0115] R 4a Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0116] R 5a R 5 R 6 R 8 R 10 R 11 R 12 R 13 and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0117] R 7 Selected from H, =O, halogenated, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0118] R 9 Selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0119] Ring A is selected from phenyl, 6-membered heteroaryl, C6 cycloalkyl, and 6-membered heterocycloalkyl;

[0120] B is a key or C 1-6 alkyl;

[0121] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution; and

[0122] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In the embodiments of formulas I-IV,

[0123] Q 1 It is C(R) 14 )2 or C(O);

[0124] Q 2 It is N;

[0125] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0126] R 3 Selected from H, halogenated and CN;

[0127] R 4 It is C 3-11 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3-11 Cycloalkyl and 3-10 membered heterocyclic alkyl groups are optionally R 4a replace;

[0128] R 4a Is it H or C? 1-6 alkyl;

[0129] R 5a R 5 R 6 R 8 R 10 R 11 R 12 R 13 and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0130] R 7 Selected from H, =O, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0131] R 9 Selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0132] Ring A is selected from phenyl, 6-membered heteroaryl, and 6-membered heterocyclic alkyl;

[0133] B is a key or C 1-6 alkyl;

[0134] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12-membered heterocycloalkyl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0135] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0136] In the embodiments of formulas I-IV:

[0137] Q 1 It is C(R) 14 )2 or C(O);

[0138] Q 2 It is N;

[0139] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0140] R 3 Selected from H, halogenated and CN;

[0141] R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace;

[0142] R 4a Is it H or C? 1-6 alkyl;

[0143] R 5a R 5 R 6 R 8 R 10 R 11 R 12 R 13 and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0144] R 7Selected from H, =O, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0145] R 9 Selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0146] Ring A is a phenyl or a 6-membered heterocyclic alkyl group;

[0147] B is a key or C 1-6 alkyl;

[0148] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0149] n is 1, 2, 3, 4, 5, or 6.

[0150] In one embodiment, the compound has the structure of Formula I:

[0151]

[0152] Or its pharmaceutically acceptable salt.

[0153] in:

[0154] Q 1 It is C(R) 14 )2 or C(O);

[0155] R 1 and R 2 Each was independently selected from halogenated, C 1-6 Alkyl groups and C≡CH;

[0156] R 3 Selected from H, halogenated and CN;

[0157] R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace;

[0158] R 4a Is it H or C? 1-6 alkyl;

[0159] R 5aR 5 R 6 and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0160] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl groups, 5-12-membered heterocyclic alkyl groups, and 6-7-membered heteroaryl groups, wherein the 5-12-membered heterocyclic alkyl groups are optionally halogenated, CN-, and C-substituted. 1-6 Alkyl substitution; and

[0161] n is 1, 2, 3, 4, 5, or 6.

[0162] In another embodiment, the compound has the structure of Formula II:

[0163]

[0164] Or its pharmaceutically acceptable salt.

[0165] in:

[0166] Q 2 It is N;

[0167] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0168] R 3 Selected from H, halogenated and CN;

[0169] R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace;

[0170] R 4a Is it H or C? 1-6 alkyl;

[0171] R 8 and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0172] R 7 Selected from H, =O, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0173] Ring A is a phenyl or a 6-membered heterocyclic alkyl group;

[0174] B is a key or C 1-6 alkyl;

[0175] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0176] n is 1, 2, 3, 4, 5, or 6.

[0177] In yet another embodiment, the compound has the structure of Formula III:

[0178]

[0179] Or its pharmaceutically acceptable salt.

[0180] in:

[0181] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0182] R 3 Selected from H, halogenated and CN;

[0183] R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace;

[0184] R 4a Is it H or C? 1-6 alkyl;

[0185] R 10 and R 11 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0186] R 9 Selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0187] Each L is independently selected from C1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0188] n is 1, 2, 3, 4, 5, or 6.

[0189] In yet another embodiment, the compound has the structure of formula IV:

[0190]

[0191] Or its pharmaceutically acceptable salt.

[0192] in:

[0193] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0194] R 3 Selected from H, halogenated and CN;

[0195] R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace;

[0196] R 4a Is it H or C? 1-6 alkyl;

[0197] R 12 and R 13 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0198] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0199] n is 1, 2, 3, 4, 5, or 6. Compounds of formulas V and VI are also provided in this paper:

[0200]

[0201] Or its pharmaceutically acceptable salt.

[0202] in:

[0203] Q 1 Selected from C(R) 14 2. C(O) and NR 14 ;

[0204] Q 3 It is CR 14 Or N;

[0205] R 1a and R 2a Each is independently selected from OH, H, and halogenated;

[0206] R 1b and R 2b Each is independently selected from halogenated and C 3-6 cycloalkyl,

[0207] Or R 1b and R 2b Together with the phenyl group it is attached to, they form C 8-12 Aryl, of which C 8-12 Aryl groups are selectively R 1 and R 2 replace;

[0208] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0209] R 3 Selected from H, halogenated, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0210] R 4 Selected from C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups, of which C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups are optionally bounded by one or two R groups. 4a replace;

[0211] Each R 4aIndependently selected from H, OH, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0212] R 14 R 15a R 15b R 15 R 16 R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0213] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the 3-12 heterocyclic alkyl group is optionally selected by one or two independently from halogen, CN and C. 1-6 Alkyl substituents; and

[0214] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0215] In one embodiment, the compound has the structure of formula V:

[0216]

[0217] Or its pharmaceutically acceptable salt.

[0218] in:

[0219] Q 1 It is C(R) 14 )2 or C(O);

[0220] Q 3 It is CH or N;

[0221] R 1a and R 2a Each is independently selected from H, OH, and halogenated;

[0222] R 1b and R 2b Together with the phenyl group it is attached to, it forms a group with R 1and R 2 Substituted naphthyl group;

[0223] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-3 Alkyl, C 3-5 cycloalkyl groups and C≡CH;

[0224] R 3 It is H or halogenated;

[0225] R 4 Selected from C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl groups are optionally surrounded by one or two R groups. 4a replace;

[0226] Each R 4a Independently selected from H, OH and C 1-6 alkyl;

[0227] R 14 R 15 and R 16 Each is independently selected from H, halogenated, and C. 1-3 Alkyl and C 1-3 Alkoxy;

[0228] R 15a and R 15b Each was independently selected from halogenated, C 1-3 Alkyl and C 1-3 Alkoxy;

[0229] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally selected by one or two independently from halogen, CN and C. 1-6 Alkyl substituents; and

[0230] n is 1, 2, 3, 4, 5, or 6.

[0231] In another embodiment, the compound has the structure of formula VI:

[0232]

[0233] Or its pharmaceutically acceptable salt.

[0234] in:

[0235] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-3 Alkyl, C 3-5 cycloalkyl groups and C≡CH;

[0236] R 3 It is H or halogenated;

[0237] R 4 Selected from C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl groups are optionally surrounded by one or two R groups. 4a replace;

[0238] Each R 4a Independently selected from H, OH and C 1-6 alkyl;

[0239] R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, and C. 1-3 Alkyl and C 1-3 Alkoxy;

[0240] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally selected by one or two independently from halogen, CN and C. 1-6 Alkyl substituents; and

[0241] n is 1, 2, 3, 4, 5, or 6.

[0242] On the one hand, this paper provides a compound of the formula AI or AIV:

[0243]

[0244]

[0245] Or its pharmaceutically acceptable salt.

[0246] in:

[0247] Q 1 Selected from C(R) 14 2. C(O) and NR 14 ;

[0248] Q 2 It is CR 14 Or N;

[0249] R 1 and R 2 Each is independently halogenated or C 2-6 alkynyl group;

[0250] R 3 Selected from H, halogenated, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0251] R 4 Selected from C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups, of which C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups are optionally R 4a replace;

[0252] R 4a Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0253] R 5a R 5 R 6 R 12 R 13 and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0254] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution; and

[0255] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0256] On the other hand, this paper provides a compound of formula VII:

[0257]

[0258] Or its pharmaceutically acceptable salt.

[0259] in:

[0260] Ring B and ring C are each independently selected from 3-12 membered heterocyclic alkyl groups, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution;

[0261] Ring D is selected from bond, C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution occurs when ring D is a bond, then Y 2 It is also a key and t is 0;

[0262] Y 1 and Y 2 Each is independently selected from bonds, O, C(O), N(H), N(C). 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy;

[0263] Z is selected from N(H), N(C) 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy;

[0264] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0265] R 3 Selected from H, halogenated, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0266] R 4 Selected from C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10Aryl and 3-10 heteroaryl groups, of which C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups are optionally R 4a replace;

[0267] R 4a Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0268] R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0269] s and t are each independently 0, 1, 2, or 3; and

[0270] u is 1 or 2.

[0271] In the embodiments of formulas I-VI:

[0272] Q 1 It is C(R) 14 )2 or C(O);

[0273] Q 2 It is N;

[0274] Q 3 It is CR 14 Or N;

[0275] R 1a and R 2a Each is independently selected from OH, H, and halogenated;

[0276] R 1b and R 2b Together with the phenyl group it is attached to, they form C 8-12 Aryl, wherein the C 8-12 Aryl groups are selectively R 1 and R 2 replace;

[0277] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0278] R3 Selected from H, halogenated and CN;

[0279] R 4 Selected from C 3-11 Cycloalkyl and 3-10 membered heterocycloalkyl, wherein C 3-11 Cycloalkyl and 3-10 membered heterocycloalkyl groups are optionally surrounded by one or two R groups. 4a replace;

[0280] Each R 4a Independently selected from H, OH and C 1-6 alkyl;

[0281] R 5a R 5 R 6 R 8 R 10 R 11 R 12 R 13 R 14 R 15a R 15b R 15 R 16 R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0282] R 7 Selected from H, =O, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0283] R 9 Selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0284] Ring A is selected from phenyl, 6-membered heteroaryl, and 6-membered heterocyclic alkyl;

[0285] B is a key or C 1-6 alkyl;

[0286] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12-membered heterocycloalkyl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0287] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0288] In the embodiments of formulas I-VI:

[0289] Q 1 It is C(R) 14 )2 or C(O);

[0290] Q 2 It is N;

[0291] Q 3 It is CR 14 Or N;

[0292] R 1a and R 2a Each is independently selected from H, OH, and halogenated;

[0293] R 1b and R 2b Together with the phenyl group it is attached to, it forms a group with R 1 and R 2 Substituted naphthyl group;

[0294] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-3 Alkyl, C 3-5 cycloalkyl groups and C≡CH;

[0295] R 3 It is H or halogenated;

[0296] R 4 Selected from C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl groups are optionally surrounded by one or two R groups. 4a replace;

[0297] Each R 4a Independently selected from H, OH and C 1-6 alkyl;

[0298] R 5a R 5 R 6 R 8 R 10 R 11 R 12 R 13 R 14 R 15a R 15b R 15 R 16 R 17aR 17b R 17 and R 18 Each is independently selected from H, halogenated, and C. 1-3 Alkyl and C 1-3 Alkoxy;

[0299] R 7 Selected from H, =O, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0300] R 9 Selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0301] Ring A is a phenyl or a 6-membered heterocyclic alkyl group;

[0302] B is a key or C 1-6 alkyl;

[0303] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0304] n is 1, 2, 3, 4, 5, or 6.

[0305] In the embodiment of formula I:

[0306] Q 1 It is C(R) 14 )2 or C(O);

[0307] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0308] R 3 Selected from H, halogenated and CN;

[0309] R 4 It is C 3-11 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3-11 Cycloalkyl and 3-10 membered heterocyclic alkyl groups are optionally R 4a replace;

[0310] R 4a Is it H or C? 1-6 alkyl;

[0311] R 5a R 5 R 6 and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0312] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12-membered heterocycloalkyl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0313] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0314] In the embodiment of formula I:

[0315] Q 1 It is C(R) 14 )2 or C(O);

[0316] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0317] R 3 Selected from H, halogenated and CN;

[0318] R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace;

[0319] R 4a Is it H or C? 1-6 alkyl;

[0320] R 5a R 5 R 6 and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0321] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0322] n is 1, 2, 3, 4, 5, or 6.

[0323] In the embodiment of formula II:

[0324] Q 2 It is N;

[0325] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0326] R 3 Selected from H, halogenated and CN;

[0327] R 4 It is C 3-11 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3-11 Cycloalkyl and 3-10 membered heterocyclic alkyl groups are optionally R 4a replace;

[0328] R 4a Is it H or C? 1-6 alkyl;

[0329] R 7 Selected from H, =O, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0330] R 8 Selected from H, C 1-6 Alkyl and C 1-6 Alkoxy;

[0331] Ring A is selected from phenyl, 6-membered heteroaryl, and 6-membered heterocyclic alkyl;

[0332] B is a key or C 1-6 alkyl;

[0333] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12-membered heterocycloalkyl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0334] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0335] In the embodiment of formula II:

[0336] Q 2 It is N;

[0337] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0338] R 3 Selected from H, halogenated and CN;

[0339] R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace;

[0340] R 4a Is it H or C? 1-6 alkyl;

[0341] R 7 Selected from H, =O, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0342] R 8 Selected from H, C 1-6 Alkyl and C 1-6 Alkoxy;

[0343] Ring A is a phenyl or a 6-membered heterocyclic alkyl group;

[0344] B is a key or C 1-6 alkyl;

[0345] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 6-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 6-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0346] n is 1, 2, 3, 4, 5, or 6.

[0347] In the embodiment of Formula III:

[0348] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0349] R 3 Selected from H, halogenated and CN;

[0350] R 4 It is C 3-11 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3-11 Cycloalkyl and 3-10 membered heterocyclic alkyl groups are optionally R 4a replace;

[0351] R 4a Is it H or C? 1-6 alkyl;

[0352] R 9 Selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0353] R 10 and R 11 Each is independently selected from H and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0354] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12-membered heterocycloalkyl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0355] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0356] In the embodiment of Formula III:

[0357] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0358] R 3 Selected from H, halogenated and CN;

[0359] R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace;

[0360] R 4a Is it H or C? 1-6 alkyl;

[0361] R9 Selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0362] R 10 and R 11 Each is independently selected from H and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0363] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 6-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 6-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0364] n is 1, 2, 3, 4, 5, or 6.

[0365] In the embodiment of formula IV:

[0366] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0367] R 3 Selected from H, halogenated and CN;

[0368] R 4 It is C 3-11 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3-11 Cycloalkyl and 3-10 membered heterocyclic alkyl groups are optionally R 4a replace;

[0369] R 4a Is it H or C? 1-6 alkyl;

[0370] R 12 and R 13 Each is independently selected from H and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0371] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12-membered heterocycloalkyl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6Alkyl substitution; and

[0372] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0373] In the embodiment of formula IV:

[0374] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0375] R 3 Selected from H, halogenated and CN;

[0376] R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace;

[0377] R 4a Is it H or C? 1-6 alkyl;

[0378] R 12 and R 13 Each is independently selected from H and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0379] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 6-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 6-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0380] n is 1, 2, 3, 4, 5, or 6.

[0381] In the embodiment of formula IV:

[0382] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0383] R 3 Selected from H, halogenated and CN;

[0384] R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R4a replace;

[0385] R 4a Is it H or C? 1-6 alkyl;

[0386] R 12 and R 13 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0387] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl groups, 5-12-membered heterocyclic alkyl groups, and 6-7-membered heteroaryl groups, wherein the 5-12-membered heterocyclic alkyl groups are optionally halogenated, CN-, and C-substituted. 1-6 Alkyl substitution; and

[0388] n is 1, 2, 3, 4, 5, or 6.

[0389] In an embodiment of formula V:

[0390] Q 1 It is C(R) 14 )2 or C(O);

[0391] Q 3 It is CR 14 Or N;

[0392] R 1a and R 2a Each is independently selected from OH, H, and halogenated;

[0393] R 1b and R 2b Together with the phenyl group it is attached to, they form C 8-12 Aryl, wherein the C 8-12 Aryl groups are selectively R 1 and R 2 replace;

[0394] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0395] R 3 Selected from H, halogenated and CN;

[0396] R 4 Selected from C 3-11Cycloalkyl and 3-10 membered heterocycloalkyl, wherein C 3-11 Cycloalkyl and 3-10 membered heterocycloalkyl groups are optionally surrounded by one or two R groups. 4a replace;

[0397] Each R 4a Independently selected from H, OH and C 1-6 alkyl;

[0398] R 14 R 15a R 15b R 15 and R 16 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0399] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the 3-12 heterocyclic alkyl group is optionally selected by one or two independently from halogen, CN and C. 1-6 Alkyl substituents; and

[0400] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0401] In an embodiment of formula V:

[0402] Q 1 It is C(R) 14 )2 or C(O);

[0403] Q 3 It is CH or N;

[0404] R 1a and R 2a Each is independently selected from H, OH, and halogenated;

[0405] R 1b and R 2b Together with the phenyl group it is attached to, it forms a group with R 1 and R 2 Substituted naphthyl group;

[0406] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-3 Alkyl, C 3-5cycloalkyl groups and C≡CH;

[0407] R 3 It is H or halogenated;

[0408] R 4 Selected from C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl groups are optionally surrounded by one or two R groups. 4a replace;

[0409] Each R 4a Independently selected from H, OH and C 1-6 alkyl;

[0410] R 14 R 15a R 15b R 15 and R 16 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0411] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl, and 5-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally selected by one or two independently from halogen, CN, and C. 1-6 Alkyl substituents; and

[0412] n is 1, 2, 3, 4, 5, or 6.

[0413] In the embodiment of formula VI:

[0414] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0415] R 3 Selected from H, halogenated and CN;

[0416] R 4 Selected from C 3-11 Cycloalkyl and 3-10 membered heterocycloalkyl, wherein C 3-11 Cycloalkyl and 3-10 membered heterocyclic alkyl groups are optionally R 4a replace;

[0417] R 4a Is it H or C? 1-6 alkyl;

[0418] R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0419] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the 3-12 heterocyclic alkyl group is optionally selected by one or two independently from halogen, CN and C. 1-6 Alkyl substituents; and

[0420] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0421] In the embodiment of formula VI:

[0422] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-3 Alkyl groups and C≡CH;

[0423] R 3 It is H or halogenated;

[0424] R 4 Selected from C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace;

[0425] R 4a Is it H or C? 1-6 alkyl;

[0426] R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, and C. 1-3 Alkyl and C 1-3 Alkoxy;

[0427] Each L is independently selected from C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl, and 5-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally selected by one or two independently from halogen, CN, and C. 1-6 Alkyl substituents; and

[0428] n is 1, 2, 3, 4, 5, or 6.

[0429] In the embodiment of formula VI:

[0430] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-3 Alkyl, C 3-5 cycloalkyl groups and C≡CH;

[0431] R 3 It is H or halogenated;

[0432] R 4 Selected from C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl groups are optionally surrounded by one or two R groups. 4a replace;

[0433] Each R 4a Independently selected from H, OH and C 1-6 alkyl;

[0434] R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, and C. 1-3 Alkyl and C 1-3 Alkoxy;

[0435] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), 5-12-membered heterocyclic alkyl and 6-7-membered heteroaryl, wherein the 5-12-membered heterocyclic alkyl is optionally selected by one or two independently from halogen, C1N and C2N. 1-6 Alkyl substituents; and

[0436] n is 1, 2, 3, 4, 5, or 6.

[0437] In an embodiment of AI:

[0438] Q 1 It is C(R) 14 )2 or C(O);

[0439] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0440] R 3 Selected from H, halogenated and CN;

[0441] R 4 It is C 3-11 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3-11 Cycloalkyl and 3-10 membered heterocyclic alkyl groups are optionally R 4a replace;

[0442] R 4a Is it H or C? 1-6 alkyl;

[0443] R 5a R 5 R 6 and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0444] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12-membered heterocycloalkyl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0445] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0446] In an embodiment of AI:

[0447] Q 1 It is C(R) 14 )2 or C(O);

[0448] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0449] R 3 Selected from H, halogenated and CN;

[0450] R4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace;

[0451] R 4a Is it H or C? 1-6 alkyl;

[0452] R 5a R 5 R 6 and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0453] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0454] n is 1, 2, 3, 4, 5, or 6.

[0455] In an embodiment of AIV:

[0456] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0457] R 3 Selected from H, halogenated and CN;

[0458] R 4 It is C 3-11 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3-11 Cycloalkyl and 3-10 membered heterocyclic alkyl groups are optionally R 4a replace;

[0459] R 4a Is it H or C? 1-6 alkyl;

[0460] R 12 and R 13 Each is independently selected from H and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0461] Each L is independently selected from C 1-6Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12-membered heterocycloalkyl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0462] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0463] In an embodiment of AIV:

[0464] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0465] R 3 Selected from H, halogenated and CN;

[0466] R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace;

[0467] R 4a Is it H or C? 1-6 alkyl;

[0468] R 12 and R 13 Each is independently selected from H and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0469] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 6-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 6-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0470] n is 1, 2, 3, 4, 5, or 6.

[0471] In an embodiment of AIV:

[0472] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0473] R3 Selected from H, halogenated and CN;

[0474] R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace;

[0475] R 4a Is it H or C? 1-6 alkyl;

[0476] R 12 and R 13 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0477] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl groups, 5-12-membered heterocyclic alkyl groups, and 6-7-membered heteroaryl groups, wherein the 5-12-membered heterocyclic alkyl groups are optionally halogenated, CN-, and C-substituted. 1-6 Alkyl substitution; and

[0478] n is 1, 2, 3, 4, 5, or 6.

[0479] In the embodiments of Formula VII, ring B and ring C are each independently selected from 3-6-membered heterocyclic alkyl groups and 5- or 6-membered heteroaryl groups, wherein the 3- or 6-membered heterocyclic alkyl groups are optionally halogenated, CN- or C-substituted. 1-6 Alkyl substitution;

[0480] Ring D is selected from bonds, 3-6-membered heterocyclic alkyl groups, and 5- or 6-membered heteroaryl groups, wherein the 3- or 6-membered heterocyclic alkyl groups are optionally halogenated, CN- or C-substituted. 1-6 Alkyl substitution occurs when ring D is a bond, then Y 2 It is also a key and t is 0;

[0481] Y 1 and Y 2 Each is independently selected from bonds, O, C(O), N(H), N(C). 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy;

[0482] Z is selected from N(H), N(C) 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy;

[0483] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0484] R 3 Selected from H, halogenated, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0485] R 4 It is a 6-8 membered heterocyclic alkyl group, which is optionally R 4a replace;

[0486] R 4a Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0487] R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0488] s and t are each independently 0, 1, 2, or 3; and

[0489] u is 1 or 2.

[0490] In the embodiment of Formula VII, ring B and ring C are each optionally halogenated independently by CN and C. 1-6 Alkyl-substituted 3-6 membered heterocyclic alkyl groups;

[0491] Ring D is a bond or optionally halogenated, CN, and C. 1-6 Alkyl-substituted 3-6 membered heterocyclic alkyl groups, provided that ring D is a bond, then Y 2 It is also a key and t is 0;

[0492] Y 1 and Y 2 Each is independently selected from bonds, O, C(O), N(H), N(C). 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy;

[0493] Z is selected from N(H), N(C) 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy;

[0494] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0495] R 3 Selected from H, halogenated, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0496] R 4 It is a 6-8 membered heterocyclic alkyl group, which is optionally R 4a replace;

[0497] R 4a Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0498] R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0499] s and t are each independently 0, 1, 2, or 3; and

[0500] u is 1 or 2.

[0501] In the embodiment of Formula VII, ring B and ring C are each optionally halogenated independently by CN and C. 1-6 Alkyl-substituted 3-6 membered heterocyclic alkyl groups;

[0502] Ring D is optionally halogenated by CN and C. 1-6 Alkyl-substituted 3-6 membered heterocyclic alkyl groups;

[0503] Y 1 and Y 2 Each is independently selected from bonds, O, C(O), N(H), and C. 1-6 alkyl;

[0504] Z is selected from N(H) and C. 1-6 alkyl;

[0505] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0506] R 3 Selected from H, halogenated, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0507] R 4 It is a 6-8 membered heterocyclic alkyl group, which is optionally R 4a replace;

[0508] R 4a Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0509] R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0510] s and t are each independently 0, 1, or 2; and

[0511] u is 1.

[0512] In the embodiment of Formula VII, rings B, C, and D are each optionally halogenated independently by CN and C. 1-6 Alkyl-substituted 5- or 6-membered heterocyclic alkyl groups.

[0513] In embodiments of formulas I-VI, R 4 Is it arbitrarily R 4a Substituted bridged 8-membered heterocyclic alkyl group.

[0514] In embodiments of formulas I-VI, R 4 yes:

[0515]

[0516] In the embodiments of formulas I-IV, R 6 It's H.

[0517] In the embodiments of formulas I-IV, R 8 It's H.

[0518] In the embodiments of formulas I-IV, R 11 It's H.

[0519] In the embodiments of formulas I-IV, R 13 It's H.

[0520] In the embodiments of formulas I-IV, R 15 It's H.

[0521] In the embodiments of formulas I-IV, R 16 It's H.

[0522] In the embodiments of formulas I-IV, R 6 R 8 R 11 and R 13 Each is H.

[0523] In the embodiments of formulas I-IV, R 15 and R 16 Each is H.

[0524] In the embodiment of formula V, R 4 It can be arbitrarily assigned to one or two Rs. 4a Substituted 6-7 membered heterocyclic alkyl groups.

[0525] In the embodiments, the compound of formula I has the structure of formula IA:

[0526]

[0527] Or its pharmaceutically acceptable salt, wherein:

[0528] Q 1 Selected from C(R) 14 2. C(O) and NR 14 ;

[0529] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0530] R 4a Selected from H, C 1-6 Alkyl, C 1-6Alkoxy and C 1-6 Halogenated alkyl groups;

[0531] R 5a R 5 R 6 and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0532] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution; and

[0533] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0534] In an embodiment of formula IA:

[0535] Q 1 It is C(R) 14 )2 or C(O);

[0536] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0537] R 4a Is it H or C? 1-6 alkyl;

[0538] R 5a R 5 R 6 and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0539] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12-membered heterocycloalkyl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocycloalkyl is optionally halogenated, CN and C1-6 Alkyl substitution; and

[0540] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0541] In an embodiment of formula IA:

[0542] Q 1 It is C(R) 14 )2 or C(O);

[0543] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0544] R 4a Is it H or C? 1-6 alkyl;

[0545] R 5a R 5 R 6 and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0546] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0547] n is 1, 2, 3, 4, 5, or 6.

[0548] In the embodiments, the compound of formula I has the structure of formula IB:

[0549]

[0550] Or its pharmaceutically acceptable salt, wherein:

[0551] Q 1 Selected from C(R) 14 2. C(O) and NR 14 ;

[0552] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0553] R 5a and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0554] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution; and

[0555] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0556] In the embodiment of formula IB:

[0557] Q 1 It is CH2 or C(O);

[0558] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0559] R 5a Independently selected from H, halogenated and C 1-6 alkyl;

[0560] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, and 5-12 membered heterocyclic alkyl, wherein the 5-12 membered heterocyclic alkyl is optionally halogenated, CN, and C. 1-6 Alkyl substitution; and

[0561] n is 4, 5, or 6.

[0562] In the embodiment of formula IB, n is 6, and each L forms the following connector: (C 1-6 alkoxy)-(6-12 membered heterocyclic alkyl)-(C 1-6 alkyl)-(6-12 membered heterocyclic alkyl)-(C 1-6 Alkyl)-(6-membered heterocyclic alkyl).

[0563] In the embodiment of formula IB, n is 6, and each L forms the following connector: (C 1-6 alkoxy)-(6-membered heterocyclic alkyl)-(C 1-6 alkyl)-(6-membered heterocyclic alkyl)-(C 1-6 Alkyl)-(6-membered heterocyclic alkyl).

[0564] In the embodiment of formula IB, n is 4, and each L forms the following connector: (C 1-6 alkoxy)-(5-12 membered heterocyclic alkyl)-(C 1-6 Alkyl)-(5-12 membered heterocyclic alkyl).

[0565] In the embodiment of formula IB, n is 4, and each L forms the following connector: (C 1-6 alkoxy)-(11-membered heterocyclic alkyl)-(C 1-6 Alkyl)-(6-membered heterocyclic alkyl).

[0566] In the embodiments of formula IB, the 11-membered heterocyclic alkyl group is a spirocyclic 11-membered heterocyclic alkyl group.

[0567] In the embodiment of formula IB, n is 6, and each L forms the following connector: (C 1-6 alkoxy)-(5-12-membered heterocyclic alkyl)-(O)-(5-12-membered heterocyclic alkyl)-(C 1-6 (alkyl)-(5-12-membered heterocyclic alkyl), wherein the 5-12-membered heterocyclic alkyl is optionally C 1-6 Alkyl substitution.

