Cereblon-based KRAS-degrading PROTAC and related applications

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 592,814, filed October 24, 2023, U.S. Provisional Patent Application No. 63 / 486,528, filed February 23, 2023, and U.S. Provisional Patent Application No. 63 / 481,672, filed January 26, 2023, which are incorporated by reference herein in their entireties. [Background technology]

[0002] Cereblon, an E3 ubiquitin ligase mimic, confers substrate specificity to ubiquitination. Its specificity for specific protein substrates makes it a more attractive therapeutic target than general proteasome inhibitors. For example, bifunctional compounds, such as those described in U.S. Patent Application Publication Nos. 2015 / 0291562 and 2014 / 0356322 (both of which are incorporated herein by reference), function to recruit endogenous proteins to E3 ubiquitin ligases for ubiquitination and degradation. Specifically, these publications describe bifunctional or proteolytic targeted chimeric compounds (PROTAC® protein degraders), which have found utility as modulators of targeted ubiquitination of various polypeptides and proteins, followed by degradation by the proteasome system. These bifunctional compounds function to recruit endogenous proteins to E3 ubiquitin ligases for degradation. In particular, the patent publication describes bifunctional, or proteolysis targeting chimeric (PROTAC) compounds that find utility as modulators of targeted ubiquitination of various polypeptides and other proteins, which are then degraded and / or otherwise inhibited by the bifunctional compounds.

[0003] The Kirsten rat sarcoma (KRAS) gene is an oncogene that encodes KRas, a small GTPase signaling protein. Ras proteins associate with the cell membrane and act as switches to transduce extracellular signals into intracellular responses, such as regulating cell division. Numerous activating or gain-of-function mutations are known in the KRas gene, and KRas is indeed the most commonly mutated gene in cancer. Gain-of-function KRas mutations have been found in approximately 30% of all human cancers, including pancreatic cancer (over 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. It has been demonstrated that KRas mutants play an important role in the initiation, maintenance, progression, and metastasis of various cancers. Mutations are often correlated with increased resistance to chemotherapy and biological therapies, such as those targeting the epidermal growth factor receptor, and poor prognosis. Despite its importance in cancer and the high incidence of mutations, there are no effective therapies that directly target this oncogene, and it is therefore considered "undruggable."

[0004] There is a continuing need in the art for effective treatments for diseases associated with overexpression, aggregation and / or overactivation of KRas. Summary of the Invention

[0005] Provided herein are compounds that target KRas and are therefore useful in the treatment of cancer. As used herein, a compound of any one of formulas I to IV: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0006] Also provided herein are compounds of formula V and VI: [ka] or a pharmaceutically acceptable salt thereof.

[0007] In certain embodiments, provided herein are compounds of formula AI or AIV: [ka] or a pharmaceutically acceptable salt thereof.

[0008] In another aspect, there is provided herein a compound of formula VII: [ka] or a pharmaceutically acceptable salt thereof is provided.

[0009] In embodiments, the compound of formula I has the structure of formula IA: [ka] or a pharmaceutically acceptable salt thereof.

[0010] In embodiments, the compound of formula I has the structure of formula IB: [ka] or a pharmaceutically acceptable salt thereof.

[0011] In embodiments, the compound of formula IB-i has the structure of formula IB-i: [ka] or a pharmaceutically acceptable salt thereof.

[0012] In embodiments, the compound of formula II has the structure of formula IIA: [ka] or a pharmaceutically acceptable salt thereof.

[0013] In embodiments, the compound of formula II has the structure of formula IIB: [ka] or a pharmaceutically acceptable salt thereof.

[0014] In embodiments, the compound of formula III has the structure of formula IIIA: [ka] or a pharmaceutically acceptable salt thereof.

[0015] In embodiments, the compound of formula IV has the structure of formula IVA: [ka] or a pharmaceutically acceptable salt thereof.

[0016] In embodiments, the compound of formula V has the structure of formula VA: [ka] or a pharmaceutically acceptable salt thereof.

[0017] In embodiments, the compound of formula VI has the structure of formula VIA: [ka] or a pharmaceutically acceptable salt thereof.

[0018] In yet another aspect, there is provided herein a compound of formula IVB: [ka] or a pharmaceutically acceptable salt thereof is provided.

[0019] Also provided herein are methods of treating or ameliorating symptoms or conditions that are modulated through or causally associated with a target protein, such as KRas.

[0020] Further provided herein are methods comprising treating a disease or disorder in a subject, the methods comprising administering to the subject an effective amount of a compound disclosed herein, or a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0021] In embodiments, the disease or disorder is cancer.

[0022] Also provided herein are methods for regulating the activity of a KRas protein, the methods comprising administering to a subject an effective amount of any of the compounds disclosed herein or pharmaceutical salts thereof, or an effective amount of a pharmaceutical composition comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier.

[0023] Also provided herein are methods for regulating the activity of cereblon protein, the methods comprising administering to a subject an effective amount of any of the compounds disclosed herein or pharmaceutical salts thereof, or an effective amount of a pharmaceutical composition comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier.

[0024] Also provided herein is a method for degrading a target protein in a cell, the method comprising contacting the cell with an effective amount of any of the compounds disclosed herein or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier. [Brief explanation of the drawings]

[0025] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several embodiments of the present disclosure and, together with the description herein, serve to explain the principles of the present disclosure. The drawings are only for the purpose of illustrating embodiments of the present disclosure and are not to be construed as limiting the present disclosure. Further objects, features, and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings showing exemplary embodiments of the present disclosure.

[0026] [Figure 1] FIG. 1 shows HiBiT degradation of various KRAS cells treated with compound 69. [Figure 2] FIG. 2 shows cell-free ubiquitination of KRAS G12D treated with compounds according to one or more embodiments of the present disclosure. [Figure 3A] Figures 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. [Figure 3B] Figures 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. [Figure 4A] Figures 4A and 4B. (A) pERK inhibition over time in AsPC-1 spheroids treated with G12D compound 69. (B) pERK inhibition over time in AsPC-1 spheroids treated with E3-inactive compound 69. [Figure 4B] Figures 4A and 4B. (A) pERK inhibition over time in AsPC-1 spheroids treated with G12D compound 69. (B) pERK inhibition over time in AsPC-1 spheroids treated with E3-inactive compound 69. [Figure 5]FIG. 5 shows caspase 3 / 7 activity in GP2d spheroids treated with G12D Compound 69, E3-inactive Compound 69, and KRAS-inactive Compound 69 after 16 hours. [Figure 6A] 6A and 6B (A) KRAS levels and cPARP induction in GP2d tumors treated with a single dose of G12D compound 69. (B) Tumor concentration and KRAS levels in GP2d tumors treated with a single dose of G12D compound 69. [Figure 6B] 6A and 6B (A) KRAS levels and cPARP induction in GP2d tumors treated with a single dose of G12D compound 69. (B) Tumor concentration and KRAS levels in GP2d tumors treated with a single dose of G12D compound 69. [Figure 7A] 7A and 7B(A) are graphs of the growth volume of GP2d tumors after treatment with vehicle or compound 69. (B) XB are graphs of the growth volume of GP2d tumors after treatment with vehicle or compound 102. [Figure 7B] 7A and 7B(A) are graphs of the growth volume of GP2d tumors after treatment with vehicle or compound 69. (B) XB are graphs of the growth volume of GP2d tumors after treatment with vehicle or compound 102. [Figure 8] FIG. 8 is a graph of the growth volume of LS180 tumors after treatment with vehicle or Compound 102. [Figure 9A] 9A and 9B (A) is a graph of the growth volume of AsPC-1 tumors after treatment with vehicle or compound 69. (B) is a graph of the growth volume of AsPC-1 tumors after treatment with vehicle or compound 102. [Figure 9B] 9A and 9B (A) is a graph of the growth volume of AsPC-1 tumors after treatment with vehicle or compound 69. (B) is a graph of the growth volume of AsPC-1 tumors after treatment with vehicle or compound 102. [Figure 10A]10A and 10B (A) is a graph of the growth volume of SW1990 tumors after treatment with vehicle or Compound 69. (B) is a graph of the growth volume of SW1990 tumors after treatment with vehicle or Compound 102. [Figure 10B] 10A and 10B (A) is a graph of the growth volume of SW1990 tumors after treatment with vehicle or Compound 69. (B) is a graph of the growth volume of SW1990 tumors after treatment with vehicle or Compound 102. [Figure 11] FIG. 11 is a graph of HPAC tumor growth volume after treatment with vehicle or Compound 69. [Figure 12] FIG. 12 is a graph of the growth volume of Panc04.03 tumors after treatment with vehicle or Compound 69. DETAILED DESCRIPTION OF THE INVENTION

[0027] definition Listed below are definitions of various terms used to describe the compounds and compositions disclosed herein. These definitions apply to the terms as they are used throughout the specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0028] 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. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those known and commonly employed in the art.

[0029] Specific compounds of the present invention may be identified herein by chemical name and / or chemical structure. In the event of any discrepancy between the chemical name and the chemical structure, the chemical structure shall prevail.

[0030] As used herein, articles such as "a" and "an" refer to one or to more than one (i.e., at least one) of the grammatical object of the article. By way of example, an "element" means one element or more than one element. Furthermore, the use of the term "including," as well as other forms of a term, such as "include," "includes," and "included," is not limiting.

[0031] As used herein, the term "about" is understood by those of skill in the art and will vary to some extent depending on the context in which the term is used. As used herein, when referring to a measurable value, such as an amount, duration, etc., the term "about" is meant to encompass a variation of ±20% or ±10%, including ±5%, ±1%, and ±0.1%, from the specified value, where such variation is appropriate to perform the disclosed methods.

[0032] As used herein, the term "administration" refers to providing a therapeutic agent to a subject. There are several techniques in the art for administering therapeutic agents, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, ocular administration, pulmonary administration, and topical administration.

[0033] The terms "treat," "treated," "treating," or "treatment" include reducing or alleviating at least one symptom associated with or caused by the condition, disorder, or disease being treated. In certain embodiments, treatment includes alleviating the symptoms of cancer.

[0034] As used herein, the term "prevent" or "prevention" means that if a disorder or disease has not occurred, the disorder or disease will not develop, or if a disorder or disease has already developed, the disorder or disease will not develop further. Also contemplated is the ability to prevent some or all of the symptoms associated with a disorder or disease.

[0035] As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In embodiments, an ex vivo cell may be part of a tissue sample excised from an organism, such as a mammal. In embodiments, an in vitro cell may be a cell in cell culture. In embodiments, an in vivo cell is a cell that resides in an organism, such as a mammal.

[0036] As used herein, the term "subject" refers to a human or non-human mammal. Non-human mammals include, for example, livestock and pets, such as sheep, cows, pigs, dogs, cats, and marine mammals. Preferably, the subject is a human.

[0037] As used herein, the terms "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to produce a desired biological result. The result may be a reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0038] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not interfere with the biological activity or properties of the compound and that is relatively non-toxic, i.e., the material may be administered to an individual without producing undesired biological effects or deleteriously interacting with any of the components of the composition in which it is contained.

[0039] As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds, 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 or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts of the present disclosure include standard non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present disclosure can be synthesized from parent compounds containing a basic or acidic moiety by standard chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred. The term "pharmaceutically acceptable salt" is not limited to mono- or 1:1 salts. For example, "pharmaceutically acceptable salts" also includes bis-salts, such as bis-hydrochlorides. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17 th ed., 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.

[0040] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the present disclosure and a pharmaceutically acceptable carrier. A pharmaceutical composition facilitates administration of a compound to a subject. There are multiple techniques in the art for administering a compound, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, ocular administration, pulmonary administration, and topical administration.

[0041] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating substance that is involved in carrying or transporting a compound useful within the present disclosure into or to a subject so that it can perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a formulation containing a compound useful within the present disclosure and not harmful to the subject. Some examples of materials which 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 carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; 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 glycerin, 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; ethyl alcohol; phosphate buffer solutions; and other non-toxic, compatible substances employed in pharmaceutical formulations.

[0042] As used herein, "pharmaceutically acceptable carrier" also includes any and all coating agents, antibacterial and antifungal agents, and absorption delaying agents that are compatible with the activity of the compounds useful within the present disclosure and are physiologically compatible with the subject. Supplementary active compounds can also be incorporated into the composition. "Pharmaceutically acceptable carrier" can also include pharmaceutically acceptable salts of the compounds disclosed herein. Other additional ingredients that can be included in pharmaceutical compositions are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA). This document is incorporated herein by reference.

[0043] As used herein, the term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical having the number of carbon atoms specified (i.e., C 1-6 Alkyl means alkyl having 1 to 6 carbon atoms, including straight or branched chain. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. 1-6 Other examples of alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0044] The term "alkenyl," when employed alone or in combination with other terms, refers to a straight- or branched-chain hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. An alkenyl group formally corresponds to an alkene in which one C—H bond is replaced by the point of attachment of the alkenyl group to the remainder of the compound. n-mThe term "alkenyl" refers to an alkenyl group having n to m carbons. 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, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0045] The term "alkynyl," when employed alone or in combination with other terms, refers to a straight- or branched-chain hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. An alkynyl group formally corresponds to an alkyne in which one C—H bond is replaced by the point of attachment of the alkyl group to the remainder of the compound. n-m The term "alkynyl" refers to an alkynyl group having n to m carbons. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0046] As used herein, the term "haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halo substituents, where alkyl and halo are as defined herein. Haloalkyl includes, by way of example only, chloromethyl, trifluoromethyl, bromoethyl, chlorofluoroethyl, and the like.

[0047] As used herein, unless otherwise stated, the terms “halo” or “halogen,” by themselves or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom, preferably a fluorine, chlorine, or bromine atom, and more preferably a fluorine or chlorine atom.

[0048] As used herein, the term "cycloalkyl" refers to a fully saturated, non-aromatic carbocyclic ring system having one, two, or three rings, in which case the rings may be fused. The term "fused" means that a second ring is present (i.e., linked or formed) by having two adjacent atoms common (i.e., shared) with the first ring. Cycloalkyl also includes bicyclic structures that may be bridged or spirocyclic in nature, with the individual rings within the bicycle varying from 3 to 8 atoms. The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptanyl, and bicyclo[1.1.1]pentyl. In embodiments, cycloalkyl refers to any of the C 3-10 In another embodiment, cycloalkyl refers to C 3-6 Refers to cycloalkyl.

[0049] As used herein, the term "heterocycloalkyl" refers to a non-aromatic carbocyclic ring system having one, two, or three rings containing one, two, or three heteroatoms, independently selected from N, O, and S, where the rings may be fused, where fused is defined above. The term "heterocycloalkyl" includes unsaturated compounds such as dihydropyridinyl, dihydropyridazinyl, dihydropyrimidinyl, and dihydropyrazinyl. Heterocycloalkyl also includes bicyclic structures that may be bridged or spirocyclic in nature, where the individual rings within the bicycle vary from 3 to 8 atoms and contain 0, 1, or 2 N, O, or S atoms.The term "heterocycloalkyl" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), and specifically includes, but is not limited to, epoxydyl, oxetanyl, tetrahydro-furanyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, 2-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 6-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 4-azabicyclo[3.1.1]hept ...3-azabi ]heptanyl, 2-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, 2-oxa-5-azabicyclo[3.2.1]octanyl Examples include azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.5]nonanyl, 3-oxaspiro[5.3]nonanyl, and 8-oxabicyclo[3.2.1]octanyl. In embodiments, heterocycloalkyl refers to 3- to 12-membered heterocycloalkyl. In embodiments, heterocycloalkyl refers to 6- to 12-membered heterocycloalkyl. In embodiments, heterocycloalkyl refers to 3- to 10-membered heterocycloalkyl. In embodiments, heterocycloalkyl refers to 6- to 8-membered heterocycloalkyl. In embodiments, heterocycloalkyl refers to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl refers to a 7-membered heterocycloalkyl. In some embodiments, heterocycloalkyl refers to a 9-membered heterocycloalkyl.In several embodiments, heterocycloalkyl refers to a 9-membered heterocycloalkyl.

[0050] A 6-membered heterocycloalkyl ring is a heteroaryl group having 6 ring atoms, in which one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 6-membered ring heterocycloalkyls include piperidinyl, piperazinyl, dioxanyl, dithianyl, morpholinyl, thiomorpholinyl, and dihydropyridinyl.

[0051] A 7-membered heterocycloalkyl ring is a heteroaryl group having 7 ring atoms, in which one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 7-membered ring heterocycloalkyls include azepinyl, oxepanyl, thiepanyl, oxathiepanyl, diazaspiro[3.3]heptanyl, and azaspiro[3.3]heptanyl.

[0052] A 9-membered heterocycloalkyl ring is a heterocycloalkyl group having 9 ring atoms, in which one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 9-membered ring heterocycloalkyls include 2-azaspiro[3.5]nonanyl and 2,7-diazaspiro[3.5]nonanyl.

[0053] An 11-membered heterocycloalkyl ring is a heteroaryl group having 11 ring atoms, in which one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 11-membered ring heterocycloalkyls include 3,9-diazaspiro[5.5]undecanyl and 3-azaspiro[5.5]undecanyl.

[0054] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring with one or more polyunsaturated rings and having aromatic properties, i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer.

[0055] As used herein, the term "aryl" refers to an aromatic carbocyclic ring system containing one, two, or three rings, where the rings may be fused, where fused is defined above. If the rings are fused, one of the rings must be fully unsaturated, and the fused ring may be fully saturated, partially unsaturated, or fully unsaturated. The term "aryl" includes, but is not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl. In some embodiments, an aryl group has 6 carbon atoms. In embodiments, an aryl group has 6 to 10 carbon atoms. In embodiments, an aryl group has 6 to 16 carbon atoms. In embodiments, an aryl group has 6 to 10 carbon atoms.

[0056] As used herein, the term "heteroaryl" means an aromatic carbocyclic ring system having one, two, or three rings containing one, two, three, or four heteroatoms, independently selected from N, O, and S, in which the rings may be fused, where fused is defined above. The term "heteroaryl" includes, but is not limited to, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-cyclopenta-[c ]pyridinyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[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]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydro-1H-indazolyl, and 4,5,6,7-tetrahydro-2H-indazolyl. In embodiments, heteroaryl is a 5- to 10-membered heteroaryl. In several embodiments, heteroaryl is a 5- to 7-membered heteroaryl. In some embodiments, the heteroaryl is a 6-7 membered heteroaryl. In some embodiments, the heteroaryl is a 6 membered heteroaryl.

[0057] A 5-membered heteroaryl ring is a heteroaryl group having 5 ring atoms, in which one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 5-membered ring heteroaryls include thienyl, furyl, 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.

[0058] A 6-membered heteroaryl ring is a heteroaryl group having 6 ring atoms, in which one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 6-membered ring heteroaryls include pyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

[0059] Where an aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety can be attached or otherwise attached to the designated moiety through different ring atoms (i.e., shown or described without a specific point of attachment being indicated), it is understood that all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridinyl" means 2-, 3-, or 4-pyridinyl, and the term "thienyl" means 2- or 3-thienyl.

[0060] As used herein, the term "independently selected" is used to indicate that, for a variable that is present at multiple positions within a genus, the identity of the variable is determined separately in each instance. For example, R is selected as a substituent on two different atoms. x When appears, two R xThe instances of R may be the same or different moieties. x This also applies when the cases are replaced with the cases of R x The identity of is determined independently of other identities.

[0061] compound Provided herein are compounds that target KRas and are therefore useful in the treatment of cancer.

[0062] In particular, herein, a compound of any one of formulas I to IV: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q 1 is C(R 14 )2, C(O), and NR 14 is selected from Q 2 is CR 14 or N, R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 3 H, halo, CN, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 4 is C 3-11 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 3- to 10-membered heteroaryl, wherein C 3-11 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10Aryl and 3- to 10-membered heteroaryl are optionally R 4a is replaced by R 4a is H, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 5a , R 5 , R 6 , R 8 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 7 H, =O, halo, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 9 H, halo, 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 bond or C 1-6 is alkyl, Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 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 heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In embodiments of Formulas I-IV, Q 1 is C(R 14 )2 or C(O), Q 2 is N, R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, R 3 is selected from H, halo and CN; R 4 is C 3-11 cycloalkyl or 3- to 10-membered heterocycloalkyl, in which case C 3-11 Cycloalkyl and 3- to 10-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 5a , R 5 , R 6 , R 8 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently H, halo, and C 1-6 Alkyl, and C 1-6 alkoxy; R 7 H, =O, halo, C 1-6 Alkyl, and C 1-6 alkoxy; R 9 H, halo, C 1-6 Alkyl, and C 1-6 alkoxy; Ring A is selected from phenyl, 6-membered heteroaryl, and 6-membered heterocycloalkyl; B is a bond or C 1-6 is alkyl, Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 3-11 cycloalkyl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0063] In some embodiments of Formulas I-IV, Q 1 is C(R 14 )2 or C(O), Q 2 is N, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 6-8 cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 5a , R 5 , R 6 , R 8 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently H, halo, and C 1-6 Alkyl, and C 1-6 alkoxy; R 7 H, =O, halo, C 1-6Alkyl, and C 1-6 alkoxy; R 9 H, halo, C 1-6 Alkyl, and C 1-6 alkoxy; Ring A is phenyl or 6-membered heterocycloalkyl; B is a bond or C 1-6 is alkyl, Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 4-7 cycloalkyl, 5- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0064] In certain embodiments, the compound has Formula I: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q 1 is C(R 14 )2 or C(O), R 1 and R 2 are independently halo, C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 6-8 cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6is alkyl, R 5a , R 5 , R 6 , and R 14 are independently H, halo, and C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), 5-12 membered heterocycloalkyl, and 6-7 membered heteroaryl, wherein the 5-12 membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0065] In another embodiment, the compound has formula II: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q 2 is N, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 6-8 cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 8 and R 14 are independently H, halo, and C 1-6 Alkyl, and C1-6 alkoxy; R 7 H, =O, halo, C 1-6 Alkyl, and C 1-6 alkoxy; Ring A is phenyl or 6-membered heterocycloalkyl; B is a bond or C 1-6 is alkyl, Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 4-7 cycloalkyl, 5- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0066] In yet another embodiment, the compound has formula III: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 6-8 cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 10 and R 11are independently H, halo, and C 1-6 Alkyl, and C 1-6 alkoxy; R 9 H, halo, C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 4-7 cycloalkyl, 5- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0067] In yet another embodiment, the compound has formula IV: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 6-8 cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 12 and R 13 are independently H, halo, and C 1-6 Alkyl, and C 1-6alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 4-7 cycloalkyl, 5- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, or 6. Also provided herein are compounds of formula V and VI: [ka] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q 1 is C(R 14 )2, C(O), and NR 14 is selected from Q 3 is CR 14 or N, R 1a and R 2a are each independently selected from OH, H, and halo; R 1b and R 2b are each independently halo and C 3-6 cycloalkyl; or R 1b and R 2b together with the phenyl to which they are attached, C 8-12 Forming an aryl, in this case C 8-12 Aryl is optionally R 1 and R 2 is replaced by R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 3 H, halo, CN, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 4 is C 3-11 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 3- to 10-membered heteroaryl, wherein C 3-11 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 3- to 10-membered heteroaryl optionally have 1 to 2 R 4a is replaced by Each R 4a are independently H, OH, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 14 , R 15a , R 15b , R 15 , R 16 , R 17a , R 17b , R 17 , and R 18 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 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 heterocycloalkyl is optionally selected from halo, CN, and C1-6 substituted with 1 or 2 substituents independently selected from alkyl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0068] In certain embodiments, the compound has formula V: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q 1 is C(R 14 )2 or C(O), Q 3 is CH or N, R 1a and R 2a are each independently selected from H, OH, and halo; R 1b and R 2b together with the phenyl to which they are attached, R 1 and R 2 forming a naphthyl substituted with R 1 and R 2 are independently H, halo, and C 1-3 Alkyl, C 3-5 cycloalkyl, and C≡CH; R 3 is H or halo, R 4 is C 6-8 cycloalkyl and 6- to 8-membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl optionally contain one or two R 4a is replaced by Each R 4a are independently H, OH, and C 1-6 alkyl, R 14 , R 15 , and R 16 are independently H, halo, and C 1-3Alkyl, and C 1-3 alkoxy; R 15a and R 15b are independently halo, C 1-3 Alkyl, and C 1-3 alkoxy; Each L is independently 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- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 substituted with 1 or 2 substituents independently selected from alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0069] In another embodiment, the compound has formula VI: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 and R 2 are independently H, halo, and C 1-3 Alkyl, C 3-5 cycloalkyl, and C≡CH; R 3 is H or halo, R 4 is C 6-8 cycloalkyl and 6- to 8-membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl optionally contain one or two R 4a is replaced by Each R 4a are independently H, OH, and C 1-6 alkyl, R 17a , R17b , R 17 , and R 18 are independently H, halo, and C 1-3 Alkyl, and C 1-3 alkoxy; Each L is independently 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- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 substituted with 1 or 2 substituents independently selected from alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0070] In certain embodiments, provided herein are compounds of formula AI or AIV: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q 1 is C(R 14 )2, C(O), and NR 14 is selected from Q 2 is CR 14 or N, R 1 and R 2 are each independently a halo or C 2-6 is alkynyl, R 3 H, halo, CN, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 4 is C 3-11 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10aryl, and 3- to 10-membered heteroaryl, wherein C 3-11 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 3- to 10-membered heteroaryl are optionally R 4a is replaced by R 4a is H, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 5a , R 5 , R 6 , R 12 , R 13 , and R 14 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 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 heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0071] In another aspect, there is provided herein a compound of formula VII: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring B and ring C are each independently 3 to 12-membered heterocycloalkyl, C 6-10aryl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, Ring D is a bond, C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 substituted with alkyl, provided that when ring D is a bond, Y 2 is also a bond and t is 0, Y 1 and Y 2 are each independently a bond, O, C(O), N(H), or N(C 1-6 alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; Z is N(H), N(C 1-6 alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 3 H, halo, CN, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 4 is C 3-11 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 3- to 10-membered heteroaryl, wherein C 3-11Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 3- to 10-membered heteroaryl are optionally R 4a is replaced by R 4a is H, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 17a , R 17b , R 17 , and R 18 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; s and t are each independently 0, 1, 2, or 3; and u is 1 or 2.