[0568] In the embodiment of formula IB, n is 6, and each L forms the following connector: (C 1-6 alkoxy)-(5-membered heterocyclic alkyl)-(O)-(6-membered heterocyclic alkyl)-(C 1-6 alkyl)-(6-membered heterocyclic alkyl), wherein the 5-membered heterocyclic alkyl is optionally C 1-6 Alkyl substitution.

[0569] In the embodiment of formula IB, n is 4, and each L forms the following connector: (C 1-6 alkoxy)-(5-12 membered heterocyclic alkyl)-(C 1-6 Alkyl)-(5-12 membered heterocyclic alkyl).

[0570] In the embodiment of formula IB, n is 4, and each L forms the following connector: (C 1-6 alkoxy)-(6-membered heterocyclic alkyl)-(C 1-6 Alkyl)-(9-membered heterocyclic alkyl).

[0571] In the embodiments of formula IB, the 9-membered heterocyclic alkyl group is a spirocyclic 9-membered heterocyclic alkyl group.

[0572] In the embodiment of formula IB, n is 4, and each L forms the following connector: (C 1-6 alkoxy)-(5-12-membered heterocyclic alkyl)-(O)-(5-12-membered heterocyclic alkyl), wherein the 5-12-membered heterocyclic alkyl is optionally C 1-6 Alkyl substitution.

[0573] In the embodiment of formula IB, n is 4, and each L forms the following connector: (C 1-6 alkoxy)-(5-membered heterocyclic alkyl)-(O)-(6-membered heterocyclic alkyl), wherein the 5-membered heterocyclic alkyl is optionally C 1-6 Alkyl substitution.

[0574] In the embodiment of formula IB, each L forms a connector:

[0575]

[0576]

[0577] In the embodiments, the compound of formula I has the structure of formula IB-i:

[0578]

[0579] Or its pharmaceutically acceptable salt.

[0580] in

[0581] Q 1 Selected from C(R) 14 2. C(O) and NR 14 ;

[0582] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups,

[0583] R 5a and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0584] Each Q L Independently, it is CR L Or N;

[0585] Each R LIndependently, it is H, halogenated, or CN; and

[0586] Each p is independently 1, 2, 3, 4, 5, or 6.

[0587] In the embodiment of formula IB-i:

[0588] Each Q L Independently, it is CR L Or N;

[0589] Each R L It is either H or halogenated independently;

[0590] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 2-6 alkynyl group;

[0591] R 3 Selected from H, halogenated and CN;

[0592] R 5a and R 14 Each is independently selected from H and C. 1-6 Alkyl and C 1-6 alkoxy groups; and

[0593] Each p is 1, 2, 3, or 4.

[0594] In the embodiment of formula IB-i:

[0595] Each Q L It can be CH or N independently;

[0596] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-3 Alkyl groups and C≡CH;

[0597] R 3 It is a halogenated product;

[0598] R 5a and R 14 Each is independently selected from H and C. 1-3 Alkyl and C 1-3 alkoxy groups; and

[0599] Each p is 1, 2, or 3.

[0600] In the embodiments, the compound of formula I has the structure of formula IC:

[0601]

[0602] Or its pharmaceutically acceptable salt.

[0603] in:

[0604] Q 1 Selected from C(R) 14 2. C(O) and NR 14 ;

[0605] Ring B and ring C are each independently selected from 3-12 membered heterocyclic alkyl groups, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution;

[0606] Ring D is selected from bond, C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution occurs when ring D is a bond, then Y 2 It is also a key and t is 0;

[0607] Y 1 and Y 2 Each is independently selected from bonds, O, C(O), N(H), N(C). 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy;

[0608] Z is selected from N(H), N(C) 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy;

[0609] R 1 Is it halogenated or C 2-6 alkynyl group;

[0610] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[0611] R 3 Selected from H, halogenated, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0612] R 4 Selected from C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups, of which C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C6-10 Aryl and 3-10 heteroaryl groups are optionally R 4a replace;

[0613] R 4a Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0614] R 5a R 5 R 6 and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0615] s and t are each independently 0, 1, 2, or 3; and

[0616] u is 1 or 2.

[0617] In embodiments of formula IC, ring B and ring C are each independently selected from 3-12-membered heterocyclic alkyl groups and 5-10-membered heteroaryl groups, wherein the 3-12-membered heterocyclic alkyl groups are optionally halogenated, CN-, and C-substituted. 1-6 Alkyl substitution.

[0618] In embodiments of the IC, ring B and ring C are each optionally halogenated, CN, and C respectively. 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups.

[0619] In an embodiment of the IC, Y 1 and Y 2 At least one of them is a bond, and at least one of s and t is 0.

[0620] In embodiments of formula IC, ring D is selected from bonds, 3-12-membered heterocyclic alkyl groups, and 5-10-membered heteroaryl groups, wherein the 3-12-membered heterocyclic alkyl groups are optionally halogenated, CN-, and C-substituted. 1-6 Alkyl substitution.

[0621] In embodiments of formula IC, ring D is selected from bonds, 3-6-membered heterocyclic alkyl groups, and 5- or 6-membered heteroaryl groups, wherein the 3- or 6-membered heterocyclic alkyl groups are optionally halogenated, CN- or C-substituted. 1-6 Alkyl substitution.

[0622] In the embodiments, the IC compound has the structure of IC-i:

[0623]

[0624] Or its pharmaceutically acceptable salt.

[0625] in:

[0626] Ring B and ring C are each independently selected from 5- or 6-membered heterocyclic alkyl groups, 9-11-membered spirocyclic heterocyclic alkyl groups, and 8-membered bridged heterocyclic alkyl groups, wherein the 5- or 6-membered heterocyclic alkyl groups, 9-11-membered spirocyclic heterocyclic alkyl groups, and 8-membered bridged heterocyclic alkyl groups are optionally halogenated, CN- or C-substituted. 1-6 Alkyl substitution;

[0627] Y 1 Selected from bonds, O, C(O), N(H), N(C) 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy;

[0628] Z is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy;

[0629] R 1 Is it halogenated or C 2-6 alkynyl group;

[0630] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group; and

[0631] s can be 0, 1, 2, or 3.

[0632] In the embodiments, the compound of formula IC-i has the structure of formula IC-ia:

[0633]

[0634] or its pharmaceutically acceptable salt

[0635] in:

[0636] Ring B is selected from 5- or 6-membered heterocyclic alkyl, 9- or 11-membered spirocyclic heterocyclic alkyl, and 8-membered fused heterocyclic alkyl, wherein the 5- or 6-membered heterocyclic alkyl, 9- or 11-membered spirocyclic heterocyclic alkyl, and 8-membered fused heterocyclic alkyl are optionally halogenated, CN- or C-substituted. 1-6 Alkyl substitution;

[0637] Q Z It is O, NH or N (C 1-6 alkyl);

[0638] Each Q L Independently, it is CR L Or N;

[0639] Each R L Independently selected from H, halogen, CN and C1-6 alkyl;

[0640] Each R C Independently halogenated or C 1-6 alkyl;

[0641] Y 1 Selected from O, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0642] R 1 Is it halogenated or C 2-6 alkynyl group;

[0643] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[0644] r is 1, 2, 3, 4, 5, or 6; and

[0645] q is 0, 1, or 2.

[0646] In the embodiments, the compound of formula IC-i has the structure of formula IC-ib:

[0647]

[0648] or its pharmaceutically acceptable salt

[0649] in:

[0650] Ring B is selected from 5- or 6-membered heterocyclic alkyl, 9- or 11-membered spirocyclic heterocyclic alkyl, and 8-membered fused heterocyclic alkyl, wherein the 5- or 6-membered heterocyclic alkyl, 9- or 11-membered spirocyclic heterocyclic alkyl, and 8-membered fused heterocyclic alkyl are optionally halogenated, CN- or C-substituted. 1-6 Alkyl substitution;

[0651] Q Z It is O, NH or N (C 1-6 alkyl);

[0652] Each Q L Independently, it is CR L Or N;

[0653] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[0654] R B Is it halogenated or C 1-6 alkyl;

[0655] Y 1 Selected from O, C 1-6 Alkyl and C 1-6Halogenated alkyl groups;

[0656] R 1 Is it halogenated or C 2-6 alkynyl group;

[0657] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[0658] r is 1, 2, 3, 4, 5, or 6; and

[0659] q is 0, 1, or 2.

[0660] In the embodiments, the compound of formula IC-ia has the structure of formula IC-iai:

[0661]

[0662] or its pharmaceutically acceptable salt

[0663] in:

[0664] Q Z It is O, NH or N (C 1-6 alkyl);

[0665] Each Q L Independently, it is CR L Or N;

[0666] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[0667] R B and R C Each is independently halogenated or C 1-6 alkyl;

[0668] Y 1 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0669] R 1 Is it halogenated or C 2-6 alkynyl group;

[0670] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[0671] r is 1, 2, 3, 4, 5, or 6;

[0672] s is 0, 1, 2, or 3; and

[0673] Each q is independently 0, 1, or 2.

[0674] In the embodiments of formula IC-iai, ring B is a 9-membered or 11-membered spirocyclic heterocyclic alkyl group.

[0675] In the embodiments, the compound of formula IC-ia has the structure of formula IC-iaii:

[0676]

[0677] or its pharmaceutically acceptable salt

[0678] in:

[0679] Each Q B Independently selected from CH, CH2, N, NH and N(C) 1-6 Alkyl), provided that at least one Q B It is N, NH or N(C) 1-6 alkyl);

[0680] Q Z It is O, NH or N (C 1-6 alkyl);

[0681] Each Q L Independently, it is CR L Or N, provided that at least one Q L It is N;

[0682] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[0683] Each R C Independently halogenated or C 1-6 alkyl;

[0684] Y 1 Selected from O, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0685] R 1 Is it halogenated or C 2-6 alkynyl group;

[0686] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[0687] r is 1, 2, 3, 4, 5, or 6; and

[0688] q is 0, 1, or 2.

[0689] In the embodiments, the compound of formula IC-ia has the structure of formula IC-iaiii:

[0690]

[0691] or its pharmaceutically acceptable salt

[0692] in:

[0693] Each Q B Independently selected from CH, CH2, N, NH and N(C) 1-6 Alkyl), provided that at least one Q B It is N, NH or N(C) 1-6 alkyl);

[0694] Q Z It is O, NH or N (C 1-6 alkyl);

[0695] Each Q L Independently, it is CR L Or N, provided that at least one Q L It is N;

[0696] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[0697] Each R C Independently halogenated or C 1-6 alkyl;

[0698] Y 1 Selected from O, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0699] R 1 Is it halogenated or C 2-6 alkynyl group;

[0700] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[0701] r is 1, 2, 3, 4, 5, or 6; and

[0702] q is 0, 1, or 2.

[0703] In the embodiments, the compound of formula IC-ia has the structure of formula IC-iaiv:

[0704]

[0705] or its pharmaceutically acceptable salt

[0706] in:

[0707] Each Q B Independently selected from CH2, N, NH and N(C) 1-6 Alkyl), provided that at least one Q B It is N, NH or N(C) 1-6 alkyl);

[0708] Q Z It is O, NH or N (C 1-6 alkyl);

[0709] Each Q L Independently, it is CR L Or N;

[0710] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[0711] Each R C Independently halogenated or C 1-6 alkyl;

[0712] Y 1 Selected from O, C(O), N(H), N(C) 1-6 Alkyl), C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0713] R 1 Is it halogenated or C 2-6 alkynyl group;

[0714] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[0715] r is 1, 2, 3, 4, 5, or 6;

[0716] s is 0, 1, 2, or 3; and

[0717] q is 0, 1, or 2.

[0718] In the embodiments, the compound of formula IC-ia has the structure of formula IC-iav:

[0719]

[0720] or its pharmaceutically acceptable salt

[0721] in:

[0722] Each Q B Independently selected from CH2, NH and N(C) 1-6Alkyl), provided that at least one Q B Is it NH or N(C) 1-6 alkyl);

[0723] Q Z It is O, NH or N (C 1-6 alkyl);

[0724] Each Q L Independently, it is CR L Or N;

[0725] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[0726] Each R C Independently halogenated or C 1-6 alkyl;

[0727] Y 1 Selected from O, C(O), N(H), N(C) 1-6 Alkyl), C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0728] R 1 Is it halogenated or C 2-6 alkynyl group;

[0729] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[0730] r is 1, 2, 3, 4, 5, or 6;

[0731] s is 0, 1, 2, or 3; and

[0732] q is 0, 1, or 2.

[0733] In the embodiments, the IC-ib compound has the structure of IC-ibi:

[0734]

[0735] or its pharmaceutically acceptable salt

[0736] in:

[0737] Each Q C Independently selected from CH, CH2, N, NH and N(C) 1-6 Alkyl), provided that at least one Q C It is N, NH or N(C) 1-6 alkyl);

[0738] QZ It is O, NH or N (C 1-6 alkyl);

[0739] Each Q L Independently, it is CR L Or N, provided that at least one Q L It is N;

[0740] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[0741] Each R B Independently halogenated or C 1-6 alkyl;

[0742] Y 1 Selected from O, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0743] R 1 Is it halogenated or C 2-6 alkynyl group;

[0744] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[0745] r is 1, 2, 3, 4, 5, or 6; and

[0746] q is 0, 1, or 2.

[0747] In the embodiments, the compound of formula IC-ib has the structure of formula IC-ibii:

[0748]

[0749] or its pharmaceutically acceptable salt

[0750] in:

[0751] Each Q C Independently selected from CH, CH2, N, NH and N(C) 1-6 Alkyl), provided that at least one Q C It is N, NH or N(C) 1-6 alkyl);

[0752] Q Z It is O, NH or N (C 1-6 alkyl);

[0753] Each Q L Independently, it is CR L Or N, provided that at least one Q LIt is N;

[0754] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[0755] Each R B Independently halogenated or C 1-6 alkyl;

[0756] Y 1 Selected from O, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0757] R 1 Is it halogenated or C 2-6 alkynyl group;

[0758] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[0759] r is 1, 2, 3, 4, 5, or 6; and

[0760] q is 0, 1, or 2.

[0761] In the embodiments, the IC compound has the structure of IC-ii:

[0762]

[0763] or its pharmaceutically acceptable salt

[0764] in:

[0765] Ring B is a 5- or 6-membered heterocyclic alkyl group or an 8-membered fused heterocyclic alkyl group, wherein the 5- or 6-membered heterocyclic alkyl group and the 8-membered fused heterocyclic alkyl group are optionally halogenated, CN- or C-substituted. 1-6 Alkyl substitution;

[0766] Q Z It is O, NH or N (C 1-6 alkyl);

[0767] Each Q L Independently, it is CR L Or N;

[0768] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[0769] Each R C Independently halogenated or C 1-6 alkyl;

[0770] Y 1Selected from O, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0771] R 1 Is it halogenated or C 2-6 alkynyl group;

[0772] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[0773] p and r are each independently 1, 2, 3, 4, 5, or 6; and

[0774] q is 0, 1, or 2.

[0775] In the embodiments of formula IC-ii, ring B is an 8-membered fused heterocyclic alkyl group.

[0776] In the embodiments, the compound of formula IC-iia has the structure of formula IC-iia:

[0777]

[0778] or its pharmaceutically acceptable salt

[0779] in:

[0780] Q Z It is O, NH or N (C 1-6 alkyl);

[0781] Each Q L Independently, it is CR L Or N;

[0782] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[0783] R B and R C Each is independently halogenated or C 1-6 alkyl;

[0784] Y 1 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0785] R 1 Is it halogenated or C 2-6 alkynyl group;

[0786] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[0787] p and r are each independently 1, 2, 3, 4, 5, or 6; and

[0788] Each q is independently 0, 1, or 2.

[0789] In the embodiments, the compound of formula IC-ii has the structure of formula IC-iib:

[0790]

[0791] or its pharmaceutically acceptable salt

[0792] in:

[0793] Each Q B Independently selected from CH2, N, NH and N(C) 1-6 Alkyl), provided that at least one Q B It is N, NH or N(C) 1-6 alkyl);

[0794] Q Z It is O, NH or N (C 1-6 alkyl);

[0795] Each Q L Independently, it is CR L Or N;

[0796] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[0797] Each R C Independently halogenated or C 1-6 alkyl;

[0798] Y 1 Selected from O, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0799] R 1 Is it halogenated or C 2-6 alkynyl group;

[0800] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[0801] p and r are each independently 1, 2, 3, 4, 5, or 6; and

[0802] q is 0, 1, or 2.

[0803] In the embodiments, the compound of formula IC-ii has the structure of formula IC-iic:

[0804]

[0805] or its pharmaceutically acceptable salt

[0806] in:

[0807] Each Q B Independently selected from CH2, NH and N(C) 1-6 Alkyl), provided that at least one Q B Is it NH or N(C) 1-6 alkyl);

[0808] Q Z It is O, NH or N (C 1-6 alkyl);

[0809] Each Q L Independently, it is CR L Or N;

[0810] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[0811] Each R C Independently halogenated or C 1-6 alkyl;

[0812] Y 1 Selected from O, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0813] R 1 Is it halogenated or C 2-6 alkynyl group;

[0814] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[0815] p and r are each independently 1, 2, 3, 4, 5, or 6; and

[0816] q is 0, 1, or 2.

[0817] In the embodiments, the compound of formula II has the structure of formula IIA:

[0818]

[0819] Or its pharmaceutically acceptable salt, wherein:

[0820] Q 2 It is CR 14 Or N;

[0821] R1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups,

[0822] R 4a Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0823] R 8 and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0824] R 7 Selected from H, =O, halogenated, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0825] Ring A is selected from phenyl, 6-membered heteroaryl, C6 cycloalkyl, and 6-membered heterocycloalkyl;

[0826] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution; and

[0827] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0828] In an embodiment of formula IIA:

[0829] Q 2 It is N;

[0830] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0831] R 4a Is it H or C?1-6 alkyl;

[0832] R 7 Selected from H, =O, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0833] R 8 Selected from H, C 1-6 Alkyl and C 1-6 Alkoxy;

[0834] Ring A is selected from phenyl, 6-membered heteroaryl, and 6-membered heterocyclic alkyl;

[0835] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12-membered heterocycloalkyl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0836] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0837] In an embodiment of formula IIA:

[0838] Q 2 It is N;

[0839] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0840] R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace;

[0841] R 4a Is it H or C? 1-6 alkyl;

[0842] R 7 Selected from H, =O, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0843] R 8 Selected from H, C 1-6 Alkyl and C 1-6 Alkoxy;

[0844] Ring A is a phenyl or a 6-membered heterocyclic alkyl group;

[0845] B is a key or C 1-6 alkyl;

[0846] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 6-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 6-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0847] n is 1, 2, 3, 4, 5, or 6.

[0848] In the embodiments, the compound of formula II has the structure of formula IIB:

[0849]

[0850] Or its pharmaceutically acceptable salt, wherein:

[0851] Q 2 It is CR 14 Or N;

[0852] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups,

[0853] R 4a Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0854] R 8 and R 14 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0855] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution; and

[0856] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0857] In an embodiment of formula IIB:

[0858] Q 2 It is N;

[0859] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0860] R 4a Is it H or C? 1-6 alkyl;

[0861] R 7 Selected from H, =O, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0862] R 8 Selected from H, C 1-6 Alkyl and C 1-6 Alkoxy;

[0863] Ring A is selected from phenyl, 6-membered heteroaryl, and 6-membered heterocyclic alkyl;

[0864] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12-membered heterocycloalkyl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0865] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0866] In an embodiment of formula IIB:

[0867] Q 2 It is N;

[0868] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0869] R 4 It is C 6-8Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace;

[0870] R 4a Is it H or C? 1-6 alkyl;

[0871] R 8 Selected from H, C 1-6 Alkyl and C 1-6 Alkoxy;

[0872] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 6-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 6-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0873] n is 1, 2, 3, 4, 5, or 6.

[0874] In the embodiments, the compound of formula III has the structure of formula IIIA:

[0875]

[0876] Or its pharmaceutically acceptable salt, wherein:

[0877] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups,

[0878] R 4a Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0879] R 9 Selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0880] R 10 and R 11 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6Halogenated alkyl groups;

[0881] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution; and

[0882] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0883] In an embodiment of formula IIIA:

[0884] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0885] R 4a Is it H or C? 1-6 alkyl;

[0886] R 9 Selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0887] R 10 and R 11 Each is independently selected from H and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0888] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12-membered heterocycloalkyl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0889] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0890] In an embodiment of formula IIIA:

[0891] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6Alkyl groups and C≡CH;

[0892] R 4a Is it H or C? 1-6 alkyl;

[0893] R 9 Selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy;

[0894] R 10 and R 11 Each is independently selected from H and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0895] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 6-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 6-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0896] n is 1, 2, 3, 4, 5, or 6.

[0897] In the embodiments, the compound of formula IV has the structure of formula IVA:

[0898]

[0899] Or its pharmaceutically acceptable salt, wherein:

[0900] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups,

[0901] R 4a Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0902] R 12 and R 13 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0903] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution; and

[0904] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0905] In an embodiment of formula IVA:

[0906] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0907] R 4a Is it H or C? 1-6 alkyl;

[0908] R 12 and R 13 Each is independently selected from H and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0909] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12-membered heterocycloalkyl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0910] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0911] In an embodiment of formula IVA:

[0912] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl groups and C≡CH;

[0913] R 4a Is it H or C? 1-6 alkyl;

[0914] R 12 and R13 Each is independently selected from H and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0915] Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 6-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 6-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and

[0916] n is 1, 2, 3, 4, 5, or 6.

[0917] In the embodiments, the compound of formula IV has the structure of formula IVB-a:

[0918]

[0919] Or its pharmaceutically acceptable salt.

[0920] in:

[0921] Each Q L Independently, it is CR L Or N;

[0922] Each R L Independently, it is H, halogenated, or CN, and

[0923] Each p is 1, 2, 3, 4, 5, or 6.

[0924] In the embodiment of formula IVB-a:

[0925] Each Q L Independently, it is CR L Or N;

[0926] Each R L It is either H or halogenated independently;

[0927] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 2-6 alkynyl group;

[0928] R 3 Selected from H, halogenated and CN;

[0929] R 12 and R 13 Each is independently selected from H and C. 1-6 Alkyl and C 1-6Alkyl groups; and each p is 1, 2, 3 or 4.

[0930] In the embodiment of formula IVB-a:

[0931] Each Q L It can be CH or N independently;

[0932] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-3 Alkyl groups and C≡CH;

[0933] R 3 It is a halogenated product;

[0934] R 12 and R 13 Each is independently selected from H and C. 1-3 Alkyl and C 1-3 Alkyl groups; and each p is 1, 2, or 3.

[0935] In the embodiments, the compound of formula IV has the structure of formula IVB:

[0936]

[0937] Or its pharmaceutically acceptable salt.

[0938] in:

[0939] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 2-6 alkynyl group;

[0940] R 3 Selected from H, halogenated and CN;

[0941] Each Q L Independently, it is CR L Or N;

[0942] Each R L Independently, it is H, halogenated, or CN, and

[0943] Each p is 1, 2, 3, 4, 5, or 6; and

[0944] R 12 and R 13 Each is independently selected from H and C. 1-6 Alkyl and C 1-6 Alkyl group.

[0945] In an embodiment of formula IVB:

[0946] Each Q LIndependently, it is CR L Or N;

[0947] Each R L It is either H or halogenated independently;

[0948] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 2-6 alkynyl group;

[0949] R 3 Selected from H, halogenated and CN;

[0950] R 12 and R 13 Each is independently selected from H and C. 1-6 Alkyl and C 1-6 alkoxy groups; and

[0951] Each p is 1, 2, 3, or 4.

[0952] In an embodiment of formula IVB:

[0953] Each Q L It can be CH or N independently;

[0954] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-3 Alkyl groups and C≡CH;

[0955] R 3 It is a halogenated product;

[0956] R 12 and R 13 Each is independently selected from H and C. 1-3 Alkyl and C 1-3 alkoxy groups; and

[0957] Each p is 1, 2, or 3.

[0958] In the embodiments, the compound of formula V has the structure of formula VA:

[0959]

[0960] Or its pharmaceutically acceptable salt, wherein:

[0961] Q 1 Selected from C(R) 14 2. C(O) and NR 14 ;

[0962] Q 3 From CR 14 Or N;

[0963] R 1a Selected from OH, H and halogenated groups;

[0964] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0965] R 4a Independently selected from H, OH, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0966] R 14 R 15a R 15b R 15 and R 16 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0967] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the 3-12 heterocyclic alkyl group is optionally selected by one or two independently from halogen, CN and C. 1-6 Alkyl substituents; and

[0968] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0969] In an embodiment of VA:

[0970] Q 1 It is C(R) 14 )2 or C(O);

[0971] Q 3 It is CR 14 Or N;

[0972] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6Alkyl, C 3-6 cycloalkyl groups and C≡CH;

[0973] R 1a It is H or OH;

[0974] R 4a Is it H or C? 1-6 alkyl;

[0975] R 14 R 15a R 15b R 15 and R 16 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[0976] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the 3-12 heterocyclic alkyl group is optionally selected by one or two independently from halogen, CN and C. 1-6 Alkyl substituents; and

[0977] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0978] In an embodiment of VA:

[0979] Q 1 It is C(R) 14 )2 or C(O);

[0980] Q 3 It is CH or N;

[0981] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-3 Alkyl, C 3-5 cycloalkyl groups and C≡CH;

[0982] R 1a It is H or OH;

[0983] R 3 It is H or halogenated;

[0984] R 4a Is it H or C? 1-6 alkyl;

[0985] R 14 R 15a R 15b R 15 and R 16 Each is independently selected from H, halogenated, and C. 1-3 Alkyl and C 1-3 Alkoxy;

[0986] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl, and 5-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally selected by one or two independently from halogen, CN, and C. 1-6 Alkyl substituents; and

[0987] n is 1, 2, 3, 4, 5, or 6.

[0988] In the embodiments, the compound of formula VI has the structure of formula VIA:

[0989]

[0990] Or its pharmaceutically acceptable salt, wherein:

[0991] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0992] R 4a Independently selected from H, OH, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0993] R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0994] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the 3-12 heterocyclic alkyl group is optionally selected by one or two independently from halogen, CN and C. 1-6 Alkyl substituents; and

[0995] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0996] In an embodiment of VIA:

[0997] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 3-6 cycloalkyl groups and C≡CH;

[0998] R 4a Is it H or C? 1-6 alkyl;

[0999] R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, and C. 1-6 Alkyl and C 1-6 Alkoxy;

[1000] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution; and

[1001] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[1002] In an embodiment of VIA:

[1003] R 1 and R 2 Each is independently selected from H, halogenated, and C. 1-3 Alkyl groups and C≡CH;

[1004] R4a Is it H or C? 1-6 alkyl;

[1005] R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, and C. 1-3 Alkyl and C 1-3 Alkoxy;

[1006] Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl, and 5-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally selected by one or two independently from halogen, CN, and C. 1-6 Alkyl substituents; and

[1007] n is 1, 2, 3, 4, 5, or 6.

[1008] In the embodiments, the compound of formula VI has the structure of formula VIAA:

[1009]

[1010] Or its pharmaceutically acceptable salt.

[1011] in:

[1012] Ring B and ring C are each independently selected from 3-12 membered heterocyclic alkyl groups, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution;

[1013] Ring D is selected from bond, C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution occurs when ring D is a bond, then Y 2 It is also a key and t is 0;

[1014] Y 1 and Y 2 Each is independently selected from bonds, O, C(O), N(H), N(C). 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy;

[1015] Z is selected from N(H), N(C) 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy;

[1016] R 1 Is it halogenated or C 2-6 alkynyl group;

[1017] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[1018] R 3 Selected from H, halogenated, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[1019] R 4 Selected from C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups, of which C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups are optionally R 4a replace;

[1020] R 4a Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[1021] R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[1022] s and t are each independently 0, 1, 2, or 3; and

[1023] u is 1 or 2.

[1024] In the embodiments of formula VIAA, ring D is selected from bonds, 3-12-membered heterocyclic alkyl groups, and 5-10-membered heteroaryl groups, wherein the 3-12-membered heterocyclic alkyl groups are optionally halogenated, CN-, and C-substituted. 1-6 Alkyl substitution.

[1025] In the embodiments of formula VIAA, ring D is selected from bonds, 3-8-membered heterocyclic alkyl groups, and 5- or 6-membered heteroaryl groups, wherein the 3-8-membered heterocyclic alkyl groups are optionally halogenated, CN- or C-substituted. 1-6 Alkyl substitution.

[1026] In the embodiments of formula VIAA, ring B is an 8-membered fused heterocyclic alkyl group.

[1027] In the embodiments, the VIAA compound has the structure of formula VIAA-i:

[1028]

[1029] Or its pharmaceutically acceptable salt.

[1030] in:

[1031] Ring B and ring C are each independently selected from 5- or 6-membered heterocyclic alkyl groups, 9-11-membered spirocyclic heterocyclic alkyl groups, and 8-membered bridged heterocyclic alkyl groups, wherein the 5- or 6-membered heterocyclic alkyl groups, 9-11-membered spirocyclic heterocyclic alkyl groups, and 8-membered bridged heterocyclic alkyl groups are optionally halogenated, CN- or C-substituted. 1-6 Alkyl substitution;

[1032] Y 1 Selected from bonds, O, C(O), N(H), N(C) 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy;

[1033] Z is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy;

[1034] R 1 Is it halogenated or C 2-6 alkynyl group;

[1035] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group; and

[1036] s can be 0, 1, 2, or 3.

[1037] In the embodiments, the compound of formula VIAA-i has the structure of formula VIAA-ia:

[1038]

[1039] or its pharmaceutically acceptable salt

[1040] in:

[1041] Ring B is selected from 5- or 6-membered heterocyclic alkyl, 9- or 11-membered spirocyclic heterocyclic alkyl, and 8-membered fused heterocyclic alkyl, wherein the 5- or 6-membered heterocyclic alkyl, 9- or 11-membered spirocyclic heterocyclic alkyl, and 8-membered fused heterocyclic alkyl are optionally halogenated, CN- or C-substituted. 1-6 Alkyl substitution;

[1042] Q Z It is O, NH or N (C 1-6 alkyl);

[1043] Each Q L Independently, it is CR L Or N;

[1044] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[1045] Each R C Independently halogenated or C 1-6 alkyl;

[1046] Y 1 Selected from O, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[1047] R 1 Is it halogenated or C 2-6 alkynyl group;

[1048] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[1049] r is 1, 2, 3, 4, 5, or 6; and

[1050] q is 0, 1, or 2.

[1051] In the embodiments, the compound of formula VIAA-ia has the structure of formula VIAA-iai:

[1052]

[1053] or its pharmaceutically acceptable salt

[1054] in:

[1055] Q Z It is O, NH or N (C 1-6 alkyl);

[1056] Each Q L Independently, it is CR L Or N;

[1057] Each R LIndependently selected from H, halogen, CN and C 1-6 alkyl;

[1058] R B and R C Each is independently halogenated or C 1-6 alkyl;

[1059] Y 1 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[1060] R 1 Is it halogenated or C 2-6 alkynyl group;

[1061] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[1062] r is 1, 2, 3, 4, 5, or 6;

[1063] s is 0, 1, 2, or 3; and

[1064] Each q is independently 0, 1, or 2.

[1065] In the embodiments, the compound of formula VIAA-ia has the structure of formula VIAA-iaii:

[1066]

[1067] or its pharmaceutically acceptable salt

[1068] in:

[1069] Each Q B Independently selected from CH, CH2, N, NH and N(C) 1-6 Alkyl), provided that at least one Q B It is N, NH or N(C) 1-6 alkyl);

[1070] Q Z It is O, NH or N (C 1-6 alkyl);

[1071] Each Q L Independently, it is CR L Or N, provided that at least one Q L It is N;

[1072] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[1073] Each RC Independently halogenated or C 1-6 alkyl;

[1074] Y 1 Selected from O, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[1075] R 1 Is it halogenated or C 2-6 alkynyl group;

[1076] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[1077] r is 1, 2, 3, 4, 5, or 6; and

[1078] q is 0, 1, or 2.

[1079] In the embodiment of formula VIAA-iaii, at least two Q B It is CH2.

[1080] In the embodiments, the compound of formula VIAA-ia has the structure of formula VIAA-iaiii:

[1081]

[1082] or its pharmaceutically acceptable salt

[1083] in:

[1084] Each Q B Independently selected from CH2, NH and N(C) 1-6 Alkyl), provided that at least one Q B Is it NH or N(C) 1-6 alkyl);

[1085] Q Z It is O, NH or N (C 1-6 alkyl);

[1086] Each Q L Independently, it is CR L Or N;

[1087] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[1088] Each R C Independently halogenated or C 1-6 alkyl;

[1089] Y 1Selected from O, C(O), N(H), N(C) 1-6 Alkyl), C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[1090] R 1 Is it halogenated or C 2-6 alkynyl group;

[1091] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[1092] r is 1, 2, 3, 4, 5, or 6;

[1093] s is 0, 1, 2, or 3; and

[1094] q is 0, 1, or 2.

[1095] In the embodiments, the compound of formula VIAA-ii has the structure of formula VIAA-iia:

[1096]

[1097] or its pharmaceutically acceptable salt

[1098] in:

[1099] Q Z It is O, NH or N (C 1-6 alkyl);

[1100] Each Q L Independently, it is CR L Or N;

[1101] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[1102] R B and R C Each is independently halogenated or C 1-6 alkyl;

[1103] Y 1 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[1104] R 1 Is it halogenated or C 2-6 alkynyl group;

[1105] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[1106] p and r are each independently 1, 2, 3, 4, 5, or 6; and

[1107] Each q is independently 0, 1, or 2.

[1108] In the embodiments, the compound of formula VIAA-ii has the structure of formula VIAA-iib:

[1109]

[1110] or its pharmaceutically acceptable salt

[1111] in:

[1112] Each Q B Independently selected from CH2, NH and N(C) 1-6 Alkyl), provided that at least one Q B Is it NH or N(C) 1-6 alkyl);

[1113] Q Z It is O, NH or N (C 1-6 alkyl);

[1114] Each Q L Independently, it is CR L Or N;

[1115] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[1116] Each R C Independently halogenated or C 1-6 alkyl;

[1117] Y 1 Selected from O, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[1118] R 1 Is it halogenated or C 2-6 alkynyl group;

[1119] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[1120] p and r are each independently 1, 2, 3, 4, 5, or 6; and

[1121] q is 0, 1, or 2.

[1122] In the embodiments, the VIAA-ii compound has the structure of the VIAA-iic compound:

[1123]

[1124] or its pharmaceutically acceptable salt

[1125] in:

[1126] Each Q B Independently selected from CH2, N, NH and N(C) 1-6 Alkyl), provided that at least one Q B It is N, NH or N(C) 1-6 alkyl);

[1127] Q Z It is O, NH or N (C 1-6 alkyl);

[1128] Each Q L Independently, it is CR L Or N;

[1129] Each R L Independently selected from H, halogen, CN and C 1-6 alkyl;

[1130] Each R C Independently halogenated or C 1-6 alkyl;

[1131] Y 1 Selected from O, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[1132] R 1 Is it halogenated or C 2-6 alkynyl group;

[1133] R 2 Selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group;

[1134] p and r are each independently 1, 2, 3, 4, 5, or 6; and

[1135] q is 0, 1, or 2.

[1136] In the embodiment of formula VIAA-iic, at least two Q B It is CH2.

[1137] Various embodiments of formulas I-VIA, VIAA, VII, AI, AIV and their various subgenera, or their pharmaceutically acceptable salts.

[1138] In the embodiment, Q 1 It is CH2 or C(O). In the embodiment, Q 2 It is N. In the embodiment, Q 3It is CH or N. In the embodiment, R 1a Selected from H and OH. In the examples, R... 1b and R 2b Together with the phenyl group it is attached to, it forms a group with R 1 and R 2 Substituted naphthyl group. In the examples, R 1 Selected from H, halogenated and C 1-6 Alkyl group. In the examples, R 1 It is H. In the embodiment, R 1 It is halogenated. In the embodiment, R 1 It is C 1-6 Alkyl group. In the examples, R 2a Selected from H and halogenated. In the examples, R 2 Selected from H, C 1-6 Alkyl groups and C≡CH. In the examples, R... 2 It is C 3-6 Cycloalkyl.

[1139] In the embodiment, R 2 It is H. In the embodiment, R 2 It is C 1-6 Alkyl group. In the examples, R 2 It is C≡CH. In the embodiment, R 3 It is halogenated.

[1140] In the embodiment, R 4 Is it arbitrarily R 4a Substituted bridged 8-membered heterocyclic alkyl group.

[1141] In embodiments of formulas I-VI, R 4 yes:

[1142]

[1143] In the embodiment, R 4a Is it H or C? 1-6 Alkyl group. In the examples, R 5a Is it H, halogenated, or C? 1-6 Alkyl group. In the examples, R 5 Is it H or C? 1-6 Alkyl group. In the examples, R 6 Is it H or C? 1-6 alkyl.

[1144] In the embodiment, R 7 Selected from H, =O, halogenated and C 1-6 Alkyl group. In the examples, R... 7 Yes = 0. In the embodiment, R 7 It is halogenated. In the embodiment, R 7 It is C1-6 Alkyl group. In the examples, R 8 Is it H or C? 1-6 Alkyl group. In the examples, R 8 It is H. In the embodiment, R 9 Selected from H, halogenated and C 1-6 Alkyl group. In the examples, R 9 It is halogenated.

[1145] In the embodiment, R 9 It is C 1-6 Alkyl group. In the examples, R 10 It is H. In the embodiment, R 11 It is H. In the embodiment, R 12 It is C 1-6 Alkyl group. In the examples, R 13 It is H. In the embodiment, R 14 Is it H or C? 1-6 Alkyl group. In the examples, R 14 It is H. In the embodiment, R 14 It is C 1-6 alkyl.

[1146] In the embodiment, R 15a Is it H, halogenated, or C? 1-6 Alkyl group. In the examples, R 15b Is it H, halogenated, or C? 1-6 Alkyl group. In the examples, R 15 Is it H or C? 1-6 Alkyl group. In the examples, R 16 Is it H or C? 1-6 Alkyl group. In the examples, R 17a and R 17b Each is independently either H or halogenated. In the embodiments, R 17 It is C 1-6 Alkyl group. In the examples, R 18 It's H.

[1147] In the examples, ring A is phenyl. In the examples, ring A is a 6-membered heterocyclic alkyl group. In the examples, ring A is dihydropyridyl. In the examples, B is a bond. In the examples, B is a C bond. 1-6 alkyl.

[1148] In the embodiment, each L is independently selected from C. 1-6 Alkyl, C 1-6 Alkoxy, C(O), 5-12 membered heterocyclic alkyl, wherein the 5-12 membered heterocyclic alkyl is optionally halogenated. In the examples, the 5-12 membered heterocyclic alkyl is a fused 8-membered heterocyclic alkyl.

[1149] In the embodiment, each L is independently selected from C. 1-6 Alkyl, C 1-6 Alkoxy and 6-12-membered heterocyclic alkyl groups, wherein the 6-12-membered heterocyclic alkyl groups are optionally halogenated.

[1150] In the embodiment, each L is independently selected from C. 1-6 Alkyl, C 1-6 Alkoxy, 6-8-membered heterocyclic alkyl and 5-6-membered heteroaryl, wherein the 6-8-membered heterocyclic alkyl is optionally halogenated.

[1151] In the embodiment, L forms the following connector: (C 1-6 alkoxy)-(6-12 membered heterocyclic alkyl)-(C 1-6 Alkyl)-(6-12 membered heterocyclic alkyl).

[1152] In this embodiment, n is 4, and each L forms the following connector: (C 1-6 alkoxy)-(6-12 membered heterocyclic alkyl)-(C 1-6 Alkyl)-(6-12 membered heterocyclic alkyl).

[1153] In this embodiment, n is 4, and each L forms the following connector: (C 1-6 alkoxy)-(6-membered heterocyclic alkyl)-(C 1-6 Alkyl)-(7-membered heterocyclic alkyl).

[1154] In this embodiment, n is 4, and each L forms the following connector: (C 1-6 alkoxy)-(6-membered heterocyclic alkyl)-(C 1-6 Alkyl)-(9-membered heterocyclic alkyl).

[1155] In this embodiment, n is 4, and each L forms the following connector: (C 1-6 alkoxy)-(6-membered heterocyclic alkyl)-(C 1-6 Alkyl)-(11-membered heterocyclic alkyl).

[1156] In this embodiment, each L forms a connector:

[1157]

[1158] In this embodiment, n is 6, and each L forms the following connector: (C 1-6 alkoxy)-(6-12 membered heterocyclic alkyl)-(C 1-6 alkyl)-(6-12 membered heterocyclic alkyl)-(C 1-6 Alkyl)-(6-membered heterocyclic alkyl).

[1159] In this embodiment, n is 6, and each L forms the following connector: (C 1-6alkoxy)-(6-membered heterocyclic alkyl)-(C 1-6 alkyl)-(6-membered heterocyclic alkyl)-(C 1-6 Alkyl)-(6-membered heterocyclic alkyl).

[1160] In this embodiment, n is 4, and each L forms the following connector: (C 1-6 alkoxy)-(5-12 membered heterocyclic alkyl)-(C 1-6 Alkyl)-(5-12 membered heterocyclic alkyl).

[1161] In this embodiment, n is 4, and each L forms the following connector: (C 1-6 alkoxy)-(11-membered heterocyclic alkyl)-(C 1-6 Alkyl)-(6-membered heterocyclic alkyl).

[1162] In the examples, the 11-membered heterocyclic alkyl group is a spirocyclic 11-membered heterocyclic alkyl group.

[1163] In this embodiment, n is 6, and each L forms the following connector: (C 1-6 alkoxy)-(5-12-membered heterocyclic alkyl)-(O)-(5-12-membered heterocyclic alkyl)-(C 1-6 (alkyl)-(5-12-membered heterocyclic alkyl), wherein the 5-12-membered heterocyclic alkyl is optionally C 1-6 Alkyl substitution.

[1164] In this embodiment, n is 6, and each L forms the following connector: (C 1-6 alkoxy)-(5-membered heterocyclic alkyl)-(O)-(6-membered heterocyclic alkyl)-(C 1-6 alkyl)-(6-membered heterocyclic alkyl), wherein the 5-membered heterocyclic alkyl is optionally C 1-6 Alkyl substitution.

[1165] In this embodiment, n is 4, and each L forms the following connector: (C 1-6 alkoxy)-(5-12 membered heterocyclic alkyl)-(C 1-6 Alkyl)-(5-12 membered heterocyclic alkyl).

[1166] In this embodiment, n is 4, and each L forms the following connector: (C 1-6 alkoxy)-(6-membered heterocyclic alkyl)-(C 1-6 Alkyl)-(9-membered heterocyclic alkyl).

[1167] In the examples, the 9-membered heterocyclic alkyl group is a spirocyclic 9-membered heterocyclic alkyl group.

[1168] In this embodiment, n is 4, and each L forms the following connector: (C 1-6alkoxy)-(5-12-membered heterocyclic alkyl)-(O)-(5-12-membered heterocyclic alkyl), wherein the 5-12-membered heterocyclic alkyl is optionally C 1-6 Alkyl substitution.

[1169] In this embodiment, n is 4, and each L forms the following connector: (C 1-6 alkoxy)-(5-membered heterocyclic alkyl)-(O)-(6-membered heterocyclic alkyl), wherein the 5-membered heterocyclic alkyl is optionally C 1-6 Alkyl substitution.

[1170] In the embodiments, the heterocyclic alkyl group contains one, two, or three heteroatoms independently selected from N, O, and S. In the embodiments, the heterocyclic alkyl group contains one or two heteroatoms independently selected from N, O, and S. In the embodiments, the heterocyclic alkyl group contains one or two heteroatoms independently selected from N and O. In the embodiments, the heterocyclic alkyl group contains one or two nitrogen heteroatoms.

[1171] In this embodiment, each L forms a connector:

[1172] In the embodiment, (L) n Selected from:

[1173]

[1174]

[1175] In selecting the compounds of the present invention, those skilled in the art will recognize that the selection of various substituents should conform to well-known principles of chemical structural connectivity and stability.

[1176] In the examples, the compounds of Formula I are selected from the compounds in Table 1 or their pharmaceutically acceptable salts.

[1177] Table 1.

[1178]

[1179]

[1180]

[1181]

[1182]

[1183]

[1184]

[1185]

[1186]

[1187]

[1188]

[1189]

[1190]

[1191]

[1192]

[1193]

[1194]

[1195]

[1196]

[1197]

[1198]

[1199]

[1200]

[1201]

[1202]

[1203]

[1204]

[1205]

[1206]

[1207]

[1208]

[1209]

[1210]

[1211]

[1212]

[1213]

[1214]

[1215]

[1216]

[1217]

[1218]

[1219]

[1220]

[1221]

[1222]

[1223]

[1224]

[1225]

[1226]

[1227]

[1228]

[1229]

[1230]

[1231]

[1232]

[1233]

[1234]

[1235]

[1236] This document also provides pharmaceutical compositions comprising any of the compounds described herein or their pharmaceutically acceptable salts and pharmaceutically acceptable carriers.

[1237] The compounds disclosed herein can exist as tautomers and optical isomers (e.g., enantiomers, diastereomers, diastereomer mixtures, racemic mixtures, etc.).

[1238] It is generally well known in the art that any compound that is converted in vivo to provide the compounds disclosed herein is a prodrug within the scope of this disclosure.

[1239] Treatment

[1240] This application relates to methods for treating or improving disease states or symptoms, which are regulated by or causally related to target proteins (i.e., KRas).

[1241] This document provides methods for treating diseases or conditions, which involve administering to a subject any compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein.

[1242] In this embodiment, the disease or condition is cancer.

[1243] In the embodiments, the cancer is bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, uterine cancer, ovarian cancer, testicular cancer, thyroid cancer, pineal cell tumor, carcinoma, cell tumor, ependymoma, ganglioglioma, ganglioneuroma, glioblastoma, glioma, leukemia, lymphoma, medulloblastoma, melanoma, meningioma, myeloma, nephroblastoma, neuroblastoma, neurofibroma, oligodendroglioma, peripheral neuroepithelial tumor, sarcoma, or schwannoma.

[1244] In one embodiment, the cancer is a teratoma. In another embodiment, the cytoma is an astrocytoma.

[1245] In the embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma. In the embodiments, the leukemia is precursor B lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, adult T-cell leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia, Philadelphia chromosome-positive chronic myeloid leukemia, or acute lymphoblastic leukemia.

[1246] In the embodiments, the lymphoma is Burkitt lymphoma, non-Hodgkin's lymphoma, precursor T-lymphoblastic lymphoma, peripheral T-cell lymphoma, precursor lymphoblastic lymphoma, diffuse large B-cell lymphoma, or B-cell lymphoma.

[1247] In this embodiment, the lymphoma is Hodgkin's lymphoma (HL).

[1248] In this embodiment, the nephroblastoma is Wilms' tumor. In this embodiment, the sarcoma is selected from carcinosarcoma, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, sarcoma, synovial sarcoma, and medullary sarcoma.

[1249] This article provides a method for modulating KRas protein activity, the method comprising administering to a subject any compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein.

[1250] This article also provides methods for modulating cerebellar protein activity, the methods comprising administering to a subject any compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein.

[1251] This document further provides a method for degrading target proteins, the method comprising contacting cells with any compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein.

[1252] Application / Dosage / Formulation

[1253] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[1254] Injectable formulations (e.g., sterile injectable aqueous or oily suspensions) can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in the form of non-toxic, parenteral-acceptable diluents or solvents, such as solutions in the form of 1,3-butanediol. Acceptable mediators and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are routinely used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid are used to prepare injectable formulations.

[1255] To prolong the action of a drug, it is generally desirable to slow the absorption of drugs administered subcutaneously or intramuscularly. This can be achieved using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of the drug then depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms is achieved by dissolving or suspending the drug in an oily medium.

[1256] The composition for rectal or vaginal application is preferably a suppository, which can be prepared by mixing the compound of the present disclosure with a suitable non-irritating excipient or carrier (such as cocoa butter, polyethylene glycol or suppository wax), which is solid at room temperature but liquid at body temperature and thus can melt in the rectal or vaginal cavity and release the active compound.

[1257] Similar solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules, which use excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol.

[1258] The active compound can also be in microencapsulated form with one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells, such as enteric coatings, release-controlled coatings, and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Normally, in addition to an inert diluent, such dosage forms may contain other substances, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may also contain a buffer.

[1259] Dosage forms for topical or transdermal application of the compounds of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives or buffers that may be required. Ophthalmic formulations, ear drops, eye ointments, powders, and solutions are also considered to be within the scope of this disclosure.

[1260] In addition to the active compounds disclosed herein, the ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin wax, starch, astragalus gum, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[1261] In addition to the compounds disclosed herein, powders and aerosols may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders or mixtures thereof. Aerosols may also contain conventional propellants such as chlorofluorocarbons (CFCs).

[1262] Transdermal patches offer the added advantage of providing controlled delivery of compounds into the body. These dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[1263] The disclosed compound can be administered intratympanicly, wherein a long, narrow, perforated needle is passed through the ear canal and through the eardrum to deliver the drug into the middle ear space, where the compound is absorbed by the inner ear.

[1264] According to the treatment methods of this disclosure, a subject's condition is treated or prevented by administering a therapeutically effective amount of the disclosed compound to the subject, wherein such an amount and duration of administration are necessary to achieve the desired outcome. As used herein, the term "therapeuticly effective amount" for a compound of this disclosure means a compound sufficient to alleviate the subject's condition symptoms. As is well understood in the medical field, a therapeutically effective amount of the disclosed compound would be used in any medical treatment with a reasonable benefit / risk ratio.

[1265] In general, the compounds disclosed herein will be administered, alone or in combination with one or more therapeutic agents, in a therapeutically effective amount using any commonly used and acceptable method known in the art. Therapeuticly effective amounts can vary considerably depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. Generally, a daily dose of about 0.03 mg / kg body weight to 2.5 mg / kg body weight has been shown to systematically achieve satisfactory results. In larger mammals (e.g., humans), the indicated daily dose is conveniently administered in the range of about 0.5 mg to about 100 mg, for example, in fractional doses up to four times daily or in a sustained-release form. Suitable unit dosage forms for oral administration contain about 1 mg to 50 mg of the active ingredient.

[1266] In embodiments, the therapeutic amount or dose of the compounds of this disclosure can range from about 0.1 mg / kg to about 500 mg / kg, and alternatively from about 1 mg / kg to about 50 mg / kg. Generally, a treatment regimen according to this disclosure comprises administering about 10 mg to about 1000 mg of the compounds of this disclosure to a subject requiring such treatment in a single or multiple daily dose. The therapeutic amount or dose will also vary depending on the route of administration and the possibility of use with other pharmaceutical agents.

[1267] When the subject's symptoms improve, a maintenance dose of the disclosed compounds, compositions, or combinations may be administered if necessary. Subsequently, as symptoms change and have been reduced to the desired level, the dose or frequency, or both, may be reduced to a level that maintains the improved symptoms, and treatment should be discontinued. However, in the event of any recurrence of disease symptoms, the subject may require long-term intermittent treatment.

[1268] However, it should be understood that the total daily dosage of the compounds and compositions disclosed herein will be determined by the attending physician within the bounds of reasonable medical judgment. The specific inhibitory dosage for any particular subject will depend on a variety of factors, including the condition being treated and its severity; the activity of the specific compound used; the specific composition used; the subject's age, weight, general health status, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field.

[1269] This disclosure also provides pharmaceutical combinations, such as kits, comprising a) a first pharmaceutical agent, which is a compound of this disclosure in free form or in a pharmaceutically acceptable salt form as disclosed herein, and b) at least one adjuvant. The kit may include instructions for use.

[1270] Examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins (such as human serum albumin); buffers (such as phosphates, glycine, sorbic acid, or potassium sorbate); mixtures of metaglycerides of saturated vegetable fatty acids; water; salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts); colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene block polymers; lanolin; and sugars (such as lactose and glucose). Sugars; starches (such as corn starch and potato starch); cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate); powdered tragacanth gum; malt; gelatin; talc; excipients (such as cocoa butter and suppository waxes); oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil; olive oil, corn oil, and soybean oil); glycols (such as propylene glycol or polyethylene glycol); esters (such as ethyl oleate and ethyl laurate); agar; buffers (such as magnesium hydroxide and aluminum hydroxide); alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; and phosphate buffer solutions. Furthermore, non-toxic, compatible lubricants such as sodium dodecyl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavorings and flavorings, preservatives, and antioxidants may also be present in the composition, according to the formulator's judgment. Protein kinase inhibitors or pharmaceutically acceptable salts thereof can be formulated into pharmaceutical compositions for administration to animals or humans. Other embodiments of this disclosure include pharmaceutical compositions comprising a certain amount of a protein inhibitor effective in treating or preventing protein kinase-mediated symptoms and a pharmaceutically acceptable carrier.

[1271] Reagent test kit

[1272] This document provides a kit comprising a compound selected from one or more compounds disclosed herein that is capable of degrading KRas, or a pharmaceutically acceptable salt thereof, and instructions for use in treating KRas-related conditions.

[1273] This disclosure provides a kit comprising a compound selected from the compounds disclosed herein that is capable of degrading KRas, or a pharmaceutically acceptable salt thereof.

[1274] This document provides kits containing the compounds disclosed herein or pharmaceutically acceptable salts thereof for the treatment of any of the indications disclosed herein.

[1275] Those skilled in the art will recognize that many equivalents exist, or can be confirmed by routine experimentation alone, of the specific procedures, embodiments, claims, and examples described herein. Such equivalents are within the scope of this disclosure and are covered by the appended claims. For example, it should be understood that modifications made using art-recognized alternatives and by routine experimentation alone, in terms of reaction conditions (including but not limited to reaction time, reaction size / volume) and experimental reagents (such as solvents, catalysts, pressure, atmospheric conditions, e.g., nitrogen atmosphere) and reducing / oxidizing agents, are within the scope of this application.

[1276] It should be understood that whenever values ​​and ranges are provided herein, all values ​​and ranges covered by these values ​​and ranges are intended to be covered within the scope of this disclosure. Furthermore, all values ​​falling within these ranges, as well as the upper or lower limits of the value ranges, are also contemplated in this application.

[1277] The following examples further illustrate aspects of this disclosure. However, they are by no means intended to limit the teachings of this disclosure.

[1278] Example

[1279] The compounds and methods disclosed herein are further illustrated by the following examples, but these examples should not be construed as further limitations. Unless otherwise stated, the practice of this disclosure will employ conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, all of which are within the scope of the art.

[1280] The following examples further illustrate aspects of this disclosure. However, they are by no means intended to limit the teachings of this disclosure.

[1281] abbreviations

[1282] AcOH or HOAc acetic acid

[1283] CBz benzyl chloroformate

[1284] Boc tert-butyloxycarbonyl

[1285] CDCl3 chloroform-d

[1286] Cs2CO3 (cesium carbonate)

[1287] DIEA (Diisopropylethylamine)

[1288] D max Maximum degradation (%)

[1289] DMF N,N-dimethylformamide

[1290] DMSO (dimethyl sulfoxide)

[1291] DMSO-d6 (dimethyl sulfoxide deuteride, C2D6SO)

[1292] DTT dithiothreitol

[1293] ESI Electro-injection Ionization

[1294] EtOH (ethanol)

[1295] eq equivalent

[1296] g gram

[1297] h hours

[1298] Hz Hertz

[1299] HCl hydrochloric acid

[1300] HPLC (High Performance Liquid Chromatography)

[1301] DC 50 Half-maximum degradation concentration

[1302] K2CO3 (potassium carbonate)

[1303] Potassium phosphate in K3PO4 aqueous solution

[1304] min minutes

[1305] m / z mass-to-charge ratio

[1306] MS mass spectrometry

[1307] MHz

[1308] MeOH (methanol)

[1309] MOM (methoxymethyl)

[1310] μL

[1311] μm micrometer

[1312] mg

[1313] mm

[1314] mL

[1315] mmol millimole

[1316] NH4Cl ammonium chloride

[1317] nM nanomolar

[1318] NMR (Nuclear Magnetic Resonance)

[1319] The complex of Pd(dppf)Cl2 [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride with dichloromethane

[1320] PMB p-methoxybenzyl

[1321] psi (pounds per square inch)

[1322] TEA Triethylamine

[1323] TFA (trifluoroacetic acid)

[1324] Tf trifluoromethanesulfonate

[1325] TIPS: Triisopropylsilyl ether

[1326] TBDPS tert-butyldiphenylsilyl

[1327] THF Tetrahydrofuran

[1328] TLC (Thin Layer Chromatography)

[1329] Synthesis program

[1330] Example 1: Synthesis of 3-[4-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (compound 43)

[1331] Step 1: Preparation of 2-chloro-3-fluoro-5-iodopyridine-4-amine

[1332]

[1333] p-TsOH (118 mg, 0.682 mmol, 0.05 equivalent) was added to a solution of 2-chloro-3-fluoro-pyridin-4-amine (2.00 g, 13.7 mmol, 1 equivalent) and NIS (3.68 g, 16.4 mmol, 1.2 equivalent) in CH3CN (15 mL), and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with EtOAc (40 mL), and the resulting mixture was washed with saturated aqueous Na2CO3 solution (2 × 30 mL), saturated aqueous Na2SO3 solution (40 mL), and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (3.63 g, 13.3 mmol, 98% yield) as a yellow solid. LC / MS (ESI) m / z: 272.8 [M+H] + . 1H-NMR (400MHz, DMSO-d6) δ8.09 (s, 1H), 6.67 (br s, 2H).