[0072] In embodiments of Formulas I-VI, Q 1 is C(R 14 )2 or C(O), Q 2 is N, Q 3 is CR 14 or N, R 1a and R 2a are each independently selected from OH, H, and halo; R 1b and R 2b together with the phenyl to which they are attached, C 8-12 Forming an aryl, in this case C 8-12 Aryl is optionally R 1 and R 2 is replaced by R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, R 3 is selected from H, halo and CN; R 4 is C 3-11 cycloalkyl and 3- to 10-membered heterocycloalkyl, wherein C 3-11 Cycloalkyl and 3- to 10-membered heterocycloalkyl optionally contain one or two R 4a is replaced by Each R 4a are independently H, OH, and C 1-6 alkyl, 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 are independently H, halo, and C 1-6 Alkyl, and C 1-6 alkoxy; R 7 H, =O, halo, C 1-6 Alkyl, and C 1-6 alkoxy; R 9 H, halo, C 1-6 Alkyl, and C 1-6 alkoxy; Ring A is selected from phenyl, 6-membered heteroaryl, and 6-membered heterocycloalkyl; B is a bond or C 1-6 is alkyl, Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 3-11cycloalkyl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0073] In embodiments of Formulas I-VI, Q 1 is C(R 14 )2 or C(O), Q 2 is N, Q 3 is CR 14 or N, R 1a and R 2a are each independently selected from H, OH, and halo; R 1b and R 2b together with the phenyl to which they are attached, R 1 and R 2 forming a naphthyl substituted with R 1 and R 2 are independently H, halo, and C 1-3 Alkyl, C 3-5 cycloalkyl, and C≡CH; R 3 is H or halo, R 4 is C 6-8 cycloalkyl and 6- to 8-membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl optionally contain one or two R 4a is replaced by Each R 4a are independently H, OH, and C 1-6 alkyl, R 5a , R 5 , R 6 , R 8 , R 10 , R11 , R 12 , R 13 , R 14 , R 15a , R 15b , R 15 , R 16 , R 17a , R 17b , R 17 , and R 18 are independently H, halo, and C 1-3 Alkyl, and C 1-3 alkoxy; R 7 H, =O, halo, C 1-6 Alkyl, and C 1-6 alkoxy; R 9 H, halo, C 1-6 Alkyl, and C 1-6 alkoxy; Ring A is phenyl or 6-membered heterocycloalkyl; B is a bond or C 1-6 is alkyl, Each L is independently 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- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0074] In an embodiment of Formula I, Q 1 is C(R 14 )2 or C(O), R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3is selected from H, halo and CN; R 4 is C 3-11 cycloalkyl or 3- to 10-membered heterocycloalkyl, in which case C 3-11 Cycloalkyl and 3- to 10-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 5a , R 5 , R 6 , and R 14 are independently H, halo, and C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 3-11 cycloalkyl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0075] In an embodiment of Formula I, Q 1 is C(R 14 )2 or C(O), R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 6-8 cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R 4ais replaced by R 4a is H or C 1-6 is alkyl, R 5a , R 5 , R 6 , and R 14 are independently H, halo, and C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 4-7 cycloalkyl, 5- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0076] In an embodiment of Formula II, Q 2 is N, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 3-11 cycloalkyl or 3- to 10-membered heterocycloalkyl, in which case C 3-11 Cycloalkyl and 3- to 10-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 7 H, =O, halo, C 1-6 Alkyl, and C 1-6 alkoxy; R 8 is H, C1-6 Alkyl, and C 1-6 alkoxy; Ring A is selected from phenyl, 6-membered heteroaryl, and 6-membered heterocycloalkyl; B is a bond or C 1-6 is alkyl, Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 3-11 cycloalkyl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0077] In an embodiment of Formula II, Q 2 is N, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 6-8 cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 7 H, =O, halo, C 1-6 Alkyl, and C 1-6 alkoxy; R 8 is H, C 1-6 Alkyl, and C 1-6 alkoxy; Ring A is phenyl or 6-membered heterocycloalkyl; B is a bond or C 1-6 is alkyl, Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 4-7 cycloalkyl, 6- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 6- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0078] In an embodiment of Formula III, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 3-11 cycloalkyl or 3- to 10-membered heterocycloalkyl, in which case C 3-11 Cycloalkyl and 3- to 10-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 9 H, halo, C 1-6 Alkyl, and C 1-6 alkoxy; R 10 and R 11 are independently H, C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C3-11 cycloalkyl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0079] In an embodiment of Formula III, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 6-8 cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 9 H, halo, C 1-6 Alkyl, and C 1-6 alkoxy; R 10 and R 11 are independently H, C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 4-7 cycloalkyl, 6- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 6- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0080] In an embodiment of Formula IV, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 3-11 cycloalkyl or 3- to 10-membered heterocycloalkyl, in which case C 3-11 Cycloalkyl and 3- to 10-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 12 and R 13 are independently H, C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 3-11 cycloalkyl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0081] In an embodiment of Formula IV, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 6-8cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 12 and R 13 are independently H, C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 4-7 cycloalkyl, 6- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 6- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0082] In an embodiment of Formula IV, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 6-8 cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 12 and R 13 are independently H, halo, and C 1-6 Alkyl, and C 1-6alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), 5-12 membered heterocycloalkyl, and 6-7 membered heteroaryl, wherein the 5-12 membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0083] In an embodiment of Formula V, Q 1 is C(R 14 )2 or C(O), Q 3 is CR 14 or N, R 1a and R 2a are each independently selected from OH, H, and halo; R 1b and R 2b together with the phenyl to which they are attached, C 8-12 Forming an aryl, in this case C 8-12 Aryl is optionally R 1 and R 2 is replaced by R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, R 3 is selected from H, halo and CN; R 4 is C 3-11 cycloalkyl and 3- to 10-membered heterocycloalkyl, wherein C 3-11 Cycloalkyl and 3- to 10-membered heterocycloalkyl optionally contain one or two R 4a is replaced by Each R4a are independently H, OH, and C 1-6 alkyl, R 14 , R 15a , R 15b , R 15 , and R 16 are independently H, halo, and C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 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 heterocycloalkyl is optionally selected from halo, CN, and C 1-6 substituted with 1 or 2 substituents independently selected from alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0084] In an embodiment of Formula V, Q 1 is C(R 14 )2 or C(O), Q 3 is CH or N, R 1a and R 2a are each independently selected from H, OH, and halo; R 1b and R 2b together with the phenyl to which they are attached, R 1 and R 2 forming a naphthyl substituted with R 1 and R 2 are independently H, halo, and C 1-3 Alkyl, C 3-5 cycloalkyl, and C≡CH; R 3 is H or halo, R 4 is C 6-8 cycloalkyl and 6- to 8-membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl optionally contain one or two R 4a is replaced by Each R 4a are independently H, OH, and C 1-6 alkyl, R 14 , R 15a , R 15b , R 15 , and R 16 are independently H, halo, and C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 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- to 12-membered heterocycloalkyl, and 5- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 substituted with 1 or 2 substituents independently selected from alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0085] In an embodiment of Formula VI, R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, R 3 is selected from H, halo and CN; R 4 is C 3-11cycloalkyl and 3- to 10-membered heterocycloalkyl, wherein C 3-11 Cycloalkyl and 3- to 10-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 17a , R 17b , R 17 , and R 18 are independently H, halo, and C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 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 heterocycloalkyl is optionally selected from halo, CN, and C 1-6 substituted with 1 or 2 substituents independently selected from alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0086] In an embodiment of Formula VI, R 1 and R 2 are independently H, halo, and C 1-3 alkyl, and C≡CH; R 3 is H or halo, R 4 is C 6-8 cycloalkyl and 6- to 8-membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R 4a is replaced by R 4ais H or C 1-6 is alkyl, R 17a , R 17b , R 17 , and R 18 are independently H, halo, and C 1-3 Alkyl, and C 1-3 alkoxy; Each L is independently 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- to 12-membered heterocycloalkyl, and 5- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 substituted with 1 or 2 substituents independently selected from alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0087] In an embodiment of Formula VI, R 1 and R 2 are independently H, halo, and C 1-3 Alkyl, C 3-5 cycloalkyl, and C≡CH; R 3 is H or halo, R 4 is C 6-8 cycloalkyl and 6- to 8-membered heterocycloalkyl, wherein C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl optionally contain one or two R 4a is replaced by Each R 4a are independently H, OH, and C 1-6 alkyl, R 17a , R 17b , R 17 , and R 18 are independently H, halo, and C 1-3 Alkyl, and C1-3 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), 5-12 membered heterocycloalkyl, and 6-7 membered heteroaryl, wherein the 5-12 membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 substituted with 1 or 2 substituents independently selected from alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0088] In an embodiment of formula AI, Q 1 is C(R 14 )2 or C(O), R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 3-11 cycloalkyl or 3- to 10-membered heterocycloalkyl, in which case C 3-11 Cycloalkyl and 3- to 10-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 5a , R 5 , R 6 , and R 14 are independently H, halo, and C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 3-11cycloalkyl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0089] In an embodiment of formula AI, Q 1 is C(R 14 )2 or C(O), R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 6-8 cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 5a , R 5 , R 6 , and R 14 are independently H, halo, and C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 4-7 cycloalkyl, 5- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0090] In an embodiment of Formula AIV, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 3-11 cycloalkyl or 3- to 10-membered heterocycloalkyl, in which case C 3-11 Cycloalkyl and 3- to 10-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 12 and R 13 are independently H, C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 3-11 cycloalkyl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0091] In an embodiment of Formula AIV, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 6-8cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 12 and R 13 are independently H, C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 4-7 cycloalkyl, 6- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 6- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0092] In an embodiment of Formula AIV, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 3 is selected from H, halo and CN; R 4 is C 6-8 cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 12 and R 13 are independently H, halo, and C 1-6 Alkyl, and C 1-6alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), 5-12 membered heterocycloalkyl, and 6-7 membered heteroaryl, wherein the 5-12 membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0093] In an embodiment of Formula VII, ring B and ring C are each independently selected from 3- to 6-membered heterocycloalkyl and 5- or 6-membered heteroaryl, wherein the 3- to 6-membered heterocycloalkyl is optionally selected from halo, CN, and C. 1-6 is substituted with alkyl, Ring D is selected from a bond, a 3- to 6-membered heterocycloalkyl, and a 5- or 6-membered heteroaryl, wherein the 3- to 6-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 substituted with alkyl, provided that when ring D is a bond, Y 2 is also a bond and t is 0, Y 1 and Y 2 are each independently a bond, O, C(O), N(H), or N(C 1-6 alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; Z is N(H), N(C 1-6 alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, and C1-6 haloalkyl; R 3 H, halo, CN, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 4 is optionally R 4a is a 6- to 8-membered heterocycloalkyl substituted with R 4a is H, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 17a , R 17b , R 17 , and R 18 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; s and t are each independently 0, 1, 2, or 3; and u is 1 or 2.

[0094] In an embodiment of Formula VII, ring B and ring C are each independently optionally selected from halo, CN and C 1-6 a 3- to 6-membered heterocycloalkyl substituted with alkyl; Ring D is a bond or optionally halo, CN and C 1-6 and 3-6 membered heterocycloalkyl substituted with alkyl, provided that when ring D is a bond, Y 2 is also a bond and t is 0, Y 1 and Y 2 are each independently a bond, O, C(O), N(H), or N(C 1-6 alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; Z is N(H), N(C 1-6 alkyl), C 1-6Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 3 H, halo, CN, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 4 is optionally R 4a is a 6- to 8-membered heterocycloalkyl substituted with R 4a is H, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 17a , R 17b , R 17 , and R 18 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; s and t are each independently 0, 1, 2, or 3; and u is 1 or 2.

[0095] In an embodiment of Formula VII, ring B and ring C are each independently optionally selected from halo, CN and C 1-6 a 3- to 6-membered heterocycloalkyl substituted with alkyl; Ring D is optionally selected from halo, CN, and C 1-6 a 3- to 6-membered heterocycloalkyl substituted with alkyl; Y 1 and Y 2are each independently a bond, O, C(O), N(H), and C 1-6 alkyl, Z is N(H) and C 1-6 alkyl, R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 3 H, halo, CN, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 4 is optionally R 4a is a 6- to 8-membered heterocycloalkyl substituted with R 4a is H, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 17a , R 17b , R 17 , and R 18 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; s and t are each independently 0, 1, or 2; and u is 1.

[0096] In an embodiment of Formula VII, ring B, ring C, and ring D are each independently optionally selected from halo, CN, and C 1-6 It is a 5- or 6-membered heterocycloalkyl substituted with alkyl.

[0097] In embodiments of Formulas I-VI, R 4 is optionally R 4ais a bridged 8-membered heterocycloalkyl substituted with

[0098] In embodiments of Formulas I-VI, R 4 is as follows: [ka]

[0099] In embodiments of Formulas I-IV, R 6 is H.

[0100] In embodiments of Formulas I-IV, R 8 is H.

[0101] In embodiments of Formulas I-IV, R 11 is H.

[0102] In embodiments of Formulas I-IV, R 13 is H.

[0103] In embodiments of Formulas I-IV, R 15 is H.

[0104] In embodiments of Formulas I-IV, R 16 is H.

[0105] In embodiments of Formulas I-IV, R 6 , R 8 , R 11 , and R 13 are H respectively.

[0106] In embodiments of Formulas I-IV, R 15 and R 16 are H respectively.

[0107] In embodiments of Formula V, R 4 optionally one or two R 4a is a 6- to 7-membered heterocycloalkyl substituted with

[0108] In embodiments, the compound of formula I has the following formula IA: [ka] or a pharmaceutically acceptable salt thereof, wherein: Q 1 is C(R 14 )2, C(O), and NR 14 is selected from R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 4a is H, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 5a , R 5 , R 6 , and R 14 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 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 heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0109] In an embodiment of Formula IA, Q 1 is C(R 14 )2 or C(O), R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 4a is H or C 1-6 is alkyl, R 5a , R 5 , R 6 , and R 14 are independently H, halo, and C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 3-11 cycloalkyl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0110] In an embodiment of Formula IA, Q 1 is C(R 14 )2 or C(O), R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 4a is H or C 1-6 is alkyl, R 5a , R 5 , R 6 , and R 14 are independently H, halo, and C 1-6 Alkyl, and C 1-6alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 4-7 cycloalkyl, 5- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0111] In embodiments, the compound of formula IB has the following formula IA: [ka] or a pharmaceutically acceptable salt thereof, wherein: Q 1 is C(R 14 )2, C(O), and NR 14 is selected from R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 5a and R 14 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10aryl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0112] In an embodiment of Formula IB, Q 1 is CH2 or C(O), R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 5a are independently H, halo and C 1-6 alkyl, Each L is independently 1-6 Alkyl, C 1-6 alkoxy, O, and 5- to 12-membered heterocycloalkyl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 4, 5 or 6.

[0113] In an embodiment of Formula IB, n is 6 and each L forms the following linker: (C 1-6 alkoxy)-(6- to 12-membered heterocycloalkyl)-(C 1-6 alkyl)-(6- to 12-membered heterocycloalkyl)-(C 1-6 alkyl)-(6-membered heterocycloalkyl).

[0114] In an embodiment of Formula IB, n is 6 and each L forms the following linker: (C 1-6 alkoxy)-(6-membered heterocycloalkyl)-(C 1-6 alkyl)-(6-membered heterocycloalkyl)-(C 1-6 alkyl)-(6-membered heterocycloalkyl).

[0115] In an embodiment of Formula IB, n is 4 and each L forms the following linker: (C 1-6 alkoxy)-(5- to 12-membered heterocycloalkyl)-(C 1-6 alkyl)-(5- to 12-membered heterocycloalkyl).

[0116] In an embodiment of Formula IB, n is 4 and each L forms the following linker: (C 1-6 alkoxy)-(11-membered heterocycloalkyl)-(C 1-6 alkyl)-(6-membered heterocycloalkyl).

[0117] In an embodiment of Formula IB, the 11-membered heterocycloalkyl is a spirocyclic 11-membered heterocycloalkyl.

[0118] In an embodiment of Formula IB, n is 6 and each L forms the following linker: (C 1-6 alkoxy)-(5- to 12-membered heterocycloalkyl)-(O)-(5- to 12-membered heterocycloalkyl)-(C 1-6 alkyl)-(5- to 12-membered heterocycloalkyl), wherein the 5- to 12-membered heterocycloalkyl is optionally selected from the group consisting of C 1-6 It is substituted with alkyl.

[0119] In an embodiment of Formula IB, n is 6 and each L forms the following linker: (C 1-6 alkoxy)-(5-membered heterocycloalkyl)-(O)-(6-membered heterocycloalkyl)-(C 1-6 alkyl)-(6-membered heterocycloalkyl), wherein the 5-membered heterocycloalkyl is optionally C 1-6 It is substituted with alkyl.

[0120] In an embodiment of Formula IB, n is 4 and each L forms the following linker: (C 1-6 alkoxy)-(5- to 12-membered heterocycloalkyl)-(C1-6 alkyl)-(5- to 12-membered heterocycloalkyl).

[0121] In an embodiment of Formula IB, n is 4 and each L forms the following linker: (C 1-6 alkoxy)-(6-membered heterocycloalkyl)-(C 1-6 alkyl)-(9-membered heterocycloalkyl).

[0122] In an embodiment of Formula IB, the 9-membered heterocycloalkyl is a spirocyclic 9-membered heterocycloalkyl.

[0123] In an embodiment of formula IB, n is 4 and each L forms the following linker: 1-6 alkoxy)-(5- to 12-membered heterocycloalkyl)-(O)-(5- to 12-membered heterocycloalkyl), wherein the 5- to 12-membered heterocycloalkyl is optionally selected from the group consisting of C 1-6 It is substituted with alkyl.

[0124] In an embodiment of Formula IB, n is 4 and each L forms the following linker: (C 1-6 alkoxy)-(5-membered heterocycloalkyl)-(O)-(6-membered heterocycloalkyl), wherein the 5-membered heterocycloalkyl is optionally C 1-6 It is substituted with alkyl.

[0125] In an embodiment of Formula IB, each L forms a linker: [ka]

[0126] In embodiments, the compound of formula IB-i has the structure of formula IB-i: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q1 is C(R 14 )2, C(O), and NR 14 is selected from R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 5a and R 14 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; Each Q L independently, CR L or N, Each R L are independently H, halo, or CN, and Each p is independently 1, 2, 3, 4, 5, or 6.

[0127] In an embodiment of Formula IB-i, Each Q L independently, CR L or N, Each R L are independently H or halo; R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, and C 2-6 alkynyl, R 3 is selected from H, halo and CN; R 5a and R 14 are independently H, C 1-6 Alkyl, and C 1-6 alkoxy, and Each p is 1, 2, 3, or 4.

[0128] In an embodiment of Formula IB-i, Each Q L are independently CH or N, R 1 and R 2 are independently H, halo, and C 1-3 alkyl, and C≡CH; R 3 is a halo, R 5a and R 14 are independently H, C 1-3 Alkyl, and C 1-3 alkoxy, and Each p is 1, 2, or 3.

[0129] In embodiments, the compound of formula I has the structure of formula IC: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q 1 is C(R 14 )2, C(O), and NR 14 is selected from Ring B and ring C are each independently 3 to 12-membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, Ring D is a bond, C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 substituted with alkyl, provided that when ring D is a bond, Y 2 is also a bond and t is 0, Y 1 and Y 2are each independently a bond, O, C(O), N(H), or N(C 1-6 alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; Z is N(H), N(C 1-6 alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, R 3 H, halo, CN, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 4 is C 3-11 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 3- to 10-membered heteroaryl, wherein C 3-11 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 3- to 10-membered heteroaryl are optionally R 4a is replaced by R 4a is H, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 5a , R 5 , R 6 , and R 14 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; s and t are each independently 0, 1, 2, or 3; and u is 1 or 2.

[0130] In an embodiment of Ring IC, Ring B and Ring C are each independently selected from 3-12 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, In an embodiment of formula IC, ring B and ring C are each independently optionally selected from halo, CN and C 1-6 It is a 3- to 12-membered heterocycloalkyl substituted with alkyl.

[0131] In embodiments of formula IC, Y 1 and Y 2 is a bond, and at least one of s and t is 0.

[0132] In an embodiment of Ring IC, Ring D is selected from a bond, a 3- to 12-membered heterocycloalkyl, and a 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C. 1-6 is substituted with alkyl, In an embodiment of Ring IC, Ring D is selected from a bond, a 3- to 6-membered heterocycloalkyl, and a 5- or 6-membered heteroaryl, wherein the 3- to 6-membered heterocycloalkyl is optionally selected from halo, CN, and C. 1-6 It is substituted with alkyl.

[0133] In embodiments, the compound of formula IC has the structure of formula IC-i: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring B and Ring C are each independently selected from 5- or 6-membered heterocycloalkyl, 9- to 11-membered spirocyclic heterocycloalkyl, and 8-membered bridged heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl, 9- to 11-membered spirocyclic heterocycloalkyl, and 8-membered bridged heterocycloalkyl are optionally selected from halo, CN, and C 1~6 is substituted with alkyl, Y 1 is a bond, O, C(O), N(H), N(C 1-6 alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; Z is C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, and s is 0, 1, 2, or 3.

[0134] In embodiments, the compound of formula IC-i has the structure of formula IC-ia: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring B is selected from 5- or 6-membered heterocycloalkyl, 9- or 11-membered spirocyclic heterocycloalkyl, and 8-membered fused heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl, 9- or 11-membered spirocyclic heterocycloalkyl, and 8-membered fused heterocycloalkyl are optionally selected from halo, CN, and C. 1~6 is substituted with alkyl, Q Z is O, NH, or N(C 1-6alkyl), Each Q L independently, CR L or N, Each R L are independently H, halo, CN and C 1-6 alkyl, Each R C are independently halo or C 1-6 is alkyl, Y 1 is O, C 1-6 Alkyl, and C 1-6 haloalkyl; R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, r is 1, 2, 3, 4, 5, or 6, and q is 0, 1, or 2.

[0135] In embodiments, the compound of formula IC-i has the structure of formula IC-ib: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring B is selected from 5- or 6-membered heterocycloalkyl, 9- or 11-membered spirocyclic heterocycloalkyl, and 8-membered fused heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl, 9- or 11-membered spirocyclic heterocycloalkyl, and 8-membered fused heterocycloalkyl are optionally selected from halo, CN, and C. 1~6 is substituted with alkyl, Q Z is O, NH, or N(C 1-6 alkyl), Each Q L independently, CR L or N, Each R Lare independently H, halo, CN and C 1-6 alkyl, R B is a halo or C 1-6 is alkyl, Y 1 is O, C 1-6 Alkyl, and C 1-6 haloalkyl; R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, r is 1, 2, 3, 4, 5, or 6, and q is 0, 1, or 2.

[0136] In embodiments, the compound of formula IC-ia has the structure of formula IC-iai: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q Z is O, NH, or N(C 1-6 alkyl), Each Q L independently, CR L or N, Each R L are independently H, halo, CN and C 1-6 alkyl, R B and R C are each independently a halo or C 1-6 is alkyl, Y 1 is C 1-6 Alkyl or C 1-6 is haloalkyl, R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C1-6 Alkyl, and C 2-6 alkynyl, r is 1, 2, 3, 4, 5, or 6; s is 0, 1, 2, or 3, and Each q is independently 0, 1, or 2.

[0137] In an embodiment of Formula IC-iai, Ring B is a 9- or 11-membered spirocyclic heterocycloalkyl.

[0138] In embodiments, the compound of formula IC-ia has the structure of formula IC-iaii: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q B are each independently CH, CH2, N, NH, and N(C 1-6 alkyl), provided that at least one Q B is N, NH, or N(C 1-6 alkyl), Q Z is O, NH, or N(C 1-6 alkyl), Q L are each independently, CR L or N, but with at least one Q L Let be N, Each R L are independently H, halo, CN and C 1-6 alkyl, Each R C are independently halo or C 1-6 is alkyl, Y 1 is O, C 1-6 Alkyl, and C 1-6 haloalkyl; R 1 is a halo or C 2-6 is alkynyl, R2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, r is 1, 2, 3, 4, 5, or 6, and q is 0, 1, or 2.

[0139] In embodiments, the compound of formula IC-ia has the structure of formula IC-iaiii: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q B are each independently CH, CH2, N, NH, and N(C 1-6 alkyl), provided that at least one Q B is N, NH, or N(C 1-6 alkyl), Q Z is O, NH, or N(C 1-6 alkyl), Q L are each independently, CR L or N, but with at least one Q L Let be N, Each R L are independently H, halo, CN and C 1-6 alkyl, Each R C are independently halo or C 1-6 is alkyl, Y 1 is O, C 1-6 Alkyl, and C 1-6 haloalkyl; R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, r is 1, 2, 3, 4, 5, or 6, and q is 0, 1, or 2.

[0140] In embodiments, the compound of formula IC-ia has the structure of formula IC-iaiv: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q B are each independently CH2, N, NH, and N(C 1-6 alkyl), provided that at least one Q B is N, NH, or N(C 1-6 alkyl), Q Z is O, NH, or N(C 1-6 alkyl), Each Q L independently, CR L or N, Each R L are independently H, halo, CN and C 1-6 alkyl, Each R C are independently halo or C 1-6 is alkyl, Y 1 are O, C(O), N(H), N(C 1-6 alkyl), C 1-6 Alkyl, and C 1-6 haloalkyl; R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, r is 1, 2, 3, 4, 5, or 6; s is 0, 1, 2, or 3, and q is 0, 1, or 2.

[0141] In embodiments, the compound of formula IC-ia has the structure of formula IC-iav: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q B are each independently CH2, NH, and N(C 1-6 alkyl), provided that at least one Q B is NH or N(C 1-6 alkyl), Q Z is O, NH, or N(C 1-6 alkyl), Each Q L independently, CR L or N, Each R L are independently H, halo, CN and C 1-6 alkyl, Each R C are independently halo or C 1-6 is alkyl, Y 1 are O, C(O), N(H), N(C 1-6 alkyl), C 1-6 Alkyl, and C 1-6 haloalkyl; R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, r is 1, 2, 3, 4, 5, or 6; s is 0, 1, 2, or 3, and q is 0, 1, or 2.

[0142] In embodiments, the compound of formula IC-ib has the structure of formula IC-ibi: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q C are each independently CH, CH2, N, NH, and N(C 1-6 alkyl), provided that at least one Q C is N, NH, or N(C 1-6 alkyl), Q Z is O, NH, or N(C 1-6 alkyl), Q L are each independently, CR L or N, but with at least one Q L Let be N, Each R L are independently H, halo, CN and C 1-6 alkyl, Each R B are independently halo or C 1-6 is alkyl, Y 1 is O, C 1-6 Alkyl, and C 1-6 haloalkyl; R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, r is 1, 2, 3, 4, 5, or 6, and q is 0, 1, or 2.

[0143] In embodiments, the compound of formula IC-ib has the structure of formula IC-ibii: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, QC are each independently CH, CH2, N, NH, and N(C 1-6 alkyl), provided that at least one Q C is N, NH, or N(C 1-6 alkyl), Q Z is O, NH, or N(C 1-6 alkyl), Q L are each independently, CR L or N, but with at least one Q L Let be N, Each R L are independently H, halo, CN and C 1-6 alkyl, Each R B are independently halo or C 1-6 is alkyl, Y 1 is O, C 1-6 Alkyl, and C 1-6 haloalkyl; R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, r is 1, 2, 3, 4, 5, or 6, and q is 0, 1, or 2.

[0144] In embodiments, the compound of formula IC has the structure of formula IC-ii: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring B is a 5- or 6-membered heterocycloalkyl, or an 8-membered fused heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl and the 8-membered fused heterocycloalkyl are optionally selected from halo, CN, and C.1-6 is substituted with alkyl, Q Z is O, NH, or N(C 1-6 alkyl), Each Q L independently, CR L or N, Each R L are independently H, halo, CN and C 1-6 alkyl, Each R C are independently halo or C 1-6 is alkyl, Y 1 is O, C 1-6 Alkyl, and C 1-6 haloalkyl; R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, p and r are each independently 1, 2, 3, 4, 5, or 6; and q is 0, 1, or 2.

[0145] In an embodiment of Formula IC-ii, Ring B is an 8-membered fused heterocycloalkyl.

[0146] In embodiments, the compound of formula IC-iia has the structure of formula IC-iia: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q Z is O, NH, or N(C 1-6 alkyl), Each Q L independently, CR L or N, Each R L are independently H, halo, CN and C 1-6alkyl, R B and R C are each independently a halo or C 1-6 is alkyl, Y 1 is C 1-6 Alkyl or C 1-6 is haloalkyl, R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, p and r are each independently 1, 2, 3, 4, 5, or 6; and Each q is independently 0, 1, or 2.

[0147] In embodiments, the compound of formula IC-ii has the structure of formula IC-iib: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q B are each independently CH2, N, NH, and N(C 1-6 alkyl), provided that at least one Q B is N, NH, or N(C 1-6 alkyl), Q Z is O, NH, or N(C 1-6 alkyl), Each Q L independently, CR L or N, Each R L are independently H, halo, CN and C 1-6 alkyl, Each R C are independently halo or C 1-6 is alkyl, Y 1 is O, C1-6 Alkyl, and C 1-6 haloalkyl; R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, p and r are each independently 1, 2, 3, 4, 5, or 6; and q is 0, 1, or 2.

[0148] In embodiments, the compound of formula IC-ii has the structure of formula IC-iic: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q B are each independently CH2, NH, and N(C 1-6 alkyl), provided that at least one Q B is NH or N(C 1-6 alkyl), Q Z is O, NH, or N(C 1-6 alkyl), Each Q L independently, CR L or N, Each R L are independently H, halo, CN and C 1-6 alkyl, Each R C are independently halo or C 1-6 is alkyl, Y 1 is O, C 1-6 Alkyl, and C 1-6 haloalkyl; R 1 is a halo or C 2-6 is alkynyl, R 2H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, p and r are each independently 1, 2, 3, 4, 5, or 6; and q is 0, 1, or 2.