[1334] Step 2: Preparation of ethyl 4-amino-6-chloro-5-fluoro-pyridine-3-carboxylate

[1335]

[1336] Triethylamine (4.85 g, 48.0 mmol, 6.68 mL, 3.6 equivalents) and Pd(PPh3)2Cl2 (935 mg, 1.33 mmol, 0.1 equivalents) were added to a solution of 2-chloro-3-fluoro-5-iodopyridin-4-amine (3.63 g, 13.3 mmol, 1 equivalent) in EtOH (70 mL), and the reaction mixture was stirred at 80 °C under CO (15 psi) for 16 h (degassed under vacuum and purged with CO several times). The reaction mixture was concentrated under reduced pressure to remove about 70% of the EtOH and then filtered. The filter cake was washed with TBME (2 × 30 mL) and then dried under reduced pressure to give the title compound (3.40 g, crude) as a yellow solid. LC / MS (ESI) m / z: 219.0 [M+H] + .

[1337] Step 3: Preparation of ethyl 6-chloro-5-fluoro-4-[(2,2,2-trichloroacetyl)carbamoylamino]pyridine-3-carboxylate

[1338]

[1339] To a solution of ethyl 4-amino-6-chloro-5-fluoro-pyridine-3-carboxylate (3.40 g, 15.6 mmol, 1 equivalent) in THF (10 mL), 2,2,2-trichloroacetyl isocyanate (3.22 g, 17.1 mmol, 2.03 mL, 1.1 equivalent) was added, and the reaction mixture was stirred at 20 °C for 1 hour under N2. The reaction mixture was concentrated under reduced pressure to give the title compound (6.10 g, crude) as a brown solid. LC / MS (ESI) m / z: 408.1 [M+H] + .

[1340] Step 4: Preparation of 7-chloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol

[1341]

[1342] Ammonia (7 M, 10.7 mL, 5 equivalents) was added to a solution of ethyl 6-chloro-5-fluoro-4-[(2,2,2-trichloroacetyl)carbamoylamino]pyridine-3-carboxylate (6.10 g, 15.0 mmol, 1 equivalent) in CH3OH (55 mL), and the reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was filtered, and the filter cake was washed with TBME (3 × 20 mL) and then dried under reduced pressure to give the title compound as a white solid (3.03 g, 14.06 mmol, 94% yield). LC / MS (ESI) m / z: 216.1 [M+H] + .

[1343] Step 5: Preparation of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine

[1344]

[1345] DIEA (4.50 g, 34.8 mmol, 6.06 mL, 3 equivalents) and POCl3 (8.89 g, 58.0 mmol, 5.39 mL, 5 equivalents) were added to a solution of 7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-2,4-diol (2.50 g, 11.6 mmol, 1 equivalent) in toluene (30 mL), and the reaction mixture was stirred at 100 °C for 1 hour under N2. The reaction mixture was concentrated under reduced pressure to give the title compound (2.9 g, crude) as a yellow oil. LC / MS (ESI) m / z: 253.7 [M+H] + .

[1346] Step 6: Preparation of tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1347]

[1348] DIEA (7.42 g, 57.4 mmol, 5 equivalents) and (1S,5R)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.44 g, 11.5 mmol, 1 equivalent) were added to a solution of 2,4,7-trichloro-8-fluoropyridino[4,3-d]pyrimidine (2.90 g, 11.5 mmol, 1 equivalent) in CH2Cl2 (50 mL) at -40 °C, and the reaction mixture was stirred at -40 °C under N2 for 0.5 h. The reaction mixture was poured into water (50 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (2 × 60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid silica gel chromatography (elution buffer: 0-25% EtOAc / petroleum ether) to give the title compound as a yellow solid (2.47 g, 5.77 mmol, 50% yield). LC / MS (ESI) m / z: 428.2 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δ9.06(s,1H),4.60-4.40(m,2H),4.31-4.22(m,2 H),3.80-3.59(m,2H),1.85-1.74(m,2H),1.66-1.57(m,2H),1.46(s,9H).

[1349] Step 7: Preparation of tert-butyl 3-[7-chloro-2-(2,2-dimethoxyethoxy)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1350]

[1351] Cs₂CO₃ (456 mg, 1.40 mmol, 1.2 equivalent) and DABCO (13 mg, 0.17 mmol, 0.1 equivalent) were added to a solution of 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (500 mg, 1.17 mmol, 1 equivalent) and 2,2-dimethoxyethanol (186 mg, 1.75 mmol, 1.5 equivalent) in CH₃CN (10 mL), and the reaction mixture was stirred at 20 °C under N₂ for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by rapid silica gel chromatography (elution: 0-15% THF / petroleum ether) to give the title compound. LC / MS(ESI) m / z: 498.3 [M+H] +. 1 H-NMR (400MHz, CDCl3) δ8.74 (s, 1H), 4.81 (t, J = 5.6Hz, 1H), 4.54-4.45 (m, 4H), 4.43-4.27 ( m,2H),3.74-3.55(m,2H),3.48(s,6H),2.02-1.90(m,2H),1.75-1.65(m,2H),1.52(s,9H).

[1352] Step 8: Preparation of 5-[2-(4-fluorophenyl)acetyl]-2,2-dimethyl-1,3-dioxane-4,6-dione

[1353]

[1354] Over 3 hours, DIEA (121 mL, 697.43 mmol, 2.2 equivalences) was slowly added to a solution of 2-(4-fluorophenyl)acetic acid (50 g, 324.38 mmol, 1.0 equivalences), 2,2-dimethyl-1,3-dioxane-4,6-dione (51.4 g, 356.82 mmol, 1.1 equivalences), and DMAP (3.4 g, 27.57 mmol, 0.085 equivalences) in CH3CN (150 mL), followed by the addition of 2,2-dimethylpropionyl chloride (44 mL, 356.82 mmol, 1.1 equivalences), while maintaining the temperature below 45 °C. The reaction mixture was stirred at 45 °C for 3 hours. The reaction solution was cooled to 0 °C. Then, HCl (500 mL, 1 M, 1.54 equivalences) was added, and the mixture was stirred at 0 °C for 30 minutes. The mixture was filtered, and the filter cake was washed with water (CH3CN:water = 1:4, 500 mL). The filter cake was dissolved in CH2Cl2 (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound as a white solid (84.5 g, 301.52 mmol, 93% yield).

[1355] Step 9: Preparation of tert-butyl 4-(4-fluorophenyl)-3-oxo-butyrate

[1356]

[1357] A solution of 5-[2-(4-fluorophenyl)acetyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (168 g, 601.25 mmol, 1.0 equivalent) in t-BuOH (500 mL) was stirred at 90 °C for 2.5 h. The reaction mixture was concentrated under vacuum to give the title compound (151 g, 598.54 mmol, 100% yield) as a yellow oil. LC / MS (ESI) m / z: 197.1 [M-56]+ .

[1358] Step 10: Preparation of 4-(4-fluorophenyl)-3-oxo-butyric acid

[1359]

[1360] TFA (293 mL, 3.95 mol, 6.60 equivalents) was added to a solution of tert-butyl 4-(4-fluorophenyl)-3-oxo-butyrate (151 g, 598.54 mmol, 1.0 equivalent) in CH2Cl2 (300 mL), and the reaction mixture was stirred at 20 °C for 1 h. The mixture was concentrated under vacuum to give the title compound as a yellow solid (115 g, 532.28 mmol, 89% yield). LC / MS (ESI) m / z: 197.1 [M+H] + .

[1361] Step 11: Preparation of 7-fluoronaphthalene-1,3-diol

[1362]

[1363] A solution of 4-(4-fluorophenyl)-3-oxo-butyric acid (115 g, 586.21 mmol, 1.0 equivalent) in CF3SO3H (1200 mL) was stirred at 20 °C for 16 h. The reaction mixture was cooled to 0 °C and slowly poured into ice water (3.0 L). The resulting precipitate was filtered, and the filter cake was dissolved in ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated NaHCO3 aqueous solution (40 mL × 2) and brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound as a red solid (54.4 g, 267.18 mmol, 46% yield). LC / MS (ESI) m / z: 179.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.19(s,1H),9.49(s,1H),7.67-7.53(m,2H),7.25-7.20(m,1H),6.64(s,1H),6.56(s,1H).

[1364] Step 12: Preparation of 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol

[1365]

[1366] Diruthenium dichloroethylene was added to a solution of 7-fluoronaphthyl-1,3-diol (43.5 g, 244.23 mmol, 1.0 equivalent), 2-bromoethynyl(triisopropyl)silane (67 g, 256.44 mmol, 1.05 equivalent), and KOAc (48 g, 488.45 mmol, 2.0 equivalent) in dioxane (300 mL) under N2 conditions; 1-isopropyl-4-methylbenzene (9.0 g, 14.65 mmol, 0.06 equivalent) was added, and the reaction mixture was stirred at 110 °C for 16 hours. The mixture was filtered and concentrated under vacuum, and the resulting residue was purified by rapid chromatography on SiO2 (gradient: 0-20% ethyl acetate / petroleum ether) to give the title compound (46.3 g, 124.11 mmol, 51% yield) as a black oil. LC / MS (ESI) m / z: 359.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.17 (s, 1H), 7.61-7.57 (m, 1H), 7.17 (t, J = 8.8Hz, 1H), 6.74 (d, J = 2.4Hz, 1H), 6.66 (d, J = 2.0Hz, 1H), 1.22-1.16 (m, 21H).

[1367] Step 13: Preparation of 7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)naphthalene-1-ol

[1368]

[1369] At 0 °C, DIEA (67.5 mL, 387.43 mmol, 3.0 equivalent) and MOMCl (14.7 mL, 193.71 mmol, 1.5 equivalent) were added to a solution of 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol (46.3 g, 129.14 mmol, 1.0 equivalent) in CH2Cl2 (450 mL), and the reaction mixture was stirred at 0 °C for 40 min. The reaction mixture was quenched at 0 °C by adding water (50 mL), and then extracted with dichloromethane (50 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by rapid chromatography over SiO2 (gradient: 0-15% dichloromethane / petroleum ether) to give the title compound as a yellow oil (26.8 g, 62.51 mmol, 48% yield). LC / MS (ESI) m / z: 403.1 [M+H] + .

[1370] Step 14: Preparation of [7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]trifluoromethanesulfonate

[1371]

[1372] Tf₂O (13.4 mL, 81.23 mmol, 1.5 equivalence) was added to a solution of 7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)naphth-1-ol (21.8 g, 54.15 mmol, 1.0 equivalence) and DIEA (28.3 mL, 162.45 mmol, 3.0 equivalence) in CH₂Cl₂ (300 mL) at -40 °C, and the reaction mixture was stirred at -40 °C for 40 min. The reaction mixture was quenched at -40 °C by adding water (150 mL), heated to 25 °C, and then extracted with dichloromethane (100 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The resulting residue was purified by rapid chromatography over SiO2 (gradient: 0-15% dichloromethane / petroleum ether) to give the title compound as a yellow oil (28 g, 51.95 mmol, 96% yield).

[1373] Step 15: Preparation of 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane

[1374]

[1375] Under N2, Pd(dppf)Cl2 (3.26 g, 4.45 mmol, 0.1 equivalent) was added to a solution of [7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]trifluoromethanesulfonate (23.8 g, 44.52 mmol, 1.0 equivalent), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentanane (22.6 g, 89.03 mmol, 2.0 equivalent) and KOAc (13.1 g, 133.55 mmol, 3.0 equivalent) in toluene (350 mL), and the reaction mixture was stirred under N2 at 110 °C for 16 hours. The mixture was then passed through a vacuum... The sample was filtered through a filter pad and washed with ethyl acetate (80 mL × 2). The filtrate was evaporated to dryness, and the resulting residue was purified by rapid chromatography over SiO2 (gradient: 0–3% ethyl acetate / petroleum ether) to give the title compound as a yellow solid (21.4 g, 27.97 mmol, 63% yield). LC / MS (ESI) m / z: 513.0 [M + H] + .

[1376] Step 16: Preparation of 3-[2-(2,2-dimethoxyethoxy)-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1377]

[1378] Under N2, tert-butyl 3-[7-chloro-2-(2,2-dimethoxyethoxy)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.803 mmol, 1.0 equivalent) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-naphthyl]ethynyl-triisopropyl - A solution of silane (494 mg, 0.964 mmol, 1.2 equivalences) in dioxane (10 mL) and H₂O (2 mL) was supplemented with K₃PO₄ (512 mg, 2.41 mmol, 3.0 equivalences) and [2-(2-aminophenyl)phenyl]palladium (1+); bis(1-adamantyl)-butylphosphine; methanesulfonate (117 mg, 0.161 mmol, 0.2 equivalences), and the reaction mixture was stirred at 85 °C under N₂ for 15 h. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by rapid chromatography over SiO₂ (gradient: 0-27% ethyl acetate / petroleum ether) to give the title compound as a yellow solid (590 mg, 0.684 mmol, 85% yield). LC / MS (ESI) m / z: 848.4 [M+H] + .

[1379] Step 17: Preparation of tert-butyl 3-[8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1380]

[1381] An aqueous solution of HCl (1.58 mL, 12 M, 25.51 equivalents) was added to a solution of 3-[2-(2,2-dimethoxyethoxy)-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (630 mg, 0.743 mmol, 1.0 equivalent) in acetone (1.6 mL), and the reaction mixture was stirred at 20 °C for 15 minutes. A solution of NaHCO3 (867 μL, 22.29 mmol, 30.0 equivalent) in water (3 mL), Boc2O (341 μL, 1.49 mmol, 2.0 equivalent), and THF (3 mL) was added, and the reaction mixture was stirred at 20 °C for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by rapid chromatography on SiO2 (gradient: 0–50% ethyl acetate / petroleum ether) to give the title compound as a yellow solid (420 mg, 386.23 μmol, 52% yield). LC / MS (ESI) m / z: 758.4 [M+H] + .

[1382] Step 18: Preparation of 2-bromo-6-[4-(dimethoxymethyl)-1-piperidinyl]benzaldehyde

[1383]

[1384] N,N-diisopropylethylamine (22.92 g, 177.33 mmol, 4.00 equivalence) was added to a solution of 4-(dimethoxymethyl)piperidine (8.47 g, 53.20 mmol, 1.20 equivalence) and 2-bromo-6-fluorobenzaldehyde (9.00 g, 44.33 mmol, 1 equivalence) in DMSO (90 mL), and the reaction mixture was stirred at 100 °C for 12 h. The residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (gradient: 0–7% ethyl acetate / petroleum ether) to give the title compound as a yellow solid (11.10 g, 32.43 mmol, 73% yield). LC / MS (ESI) m / z: 344.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ10.22(s,1H),7.31-7.28(m,2H),7.14-7.04(m,1H),4.19-4.13(m,1H),3.42(s,6H),3.36-3 .28(m,2H),2.86(dd,J=2.0,12.0Hz,2H),1.93-1.84(m,2H),1.78(dd,J=4.0,7.2,15.2Hz,1H),1.65-1.54(m,2H).

[1385] Step 19: Preparation of 3-[[2-bromo-6-[4-(dimethoxymethyl)-1-piperidinyl]phenyl]methylamino]piperidin-2,6-dione]

[1386]

[1387] Sodium acetate (7.55 g, 92.04 mmol, 3.00 equivalent) was added to a solution of 3-aminopiperidine-2,6-dione (5.05 g, 30.68 mmol, 1.00 equivalent, hydrochloride) in methanol (100 mL) and dichloromethane (100 mL), and the resulting mixture was stirred at 25 °C for 1 hour. Then, 2-bromo-6-[4-(dimethoxymethyl)-1-piperidinyl]benzaldehyde (10.50 g, 30.68 mmol, 1.00 equivalent) and 2-methylpyridinium borane (6.56 g, 61.36 mmol, 2.00 equivalent) were added, and the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was filtered, and the filtrate was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic extract was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was ground with ethyl acetate / petroleum (3:1) to give the title compound as a purple solid (10.70 g, 23.55 mmol, 77% yield). LC / MS (ESI) m / z: 456.1 [M+H] + . 1H NMR(400MHz, CDCl3)δ10.78(s,1H),7.36-7.29(m,1H),7.21-7.11(m,2H),4.12( d,J=6.8Hz,1H),3.99-3.82(m,2H),3.30-3.27(m,6H),3.23(dd,J=4.8,11.2Hz,1 H),3.09(d,J=10.8Hz,1H),3.01-2.81(m,1H),2.77-2.65(m,1H),2.60-2.53(m, 2H),2.48-2.41(m,1H),2.35-2.22(m,1H),1.80-1.61(m,4H),1.51-1.30(m,2H).

[1388] Step 20: Preparation of 3-[4-[4-(dimethoxymethyl)-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione

[1389]

[1390] To a solution of 3-[[2-bromo-6-[4-(dimethoxymethyl)-1-piperidinyl]phenyl]methylamino]piperidin-2,6-dione (10.70 g, 23.55 mmol, 1.00 equivalent) in DMF (150 mL), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(ii) (3.45 g, 4.71 mmol, 0.20 equivalent) and diisopropylethylamine (9.13 g, 70.65 mmol, 3.00 equivalent) were added, and the reaction mixture was degassed and purged with carbon dioxide (3X), then stirred at 80 °C for 12 h under a carbon dioxide (50 Psi) atmosphere. The reaction mixture was filtered, and the filtrate was diluted with water (200 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 (250*80mm*15μm); mobile phase: [20-50% CH3CN / water (trifluoroacetic acid)]) to give the title compound as a white solid (2.60 g, 6.48 mmol, 27% yield). LC / MS (ESI) m / z: 402.2 [M+H] + .

[1391] Step 21: Preparation of 1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]piperidin-4-carboxaldehyde

[1392]

[1393] Trifluoroacetic acid (60 mg, 0.52 mmol, 3.00 equivalent) was added to a solution of 3-[4-[4-(dimethoxymethyl)-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (70 mg, 0.17 mmol, 1.00 equivalent) in dichloromethane (2 mL), and the reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (80 mg, crude) as a colorless oil. LC / MS (ESI) m / z: 356.2 [M+H] + .

[1394] Step 22: Preparation of tert-butyl piperidinium ester of 4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]piperidin-1-carboxylic acid

[1395]

[1396] To a solution of 1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]piperidin-4-carboxaldehyde (340 mg, 0.95 mmol, 1 equivalent) in dimethyl sulfoxide (3 mL) and dichloromethane (3 mL), N-methylmorpholine (484 mg, 4.78 mmol, 0.5 mL, 5 equivalents), tert-butyl 4-(4-piperidinylmethyl)piperidin-1-carboxylate (324 mg, 1.15 mmol, 1.2 equivalents), and acetic acid (57 mg, 0.95 mmol, 0.1 mL, 1 equivalent) were added, and the resulting mixture was stirred at 25 °C for 1 hour. Then, sodium triacetoxyborohydride (406 mg, 1.91 mmol, 2 equivalents) was added, and the reaction mixture was stirred at 25 °C for 15 hours. The mixture was diluted with water (15 mL) and extracted with 5:1 dichloromethane / isopropanol (10 × 3 mL). The organic extract was washed with brine (10 × 3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by rapid silica gel chromatography (gradient: 0-100% ethyl acetate / petroleum ether gradient) to give the title compound as a yellow oil (312 mg, 0.50 mmol, 52% yield). LC / MS (ESI) m / z: 622.5 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.46-7.40(m,1H),7.30(d,J=7.2Hz,1H),7.16(d,J=7.6H z,1H),5.14-5.08(m,1H),4.43(d,J=17.2Hz,1H),4.29(d,J=17.2Hz,1H),4.13(s,1H),3.92(s,2 H),3.34(d,J=0.8Hz,4H),3.16(s,4H),2.77(d,J=10.8Hz,5H),1.99-1.89(m,6H),1.76-1.71(m, 4H), 1.60 (d, J = 12.4Hz, 4H), 1.38 (s, 9H), 1.12 (s, 2H), 1.03 (d, J = 6.0Hz, 1H), 0.95-0.90 (m, 2H).

[1397] Step 23: Preparation of 3-[1-oxo-4-[4-[[4-(4-piperidinylmethyl)-1-piperidinyl]methyl]-1-piperidinyl]isoindoline-2-yl]piperidin-2,6-dione

[1398]

[1399] Trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 20.38 equivalents) was added to a solution of 4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]piperidin-1-carboxylic acid tert-butyl ester (412 mg, 0.66 mmol, 1 equivalent) in dichloromethane (3 mL), and the reaction mixture was stirred at 25 °C for 2 h. The mixture was concentrated under vacuum, and the resulting residue was purified by preparative HPLC (column: Unisil 3-100C18 Ultra 150*50 mm*3 μm; mobile phase: [1-18% CH3CN / water (formic acid)]) to give the title compound as a yellow solid (200 mg, 0.38 mmol, 58% yield). LC / MS (ESI) m / z: 522.4 [M+H] + .

[1400] Step 24: Preparation of 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]-8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1401]

[1402] Add 4-methylmorpholine (26 mg, 0.26 mmol, 28 μL, 1.5 equivalent) to a solution of 3-[1-oxo-4-[4-[[4-(4-piperidinylmethyl)-1-piperidinyl]methyl]-1-piperidinyl]isoindoline-2-yl]piperidin-2,6-dione (90 mg, 0.17 mmol, 1 equivalent) in 1,2-dichloroethane (5 mL) and dimethyl sulfoxide (5 mL), and stir the resulting mixture at 25 °C for 15 minutes. Then, 3-[8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (144 mg, 0.19 mmol, 1.1 equivalents) was added, and the mixture was stirred at 25 °C for 0.5 h. Sodium triacetoxyborohydride (110 mg, 0.52 mmol, 3 equivalents) was added, and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with water (20 mL), and the resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to give the title compound as a yellow solid (110 mg, 0.09 mmol, 50% yield). LC / MS (ESI) m / z: 1263.7 [M+H] + .

[1403] Step 25: Preparation of tert-butyl 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid

[1404]

[1405] Cesium fluoride (240 mg, 1.58 mmol, 20 equivalents) was added to a solution of 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]-8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100 mg, 0.08 mmol, 1 equivalent) in DMF (3 mL) and the reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched with water (20 mL), and the resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound as a yellow oil (80 mg, 0.07 mmol, 91% yield). LC / MS (ESI) m / z: 1107.7 [M+H] + .

[1406] Step 26: Preparation of 3-[4-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (compound 43)

[1407]

[1408] A solution of 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (80 mg, 0.07 mmol, 1 equivalent) in formic acid (4 mL) was stirred at 25 °C for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by preparative HPLC {column: Phenomenex luna C18 150*40mm*15μm; mobile phase: [2-32% CH3CN / water (formic acid)]} to give the title compound (62.7 mg, 0.05 mmol, 78% yield, formate) as a yellow solid.

[1409] Example 2: Synthesis of 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (compound 35)

[1410] Step 1: Preparation of 2,6-dibenzyloxypyridine-3-amine

[1411]

[1412] Potassium tert-butoxide (17.21 g, 153.37 mmol, 2.5 equivalents) was added fractionally to a medium solution of benzyl alcohol (16.59 g, 153.37 mmol, 2.5 equivalents) in tetrahydrofuran (200 mL), and the resulting mixture was stirred at 25 °C for 2 h. Then, 2,6-dichloropyridin-3-amine (10 g, 61.35 mmol, 1 equivalent) was added, and the reaction mixture was stirred at 75 °C for 24 h. The mixture was cooled to 25 °C and diluted with ethyl acetate (600 mL). The organic layer was washed with water (100 mL × 3), and the aqueous layer was extracted with ethyl acetate (100 mL × 2). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10:1), followed by preparative HPLC (column: Welch Ultimate XB-Diol 250*50*10μm; mobile phase: [heptane-EtOH (0.1% NH4OH)]; B%: 1%-10%, 15 min) to give the title compound (3.1 g, 10.12 mmol, 16% yield) as a black-orange oil. LC / MS (ESI) m / z: 307.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.51-7.30(m,10H),6.99(d,J=8.0Hz,1H),6.28(d,J=8.0Hz,1H),5.39(s,2H),5.28(s,2H),3.27-2.56(m,2H).

[1413] Step 2: Preparation of 4-bromo-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-1-one

[1414]

[1415] N,N-diisopropylethylamine (1.52 g, 11.75 mmol, 1 equivalent) was added to a solution of 2,6-dibenzyloxypyridine-3-amine (1.2 g, 3.92 mmol, 1 equivalent) in N,N-dimethylacetamide (12 mL), and the reaction mixture was stirred at 120 °C for 12 h. The mixture was cooled to 25 °C, diluted with water (50 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic extracts were washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4:1) to give the title compound as a yellow solid (1.45 g, 2.89 mmol, 74% yield). LC / MS (ESI) m / z: 501.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.89 (d, J=7.6Hz, 1H), 7.70 (dd, J=2.0, 7.6Hz, 2H), 7.49 -7.28(m,11H),6.50(d,J=8.4Hz,1H),5.43(s,2H),5.35(s,2H),4.70(s,2H).

[1416] Step 3: Preparation of tert-butyl piperidine-1-carboxylate

[1417]

[1418] To a mixture of 4-bromo-2-(2,6-dibenzyloxy-3-pyridyl)isoindoline-1-one (260 mg, 0.52 mmol, 1 equivalent), tert-butyl 4-(4-piperidinylmethyl)piperidin-1-carboxylate (195 mg, 0.57 mmol, 1.1 equivalent, acetate), and cesium carbonate (507 mg, 1.56 mmol, 3 equivalent) in dioxane (5 mL), [2-(2-aminophenyl)phenyl]chloro-palladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphine (41 mg, 0.05 mmol, 0.1 equivalent) was added, and the reaction mixture was degassed and purged with nitrogen (3X), then stirred at 100 °C for 12 h. The reaction mixture was cooled to 25 °C, diluted with water (30 mL), and extracted with ethyl acetate (20 mL × 2). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by preparative TLC (petroleum ether / ethyl acetate = 3 / 1) to give the title compound as a pale yellow gel (320 mg, 0.46 mmol, 87% yield). LC / MS (ESI) m / z: 703.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.81 (d, J=8.4Hz, 1H), 7.52-7.25 (m, 13H), 7.14 (d, J= 8.0Hz,1H),6.55(d,J=8.4Hz,1H),5.38(d,J=9.6Hz,4H),4.73(s,2H),3.92(br d,J=11.2Hz,2H),3.36(br s,2H),2.69(br t,J=10.8Hz,4H),1.71(br d,J=11.2Hz,2H),1.62(br d,J=12.8Hz,2H),1.56-1.44(m,2H),1.38(s,9H),1.26-1.18(m,3H),1.06-0.86(m,2H).

[1419] Step 4: Preparation of tert-butyl piperidine-1-carboxylate

[1420]

[1421] Under nitrogen atmosphere, a palladium / activated carbon catalyst (0.1 g, 10% purity) was added to a solution of 4-[[1-[2-(2,6-dibenzyloxy-3-pyridyl)-1-oxo-isoindoline-4-yl]-4-piperidinyl]methyl]piperidin-1-carboxylic acid tert-butyl ester (320 mg, 0.46 mmol, 1 equivalent) in ethyl acetate (10 mL), and the resulting suspension was degassed and purged with hydrogen (3X), then stirred at 25 °C for 16 hours under hydrogen (15 Psi). The mixture was then passed through... The sample was filtered through a pad, and the filtrate was concentrated under vacuum. The resulting residue was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to give the title compound as a white solid (110 mg, 0.21 mmol, 46% yield). LC / MS (ESI) m / z: 547.3 [M + Na] + . 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.49-7.39(m,1H),7.29(d,J=7.2Hz,1H),7.15(d,J=8.0Hz,1H),5.11(dd,J=5.2,13.2Hz,1H),4.49-4.36(m, 1H),4.34-4.22(m,1H),3.92(brd,J=12.0Hz,2H),3.42-3.34(m,2H),3.31 (s,1H),2.99-2.83(m,1H),2.80-2.55(m,5H),2.05-1.90(m,1H),1.75(br d,J=11.6Hz,2H),1.63(br d,J=12.4Hz,2H),1.58-1.47(m,2H),1.39(s,9H),1.25(br d,J=12.0Hz,2H),1.17(br t,J=6.8Hz,2H),1.04-0.87(m,2H).

[1422] Step 5: Preparation of 3-[1-oxo-4-[4-(4-piperidinylmethyl)-1-piperidinyl]isoindololin-2-yl]piperidin-2,6-dione

[1423]

[1424] A solution of tert-butyl piperidinyl ester (220 mg, 0.42 mmol, 1 equivalent) in dichloromethane (5 mL) was mixed with trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 32.21 equivalents), and the reaction mixture was stirred at 25 °C for 0.5 h. The solution was concentrated under vacuum to give the title compound (220 mg, crude, trifluoroacetate) as a white solid. LC / MS (ESI) m / z: 425.1 [M+H] + .

[1425] Step 6: Preparation of 3-[2-[2-[4-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]-8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1426]

[1427] Add 4-methylmorpholine (124 mg, 1.23 mmol, 0.1 mL, 3 equivalents) to a solution of 3-[1-oxo-4-[4-(4-piperidinylmethyl)-1-piperidinyl]isoindololin-2-yl]piperidin-2,6-dione (220 mg, 0.41 mmol, 1 equivalent, trifluoroacetate) in DMSO (3 mL) and 1,2-dichloroethane (3 mL), followed by the addition of 3-[8-fluoro-7-[ 7-Fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (248 mg, 0.32 mmol, 0.8 equivalents) and acetic acid (25 mg, 0.41 mmol, 1 equivalent) were added, and the resulting mixture was stirred at 25 °C for 0.5 h. Then, sodium triacetoxyborohydride (260 mg, 1.23 mmol, 3 equivalents) was added, and the reaction mixture was stirred at 25 °C for 12 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to give the title compound as a white solid (230 mg, 0.20 mmol, 48% yield). LC / MS (ESI) m / z: 1166.6 [M+H] + .

[1428] Step 7: Preparation of 3-[2-[2-[4-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1429]

[1430] Add cesium fluoride (449 mg, 2.96 mmol, 15 equivalents) to a solution of 3-[2-[2-[4-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]-8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (230 mg, 0.20 mmol, 1 equivalent) in DMF (6 mL), and stir the reaction mixture at 25 °C for 1.5 h. The mixture was diluted with ethyl acetate (200 mL), and the organic layer was washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to give the title compound as a pale yellow solid (110 mg, 0.11 mmol, 55% yield). LC / MS (ESI) m / z: 1010.1 [M+H] + .

[1431] Step 8: Preparation of 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (compound 35)

[1432]

[1433] Add trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 124.03 equivalents) to a solution of 3-[2-[2-[4-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (110 mg, 0.11 mmol, 1 equivalent) in dichloromethane (5 mL), and stir the reaction mixture at 25 °C for 0.5 h. The solution was concentrated, and the resulting residue was purified by preparative HPLC (column: Unisil 3-100C18 Ultra 150*50mm*3μm; mobile phase: [9-39% CH3CN / water (formic acid)]) followed by preparative HPLC (column: Unisil 3-100C18 Ultra 150*50mm*3μm; mobile phase: [8-38% CH3CN / water (formic acid)]) to give the title compound (14.8 mg, 0.01 mmol, 13% yield, formate) as a yellow solid.

[1434] Example 3: Synthesis of 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (compound 55)

[1435] Step 1: Preparation of 8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol

[1436]

[1437] A solution of naphthalene-1,3-diol (50 g, 312.17 mmol, 1 equivalent), 2-bromoethynyl(triisopropyl)silane (97.87 g, 374.60 mmol, 1.2 equivalent), ruthenium dichloro; 1-isopropyl-4-methylbenzene (19.12 g, 31.22 mmol, 0.1 equivalent) and potassium acetate (61.27 g, 624.34 mmol, 2 equivalent) in dioxane (600 mL) was stirred at 110 °C for 12 hours under nitrogen. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20:1) to give the title compound as a yellow solid (70 g, 205.56 mmol, 65% yield). LC / MS (ESI) m / z: 341.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δ9.30(s,1H),7.62(d,J=8.4Hz,1H),7.47(d,J=6.4,1H),7.33-7.28(m,1H), 6.75(d,J=2.4Hz,1H),6.64(d,J=2.8Hz,1H),4.15(s,1H),1.23-1.20(m,3H),1.19-1.17(m,18H).

[1438] Step 2: Preparation of 3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)naphthalene-1-ol

[1439]

[1440] At 0 °C, chloro(methoxy)methane (96.44 g, 1.20 mol, 91 mL, 1.51 equivalents) was added to a solution of 8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol (270 g, 792.88 mmol, 1 equivalent) and N,N-diisopropylethylamine (307.42 g, 2.38 mol, 414 mL, 3 equivalents) in dichloromethane (2.5 L), and the reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was diluted with water (1000 mL) and extracted with dichloromethane (1000 mL × 2). The combined organic extracts were washed with brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give the title compound as a yellow oil (185 g, 481.04 mmol, 61% yield). 1H NMR (400MHz, CDCl3) δ9.26 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 6.4, 1H), 7.34-7.29 (m, 1H), 7.00 -6.96(m,1H),6.77(d,J=2.4Hz,1H),5.27(s,2H),3.51(s,3H),1.27-1.22(m,3H),1.20-1.17(m,18H).

[1441] Step 3: Preparation of [3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]trifluoromethanesulfonate

[1442]

[1443] At -40°C, trifluoromethanesulfonyltrifluoromethanesulfonate (192.58 g, 682.56 mmol, 113 mL, 1.5 equivalent) was added dropwise to a solution of 3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)naphth-1-ol (175 g, 455.04 mmol, 1 equivalent) and N,N-diisopropylethylamine (176.43 g, 1.37 mol, 238 mL, 3 equivalent) in dichloromethane (2 L), and the reaction mixture was stirred at -40°C for 1 hour under nitrogen. The reaction mixture was quenched with water (500 mL) and extracted with dichloromethane (300 mL × 2). The combined organic extracts were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to give the title compound as a yellow oil (91 g, 144.69 mmol, 92% yield). 1 H NMR (400MHz, CDCl3) δ7.77-7.71(m,2H),7.47-7.41(m,2H),7.31(d,J=2.4,1H),5.29(s,2H),3.53(s,3H),1.28-1.22(m,3H),1.19-1.14(m,18H).

[1444] Step 4: Preparation of triisopropyl-[2-[6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-naphthyl]ethynyl]-silane

[1445]

[1446] A mixture of [3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]trifluoromethanesulfonate (192 g, 371.63 mmol, 1 equivalent), 4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (61.83 g, 483.12 mmol, 70 mL, 1.3 equivalent), triethylamine (112.82 g, 1.11 mol, 155 mL, 3 equivalent), and cyclopentyl(diphenyl)phosphine; dichloromethane; dichloropalladium; iron (30.35 g, 37.16 mmol, 0.1 equivalent) in acetonitrile (2 L) was stirred at 80 °C for 12 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20:1) to give the title compound as a yellow solid (165 g, 333.64 mmol, 89% yield). LC / MS (ESI) m / z: 495.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.73-7.65(m,2H),7.47(d,J=2.4Hz,1H),7.40-7.33(m,2H) ,5.29(s,2H),3.51(s,3H),1.44(s,12H),1.20-1.18(m,3H),1.17-1.15(m,18H).

[1447] Step 5: Preparation of 2-[8-ethynyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[1448]

[1449] A solution of triisopropyl-[2-[6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-naphthyl]ethynyl]silane (81 g, 163.79 mmol, 1 equivalent) and cesium fluoride (497.59 g, 3.28 mol, 20 equivalent) in DMF (1.6 L) was stirred at 20 °C for 5 h. The reaction mixture was diluted with water (2000 mL) and extracted with ethyl acetate (2000 mL × 2). The combined organic extracts were washed with brine (2000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 0 to 1 / 1) to give the title compound (17 g, 57.79 mmol, 94% yield) as a yellow oil. LC / MS (ESI) m / z: 339.0 [M+H] + . 1H NMR(400MHz, CDCl3) δ7.75(d,J=8.4Hz,1H),7.67(d,J=10.0Hz,1H),7.46-7.40( m,2H),7.39-7.34(m,1H),5.29(s,2H),3.52(s,3H),3.36(s,1H),1.45(s,12H).

[1450] Step 6: Preparation of 2-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[1451]

[1452] Palladium / activated carbon (5 g, 10% purity) was added to 2-[8-ethynyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (25 g, 73.92 mmol, 1 equivalent) dissolved in methanol (300 mL) and tetrahydrofuran (300 mL), and the reaction mixture was stirred at 20 °C for 5 hours under a hydrogen atmosphere (15 psi). The reaction mixture was then passed through... The mixture was filtered and the filtrate was concentrated to give the title compound as a yellow oil (14 g, 46.95 mmol, 81% yield). 1 H NMR (400MHz, CDCl3) δ7.60(d,J=7.6Hz,1H),7.42(d,J=2.8,1H),7.40-7.37(m,1H),7.35(t,J=4.0, 2.4Hz,3H),7.27-7.24(m,1H),5.29(s,2H),3.52(m,3H),1.45(s,12H),1.36(t,J=7.6,7.2Hz,3H).

[1453] Step 7: Preparation of tert-butyl 3-[2-(2,2-dimethoxyethoxy)-7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1454]

[1455] To 3-[7-chloro-2-(2,2-dimethoxyethoxy)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.6 g, 3.21 mmol, 1 equivalent) and 2-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (1.28 g) Cs₂CO₃ (2.62 g, 8.03 mmol, 2.5 equivalents) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (418.8 mg, 0.643 mmol, 0.2 equivalents) were added to a solution of dioxane (15 mL) and H₂O (3 mL), and the reaction mixture was stirred at 110 °C under N₂ for 16 h. The mixture was diluted with EtOAc (150 mL), and the combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by rapid chromatography on silica gel (gradient: 10–30% EtOAc / petroleum ether) to give the title compound as a brown solid (0.922 g, 1.28 mmol, 40% yield). LC / MS (ESI) m / z: 678.4 [M+H] + .

[1456] Step 8: Preparation of tert-butyl 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1457]

[1458] To a solution of 3-[2-(2,2-dimethoxyethoxy)-7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100 mg, 0.148 mmol, 1 equivalent) in acetone (0.37 mL), concentrated HCl (12 M, 0.37 mL, 30 equivalent) was added dropwise, and the reaction mixture was stirred at 20 °C for 5 minutes (a total of 9 batches were performed). A saturated aqueous solution of NaHCO3 was then added until pH = 8, and the resulting mixture was filtered and washed with water (10 mL) and petroleum ether (10 mL) to give a yellow solid of 2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyacetaldehyde (640 mg crude). A solution of Boc2O (343.8 mg, 1.58 mmol, 1.2 equivalents) and NaHCO3 (330.8 mg, 3.94 mmol, 3 equivalents) in H2O (2.5 mL) was then added, and the reaction mixture was stirred at 20 °C for 2 hours. The mixture was diluted with EtOAc (120 mL), and the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by rapid chromatography on silica gel (gradient: 10-50% EtOAc / petroleum ether) to give the title compound as a yellow solid (430 mg, 46% yield). LC / MS (ESI) m / z: 588.4 [M+H] + .

[1459] Step 9: Preparation of 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1460]

[1461] To 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (150 mg, 0.255 mmol, 1 equivalent) and 3-[1-oxo-4-[4-[[4-(4-piperidinylmethyl)-1-piperidinyl]methyl]-1-piperidinyl]isoindoline-2-yl]piperidin-2,6-dione ( 222 mg (0.262 mmol, 75% purity, 1.03 equivalents, TFA) was added to a solution of isopropanol (3.5 mL) and dichloromethane (5 mL) along with NaOAc (42 mg, 0.51 mmol, 2 equivalents), AcOH (107 mg, 1.79 mmol, 102 μL, 7 equivalents), and a 2-methylpyridineborane complex (82 mg, 0.77 mmol, 3 equivalents). The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by rapid chromatography on SiO2 (gradient: 0-20% methanol / dichloromethane) to give the title compound as a white solid (255 mg, 0.233 mmol, 91% yield). LC / MS (ESI) m / z: 1093.4 [M+H] + .

[1462] Step 10: Preparation of 3-[4-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (compound 55)

[1463]

[1464] A solution of 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (155 mg, 0.142 mmol, 1 equivalent) in HCOOH (5 mL) was stirred at 20 °C for 4 hours. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by preparative HPLC (column: YMC Triart 30*150 mm*7 μm; mobile phase: [13-43% CH3CN / water (formic acid)]). The pure fractions were combined and dried by freeze-drying to give the title compound (51.4 mg, 0.048 mmol, 34% yield, formate) as a white solid.

[1465] Example 4: Synthesis of 3-[4-[[4-[[1-[2-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (compound 42)

[1466]

[1467] Add 4-methylmorpholine (15 mg, 0.15 mmol, 1.5 equivalence) to a solution of 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (110 mg, 0.10 mmol, 1 equivalent, trifluoroacetate) in dichloromethane (2 mL) and methanol (2 mL), and stir the mixture at 25 °C for 15 minutes. Formaldehyde (40 mg, 0.50 mmol, 37% purity, 5 equivalents) was then added, and the resulting mixture was stirred at 25 °C for 0.5 h. Sodium triacetoxyborohydride (63 mg, 0.30 mmol, 3 equivalents) was then added, and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated, and the resulting residue was purified by preparative HPLC {column: Unisil 3-100C18 Ultra 150*50 mm*3 μm; mobile phase: [1-31% CH3CN / water (formic acid)]} to give the title compound as a white solid (61.0 mg, 0.06 mmol, 56% yield).

[1468] Example 5: Synthesis of 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidin-2,6-dione (compound 28)

[1469] Step 1: Preparation of 7-bromo-1-methylindoline-2,3-dione

[1470]

[1471] A solution of iodomethane (8.44 g, 59.43 mmol, 1 equivalent), potassium carbonate (11.01 g, 79.64 mmol, 1.5 equivalent), and water (1.2 mL) in DMF (60 mL) was added dropwise. The reaction mixture was stirred at 25 °C for 2 hours. Then, water (120 mL) was added, and the mixture was stirred at 0 °C for 1 hour. The resulting precipitate was collected by filtration, washed with water (50 mL × 2), and dried under vacuum to give the title compound as a red solid (8 g, 33.33 mmol, 62% yield). LC / MS (ESI) m / z: 242.3 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ7.81 (br d, J=7.6Hz, 1H) 7.55 (br d, J=7.2Hz, 1H) 7.05 (t, J=8.0Hz, 1H) 3.47 (s, 3H).

[1472] Step 2: Preparation of 3-bromo-2-(methylamino)benzoic acid

[1473]

[1474] Hydrogen peroxide aqueous solution (38 g, 335.15 mmol, 32.20 mL, 30% purity, 10.06 equivalents) was added dropwise to a mixture of 7-bromo-1-methyldihydroindole-2,3-dione (8 g, 33.33 mmol, 1 equivalent) and sodium hydroxide (2 M, 199.96 mL, 12) at below 15 °C, and the reaction mixture was stirred at 25 °C for 5 h. After adjusting the pH to 4.0 with hydrochloric acid (1 M), the mixture was stirred at 10 °C for 1 h and then extracted with ethyl acetate (80 mL × 3). The combined organic extracts were washed with water (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound (6.0 g, crude) as a brown oil. LC / MS (ESI) m / z: 252.2 [M + Na] + .

[1475] Step 3: Preparation of 7-bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one

[1476]

[1477] Diphenylphosphobenzoic acid (6 g, 26.08 mmol, 1 equivalent, crude) and N,N-diisopropylethylamine (5.04 g, 39.01 mmol, 6.80 mL, 1.50 equivalent) in DMF (40 mL) were added dropwise at 75 °C, and the reaction mixture was stirred at 75 °C for 3 h. Water (30 mL) was added at 25 °C, and the mixture was stirred at 0 °C for 0.5 h. The resulting precipitate was collected by filtration, washed with water (30 mL) and diisopropyl ether (15 mL), and then dried under vacuum at 50 °C to give the title compound as a grayish-white solid (4 g, 17.62 mmol, 67% yield). LC / MS (ESI) m / z: 226.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.17 (br s, 1H) 7.14 (dd, J = 8.0, 1.2Hz, 1H) 6.96-6.99 (m, 1H) 6.88-6.93 (m, 1H) 3.55 (s, 3H).

[1478] Step 4: Preparation of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

[1479]

[1480] Potassium 2-methylprop-2-ol (1M, 10.67 mL, 1.21 equivalent) was added to a solution of 7-bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (2.00 g, 8.81 mmol, 1 equivalent) in tetrahydrofuran (40 mL), and the resulting mixture was stirred at 0 °C for 0.5 h. Then, 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonic acid (4.2 g, 11.01 mmol, 1.25 equivalent) dissolved in tetrahydrofuran (20 mL) was added dropwise, and the reaction mixture was stirred at 0–25 °C for 0.5 h. The reaction mixture was quenched by adding 10% ammonium chloride solution (10 mL) at 0 °C, and the resulting mixture was stirred at 0 °C for 1 h, followed by extraction with ethyl acetate (50 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1 to 1 / 1) to give the title compound as a white solid (3.5 g, 7.64 mmol, 87% yield). LC / MS (ESI) m / z: 460.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.24 (dd, J=0.8, 8.0Hz, 1H), 7.22-7.18 (m, 2H), 7.11-7.04 (br m,1H),6.97-6.92(m,1H),6.88-6.82(m,2H),5.57(dd,J=5.6,12.8Hz,1H),4.79(q,J=14.4 Hz,2H),3.72(s,3H),3.64(s,3H),3.12-2.97(m,1H),2.89-2.64(m,2H),2.13-2.01(m,1H).

[1481] Step 5: Preparation of tert-butyl piperidine-1-carboxylate (1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidinyl]methyl]piperidin-1-carboxylate

[1482]

[1483] Cesium carbonate (2.13 g, 6.54 mmol, 3 equivalents) and 1,3-bis[2H-imidazol-1-yl]-1-(4-methoxybenzyl)piperidin-2,6-dione (1 g, 2.18 mmol, 1 equivalent) and tert-butyl 4-(4-piperidinylmethyl)piperidin-1-carboxylate (1.12 g, 3.27 mmol, 1.5 equivalents, acetic acid) in N,N-dimethylacetamide (20 mL) were added to a solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-cation-2-anion; 3-chloropyridine; and palladium dichloro (212 mg, 0.22 mmol, 9.99 e-2 equivalents), and the reaction mixture was stirred at 90 °C for 2 h. The mixture was cooled to 25°C, and the residue was poured into water (50 mL) and stirred for 2 minutes. The aqueous phase was extracted with ethyl acetate (10 mL × 3), and the combined organic extracts were washed with brine (10 mL × 2) and dried over anhydrous sodium sulfate. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15μm; mobile phase: [68-98% CH3CN / water (formic acid)]) to give the title compound as a yellow solid (150 mg, 0.23 mmol, 10% yield). LC / MS (ESI) m / z: 660.4 [M+H] + .

[1484] Step 6: Preparation of 3-[3-methyl-2-oxo-4-[4-(4-piperidinylmethyl)-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione

[1485]

[1486] Methanesulfonic acid (405 mg, 4.21 mmol, 0.3 mL, 17.38 equivalents) was added to a solution of 4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidinyl]methyl]piperidin-1-carboxylic acid tert-butyl ester (160 mg, 0.24 mmol, 1 equivalent) in toluene (1 mL), and the reaction mixture was stirred at 120 °C for 2 hours. The mixture was concentrated under reduced pressure at 45 °C to give the title compound (110 mg, crude) as a white solid.

[1487] Step 7: Preparation of tert-butyl 3-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1488]

[1489] At 25 °C, tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5 g, 11.67 mmol, 1 equivalent) and 1,4-diazabicyclo[2.2.2]octane (261.90 mg, 2.33 mmol, 256.77 μL, 0.2 equivalent) in acetonitrile (50 mL) were added to a solution of 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)octane (261.90 mg, 2.33 mmol, 256.77 μL, 0.2 equivalent), and the reaction mixture was stirred at 50 °C for 5 hours. The mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give the title compound as a yellow solid (4 g, 7.04 mmol, 60% yield). LC / MS (ESI) m / z: 568.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.73 (s, 1H), 4.56 (t, J = 5.6Hz, 2H), 4.48 (br d,J=12.8Hz,2H),4.42-4.28(m,2H),4.07-3.98(m,2H),3.74-3.60(m,2H),2.00-1.90(m,2H),1.72(br d,J=7.6Hz,2H),1.52(s,9H),0.92-0.86(m,9H),0.09(s,6H).

[1490] Step 8: Preparation of tert-butyl 3-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid.

[1491]

[1492] 3-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl tert-butyl ester (4 g, 7.04 mmol, 1 equivalent), 2-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane A mixture of dioxane (3.13 g, 9.15 mmol, 1.3 equivalents), potassium phosphate (4.48 g, 21.12 mmol, 3 equivalents), and [2-(2-aminophenyl)phenyl]palladium (1+); bis(1-adamantyl)-butylphosphine; and methanesulfonate (513 mg, 704.03 μmol, 0.1 equivalents) in dioxane (50 mL) and water (6 mL) was stirred at 90 °C for 12 h under nitrogen. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1:1) to give the title compound (4.4 g, 5.88 mmol, 83% yield) as a yellow solid.

[1493] Step 9: Preparation of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-(2-hydroxyethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1494]

[1495] Cesium fluoride (26.81 g, 176.48 mmol, 30 equivalents) was added to a solution of 3-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (4.4 g, 5.88 mmol, 1 equivalent) in DMF (40 mL), and the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give the title compound as a yellow solid (3.7 g, 5.84 mmol, 99% yield). 1H NMR (400MHz, CDCl3) δ9.04(s,1H),7.71(d,J=8.0Hz,1H),7.54(d,J=2.8Hz,1H),7.42(t,J=7.6Hz,1 H),7.24(d,J=7.2Hz,1H),7.19(d,J=2.8Hz,1H),5.31(d,J=1.7Hz,2H),4.70-4.59(m,3H),4.53(br d,J=12.4Hz,1H),4.48-4.32(m,2H),4.06-3.98(m,2H),3.83-3.61(m,2H),3.52(s,3H),2.35(br dd,J=7.6,10.8Hz,2H),2.04-1.97(m,2H),1.86-1.64(m,2H),1.53(s,9H),0.95(t,J=7.6Hz,3H).

[1496] Step 10: Preparation of (1R,5S)-3-(7-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1497]

[1498] At -78°C, a solution of dimethyl sulfoxide (771 mg, 9.86 mmol, 0.8 mL, 2.5 equivalents) in dichloromethane (10 mL) was added dropwise to a solution of oxaloyl chloride (751 mg, 5.92 mmol, 0.5 mL, 1.5 equivalents) in dichloromethane (10 mL). After 15 minutes, a solution of 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-(2-hydroxyethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.5 g, 3.95 mmol, 1 equivalent) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at -78°C for 30 minutes. Triethylamine (2.00 g, 19.73 mmol, 2.8 mL, 5 equivalents) was then added, and the reaction mixture was stirred at the same temperature of -78 °C for 30 min, followed by warming to 25 °C over 1 hour. The reaction mixture was quenched with saturated sodium sulfite solution (20 mL), and the resulting mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give the title compound as a yellow solid (1.8 g, 2.85 mmol, 72% yield). LC / MS (ESI) m / z: 632.3 [M+H] + .

[1499] Step 11: Preparation of tert-butyl 3-[2-[2-[4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]-7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid

[1500]

[1501] Diisopropylethylamine (119 mg, 0.92 mmol, 0.2 mL, 5 equivalents) and (1R,5S)-3-(7-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (128 mg, 0.20 mmol, 1.1 equivalents) were added to a solution of 3-[3-methyl-2-oxo-4-[4-(4-piperidinylmethyl)-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (102 mg, 0.18 mmol, 1 equivalent, trifluoroacetic acid) in dichloromethane (1 mL) and isopropanol (1 mL). The resulting mixture was stirred at 25 °C for 1 hour. Sodium triacetoxyborohydride (117 mg, 0.55 mmol, 3 equivalents) was then added, and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (15 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to give the title compound as a white solid (86 mg, 0.08 mmol, 44% yield). LC / MS (ESI) m / z: 1055.7 [M+H] + .

[1502] Step 12: Preparation of 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidin-2,6-dione (compound 28)

[1503]

[1504] Trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 173.81 equivalents) was added to a solution of 3-[2-[2-[4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]-7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (82 mg, 0.08 mmol, 1 equivalent) in dichloromethane (1 mL), and the reaction mixture was stirred at 25 °C for 0.5 h. The solvent was concentrated under a nitrogen stream, and the crude product was purified by reversed-phase HPLC (Phenomenex luna C18 column 150*25mm*10μm; mobile phase: [9-39% CH3CN / water (formic acid)]) to give the title compound (26.2 mg, 0.03 mmol, 32% yield, diformate) as a white solid.

[1505] Example 6: Synthesis of 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (compound 56)

[1506]

[1507] The title compound was prepared in a similar manner to that of 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (diformate, a white solid).

[1508] Example 7: Synthesis of 3-[4-[4-[[1-[2-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (compound 41)

[1509]

[1510] 4-Methylmorpholine (10 mg, 0.10 mmol, 1.5 equivalents) was added to a solution of formaldehyde (28 mg, 0.35 mmol, 37% purity, 5 equivalents) in dichloromethane (2 mL) and methanol (2 mL), and the resulting mixture was stirred at 25 °C for 15 minutes. Then 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyridino[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (70 mg, 0.07 mmol, 1 equivalent, trifluoroacetate) was added, and the mixture was stirred at 25 °C for 0.5 hours. Sodium triacetoxyborohydride (44 mg, 0.21 mmol, 3 equivalents) was then added, and the reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by preparative HPLC {column: Unisil 3-100C18 Ultra 150*50 mm*3 μm; mobile phase: 9-39% CH3CN in [water (formic acid)]} to give the title compound (65.1 mg, 0.06 mmol, 94% yield, formate) as a white solid.

[1511] Example 8: Synthesis of 5-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (compound 67)

[1512] Step 1: Preparation of tert-butyl piperidine-1-carboxylate 4-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-5-yl]-4-piperidinyl]methyl]piperidine-1-carboxylate

[1513]

[1514] At 25 °C, diisopropylethylamine (5.43 mmol, 946 μL, 3.0 equivalent) was added in a single batch to a mixture of 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-isoindoline-1,3-dione (500 mg, 1.81 mmol, 1.0 equivalent) and 4-(4-piperidinylmethyl)piperidin-1-carboxylic acid tert-butyl ester (613 mg, 2.17 mmol, 1.2 equivalent) in DMSO (10 mL), and the reaction mixture was stirred at 100 °C for 2 hours. The mixture was diluted with water (20 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 4). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude product was purified by rapid chromatography on SiO2 (gradient: 0-41% ethyl acetate / petroleum ether) to give the title compound as a yellow solid (310 mg, 0.541 mmol, 30% yield). LC / MS (ESI) m / z: 539.3 [M+H] + .

[1515] Step 2: Preparation of 2-(2,6-dioxo-3-piperidinyl)-5-[4-(4-piperidinylmethyl)-1-piperidinyl]isoindoline-1,3-dione

[1516]

[1517] To a solution of tert-butyl piperidinyl ester (93 mg, 0.173 mmol, 1.0 equivalent) in dichloromethane (2 mL), HCl / dioxane (4 M, 432 μL, 10.0 equivalent) was added, and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under vacuum to give the title compound as a white solid (75 mg, 0.147 mmol, 85% yield). LC / MS (ESI) m / z: 439.0 [M+H] + .

[1518] Step 3: Preparation of 5-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (compound 67)

[1519]

[1520] In a similar manner to 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione, from 3-[7-(8-ethyl The title compound was prepared by means of tert-butyl octane-8-carboxylate (-3-hydroxy-1-naphthyl)-8-fluoro-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(2,6-dioxo-3-piperidinyl)-5-[4-(4-piperidinylmethyl)-1-piperidinyl]isoindoline-1,3-dione, and purified by preparative HPLC (column: Ultimate C18 100*30mm*10μm; mobile phase: [5-50% CH3CN / water (formic acid)]). The purified fractions were combined and then lyophilized to give the title compound (32.1 mg, 0.035 mmol, 79% yield, formate) as a yellow solid.

[1521] Example 9: Synthesis of 4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (compound 66)

[1522] Step 1: Preparation of tert-butyl piperidine-1-carboxylate 4-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-4-yl]-4-piperidinyl]methyl]piperidine-1-carboxylate

[1523]

[1524] Diisopropylethylamine (4.34 mmol, 757 μL, 3.0 equivalent) was added to a solution of 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindoline-1,3-dione (400 mg, 1.45 mmol, 1.0 equivalent) and 4-(4-piperidinylmethyl)piperidin-1-carboxylic acid tert-butyl ester (450 mg, 1.59 mmol, 1.1 equivalent) in DMSO (10 mL), and the reaction mixture was stirred at 100 °C for 2 h. The mixture was diluted with ethyl acetate (60 mL), washed with water (20 mL × 9) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by rapid chromatography on SiO2 (gradient: 0-29% ethyl acetate / petroleum ether) to give the title compound as a yellow solid (610 mg, 0.789 mmol, 55% yield). LC / MS (ESI) m / z: 483.3 [M-C4H8+H] + .