[0149] In embodiments, the compound of formula II has the structure of formula IIA: [ka] or a pharmaceutically acceptable salt thereof, wherein: Q 2 is CR 14 or N, R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 4a is H, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 8 and R 14 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 7 H, =O, halo, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; Ring A is selected from phenyl, 6-membered heteroaryl, C6 cycloalkyl, and 6-membered heterocycloalkyl; Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Haloalkoxy, 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 heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0150] In an embodiment of Formula IIA, Q 2 is N, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 4a is H or C 1-6 is alkyl, R 7 H, =O, halo, C 1-6 Alkyl, and C 1-6 alkoxy; R 8 is H, C 1-6 Alkyl, and C 1-6 alkoxy; Ring A is selected from phenyl, 6-membered heteroaryl, and 6-membered heterocycloalkyl; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 3-11 cycloalkyl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0151] In an embodiment of Formula IIA, Q 2 is N, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 4 is C 6-8 cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 7 H, =O, halo, C 1-6 Alkyl, and C 1-6 alkoxy; R 8 is H, C 1-6 Alkyl, and C 1-6 alkoxy; Ring A is phenyl or 6-membered heterocycloalkyl; B is a bond or C 1-6 is alkyl, Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 4-7 cycloalkyl, 6- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 6- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0152] In embodiments, the compound of formula II has the structure of formula IIB: [ka] or a pharmaceutically acceptable salt thereof, wherein: Q 2 is CR 14 or N, R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 4a is H, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 8 and R 14 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 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 heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0153] In an embodiment of Formula IIB, Q 2 is N, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R4a is H or C 1-6 is alkyl, R 7 H, =O, halo, C 1-6 Alkyl, and C 1-6 alkoxy; R 8 is H, C 1-6 Alkyl, and C 1-6 alkoxy; Ring A is selected from phenyl, 6-membered heteroaryl, and 6-membered heterocycloalkyl; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 3-11 cycloalkyl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0154] In an embodiment of Formula IIB, Q 2 is N, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 4 is C 6-8 cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C 6-8 Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R 4a is replaced by R 4a is H or C 1-6 is alkyl, R 8 is H, C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 4-7 cycloalkyl, 6- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 6- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0155] In embodiments, the compound of formula III has the structure of formula IIIA: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 4a is H, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 9 H, halo, C 1-6 Alkyl, and C 1-6 alkoxy; R 10 and R 11 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, O, C(O), N(H), N(C 1-6alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0156] In an embodiment of Formula IIIA, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 4a is H or C 1-6 is alkyl, R 9 H, halo, C 1-6 Alkyl, and C 1-6 alkoxy; R 10 and R 11 are independently H, C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 3-11 cycloalkyl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0157] In an embodiment of Formula IIIA, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R4a is H or C 1-6 is alkyl, R 9 H, halo, C 1-6 Alkyl, and C 1-6 alkoxy; R 10 and R 11 are independently H, C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 4-7 cycloalkyl, 6- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 6- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0158] In embodiments, the compound of formula IV has the structure of formula IVA: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 4a is H, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 12 and R 13 are independently H, halo, and C 1-6 Alkyl, C 1-6Alkoxy, and C 1-6 haloalkyl; Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 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 heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0159] In an embodiment of Formula IVA, R 1 and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 4a is H or C 1-6 is alkyl, R 12 and R 13 are independently H, C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 3-11 cycloalkyl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0160] In an embodiment of Formula IVA, R 1and R 2 are independently H, halo, and C 1-6 alkyl, and C≡CH; R 4a is H or C 1-6 is alkyl, R 12 and R 13 are independently H, C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 4-7 cycloalkyl, 6- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 6- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0161] In embodiments, the compound of formula IV has the structure of formula IVB-a: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Each Q L independently, CR L or N, Each R L are independently H, halo, or CN, and Each p is 1, 2, 3, 4, 5, or 6.

[0162] In an embodiment of Formula IVB-a, Each Q L independently, CR L or N, Each R L are independently H or halo; R 1 and R 2are independently H, halo, and C 1-6 Alkyl, and C 2-6 alkynyl, R 3 is selected from H, halo and CN; R 12 and R 13 are independently H, C 1-6 Alkyl, and C 1-6 alkoxy, and Each p is 1, 2, 3, or 4.

[0163] In an embodiment of Formula IVB-a, Each Q L are independently CH or N, R 1 and R 2 are independently H, halo, and C 1-3 alkyl, and C≡CH; R 3 is a halo, R 12 and R 13 are independently H, C 1-3 Alkyl, and C 1-3 alkoxy, and Each p is 1, 2, or 3.

[0164] In embodiments, the compound of formula IV has the structure of formula IVB: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, and C 2-6 alkynyl, R 3 is selected from H, halo and CN; Each Q L independently, CR L or N, Each R L are independently H, halo, or CN, and each p is 1, 2, 3, 4, 5, or 6, and R 12 and R 13 are independently H, C 1-6 Alkyl, and C 1-6 Alkoxy is selected from:

[0165] In an embodiment of Formula IVB, Each Q L independently, CR L or N, Each R L are independently H or halo; R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, and C 2-6 alkynyl, R 3 is selected from H, halo and CN; R 12 and R 13 are independently H, C 1-6 Alkyl, and C 1-6 alkoxy, and Each p is 1, 2, 3, or 4.

[0166] In an embodiment of Formula IVB, Each Q L are independently CH or N, R 1 and R 2 are independently H, halo, and C 1-3 alkyl, and C≡CH; R 3 is a halo, R 12 and R 13 are independently H, C 1-3 Alkyl, and C 1-3 alkoxy, and Each p is 1, 2, or 3.

[0167] In embodiments, the compound of formula V has the structure of formula VA: [ka] or a pharmaceutically acceptable salt thereof, wherein: Q 1 is C(R 14 )2, C(O), and NR 14 is selected from Q 3 is CR 14 or N, R 1a is selected from OH, H, and halo; R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 4a are independently H, OH, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 14 , R 15a , R 15b , R 15 , and R 16 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10aryl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 substituted with 1 or 2 substituents independently selected from alkyl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0168] In an embodiment of Formula VA, Q 1 is C(R 14 )2 or C(O), Q 3 is CR 14 or N, R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 3-6 cycloalkyl, and C≡CH; R 1a is H or OH, R 4a is H or C 1-6 is alkyl, R 14 , R 15a , R 15b , R 15 , and R 16 are independently H, halo, and C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 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 heterocycloalkyl is optionally selected from halo, CN, and C 1-6 substituted with 1 or 2 substituents independently selected from alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0169] In an embodiment of Formula VA, Q 1 is C(R 14 )2 or C(O), Q 3 is CH or N, R 1 and R 2 are independently H, halo, and C 1-3 Alkyl, C 3-5 cycloalkyl, and C≡CH; R 1a is H or OH, R 3 is H or halo, R 4a is H or C 1-6 is alkyl, R 14 , R 15a , R 15b , R 15 , and R 16 are independently H, halo, and C 1-3 Alkyl, and C 1-3 alkoxy; Each L is independently 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- to 12-membered heterocycloalkyl, and 5- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 substituted with 1 or 2 substituents independently selected from alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0170] In embodiments, the compound of formula VI has the following formula VIA: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 4a are independently H, OH, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 17a , R 17b , R 17 , and R 18 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 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 heterocycloalkyl is optionally selected from halo, CN, and C 1-6 substituted with 1 or 2 substituents independently selected from alkyl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0171] In an embodiment of Formula VIA, R 1 and R 2 are independently H, halo, and C 1-6 Alkyl, C 3-6 cycloalkyl, and C≡CH; R4a is H or C 1-6 is alkyl, R 17a , R 17b , R 17 , and R 18 are independently H, halo, and C 1-6 Alkyl, and C 1-6 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 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 heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, and n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0172] In an embodiment of Formula VIA, R 1 and R 2 are independently H, halo, and C 1-3 alkyl, and C≡CH; R 4a is H or C 1-6 is alkyl, R 17a , R 17b , R 17 , and R 18 are independently H, halo, and C 1-3 Alkyl, and C 1-3 alkoxy; Each L is independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C(O), N(H), N(C 1-6 alkyl), C 4-7cycloalkyl, 5- to 12-membered heterocycloalkyl, and 5- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 substituted with 1 or 2 substituents independently selected from alkyl, and n is 1, 2, 3, 4, 5 or 6.

[0173] In embodiments, the compound of formula VI has the structure of formula VIAA: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring B and ring C are each independently 3 to 12-membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 is substituted with alkyl, Ring D is a bond, C 3-11 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl is optionally selected from halo, CN, and C 1-6 substituted with alkyl, provided that when ring D is a bond, Y 2 is also a bond and t is 0, Y 1 and Y 2 are each independently a bond, O, C(O), N(H), or N(C 1-6 alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; Z is N(H), N(C 1-6 alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; R1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, R 3 H, halo, CN, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 4 is C 3-11 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 3- to 10-membered heteroaryl, wherein C 3-11 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 3- to 10-membered heteroaryl are optionally R 4a is replaced by R 4a is H, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; R 17a , R 17b , R 17 , and R 18 are independently H, halo, and C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkyl; s and t are each independently 0, 1, 2, or 3; and u is 1 or 2.

[0174] In Ring VIAA embodiments, Ring D is selected from a bond, a 3- to 12-membered heterocycloalkyl, and a 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C. 1-6 is substituted with alkyl, In an embodiment of Ring VIAA, Ring D is selected from a bond, a 3- to 8-membered heterocycloalkyl, and a 5- or 6-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl is optionally selected from halo, CN, and C. 1-6 It is substituted with alkyl.

[0175] In an embodiment of Formula VIAA, Ring B is an 8-membered fused heterocycloalkyl.

[0176] In embodiments, the compound of formula VIAA has the structure of formula VIAA-i: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring B and Ring C are each independently selected from 5- or 6-membered heterocycloalkyl, 9- to 11-membered spirocyclic heterocycloalkyl, and 8-membered bridged heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl, 9- to 11-membered spirocyclic heterocycloalkyl, and 8-membered bridged heterocycloalkyl are optionally selected from halo, CN, and C 1~6 is substituted with alkyl, Y 1 is a bond, O, C(O), N(H), N(C 1-6 alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; Z is C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, and s is 0, 1, 2, or 3.

[0177] In embodiments, the compound of formula VIAA-i has the structure of formula VIAA-ia: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring B is selected from 5- or 6-membered heterocycloalkyl, 9- or 11-membered spirocyclic heterocycloalkyl, and 8-membered fused heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl, 9- or 11-membered spirocyclic heterocycloalkyl, and 8-membered fused heterocycloalkyl are optionally selected from halo, CN, and C. 1~6 is substituted with alkyl, Q Z is O, NH, or N(C 1-6 alkyl), Each Q L independently, CR L or N, Each R L are independently H, halo, CN and C 1-6 alkyl, Each R C are independently halo or C 1-6 is alkyl, Y 1 is O, C 1-6 Alkyl, and C 1-6 haloalkyl; R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, r is 1, 2, 3, 4, 5, or 6, and q is 0, 1, or 2.

[0178] In embodiments, the compound of formula VIAA-ia has the structure of formula VIAA-iai: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q Z is O, NH, or N(C 1-6 alkyl), Each Q L independently, CR L or N, Each R L are independently H, halo, CN and C 1-6 alkyl, R B and R C are each independently a halo or C 1-6 is alkyl, Y 1 is C 1-6 Alkyl or C 1-6 is haloalkyl, R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, r is 1, 2, 3, 4, 5, or 6; s is 0, 1, 2, or 3, and Each q is independently 0, 1, or 2.

[0179] In embodiments, the compound of formula VIAA-ia has the structure of formula VIAA-iaii: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q B are each independently CH, CH2, N, NH, and N(C 1-6 alkyl), provided that at least one Q B is N, NH, or N(C 1-6 alkyl), QZ is O, NH, or N(C 1-6 alkyl), Q L are each independently, CR L or N, but with at least one Q L Let be N, Each R L are independently H, halo, CN and C 1-6 alkyl, Each R C are independently halo or C 1-6 is alkyl, Y 1 is O, C 1-6 Alkyl, and C 1-6 haloalkyl; R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, r is 1, 2, 3, 4, 5, or 6, and q is 0, 1, or 2.

[0180] In embodiments of Formula VIAA-iaii, at least two Q B is CH2.

[0181] In embodiments, the compound of formula VIAA-ia has the structure of formula VIAA-iaiii: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q B are each independently CH2, NH, and N(C 1-6 alkyl), provided that at least one Q B is NH or N(C 1-6 alkyl), Q Zis O, NH, or N(C 1-6 alkyl), Each Q L independently, CR L or N, Each R L are independently H, halo, CN and C 1-6 alkyl, Each R C are independently halo or C 1-6 is alkyl, Y 1 are O, C(O), N(H), N(C 1-6 alkyl), C 1-6 Alkyl, and C 1-6 haloalkyl; R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, r is 1, 2, 3, 4, 5, or 6; s is 0, 1, 2, or 3, and q is 0, 1, or 2.

[0182] In embodiments, the compound of formula VIAA-ii has the structure of formula VIAA-iia: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q Z is O, NH, or N(C 1-6 alkyl), Each Q L independently, CR L or N, Each R L are independently H, halo, CN and C 1-6 alkyl, R B and R Care each independently a halo or C 1-6 is alkyl, Y 1 is C 1-6 Alkyl or C 1-6 is haloalkyl, R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, p and r are each independently 1, 2, 3, 4, 5, or 6; and Each q is independently 0, 1, or 2.

[0183] In embodiments, the compound of formula VIAA-ii has the structure of formula VIAA-iib: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q B are each independently CH2, NH, and N(C 1-6 alkyl), provided that at least one Q B is NH or N(C 1-6 alkyl), Q Z is O, NH, or N(C 1-6 alkyl), Each Q L independently, CR L or N, Each R L are independently H, halo, CN and C 1-6 alkyl, Each R C are independently halo or C 1-6 is alkyl, Y 1 is O, C 1-6 Alkyl, and C 1-6 haloalkyl; R1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, p and r are each independently 1, 2, 3, 4, 5, or 6; and q is 0, 1, or 2.

[0184] In embodiments, the compound of formula VIAA-ii has the structure of formula VIAA-iic: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Q B are each independently CH2, N, NH, and N(C 1-6 alkyl), provided that at least one Q B is N, NH, or N(C 1-6 alkyl), Q Z is O, NH, or N(C 1-6 alkyl), Each Q L independently, CR L or N, Each R L are independently H, halo, CN and C 1-6 alkyl, Each R C are independently halo or C 1-6 is alkyl, Y 1 is O, C 1-6 Alkyl, and C 1-6 haloalkyl; R 1 is a halo or C 2-6 is alkynyl, R 2 H, halo, C 1-6 Alkyl, and C 2-6 alkynyl, p and r are each independently 1, 2, 3, 4, 5, or 6; and q is 0, 1, or 2.

[0185] In embodiments of formula VIAA-iic, at least two Q B is CH2.

[0186] Various embodiments of Formulas I-VIA, VIAA, VII, AI, AIV, and various subgene formulae thereof, or pharmaceutically acceptable salts thereof In some embodiments, Q 1 is CH or C(O). In some embodiments, Q 2 is N. In some embodiments, Q 3 is CH or N. In some embodiments, R 1a is selected from H and OH. In some embodiments, R 1b and R 2b together with the phenyl to which they are attached, R 1 and R 2 In some embodiments, R 1 H, halo, and C 1-6 In some embodiments, R 1 is H. In some embodiments, R 1 is halo. In some embodiments, R 1 is C 1-6 In some embodiments, R 2a is selected from H and halo. In some embodiments, R 2 is H, C 1-6 alkyl, and C≡CH. In some embodiments, R 2 is C 3-6 It is cycloalkyl.

[0187] In some embodiments, R 2 is H. In some embodiments, R 2 is C 1-6 In some embodiments, R 2 is C≡CH. In some embodiments, R 3 is a halo.

[0188] In some embodiments, R 4 is optionally R 4a is a bridged 8-membered heterocycloalkyl substituted with

[0189] In embodiments of Formulas I-VI, R 4 is as follows: [ka]

[0190] In some embodiments, R 4a is H or C 1-6 In some embodiments, R 5a is H, halo, or C 1-6 In some embodiments, R 5 is H or C 1-6 In some embodiments, R 6 is H or C 1-6 It is alkyl.

[0191] In some embodiments, R 7 H, =O, halo, and C 1-6 In some embodiments, R is selected from alkoxy. 7 is ═O. In some embodiments, R 7 is halo. In some embodiments, R 7 is C 1-6 In some embodiments, R 8 is H or C 1-6 In some embodiments, R 8 is H. In some embodiments, R 9 H, halo, and C 1-6 In some embodiments, R is selected from alkoxy. 9 is a halo.

[0192] In some embodiments, R 9 is C 1-6 In some embodiments, R10 is H. In some embodiments, R 11 is H. In some embodiments, R 12 is C 1-6 In some embodiments, R 13 is H. In some embodiments, R 14 is H or C 1-6 In some embodiments, R 14 is H. In some embodiments, R 14 is C 1-6 It is alkyl.

[0193] In some embodiments, R 15a is H, halo, or C 1-6 In some embodiments, R 15b is H, halo, or C 1-6 In some embodiments, R 15 is H or C 1-6 In some embodiments, R 16 is H or C 1-6 In some embodiments, R 17a and R 17b are each independently H or halo. In some embodiments, R 17 is C 1-6 In some embodiments, R 18 is H.

[0194] In embodiments, Ring A is phenyl. In embodiments, Ring A is 6-membered heterocycloalkyl. In embodiments, Ring A is dihydropyridinyl. In embodiments, B is a bond. In embodiments, B is C 1-6 It is alkyl.

[0195] In some embodiments, each L is independently C 1-6 Alkyl, C 1-6and alkoxy, C(O), 5- to 12-membered heterocycloalkyl, where the 5- to 12-membered heterocycloalkyl is optionally substituted with halo. In some embodiments, the 5- to 12-membered heterocycloalkyl is a fused 8-membered heterocycloalkyl.

[0196] In some embodiments, each L is independently C 1-6 Alkyl, C 1-6 and 6- to 12-membered heterocycloalkyl, wherein the 6- to 12-membered heterocycloalkyl is optionally substituted with halo.

[0197] In some embodiments, each L is independently C 1-6 Alkyl, C 1-6 and selected from alkoxy, 6- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein the 6- to 8-membered heterocycloalkyl is optionally substituted with halo.

[0198] In some embodiments, L forms the following linker: (C 1-6 alkoxy)-(6- to 12-membered heterocycloalkyl)-(C 1-6 alkyl)-(6- to 12-membered heterocycloalkyl).

[0199] In some embodiments, n is 4 and each L forms a linker as follows: (C 1-6 alkoxy)-(6- to 12-membered heterocycloalkyl)-(C 1-6 alkyl)-(6- to 12-membered heterocycloalkyl).

[0200] In some embodiments, n is 4 and each L forms a linker as follows: (C 1-6 alkoxy)-(6-membered heterocycloalkyl)-(C 1-6 alkyl)-(7-membered heterocycloalkyl).

[0201] In some embodiments, n is 4 and each L forms a linker as follows: (C 1-6 alkoxy)-(6-membered heterocycloalkyl)-(C 1-6 alkyl)-(9-membered heterocycloalkyl).

[0202] In some embodiments, n is 4 and each L forms a linker as follows: (C 1-6 alkoxy)-(6-membered heterocycloalkyl)-(C 1-6 alkyl)-(11-membered heterocycloalkyl).

[0203] In some embodiments, each L forms a linker: [ka]

[0204] In some embodiments, n is 6 and each L forms a linker as follows: (C 1-6 alkoxy)-(6- to 12-membered heterocycloalkyl)-(C 1-6 alkyl)-(6- to 12-membered heterocycloalkyl)-(C 1-6 alkyl)-(6-membered heterocycloalkyl).

[0205] In some embodiments, n is 6 and each L forms a linker as follows: (C 1-6 alkoxy)-(6-membered heterocycloalkyl)-(C 1-6 alkyl)-(6-membered heterocycloalkyl)-(C 1-6 alkyl)-(6-membered heterocycloalkyl).

[0206] In some embodiments, n is 4 and each L forms a linker as follows: (C 1-6 alkoxy)-(5- to 12-membered heterocycloalkyl)-(C 1-6 alkyl)-(5- to 12-membered heterocycloalkyl).

[0207] In some embodiments, n is 4 and each L forms a linker as follows: (C 1-6 alkoxy)-(11-membered heterocycloalkyl)-(C 1-6 alkyl)-(6-membered heterocycloalkyl).

[0208] In embodiments, the 11-membered heterocycloalkyl is a spirocyclic 11-membered heterocycloalkyl.

[0209] In some embodiments, n is 6 and each L forms a linker as follows: (C 1-6 alkoxy)-(5- to 12-membered heterocycloalkyl)-(O)-(5- to 12-membered heterocycloalkyl)-(C 1-6 alkyl)-(5- to 12-membered heterocycloalkyl), wherein the 5- to 12-membered heterocycloalkyl is optionally selected from the group consisting of C 1-6 It is substituted with alkyl.

[0210] In some embodiments, n is 6 and each L forms a linker as follows: (C 1-6 alkoxy)-(5-membered heterocycloalkyl)-(O)-(6-membered heterocycloalkyl)-(C 1-6 alkyl)-(6-membered heterocycloalkyl), wherein the 5-membered heterocycloalkyl is optionally C 1-6 It is substituted with alkyl.

[0211] In some embodiments, n is 4 and each L forms a linker as follows: (C 1-6 alkoxy)-(5- to 12-membered heterocycloalkyl)-(C 1-6 alkyl)-(5- to 12-membered heterocycloalkyl).

[0212] In some embodiments, n is 4 and each L forms a linker as follows: (C 1-6 alkoxy)-(6-membered heterocycloalkyl)-(C 1-6alkyl)-(9-membered heterocycloalkyl).

[0213] In embodiments, the 9-membered heterocycloalkyl is a spirocyclic 9-membered heterocycloalkyl.

[0214] In some embodiments, n is 4 and each L forms a linker as follows: (C 1-6 alkoxy)-(5- to 12-membered heterocycloalkyl)-(O)-(5- to 12-membered heterocycloalkyl), wherein the 5- to 12-membered heterocycloalkyl is optionally selected from the group consisting of C 1-6 It is substituted with alkyl.

[0215] In some embodiments, n is 4 and each L forms a linker as follows: (C 1-6 alkoxy)-(5-membered heterocycloalkyl)-(O)-(6-membered heterocycloalkyl), wherein the 5-membered heterocycloalkyl is optionally C 1-6 It is substituted with alkyl.

[0216] In embodiments, heterocycloalkyl contains 1, 2, or 3 heteroatoms independently selected from N, O, and S. In embodiments, heterocycloalkyl contains 1 or 2 heteroatoms independently selected from N, O, and S. In embodiments, heterocycloalkyl contains 1 or 2 heteroatoms independently selected from N and O. In embodiments, heterocycloalkyl contains 1 or 2 nitrogen heteroatoms.

[0217] In some embodiments, each L forms a linker: [ka]

[0218] In some embodiments, (L) n is selected from the following: [ka] [ka] In selecting compounds of the present invention, one of skill in the art will recognize that various substituents are selected according to known principles of connectivity and stability of chemical structures.

[0219] In embodiments, the compound of Formula I is selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof. [Table 1] TIFF2026505002000069.tif216167TIFF2026505002000070.tif219165TIFF2026505002000071.tif220166TIFF2026505002000072.tif188165TIFF2026505002000073.tif235165TIFF2026505002000074.tif222165TIFF2026505002000075.tif217164TIFF2026505002000076.tif192166TIFF2026505002000077.tif230164TIFF2026505002000078.tif207165TIFF2026505002000079.tif206166TIFF2026505002000080.tif216165TIFF2026505002000081.tif213166TIFF2026505002000082.tif200164TIFF2026505002000083.tif215165TIFF2026505002000084.tif202164TIFF2026505002000085.tif204165TIFF2026505002000086.tif221166TIFF2026505002000087.tif216165TIFF2026505002000088.tif184164TIFF2026505002000089.tif217165TIFF2026505002000090.tif237165TIFF2026505002000091.tif221165TIFF2026505002000092.tif210165TIFF2026505002000093.tif212165TIFF2026505002000094.tif208165TIFF2026505002000095.tif225165TIFF2026505002000096.tif194165TIFF2026505002000097.tif223165TIFF2026505002000098.tif227165TIFF2026505002000099.tif224165TIFF2026505002000100.tif213165TIFF2026505002000101.tif197165TIFF2026505002000102.tif196164TIFF2026505002000103.tif212166TIFF2026505002000104.t if193165TIFF2026505002000105.tif238164TIFF2026505002000106.tif220165TIFF2026505002000107.ti f200165TIFF2026505002000108.tif201165TIFF2026505002000109.tif198165TIFF2026505002000110.tif 208165TIFF2026505002000111.tif214165TIFF2026505002000112.tif201164TIFF2026505002000113.tif23 3165TIFF2026505002000114.tif193165TIFF2026505002000115.tif219165TIFF2026505002000116.tif202 164TIFF2026505002000117.tif217165TIFF2026505002000118.tif207165TIFF2026505002000119.tif1991 65TIFF2026505002000120.tif196165TIFF2026505002000121.tif205165TIFF2026505002000122.tif21216 5TIFF2026505002000123.tif215164TIFF2026505002000124.tif205165TIFF2026505002000125.tif216165.

[0220] Also provided herein are pharmaceutical compositions comprising any of the compounds described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0221] The compounds disclosed herein may exist as tautomers and optical isomers (eg, enantiomers, diastereomers, diastereomeric mixtures, racemic mixtures, etc.).

[0222] It is generally known in the art that any compound that is converted in vivo to provide a compound disclosed herein is a prodrug within the scope of this disclosure.

[0223] Treatment method The present application relates to methods of treating or ameliorating symptoms or conditions that are regulated through or causally associated with a target protein, namely KRas.

[0224] Provided herein are methods of treating a disease or disorder comprising administering to a subject any of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0225] In embodiments, the disease or disorder is cancer.

[0226] In embodiments, the cancer is bladder cancer, colon cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, uterine cancer, ovarian cancer, testicular cancer, thyroid cancer, pineal cell tumor, carcinoma, carcinoma, ependymoma, ganglioglioma, ganglioneuroma, glioblastoma, glioma, leukemia, lymphoma, medulloblastoma, melanoma, meningioma, myeloma, nephroblastoma, neuroblastoma, neurofibroma, oligodendroglioma, peripheral neuroepithelioma, sarcoma, or schwannoma.

[0227] In embodiments, the carcinoma is a teratocarcinoma. In embodiments, the carcinoma is an astrocytoma.

[0228] In embodiments, the carcinoma is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma. In 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.

[0229] In embodiments, the lymphoma is Burkitt's 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.

[0230] In embodiments, the lymphoma is Hodgkin's lymphoma (HL).

[0231] In embodiments, the nephroblastoma is Wilms' tumor. In embodiments, the sarcoma is selected from carcinosarcoma, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, synovial sarcoma, and meningeal sarcoma.

[0232] Provided herein are methods for modulating the activity of a KRas protein, comprising administering to a subject any of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0233] Also provided herein are methods of modulating the activity of a cereblon protein, comprising administering to a subject any of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0234] Further provided herein is a method for degrading a target protein, comprising contacting a cell with any of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0235] Administration / Dosage / Formulation Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms can also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions can also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and perfumes.

[0236] Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution (USP), and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any brand of fixed oil, including synthetic monoglycerides or diglycerides, may be employed. In addition, fatty acids, such as oleic acid, are used in the preparation of injectable solutions.

[0237] In order to prolong the effect of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This delay may be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of subsequent absorption of the drug depends on its dissolution rate, which in turn may depend on the size and crystalline form of the crystals. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0238] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing a compound of the present disclosure with a suitable non-irritating excipient or carrier, such as, for example, cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ambient temperature but liquid at body temperature, i.e., melts in the rectum or vaginal cavity, releasing the active compound.

[0239] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0240] The active compound may also be in the form of a microcapsule encapsulated with one or more excipients, as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings or shells, such as enteric coatings, release-controlling coatings, and other coatings known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. As is common practice, such dosage forms may also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also contain a buffering agent.

[0241] The dosage form for topical or transdermal administration of the compound of the present disclosure includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch.The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier, and any necessary preservative or buffer, if necessary.Ophthalmic preparations, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of the present disclosure.

[0242] The ointments, pastes, creams, and gels may contain, in addition to the active compounds of the present disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0243] Powders and sprays can contain, in addition to the compounds of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays can additionally contain conventional propellants, such as, for example, chlorofluorohydrocarbons.

[0244] Transdermal patches have the additional advantage of controlling the delivery of compounds to the body.Such dosage forms can be prepared by dissolving or dispensing the compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound through the skin.The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0245] The compounds of the present disclosure may also be administered intratympanically, where a long, narrow-bore needle is passed through the ear canal and through the tympanic membrane, delivering the medication into the middle ear space where it is absorbed by the inner ear.

[0246] According to the therapeutic method of the present disclosure, a disorder is treated or prevented in a subject, for example, a human or other animal, by administering to the subject a therapeutically effective amount of a compound of the present disclosure in an amount and for a time necessary to achieve the desired result. As used herein, the term "therapeutically effective amount" of a compound of the present disclosure means a compound sufficient to reduce the symptoms of the disorder in the subject. As is well understood in the medical field, a therapeutically effective amount of a compound of the present disclosure will have a reasonable benefit / risk ratio applicable to any medical treatment.

[0247] Generally, the compounds of the present disclosure, either alone or in combination with one or more therapeutic agents, are administered in a therapeutically effective amount by any of the conventional and acceptable methods known in the art. The therapeutically effective amount can vary widely 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, satisfactory results have been shown to be obtained systemically at a daily dose of about 0.03 to 2.5 mg per kg of body weight. In larger mammals, such as humans, the applicable daily dose ranges from about 0.5 mg to about 100 mg, and may be administered conveniently, for example, in divided doses up to four times a day, or in a delayed form. Suitable unit dosage forms for oral administration contain about 1 to 50 mg of the active ingredient.

[0248] In embodiments, the therapeutic amount or dose of a compound of the present disclosure may range from about 0.1 mg / kg to about 500 mg / kg, or from about 1 to about 50 mg / kg. Generally, a treatment regimen according to the present disclosure involves administering to a subject in need of such treatment about 10 mg to about 1000 mg of a compound of the present disclosure per day, in single or multiple doses. The therapeutic amount or dose will also vary depending on the route of administration, as well as the possibility of concurrent use with other agents.

[0249] When the condition of the subject improves, the maintenance dose of the compound, composition or combination of the present disclosure can be administered as needed.After that, the dose or the administration frequency or both can be reduced according to the symptoms to the level that the improved condition is maintained.When the condition is alleviated to the desired level, the treatment should be stopped.However, the subject may need to be intermittently treated on a long-term basis when any disease symptoms recur.

[0250] However, it is understood that the total daily amount of compound and composition of the present disclosure is determined by attending physician within the scope of sound medical judgment.The specific inhibitory dose for any specific subject depends on various factors, including the disorder that is treated and the severity of the disorder; the activity of the specific compound that is used; the specific composition that is used; the age, weight, general health condition, sex and diet of subject; the time of administration, route of administration and the excretion rate of the specific compound that is used; treatment period; the drug that is used in combination with the specific compound that is used or at the same time; and similar factors known in medical field.

[0251] The present disclosure also provides pharmaceutical combinations, e.g., kits, comprising: a) a first agent that is a presently disclosed compound disclosed herein, in free form or in the form of a pharmaceutically acceptable salt; and b) at least one co-agent. The kit can include instructions for its administration.

[0252] Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphates, glycine, sorbic acid, and potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene polyoxypropylene-block polymers; wool fat; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch. Examples of suitable granules include starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; 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; ethyl alcohol; and phosphate buffer solution. In addition, non-toxic and compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavorings, and perfuming agents, preservatives, and antioxidants may also be present in the composition according to the discretion of the formulator. The protein kinase inhibitor or pharmaceutical salts thereof may be formulated into pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions, containing an amount of the protein inhibitor effective to treat or prevent a protein kinase-mediated condition, are other embodiments of the present disclosure.

[0253] kit Provided herein are kits comprising a compound capable of degrading KRas, selected from one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and instructions for use in treating a disorder associated with KRas.

[0254] The present disclosure provides a kit comprising a compound capable of degrading KRas selected from the compounds disclosed herein, or a pharmaceutically acceptable salt thereof.

[0255] Provided herein are kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for the treatment of any of the indications disclosed herein.

[0256] Those skilled in the art will recognize or be able to ascertain using routine experimentation many equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are within the scope of this disclosure and the claims appended hereto. It is understood that art-recognized substitutions and variations using routine experimentation in reaction conditions, including, but not limited to, reaction time, reaction size / volume, and experimental reagents such as solvents, catalysts, pressure, atmospheric conditions such as a nitrogen atmosphere, and reducing / oxidizing agents, are within the scope of this application.

[0257] Wherever values ​​and ranges are provided herein, it is understood that all values ​​and ranges encompassed by those values ​​and ranges are encompassed within the scope of the present disclosure. Moreover, all values ​​within those ranges, as well as the upper and lower limits of ranges of values, are also contemplated by the present application.

[0258] The following examples further illustrate aspects of the present disclosure, but are in no way intended to be limitations on the teachings of the present disclosure as described. [Example]

[0259] The compounds and methods disclosed herein are further illustrated by the following examples, which should not be construed as further limiting. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, within the skill of the art.

[0260] The following examples further illustrate aspects of the present disclosure, but are in no way intended to be limitations on the teachings of the present disclosure as described.

[0261] Abbreviation AcOH or HOAc acetic acid CBz benzyl chloroformate Boc tert-butoxycarbonyl CDCl3 chloroform-d Cs2CO3 Cesium Carbonate DIEA Diisopropylethylamine Dmax DMF maximum resolution (%) N,N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d6 DTT Deuterated dimethyl sulfoxide (C2D6SO) Dithiothreitol ESI electrospray ionization EtOH ethanol eq equivalent g grams h time Hz Hertz HCl Hydrochloric acid HPLC High-Performance Liquid Chromatography DC 50 50% decomposition concentration K2CO3 Potassium Carbonate K3PO4 Potassium Phosphate min m / z mass / charge MS mass spectrometry MHz Megahertz MeOH Methanol MOM methoxymethyl μL microliter μm micrometer mg milligram mm millimeters mL milliliter mmol millimolar NH4Cl Ammonium chloride nM NMR nanomolar Nuclear magnetic resonance Pd(dppf)Cl2 [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane PMB para-methoxybenzyl psi pounds per square inch TEA Triethylamine TFA trifluoroacetic acid Tf trifluoromethanesulfonate TIPS Triisopropylsilyl Ether TBDPS tert-butyldiphenylsilyl THF tetrahydrofuran TLC thin layer chromatography

[0262] Synthesis procedure Example 1 Synthesis of 3-[4-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]methyl]-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound 43) Step 1: Preparation of 2-chloro-3-fluoro-5-iodo-pyridin-4-amine [ka] To a solution of 2-chloro-3-fluoro-pyridin-4-amine (2.00 g, 13.7 mmol, 1 equiv.) and NIS (3.68 g, 16.4 mmol, 1.2 equiv.) in CH3CN (15 mL) was added p-TsOH (118 mg, 0.682 mmol, 0.05 equiv.), 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 (2 × 30 mL), saturated aqueous Na2SO3 (40 mL), 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] + . 1 H-NMR (400MHz, DMSO-d6) δ 8.09 (s, 1H), 6.67 (br s, 2H).

[0263] Step 2: Preparation of ethyl 4-amino-6-chloro-5-fluoro-pyridine-3-carboxylate [ka] To a solution of 2-chloro-3-fluoro-5-iodo-pyridin-4-amine (3.63 g, 13.3 mmol, 1 equiv.) in EtOH (70 mL) were added triethylamine (4.85 g, 48.0 mmol, 6.68 mL, 3.6 equiv.) and Pd(PPh3)2Cl2 (935 mg, 1.33 mmol, 0.1 equiv.), and the reaction mixture was stirred at 80 °C under CO (15 psi) (degassed under vacuum and purged with CO several times) for 16 h. The reaction mixture was concentrated under reduced pressure to remove approximately 70% of the EtOH and 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] + .

[0264] Step 3: Preparation of ethyl 6-chloro-5-fluoro-4-[(2,2,2-trichloroacetyl)carbamoylamino]pyridine-3-carboxylate [ka] To a solution of ethyl 4-amino-6-chloro-5-fluoro-pyridine-3-carboxylate (3.40 g, 15.6 mmol, 1 equiv.) in THF (10 mL) was added 2,2,2-trichloroacetyl isocyanate (3.22 g, 17.1 mmol, 2.03 mL, 1.1 equiv.) and the reaction mixture was stirred under N2 at 20 °C for 1 h. 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] + .

[0265] Step 4: Preparation of 7-chloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol [ka] 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 equiv.) in CHOH (55 mL) was added ammonia (7 M, 10.7 mL, 5 equiv.), and the reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was filtered, and the filter cake was washed with TBME (3×20 mL), then dried under reduced pressure to give the title compound (3.03 g, 14.06 mmol, 94% yield) as a white solid. LC / MS (ESI) m / z: 216.1 [M+H] + .

[0266] Step 5: Preparation of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine [ka] To a solution of 7-chloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol (2.50 g, 11.6 mmol, 1 equiv.) in toluene (30 mL) was added DIEA (4.50 g, 34.8 mmol, 6.06 mL, 3 equiv.) and POCl (8.89 g, 58.0 mmol, 5.39 mL, 5 equiv.), and the reaction mixture was stirred at 100° C. under N for 1 h. 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] + .

[0267] 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 [ka] To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (2.90 g, 11.5 mmol, 1 equiv.) in CHCl (50 mL) was added DIEA (7.42 g, 57.4 mmol, 5 equiv.) and tert-butyl (1S,5R)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.44 g, 11.5 mmol, 1 equiv.) at −40° C. and stirred under N at −40° C. for 0.5 h. The reaction mixture was poured into water (50 mL) and extracted with CHCl (3 × 50 mL). The combined organic phase was washed with brine (2 × 60 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (eluent: 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] + . 1H-NMR(400MHz,DMSO-d6)δ 9.06(s,1H),4.60~4.40(m,2H),4.31~4.22(m,2H),3.80~3.59(m,2H),1.85~1.74(m,2H),1.66~1.57(m,2H),1.46(s,9H).

[0268] 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 [ka] To a solution 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 (500 mg, 1.17 mmol, 1 equiv.) and 2,2-dimethoxyethanol (186 mg, 1.75 mmol, 1.5 equiv.) in CH3CN (10 mL) was added Cs2CO3 (456 mg, 1.40 mmol, 1.2 equiv.) and DABCO (13 mg, 0.17 mmol, 0.1 equiv.), 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 the crude product. The crude product was purified by flash silica gel chromatography (eluent: 0-15% THF / petroleum ether) to give the title compound. LC / MS(ESI)m / z:498.3[M+H] + . 1 H-NMR(400MHz,CDCl3)δ 8.74(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).

[0269] Step 8: Preparation of 5-[2-(4-fluorophenyl)acetyl]-2,2-dimethyl-1,3-dioxane-4,6-dione [ka] To a solution of 2-(4-fluorophenyl)acetic acid (50 g, 324.38 mmol, 1.0 equiv.), 2,2-dimethyl-1,3-dioxane-4,6-dione (51.4 g, 356.82 mmol, 1.1 equiv.), and DMAP (3.4 g, 27.57 mmol, 0.085 equiv.) in CHCN (150 mL) was added DIEA (121 mL, 697.43 mmol, 2.2 equiv.) followed by 2,2-dimethylpropanoyl chloride (44 mL, 356.82 mmol, 1.1 equiv.) slowly over 3 h while maintaining the temperature below 45 °C. The reaction mixture was stirred at 45 °C for 3 h. The reaction was cooled to 0 °C. HCl (500 mL, 1 M, 1.54 equiv.) was then added, and the mixture was stirred at 0 °C for 30 min. The mixture was filtered, and the filter cake was washed with water (CHCN:water = 1:4, 500 mL). The filter cake was dissolved in CHCl (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (84.5 g, 301.52 mmol, 93% yield) as a white solid.

[0270] Step 9: Preparation of tert-butyl 4-(4-fluorophenyl)-3-oxo-butanoate [ka] A solution of 5-[2-(4-fluorophenyl)acetyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (168 g, 601.25 mmol, 1.0 equiv) in t-BuOH (500 mL) was stirred at 90° C. for 2.5 hours. The reaction mixture was concentrated in vacuo to give the title compound as a yellow oil (151 g, 598.54 mmol, 100% yield). LC / MS (ESI) m / z: 197.1 [M-56] + .

[0271] Step 10: Preparation of 4-(4-fluorophenyl)-3-oxo-butanoic acid [ka] To a solution of tert-butyl 4-(4-fluorophenyl)-3-oxo-butanoate (151 g, 598.54 mmol, 1.0 equiv) in CHCl (300 mL) was added TFA (293 mL, 3.95 mol, 6.60 equiv) and the reaction mixture was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo 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] + .

[0272] Step 11: Preparation of 7-fluoronaphthalene-1,3-diol [ka] A solution of 4-(4-fluorophenyl)-3-oxobutanoic acid (115 g, 586.21 mmol, 1.0 equiv) in CFSOH (1200 mL) was stirred at 20 °C for 16 hours. The reaction 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 phase was washed with saturated aqueous NaHCO (40 mL × 2) and brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo 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) δ 10.19(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).

[0273] Step 12: Preparation of 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol [ka] To a solution of 7-fluoronaphthalene-1,3-diol (43.5 g, 244.23 mmol, 1.0 equiv), 2-bromoethynyl(triisopropyl)silane (67 g, 256.44 mmol, 1.05 equiv), and KOAc (48 g, 488.45 mmol, 2.0 equiv) in dioxane (300 mL), ruthenium dichloride and 1-isopropyl-4-methyl-benzene (9.0 g, 14.65 mmol, 0.06 equiv) were added under N2, and the reaction mixture was stirred at 110 °C for 16 h. The mixture was filtered and concentrated in vacuo, and the resulting residue was purified by flash chromatography on SiO2 (gradient: 0 to 20% ethyl acetate in 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)δ 9.17(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).

[0274] Step 13: Preparation of 7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)naphthalen-1-ol [ka] To a solution of 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol (46.3 g, 129.14 mmol, 1.0 equiv) in CHCl (450 mL) at 0 °C, DIEA (67.5 mL, 387.43 mmol, 3.0 equiv) and MOMCl (14.7 mL, 193.71 mmol, 1.5 equiv) were added, and the reaction mixture was stirred at 0 °C for 40 min. The reaction was quenched by the addition of water (50 mL) at 0 °C 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 in vacuo. The resulting residue was purified by flash chromatography on SiO (gradient: 0-15% dichloromethane in petroleum ether) to give the title compound (26.8 g, 62.51 mmol, 48% yield) as a yellow oil. LC / MS (ESI) m / z: 403.1 [M+H] + .

[0275] Step 14: Preparation of [7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]trifluoromethanesulfonate [ka] To a solution of 7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)naphthalen-1-ol (21.8 g, 54.15 mmol, 1.0 equiv.) and DIEA (28.3 mL, 162.45 mmol, 3.0 equiv.) in CHCl (300 mL) at −40° C., TfO (13.4 mL, 81.23 mmol, 1.5 equiv.) was added, and the reaction mixture was stirred at −40° C. for 40 minutes. The reaction was quenched by the addition of water (150 mL) at −40° C., warmed 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 in vacuo. The resulting residue was purified by flash chromatography on SiO.sub.2 (gradient: 0-15% dichloromethane in petroleum ether) to afford the title compound (28 g, 51.95 mmol, 96% yield) as a yellow oil.

[0276] Step 15: Preparation of 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane [ka] To a solution of [7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]trifluoromethanesulfonate (23.8 g, 44.52 mmol, 1.0 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (22.6 g, 89.03 mmol, 2.0 equiv), and KOAc (13.1 g, 133.55 mmol, 3.0 equiv) in toluene (350 mL) was added Pd(dppf)Cl (3.26 g, 4.45 mmol, 0.1 equiv) under N and the reaction mixture was stirred at 110 °C under N for 16 h. The mixture was filtered under vacuum through a Celite® pad and rinsed with ethyl acetate (80 mL x 2). The filtrate was evaporated to dryness, and the resulting residue was purified by flash chromatography on SiO2 (gradient: 0-3% ethyl acetate in 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] + .

[0277] Step 16: Preparation of tert-butyl 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-carboxylate [ka] 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 equiv.) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl- To a solution of orchid (494 mg, 0.964 mmol, 1.2 equiv.) in dioxane (10 mL) and HO (2 mL) was added KPO (512 mg, 2.41 mmol, 3.0 equiv.) and [2-(2-aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphane; methanesulfonate (117 mg, 0.161 mmol, 0.2 equiv.) under N. The reaction mixture was stirred at 85 °C under N for 15 h. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography on SiO (gradient: 0–27% ethyl acetate in petroleum ether) to afford the title compound (590 mg, 0.684 mmol, 85% yield) as a yellow solid. LC / MS (ESI) m / z: 848.4 [M+H] + .

[0278] 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 [ka] To a solution of tert-butyl 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-carboxylate (630 mg, 0.743 mmol, 1.0 equiv) in acetone (1.6 mL) was added aqueous HCl (1.58 mL, 12 M, 25.51 equiv) and the reaction mixture was stirred at 20 °C for 15 min. A solution of NaHCO3 (867 μL, 22.29 mmol, 30.0 equiv.) in water (3 mL), Boc2O (341 μL, 1.49 mmol, 2.0 equiv.), and THF (3 mL) was added, and the reaction mixture was stirred at 20 °C for 1 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography on SiO2 (gradient: 0-50% ethyl acetate in petroleum ether) to afford the title compound (420 mg, 386.23 μmol, 52% yield) as a yellow solid. LC / MS (ESI) m / z: 758.4 [M+H] + .

[0279] Step 18: Preparation of 2-bromo-6-[4-(dimethoxymethyl)-1-piperidyl]benzaldehyde [ka] To a solution of 4-(dimethoxymethyl)piperidine (8.47 g, 53.20 mmol, 1.20 equiv) and 2-bromo-6-fluorobenzaldehyde (9.00 g, 44.33 mmol, 1 equiv) in DMSO (90 mL) was added N,N-diisopropylethylamine (22.92 g, 177.33 mmol, 4.00 equiv), 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 flash silica gel chromatography (gradient: 0–7% ethyl acetate / petroleum ether) to afford the title compound (11.10 g, 32.43 mmol, 73% yield) as a yellow solid. LC / MS(ESI)m / z:344.1[M+H] + . 1 H NMR(400MHz,CDCl3)δ 10.22(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).

[0280] Step 19: Preparation of 3-[[2-bromo-6-[4-(dimethoxymethyl)-1-piperidyl]phenyl]methylamino]piperidine-2,6-dione [ka] To a solution of 3-aminopiperidine-2,6-dione (5.05 g, 30.68 mmol, 1.00 equiv., hydrochloride salt) in methanol (100 mL) and dichloromethane (100 mL) was added sodium acetate (7.55 g, 92.04 mmol, 3.00 equiv.), and the resulting mixture was stirred at 25° C. for 1 hour. 2-Bromo-6-[4-(dimethoxymethyl)-1-piperidyl]benzaldehyde (10.50 g, 30.68 mmol, 1.00 equiv.) and 2-methylpyridineborane (6.56 g, 61.36 mmol, 2.00 equiv.) were then 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 then 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 triturated 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] + . 1 H NMR (400 MHz, CDCl3) δ 10.78(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,1H),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).

[0281] Step 20: Preparation of 3-[4-[4-(dimethoxymethyl)-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione [ka] To a solution of 3-[[2-bromo-6-[4-(dimethoxymethyl)-1-piperidyl]phenyl]methylamino]piperidine-2,6-dione (10.70 g, 23.55 mmol, 1.00 equiv.) in DMF (150 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (3.45 g, 4.71 mmol, 0.20 equiv.) and diisopropylethylamine (9.13 g, 70.65 mmol, 3.00 equiv.). The reaction mixture was degassed, purged with carbon dioxide (3X), and then stirred at 80 °C under an atmosphere of carbon dioxide (50 Psi) for 12 hours. The reaction mixture was filtered, and the filtrate was diluted with water (200 mL) and then 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 in water (trifluoroacetic acid)]) to give the title compound as a white solid (2.60g, 6.48mmol, 27% yield). LC / MS (ESI) m / z: 402.2 [M+H] + .

[0282] Step 21: Preparation of 1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperidine-4-carbaldehyde [ka] To a solution of 3-[4-[4-(dimethoxymethyl)-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (70 mg, 0.17 mmol, 1.00 equiv.) in dichloromethane (2 mL) was added trifluoroacetic acid (60 mg, 0.52 mmol, 3.00 equiv.), 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] + .

[0283] Step 22: Preparation of tert-butyl 4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]piperidine-1-carboxylate [ka] To a solution of 1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperidine-4-carbaldehyde (340 mg, 0.95 mmol, 1 equiv.) in dimethyl sulfoxide (3 mL) and dichloromethane (3 mL), N-methylmorpholine (484 mg, 4.78 mmol, 0.5 mL, 5 equiv.), tert-butyl 4-(4-piperidylmethyl)piperidine-1-carboxylate (324 mg, 1.15 mmol, 1.2 equiv.), and acetic acid (57 mg, 0.95 mmol, 0.1 mL, 1 equiv.) were added, and the resulting mixture was stirred for 1 hour at 25° C. Sodium triacetoxyborohydride (406 mg, 1.91 mmol, 2 equiv.) was then 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 mL x 3). The organic extract was washed with brine (10 x 3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (gradient: 0 to 100% ethyl acetate in petroleum ether) to afford the title compound (312 mg, 0.50 mmol, 52% yield) as a yellow oil. LC / MS (ESI) m / z: 622.5 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 10.98(s,1H),7.46~7.40(m,1H),7.30(d,J=7.2Hz,1H),7.16(d,J=7.6Hz,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,2H),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).

[0284] Step 23: Preparation of 3-[1-oxo-4-[4-[[4-(4-piperidylmethyl)-1-piperidyl]methyl]-1-piperidyl]isoindolin-2-yl]piperidine-2,6-dione [ka] To a solution of tert-butyl 4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]piperidine-1-carboxylate (412 mg, 0.66 mmol, 1 equiv.) in dichloromethane (3 mL), trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 20.38 equiv.) was added, and the reaction mixture was stirred for 2 hours at 25° C. The mixture was concentrated in vacuo, and the resulting residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [1-18% CH3CN in water (formic acid)]) to give the title compound (200 mg, 0.38 mmol, 58% yield) as a yellow solid. LC / MS(ESI)m / z:522.4[M+H] + .

[0285] Step 24: Preparation of tert-butyl 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]-1-piperidyl]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-carboxylate [ka] To a solution of 3-[1-oxo-4-[4-[[4-(4-piperidylmethyl)-1-piperidyl]methyl]-1-piperidyl]isoindolin-2-yl]piperidine-2,6-dione (90 mg, 0.17 mmol, 1 equiv) in 1,2-dichloroethane (5 mL) and dimethyl sulfoxide (5 mL) was added 4-methylmorpholine (26 mg, 0.26 mmol, 28 μL, 1.5 equiv), and the resulting mixture was stirred at 25° C. for 15 minutes. Then, 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 (144 mg, 0.19 mmol, 1.1 equiv.) was added, and the mixture was stirred at 25° C. for 0.5 h. Sodium triacetoxyborohydride (110 mg, 0.52 mmol, 3 equiv.) was added, and the reaction mixture was stirred at 25° C. for 2 h. The reaction was quenched with water (20 mL), and the resulting mixture was extracted with ethyl acetate (20 mL×3). The combined organic extracts were extracted 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] + .

[0286] Step 25: Preparation of tert-butyl 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]-1-piperidyl]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-carboxylate [ka] To a solution of tert-butyl 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]-1-piperidyl]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-carboxylate (100 mg, 0.08 mmol, 1 equiv.) in DMF (3 mL) at 20° C. was added cesium fluoride (240 mg, 1.58 mmol, 20 equiv.). The reaction mixture was stirred at 20° C. for 2 hours. The reaction was quenched with water (20 mL), and the resulting mixture was extracted with ethyl acetate (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (80 mg, 0.07 mmol, 91% yield) as a yellow oil. LC / MS (ESI) m / z: 1107.7 [M+H] + .

[0287] Step 26: Preparation of 3-[4-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]methyl]-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound 43) [ka] A solution of tert-butyl 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]-1-piperidyl]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-carboxylate (80 mg, 0.07 mmol, 1 equiv) 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*40 mm*15 μm; mobile phase: [2-32% CHCN in water (formic acid)]) to give the title compound (62.7 mg, 0.05 mmol, 78% yield, formate salt) as a yellow solid.

[0288] Example 2 Synthesis of 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound 35)

[0289] Step 1: Preparation of 2,6-dibenzyloxypyridin-3-amine [ka] To a solution of phenylmethanol (16.59 g, 153.37 mmol, 16.0 mL, 2.5 equiv.) in tetrahydrofuran (200 mL), potassium tert-butoxide (17.21 g, 153.37 mmol, 2.5 equiv.) was added in several portions, and the resulting mixture was stirred at 25° C. for 2 hours. 2,6-Dichloropyridin-3-amine (10 g, 61.35 mmol, 1 equiv.) was then added, and the reaction mixture was stirred at 75° C. for 24 hours. The mixture was cooled to 25° C. and then diluted with ethyl acetate (600 mL). The organic phase was washed with water (100 mL × 3), and the aqueous phase was washed with ethyl acetate (100 mL × 2). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. 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 * 10 μm; mobile phase: [heptane-EtOH (0.1% NH OH)]; B%: 1% to 10%, 15 min) to obtain the title compound as a black-orange oil (3.1 g, 10.12 mmol, 16% yield). LC / MS (ESI) m / z: 307.4 [M + H] + . 1 H NMR(400MHz, CDCl3)δ 7.51~7.30(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).

[0290] Step 2: Preparation of 4-bromo-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-1-one [ka] To a solution of 2,6-dibenzyloxypyridin-3-amine (1.2 g, 3.92 mmol, 1 equiv.) and methyl 3-bromo-2-(bromomethyl)benzoate (1.21 g, 3.92 mmol, 1 equiv.) in N,N-dimethylacetamide (12 mL) was added N,N-diisopropylethylamine (1.52 g, 11.75 mmol, 2.1 mL, 3 equiv.), and the reaction mixture was stirred at 120° C. for 12 hours. 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 in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4:1) to give the title compound (1.45 g, 2.89 mmol, 74% yield) as a yellow solid. LC / MS (ESI) m / z: 501.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.89(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).

[0291] Step 3: Preparation of tert-butyl 4-[[1-[2-(2,6-dibenzyloxy-3-pyridyl)-1-oxo-isoindolin-4-yl]-4-piperidyl]methyl]piperidine-1-carboxylate [ka] To a mixture of 4-bromo-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-1-one (260 mg, 0.52 mmol, 1 equiv), tert-butyl 4-(4-piperidylmethyl)piperidine-1-carboxylate (195 mg, 0.57 mmol, 1.1 equiv, acetate salt), and cesium carbonate (507 mg, 1.56 mmol, 3 equiv) in dioxane (5 mL) was added [2-(2-aminophenyl)phenyl]chloropalladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (41 mg, 0.05 mmol, 0.1 equiv), and the reaction mixture was degassed and purged with nitrogen (3×), then stirred at 100° C. for 12 hours. The reaction mixture was cooled to 25°C, diluted with water (30 mL), and extracted with ethyl acetate (20 mL x 2). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by preparative TLC (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (320 mg, 0.46 mmol, 87% yield) as a light yellow gum. LC / MS (ESI) m / z: 703.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.81(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).