[1525] Step 2: Preparation of 2-(2,6-dioxo-3-piperidinyl)-4-[4-(4-piperidinylmethyl)-1-piperidinyl]isoindoline-1,3-dione

[1526]

[1527] A solution of tert-butyl piperidinyl ester (200 mg, 0.371 mmol, 1.0 equivalent) in dichloromethane (2 mL) was added to HCl / dioxane (4 M, 928 μL, 10.0 equivalent), and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under vacuum to give the title compound as a yellow solid (139 mg, 285 mmol, 77% yield). LC / MS (ESI) m / z: 439.3 [M+H] + .

[1528] Step 3: Preparation of 4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (compound 66)

[1529]

[1530] In a similar manner to 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione, from 3-[7-(8-ethyl The title compound was prepared by means of tert-butyl octane-8-carboxylate (-3-hydroxy-1-naphthyl)-8-fluoro-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(2,6-dioxo-3-piperidinyl)-4-[4-(4-piperidinylmethyl)-1-piperidinyl]isoindoline-1,3-dione, and purified by preparative HPLC (column: Xtimate C18 100*30mm*10μm; mobile phase: [10-50% CH3CN / water (formic acid)]). The purified fractions were combined and then lyophilized to give the title compound (21.2 mg, 0.022 mmol, 57% yield, formate) as a yellow solid.

[1531] Example 10: Synthesis of 4-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (compound 57)

[1532] Step 1: Preparation of 4-[4-(dimethoxymethyl)-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione

[1533]

[1534] To a solution of 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindoline-1,3-dione (800 mg, 2.90 mmol, 1.0 equivalence) in dimethyl sulfoxide (8 mL), 4-(dimethoxymethyl)piperidine (553 mg, 3.48 mmol, 1.2 equivalence) was added, and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water (10 mL) and then extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with water (20 mL × 3) and concentrated under reduced pressure. The crude product was purified by rapid chromatography on SiO2 (gradient: 0–4% methanol / dichloromethane) to give the title compound as a yellow solid (929 mg, 2.10 mmol, 72% yield). LC / MS (ESI) m / z: 416.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.97(s,1H),7.64-7.60(m,1H),7.46-7.43(m,1H),5.00-4.95(m,1H),3.79-3.75(m,2H) ,3.40(s,6H).2.93-2.72(m,4H),2.16-2.11(m,1H),1.94-1.91(m,2H),1.87-1.82(m,1H),1.70-1.57(m,4H).

[1535] Step 2: Preparation of 1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-4-yl]piperidin-4-carboxaldehyde

[1536]

[1537] Hydrochloric acid (1 M, 8.30 mL, 7.5 equivalences) was added to a solution of 4-[4-(dimethoxymethyl)-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (460 mg, 1.11 mmol, 1.0 equivalences) in tetrahydrofuran (9 mL), and the reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was adjusted to pH 7 by adding saturated sodium bicarbonate solution, and then extracted with ethyl acetate (20 mL × 3). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure to give the title compound as a yellow solid (398 mg, 0.98 mmol, 88% yield). LC / MS (ESI) m / z: 370.1 [M + H] + . 1H NMR(400MHz, CDCl3)δ9.75(s,1H),7.96(s,1H),7.68-7.64(m,1H),7.53-7.51(m,1H),5.00-4.96(m,1H) ,3.72-3.70(m,2H),3.21(s,2H).2.94-2.73(m,4H),2.55-2.52(m,1H),2.18-2.14(m,2H),1.58(s,2H).

[1538] Step 3: Preparation of tert-butyl piperidinium ester of 4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-4-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]piperidin-1-carboxylic acid

[1539]

[1540] At 20 °C, acetic acid (259 mg, 4.31 mmol, 0.25 mL, 4 equivalents) and 2-methylpyridineborane (461 mg, 4.31 mmol, 4 equivalents) were added in a single step to a solution of 1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-4-yl]piperidine-4-carboxylic acid (tert-butyl ester) in isopropanol (3 mL) and dichloromethane (3 mL), and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was adjusted to pH 6 by adding triethylamine and then concentrated. The crude product was purified by rapid chromatography (gradient: 0-100% ethyl acetate / petroleum ether) to give the title compound as a yellow solid (541 mg, 0.77 mmol, 71% yield). LC / MS (ESI) m / z: 636.4 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.59-7.55(m,1H),7.37(d,J=3.2Hz,1H),7.17(d,J=4.4Hz,1H) ,4.98-4.94(m,1H),4.10-4.08(m,2H),3.76-3.71(m,2H),3.15-3.09(m,2H),2.95-2. 65(m,7H),2.47(s,2H),2.23-2.16(m,1H),2.14-2.09(m,1H),2.05(s,2H),1.98-1.88 (m,3H),1.72-1.49(m,8H),1.46(s,9H),1.43(s,1H),1.20(s,2H),1.11-1.01(m,2H).

[1541] Step 4: Preparation of 2-(2,6-dioxo-3-piperidinyl)-4-[4-[[4-(4-piperidinylmethyl)-1-piperidinyl]methyl]-1-piperidinyl]isoindoline-1,3-dione

[1542]

[1543] A solution of tert-butyl piperidinyl ester (130 mg, 0.20 mmol, 1 equivalent) in dichloromethane (2 mL) was mixed with trifluoroacetic acid (466 mg, 4.09 mmol, 0.3 mL, 20 equivalents), and the reaction mixture was stirred at 20 °C for 1 hour. The mixture was concentrated to give the title compound (328 mg, crude, TFA) as a yellow oil. LC / MS (ESI) m / z: 536.3 [M+H] + .

[1544] Step 5: Preparation of 4-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (compound 57)

[1545] In a similar manner to 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione, from 3-[7-(8-ethyl-3-hydroxy-1 The title compound was prepared by starting with tert-butyl octane-8-carboxylate (-naphthyl)-8-fluoro-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(2,6-dioxo-3-piperidinyl)-4-[4-[[4-(4-piperidinylmethyl)-1-piperidinyl]methyl]-1-piperidinyl]isoindoline-1,3-dione, and was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [3-43% CH3CN / water (formic acid)]), followed by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [3-33% CH3CN / water (formic acid)]). The pure fractions were combined and dried by freeze-drying to give the title compound (49.1 mg, 0.05 mmol, 48% yield, 27% yield, formate) as a yellow solid.

[1546] Example 11: Synthesis of 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 63)

[1547] Step 1: Preparation of (2S)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester

[1548]

[1549] TEA (56.2 g, 556 mmol, 2.3 equivalents) and Cb2Cl (53.6 g, 314 mmol, 1.3 equivalents) were added to a solution of (2S)-pyrrolidine-2-carboxylate hydrochloride (40.0 g, 242 mmol, 1 equivalent) in CH2Cl2 (500 mL), and the reaction mixture was stirred at 25 °C under N2 for 16 h. The reaction mixture was washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (gradient: 0-10% THF / petroleum ether) to give the title compound (60.6 g, 230 mmol, 95% yield) as a colorless oil. LC / MS (ESI) m / z: 264.0 [M+H] + .

[1550] Step 2: Preparation of 2-methyl 1-benzyl 2-but-3-enylpyrrolidine-1,2-dicarboxylic acid

[1551]

[1552] LiHMDS (1M, 125mL, 1.2 equivalents) was added to a stirred solution of (2S)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (27.5 g, 104 mmol, 1 equivalent) in THF (300 mL) at -78 °C, and the reaction mixture was stirred at -78 °C under N2 for 0.5 h. Then, 4-bromobut-1-ene (28.2 g, 209 mmol, 2 equivalents) was added at -78 °C, and the reaction mixture was stirred at 20 °C under N2 for 16 h. Two batches were performed. The reaction mixture was quenched by adding saturated NH4Cl solution (300 mL) and extracted with EtOAc (2 × 300 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (gradient: 0-8% THF / petroleum ether) to give the title compound as a yellow oil (44.9 g, 141 mmol, 68% yield). LC / MS (ESI) m / z: 318.0 [M+H] + .

[1553] Step 3: Preparation of 2-[2-(ethylene oxide-2-yl)ethyl]pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester

[1554]

[1555] To a solution of 2-but-3-enylpyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (44.9 g, 141 mmol, 1 equivalent) in CH2Cl2 (600 mL), m-CPBA (33.6 g, 156 mmol, 80% purity, 1.1 equivalent) was added, and the reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered, and the filtrate was washed with saturated aqueous NaHSO3 solution (300 mL), NaHCO3 (2 × 200 mL), and brine (200 mL), then dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (gradient: 0–15% THF / petroleum ether) to give the title compound (37.5 g, 112 mmol, 80% yield) as a colorless oil. LC / MS (ESI) m / z: 334.2 [M+H] + .

[1556] Step 4: Preparation of methyl 3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizine-8-carboxylate

[1557]

[1558] Pd / C (3.0 g, 10% purity) was added to a solution of 2-[2-(ethylene oxide-2-yl)ethyl]pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (37.5 g, 112 mmol, 1 equivalent) in CH3OH (400 mL), and the reaction mixture was stirred at 25 °C under H2 (15 psi) for 16 h (degassed under vacuum and purged several times with H2). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (22.4 g, 112 mmol, 100% yield) as a yellow oil.

[1559] Step 5: Preparation of methyl (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine-7a(5H)-formate and methyl (3R,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine-7a(5H)-formate

[1560]

[1561] TBDPSCl (37.1 g, 135 mmol, 1.2 equivalent) was added to a solution of methyl 3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-8-carboxylate (22.4 g, 112 mmol, 1 equivalent) and imidazole (9.95 g, 146 mmol, 1.3 equivalent) in CH2Cl2 (300 mL), and the reaction mixture was stirred at 25 °C under N2 for 16 h. The reaction mixture was quenched by adding water (100 mL) and extracted with CH2Cl2 (3 × 100 mL). The combined organic extracts were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (gradient: 0–10% THF / petroleum ether). First, methyl (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (24.3 g, 39.7 mmol, 35% yield) was eluted and separated into a colorless oil (LC / MS (ESI) m / z: 438.2 [M+H)). + Then, methyl (3R,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (20.8 g, 43.0 mmol, 38% yield) was eluted and separated as a colorless oil (LC / MS (ESI) m / z: 438.3 [M+H)). + ).

[1562] Step 6: Preparation of methyl (3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-carboxylate and methyl (3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-carboxylate

[1563]

[1564] Methyl (3R,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-carboxylate (20.8 g, 47.5 mmol, 1 equivalent) was separated by SFC (column: REGIS(s,s)WHELK-O1 (250 mm * 50 mm, 10 μm); mobile phase: [0.1% NH4OH EtOH]; B%: 25%, flow rate: 140 mL / min) to give the first eluted enantiomer (3R,8R)-3-[(tert-butyl(diphenyl)silyl)oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-8-carboxylate (9.78 g, 22.35 mmol, 47% yield) as a colorless oil (LC / MS (ESI) m / z: 438.2 [M+H)). + ), and the enantiomer (3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-carboxylate methyl ester (8.81 g, 20.1 mmol, 42.36% yield) eluted later as a colorless oil (LC / MS (ESI) m / z: 438.3 [M+H)). + ).

[1565] Step 7: Preparation of [(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol

[1566]

[1567] At 0 °C, LiAlH4 (280 mg, 7.38 mmol, 1.2 equivalent) was added to a solution of (3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-carboxylate (2.69 g, 6.15 mmol, 1 equivalent) in THF (30 mL), and the reaction mixture was stirred at 0 °C under N2 for 1 hour. The reaction mixture was quenched by sequentially adding water (300 μL), 15% NaOH aqueous solution (300 μL), and water (900 μL), and then diluted with EtOAc (30 mL). The resulting suspension was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (gradient: 0-10% CH3OH / CH2Cl2) to give the title compound as a yellow oil (2.07 g, 5.05 mmol, 82% yield). LC / MS (ESI) m / z: 410.1 [M+H] + .

[1568] Step 8: Preparation of tert-butyl 3-[2-[[(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1569]

[1570] A solution of [(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (1.00 g, 2.44 mmol, 1 equivalent) and 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.05 g, 2.44 mmol, 1 equivalent) in dioxane (30 mL) was mixed with Cs₂CO₃ (954 mg, 2.93 mmol, 1.2 equivalent) and DABCO (109 mg, 0.976 mmol, 0.4 equivalent), and the reaction mixture was stirred at 25 °C under N₂ for 40 hours. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by rapid silica gel chromatography (gradient: 0-20% THF / petroleum ether) to give the title compound as a yellow solid (1.16 g, 1.13 mmol, 46% yield). LC / MS (ESI) m / z: 801.2 [M+H] + .

[1571] Step 9: Preparation of tert-butyl 3-[2-[[(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1572]

[1573] Add to a solution of 3-[2-[[(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (800 mg, 0.998 mmol, 1 equivalent) and 2-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (376 mg, 1.10 mmol, 1.1 equivalent) in dioxane (20 mL) APd G3 (145 mg, 0.199 mmol, 0.2 equivalents) and K2CO3 (2.2 M, 2.04 mL, 4.5 equivalents) were added, and the reaction mixture was stirred at 100 °C under N2 for 12 hours (degassed under vacuum and purged several times with N2). The reaction mixture was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (gradient: 0-30% THF / petroleum ether) to give the title compound as a yellow solid (695 mg, 0.446 mmol, 63% purity). LC / MS (ESI) m / z: 981.3 [M+H] + .

[1574] Step 10: Preparation of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3R,8R)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid

[1575]

[1576] To a solution of 3-[2-[[(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300 mg, 0.192 mmol, 63% purity, 1 equivalent) in THF (3 mL), TBAF (1 M, 458.59 μL, 1.5 equivalent) was added, and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched by adding water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine (3 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by preparative TLC (acidic silica gel, EtOAc) to give the title compound as a yellow solid (201 mg, 0.271 mmol, 44% yield). LC / MS (ESI) m / z: 743.1 [M+H] + .

[1577] Step 11: Preparation of tert-butyl 3-[2-[[(3R,8R)-3-[[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-5-yl]piperazin-1-carbonyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid

[1578]

[1579] Triethylamine (65 mg, 0.65 mmol, 8 equivalents), DMAP (1 mg, 0.008 mmol, 0.1 equivalents), and (4-nitrophenyl)chlorocarbamate (33 mg, 0.16 mmol, 2 equivalents) were added to a solution of 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3R,8R)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (60 mg, 0.081 mmol, 1 equivalent) in THF (3 mL), and the reaction mixture was stirred at 25 °C under N2 for 16 hours. Then 2-(2,6-dioxo-3-piperidinyl)-5-piperazin-1-yl-isoindoline-1,3-dione (40.55 mg, 88.84 μmol, 1.1 equivalents, TFA) was added, and the reaction mixture was stirred at 25 °C for 1 hour under N2. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by rapid chromatography on SiO2 (gradient: 0-5% methanol / dichloromethane) to give the title compound as a yellow solid (77 mg, 0.069 mmol, 86% yield). LC / MS (ESI) m / z: 1111.3 [M+H] + .

[1580] Step 12: Preparation of 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 63)

[1581]

[1582] A solution of 3-[2-[[(3R,8R)-3-[[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-5-yl]piperazin-1-carbonyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (77 mg, 0.069 mmol, 1 equivalent) in HCOOH (5 mL) was stirred at 25 °C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [0-40% CH3CN / water (formic acid)]). The purified fractions were combined and dried by lyophilization to give the title compound (25.0 mg, 0.025 mmol, 36% yield, formate) as a yellow solid.

[1583] Example 12: Synthesis of 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 62)

[1584] Step 1: Preparation of [(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol

[1585]

[1586] At 0 °C, methyl (3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-carboxylate (1.57 g, 3.59 mmol, 1 equivalent) in THF (20 mL) was added to LiAlH4 (163 mg, 4.30 mmol, 1.2 equivalent), and the reaction mixture was stirred at 0 °C under N2 for 1 h. The reaction mixture was quenched by sequentially adding water (200 μL), 15% NaOH aqueous solution (200 μL), and water (600 μL), and then diluted with EtOAc (30 mL). The resulting suspension was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (gradient: 0-10% CH3OH / CH2Cl2) to give the title compound (911 mg, 2.22 mmol, 62% yield) as a yellow oil. LC / MS (ESI) m / z: 410.3 [M+H] + .

[1587] Step 2: Preparation of tert-butyl 3-[2-[[(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1588]

[1589] Cs₂CO₃ (868 mg, 2.66 mmol, 1.2 equivalent) and DABCO (75 mg, 0.67 mmol, 0.3 equivalent) were added to a solution of [(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (911 mg, 2.22 mmol, 1 equivalent) and 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (951 mg, 2.22 mmol, 1 equivalent) in dioxane (30 mL), and the reaction mixture was stirred at 25 °C under N₂ for 16 hours. Additional DABCO (25 mg, 0.22 mmol, 0.1 equivalence) was added, and the reaction mixture was stirred at 25 °C under N2 for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC (35–65% CH3CN / water (0.225% formic acid)). The purified fractions were combined and dried by lyophilization to give the title compound as a yellow solid (794 mg, 0.991 mmol, 45% yield). LC / MS (ESI) m / z: 801.2 [M+H] + .

[1590] Step 3: Preparation of tert-butyl 3-[2-[[(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1591]

[1592] Add K3PO4 (1.5M, 125μL, 1.5 equivalents) to a solution of 3-[2-[[(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100 mg, 0.125 mmol, 1 equivalent) and 2-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (51 mg, 0.15 mmol, 1.2 equivalents) in dioxane (2.5 mL). APd G3 (18 mg, 0.025 mmol, 0.2 equivalents) was added, and the reaction mixture was stirred at 100 °C for 12 hours under N2 (degassed under vacuum and purged several times with N2). The reaction mixture was quenched by adding water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (gradient: 0–20% THF / petroleum ether) to give the title compound as a yellow solid (162 mg, 0.165 mmol, 66% yield). LC / MS (ESI) m / z: 981.3 [M+H] + .

[1593] Step 4: Preparation of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3S,8S)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid

[1594]

[1595] To a solution of 3-[2-[[(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (162 mg, 0.165 mmol, 1 equivalent) in THF (2 mL), TBAF (1 M, 0.248 mL, 1.5 equivalent) was added, and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched by adding water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine (3 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by preparative TLC (acidic silica gel, EtOAc) to give the title compound as a yellow solid (59 mg, 0.079 mmol, 48% yield). LC / MS (ESI) m / z: 743.1 [M+H] + .

[1596] Step 5: Preparation of 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 62)

[1597]

[1598] In a similar manner to 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester, from 3 The title compound was prepared by starting with tert-butyl octane-8-carboxylate [7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3S,8S)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, and purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [0-40% CH3CN / water (formic acid)]). The purified fractions were combined and lyophilized to give the title compound (36.5 mg, 0.036 mmol, 56% yield, formate) as a yellow solid.

[1599] Example 13: Synthesis of 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 59)

[1600] Step 1: Preparation of 5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-1-one

[1601]

[1602] Diisopropylethylamine (3.41 mL, 19.58 mmol, 3.0 equivalent) was added to a mixture of 2,6-dibenzyloxypyridine-3-amine (2 g, 6.53 mmol, 1.0 equivalent) and methyl 4-bromo-2-(bromomethyl)benzoate (2.01 g, 6.53 mmol, 1.0 equivalent) in DMA (20 mL), and the reaction mixture was stirred at 125 °C for 15 hours. The mixture was cooled and then diluted with EtOAc (40 mL) and water (30 mL). The organic layers were separated, and the aqueous layer was extracted with EtOAc (30 mL × 3). The combined organic extracts were washed with water (30 mL × 3) and brine (30 mL × 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by rapid chromatography over SiO2 (gradient: 0-15% ethyl acetate / petroleum ether) to give the title compound as a yellow solid (1.3 g, 2.44 mmol, 37% yield). LC / MS (ESI) m / z: 502.9 [M+H] + .

[1603] Step 2: Preparation of tert-butyl 4-[2-(2,6-dibenzyloxy-3-pyridyl)-1-oxo-isoindoline-5-yl]piperazine-1-carboxylate

[1604]

[1605] To a solution of 5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-1-one (1.3 g, 2.44 mmol, 94% purity, 1.0 equivalent) dissolved in dioxane (20 mL), tert-butyl piperazine-1-carboxylate (680.93 mg, 3.66 mmol, 1.5 equivalent), Cs₂CO₃ (2.38 g, 7.31 mmol, 3.0 equivalent), and [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphine (191.77 mg, 243.73 μmol, 0.1 equivalent) were added, and the reaction mixture was stirred at 110 °C for 15 hours under a nitrogen atmosphere. The reaction mixture was cooled, diluted with water (20 mL), and extracted with EtOAc (20 mL × 3). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid chromatography over SiO₂ (gradient: 0-50% ethyl acetate / petroleum ether) to give the title compound as a yellow solid (0.8 g, 1.13 mmol, 47% yield). LC / MS (ESI) m / z: 607.2 [M+H] + .

[1606] Step 3: Preparation of tert-butyl piperazine-1-carboxylate

[1607]

[1608] Pd / C (0.1 g, 1.13 mmol, 86% purity, 1.0 equivalent) was added to a solution of 4-[2-(2,6-dibenzyloxy-3-pyridyl)-1-oxo-isoindoline-5-yl]piperazine-1-carboxylic acid tert-butyl ester (800 mg, 1.13 mmol, 86% purity, 1.0 equivalent) in EtOAc (20 mL) under Ar atmosphere, and the resulting suspension was degassed under vacuum and purged several times with H2. The reaction mixture was stirred at 50 °C for 15 hours under H2 (15 psi). The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (20 mL). Pd / C (0.2 g, 1.13 mmol, 10% purity, 1.0 equivalent) was added under Ar atmosphere, and the suspension was degassed under vacuum and purged several times with H2. The reaction mixture was stirred at 50°C for 15 hours under H2 (15 psi). The mixture was filtered, and the filter cake was washed with 10:1 CH2Cl2 / CH3OH (50 mL). The solvent was concentrated under reduced pressure to give the title compound (380 mg, crude) as a purple solid. LC / MS (ESI) m / z: 429.0 [M+H] + .

[1609] Step 4: Preparation of 3-(1-oxo-5-piperazin-1-yl-isoindoline-2-yl)piperidine-2,6-dione

[1610]

[1611] TFA (1 mL, 13.51 mmol, 96.45 equivalents) was added to tert-butyl piperazine-1-carboxylate (60 mg, 140.03 μmol, 1.0 equivalent) dissolved in CH₂Cl₂ (1 mL), and the reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (123.89 mg, crude, TFA salt) as a dark brown oil. LC / MS (ESI) m / z: 329.1 [M+H] + .

[1612] Step 5: Synthesis of 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 59)

[1613]

[1614] In a similar manner to 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-3-yl]methyl ester, from 3-[7-[8-ethyl-3-(methoxy The title compound was prepared by means of methoxy]-1-naphthyl]-8-fluoro-2-[[(3R,8R)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 3-(1-oxo-5-piperazin-1-yl-isoindoline-2-yl)piperidine-2,6-dione, and the title compound was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [2-42% CH3CN / water (formic acid)]). The pure fractions were combined and concentrated under reduced pressure, then lyophilized to give the title compound (32.0 mg, 31.65 μmol, 20% yield, formate) as a grayish-white solid.

[1615] Example 14: Synthesis of 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 58)

[1616]

[1617] In a similar manner to 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-3-yl]methyl ester, from 3-[7-[8-ethyl-3-(methoxy The title compound was prepared by means of methoxy]-1-naphthyl]-8-fluoro-2-[[(3S,8S)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 3-(1-oxo-5-piperazin-1-yl-isoindoline-2-yl)piperidine-2,6-dione, and the title compound was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [2-42% CH3CN / water (formic acid)]). The pure fractions were combined and concentrated under reduced pressure, then lyophilized to give the title compound (31.6 mg, 32.43 μmol, 24% yield, formate) as a grayish-white solid.

[1618] Example 15: Synthesis of 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-4-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 65)

[1619] Step 1: Preparation of tert-butyl piperazine-1-carboxylate

[1620]

[1621] Diisopropylethylamine (0.946 mL, 5.43 mmol, d = 0.742 g / mL, 3.0 equivalent) was added to a solution of 2-(2,6-dioxo-3-piperidinyl)-4-fluoro-isoindoline-1,3-dione (500 mg, 1.81 mmol, 1.0 equivalent) and piperazine-1-carboxylic acid tert-butyl ester (405 mg, 2.17 mmol, 1.2 equivalent) in DMSO (8 mL), and the reaction mixture was stirred at 100 °C for 3 hours. The mixture was diluted with H₂O (20 mL), and the aqueous phase was extracted with dichloromethane (30 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The resulting residue was purified by rapid chromatography over SiO2 (gradient: 0-2% methanol / dichloromethane) to give the title compound as a yellow oil (600 mg, 1.10 mmol, 61% yield). LC / MS (ESI) m / z: 386.9 [M-55] + . 1 H NMR (400MHz, CDCl3) δ7.94(s,1H),7.56(dd,J=7.2,8.4Hz,1H),7.39(d,J=7.0Hz,1H),7.17(d,J=8.4Hz,1H),4.90(dd, J=5.2,12.4Hz,1H),3.60(t,J=4.8Hz,4H),3.31-3.17(m,4H),2.88-2.62(m,3H),2.11-2.01(m,1H),1.44-1.38(m,9H).

[1622] Step 2: Preparation of 2-(2,6-dioxo-3-piperidinyl)-4-(piperazin-1-yl)isoindoline-1,3-dione

[1623]

[1624] TFA (6.0 mL, 81.04 mmol, d = 1.54 g / mL, 59.8 equivalents) was added to a solution of 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-4-yl]piperazine-1-carboxylic acid tert-butyl ester (600 mg, 1.10 mmol, 1.0 equivalent) in CH2Cl2 (8 mL), and the reaction mixture was stirred at 20 °C for 0.5 h. The mixture was concentrated under vacuum to give the title compound (620 mg, crude, TFA) as a yellow solid. LC / MS (ESI) m / z: 343.1 [M+H] + .

[1625] Step 3: Preparation of 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-4-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 65)

[1626]

[1627] In a similar manner to 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester, from 3-[7-[8-ethyl-3-(methoxymethyl] The title compound was prepared by starting with tert-butyl octane-8-carboxylate ((3R,8R)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(2,6-dioxo-3-piperidinyl)-4-(piperazin-1-yl)isoindoline-1,3-dione, and purified by preparative HPLC (conditions: [2-42% CH3CN / water (formic acid)]; column: Phenomenex C18 75*30mm*3μm; flow rate: 25mL / min). The pure fractions were combined and lyophilized to give the title compound (36.3 mg, 0.037 mmol, 49% yield, formate) as a yellow solid.

[1628] Example 16: Synthesis of 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-4-yl]piperazin-1-carboxylic acid [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 64)

[1629]

[1630] In a similar manner to 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester, from 3-[7-[8-ethyl-3-(methoxymethyl] The title compound was prepared by starting with tert-butyl octane-8-carboxylate ((3S,8S)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindoline-1,3-dione, and purified by preparative HPLC (conditions: [2-42% CH3CN / water (formic acid)]; column: Phenomenex C18 75*30mm*3μm; flow rate: 25mL / min). The pure fractions were combined and lyophilized to give the title compound (31.0 mg, 0.031 mmol, 47% yield, formate) as a yellow solid.

[1631] Example 17: Synthesis of 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 61)

[1632] Step 1: Preparation of tert-butyl piperazine-1-carboxylate

[1633]

[1634] Cs₂CO₃ (975 mg, 2.99 mmol, 3.0 equivalent) and [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphine (78 mg, 0.100 mmol, 0.1 equivalent) were added to a solution of 4-bromo-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-1-one (500 mg, 0.997 mmol, 1.0 equivalent) and piperazine-1-carboxylic acid tert-butyl ester (279 mg, 1.50 mmol, 1.5 equivalent) in dioxane (6 mL). The reaction mixture was stirred at 110 °C for 12 hours. The mixture was filtered and concentrated, and the resulting residue was purified by rapid chromatography over SiO2 (gradient: 0-30% ethyl acetate / petroleum ether) to give the title compound as a yellow solid (410 mg, 0.642 mmol, 64% yield). LC / MS (ESI) m / z: 607.2 [M+H] + .

[1635] Step 2: Preparation of tert-butyl piperazine-1-carboxylate

[1636]

[1637] Pd / C (200 mg, 10% purity) was added to a solution of 4-[2-(2,6-dibenzyloxy-3-pyridyl)-1-oxo-isoindoline-4-yl]piperazine-1-carboxylic acid tert-butyl ester (410 mg, 0.642 mmol, 1.0 equivalent) in EtOAc (10 mL), and the reaction mixture was stirred at 50 °C for 12 h under H2 (15 psi). The reaction solution was filtered and concentrated under vacuum to give the title compound (300 mg, crude) as a pale yellow oil. LC / MS (ESI) m / z: 429.1 [M+H] + .