[0292] Step 4: Preparation of tert-butyl 4-[[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-4-piperidyl]methyl]piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-[[1-[2-(2,6-dibenzyloxy-3-pyridyl)-1-oxo-isoindolin-4-yl]-4-piperidyl]methyl]piperidine-1-carboxylate (320 mg, 0.46 mmol, 1 equiv.) in ethyl acetate (10 mL), palladium on activated carbon catalyst (0.1 g, 10% purity) was added under nitrogen. The resulting suspension was degassed, purged with hydrogen (3×), and then stirred under hydrogen (15 Psi) at 25° C. for 16 hours. The mixture was filtered through a Celite® bed, and the filtrate was concentrated in vacuo. The resulting residue was purified by preparative TLC (dichloromethane / methanol=10 / 1) to give the title compound (110 mg, 0.21 mmol, 46% yield) as a white solid. LC / MS (ESI) m / z: 547.3 [M+Na] + . 1 H NMR(400MHz,DMSO-d6)δ 10.98(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(br d,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).

[0293] Step 5: Preparation of 3-[1-oxo-4-[4-(4-piperidylmethyl)-1-piperidyl]isoindolin-2-yl]piperidine-2,6-dione [ka] To a solution of tert-butyl 4-[[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-4-piperidyl]methyl]piperidine-1-carboxylate (220 mg, 0.42 mmol, 1 equiv.) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 32.21 equiv.), and the reaction mixture was stirred at 25° C. for 0.5 h. The solution was concentrated in vacuo to give the title compound (220 mg, crude, trifluoroacetate salt) as a white solid. LC / MS (ESI) m / z: 425.1 [M+H] + .

[0294] Step 6: Preparation of tert-butyl 3-[2-[2-[4-[[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-4-piperidyl]methyl]-1-piperidyl]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-carboxylate [ka] To a solution of 3-[1-oxo-4-[4-(4-piperidylmethyl)-1-piperidyl]isoindolin-2-yl]piperidine-2,6-dione (220 mg, 0.41 mmol, 1 equiv., trifluoroacetate salt) in DMSO (3 mL) and 1,2-dichloroethane (3 mL) was added 4-methylmorpholine (124 mg, 1.23 mmol, 0.1 mL, 3 equiv.), followed by 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 (248 mg, 0.32 mmol, 0.8 equiv) and acetic acid (25 mg, 0.41 mmol, 1 equiv) were added and the resulting mixture was stirred at 25° C. for 0.5 h.

[0295] Sodium triacetoxyborohydride (260 mg, 1.23 mmol, 3 equiv.) was then added, and the reaction mixture was stirred at 25° C. for 12 hours. 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 in vacuo. The resulting residue was purified by preparative TLC (dichloromethane / methanol=10 / 1) to give the title compound (230 mg, 0.20 mmol, 48% yield) as a white solid. LC / MS (ESI) m / z: 1166.6 [M+H] + .

[0296] Step 7: Preparation of tert-butyl 3-[2-[2-[4-[[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-4-piperidyl]methyl]-1-piperidyl]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-carboxylate [ka] To a solution of tert-butyl 3-[2-[2-[4-[[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-4-piperidyl]methyl]-1-piperidyl]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-carboxylate (230 mg, 0.20 mmol, 1 equiv) in DMF (6 mL), cesium fluoride (449 mg, 2.96 mmol, 15 equiv) was added and the reaction mixture was stirred at 25 °C for 1.5 h. The mixture was diluted with ethyl acetate (200 mL), and the organic phase was washed with brine (20 mL x 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 light yellow solid (110 mg, 0.11 mmol, 55% yield). LC / MS (ESI) m / z: 1010.1 [M+H] + .

[0297] Step 8: Preparation of 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound 35) [ka] To a solution of tert-butyl 3-[2-[2-[4-[[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-4-piperidyl]methyl]-1-piperidyl]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-carboxylate (110 mg, 0.11 mmol, 1 equiv) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 124.03 equiv) and the reaction mixture was stirred at 25 °C for 0.5 h. The solution was concentrated and the resulting residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [9-39% CH3CN in water (formic acid)]), followed by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [8-38% CH3CN in water (formic acid)]) to give the title compound (14.8 mg, 0.01 mmol, 13% yield, formate salt) as a yellow solid.

[0298] Example 3 Synthesis of 3-[4-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]methyl]-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound 55) Step 1: Preparation of 8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol [ka] A solution of naphthalene-1,3-diol (50 g, 312.17 mmol, 1 equiv.), 2-bromoethynyl(triisopropyl)silane (97.87 g, 374.60 mmol, 1.2 equiv.), ruthenium dichloride; 1-isopropyl-4-methyl-benzene (19.12 g, 31.22 mmol, 0.1 equiv.), and potassium acetate (61.27 g, 624.34 mmol, 2 equiv.) in dioxane (600 mL) was stirred at 110 °C under nitrogen for 12 h. 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 (70 g, 205.56 mmol, 65% yield) as a yellow solid. LC / MS (ESI) m / z: 341.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 9.30(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).

[0299] Step 2: Preparation of 3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)naphthalen-1-ol [ka] To a solution of 8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol (270 g, 792.88 mmol, 1 equiv.) and N,N-diisopropylethylamine (307.42 g, 2.38 mol, 414 mL, 3 equiv.) in dichloromethane (2.5 L) at 0 °C, chloro(methoxy)methane (96.44 g, 1.20 mol, 91 mL, 1.51 equiv.) was added, and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with water (1000 mL) and extracted with dichloromethane (1000 mL x 2). The combined organic extracts were extracted with brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give the title compound (185 g, 481.04 mmol, 61% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 6.4 Hz, 1H), 7.34–7.29 (m, 1H), 7.00–6.96 (m, 1H), 6.77 (d, J = 2.4 Hz, 1H), 5.27 (s, 2H), 3.51 (s, 3H), 1.27–1.22 (m, 3H), 1.20–1.17 (m, 1H).

[0300] Step 3: Preparation of [3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]trifluoromethanesulfonate [ka] To a solution of 3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)naphthalen-1-ol (175 g, 455.04 mmol, 1 equiv.) and N,N-diisopropylethylamine (176.43 g, 1.37 mol, 238 mL, 3 equiv.) in dichloromethane (2 L) at −40° C., trifluoromethylsulfonyl trifluoromethanesulfonate (192.58 g, 682.56 mmol, 113 mL, 1.5 equiv.) was added dropwise, and the resulting mixture was stirred under nitrogen at −40° C. for 1 h. 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 residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to give the title compound (91 g, 144.69 mmol, 92% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.77-7.71 (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).

[0301] Step 4: Preparation of triisopropyl-[2-[6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl]silane [ka] A mixture of [3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]trifluoromethanesulfonate (192 g, 371.63 mmol, 1 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (61.83 g, 483.12 mmol, 70 mL, 1.3 equiv.), triethylamine (112.82 g, 1.11 mol, 155 mL, 3 equiv.), and cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium; and iron (30.35 g, 37.16 mmol, 0.1 equiv.) in acetonitrile (2 L) was stirred at 80° C. under nitrogen 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 (165 g, 333.64 mmol, 89% yield) as a yellow solid. LC / MS (ESI) m / z: 495.4 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.73~7.65(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).

[0302] Step 5: Preparation of 2-[8-ethynyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] A solution of triisopropyl-[2-[6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl]silane (81 g, 163.79 mmol, 1 equiv.) and cesium fluoride (497.59 g, 3.28 mol, 20 equiv.) 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 x 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] + . 1 H NMR(400MHz,CDCl3)δ 7.75(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).

[0303] Step 6: Preparation of 2-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a solution of 2-[8-ethynyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25 g, 73.92 mmol, 1 equiv) in methanol (300 mL) and tetrahydrofuran (300 mL) was added palladium on activated carbon (5 g, 10% purity), and the reaction mixture was stirred under a hydrogen atmosphere (15 psi) at 20° C. for 5 hours. The reaction mixture was filtered through Celite®, and the filtrate was concentrated to give the title compound (14 g, 46.95 mmol, 81% yield) as a yellow oil. 1H NMR(400MHz,CDCl3)δ 7.60(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).

[0304] 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 [ka] 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 (1.6 g, 3.21 mmol, 1 equiv.) and 2-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.28 To a solution of CsCO (2.62 g, 8.03 mmol, 2.5 equiv) (Cs, 3.73 mmol, 1.16 equiv) in dioxane (15 mL) and HO (3 mL) were added [CsCO] (2.62 g, 8.03 mmol, 2.5 equiv) and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (418.8 mg, 0.643 mmol, 0.2 equiv), and the reaction mixture was stirred at 110 °C under N for 16 h. The mixture was diluted with EtOAc (150 mL), and the combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (gradient: 10–30% EtOAc in petroleum ether) to give the title compound (0.922 g, 1.28 mmol, 40% yield) as a brown solid. LC / MS(ESI)m / z:678.4[M+H] + .

[0305] 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 [ka] To a solution 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 (100 mg, 0.148 mmol, 1 equiv) in acetone (0.37 mL) was added concentrated HCl (12 M, 0.37 mL, 30 equiv) dropwise and the reaction mixture was stirred at 20° C. for 5 min (a total of 9 batches were performed). Saturated aqueous NaHCO was then added until the pH reached 8, and the resulting mixture was filtered and washed with water (10 mL) and petroleum ether (10 mL) to give 2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyacetaldehyde (640 mg, crude) as a yellow solid. A solution of BocO (343.8 mg, 1.58 mmol, 1.2 equiv.) and NaHCO (330.8 mg, 3.94 mmol, 3 equiv.) in HO (2.5 mL) was then added, and the reaction mixture was stirred at 20 °C for 2 h. 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 flash chromatography on silica gel (gradient: 10-50% EtOAc in petroleum ether) to give the title compound as a yellow solid (430 mg, 46% yield). LC / MS (ESI) m / z: 588.4 [M+H] + .

[0306] Step 9: Preparation of tert-butyl 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]-1-piperidyl]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-carboxylate [ka] 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 (150 mg, 0.255 mmol, 1 equiv.) and 3-[1-oxo-4-[4-[[4-(4-piperidylmethyl)-1-piperidyl]methyl]-1-piperidyl]isoindolin-2-yl]piperidine To a solution of lysine-2,6-dione (222 mg, 0.262 mmol, 75% purity, 1.03 equiv., TFA) in isopropanol (3.5 mL) and dichloromethane (5 mL), NaOAc (42 mg, 0.51 mmol, 2 equiv.), AcOH (107 mg, 1.79 mmol, 102 μL, 7 equiv.), and 2-picoline borane complex (82 mg, 0.77 mmol, 3 equiv.) were added, and 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 flash chromatography on SiO (gradient: 0-20% methanol / dichloromethane) to give the title compound (255 mg, 0.233 mmol, 91% yield) as a white solid. LC / MS (ESI) m / z: 1093.4 [M+H] + .

[0307] Step 10: Preparation of 3-[4-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]methyl]-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound 55) [ka] A solution of tert-butyl 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]-1-piperidyl]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-carboxylate (155 mg, 0.142 mmol, 1 equiv.) in HCOOH (5 mL) was stirred for 4 h at 20 ° C. The reaction 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% CHCN in water (formic acid)]). Pure fractions were combined and dried by lyophilization to give the title compound (51.4 mg, 0.048 mmol, 34% yield, formate salt) as a white solid.

[0308] Example 4 Synthesis of 3-[4-[4-[[4-[[1-[2-[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]methyl]-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound 42) [ka] To a solution of 3-[4-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]methyl]-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (110 mg, 0.10 mmol, 1 equiv., trifluoroacetate salt) in dichloromethane (2 mL) and methanol (2 mL) was added 4-methylmorpholine (15 mg, 0.15 mmol, 1.5 equiv.) and the mixture was stirred at 25° C. for 15 minutes. Formaldehyde (40 mg, 0.50 mmol, 37% purity, 5 equiv.) was then added, and the resulting mixture was stirred at 25°C for 0.5 h. Sodium triacetoxyborohydride (63 mg, 0.30 mmol, 3 equiv.) 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 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [1-31% CH3CN in water (formic acid)]) to give the title compound (61.0 mg, 0.06 mmol, 56% yield) as a white solid.

[0309] Example 5 Synthesis of 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 28)

[0310] Step 1: Preparation of 7-bromo-1-methylindoline-2,3-dione [ka] To a mixture of 7-bromoindoline-2,3-dione (12 g, 53.09 mmol, 1 equiv.), potassium carbonate (11.01 g, 79.64 mmol, 1.5 equiv.), and water (1.2 mL) in DMF (60 mL) was added dropwise a solution of methyl iodide (8.44 g, 59.43 mmol, 3.7 mL, 1.12 equiv.) in DMF (24 mL). The reaction mixture was stirred at 25° C. for 2 hours. Water (120 mL) was then 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 in vacuo to give the title compound (8 g, 33.33 mmol, 62% yield) as a red solid. LC / MS (ESI) m / z: 242.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 7.81 (br d, J = 7.6 Hz, 1H) 7.55 (br d, J = 7.2 Hz, 1H) 7.05 (t, J = 8.0 Hz, 1H) 3.47 (s, 3H).

[0311] Step 2: Preparation of 3-bromo-2-(methylamino)benzoic acid [ka] Aqueous hydrogen peroxide (38 g, 335.15 mmol, 32.20 mL, 30% purity, 10.06 equiv.) was added dropwise to a mixture of 7-bromo-1-methylindoline-2,3-dione (8 g, 33.33 mmol, 1 equiv.) and sodium hydroxide (2 M, 199.96 mL, 12 equiv.) 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 x 3). The combined organic extracts were washed with water (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (6.0 g, crude) as a brown oil. LC / MS (ESI) m / z: 252.2 [M+Na] + .

[0312] Step 3: Preparation of 7-bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one [ka] To a solution of 3-bromo-2-(methylamino)benzoic acid (6 g, 26.08 mmol, 1 equiv., crude) and N,N-diisopropylethylamine (5.04 g, 39.01 mmol, 6.80 mL, 1.50 equiv.) in DMF (40 mL) was added diphenylphosphoryl azide (10.76 g, 39.10 mmol, 8.47 mL, 1.50 equiv.) 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 in vacuo at 50° C. to give the title compound (4 g, 17.62 mmol, 67% yield) as an off-white solid. LC / MS(ESI)m / z:226.9[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 11.17 (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).

[0313] 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 [ka] To a solution of 7-bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (2.00 g, 8.81 mmol, 1 equiv.) in tetrahydrofuran (40 mL) was added potassium 2-methylpropan-2-olate (1 M, 10.67 mL, 1.21 equiv.), and the resulting mixture was stirred at 0 °C for 0.5 h. Then, a solution of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (4.2 g, 11.01 mmol, 1.25 equiv.) in tetrahydrofuran (20 mL) was added dropwise, and the reaction mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched by the addition of 10% ammonium chloride solution (10 mL) at 0 °C, and the resulting mixture was stirred at 0 °C for 1 h. It was then extracted with ethyl acetate (50 mL x 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 (3.5 g, 7.64 mmol, 87% yield) as a white solid. LC / MS (ESI) m / z: 460.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.24(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).

[0314] Step 5: Preparation of tert-butyl 4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]methyl]piperidine-1-carboxylate [ka] 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (1 g, 2.18 mmol, 1 equiv.) and tert-butyl To a solution of 4-(4-piperidylmethyl)piperidine-1-carboxylate (1.12 g, 3.27 mmol, 1.5 equiv., acetic acid) in N,N-dimethylacetamide (20 mL) was added cesium carbonate (2.13 g, 6.54 mmol, 3 equiv.) and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; and dichloropalladium (212 mg, 0.22 mmol, 9.99 e-2 equiv.). The reaction mixture was stirred at 90 °C for 2 h. The mixture was cooled to 25 °C, and the residue was poured into ice-water (50 mL) and stirred for 2 min. 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*40 mm*15 μm; mobile phase: [68-98% CH3CN in water (formic acid)]) to give the title compound (150 mg, 0.23 mmol, 10% yield) as a yellow solid. LC / MS (ESI) m / z: 660.4 [M+H] + .

[0315] Step 6: Preparation of 3-[3-methyl-2-oxo-4-[4-(4-piperidylmethyl)-1-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione [ka] To a solution of tert-butyl 4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]methyl]piperidine-1-carboxylate (160 mg, 0.24 mmol, 1 equiv) in toluene (1 mL) was added methanesulfonic acid (405 mg, 4.21 mmol, 0.3 mL, 17.38 equiv) 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.

[0316] 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 [ka] To a solution 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 (5 g, 11.67 mmol, 1 equiv.) and 1,4-diazabicyclo[2.2.2]octane (261.90 mg, 2.33 mmol, 256.77 μL, 0.2 equiv.) in acetonitrile (50 mL) at 25 °C, 2-[tertbutyl(dimethyl)silyl]oxyethanol (2.47 g, 14.01 mmol, 1.2 equiv.) and cesium carbonate (11.41 g, 35.02 mmol, 3 equiv.) were added, and the reaction mixture was stirred at 50 °C for 5 h. 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 (4 g, 7.04 mmol, 60% yield) as a yellow solid. LC / MS (ESI) m / z: 568.3 [M+H] + . 1H NMR(400MHz,CDCl3)δ 8.73(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).

[0317] 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-carboxylate [ka] tert-Butyl 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 (4 g, 7.04 mmol, 1 equiv.), 2-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.13 g, 9.15 mmol, 1.3 equiv.), potassium phosphate (4.48 g, 21.12 mmol, 3 equiv.), and [2-(2- A mixture of bis(1-adamantyl)butylphosphane methanesulfonate (513 mg, 704.03 μmol, 0.1 equiv.) in dioxane (50 mL) and water (6 mL) was stirred at 90° C. under nitrogen for 12 hours. 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.

[0318] 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 [ka] To a solution 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-carboxylate (4.4 g, 5.88 mmol, 1 equiv.) in DMF (40 mL) at 25 °C, cesium fluoride (26.81 g, 176.48 mmol, 30 equiv.) was added, and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were extracted 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)δ 9.04(s,1H),7.71(d,J=8.0Hz,1H),7.54(d,J=2.8Hz,1H),7.42(t,J=7.6Hz,1H),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).

[0319] Step 10: Preparation of tert-butyl (1R,5S)-3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] 1758671112361_0 A solution of oxalyl chloride (771 mg, 9.86 mmol, 0.8 mL, 2.5 equiv.) in 10 mL of dichloromethane was added dropwise to a solution of oxalyl chloride (751 mg, 5.92 mmol, 0.5 mL, 1.5 equiv.) in 10 mL of dichloromethane at −78° C. After 15 minutes, a solution 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 (2.5 g, 3.95 mmol, 1 equiv.) in 10 mL of dichloromethane 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 equiv.) was then added, and the reaction mixture was stirred at -78 °C for 30 minutes. It was then warmed to 25 °C over 1 hour. The reaction was quenched with saturated sodium sulfite solution (20 mL), and the resulting mixture was extracted with dichloromethane (20 mL x 3). The combined organic phase was 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 (1.8 g, 2.85 mmol, 72% yield) as a yellow solid. LC / MS (ESI) m / z: 632.3 [M+H] + .

[0320] Step 11: Preparation of tert-butyl 3-[2-[2-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]methyl]-1-piperidyl]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-carboxylate [ka] To a solution of 3-[3-methyl-2-oxo-4-[4-(4-piperidylmethyl)-1-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (102 mg, 0.18 mmol, 1 equiv., trifluoroacetic acid) in dichloromethane (1 mL) and isopropyl alcohol (1 mL) was added diisopropylethylamine (119 mg, 0.92 mmol, 0.2 mL, 5 equiv.) and tert-butyl (1R,5S)-3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (128 mg, 0.20 mmol, 1.1 equiv) was added, and the resulting mixture was stirred at 25° C. for 1 hour. Sodium triacetoxyborohydride (117 mg, 0.55 mmol, 3 equiv) 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 in vacuo. 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] + .

[0321] Step 12: Preparation of 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 28) [ka] To a solution of tert-butyl 3-[2-[2-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]methyl]-1-piperidyl]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-carboxylate (82 mg, 0.08 mmol, 1 equiv) in dichloromethane (1 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 173.81 equiv) and the reaction mixture was stirred at 25 °C for 0.5 h. The solvent was concentrated under a stream of nitrogen, and the crude product was purified by reverse-phase HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [9-39% CH3CN in water (formic acid)]) to give the title compound as a white solid (26.2 mg, 0.03 mmol, 32% yield, bis-formate salt).

[0322] Example 6 Synthesis of 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound 56) [ka] The title compound was prepared in a similar manner to 3-[4-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]methyl]-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (bis-formate salt, white solid).

[0323] 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]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound 41) [ka] To a solution of formaldehyde (28 mg, 0.35 mmol, 37% purity, 5 equiv.) in dichloromethane (2 mL) and methanol (2 mL) was added 4-methylmorpholine (10 mg, 0.10 mmol, 1.5 equiv.), and the resulting mixture was stirred at 25° C. for 15 min. 3-[4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (70 mg, 0.07 mmol, 1 equiv., trifluoroacetate salt) was then added and the mixture was stirred for 0.5 h at 25° C. Sodium triacetoxyborohydride (44 mg, 0.21 mmol, 3 equiv.) 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 3-100 C18 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 salt) as a white solid.

[0324] Example 8 Synthesis of 5-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Compound 67)

[0325] Step 1: Preparation of tert-butyl 4-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]methyl]piperidine-1-carboxylate [ka] To a mixture of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (500 mg, 1.81 mmol, 1.0 equiv.) and tert-butyl 4-(4-piperidylmethyl)piperidine-1-carboxylate (613 mg, 2.17 mmol, 1.2 equiv.) in DMSO (10 mL), diisopropylethylamine (5.43 mmol, 946 μL, 3.0 equiv.) was added in one portion at 25 °C, and the reaction mixture was stirred at 100 °C for 2 h. 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 extracted with brine (30 mL), dried over anhydrous NaSO, and concentrated in vacuo. The crude product was purified by flash chromatography on SiO2 (gradient: 0 to 41% ethyl acetate in 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] + .

[0326] Step 2: Preparation of 2-(2,6-dioxo-3-piperidyl)-5-[4-(4-piperidylmethyl)-1-piperidyl]isoindoline-1,3-dione [ka] To a solution of tert-butyl 4-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]methyl]piperidine-1-carboxylate (93 mg, 0.173 mmol, 1.0 equiv.) in dichloromethane (2 mL), HCl / dioxane (4 M, 432 μL, 10.0 equiv.) was added and the reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound (75 mg, 0.147 mmol, 85% yield) as a white solid. LC / MS (ESI) m / z: 439.0 [M+H] + .

[0327] Step 3: Preparation of 5-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Compound 67) [ka] The title compound was prepared by 3-[4-[4-[[1-[2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(2,6-dioxo-3-piperidyl)-5-[4-(4-piperidylmethyl)-1-piperidyl]isoindoline-1,3-dione.

[0049] This compound was prepared in a similar manner to -[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]methyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione and purified by preparative HPLC (column: Xtimate C18 100*30 mm*10 μm; mobile phase: [5-50% CHCN in water (formic acid)]). Pure fractions were combined and lyophilized to give the title compound (32.1 mg, 0.035 mmol, 79% yield, formate salt) as a yellow solid.

[0328] Example 9 Synthesis of 4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Compound 66)

[0329] Step 1: Preparation of tert-butyl 4-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]-4-piperidyl]methyl]piperidine-1-carboxylate [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (400 mg, 1.45 mmol, 1.0 equiv.) and tert-butyl 4-(4-piperidylmethyl)piperidine-1-carboxylate (450 mg, 1.59 mmol, 1.1 equiv.) in DMSO (10 mL) was added diisopropylethylamine (4.34 mmol, 757 μL, 3.0 equiv.), 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 x 9), brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography on SiO (gradient: 0 to 29% ethyl acetate in petroleum ether) to afford the title compound (610 mg, 0.789 mmol, 55% yield) as a yellow solid. LC / MS(ESI)m / z:483.3[M-C4H8+H] + .

[0330] Step 2: Preparation of 2-(2,6-dioxo-3-piperidyl)-4-[4-(4-piperidylmethyl)-1-piperidyl]isoindoline-1,3-dione [ka] To a solution of tert-butyl 4-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]-4-piperidyl]methyl]piperidine-1-carboxylate (200 mg, 0.371 mmol, 1.0 equiv.) in dichloromethane (2 mL), HCl / dioxane (4 M, 928 μL, 10.0 equiv.) was added and the reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound (139 mg, 285 mmol, 77% yield) as a yellow solid. LC / MS (ESI) m / z: 439.3 [M+H] + .

[0331] Step 3: Preparation of 4-[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Compound 66) [ka] The title compound was prepared by 3-[4-[4-[[1-[2-oxoethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-(2,6-dioxo-3-piperidyl)-4-[4-(4-piperidylmethyl)-1-piperidyl]isoindoline-1,3-dione.

[0049] This compound was prepared in a similar manner to -[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]methyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione and purified by preparative HPLC (column: Xtimate C18 100*30 mm*10 μm; mobile phase: [10-50% CHCN in water (formic acid)]). Pure fractions were combined and lyophilized to give the title compound (21.2 mg, 0.022 mmol, 57% yield, formate salt) as a yellow solid.

[0332] Example 10 Synthesis of 4-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]methyl]-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Compound 57)

[0333] Step 1: Preparation of 4-[4-(dimethoxymethyl)-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (800 mg, 2.90 mmol, 1.0 equiv.) in dimethyl sulfoxide (8 mL) was added 4-(dimethoxymethyl)piperidine (553 mg, 3.48 mmol, 1.2 equiv.), 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 flash chromatography on SiO (gradient: 0-4% methanol in dichloromethane) to give the title compound (929 mg, 2.10 mmol, 72% yield) as a yellow solid. LC / MS (ESI) m / z: 416.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.97(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,6) H).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).

[0334] Step 2: Preparation of 1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperidine-4-carbaldehyde [ka] To a solution of 4-[4-(dimethoxymethyl)-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (460 mg, 1.11 mmol, 1.0 equiv.) in tetrahydrofuran (9 mL) was added hydrochloric acid (1 M, 8.30 mL, 7.5 equiv.), and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was adjusted to pH = 7 by adding saturated sodium bicarbonate solution, and then extracted with ethyl acetate (20 mL x 3). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give the title compound (398 mg, 0.98 mmol, 88% yield) as a yellow solid. LC / MS (ESI) m / z: 370.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 9.75(s,1H),7.96(s,1H),7.68~7.64(m,1H),7.53~7.51(m,1H),5.00~4.96(m,1H),3.72~3.7 0(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).

[0335] Step 3: Preparation of tert-butyl 4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]piperidine-1-carboxylate [ka] To a solution of 1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperidine-4-carbaldehyde (398 mg, 1.08 mmol, 1 equiv.) and tert-butyl 4-(4-piperidylmethyl)piperidine-1-carboxylate (304 mg, 1.08 mmol, 1 equiv.) in isopropanol (3 mL) and dichloromethane (3 mL) were added acetic acid (259 mg, 4.31 mmol, 0.25 mL, 4 equiv.) and 2-methylpyridineborane (461 mg, 4.31 mmol, 4 equiv.) in one portion at 20° C., and the reaction mixture was stirred for 1 hour at 20° C. The reaction mixture was adjusted to pH=6 by the addition of triethylamine and then concentrated. The crude product was purified by flash chromatography (gradient: 0-100% ethyl acetate in 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] + . 1 H NMR(400MHz,CDCl3)δ 7.59~7.55(m,1H),7.37(d,J=3.2Hz,1H),7.17(d,J=4.4Hz,1H),4.98~4.94(m,1 H),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,3 H), 1.72~1.49(m,8H),1.46(s,9H),1.43(s,1H),1.20(s,2H),1.11~1.01(m,2H).

[0336] Step 4: Preparation of 2-(2,6-dioxo-3-piperidyl)-4-[4-[[4-(4-piperidylmethyl)-1-piperidyl]methyl]-1-piperidyl]isoindoline-1,3-dione [ka] To a solution of tert-butyl 4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]piperidine-1-carboxylate (130 mg, 0.20 mmol, 1 equiv.) in dichloromethane (2 mL) was added trifluoroacetic acid (466 mg, 4.09 mmol, 0.3 mL, 20 equiv.), 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] + . Step 5: Preparation of 4-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]methyl]-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Compound 57) The title compound was prepared by 3-[4-[[4-(4-piperidylmethyl)-1-piperidyl]methyl]-1-piperidyl]isoindoline-1,3-dione starting from 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 and 2-(2,6-dioxo-3-piperidyl)-4-[4-[[4-(4-piperidylmethyl)-1-piperidyl]methyl]-1-piperidyl]isoindoline-1,3-dione. -[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]methyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione was prepared in a similar manner and purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [3-43% CH3CN in water (formic acid)]) followed by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [3-33% CH3CN in water (formic acid)]). Pure fractions were combined and dried by lyophilization to give the title compound as a yellow solid (49.1 mg, 0.05 mmol, 48% yield, 27% yield, formate salt).

[0337] Example 11: Synthesis of [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate (Compound 63)

[0338] Step 1: Preparation of 1-benzyl 2-methyl(2S)-pyrrolidine-1,2-dicarboxylate [ka] To a solution of (2S)-methylpyrrolidine-2-carboxylate hydrochloride (40.0 g, 242 mmol, 1 equiv.) in CHCl (500 mL), TEA (56.2 g, 556 mmol, 2.3 equiv.) and CbzCl (53.6 g, 314 mmol, 1.3 equiv.) were added, and the reaction mixture was stirred at 25 °C under N for 16 h. The reaction mixture was washed with water (100 mL), brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (gradient: 0-10% THF in petroleum ether) to afford the title compound (60.6 g, 230 mmol, 95% yield) as a colorless oil. LC / MS (ESI) m / z: 264.0 [M+H] + .

[0339] Step 2: Preparation of 1-benzyl 2-methyl 2-but-3-enylpyrrolidine-1,2-dicarboxylate [ka] To a stirred solution of 1-benzyl 2-methyl(2S)-pyrrolidine-1,2-dicarboxylate (27.5 g, 104 mmol, 1 equiv.) in THF (300 mL) at −78° C., LiHMDS (1 M, 125 mL, 1.2 equiv.) was added, and the reaction mixture was stirred at −78° C. for 0.5 h under N. 4-Bromobut-1-ene (28.2 g, 209 mmol, 2 equiv.) was then added at −78° C., and the reaction mixture was stirred at 20° C. under N 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 flash silica gel chromatography (gradient: 0-8% THF in petroleum ether) to give the title compound (44.9 g, 141 mmol, 68% yield) as a yellow oil. LC / MS (ESI) m / z: 318.0 [M+H] + .

[0340] Step 3: Preparation of 1-benzyl 2-methyl 2-[2-(oxiran-2-yl)ethyl]pyrrolidine-1,2-dicarboxylate [ka] To a solution of 1-benzyl 2-methyl 2-but-3-enylpyrrolidine-1,2-dicarboxylate (44.9 g, 141 mmol, 1 equiv.) in CHCl (600 mL) was added m-CPBA (33.6 g, 156 mmol, 80% purity, 1.1 equiv.), 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 NaHSO (300 mL), NaHCO (2 × 200 mL), and brine (200 mL), then dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (gradient: 0–15% THF in 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] + .

[0341] Step 4: Preparation of methyl 3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolidine-8-carboxylate [ka] To a solution of 1-benzyl 2-methyl 2-[2-(oxiran-2-yl)ethyl]pyrrolidine-1,2-dicarboxylate (37.5 g, 112 mmol, 1 equiv.) in CHOH (400 mL) was added Pd / C (3.0 g, 10% purity), and the reaction mixture was stirred under N (15 psi) at 25 °C for 16 h (degassed under vacuum and purged with H several times). 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.

[0342] Step 5: Preparation of methyl (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate and methyl (3R,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate [ka] To a solution of methyl 3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolidine-8-carboxylate (22.4 g, 112 mmol, 1 equiv.) and imidazole (9.95 g, 146 mmol, 1.3 equiv.) in CHCl (300 mL), TBDPSCl (37.1 g, 135 mmol, 1.2 equiv.) was added, and the reaction mixture was stirred at 25 °C under N for 16 h. The reaction mixture was quenched by adding water (100 mL) and extracted with CHCl (3 × 100 mL). The combined organic extracts were washed with brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (gradient: 0–10% THF in petroleum ether). Methyl (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (24.3 g, 39.7 mmol, 35% yield) was first eluted and isolated as a colorless oil (LC / MS (ESI) m / z: 438.2 [M+H] + ) Methyl (3R,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (20.8 g, 43.0 mmol, 38% yield) was then eluted and isolated as a colorless oil (LC / MS (ESI) m / z: 438.3 [M+H] + ).

[0343] Step 6: Preparation of methyl (3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidine-8-carboxylate and methyl (3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidine-8-carboxylate [ka] Methyl (3R,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (20.8 g, 47.5 mmol, 1 equiv.) was purified 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, methyl (3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidine-8-carboxylate (9.78 g, 22.35 mmol, 47% yield) as a colorless oil (LC / MS (ESI) m / z: 438.2 [M+H] + ), followed by the enantiomer methyl (3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidine-8-carboxylate (8.81 g, 20.1 mmol, 42.36% yield) as a colorless oil (LC / MS (ESI) m / z: 438.3 [M+H] + ).

[0344] Step 7: Preparation of [(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol [ka] To a solution of methyl (3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidine-8-carboxylate (2.69 g, 6.15 mmol, 1 equiv.) in THF (30 mL) at 0 °C, LiAlH (280 mg, 7.38 mmol, 1.2 equiv.) was added, and the reaction mixture was stirred at 0 °C for 1 h under N. The reaction mixture was quenched by the sequential addition of water (300 μL), 15% NaOH (300 μL), and water (900 μL), and then diluted with EtOAc (30 mL). The resulting suspension was dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (gradient: 0-10% CHOH in 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] + .

[0345] Step 8: Preparation of tert-butyl 3-[2-[[(3R,8R)-3-[[tert-butyl (diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of [(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (1.00 g, 2.44 mmol, 1 equiv.) and tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.05 g, 2.44 mmol, 1 equiv.) in dioxane (30 mL) was added CsCO (954 mg, 2.93 mmol, 1.2 equiv.) and DABCO (109 mg, 0.976 mmol, 0.4 equiv.), and the reaction mixture was stirred at 25 °C under N for 40 h. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel chromatography (gradient: 0-20% THF in 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] + .

[0346] Step 9: Preparation of tert-butyl 3-[2-[[(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-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-carboxylate [ka] To a solution of tert-butyl 3-[2-[[(3R,8R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 0.998 mmol, 1 equiv.) and 2-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (376 mg, 1.10 mmol, 1.1 equiv.) in dioxane (20 mL) was added CataCXium® A Pd G3 (145 mg, 0.199 mmol, 0.2 equiv) and K2CO3 (2.2 M, 2.04 mL, 4.5 equiv) were added, and the reaction mixture was stirred under N2 at 100 °C for 12 h (degassed under vacuum and purged with N2 several times). The reaction mixture was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (gradient: 0-30% THF in 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] + . 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-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-[2-[[(3R,8R)-3-[[tert-butyl (diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-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-carboxylate (300 mg, 0.192 mmol, 63% purity, 1 equiv.) in THF (3 mL) was added TBAF (1 M, 458.59 μL, 1.5 equiv.), and the reaction mixture was stirred for 3 h at 25° C. The reaction mixture was quenched by the addition of water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (3x10 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] + .

[0347] Step 11: Preparation of tert-butyl 3-[2-[[(3R,8R)-3-[[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carbonyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-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-carboxylate [ka] To a solution of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3R,8R)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.081 mmol, 1 equiv.) in THF (3 mL) was added triethylamine (65 mg, 0.65 mmol, 8 equiv.), DMAP (1 mg, 0.008 mmol, 0.1 equiv.), and (4-nitrophenyl)carbonochloridate (33 mg, 0.16 mmol, 2 equiv.), and the reaction mixture was stirred at 25 °C under N for 16 h. 2-(2,6-Dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione (40.55 mg, 88.84 μmol, 1.1 equiv., TFA) was then added, and the reaction mixture was stirred at 25° C. under N for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on SiO (gradient: 0-5% methanol in dichloromethane) to give the title compound (77 mg, 0.069 mmol, 86% yield) as a yellow solid. LC / MS (ESI) m / z: 1111.3 [M+H] + .

[0348] Step 12: Preparation of [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate (Compound 63) [ka] A solution of tert-butyl 3-[2-[[(3R,8R)-3-[[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carbonyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-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-carboxylate (77 mg, 0.069 mmol, 1 equiv) in HCOOH (5 mL) was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [0-40% CHCN in water (formic acid)]). Pure fractions were combined and dried by lyophilization to give the title compound (25.0 mg, 0.025 mmol, 36% yield, formate salt) as a yellow solid.

[0349] Example 12: Synthesis of [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate (Compound 62)

[0350] Step 1: Preparation of [(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol [ka] To a solution of methyl (3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidine-8-carboxylate (1.57 g, 3.59 mmol, 1 equiv.) in THF (20 mL) at 0 °C, LiAlH (163 mg, 4.30 mmol, 1.2 equiv.) was added, and the reaction mixture was stirred at 0 °C for 1 h under N. The reaction mixture was quenched by the sequential addition of water (200 μL), 15% aqueous NaOH (200 μL), and water (600 μL), and then diluted with EtOAc (30 mL). The resulting suspension was dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (gradient: 0-10% CHOH in CH2Cl2) to give the title compound as a yellow oil (911 mg, 2.22 mmol, 62% yield). LC / MS (ESI) m / z: 410.3 [M+H] + .

[0351] Step 2: Preparation of tert-butyl 3-[2-[[(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of [(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (911 mg, 2.22 mmol, 1 equiv.) and tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (951 mg, 2.22 mmol, 1 equiv.) in dioxane (30 mL) was added CsCO (868 mg, 2.66 mmol, 1.2 equiv.) and DABCO (75 mg, 0.67 mmol, 0.3 equiv.), and the reaction mixture was stirred at 25 °C under N for 16 h. Additional DABCO (25 mg, 0.22 mmol, 0.1 equiv) was added, and the reaction mixture was stirred under N at 25 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC (35-65% CHCN in water (0.225% formic acid)). Pure fractions were combined and lyophilized to dryness 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] + .

[0352] Step 3: Preparation of tert-butyl 3-[2-[[(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-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-carboxylate [ka] To a solution of tert-butyl 3-[2-[[(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.125 mmol, 1 equiv.) and 2-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (51 mg, 0.15 mmol, 1.2 equiv.) in dioxane (2.5 mL) was added KPO (1.5 M, 125 μL, 1.5 equiv.) and CataCXium® A Pd G3 (18 mg, 0.025 mmol, 0.2 equiv) was added, and the reaction mixture was stirred under N2 at 100 °C for 12 h (degassed under vacuum and purged with N2 several times). The reaction mixture was quenched by adding water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (gradient: 0-20% THF in 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] + .

[0353] 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-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-[2-[[(3S,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-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-carboxylate (162 mg, 0.165 mmol, 1 equiv.) in THF (2 mL) was added TBAF (1 M, 0.248 mL, 1.5 equiv.), and the reaction mixture was stirred for 3 h at 25° C. The reaction mixture was quenched by the addition of water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (3x10 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] + .

[0354] Step 5: Preparation of [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate (Compound 62) [ka] The title compound was prepared starting from tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3S,8S)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, by the addition of [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octane

[0049] This was prepared in a similar manner to

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0059]

[0059]

[0062] [0059 ...

[0355] Example 13 Synthesis of [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (Compound 59)

[0356] Step 1: Preparation of 5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-1-one [ka] To a mixture of 2,6-dibenzyloxypyridin-3-amine (2 g, 6.53 mmol, 1.0 equiv.) and methyl 4-bromo-2-(bromomethyl)benzoate (2.01 g, 6.53 mmol, 1.0 equiv.) in DMA (20 mL) was added diisopropylethylamine (3.41 mL, 19.58 mmol, 3.0 equiv.), and the reaction mixture was stirred at 125 °C for 15 h. The mixture was cooled and then diluted with EtOAc (40 mL) and water (30 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with water (30 mL x 3), brine (30 mL x 3), dried over Na SO , filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on SiO (gradient: 0-15% ethyl acetate in petroleum ether) to give the title compound (1.3 g, 2.44 mmol, 37% yield) as a yellow solid. LC / MS (ESI) m / z: 502.9 [M+H] + .

[0357] Step 2: Preparation of tert-butyl 4-[2-(2,6-dibenzyloxy-3-pyridyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate [ka] 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 equiv) in dioxane (20 mL), tert-butyl piperazine-1-carboxylate (680.93 mg, 3.66 mmol, 1.5 equiv), CsCO (2.38 g, 7.31 mmol, 3.0 equiv), and [2-(2-aminophenyl)phenyl]chloropalladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (191.77 mg, 243.73 μmol, 0.1 equiv) were added, and the reaction mixture was stirred at 110 °C for 15 h under a N atmosphere. The reaction was cooled, diluted with water (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on SiO2 (gradient: 0 to 50% ethyl acetate in petroleum ether) to give the title compound (0.8 g, 1.13 mmol, 47% yield) as a yellow solid. LC / MS (ESI) m / z: 607.2 [M+H] + .

[0358] Step 3: Preparation of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-[2-(2,6-dibenzyloxy-3-pyridyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (800 mg, 1.13 mmol, 86% purity, 1.0 equiv.) in EtOAc (20 mL) was added Pd / C (0.1 g, 1.13 mmol, 10% purity, 1.0 equiv.) under Ar atmosphere, and the resulting suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 (15 psi) at 50 °C for 15 h. 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 equiv.) was added under Ar, and the suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H (15 psi) at 50° C. for 15 h. The mixture was filtered and the 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] + .

[0359] Step 4: Preparation of 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione [ka] To a solution of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (60 mg, 140.03 μmol, 1.0 equiv.) in CHCl (1 mL) was added TFA (1 mL, 13.51 mmol, 96.45 equiv.), and the reaction mixture was stirred at 25° C. for 1 h. 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] + .

[0360] Step 5: Preparation of [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (Compound 59) [ka] The title compound was prepared by tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3R,8R)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione. -[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate was prepared in a similar manner and purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [2-42% CH3CN in water (formic acid)]). Pure fractions were combined, concentrated under reduced pressure, and then lyophilized to afford the title compound (32.0 mg, 31.65 μmol, 20% yield, formate salt) as an off-white solid.

[0361] Example 14: Synthesis of [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (Compound 58) [ka] The title compound was prepared by tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3S,8S)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione, followed by 2-chloro-2-[[(3R,8R)-8 -[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate was prepared in a similar manner and purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [2-42% CH3CN in water (formic acid)]). Pure fractions were combined, concentrated under reduced pressure, and then lyophilized to give the title compound (31.6 mg, 32.43 μmol, 24% yield, formate salt) as an off-white solid.

[0362] Example 15: Synthesis of [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperazine-1-carboxylate (Compound 65)

[0363] Step 1: Preparation of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperazine-1-carboxylate [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (500 mg, 1.81 mmol, 1.0 equiv) and tert-butyl piperazine-1-carboxylate (405 mg, 2.17 mmol, 1.2 equiv) in DMSO (8 mL) was added diisopropylethylamine (0.946 mL, 5.43 mmol, d = 0.742 g / mL, 3.0 equiv), and the reaction mixture was stirred at 100 °C for 3 h. The mixture was diluted with HO (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 NaSO, filtered, and concentrated. The resulting residue was purified by flash chromatography on SiO (gradient: 0-2% methanol in dichloromethane) to give the title compound (600 mg, 1.10 mmol, 61% yield) as a yellow oil. LC / MS (ESI) m / z: 386.9 [M-55] + . 1H NMR(400MHz,CDCl3)δ 7.94(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).

[0364] Step 2: Preparation of 2-(2,6-dioxo-3-piperidyl)-4-(piperazin-1-yl)isoindoline-1,3-dione [ka] To a solution of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperazine-1-carboxylate (600 mg, 1.10 mmol, 1.0 equiv) in CHCl (8 mL) was added TFA (6.0 mL, 81.04 mmol, d=1.54 g / mL, 59.8 equiv), and the reaction mixture was stirred at 20° C. for 0.5 h. The mixture was concentrated in vacuo to give the title compound (620 mg, crude, TFA) as a yellow solid. LC / MS (ESI) m / z: 343.1 [M+H] + .

[0365] Step 3: Preparation of [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperazine-1-carboxylate (Compound 65) [ka] The title compound was prepared by tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3R,8R)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolidin-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-piperidyl)-4-(piperazin-1-yl)isoindoline-1,3-dione, [(3R,8 R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate was prepared in a similar manner and purified by preparative HPLC (conditions: [2-42% CH3CN in water (formic acid)]; column: Phenomenex C18 75*30 mm*3 μm; flow rate: 25 mL / min). Pure fractions were combined and lyophilized to give the title compound (36.3 mg, 0.037 mmol, 49% yield, formate salt) as a yellow solid.

[0366] Example 16: Synthesis of [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperazine-1-carboxylate (Compound 64) [ka] The title compound was prepared starting from tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3S,8S)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolidin-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, [(3R, (8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate was prepared in a similar manner and purified by preparative HPLC (conditions: [2-42% CHCN in water (formic acid)]; column: Phenomenex C18 75*30 mm*3 μm; flow rate: 25 mL / min). Pure fractions were combined and lyophilized to give the title compound (31.0 mg, 0.031 mmol, 47% yield, formate salt) as a yellow solid.

[0367] Example 17: Synthesis of [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate (Compound 61)

[0368] Step 1: Preparation of tert-butyl 4-[2-(2,6-dibenzyloxy-3-pyridyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate [ka] To a solution of 4-bromo-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-1-one (500 mg, 0.997 mmol, 1.0 equiv) and tert-butyl piperazine-1-carboxylate (279 mg, 1.50 mmol, 1.5 equiv) in dioxane (6 mL) was added CsCO (975 mg, 2.99 mmol, 3.0 equiv) and [2-(2-aminophenyl)phenyl]chloropalladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (78 mg, 0.100 mmol, 0.1 equiv), and the reaction mixture was stirred at 110 °C for 12 h. The mixture was filtered and concentrated, and the resulting residue was purified by flash chromatography on SiO2 (gradient: 0 to 30% ethyl acetate in petroleum ether) to give the title compound (410 mg, 0.642 mmol, 64% yield) as a yellow solid. LC / MS (ESI) m / z: 607.2 [M+H] + .

[0369] Step 2: Preparation of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-[2-(2,6-dibenzyloxy-3-pyridyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate (410 mg, 0.642 mmol, 1.0 equiv) in EtOAc (10 mL) was added Pd / C (200 mg, 10% purity) and the reaction mixture was stirred under H (15 psi) at 50° C. for 12 hours. The reaction was filtered and concentrated in vacuo to give the title compound (300 mg, crude) as a light yellow oil. LC / MS (ESI) m / z: 429.1 [M+H] + .

[0370] Step 3: Preparation of 3-(1-oxo-4-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione [ka] To a solution of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate (300 mg, 0.700 mmol, 1.0 equiv) in CHCl (4 mL) was added TFA (3.0 mL, 40.52 mmol, d=1.54 g / mL, 57.9 equiv) and the reaction mixture was stirred at 20° C. for 0.5 h. The reaction was concentrated in vacuo to give the title compound (310 mg, crude, TFA) as a yellow solid. LC / MS (ESI) m / z: 329.0 [M+H] + .

[0371] Step 4: Preparation of [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate (Compound 61) [ka] The title compound was prepared by tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3R,8R)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 3-(1-oxo-4-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione, [(3R, (8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate was prepared in a similar manner and purified by preparative HPLC (5-40% CHCN in water (formic acid)]; gradient time: 25 min; column: Phenomenex C18 75*30 mm*3 μm; flow rate: 25 mL / min). Pure fractions were combined and lyophilized to give the title compound as a white solid (28.3 mg, 29.14 μmol, 38% yield, formate salt).

[0372] Example 18: Synthesis of [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate (Compound 60) [ka] The title compound was prepared starting from tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3S,8S)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 3-(1-oxo-4-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione, [(3R, (8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate was prepared in a similar manner and purified by preparative HPLC (5-40% CHCN in water (formic acid)]; gradient time: 25 min; column: Phenomenex C18 75*30 mm*3 μm; flow rate: 25 mL / min). Pure fractions were combined and lyophilized to give the title compound (22.9 mg, 0.024 mmol, 33% yield, formate salt) as a white solid.

[0373] Example 19: Synthesis of [(3R,8R)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (Compound 48) [ka] [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl To a solution of 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (85.0 mg, 0.086 mmol, 1.0 equiv., HCl) in CHCl (2 mL) and CHOH (2 mL), formaldehyde (0.429 mmol, 32.0 μL, 37% purity, 5.0 equiv.) and 2-methylpyridineborane (14.0 mg, 0.129 mmol, 1.5 equiv.) were added, and the reaction mixture was stirred at 25° C. for 1 h. 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% CHCN in water (formic acid)]). The pure fractions were lyophilized to give the title compound (17.9 mg, 0.017 mmol, 20% yield, formate salt) as a yellow solid.

[0374] Example 20: Synthesis of [(3S,8S)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (Compound 47) [ka] The title compound was prepared in a similar manner to [(3R,8R)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate and purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [5-35% CH3CN in water (formic acid)]). The pure fractions were lyophilized to give the title compound (40.5 mg, 0.040 mmol, 29% yield, formate salt) as a yellow solid.

[0375] Example 21: Synthesis of [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (Compound 53) Step 1: Preparation of tert-butyl 4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (430 mg, 1.00 mmol, 1.0 equiv) in DMA (5 mL) was added CsCO (654.0 mg, 2.01 mmol, 2.0 equiv) and CHI (2.01 mmol, 125 μL, 2.0 equiv), 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 NaSO, 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] + .

[0376] Step 2: Preparation of 1-methyl-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione [ka] To a solution of tert-butyl 4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (420 mg, 949.14 μmol, 1 equiv.) in CHCl (5 mL), HCl / dioxane (5 mL, 4 M) was added, and the reaction mixture was stirred at 25° C. for 0.5 h. Petroleum ether (30 mL) was then 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] + .

[0377] 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-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carbonyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3R,8R)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 0.1 mmol, 1.0 equiv) in THF (3 mL) was added triethylamine (1.08 mmol, 150 μL, 10 equiv), DMAP (1.0 mg, 0.001 mmol, 0.1 equiv), and (4-nitrophenyl) carbonochloridate (37.0 mg, 0.183 mmol, 1.7 equiv), and the reaction mixture was stirred at 40 °C for 15 h. 1-Methyl-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (45.0 mg, 0.118 mmol, 1.1 equiv., HCl) was then added, and the reaction mixture was stirred at 40° C. for 1 h. The mixture was concentrated, and the resulting residue was purified by flash chromatography on SiO (gradient: 0-5% methanol in dichloromethane) to afford the title compound (100 mg, 0.056 μmol, 53% yield) as a yellow solid. LC / MS (ESI) m / z: 1111.4 [M+H] + .

[0378] Step 4: Preparation of [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (Compound 53) [ka] A mixture 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-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carbonyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.09 mmol, 1 equiv) in CHCl (2 mL) and 4 M HCl / dioxane (2 mL) was stirred at 25 °C for 0.5 h. Petroleum ether (30 mL) was then added, and the resulting mixture was stirred at 25°C for 0.5 h. The resulting precipitate was collected and purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [5-40% CHCN in water (formic acid)]). The pure fractions were lyophilized to give the title compound (29.7 mg, 28.79 μmol, 32% yield, formate salt) as a white solid.

[0379] Example 22: Synthesis of [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (Compound 50) [ka] The title compound was prepared starting from tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3S,8S)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octane-3

[0049] 4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (compound 53) was prepared in a similar manner as above and purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [5-40% CHCN in water (formic acid)]). Pure fractions were lyophilized to afford the title compound (30.2 mg, 0.029 mmol, 32% yield, formate salt) as a white solid.

[0380] Example 23: Synthesis of [(3R,8R)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate (Compound 51) [ka] The title compound was prepared by the procedure of (3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl Starting from 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate, [(3R,8R)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate was prepared in the same manner as [(3R,8R)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate], the eluate was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [5-35% Aqueous solution of CH3CN (formic acid)]) to afford the title compound (22.2 mg, 0.021 mmol, 35% yield, formate salt) as a white solid.

[0381] Example 24: Synthesis of [(3S,8S)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate (Compound 49) [ka] The title compound was synthesized by the method of claim 1, wherein the hydroxyl group is [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl Starting from 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate, [(3R,8R)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate was prepared in the same manner as [(3R,8R)-8-[[7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolidin-3-yl]methyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate], the eluate was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; gradient: 5%~35% Purification with CH3CN in water (NH4HCO3); gradient time: 25 min; retention time: 4 min; flow rate: 25 mL / min gave the title compound (58.3 mg, 0.059 mmol, 52% yield) as a yellow solid.

[0382] Example 25: Synthesis of [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate (Compound 54) Step 1: Preparation of tert-butyl 4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate (400 mg, 0.934 mmol, 1.0 equiv) in DMF (8 mL) at 0 °C, CsCO (608 mg, 1.87 mmol, 2.0 equiv) and CHI (0.116 mL, 1.87 mmol, d = 2.28 g / mL, 2.0 equiv) were added, and the reaction mixture was stirred under N at 20 °C for 3 h. The mixture was diluted with HO (30 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic extracts were washed with water (20 mL x 3) and brine (20 mL x 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the title compound (490 mg, crude) as a yellow solid. LC / MS (ESI) m / z: 387.2 [M-55] + .

[0383] Step 2: Preparation of 1-methyl-3-(1-oxo-4-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione [ka] To a solution of tert-butyl 4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate (50 mg, 0.113 mmol, 1 equiv.) in CHCl (1 mL) was added 4M HCl / EtOAc (1 mL), and the reaction mixture was stirred at 20° C. for 20 minutes. The mixture was concentrated under reduced pressure to give the title compound (40 mg, 0.106 mmol, 93% yield, HCl salt) as a yellow solid. LC / MS (ESI) m / z: 343.0 [M+H] + .

[0384] Step 3: Preparation of [(3R,8R)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate (Compound 54) [ka] The title compound was prepared by tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3R,8R)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolidin-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-isoindolin-2-yl)piperidine-2,6-dione, [(3R,8R)-8-[ [4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (compound 53) was prepared in a similar manner and purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [5-40% CH3CN in water (formic acid)]). Pure fractions were combined and dried by lyophilization to give the title compound (30.8 mg, 0.030 mmol, 46% yield, formate salt) as a white solid.

[0385] Example 26. Synthesis of [(3S,8S)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]piperazine-1-carboxylate (Compound 52) [ka] The title compound was prepared by tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(3S,8S)-3-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolidin-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-isoindolin-2-yl)piperidine-2,6-dione, [(3R,8R)- 8-[[4-(3,8-diazabicyclo[3.2.1]octan-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-hexahydropyrrolidin-3-yl]methyl 4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (compound 53) was prepared in a similar manner and purified by preparative HPLC (gradient: 5–45% CHCN in water (formic acid); gradient time: 28 min; retention time: 3 min; flow rate: 25 mL / min). Pure fractions were combined and lyophilized under reduced pressure to give the title compound (17.0 mg, 17.46 μmol, 28% yield, formate salt) as a white solid.

[0386] Example 27 Synthesis of 3-[6-(1-{2-[(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy]ethyl}piperidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (Compound 36) Step 1: Preparation of tert-butyl 3-(2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)ethoxy)-7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution 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 (51 μmol) in dichloromethane (1 mL) and isopropyl alcohol (0.1 mL), 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (54 μmol), 2-methylpyridine borane 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).

[0387] Step 2: Preparation of 3-[6-(1-{2-[(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy]ethyl}piperidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (Compound 36) [ka] To a solution of tert-butyl 3-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-1-piperidyl]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-carboxylate (44 μmol) in hexafluoroisopropanol (1 mL), trifluoroacetic acid (0.2 mL) was added and stirred for 0.5 h at 25 °C. The reaction mixture was purified by preparative HPLC (Welch Xtimate C18 150 x 25 mm x 5 μm; A: water with 0.225% v / v FA; B: acetonitrile; B%: 20-60, 25 min), followed by lyophilization, to give the title compound.

[0388] Compounds 1–8, 10–22, 25–27, 31–34, and 37–40 were prepared using procedures similar to those used to prepare compound 36.