[1638] Step 3: Preparation of 3-(1-oxo-4-piperazin-1-yl-isoindoline-2-yl)piperidine-2,6-dione

[1639]

[1640] TFA (3.0 mL, 40.52 mmol, d = 1.54 g / mL, 57.9 equivalents) was added to a solution of 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]piperazine-1-carboxylic acid tert-butyl ester (300 mg, 0.700 mmol, 1.0 equivalent) in CH2Cl2 (4 mL), and the reaction mixture was stirred at 20 °C for 0.5 h. The reaction solution was concentrated under vacuum to give the title compound (310 mg, crude, TFA) as a yellow solid. LC / MS (ESI) m / z: 329.0 [M+H] + .

[1641] Step 4: Preparation of 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 61)

[1642]

[1643] In a similar manner to 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester, from 3- The title compound was prepared starting with [7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3R,8R)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 3-(1-oxo-4-piperazin-1-yl-isoindoline-2-yl)piperidine-2,6-dione.

[1644] The title compound was purified by preparative HPLC (5-40% CH3CN / water (formic acid); gradient time: 25 min; column: Phenomenex C18 75*30 mm*3 μm; flow rate: 25 mL / min). The purified fractions were combined and lyophilized to give the title compound (28.3 mg, 29.14 μmol, 38% yield, formate) as a white solid.

[1645] Example 18: Synthesis of 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]piperazin-1-carboxylic acid [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 60)

[1646]

[1647] In a similar manner to 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester, from 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro The title compound was prepared by starting with tert-butyl octane-8-carboxylate and 3-(1-oxo-4-piperazin-1-yl-isoindoline-2-yl)piperidine-2,6-dione, and purified by preparative HPLC (5-40% CH3CN / water (formic acid); gradient time: 25 min; column: Phenomenex C18 75*30mm*3μm; flow rate: 25 mL / min). The purified fractions were combined and lyophilized to give the title compound (22.9 mg, 0.024 mmol, 33% yield, formate) as a white solid.

[1648] Example 19: Synthesis of 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 48)

[1649]

[1650] To 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizine-3 [-methyl]methyl ester (85.0 mg, 0.086 mmol, 1.0 equivalent, HCl) was added to a solution of CH2Cl2 (2 mL) and CH3OH (2 mL) with formaldehyde (0.429 mmol, 32.0 μL, 37% purity, 5.0 equivalent) and 2-methylpyridinium borane (14.0 mg, 0.129 mmol, 1.5 equivalent), and the reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated, and the crude product was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [5-35% CH3CN / water (formic acid)]). The purified fraction was lyophilized to give the title compound (17.9 mg, 0.017 mmol, 20% yield, formate) as a yellow solid.

[1651] Example 20: Synthesis of 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3S,8S)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 47)

[1652]

[1653] The title compound was prepared in a manner similar to that of 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester, and was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [5-35% CH3CN / water (formic acid)]). The pure fraction was lyophilized to give the title compound (40.5 mg, 0.040 mmol, 29% yield, formate) as a yellow solid.

[1654] Example 21: Synthesis of 4-[2-(1-methyl-2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 53)

[1655] Step 1: Preparation of tert-butyl piperazine-1-carboxylate

[1656]

[1657] To a solution of 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazine-1-carboxylic acid tert-butyl ester (430 mg, 1.00 mmol, 1.0 equivalent) in DMA (5 mL), Cs₂CO₃ (654.0 mg, 2.01 mmol, 2.0 equivalent) and CH₃I (2.01 mmol, 125 μL, 2.0 equivalent) were added, and the reaction mixture was stirred at 25 °C for 2 h. The mixture was filtered, diluted with water (15 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with brine (15 mL × 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (420 mg, crude) as a yellow solid. LC / MS (ESI) m / z: 443.1 [M + H] + .

[1658] Step 2: Preparation of 1-methyl-3-(1-oxo-5-piperazin-1-yl-isoindoline-2-yl)piperidine-2,6-dione

[1659]

[1660] To a solution of 4-[2-(1-methyl-2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazine-1-carboxylic acid tert-butyl ester (420 mg, 949.14 μmol, 1 equivalent) in CH2Cl2 (5 mL), HCl / dioxane (5 mL, 4 M) was added, and the reaction mixture was stirred at 25 °C for 0.5 h. Then, petroleum ether (30 mL) was added, and the resulting mixture was stirred at 25 °C for 0.5 h. The resulting precipitate was filtered to give the title compound (350 mg, crude, HCl salt) as a yellow solid. LC / MS (ESI) m / z: 343.0 [M+H]+ .

[1661] Step 3: Preparation of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3R,8R)-3-[[4-[2-(1-methyl-2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carbonyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid

[1662]

[1663] Triethylamine (1.08 mmol, 150 μL, 10 equivalents), DMAP (1.0 mg, 0.001 mmol, 0.1 equivalents), and (4-nitrophenyl)chlorocarbamate (37.0 mg, 0.183 mmol, 1.7 equivalents) were added to a solution of 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3R,8R)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (80 mg, 0.1 mmol, 1.0 equivalents) in THF (3 mL), and the reaction mixture was stirred at 40 °C for 15 hours. Then, 1-methyl-3-(1-oxo-5-piperazin-1-yl-isoindoline-2-yl)piperidine-2,6-dione (45.0 mg, 0.118 mmol, 1.1 equivalents, HCl) was added, and the reaction mixture was stirred at 40 °C for 1 hour. The mixture was concentrated, and the resulting residue was purified by rapid chromatography on SiO2 (gradient: 0-5% methanol / dichloromethane) to give the title compound as a yellow solid (100 mg, 0.056 μmol, 53% yield). LC / MS (ESI) m / z: 1111.4 [M+H] + .

[1664] Step 4: Preparation of 4-[2-(1-methyl-2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 53)

[1665]

[1666] A mixture of 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3R,8R)-3-[[4-[2-(1-methyl-2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carbonyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100 mg, 0.09 mmol, 1 equivalent) in CH2Cl2 (2 mL) and 4M HCl / dioxane (2 mL) was stirred at 25 °C for 0.5 h. Then petroleum ether (30 mL) was added, and the resulting mixture was stirred at 25 °C for 0.5 h. The precipitate was collected and purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [5-40% CH3CN / water (formic acid)]). The purified fraction was lyophilized to give the title compound (29.7 mg, 28.79 μmol, 32% yield, formate) as a white solid.

[1667] Example 22: Synthesis of 4-[2-(1-methyl-2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 50)

[1668]

[1669] Similar to 4-[2-(1-methyl-2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 53). The title compound was prepared by means of 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3S,8S)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, and purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [5-40% CH3CN / water (formic acid)]). The purified fraction was lyophilized to give the title compound (30.2 mg, 0.029 mmol, 32% yield, formate) as a white solid.

[1670] Example 23: Synthesis of 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 51)

[1671]

[1672] In a similar manner to 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester, from 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester. The title compound was prepared by starting with methyl 4-(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl] ester and purified by preparative HPLC (column: Phenomenex C1875*30mm*3μm; mobile phase: [5-35% CH3CN / water (formic acid)]) to give the title compound as a white solid (22.2 mg, 0.021 mmol, 35% yield, formate).

[1673] Example 24: Synthesis of 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]piperazin-1-carboxylic acid [(3S,8S)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 49)

[1674]

[1675] In a similar manner to 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester, from 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester. The title compound was prepared by means of [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester. The title compound was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; gradient: 5%-35% CH3CN / water (NH4HCO3); gradient time: 25 min; hold time: 4 min; flow rate: 25 mL / min) to give the title compound as a yellow solid (58.3 mg, 0.059 mmol, 52% yield).

[1676] Example 25: Synthesis of 4-[2-(1-methyl-2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 54)

[1677] Step 1: Preparation of tert-butyl piperazine-1-carboxylate

[1678]

[1679] Cs₂CO₃ (608 mg, 1.87 mmol, 2.0 equivalent) and CH₃I (0.116 mL, 1.87 mmol, d = 2.28 g / mL, 2.0 equivalent) were added to a solution of 4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]piperazine-1-carboxylic acid tert-butyl ester (400 mg, 0.934 mmol, 1.0 equivalent) in DMF (8 mL) at 0 °C, and the reaction mixture was stirred at 20 °C under N₂ for 3 h. The mixture was diluted with H₂O (30 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic extracts were washed with water (20 mL × 3) and brine (20 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give the title compound (490 mg, crude) as a yellow solid. LC / MS (ESI) m / z: 387.2 [M-55] + .

[1680] Step 2: Preparation of 1-methyl-3-(1-oxo-4-piperazin-1-yl-isoindoline-2-yl)piperidine-2,6-dione

[1681]

[1682] To a solution of 4-[2-(1-methyl-2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.113 mmol, 1 equivalent) in CH₂Cl₂ (1 mL), 4 M HCl / EtOAc (1 mL) was added, and the reaction mixture was stirred at 20 °C for 20 min. The mixture was concentrated under reduced pressure to give the title compound as a yellow solid (40 mg, 0.106 mmol, 93% yield, HCl salt). LC / MS (ESI) m / z: 343.0 [M+H] + .

[1683] Step 3: Preparation of 4-[2-(1-methyl-2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 54)

[1684]

[1685] In a similar manner to 4-[2-(1-methyl-2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 53), from 3-[7-[8-ethyl-3-(methyl The title compound was prepared by means of tert-butyl octane-8-carboxylate ((3R,8R)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolazin-8-yl)methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 1-methyl-3-(1-oxo-4-piperazin-1-yl-isoindoline-2-yl)piperidine-2,6-dione, and purified by preparative HPLC (column: Phenomenex C1875*30mm*3μm; mobile phase: [5-40% CH3CN / water (formic acid)]). The purified fractions were combined and lyophilized to give the title compound (30.8 mg, 0.030 mmol, 46% yield, formate) as a white solid.

[1686] Example 26: Synthesis of 4-[2-(1-methyl-2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]piperazin-1-carboxylic acid [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 52)

[1687]

[1688] In a similar manner to 4-[2-(1-methyl-2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]piperazin-1-carboxylic acid [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolazin-3-yl]methyl ester (compound 53), from 3-[7-[8-ethyl-3- The title compound was prepared by starting with tert-butyl octane-8-carboxylate and 1-methyl-3-(1-oxo-4-piperazin-1-yl-isoindoline-2-yl)piperidine-2,6-dione, and purified by preparative HPLC (gradient: 5-45% CH3CN / water (formic acid); gradient time: 28 min; hold time: 3 min; flow rate: 25 mL / min). The purified fractions were combined and lyophilized under reduced pressure to give the title compound (17.0 mg, 17.46 μmol, 28% yield, formate) as a white solid.

[1689] Example 27: Synthesis of 3-[6-(1-{2-[(4-{3,8-diazabicyclo[3.2.1]oct-3-yl}-7-(8-ethyl-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy]ethyl}piperidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidin-2,6-dione (compound 36)

[1690] Step 1: Preparation of 3-(2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-yl)ethoxy)-7-(8-ethyl-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1691]

[1692] To a solution of 3-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (51 μmol) in dichloromethane (1 mL) and isopropanol (0.1 mL), 3-(1-oxo-5-(piperidin-4-yl)isoindololin-2-yl)piperidin-2,6-dione (54 μmol), 2-methylpyridineborane complex (255 μmol), and acetic acid (204 μmol) were added, and the mixture was stirred at 20 °C for 1 hour. The reaction mixture was filtered and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the product.

[1693] Step 2: Preparation of 3-[6-(1-{2-[(4-{3,8-diazabicyclo[3.2.1]oct-3-yl}-7-(8-ethyl-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy]ethyl}piperidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidin-2,6-dione (compound 36)

[1694]

[1695] A solution of 3-[2-[2-[4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-yl]-1-piperidinyl]ethoxy]-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (44 μmol) in hexafluoroisopropanol (1 mL) was mixed with 0.2 mL of trifluoroacetic acid and stirred at 25 °C for 0.5 h. The reaction mixture was purified by preparative HPLC (Welch Xtimate C18 150 x 25 mm x 5 μm; A: water containing 0.225% v / v FA, B: acetonitrile; B%: 20–60; 25 min) and then lyophilized to give the title compound.

[1696] Compounds 1-8, 10-22, 25-27, 31-34 and 37-40 were prepared using a procedure similar to that used to prepare compound 36.

[1697] Example 28: Synthesis of 3-[5-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-4-fluoro-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (compound 69)

[1698] Step 1: Preparation of methyl 2-bromo-3,4-difluorobenzoate

[1699]

[1700] Thionyl chloride (200.8 g, 1.69 mol, 122.4 mL, 2 equivalents) was added dropwise to a solution of 2-bromo-3,4-difluorobenzoic acid (200 g, 843.8 mmol, 1 equivalent) in methanol (1.5 L) at 0 °C, and the reaction mixture was stirred at 70 °C for 12 h. The mixture was concentrated under vacuum, and the residue was diluted with water (600 mL) and extracted with EtOAc (3 × 200 mL). The combined organic extracts were washed with brine (2 × 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound (208 g, 98%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.68 (ddd, J=2.0, 5.4, 8.8Hz, 1H), 7.25-7.14 (m, 1H), 3.94 (s, 3H).

[1701] Step 2: Preparation of methyl 2-bromo-4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorobenzoate

[1702]

[1703] Diisopropylethylamine (321.3 g, 2.49 mol, 433.0 mL, 3 equivalents) and 4-(dimethoxymethyl)piperidine (138.5 g, 870.03 mmol, 1.05 equivalents) were added to a solution of methyl 2-bromo-3,4-difluorobenzoate (208 g, 828.60 mmol, 1 equivalent) in dimethyl sulfoxide (1500 mL), and the reaction mixture was stirred at 100 °C for 12 hours. The mixture was poured into water (1 L), and the aqueous mixture was extracted with EtOAc (3 × 300 mL). The combined organic extracts were washed with brine (3 × 500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (gradient: 1-50% EtOAc / petroleum ether) to give the title compound (244 g, 75%) as a white solid. LC / MS(ESI)m / z:390.0,392.0[M+H] + . 1 H NMR (400MHz, CDCl3) δ7.62(dd,J=1.0,8.6Hz,1H),6.84(t,J=8.4Hz,1H),4.09(d,J=7.0Hz,1H),3.89(s,3H),3.59(br d,J=12.2Hz,2H),3.38(s,6H),2.74(br t,J=11.6Hz,2H),1.92-1.76(m,3H),1.50(br dd,J=3.4,11.8Hz,2H).

[1704] Step 3: Preparation of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluoro-2-vinylbenzoate

[1705]

[1706] To a solution of methyl 2-bromo-4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorobenzoate (170 g, 435.63 mmol, 1 equivalent) and potassium vinyltrifluoroborate (175.06 g, 1.31 mol, 3 equivalents) in dioxane (1.3 L) and water (250 mL), bis(diphenylphosphine)ferrocene]dichloropalladium(II)dichloromethane (17.8 g, 21.78 mmol, 0.05 equivalents) and sodium carbonate (115.4 g, 1.09 mol, 2.5 equivalents) were added, and the reaction mixture was stirred at 110 °C for 12 hours. Water (1 L) was then added, and the aqueous mixture was extracted with EtOAc (3 × 600 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (1-25% EtOAc / petroleum ether) to give the title compound (123 g, 83%) as a white solid. LC / MS (ESI) m / z: 338.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.64(dd,J=1.2,8.6Hz,1H),7.04(dd,J=11.8,17.8Hz,1H),6.83(t,J=8.4Hz,1H),5.74-5.46 (m,2H),4.11(d,J=7.2Hz,1H),3.85(s,3H),3.64-3.52(m,2H),3.38(s,6H),2.71(dt,J=1.8,12.0Hz,2H),1.86(br dd,J=1.6,13.0Hz,3H),1.53(br dd,J=3.6,12.0Hz,2H).

[1707] Step 4: Preparation of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluoro-2-carboxymethylbenzoate

[1708]

[1709] To a solution of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluoro-2-vinylbenzoate (50 g, 148.20 mmol, 1 equivalent) in dioxane (450 mL) and water (150 mL), 2,6-dimethylpyridine (31.8 g, 296.40 mmol, 34.5 mL, 2 equivalents), potassium osmium tetroxide (VI) dihydrate (1.1 g, 2.96 mmol, 0.02 equivalents), and sodium periodate (126.79 g, 592.79 mmol, 32.85 mL, 4 equivalents) were added, and the reaction mixture was stirred at 20 °C for 1 hour. Water (300 mL) was then added, and the resulting mixture was filtered. The filtrate was extracted with EtOAc (2 × 200 mL), and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (1-50% EtOAc / petroleum ether) to give the title compound as a yellow solid (36 g, 72% yield). 1 H NMR (400MHz, CDCl3) δ10.42(s,1H),7.65(dd,J=0.8,8.4Hz,1H),7.01(t,J=8.4Hz,1H),4.09(d,J=7.0Hz,1H),3.90(s,3H),3.63(br d,J=12.2Hz,2H),3.45-3.32(m,6H),2.84-2.69(m,2H),1.93-1.73(m,3H),1.51(br d,J=3.6Hz,2H).

[1710] Step 5: Preparation of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1-oxoisoindololin-2-yl)piperidin-2,6-dione

[1711]

[1712] Sodium acetate (25.4 g, 309.41 mmol, 3 equivalents) was added to a solution of 3-aminopiperidine-2,6-dione (20.4 g, 123.76 mmol, 1.2 equivalents, hydrochloride) in methanol (350 mL), followed by the addition of methyl 4-[4-(dimethoxymethyl)-1-piperidinyl]-3-fluoro-2-carboxymethylbenzoate (35 g, 103.14 mmol, 1 equivalent) and sodium cyanoborohydride (13.0 g, 206.27 mmol, 2 equivalents), and the reaction mixture was stirred at 40 °C for 12 hours. The mixture was filtered, and the filter cake was washed with methanol (2 × 20 mL). The filter cake was milled twice with water (600 mL) at 20 °C for 30 minutes. The resulting material was collected and dried under vacuum to give the title compound (37 g, 85%) as a purple solid. LC / MS (ESI) m / z: 420.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.97 (s, 1H), 7.46 (d, J = 8.2Hz, 1H), 7.23-7.05 (m, 1H), 5.15-4.99 (m, 1H), 4.52-4.42 (m ,1H),4.36-4.26(m,1H),4.12(d,J=6.4Hz,1H),3.49(brd,J=4.8Hz,2H),3.33(s,6H),2.98-2.85(m,1H),2.74(br t,J=12.0Hz,2H),2.61(br s,1H),2.46-2.34(m,1H),2.03-1.93(m,1H),1.74(br d,J=10.4Hz,3H),1.40(br d,J=10.2Hz,2H).

[1713] Step 6: Preparation of 1-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindoline-5-yl)piperidin-4-carboxaldehyde

[1714]

[1715] To a solution of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1-oxoisoindoline-2-yl)piperidin-2,6-dione (37 g, 88.21 mmol, 1 equivalent) in acetone (350 mL) and water (35 mL), p-toluenesulfonic acid (3.0 g, 17.64 mmol, 0.2 equivalent) was added, and the reaction mixture was stirred at 70 °C for 12 h. The mixture was filtered, and the filter cake was washed with acetone (3 × 30 mL). The resulting material was collected and dried under vacuum to give the title compound (29 g, 88%) as a white compound. LC / MS (ESI) m / z: 374.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),9.65(s,1H),7.47(d,J=8.2Hz,1H),7.17(br t,J=7.8Hz,1H),5.07(br dd,J=5.0,13.2Hz,1H),4.56-4.43(m,1H),4.38-4.22(m,1H),3.50-3.37(m,2H),3.00-2.82(m,3H),2.64-2.52(m,2H),2.43(br d,J=4.2Hz,1H),2.03-1.93(m,3H),1.66(br d,J=10.0Hz,2H).

[1716] Step 7: Preparation of tert-butyl piperidinium ester of 4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-4-fluoro-1-oxo-isoindoline-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]piperidin-1-carboxylic acid

[1717]

[1718] The preparation of 1-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindoline-5-yl)piperidin-4-carboxaldehyde (1.0 g, 2.68 mmol, 1 equivalent) and tert-butyl 4-(4-piperidinylmethyl)piperidin-1-carboxylate (1.69 g, 3.21 mmol, 1.2 equivalent, acetate) in dichloromethane (10 mL) and dimethyl sulfoxide (10 mL) was carried out at 25 °C. Diisopropylethylamine (346 mg, 2.68 mmol, 0.4 mL, 1.0 equivalent) was then added, and the resulting mixture was stirred under nitrogen for 15 min. Sodium triacetoxyborohydride (1.70 g, 8.03 mmol, 3 equivalent) was then added, and the reaction mixture was stirred at 25 °C for 1 h. The mixture was diluted with dichloromethane (50 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (dichloromethane / methanol = 5 / 1) to give the title compound as a white solid (1.3 g, 2.03 mmol, 75% yield). LC / MS (ESI) m / z: 640.3 [M+H] + .

[1719] Step 8: Preparation of 3-[4-fluoro-1-oxo-5-[4-[[4-(4-piperidinylmethyl)-1-piperidinyl]methyl]-1-piperidinyl]isoindoline-2-yl]piperidin-2,6-dione

[1720]

[1721] Trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL, 30.32 equivalents) was added to a solution of tert-butyl piperidinium-1-carboxylate (570 mg, 0.89 mmol, 1 equivalent) in dichloromethane (6 mL), and the reaction mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated under vacuum to give the title compound (580 mg, crude, trifluoroacetate) as a brown solid. LC / MS (ESI) m / z: 540.5 [M+H] + .

[1722] Step 9: Preparation of 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-4-fluoro-1-oxo-isoindoline-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]-8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1723]

[1724] Diisopropylethylamine (230 mg, 1.78 mmol, 0.3 mL) was added to a solution of 3-[4-fluoro-1-oxo-5-[4-[[4-(4-piperidinylmethyl)-1-piperidinyl]methyl]-1-piperidinyl]isoindoline-2-yl]piperidin-2,6-dione (578 mg, 0.88 mmol, 1.49 equivalents, trifluoroacetate) in dichloromethane (5 mL) and isopropanol (5 mL). 3-[8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (450 mg, 593.72 μmol, 1 equivalent) was added, and the resulting mixture was stirred at 25 °C for 10 min. Then, sodium triacetoxyborohydride (377 mg, 1.78 mmol, 3 equivalent) was added, and the reaction mixture was stirred at 25 °C for 0.5 h. The mixture was diluted with water (20 mL) and extracted with dichloromethane (2 × 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (CH2Cl2 / CH3OH = 20 / 1 to 6 / 1) to give the title compound as a pale yellow solid (470 mg, 0.36 mmol, 61% yield). LC / MS (ESI) m / z: 1281.9 [M+H] + .

[1725] Step 10: Preparation of 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-4-fluoro-1-oxo-isoindoline-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1726]

[1727] Cesium fluoride (1.09 g, 7.18 mmol, 0.2 mL, 20 equivalents) was added to a mixture of 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-4-fluoro-1-oxo-isoindoline-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]-8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (460 mg, 0.35 mmol, 1 equivalent) in DMF (5 mL) and the reaction mixture was stirred at 25 °C for 2 hours. The mixture was diluted with dichloromethane (50 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (CH2Cl2 / CH3OH = 5 / 1) to give the title compound as a white solid (168 mg, 0.14 mmol, 41% yield). LC / MS (ESI) m / z: 563.6 [M / 2+H] + .

[1728] Step 11: Preparation of 3-[5-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidinyl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-4-fluoro-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (compound 69)

[1729]

[1730] Add hydrochloric acid / dioxane (4M, 0.5mL, 13.40 equivalents) to a solution of 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-4-fluoro-1-oxo-isoindoline-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-1-piperidinyl]ethoxy]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (168 mg, 0.14 mmol, 1 equivalent) in dichloromethane (1.5 mL), and stir the reaction mixture at 25 °C for 15 min. Dilute the mixture with petroleum ether (6 mL) and adjust the pH to 6. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [6-36% CH3CN / water (formic acid)]) to give the title compound (91.0 mg, 0.08 mmol, 56% yield, formate) as a yellow solid.

[1731] Example 29: Synthesis of 3-[5-[4-[[3-[[1-[[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-3,9-diazaspiro[5.5]undecane-9-yl]methyl]-1-piperidinyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidin-2,6-dione (compound 193)

[1732] Step 1: Preparation of 2,6-bis(benzyloxy)-3-nitropyridine

[1733]

[1734] Cesium carbonate (127.21 g, 390 mmol) was added in a single batch to a mixture of 2,6-dichloro-3-nitropyridine (25.0 g, 156 mmol) and benzyl alcohol (40.6 mL, 390 mmol) in acetonitrile (500 mL) under a nitrogen atmosphere, and the mixture was stirred at 60 °C for 6 hours. The mixture was cooled to 20 °C, filtered, and the filtrate was concentrated under reduced pressure. The residue was ground with petroleum ether / methyl tert-butyl ether (1:1, 500 mL) to give the title compound (49 g, 93%) as a yellow solid.

[1735] Step 2: Preparation of 2,6-bis(benzyloxy)pyridine-3-amine

[1736]

[1737] Iron (126.19 g, 2.26 mol) was added to a mixture of 2,6-bis(benzyloxy)-3-nitropyridine (95.0 g, 282 mmol) and ammonium chloride (226.6 g, 4.2 mol) in isopropanol (950 mL) and water (475 mL) under a nitrogen atmosphere, and the mixture was stirred at 90 °C for 16 hours. The mixture was cooled to 20 °C and filtered. The filtrate was poured into ice water (w / w = 1 / 1, 1000 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (2 × 1000 mL). The combined organic phases were washed with brine (3 × 1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (1% to 20% hexane / ethanol, within 15 minutes) to give the title compound (61 g, 70%) as a brown oil. LC / MS (ESI) m / z: 307.2 [M+H] + .

[1738] Step 3: Preparation of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridine-3-amine

[1739]

[1740] A solution of bis(benzyloxy)pyridine-3-amine (5.0 g, 16 mmol) and 4-bromo-1-fluoro-2-nitrobenzene (2.4 mL, 20 mmol) in tetrahydrofuran (50 mL) was added to a solution of lithium bis(trimethylsilyl)amino in tetrahydrofuran (1 M, 24.5 mL), and the mixture was stirred at -78 °C for 1 h, followed by stirring at 25 °C for 11 h under a nitrogen atmosphere. The reaction mixture was slowly quenched with saturated ammonium chloride solution to adjust the pH to 8–9, and then extracted with ethyl acetate (300 mL). The organic layer was washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 100 / 1) to give the title compound (9 g, crude) as a brown oil. LC / MS (ESI) m / z: 508.1 [M+H] + .

[1741] Step 4: Preparation of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine

[1742]

[1743] Iron (4.41 g, 79 mmol) and a saturated aqueous solution of ammonium chloride (8.45 g, 128 mmol) were added to a solution of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridine-3-amine (8.0 g, 16 mmol) in ethanol (100 mL) and water (50 mL), and the mixture was stirred at 80 °C for 4 hours. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (300 mL). The organic layer was washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give the title compound (2.8 g, 37%) as a brown solid.

[1744] Step 5: Preparation of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one

[1745]

[1746] 4-Dimethylaminopyridine (4.77 g, 29 mmol) was added to a solution of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine (2.8 g, 6 mmol) in N,N-dimethylformamide (30 mL), and the mixture was stirred at 120 °C for 2 hours. The reaction solution was poured into water, and the resulting precipitate was filtered and dried to give the title compound (2.8 g, 94%) as a yellow solid. LC / MS (ESI) m / z: 504.1 [M+H] + .

[1747] Step 6: Preparation of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one

[1748]

[1749] Sodium hydride (191 mg, 4.8 mmol, 60%) was added to a solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one (1.2 g, 2 mmol) in tetrahydrofuran (20 mL) at 0 °C, and the reaction mixture was stirred for 0.5 h. Iodimethane (0.2 mL, 4 mmol) was then added at 0 °C, and the mixture was warmed to 25 °C and stirred for 15.5 h. The reaction mixture was diluted with saturated ammonium chloride aqueous solution (10 mL), and the resulting mixture was extracted with ethyl acetate (200 mL). The organic extract was washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give the title compound (1.1 g, crude) as a yellow oil. LC / MS (ESI) m / z: 516.4 [M+H] + .

[1750] Step 7: Preparation of 1-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(dimethoxymethyl)-1-piperidinyl]-3-methyl-benzimidazol-2-one

[1751]

[1752] XPhos Pd G2 (152 mg, 0.2 mmol) and cesium carbonate (1.89 g, 5.8 mmol) were added to a solution of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (1 g, 2 mmol) and 4-(dimethoxymethyl)piperidine (308 mg, 1.9 mmol) in 1,4-dioxane (15 mL), and the mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 1 / 2) to give the title compound (760 mg, 66%) as a brown oil. LC / MS (ESI) m / z: 595.4 [M+H] + .