[0389] Example 28: Synthesis of 3-[5-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]methyl]-1-piperidyl]-4-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound 69) Step 1: Preparation of methyl 2-bromo-3,4-difluorobenzoate [ka] To a solution of 2-bromo-3,4-difluorobenzoic acid (200 g, 843.8 mmol, 1 equiv) in methanol (1.5 L) at 0 °C, thionyl dichloride (200.8 g, 1.69 mol, 122.4 mL, 2 equiv) was added dropwise and the reaction mixture was stirred at 70 °C for 12 h. The mixture was concentrated in vacuo, and the residue was diluted with water (600 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (208 g, 98%) as a yellow oil. 1H NMR (400MHz, CDCl3) δ 7.68 (ddd, J=2.0, 5.4, 8.8Hz, 1H), 7.25~7.14 (m, 1H), 3.94 (s, 3H).

[0390] Step 2: Preparation of methyl 2-bromo-4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorobenzoate [ka] To a solution of methyl 2-bromo-3,4-difluorobenzoate (208 g, 828.60 mmol, 1 equiv.) in dimethyl sulfoxide (1500 mL), diisopropylethylamine (321.3 g, 2.49 mol, 433.0 mL, 3 equiv.) and 4-(dimethoxymethyl)piperidine (138.5 g, 870.03 mmol, 1.05 equiv.) were added, and the reaction mixture was stirred at 100 °C for 12 h. 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 in vacuo. The residue was purified by silica gel chromatography (gradient: 1–50% EtOAc in 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] + . 1H NMR(400MHz,CDCl3)δ 7.62(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).

[0391] Step 3: Methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluoro-2-vinylbenzoate [ka] To a solution of methyl 2-bromo-4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorobenzoate (170 g, 435.63 mmol, 1 equiv.) and potassium vinyltrifluoroborate (175.06 g, 1.31 mol, 3 equiv.) in dioxane (1.3 L) and water (250 mL), bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (17.8 g, 21.78 mmol, 0.05 equiv.) and sodium carbonate (115.4 g, 1.09 mol, 2.5 equiv.) were added, and the reaction mixture was stirred at 110 °C for 12 h. Water (1 L) was then added, and the aqueous mixture was extracted with EtOAc (3 x 600 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (1-25% EtOAc in petroleum ether) to give the title compound as a white solid (123 g, 83%). LC / MS (ESI) m / z: 338.1 [M+H] + . 1H NMR(400MHz,CDCl3)δ 7.64(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).

[0392] Step 4: Methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluoro-2-formylbenzoate [ka] To a solution of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluoro-2-vinylbenzoate (50 g, 148.20 mmol, 1 equiv.) in dioxane (450 mL) and water (150 mL), 2,6-lutidine (31.8 g, 296.40 mmol, 34.5 mL, 2 equiv.), potassium osmate(VI) dihydrate (1.1 g, 2.96 mmol, 0.02 equiv.), and sodium periodate (126.79 g, 592.79 mmol, 32.85 mL, 4 equiv.) were added, and the reaction mixture was stirred at 20° C. for 1 h. 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 in vacuo. The residue was purified by silica gel chromatography (1–50% EtOAc in petroleum ether) to give the title compound as a yellow solid (36 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 7.65 (dd, J = 0.8, 8.4 Hz, 1H), 7.01 (t, J = 8.4 Hz, 1H), 4.09 (d, J = 7.0 Hz, 1H), 3.90 (s, 3H), 3.63 (br d, J = 12.2 Hz, 2H), 3.45–3.32 (m, 6H), 2.84–2.69 (m, 2H), 1.93–1.73 (m, 3H), 1.51 (br d, J = 3.6 Hz, 2H).

[0393] Step 5: Preparation of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] To a solution of 3-aminopiperidine-2,6-dione (20.4 g, 123.76 mmol, 1.2 equiv., hydrochloride salt) in methanol (350 mL) was added sodium acetate (25.4 g, 309.41 mmol, 3 equiv.), followed by methyl 4-[4-(dimethoxymethyl)-1-piperidyl]-3-fluoro-2-formylbenzoate (35 g, 103.14 mmol, 1 equiv.) and sodium cyanoborohydride (13.0 g, 206.27 mmol, 2 equiv.), and the reaction mixture was stirred at 40° C. for 12 hours. The mixture was filtered, and the cake was washed with methanol (2×20 mL). The cake was triturated 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)δ 10.97(s,1H),7.46(d,J=8.2Hz,1H),7.23~7.05(m,1H),5.15~4.99(m,1 H),4.52~4.42(m,1H),4.36~4.26(m,1H),4.12(d,J=6.4Hz,1H),3.49(br d,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).

[0394] Step 6: Preparation of 1-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-4-carbaldehyde [ka] To a solution of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (37 g, 88.21 mmol, 1 equiv.) in acetone (350 mL) and water (35 mL) was added p-toluenesulfonic acid (3.0 g, 17.64 mmol, 0.2 equiv.) and the reaction mixture was stirred at 70° C. for 12 hours. The mixture was filtered and the 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 solid. LC / MS (ESI) m / z: 374.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.97(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).

[0395] Step 7: Preparation of tert-butyl 4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-1-oxo-isoindolin-5-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]piperidine-1-carboxylate [ka] To a mixture of 1-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (1.0 g, 2.68 mmol, 1 equiv.) and tert-butyl 4-(4-piperidylmethyl)piperidine-1-carboxylate (1.69 g, 3.21 mmol, 1.2 equiv., acetate salt) in dichloromethane (10 mL) and dimethyl sulfoxide (10 mL) was added diisopropylethylamine (346 mg, 2.68 mmol, 0.4 mL, 1.0 equiv.) at 25° C. The resulting mixture was stirred under nitrogen for 15 minutes. Sodium triacetoxyborohydride (1.70 g, 8.03 mmol, 3 equiv.) was then added, and the reaction mixture was stirred at 25° C. for 1 hour. 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] + .

[0396] Step 8: Preparation of 3-[4-fluoro-1-oxo-5-[4-[[4-(4-piperidylmethyl)-1-piperidyl]methyl]-1-piperidyl]isoindolin-2-yl]piperidine-2,6-dione [ka] To a solution of tert-butyl 4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-1-oxo-isoindolin-5-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]piperidine-1-carboxylate (570 mg, 0.89 mmol, 1 equiv.) in dichloromethane (6 mL) was added trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL, 30.32 equiv.) and the reaction mixture was stirred at 25° C. for 0.5 h. The mixture was concentrated in vacuo to give the title compound (580 mg, crude, trifluoroacetate salt) as a brown gum. LC / MS (ESI) m / z: 540.5 [M+H]+ .

[0397] Step 9: Preparation of tert-butyl 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-1-oxo-isoindolin-5-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]-1-piperidyl]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-carboxylate [ka] To a solution of 3-[4-fluoro-1-oxo-5-[4-[[4-(4-piperidylmethyl)-1-piperidyl]methyl]-1-piperidyl]isoindolin-2-yl]piperidine-2,6-dione (578 mg, 0.88 mmol, 1.49 equiv., trifluoroacetate salt) in dichloromethane (5 mL) and isopropanol (5 mL) was added diisopropylethylamine (230 mg, 1.78 mmol, 0.3 mL, 3 equiv.), followed by 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 (450 mg, 593.72 μmol, 1 equiv.) was added, and the resulting mixture was stirred at 25° C. for 10 minutes. Sodium triacetoxyborohydride (377 mg, 1.78 mmol, 3 equiv.) was then added, and the reaction mixture was stirred at 25° C. for 0.5 hours. 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 in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2 / CH3OH = 20 / 1 to 6 / 1) to give the title compound (470 mg, 0.36 mmol, 61% yield) as a light yellow solid. LC / MS (ESI) m / z: 1281.9 [M+H]+ .

[0398] Step 10: Preparation of tert-butyl 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-1-oxo-isoindolin-5-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]-1-piperidyl]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-carboxylate [ka] To a mixture of tert-butyl 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-1-oxo-isoindolin-5-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]-1-piperidyl]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-carboxylate (460 mg, 0.35 mmol, 1 equiv.) in DMF (5 mL) at 25° C., cesium fluoride (1.09 g, 7.18 mmol, 0.2 mL, 20 equiv.) was added, 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 column chromatography (CH2Cl2 / CH3OH=5 / 1) to give the title compound (168 mg, 0.14 mmol, 41% yield) as a white solid. LC / MS (ESI) m / z: 563.6 [M / 2+H] + .

[0399] Step 11: Preparation of 3-[5-[4-[[4-[[1-[2-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxyethyl]-4-piperidyl]methyl]-1-piperidyl]methyl]-1-piperidyl]-4-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound 69) [ka] To a solution of tert-butyl 3-[2-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-1-oxo-isoindolin-5-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]-1-piperidyl]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-carboxylate (168 mg, 0.14 mmol, 1 equiv.) in dichloromethane (1.5 mL) was added hydrochloric acid in dioxane (4 M, 0.5 mL, 13.40 equiv.), and the reaction mixture was stirred for 15 minutes at 25° C. The mixture was diluted with petroleum ether (6 mL), and the pH was adjusted to 6. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [6-36% CH3CN in water (formic acid)]) to give the title compound as a yellow solid (91.0mg, 0.08mmol, 56% yield, formate salt).

[0400] Example 29 Synthesis of 3-[5-[4-[[3-[[1-[[4-(3,8-diazabicyclo[3.2.1]octan-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]undecan-9-yl]methyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 193) Step 1: Preparation of 2,6-bis(benzyloxy)-3-nitropyridine [ka] To a mixture of 2,6-dichloro-3-nitropyridine (25.0 g, 156 mmol) and phenylmethanol (40.6 mL, 390 mmol) in acetonitrile (500 mL) was added cesium carbonate (127.21 g, 390 mmol) in one portion under a nitrogen atmosphere, and the mixture was stirred at 60 °C for 6 h. The mixture was cooled to 20 °C, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with petroleum ether / methyl tert-butyl ether (1:1, 500 mL) to give the title compound (49 g, 93%) as a yellow solid.

[0401] Step 2: Preparation of 2,6-bis(benzyloxy)pyridin-3-amine [ka] 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), iron (126.19 g, 2.26 mol) was added under a nitrogen atmosphere, and the mixture was stirred at 90 °C for 16 h. 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 min. The aqueous layer was extracted with ethyl acetate (2 × 1000 mL). The combined organic phase was 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 over 15 min) to give the title compound (61 g, 70%) as a brown oil. LC / MS(ESI)m / z:307.2[M+H] + .

[0402] Step 3: Preparation of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin-3-amine [ka] To a solution of 2,6-bis(benzyloxy)pyridin-3-amine (5.0 g, 16 mmol) and 4-bromo-1-fluoro-2-nitro-benzene (2.4 mL, 20 mmol) in tetrahydrofuran (50 mL) was added a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 24.5 mL). The mixture was stirred at -78 °C for 1 h and then at 25 °C for 11 h under a nitrogen atmosphere. The reaction was slowly quenched with saturated ammonium chloride solution, the pH was adjusted to 8-9, and then extracted with ethyl acetate (300 mL). The organic phase 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] + .

[0403] Step 4: Preparation of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine [ka] To a solution of 2,6-dibenzyloxy-N-(4-bromo-2-nitrophenyl)pyridin-3-amine (8.0 g, 16 mmol) in ethanol (100 mL) and water (50 mL) was added iron (4.41 g, 79 mmol) and saturated aqueous ammonium chloride (8.45 g, 128 mmol), 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 phase 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, then 10 / 1) to give the title compound (2.8 g, 37%) as a brown solid.

[0404] Step 5: Preparation of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one [ka] 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) was added 4-dimethylaminopyridine (4.77 g, 29 mmol), and the mixture was stirred at 120° C. for 2 hours. The reaction 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] + .

[0405] Step 6: Preparation of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one [ka] 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) was added sodium hydride (191 mg, 4.8 mmol, 60%) at 0°C, and the reaction mixture was stirred for 0.5 h. Iodomethane (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 aqueous ammonium chloride (10 mL), and the resulting mixture was extracted with ethyl acetate (200 mL). The organic extract was washed with brine (3 x 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] + .

[0406] Step 7: Preparation of 1-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(dimethoxymethyl)-1-piperidyl]-3-methyl-benzimidazol-2-one [ka] 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), XPhos Pd G2 (152 mg, 0.2 mmol) and cesium carbonate (1.89 g, 5.8 mmol) were added, and the mixture was stirred at 100 °C for 16 hours. 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, then 1 / 2) to give the title compound (760 mg, 66%) as a brown oil. LC / MS (ESI) m / z: 595.4 [M+H] + .

[0407] Step 8: Preparation of 3-[5-[4-(dimethoxymethyl)-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione [ka] To a solution of 1-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(dimethoxymethyl)-1-piperidyl]-3-methyl-benzimidazol-2-one (1.2 g, 2 mmol) in tetrahydrofuran (10 mL) was added 10% palladium on carbon (300 mg) under a nitrogen atmosphere, and the suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was stirred under hydrogen (50 psi) at 50° C. for 16 hours. 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] + .

[0408] Step 9: 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-carbaldehyde [ka] To a solution of 3-[5-[4-(dimethoxymethyl)-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (430 mg, 1 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (0.1 mL, 1 mmol), and the mixture was stirred at 25° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was triturated 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] + .

[0409] Step 10: Preparation of tert-butyl 9-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate [ka] To a solution of 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-carbaldehyde (250 mg, 0.7 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (189 mg, 0.7 mmol) in dichloromethane (5 mL) and dimethyl sulfoxide (2 mL) was added acetic acid (41 mg, 0.7 mmol) and sodium triacetoxyborohydride (286 mg, 1.4 mmol), and the mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with water (15 mL) and extracted with dichloromethane (3×30 mL). The combined organic extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (280 mg, 68%) as a green oil. LC / MS (ESI) m / z: 609.4 [M+H] + .

[0410] Step 11: Preparation of 3-[5-[4-(3,9-diazaspiro[5.5]undecan-3-ylmethyl)-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione [ka] To a solution of tert-butyl 9-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (410 mg, 0.7 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3.0 mL, 40 mmol) at 25 °C, and the reaction mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure, and the residue was triturated with ethyl acetate / methyl tert-butyl ether (1 / 10, 50 mL) to give the title compound (490 mg, crude, di-trifluoroacetate) as a light yellow solid. LC / MS (ESI) m / z: 509.3 [M+H] + .

[0411] Step 12: Preparation of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine [ka] To a mixture of phosphorus oxychloride (240 mL, 2.6 mol) and N,N-diisopropylethylamine (100 mL) was added 7-chloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol (24.0 g, 111 mmol) at 0 °C, and the mixture was stirred at 90 °C for 2 hours. The reaction mixture was concentrated, and the residue was diluted with water (500 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic extracts were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1, then 3 / 1) to give the title compound (14 g, 49%) as a yellow solid.

[0412] Step 13: 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 [ka] To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (11 g, 43 mmol) and N,N-diisopropylethylamine (22.8 mL, 131 mmol) in N,N-dimethylformamide (100 mL) at −60° C., tert-butyl (1S,5R)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.32 g, 39 mmol) was added, and the reaction mixture was stirred at −60° C. for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (14 g, 81%) as a yellow oil. LC / MS (ESI) m / z: 428.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ 8.85(s,1H),4.65~4.35(m,4H),3.90~3.55(m,2H),2.05~1.90(m,2H),1.72~1.60(m,2H),1.53(s,9H).

[0413] Step 14: Preparation of tert-butyl 3-[7-chloro-8-fluoro-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of [1-(hydroxymethyl)cyclopropyl]methanol (9.54 g, 93 mmol) in tetrahydrofuran (200 mL) was added lithium tert-butoxide (1 M, 70 mL), and the resulting mixture was stirred for 0.5 hours. A solution 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 (20 g, 47 mmol) in tetrahydrofuran (200 mL) was then added dropwise at 20° C., and the reaction mixture was stirred at 50° C. for 1.5 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / dichloromethane = 5 / 1, then petroleum ether / dichloromethane / ethyl acetate = 5 / 1 / 5) to give the title compound (9.54 g, 41%) as a white solid. LC / MS(ESI)m / z:494.3[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.90(s,1H),4.63(s,1H),4.47(d,J=12.4Hz,2H),4.32~4.20(m,4H),3.61(d,J=12.4Hz,2H),3 .40~3.27(m,2H),1.78(d,J=4.0Hz,2H),1.62(d,J=7.6Hz,2H),1.46(s,9H),0.60~0.42(m,4H).

[0414] Step 15: Preparation of tert-butyl 3-[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropyl silylethynyl)-1-naphthyl]-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] tert-Butyl 3-[7-chloro-8-fluoro-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.54 g, 19 mmol), 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl A mixture of pyr-silane (10.9 g, 21 mmol), potassium phosphate (12.3 g, 58 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) (1.41 g, 2 mmol) in 1,4-dioxane (180 mL) and water (30 mL) was degassed and purged with nitrogen (3X), then stirred at 90 °C under a nitrogen atmosphere for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0-50% ethyl acetate / petroleum ether) to give the title compound (15.88 g, 97%) as a yellow solid. LC / MS (ESI) m / z: 844.7 [M+H] + .

[0415] Step 16: Preparation of tert-butyl 3-[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[(1-formylcyclopropyl)methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5 g, 6 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (7.0 mL, 12 mmol), and the mixture was stirred at 20 °C for 12 hours. The mixture was poured into a mixture of saturated sodium thiosulfate solution (50 mL), sodium bicarbonate solution (50 mL), and water (50 mL). After stirring for 5 minutes, the aqueous phase was extracted with dichloromethane (2 × 50 mL). The combined organic extracts were washed with brine (2x100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1, then 2 / 1) to give the title compound (3.51g, 70%) as a yellow solid. LC / MS (ESI) m / z: 842.4 [M+H] + .

[0416] Step 17: Preparation of tert-butyl 3-[2-[[1-[[9-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methyl]-3,9-diazaspiro[5.5]undecan-3-yl]methyl]cyclopropyl]methoxy]-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-carboxylate [ka] To a solution of 3-[5-[4-(3,9-diazaspiro[5.5]undecan-3-ylmethyl)-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (648 mg, 0.9 mmol, 2 trifluoroacetate salt) in dichloromethane (7 mL) and dimethyl sulfoxide (7 mL) was added N,N-diisopropylethylamine (0.8 mL, 4 mmol), and the resulting mixture was stirred at 25° C. for 0.5 h. Then tert-butyl 3-[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[(1-formylcyclopropyl)methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (741 mg, 0.9 mmol), acetic acid (0.5 mL, 9 mmol), and 2-methylpyridineborane (470 mg, 4 mmol) were added, and the reaction mixture was stirred at 40° C. for 12 hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane / methanol = 1:0, then 10:1) to give the title compound (334 mg, 28%) as a yellow oil. LC / MS (ESI) m / z: 1335.7 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),9.16(s,1H),8.10(dd,J=6.0,9.2Hz,1H),7.74(d,J=2.8Hz,1H),7.56(t,J=8.8Hz,1H),7.33(d,J=2.4Hz,1H) ,6.93(d,J=8.4Hz,1H),6.82(s,1H),6.63(d,J=8.4Hz,1H),5.75(s,2H),5.36(s,4H),4.38~4.16(m,6H),3.81~3.69(m,1H) ,3.66~3.51(m,3H),3.50~3.39(m,5H),3.17(d,J=5.2Hz,5H),3.01~2.87(m,3H),2.74~2.56(m,6H),2.44~2.32(m,5H),1.9 3~1.85(m,5H),1.70~1.60(m,4H),1.46(s,9H),1.40~1.28(m,4H),0.81(t,J=7.6Hz,18H),0.64(s,2H),0.52~0.41(m,5H).

[0417] Step 18: Preparation of tert-butyl 3-[2-[[1-[[9-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methyl]-3,9-diazaspiro[5.5]undecan-3-yl]methyl]cyclopropyl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-[2-[[1-[[9-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methyl]-3,9-diazaspiro[5.5]undecan-3-yl]methyl]cyclopropyl]methoxy]-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-carboxylate (334 mg, 0.3 mmol) in N,N-dimethylformamide (5 mL), cesium fluoride (1.14 g, 7.5 mmol) was added and the reaction mixture was stirred at 25 ° C. for 1 hour. The reaction was poured into ice water (40 mL) and the aqueous phase was extracted with tetrahydrofuran / ethyl acetate (1 / 1, 2 x 20 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (256 mg, 86%) as a yellow solid. LC / MS (ESI) m / z: 1178.8 [M+H] + .

[0418] Step 19: Preparation of 3-[5-[4-[[3-[[1-[[4-(3,8-diazabicyclo[3.2.1]octan-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]undecan-9-yl]methyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione [ka] To a solution of tert-butyl 3-[2-[[1-[[9-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methyl]-3,9-diazaspiro[5.5]undecan-3-yl]methyl]cyclopropyl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (256 mg, 0.2 mmol) in dichloromethane (3 mL), a solution of 4 M HCl in 1,4-dioxane (3 mL) was added and the reaction mixture was stirred at 25 ° C. for 15 minutes. The reaction mixture was suspended in petroleum ether (20 mL) and filtered. The filter cake was dissolved in dimethyl sulfoxide (3 mL) and basified with N,N-diisopropylethylamine. The residue was purified by preparative HPLC (1% to 28% aqueous acetonitrile (formic acid) over 10 min) to give the title compound (31.9 mg, 12%, di-formate salt) as a yellow solid. LC / MS (ESI) m / z: 1034.6 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),9.04(s,1H),8.20(s,2H),7.97(dd,J=6.0,9.2Hz,1H),7.51~7.35(m,2H),7.16(d,J=2.4Hz,1H),6.91(d,J=8. 8Hz,1H),6.80(d,J=2.0Hz,1H),6.62(dd,J=2.0,8.8Hz,1H),5.28(dd,J=5.2,12.8Hz,1H),4.52(d,J=11.6Hz,1H),4.36~4.2 2(m,4H),3.95~3.90(m,2H),3.56(d,J=12.4Hz,6H),3.29(s,4H),2.89(s,1H),2.74~2.54(m,4H),2.41~2.30(m,9H),2.19(d ,J=6.8Hz,2H),2.02~1.94(m,1H),1.82~1.67(m,6H),1.62(s,1H),1.38(s,7H),1.28~1.16(m,3H),0.64(s,2H),0.42(s,2H).

[0419] Example 30 Synthesis of 3-{5-[4-({4-[(1-{[(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy]methyl}cyclopropyl)methyl]piperazin-1-yl}methyl)piperidin-1-yl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl}piperidine-2,6-dione (Compound 188) [ka] The title compound was made in a similar manner to 3-[5-[4-[[3-[[1-[[4-(3,8-diazabicyclo[3.2.1]octan-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]undecan-9-yl]methyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (yellow solid, formate salt). LC / MS(ESI)m / z:966.7[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 11.04(s,1H),9.04(s,1H),8.21(s,2H),7.97(dd,J=6.0,9.2Hz,1H),7.46 (t,J=9.2Hz,1H),7.39(d,J=2.4Hz,1H),7.18(d,J=2.4Hz,1H),6.91(d,J= 8.4Hz,1H),6.80(d,J=2.0Hz,1H),6.61(dd,J=2.0,8.8Hz,1H),5.27(dd,J =5.2,12.8Hz,1H),4.53(d,J=12.4Hz,1H),4.37~4.27(m,3H),3.93(s,1H), 3.69(s,5H),3.61(d,J=13.2Hz,4H),3.55(d,J=11.6Hz,4H),3.29(s,3H), 2.91~2.83(m,1H),2.70~2.64(m,1H),2.62(d,J=2.4Hz,1H),2.61~2.55(m, 2H),2.36~2.26(m,5H),2.12(d,J=7.2Hz,2H),2.02~1.94(m,1H),1.81~1. 68(m,6H),1.65~1.53(m,1H),1.27~1.15(m,2H),0.64(s,2H),0.41(s,2H).

[0420] Example 31 Synthesis of 3-{4-chloro-5-[4-({4-[(1-{[(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy]methyl}cyclopropyl)methyl]piperazin-1-yl}methyl)piperidin-1-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (Compound 186) [ka] The title compound was made in a similar manner to 3-[5-[4-[[3-[[1-[[4-(3,8-diazabicyclo[3.2.1]octan-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]undecan-9-yl]methyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (yellow solid, formate salt). LC / MS(ESI)m / z:985.6[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.98(s,1H),9.03(s,1H),8.21(s,1H),7.97(dd,J=6.0,9.2Hz,1H),7.63(d,J=8.4H z,1H),7.46(t,J=8.8Hz,1H),7.39(d,J=2.4Hz,1H),7.29~7.21(m,1H),7.17(d,J=2.4 Hz,1H),5.09(dd,J=5.2,13.6Hz,1H),4.56~4.47(m,1H),4.45~4.36(m,1H),4.34~4. 20(m,4H),3.94(s,1H),3.71~3.54(m,6H),3.39~3.34(m,2H),2.94~2.85(m,1H),2.75 2.65(m,2H),2.62~2.56(m,1H),2.47~2.22(m,10H),2.18~2.11(m,2H),2.04~1.93(m,1H),1. 84~1.75(m,2H),1.74~1.56(m,5H),1.36~1.18(m,2H),0.69~0.58(m,2H),0.47~0.35(m,2H).

[0421] Example 32 Synthesis of 3-{5-[4-({1-[(1-{[(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy]methyl}cyclopropyl)methyl]piperidin-4-yl}methyl)piperidin-1-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (Compound 99) [ka] The title compound was made in a similar manner to 3-[5-[4-[[3-[[1-[[4-(3,8-diazabicyclo[3.2.1]octan-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]undecan-9-yl]methyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (yellow solid, formate salt). LC / MS(ESI)m / z:950.4[M+H] + ; 1H NMR(400MHz,CD3OD-d4)δ 9.01(s,1H),7.89~7.83(m,1H),7.60(d,J=8.4Hz,1H),7.36~7.29(m,2H),7.21(d,J=2.4Hz,1H),7.07~7.02(m,2H),5.13~5.07(m,1H),4.63(br t,J=13.6Hz,3H),4.51~4.47(m,1H),4.40~4.32(m,3H),3.88(br d,J=11.6Hz,2H),3.75~3.65(m,4H),3.37(s,1H),3.23~3.13(m,2H),2.91~2.74(m,4H),2.62~2.39(m,3H),2.18~2 .07(m,2H),1.90~1.69(m,8H),1.64~1.53(m,1H),1.51~1.40(m,1H),1.29~1.14(m,6H),0.80~0.71(m,2H),0.56(br s,2H).

[0422] Example 33 Synthesis of 3-{4-chloro-5-[4-({1-[(1-{[(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy]methyl}cyclopropyl)methyl]piperidin-4-yl}methyl)piperazin-1-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione (Compound 187) [ka] The title compound was made in a similar manner to 3-[5-[4-[[3-[[1-[[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cycl...