[1753] Step 8: Preparation of 3-[5-[4-(dimethoxymethyl)-1-piperidinyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidin-2,6-dione

[1754]

[1755] Under a nitrogen atmosphere, 10% carbon-supported palladium (300 mg) was added to a solution of 1-(2,6-dibenzyloxy-3-pyridinyl)-5-[4-(dimethoxymethyl)-1-piperidinyl]-3-methyl-benzimidazol-2-one (1.2 g, 2 mmol) in tetrahydrofuran (10 mL), and the suspension was degassed under vacuum and purged several times with hydrogen. The reaction mixture was stirred at 50 °C for 16 hours under hydrogen (50 psi). The mixture was filtered and concentrated under reduced pressure to give the title compound (430 mg, 51%) as a brown oil. LC / MS (ESI) m / z: 417.3 [M+H] + .

[1756] Step 9: Preparation of 1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-carboxaldehyde

[1757]

[1758] Trifluoroacetic acid (0.1 mL, 1 mmol) was added to a solution of 3-[5-[4-(dimethoxymethyl)-1-piperidinyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidin-2,6-dione (430 mg, 1 mmol) in dichloromethane (10 mL), and the mixture was stirred at 25 °C for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was ground with ethyl acetate / methyl tert-butyl ether (1 / 10, 60 mL) to give the title compound (380 mg, 99%) as a green oil. LC / MS (ESI) m / z: 389.3 [M + H3O] + .

[1759] Step 10: Preparation of tert-butyl 9-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]methyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate

[1760]

[1761] Acetic acid (41 mg, 0.7 mmol) and sodium triacetoxyborohydride (286 mg, 1.4 mmol) were added to a solution of 1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidin-4-carboxaldehyde (250 mg, 0.7 mmol) and 3,9-diazaspiro[5.5]undecane-3-carboxylic acid t...

Claims

1. A compound of any one of formulas I-IV: Or its pharmaceutically acceptable salt. in: Q 1 Selected from C(R) 14 2. C(O) and NR 14 ; Q 2 It is CR 14 Or N; R 1 and R 2 Each is independently selected from H, halogenated, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups, R 3 Selected from H, halogenated, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; R 4 Selected from C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups, of which C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups are selectively substituted. R 4a replace; R 4a Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; R 5a R 5 R 6 R 8 R 10 R 11 R 12 R 13 and R 14 Each is independently selected from H, halogenated, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; R 7 Selected from H, =O, halogenated, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; R 9 Selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy; Ring A is selected from phenyl, 6-membered heteroaryl, C6 cycloalkyl, and 6-membered heterocycloalkyl; B is a key or C 1-6 alkyl; Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

2. The compound according to claim 1, wherein: Q 1 It is C(R) 14 )2 or C(O); Q 2 It is N; R 1 and R 2 Each is independently selected from H, halogenated, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; R 3 Selected from H, halogenated and CN; R 4 It is C 3-11 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3-11 Cycloalkyl and 3-10 membered heterocyclic alkyl groups are optionally R 4a replace; R 4a Is it H or C? 1-6 alkyl; R 5a R 5 R 6 R 8 R 10 R 11 R 12 R 13 and R 14 Each is independently selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy; R 7 Selected from H, =O, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy; R 9 Selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy; Ring A is selected from phenyl, 6-membered heteroaryl, and 6-membered heterocyclic alkyl; B is a key or C 1-6 alkyl; Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12-membered heterocycloalkyl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and n is 1, 2, 3, 4, 5, 6, 7 or 8.

3. The compound according to claim 1 or 2, wherein: Q 1 It is C(R) 14 )2 or C(O); Q 2 It is N; R 1 and R 2 Each is independently selected from H, halogenated, C 1-6 Alkyl groups and C≡CH; R 3 Selected from H, halogenated and CN; R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace; R 4a Is it H or C? 1-6 alkyl; R 5a R 5 R 6 R 8 R 10 R 11 R 12 R 13 and R 14 Each is independently selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy; R 7 Selected from H, =O, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy; R 9 Selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy; Ring A is a phenyl or a 6-membered heterocyclic alkyl group; B is a key or C 1-6 alkyl; Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and n is 1, 2, 3, 4, 5, or 6.

4. The compound according to any one of claims 1 to 3, wherein the compound has the structure of formula I. Or its pharmaceutically acceptable salt. in: Q 1 It is C(R) 14 )2 or C(O); R 1 and R 2 Each was independently selected from halogenated, C 1-6 Alkyl groups and C≡CH; R 3 Selected from H, halogenated and CN; R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace; R 4a Is it H or C? 1-6 alkyl; R 5a R 5 R 6 and R 14 Each is independently selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy; Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl groups, 5-12-membered heterocyclic alkyl groups, and 6-7-membered heteroaryl groups, wherein the 5-12-membered heterocyclic alkyl groups are optionally halogenated, CN-, and C-substituted. 1-6 Alkyl substitution; and n is 1, 2, 3, 4, 5, or 6.

5. The compound according to any one of claims 1 to 3, wherein the compound has the structure of formula II, Or its pharmaceutically acceptable salt. in: Q 2 It is N; R 1 and R 2 Each is independently selected from H, halogenated, C 1-6 Alkyl groups and C≡CH; R 3 Selected from H, halogenated and CN; R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace; R 4a Is it H or C? 1-6 alkyl; R 8 and R 14 Each is independently selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy; R 7 Selected from H, =O, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy; Ring A is a phenyl or a 6-membered heterocyclic alkyl group; B is a key or C 1-6 alkyl; Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and n is 1, 2, 3, 4, 5, or 6.

6. The compound according to any one of claims 1 to 3, wherein the compound has the structure of formula III, Or its pharmaceutically acceptable salt. in: R 1 and R 2 Each is independently selected from H, halogenated, C 1-6 Alkyl groups and C≡CH; R 3 Selected from H, halogenated and CN; R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace; R 4a Is it H or C? 1-6 alkyl; R 10 and R 11 Each is independently selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy; R 9 Selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy; Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and n is 1, 2, 3, 4, 5, or 6.

7. The compound according to any one of claims 1 to 3, wherein the compound has the structure of formula IV. Or its pharmaceutically acceptable salt. in: R 1 and R 2 Each is independently selected from H, halogenated, C 1-6 Alkyl groups and C≡CH; R 3 Selected from H, halogenated and CN; R 4 It is C 6-8 Cycloalkyl or 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocyclic alkyl groups are optionally R 4a replace; R 4a Is it H or C? 1-6 alkyl; R 12 and R 13 Each is independently selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy; Each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally halogenated, CN and C 1-6 Alkyl substitution; and n is 1, 2, 3, 4, 5, or 6.

8. A compound of formula V or VI: Or its pharmaceutically acceptable salt. in: Q 1 Selected from C(R) 14 2. C(O) and NR 14 ; Q 3 It is CR 14 Or N; R 1a and R 2a Each is independently selected from OH, H, and halogenated; R 1b and R 2b Each is independently selected from halogenated and C 3-6 cycloalkyl, Or R 1b and R 2b Together with the phenyl group it is attached to, they form C 8-12 Aryl, of which C 8-12 Aryl groups are selectively R 1 and R 2 replace; R 1 and R 2 Each is independently selected from H, halogenated, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; R 3 Selected from H, halogenated, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; R 4 Selected from C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups, of which C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups are optionally bounded by one or two R groups. 4a replace; Each R 4a Independently selected from H, OH, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; R 14 R 15a R 15b R 15 R 16 R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the 3-12 heterocyclic alkyl group is optionally selected by one or two independently from halogen, CN and C. 1-6 Alkyl substituents; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

9. The compound according to claim 8, wherein: Q 1 It is C(R) 14 )2 or C(O); Q 3 It is CR 14 Or N; R 1a and R 2a Each is independently selected from OH, H, and halogenated; R 1b and R 2b Together with the phenyl group it is attached to, they form C 8-12 Aryl, of which C 8-12 Aryl groups are selectively R 1 and R 2 replace; R 1 and R 2 Each is independently selected from H, halogenated, C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group; R 3 Selected from H, halogenated and CN; R 4 Selected from C 3-11 Cycloalkyl and 3-10 membered heterocyclic alkyl groups, wherein C 3-11 Cycloalkyl and 3-10 membered heterocycloalkyl groups are optionally surrounded by one or two R groups. 4a replace; Each R 4a Independently selected from H, OH and C 1-6 alkyl; R 14 R 15a R 15 R 15b R 16 R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, C 1-6 Alkyl and C 1-6 Alkoxy; Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12-membered heterocycloalkyl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocycloalkyl is optionally selected by one or two independently from halogen, CN and C. 1-6 Alkyl substituents; and n is 1, 2, 3, 4, 5, 6, 7 or 8.

10. The compound according to claim 8 or 9, wherein: Q 1 It is C(R) 14 )2 or C(O); Q 3 It is CH or N; R 1a and R 2a Each is independently selected from H, OH, and halogenated; R 1b and R 2b Together with the phenyl group it is attached to, it forms a group with R 1 and R 2 Substituted naphthyl group; R 1 and R 2 Each is independently selected from H, halogenated, C 1-3 Alkyl, C 3-5 cycloalkyl groups and C≡CH; R 3 It is H or halogenated; R 4 Selected from C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl groups are optionally surrounded by one or two R groups. 4a replace; Each R 4a Independently selected from H, OH and C 1-6 alkyl; R 14 R 15a R 15b R 15 R 16 R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, C 1-3 Alkyl and C 1-3 Alkoxy; Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, wherein the 5-12-membered heterocycloalkyl is optionally selected by one or two independently from halogen, CN and C. 1-6 Alkyl substituents; and n is 1, 2, 3, 4, 5, or 6.

11. The compound according to any one of claims 8 to 10, wherein the compound has the structure of formula V, Or its pharmaceutically acceptable salt. in: Q 1 It is C(R) 14 )2 or C(O); Q 3 It is CH or N; R 1a and R 2a Each is independently selected from H, OH, and halogenated; R 1b and R 2b Together with the phenyl group it is attached to, it forms a group with R 1 and R 2 Substituted naphthyl group; R 1 and R 2 Each is independently selected from H, halogenated, C 1-3 Alkyl, C 3-5 cycloalkyl groups and C≡CH; R 3 It is H or halogenated; R 4 Selected from C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl groups are optionally surrounded by one or two R groups. 4a replace; Each R 4a Independently selected from H, OH and C 1-6 alkyl; R 14 R 15 and R 16 Each is independently selected from H, halogenated, C 1-3 Alkyl and C 1-3 Alkoxy; R 15a and R 15b Each was independently selected from halogenated, C 1-3 Alkyl and C 1-3 Alkoxy; Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, among which The 5-12 membered heterocyclic alkyl group is optionally separated by one or two independently selected from halogenated, CN and C. 1-6 Alkyl substituents; and n is 1, 2, 3, 4, 5, or 6.

12. The compound according to any one of claims 8 to 10, wherein the compound has the structure of formula VI, Or its pharmaceutically acceptable salt. in: R 1 and R 2 Each is independently selected from H, halogenated, C 1-3 Alkyl, C 3-5 cycloalkyl groups and C≡CH; R 3 It is H or halogenated; R 4 Selected from C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6-8 membered heterocycloalkyl groups are optionally surrounded by one or two R groups. 4a replace; Each R 4a Independently selected from H, OH and C 1-6 alkyl; R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, C 1-3 Alkyl and C 1-3 Alkoxy; Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C) 1-6 Alkyl), C 4-7 Cycloalkyl, 5-12-membered heterocycloalkyl and 6-7-membered heteroaryl, among which The 5-12 membered heterocyclic alkyl group is optionally separated by one or two independently selected from halogenated, CN and C. 1-6 Alkyl substituents; and n is 1, 2, 3, 4, 5, or 6.

13. A compound of formula AI or AIV: Or its pharmaceutically acceptable salt. in: Q 1 Selected from C(R) 14 2. C(O) and NR 14 ; R 1 and R 2 Each is independently halogenated or C 2-6 alkynyl group; R 3 Selected from H, halogenated, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; R 4 Selected from C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups, of which C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups are optionally R 4a replace; R 4a Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; R 5a R 5 R 6 R 12 R 13 and R 14 Each is independently selected from H, halogenated, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; Each L is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, O, C(O), N(H), N(C) 1-6 Alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

14. A compound of formula VII: Or its pharmaceutically acceptable salt. in: Ring B and ring C are each independently selected from 3-12 membered heterocyclic alkyl groups, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution; Ring D is selected from bond, C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl group is optionally halogenated, CN- and C-substituted. 1-6 Alkyl substitution occurs when ring D is a bond, then Y 2 It is also a key and t is 0; Y 1 and Y 2 Each is independently selected from bonds, O, C(O), N(H), N(C). 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy; Z is selected from N(H), N(C) 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy; R 1 and R 2 Each is independently selected from H, halogenated, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; R 3 Selected from H, halogenated, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; R 4 Selected from C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups, of which C 3-11 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl and 3-10 heteroaryl groups are selectively substituted. R 4a replace; R 4a Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; R 17a R 17b R 17 and R 18 Each is independently selected from H, halogenated, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; s and t are each independently 0, 1, 2, or 3; and u is 1 or 2.

15. The compound according to any one of claims 1 to 14, wherein R 4 Is it arbitrarily R 4a Substituted bridged 8-membered heterocyclic alkyl group.

16. The compound according to any one of claims 1 to 15, wherein R 4 yes:

17. The compound according to any one of claims 1 to 4 and 15, wherein the compound has the structure of formula IA: Or its pharmaceutically acceptable salt.

18. The compound according to any one of claims 1 to 3, 5 and 15, wherein the compound has the structure of formula IIA: Or its pharmaceutically acceptable salt.

19. The compound according to any one of claims 1 to 3, 5 and 15, wherein the compound has the structure of formula IIB: Or its pharmaceutically acceptable salt.

20. The compound according to any one of claims 1 to 3, 6 and 15, wherein the compound has the structure of formula IIIA: Or its pharmaceutically acceptable salt.

21. The compound according to any one of claims 1 to 3, 7 and 15, wherein the compound has the structure of formula IVA: Or its pharmaceutically acceptable salt.

22. The compound according to any one of claims 8 to 11, wherein the compound has the structure of formula VA, Or its pharmaceutically acceptable salt.

23. The compound according to any one of claims 8 to 10 and 12, wherein the compound has the structure of formula VIA: Or its pharmaceutically acceptable salt.

24. The compound according to any one of claims 1 to 4, 8 to 11, 13, 15 to 17 and 22, wherein Q 1 It is CH2 or C(O).

25. The compound according to any one of claims 1 to 3, 5, 15, 16, 18 and 19, wherein Q 2 It is N.

26. The compound according to any one of claims 1 to 25, wherein R 1 Selected from H, halogenated and C 1-6 alkyl.

27. The compound according to any one of claims 1 to 25, wherein R 1 It's H.

28. The compound according to any one of claims 1 to 25, wherein R 1 It is halogenated.

29. The compound according to any one of claims 1 to 25, wherein R 1 It is C 1-6 alkyl.

30. The compound according to any one of claims 1 to 29, wherein R 2 Selected from H, C 1-6 Alkyl groups and C≡CH.

31. The compound according to any one of claims 1 to 30, wherein R 2 It's H.

32. The compound according to any one of claims 1 to 30, wherein R 2 It is C 1-6 alkyl.

33. The compound according to any one of claims 1 to 30, wherein R 2 It is C≡CH.

34. The compound according to any one of claims 1 to 16 and 24 to 33, wherein R 3 It is halogenated.

35. The compound according to any one of claims 1 to 34, wherein R 4a Is it H or C? 1-6 alkyl.

36. The compound according to any one of claims 1 to 34, wherein R 4a Selected from OH and C 1-6 alkyl.

37. The compound according to any one of claims 1 to 4, 13, 15 to 17 and 24 to 36, wherein R 5a Is it H, halogenated, or C? 1-6 Alkyl group.

38. The compound according to any one of claims 1 to 4, 13, 15 to 17 and 24 to 37, wherein R 5 Is it H or C? 1-6 alkyl.

39. The compound according to any one of claims 1 to 4, 13, 15 to 17 and 24 to 37, 35, wherein R 6 Is it H or C? 1-6 alkyl.

40. The compound according to any one of claims 1 to 3, 5, 15, 16, 18 and 24 to 36, wherein R 7 Selected from H, =O, halogenated and C 1-6 Alkyl group.

41. The compound according to any one of claims 1 to 3, 5, 15, 16, 18, 24 to 36 and 40, wherein R 7 Yes = O.

42. The compound according to any one of claims 1 to 3, 5, 15, 16, 18, 24 to 36 and 40, wherein R 7 It is halogenated.

43. The compound according to any one of claims 1 to 3, 5, 15, 16, 18, 24 to 36 and 40, wherein R 7 It is C 1-6 Alkyl group.

44. The compound according to any one of claims 1 to 3, 5, 15, 16, 18, 24 to 36 and 40 to 43, wherein R 8 Is it H or C? 1-6 alkyl.

45. The compound according to any one of claims 1 to 3, 5, 15, 16, 18, 24 to 36 and 40 to 44, wherein R 8 It's H.

46. ​​The compound according to any one of claims 1 to 3, 6, 15, 16, 20 and 26 to 36, wherein R 9 Selected from H, halogenated and C 1-6 Alkyl group.

47. The compound according to any one of claims 1 to 3, 6, 15, 16, 20, 26 to 36 and 46, wherein R 9 It is halogenated.

48. The compound according to any one of claims 1 to 3, 6, 15, 16, 18, 26 to 36, 46 and 47, wherein R 9 It is C 1-6 Alkyl group.

49. The compound according to any one of claims 1 to 3, 6, 15, 16, 18, 26 to 36 and 46 to 48, wherein R 10 It's H.

50. The compound according to any one of claims 1 to 3, 6, 15, 16, 18, 26 to 36, and 46 to 49, wherein R 11 It's H.

51. The compound according to any one of claims 1 to 3, 7, 15, 16, 21 and 26 to 36, wherein R 12 It is C 1-6 alkyl.

52. The compound according to any one of claims 1 to 3, 7, 15, 16, 21, 26 to 36 and 51, wherein R 13 It's H.

53. The compound according to any one of claims 1 to 5, 8 to 11, 13 to 19, 22 and 24 to 45, wherein R 14 Is it H or C? 1-6 alkyl.

54. The compound according to any one of claims 1 to 5, 8 to 11, 13 to 19, 22, 24 to 45 and 53, wherein R 14 It's H.

55. The compound according to any one of claims 1 to 5, 8 to 11, 13 to 19, 22, 24 to 45 and 53, wherein R 14 It is C 1-6 alkyl.

56. The compound according to any one of claims 1 to 3, 5, 15, 16, 18, 25 to 36, 40 to 45 and 53 to 55, wherein ring A is phenyl.

57. The compound according to any one of claims 1 to 3, 5, 15, 16, 18, 25 to 36, 40 to 45 and 53 to 55, wherein ring A is a 6-membered heterocyclic alkyl group.

58. The compound according to any one of claims 1 to 3, 5, 15, 16, 18, 25 to 36, 40 to 45, 53 to 55 and 57, wherein ring A is dihydropyridyl.

59. The compound according to any one of claims 1 to 3, 5, 15, 16, 18, 25 to 36, 40 to 45 and 53 to 58, wherein B is a bond.

60. The compound according to any one of claims 1 to 3, 5, 15, 16, 18, 25 to 36, 40 to 45, and 53 to 58, wherein B is C. 1-6 alkyl.

61. The compound according to any one of claims 8 to 11, 15, 16, 22, 24 and 26 to 36, wherein Q 3 It is N.

62. The compound according to any one of claims 8 to 11, 15, 22, 24, 26 to 36, 56 and 61, wherein R 1a It is H or OH.

63. The compound according to any one of claims 8 to 11, 15, 22, 26 to 36, 56, 61 and 62, wherein R 1a It's H.

64. The compound according to any one of claims 8 to 11, 15, 22, 26 to 36, 56, 61 and 62, wherein R 1a It is OH.

65. The compound according to any one of claims 8 to 11, 15, 22, 26 to 36, 56 and 61 to 64, wherein R 2a It's H.

66. The compound according to any one of claims 8 to 11, 15, 22, 26 to 36, 56 and 61 to 65, wherein R 15a Is it H, halogenated, or C? 1-6 Alkyl group.

67. The compound according to any one of claims 8 to 11, 15, 22, 26 to 36, 56 and 61 to 66, wherein R 15b Is it H or C? 1-6 alkyl.

68. The compound according to any one of claims 8 to 11, 15, 22, 26 to 36, 56 and 61 to 67, wherein R 15 Is it H or C? 1-6 alkyl.

69. The compound according to any one of claims 8 to 11, 15, 22, 26 to 36, 56 and 61 to 68, wherein R 16 Is it H or C? 1-6 alkyl.

70. The compound according to any one of claims 8 to 10, 12, 14 to 16, and 26 to 36, wherein R 17a and R 17b Each is either H or halogenated independently.

71. The compound according to any one of claims 8 to 10, 12, 14 to 16, 26 to 36 and 70, wherein R 17 It is C 1-6 alkyl.

72. The compound according to any one of claims 8 to 10, 12, 14 to 16, 26 to 36, 70 and 71, wherein R 18 It is H.

73. The compound according to any one of claims 1 to 13 and 15 to 72, wherein each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C(O), 5-12 membered heterocyclic alkyl, wherein the 5-12 membered heterocyclic alkyl is optionally halogenated.

74. The compound according to claim 73, wherein the 5-12 membered heterocyclic alkyl group is a fused 8-membered heterocyclic alkyl group.

75. The compound according to any one of claims 1 to 13 and 15 to 72, wherein each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and 6-12-membered heterocyclic alkyl, wherein the 6-12-membered heterocyclic alkyl is optionally halogenated or C-substituted. 1-6 Alkyl substitution.

76. The compound according to any one of claims 1 to 13 and 15 to 72, wherein each L is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, 6-8-membered heterocyclic alkyl and 5-6-membered heteroaryl, wherein the 6-8-membered heterocyclic alkyl is optionally halogenated.

77. The compound according to any one of claims 1 to 13, 15 to 72 and 75, wherein n is 4, and each L forms a connector with the following structure: (C 1-6 alkoxy)-(6-12 membered heterocyclic alkyl)-(C 1-6 Alkyl)-(6-12 membered heterocyclic alkyl).

78. The compound of claim 77, wherein each L forms a connector:

79. The compound according to any one of claims 1 to 13 and 15 to 72, wherein each L is independently selected from O, C 1-6 Alkyl, C 1-6 Alkoxy and 5-12 membered heterocyclic alkyl, wherein the 5-12 membered heterocyclic alkyl is optionally C 1-6 Alkyl substitution.

80. The compound according to any one of claims 1 to 13, 15 to 72 and 79, wherein n is 6, and each L forms a connector: (C 1-6 alkoxy)-(6-12 membered heterocyclic alkyl)-(C 1-6 alkyl)-(6-12 membered heterocyclic alkyl)-(C 1-6 Alkyl)-(6-membered heterocyclic alkyl).

81. The compound according to any one of claims 1 to 13, 15 to 72, 79 and 80, wherein n is 6, and each L forms a connector: (C 1-6 alkoxy)-(6-membered heterocyclic alkyl)-(C 1-6 alkyl)-(6-membered heterocyclic alkyl)-(C 1-6 Alkyl)-(6-membered heterocyclic alkyl).

82. The compound according to any one of claims 1 to 13, 15 to 72 and 79, wherein n is 4, and each L forms a connector: (C 1-6 alkoxy)-(5-12 membered heterocyclic alkyl)-(C 1-6 Alkyl)-(5-12 membered heterocyclic alkyl).

83. The compound according to any one of claims 1 to 13, 15 to 72, 79 and 82, wherein n is 4, and each L forms a connector: (C 1-6 alkoxy)-(11-membered heterocyclic alkyl)-(C 1-6 Alkyl)-(6-membered heterocyclic alkyl).

84. The compound according to any one of claims 83, wherein the 11-membered heterocyclic alkyl group is a spirocyclic 11-membered heterocyclic alkyl group.

85. The compound according to any one of claims 1 to 13, 15 to 72 and 79, wherein n is 6, and each L forms a connector: (C 1-6 alkoxy)-(5-12-membered heterocyclic alkyl)-(O)-(5-12-membered heterocyclic alkyl)-(C 1-6 (alkyl)-(5-12-membered heterocyclic alkyl), wherein the 5-12-membered heterocyclic alkyl is optionally C 1-6 Alkyl substitution.

86. The compound according to any one of claims 1 to 13, 15 to 72, 79 and 85, wherein n is 6, and each L forms a connector: (C 1-6 alkoxy)-(5-membered heterocyclic alkyl)-(O)-(6-membered heterocyclic alkyl)-(C 1-6 alkyl)-(6-membered heterocyclic alkyl), wherein the 5-membered heterocyclic alkyl is optionally C 1-6 Alkyl substitution.

87. The compound according to any one of claims 1 to 13, 15 to 72 and 79, wherein n is 4, and each L forms a connector with the following structure: (C 1-6 alkoxy)-(5-12 membered heterocyclic alkyl)-(C 1-6 Alkyl)-(5-12 membered heterocyclic alkyl).

88. The compound according to any one of claims 1 to 13, 15 to 72, 79 and 87, wherein n is 4, and each L forms a connector: (C 1-6 alkoxy)-(6-membered heterocyclic alkyl)-(C 1-6 Alkyl)-(9-membered heterocyclic alkyl).

89. The compound according to claim 88, wherein the 9-membered heterocyclic alkyl group is a spirocyclic 9-membered heterocyclic alkyl group.

90. The compound according to any one of claims 1 to 13, 15 to 72 and 79, wherein n is 4, and each L forms a connector with the following structure: (C 1-6 alkoxy)-(5-12-membered heterocyclic alkyl)-(O)-(5-12-membered heterocyclic alkyl), wherein the 5-12-membered heterocyclic alkyl is optionally C 1-6 Alkyl substitution.

91. The compound according to any one of claims 1 to 13, 15 to 72, 79 and 90, wherein n is 4, and each L forms a connector: (C 1-6 alkoxy)-(5-membered heterocyclic alkyl)-(O)-(6-membered heterocyclic alkyl), wherein the 5-membered heterocyclic alkyl is optionally C 1-6 Alkyl substitution.

92. The compound according to any one of claims 1 to 13, 15 to 72, and 79 to 91, wherein each L forms a connector:

93. The compound according to any one of claims 1 to 13, 15 to 72, 78 and 92, wherein (L) n Selected from:

94. A compound of formula IVB: Or its pharmaceutically acceptable salt. in: R 1 and R 2 Each is independently selected from H, halogenated, C 1-6 Alkyl and C 2-6 alkynyl group; R 3 Selected from H, halogenated and CN; Each Q L Independently is CR L Or N; Each R L It can be H, halogenated, or CN independently; Each p is 1, 2, 3, 4, 5, or 6; and R 12 and R 13 Each is independently selected from H and C. 1-6 Alkyl and C 1-6 Alkyl group.

95. The compound according to any one of claims 1 to 94, wherein the compound is selected from the compounds in Table 1 or pharmaceutically acceptable salts thereof.

96. A pharmaceutical composition comprising a compound according to any one of claims 1 to 95, and a pharmaceutically acceptable carrier.

97. A method of treating a subject with cancer, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 95 or a pharmaceutical composition according to claim 96.

98. The method according to claim 97, wherein the cancer is selected from bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, uterine cancer, ovarian cancer, testicular cancer, thyroid cancer, pineal cell carcinoma, carcinoma, cell tumor, ependymoma, ganglioglioma, ganglioneuroma, glioblastoma, glioma, leukemia, lymphoma, medulloblastoma, melanoma, meningioma, myeloma, nephroblastoma, neuroblastoma, neurofibroma, oligodendroglioma, peripheral neuroepithelial tumor, sarcoma, and schwannoma.

99. The method of claim 98, wherein the cancer is a teratoma.

100. The method of claim 98, wherein the cytoma is an astrocytoma.

101. The method of claim 98, wherein the carcinoma is selected from squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma.

102. The method according to claim 98, wherein the leukemia is selected from precursor B lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, adult T-cell leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia, Philadelphia chromosome-positive chronic myeloid leukemia, and acute lymphoblastic leukemia.

103. The method according to claim 98, wherein the lymphoma is selected from Burkitt lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, precursor T-lymphoblastic lymphoma, peripheral T-cell lymphoma, precursor lymphoblastic lymphoma, diffuse large B-cell lymphoma, and B-cell lymphoma.

104. The method of claim 98, wherein the nephroblastoma is Wilms' tumor.

105. The method according to claim 98, wherein the sarcoma is selected from carcinosarcoma, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myoma, synovial sarcoma, and medullary sarcoma.

106. A method for degrading a target protein in a cell, the method comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 95 or a pharmaceutical composition according to claim 96, wherein the compound achieves the degradation of the target protein.

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