Claims

1. A compound of any one of formulas I-IV: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, Q １ is C(R １４ ) ２ , C(O), and NR １４ is selected from Q ２ is CR １４ or N, R １ and R ２ are each independently H, halo, or C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, and C １－６ haloalkyl; R ３ H, halo, CN, C １－６ Alkyl, C １－６ Alkoxy, and C １－６ haloalkyl; R ４ is C ３－１１ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 3- to 10-membered heteroaryl, wherein C ３－１１ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ Aryl, and 3- to 10-membered heteroaryl are optionally R ４ａ is replaced by R ４ａ is H, C １－６ Alkyl, C １－６ Alkoxy, and C １－６ haloalkyl; R ５ａ , R ５ , R ６ , R ８ , R １０ , R １１ , R １２ , R １３ , and R １４ are each independently H, halo, or C １－６ Alkyl, C １－６ Alkoxy, and C １－６ haloalkyl; R ７ H, =O, halo, C １－６ Alkyl, C １－６ Alkoxy, and C １－６ haloalkyl; R ９ is H, halo, C １－６ Alkyl, and C １－６ alkoxy; Ring A is phenyl, 6-membered heteroaryl, C ６ cycloalkyl, and 6-membered heterocycloalkyl; B is a bond or C １－６ is alkyl, Each L is independently C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, O, C(O), N(H), N(C １－６ alkyl), C ３－１１ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ６－１０ aryl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl is optionally selected from halo, CN, and C １－６ is substituted with alkyl, and The compound wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

2. Q １ is C(R １４ ) ２ or C(O), Q ２ is N, R １ and R ２ are each independently H, halo, or C １－６ Alkyl, C ２－６ alkenyl, and C ２－６ alkynyl, R ３ is selected from H, halo and CN; R ４ is C ３－１１ cycloalkyl or 3- to 10-membered heterocycloalkyl, in which case C ３－１１ Cycloalkyl and 3- to 10-membered heterocycloalkyl are optionally R ４ａ is replaced by R ４ａ is H or C １－６ is alkyl, R ５ａ , R ５ , R ６ , R ８ , R １０ , R １１ , R １２ , R １３ , and R １４ are each independently H, halo, or C １－６ Alkyl, and C １－６ alkoxy; R ７ H, =O, halo, C １－６ Alkyl, and C １－６ alkoxy; R ９ is H, halo, C １－６ Alkyl, and C １－６ alkoxy; Ring A is selected from phenyl, 6-membered heteroaryl, and 6-membered heterocycloalkyl; B is a bond or C １－６ is alkyl, Each L is independently C １－６ Alkyl, C １－６ Alkoxy, O, C(O), N(H), N(C １－６ alkyl), C ３－１１ cycloalkyl, 3- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C １－６ is substituted with alkyl, and 2. The compound of claim 1, wherein n is 1, 2, 3, 4, 5, 6, 7, or 8.

3. Q １ is C(R １４ ) ２ or C(O), Q ２ is N, R １ and R ２ are each independently H, halo, or C １－６ alkyl, and C≡CH; R ３ is selected from H, halo and CN; R ４ is C ６－８ cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C ６－８ Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R ４ａ is replaced by R ４ａ is H or C １－６ is alkyl, R ５ａ , R ５ , R ６ , R ８ , R １０ , R １１ , R １２ , R １３ , and R １４ are each independently H, halo, or C １－６ Alkyl, and C １－６ alkoxy; R ７ H, =O, halo, C １－６ Alkyl, and C １－６ alkoxy; R ９ is H, halo, C １－６ Alkyl, and C １－６ alkoxy; Ring A is phenyl or 6-membered heterocycloalkyl; B is a bond or C １－６ is alkyl, Each L is independently C １－６ Alkyl, C １－６ Alkoxy, O, C(O), N(H), N(C １－６ alkyl), C ４－７ cycloalkyl, 5- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C １－６ is substituted with alkyl, and 3. The compound of claim 1 or 2, wherein n is 1, 2, 3, 4, 5 or 6.

4. The compound has formula I: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, During the ceremony, Q １ is C(R １４ ) ２ or C(O), R １ and R ２ are each independently halo, C １－６ alkyl, and C≡CH; R ３ is selected from H, halo and CN; R ４ is C ６－８ cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C ６－８ Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R ４ａ is replaced by R ４ａ is H or C １－６ is alkyl, R ５ａ , R ５ , R ６ , and R １４ are each independently H, halo, or C １－６ Alkyl, and C １－６ alkoxy; Each L is independently C １－６ Alkyl, C １－６ Alkoxy, O, C(O), N(H), N(C １－６ alkyl), 5-12 membered heterocycloalkyl, and 6-7 membered heteroaryl, wherein the 5-12 membered heterocycloalkyl is optionally selected from halo, CN, and C １－６ is substituted with alkyl, and The compound according to any one of claims 1 to 3, wherein n is 1, 2, 3, 4, 5 or 6.

5. The compound has the formula II: 【Transformation 3】 or a pharmaceutically acceptable salt thereof, During the ceremony, Q ２ is N, R １ and R ２ are each independently H, halo, or C １－６ alkyl, and C≡CH; R ３ is selected from H, halo and CN; R ４ is C ６－８ cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C ６－８ Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R ４ａ is replaced by R ４ａ is H or C １－６ is alkyl, R ８ and R １４ are each independently H, halo, or C １－６ Alkyl, and C １－６ alkoxy; R ７ H, =O, halo, C １－６ Alkyl, and C １－６ alkoxy; Ring A is phenyl or 6-membered heterocycloalkyl; B is a bond or C １－６ is alkyl, Each L is independently C １－６ Alkyl, C １－６ Alkoxy, O, C(O), N(H), N(C １－６ alkyl), C ４－７ cycloalkyl, 5- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C １－６ is substituted with alkyl, and The compound according to any one of claims 1 to 3, wherein n is 1, 2, 3, 4, 5 or 6.

6. The compound has the formula III: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ and R ２ are each independently H, halo, or C １－６ alkyl, and C≡CH; R ３ is selected from H, halo and CN; R ４ is C ６－８ cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C ６－８ Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R ４ａ is replaced by R ４ａ is H or C １－６ is alkyl, R １０ and R １１ are each independently H, halo, or C １－６ Alkyl, and C １－６ alkoxy; R ９ is H, halo, C １－６ Alkyl, and C １－６ alkoxy; Each L is independently C １－６ Alkyl, C １－６ Alkoxy, O, C(O), N(H), N(C １－６ alkyl), C ４－７ cycloalkyl, 5- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C １－６ is substituted with alkyl, and The compound according to any one of claims 1 to 3, wherein n is 1, 2, 3, 4, 5 or 6.

7. The compound is represented by formula IV: 【Transformation 5】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ and R ２ are each independently H, halo, or C １－６ alkyl, and C≡CH; R ３ is selected from H, halo and CN; R ４ is C ６－８ cycloalkyl or 6- to 8-membered heterocycloalkyl, in which case C ６－８ Cycloalkyl and 6- to 8-membered heterocycloalkyl are optionally R ４ａ is replaced by R ４ａ is H or C １－６ is alkyl, R １２ and R １３ are each independently H, halo, or C １－６ Alkyl, and C １－６ alkoxy; Each L is independently C １－６ Alkyl, C １－６ Alkoxy, O, C(O), N(H), N(C １－６ alkyl), C ４－７ cycloalkyl, 5- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C １－６ is substituted with alkyl, and The compound according to any one of claims 1 to 3, wherein n is 1, 2, 3, 4, 5 or 6.

8. A compound of formula V or VI: 【Transformation 6】 or a pharmaceutically acceptable salt thereof, During the ceremony, Q １ is C(R １４ ) ２ , C(O), and NR １４ is selected from Q ３ is CR １４ or N, R １ａ and R ２ａ are each independently selected from OH, H, and halo; R １ｂ and R ２ｂ are each independently halo and C ３－６ cycloalkyl; or R １ｂ and R ２ｂ together with the phenyl to which they are attached, form C ８－１２ aryl, in which case C ８－１２ The aryl is optionally R １ and R ２ is replaced by R １ and R ２ are each independently H, halo, or C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, and C １－６ haloalkyl; R ３ H, halo, CN, C １－６ Alkyl, C １－６ Alkoxy, and C １－６ haloalkyl; R ４ is C ３－１１ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 3- to 10-membered heteroaryl, wherein C ３－１１ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ Aryl and 3- to 10-membered heteroaryl optionally have 1 to 2 R ４ａ is replaced by Each R ４ａ are independently H, OH, C １－６ Alkyl, C １－６ Alkoxy, and C １－６ haloalkyl; R １４ , R １５ａ , R １５ｂ , R １５ , R １６ , R １７ａ , R １７ｂ , R １７ , and R １８ are each independently H, halo, or C １－６ Alkyl, C １－６ Alkoxy, and C １－６ haloalkyl; Each L is independently C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, O, C(O), N(H), N(C １－６ alkyl), C ３－１１ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ６－１０ aryl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl is optionally selected from halo, CN, and C １－６ substituted with 1 or 2 substituents independently selected from alkyl, and The compound wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

9. Q １ is C(R １４ ) ２ or C(O), Q ３ is CR １４ or N, R １ａ and R ２ａ are each independently selected from OH, H, and halo; R １ｂ and R ２ｂ together with the phenyl to which they are attached, form C ８－１２ aryl, in which case C ８－１２ The aryl is optionally R １ and R ２ is replaced by R １ and R ２ are each independently H, halo, or C １－６ Alkyl, C ３－６ Cycloalkyl, C ２－６ alkenyl, and C ２－６ alkynyl, R ３ is selected from H, halo and CN; R ４ is C ３－１１ cycloalkyl and 3- to 10-membered heterocycloalkyl, wherein C ３－１１ Cycloalkyl and 3- to 10-membered heterocycloalkyl optionally have one or two R ４ａ is replaced by Each R ４ａ are independently 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 are each independently H, halo, or C １－６ Alkyl, and C １－６ alkoxy; Each L is independently 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- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C １－６ substituted with 1 or 2 substituents independently selected from alkyl, and 9. The compound of claim 8, wherein n is 1, 2, 3, 4, 5, 6, 7, or 8.

10. Q １ is C(R １４ ) ２ or C(O), Q ３ is CH or N, R １ａ and R ２ａ are each independently selected from H, OH, and halo; R １ｂ and R ２ｂ together with the phenyl to which they are attached, R １ and R ２ forming a naphthyl substituted with R １ and R ２ are each independently H, halo, or C １－３ Alkyl, C ３－５ cycloalkyl, and C≡CH; R ３ is H or halo, R ４ is C ６－８ cycloalkyl and 6- to 8-membered heterocycloalkyl, wherein C ６－８ Cycloalkyl and 6- to 8-membered heterocycloalkyl optionally have one or two R ４ａ is replaced by Each R ４ａ are independently 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 are each independently H, halo, or C １－３ Alkyl, and C １－３ alkoxy; Each L is independently 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- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C １－６ substituted with 1 or 2 substituents independently selected from alkyl, and 10. The compound of claim 8 or 9, wherein n is 1, 2, 3, 4, 5 or 6.

11. The compound has formula V: 【Transformation 7】 or a pharmaceutically acceptable salt thereof, During the ceremony, Q １ is C(R １４ ) ２ or C(O), Q ３ is CH or N, R １ａ and R ２ａ are each independently selected from H, OH, and halo; R １ｂ and R ２ｂ together with the phenyl to which they are attached, R １ and R ２ forming a naphthyl substituted with R １ and R ２ are each independently H, halo, or C １－３ Alkyl, C ３－５ cycloalkyl, and C≡CH; R ３ is H or halo, R ４ is C ６－８ cycloalkyl and 6- to 8-membered heterocycloalkyl, wherein C ６－８ Cycloalkyl and 6- to 8-membered heterocycloalkyl optionally have one or two R ４ａ is replaced by Each R ４ａ are independently H, OH, and C １－６ alkyl, R １４ , R １５ , and R １６ are each independently H, halo, or C １－３ Alkyl, and C １－３ alkoxy; R １５ａ and R １５ｂ are each independently halo, C １－３ Alkyl, and C １－３ alkoxy; Each L is independently 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- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C １－６ substituted with 1 or 2 substituents independently selected from alkyl, and The compound according to any one of claims 8 to 10, wherein n is 1, 2, 3, 4, 5 or 6.

12. The compound has formula VI: 【Transformation 8】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ and R ２ are each independently H, halo, or C １－３ Alkyl, C ３－５ cycloalkyl, and C≡CH; R ３ is H or halo, R ４ is C ６－８ cycloalkyl and 6- to 8-membered heterocycloalkyl, wherein C ６－８ Cycloalkyl and 6- to 8-membered heterocycloalkyl optionally have one or two R ４ａ is replaced by Each R ４ａ are independently H, OH, and C １－６ alkyl, R １７ａ , R １７ｂ , R １７ , and R １８ are each independently H, halo, or C １－３ Alkyl, and C １－３ alkoxy; Each L is independently 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- to 12-membered heterocycloalkyl, and 6- to 7-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from halo, CN, and C １－６ substituted with 1 or 2 substituents independently selected from alkyl, and The compound according to any one of claims 8 to 10, wherein n is 1, 2, 3, 4, 5 or 6.

13. Compounds of formula AI or AIV: 【Chemistry 9】 or a pharmaceutically acceptable salt thereof, During the ceremony, Q １ is C(R １４ ) ２ , C(O), and NR １４ is selected from R １ and R ２ are each independently halo or C ２－６ is alkynyl, R ３ H, halo, CN, C １－６ Alkyl, C １－６ Alkoxy, and C １－６ haloalkyl; R ４ is C ３－１１ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 3- to 10-membered heteroaryl, wherein C ３－１１ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ Aryl, and 3- to 10-membered heteroaryl are optionally R ４ａ is replaced by R ４ａ is H, C １－６ Alkyl, C １－６ Alkoxy, and C １－６ haloalkyl; R ５ａ , R ５ , R ６ , R １２ , R １３ , and R １４ are each independently H, halo, or C １－６ Alkyl, C １－６ Alkoxy, and C １－６ haloalkyl; Each L is independently C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, O, C(O), N(H), N(C １－６ alkyl), C ３－１１ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ６－１０ aryl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl is optionally selected from halo, CN, and C １－６ is substituted with alkyl, and The compound wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

14. Compound of Formula VII: 【Chemistry 10】 or a pharmaceutically acceptable salt thereof, During the ceremony, Ring B and ring C are each independently 3 to 12 membered heterocycloalkyl, C ６－１０ aryl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl is optionally selected from halo, CN, and C １－６ is substituted with alkyl, Ring D is a bond, C ３－１１ cycloalkyl, 3- to 12-membered heterocycloalkyl, C ６－１０ aryl, and 5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl is optionally selected from halo, CN, and C １－６ substituted with alkyl, provided that when ring D is a bond, Y ２ is also a bond and t is 0, Y １ and Y ２ are each independently a bond, O, C(O), N(H), N(C １－６ alkyl), C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ alkoxy; Z is N(H), N(C １－６ alkyl), C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ alkoxy; R １ and R ２ are each independently H, halo, or C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, and C １－６ haloalkyl; R ３ H, halo, CN, C １－６ Alkyl, C １－６ Alkoxy, and C １－６ haloalkyl; R ４ is C ３－１１ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 3- to 10-membered heteroaryl, wherein C ３－１１ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ Aryl, and 3- to 10-membered heteroaryl are optionally R ４ａ is replaced by R ４ａ is H, C １－６ Alkyl, C １－６ Alkoxy, and C １－６ haloalkyl; R １７ａ , R １７ｂ , R １７ , and R １８ are each independently H, halo, or C １－６ Alkyl, C １－６ Alkoxy, and C １－６ haloalkyl; s and t are each independently 0, 1, 2, or 3; and The compound wherein u is 1 or 2.

15. R ４ is optionally R ４ａ 15. The compound of any one of claims 1 to 14, which is a bridged 8-membered heterocycloalkyl substituted with:

16. R ４ The compound according to any one of claims 1 to 15, wherein: 【Chemistry 11】

17. The compound has formula IA: 【Chemistry 12】 16. The compound of any one of claims 1 to 4 and 15, having the structure: or a pharmaceutically acceptable salt thereof.

18. The compound has formula IIA: 【Chemistry 13】 16. The compound of any one of claims 1 to 3, 5 and 15, having the structure: or a pharmaceutically acceptable salt thereof.

19. The compound has formula IIB: 【Chemistry 14】 16. The compound of any one of claims 1 to 3, 5 and 15, having the structure: or a pharmaceutically acceptable salt thereof.

20. The compound has the formula IIIA: 【Chemistry 15】 16. The compound of any one of claims 1 to 3, 6 and 15, having the structure: or a pharmaceutically acceptable salt thereof.

21. The compound has formula IVA: 【Chemistry 16】 16. The compound of any one of claims 1 to 3, 7 and 15, having the structure: or a pharmaceutically acceptable salt thereof.

22. The compound has the formula VA: 【Chemistry 17】 12. The compound of any one of claims 8 to 11, having the structure: or a pharmaceutically acceptable salt thereof.

23. The compound has the formula VIA: [Chemistry 18] 13. The compound of any one of claims 8 to 10 and 12, having the structure: or a pharmaceutically acceptable salt thereof.

24. Q １ is CH ２ or C(O).

25. Q ２ The compound according to any one of claims 1 to 3, 5, 15, 16, 18 and 19, wherein is N.

26. R １ H, halo and C １－６ 26. The compound of any one of claims 1 to 25, wherein the alkyl is selected from:

27. R １ The compound of any one of claims 1 to 25, wherein is H.

28. R １ The compound of any one of claims 1 to 25, wherein is halo.

29. R １ is C １－６ The compound of any one of claims 1 to 25, which is alkyl.

30. R ２ is H, C １－６ 30. The compound of any one of claims 1 to 29, wherein the alkyl is selected from alkyl, and C≡CH.

31. R ２ The compound of any one of claims 1 to 30, wherein is H.

32. R ２ is C １－６ The compound of any one of claims 1 to 30, which is alkyl.

33. R ２ The compound of any one of claims 1 to 30, wherein is C≡CH.

34. R ３ The compound of any one of claims 1 to 16 and 24 to 33, wherein is halo.

35. R ４ａ is H or C １－６ 35. The compound of any one of claims 1 and 8 to 34, wherein the compound is alkyl.

36. Each R ４ａ is OH and C １－６ 35. The compound of any one of claims 1 and 8 to 34, wherein the aryl group is selected from alkyl.

37. R ５ａ is H, halo or C １－６ The compound of any one of claims 1 to 4, 13, 15 to 17, and 24 to 36, which is alkoxy.

38. R ５ is H or C １－６ The compound of any one of claims 1 to 4, 13, 15 to 17, and 24 to 37, wherein the compound is alkyl.

39. R ６ is H or C １－６ The compound according to any one of claims 1 to 4, 13, 15 to 17, and 24 to 37, 35, which is alkyl.

40. R ７ is H, ═O, halo and C １－６ The compound of any one of claims 1 to 3, 5, 15, 16, 18, and 24 to 36, wherein the compound is selected from alkoxy.

41. R ７ The compound of any one of claims 1 to 3, 5, 15, 16, 18, 24 to 36, and 40, wherein is =O.

42. R ７ The compound of any one of claims 1 to 3, 5, 15, 16, 18, 24 to 36, and 40, wherein is halo.

43. R ７ is C １－６ The compound of any one of claims 1 to 3, 5, 15, 16, 18, 24 to 36, and 40, which is alkoxy.

44. R ８ is H or C １－６ The compound of any one of claims 1 to 3, 5, 15, 16, 18, 24 to 36, and 40 to 43, wherein the compound is alkyl.

45. R ８ The compound of any one of claims 1 to 3, 5, 15, 16, 18, 24 to 36, and 40 to 44, wherein is H.

46. R ９ H, halo and C １－６ 37. The compound of any one of claims 1 to 3, 6, 15, 16, 20 and 26 to 36, wherein the compound is selected from alkoxy.

47. R ９ The compound of any one of claims 1 to 3, 6, 15, 16, 20, 26 to 36, and 46, wherein is halo.

48. R ９ is C １－６ 48. The compound of any one of claims 1 to 3, 6, 15, 16, 18, 26 to 36, 46 and 47, which is alkoxy.

49. R １０ is H.

50. R １１ The compound of any one of claims 1 to 3, 6, 15, 16, 18, 26 to 36, and 46 to 49, wherein

51. R １２ is C １－６ The compound of any one of claims 1 to 3, 7, 15, 16, 21, and 26 to 36, wherein the compound is alkyl.

52. R １３ The compound of any one of claims 1 to 3, 7, 15, 16, 21, 26 to 36, and 51, wherein

53. R １４ is H or C １－６ The compound of any one of claims 1 to 5, 8 to 11, 13 to 19, 22, and 24 to 45, wherein the compound is alkyl.

54. R １４ is H.

55. R １４ is C １－６ 54. The compound of any one of claims 1 to 5, 8 to 11, 13 to 19, 22, 24 to 45, and 53, wherein the compound is alkyl.

56. 56. The compound of 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. 56. The compound of any one of claims 1-3, 5, 15, 16, 18, 25-36, 40-45, and 53-55, wherein ring A is a 6-membered heterocycloalkyl.

58. 60. The compound of any one of claims 1-3, 5, 15, 16, 18, 25-36, 40-45, 53-55, and 57, wherein ring A is dihydropyridinyl.

59. 59. The compound of any one of claims 1-3, 5, 15, 16, 18, 25-36, 40-45, and 53-58, wherein B is a bond.

60. B is C １－６ The compound of any one of claims 1 to 3, 5, 15, 16, 18, 25 to 36, 40 to 45, and 53 to 58, wherein the compound is alkyl.

61. Q ３ The compound according to any one of claims 8 to 11, 15, 16, 22, 24, and 26 to 36, wherein is N.

62. R １ａ is H or OH.

63. R １ａ The compound of any one of claims 8 to 11, 15, 22, 26 to 36, 56, 61, and 62, wherein

64. R １ａ The compound of any one of claims 8 to 11, 15, 22, 26 to 36, 56, 61, and 62, wherein is OH.

65. R ２ａ The compound of any one of claims 8 to 11, 15, 22, 26 to 36, 56, and 61 to 64, wherein is H.

66. R １５ａ is H, halo, or C １－６ The compound of any one of claims 8 to 11, 15, 22, 26 to 36, 56, and 61 to 65, which is alkoxy.

67. R １５ｂ is H or C １－６ The compound of any one of claims 8 to 11, 15, 22, 26 to 36, 56, and 61 to 66, which is alkyl.

68. R １５ is H or C １－６ The compound of any one of claims 8 to 11, 15, 22, 26 to 36, 56, and 61 to 67, wherein the compound is alkyl.

69. R １６ is H or C １－６ The compound of any one of claims 8 to 11, 15, 22, 26 to 36, 56, and 61 to 68, wherein the compound is alkyl.

70. R １７ａ and R １７ｂ and n is independently H or halo.

71. R １７ is C １－６ 71. The compound of any one of claims 8-10, 12, 14-16, 26-36, and 70, which is alkyl.

72. R １８ The compound of any one of claims 8 to 10, 12, 14 to 16, 26 to 36, 70, and 71, wherein

73. Each L is independently C １－６ Alkyl, C １－６ 73. The compound of any one of claims 1-13 and 15-72, wherein the 5- to 12-membered heterocycloalkyl is selected from alkoxy, C(O), and 5- to 12-membered heterocycloalkyl, wherein the 5- to 12-membered heterocycloalkyl is optionally substituted with halo.

74. 74. The compound of claim 73, wherein the 5- to 12-membered heterocycloalkyl is a fused 8-membered heterocycloalkyl.

75. Each L is independently C １－６ Alkyl, C １－６ alkoxy, and 6- to 12-membered heterocycloalkyl, wherein the 6- to 12-membered heterocycloalkyl is optionally selected from halo, or C １－６ The compound of any one of claims 1 to 13 and 15 to 72, which is substituted with alkyl.

76. Each L is independently C １－６ Alkyl, C １－６ 73. The compound of any one of claims 1-13 and 15-72, wherein the 6-8 membered heterocycloalkyl is optionally substituted with halo and is selected from alkoxy, 6- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein the 6- to 8-membered heterocycloalkyl is optionally substituted with halo.

77. n is 4 and each L is a linker as follows: １－６ alkoxy)-(6- to 12-membered heterocycloalkyl)-(C １－６ 80. The compound of any one of claims 1 to 13, 15 to 72, and 75, which forms a 6- to 12-membered heterocycloalkyl)-(alkyl).

78. Each L is a linker 【Chemistry 19】 78. The compound of claim 77, wherein

79. Each L is independently O, C １－６ Alkyl, C １－６ alkoxy, and 5- to 12-membered heterocycloalkyl, wherein the 5- to 12-membered heterocycloalkyl is optionally selected from C １－６ The compound of any one of claims 1 to 13 and 15 to 72, which is substituted with alkyl.

80. n is 6 and each L is a linker as follows: １－６ alkoxy)-(6- to 12-membered heterocycloalkyl)-(C １－６ alkyl)-(6- to 12-membered heterocycloalkyl)-(C １－６ 80. The compound of any one of claims 1 to 13, 15 to 72 and 79, wherein the compound forms a 6-membered heterocycloalkyl)-(alkyl).

81. n is 6 and each L is a linker as follows: １－６ alkoxy)-(6-membered heterocycloalkyl)-(C １－６ alkyl)-(6-membered heterocycloalkyl)-(C １－６ 81. The compound of any one of claims 1 to 13, 15 to 72, 79, and 80, which forms a 6-membered heterocycloalkyl)-(alkyl).

82. n is 4 and each L is a linker as follows: １－６ alkoxy)-(5- to 12-membered heterocycloalkyl)-(C １－６ 80. The compound of any one of claims 1 to 13, 15 to 72, and 79, which forms a 5- to 12-membered heterocycloalkyl)-(alkyl).

83. n is 4 and each L is a linker as follows: １－６ alkoxy)-(11-membered heterocycloalkyl)-(C １－６ 83. The compound of any one of claims 1 to 13, 15 to 72, 79, and 82, which forms a 6-membered heterocycloalkyl)-(alkyl).

84. 84. The compound of any one of claims 83, wherein said 11-membered heterocycloalkyl is a spirocyclic 11-membered heterocycloalkyl.

85. n is 6 and each L is a linker as follows: １－６ alkoxy)-(5- to 12-membered heterocycloalkyl)-(O)-(5- to 12-membered heterocycloalkyl)-(C １－６ alkyl)-(5- to 12-membered heterocycloalkyl), wherein the 5- to 12-membered heterocycloalkyl is optionally selected from the group consisting of C １－６ 80. The compound of any one of claims 1 to 13, 15 to 72, and 79, wherein the compound forms:

86. n is 6 and each L is a linker as follows: １－６ alkoxy)-(5-membered heterocycloalkyl)-(O)-(6-membered heterocycloalkyl)-(C １－６ alkyl)-(6-membered heterocycloalkyl), wherein the 5-membered heterocycloalkyl is optionally C １－６ 86. The compound of any one of claims 1 to 13, 15 to 72, 79, and 85, wherein the compound forms:

87. n is 4 and each L is a linker as follows: １－６ alkoxy)-(5- to 12-membered heterocycloalkyl)-(C １－６ 80. The compound of any one of claims 1 to 13, 15 to 72, and 79, which forms a 5- to 12-membered heterocycloalkyl)-(alkyl).

88. n is 4 and each L is a linker as follows: １－６ alkoxy)-(6-membered heterocycloalkyl)-(C １－６ 90. The compound of any one of claims 1 to 13, 15 to 72, 79, and 87, which forms a 9-membered heterocycloalkyl)-(alkyl).

89. 89. The compound of claim 88, wherein the 9-membered heterocycloalkyl is a spirocyclic 9-membered heterocycloalkyl.

90. n is 4 and each L is a linker as follows: １－６ alkoxy)-(5- to 12-membered heterocycloalkyl)-(O)-(5- to 12-membered heterocycloalkyl), wherein the 5- to 12-membered heterocycloalkyl is optionally selected from the group consisting of C １－６ 80. The compound of any one of claims 1 to 13, 15 to 72, and 79, wherein the compound forms:

91. n is 4 and each L is a linker as follows: １－６ alkoxy)-(5-membered heterocycloalkyl)-(O)-(6-membered heterocycloalkyl), wherein the 5-membered heterocycloalkyl is optionally C １－６ 91. The compound of any one of claims 1 to 13, 15 to 72, 79, and 90, wherein the compound forms:

92. Each L is a linker 【Chemistry 20】 The compound according to any one of claims 1 to 13, 15 to 72, and 79 to 91, which forms

93. (L) ｎ The compound of any one of claims 1 to 13, 15 to 72, 78, and 92, wherein: 【Chemistry 21】 【change】

94. Compound of Formula IVB: 【Chemistry 22】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ and R ２ are each independently H, halo, or C １－６ Alkyl, and C ２－６ alkynyl, R ３ is selected from H, halo and CN; Each Q Ｌ is independent, CR Ｌ or N, Each R Ｌ are independently H, halo, or CN; each p is 1, 2, 3, 4, 5, or 6; and R １２ and R １３ are each independently H, C １－６ Alkyl, and C １－６ The compound selected from: alkoxy.

95. 95. The compound of any one of claims 1 to 94, wherein the compound is selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

96. A pharmaceutical composition comprising a compound according to any one of claims 1 to 95 and a pharmaceutically acceptable salt.

97. 97. A method of treating cancer in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 95, or an effective amount of the pharmaceutical composition of claim 96.

98. 98. The method of claim 97, wherein the cancer is selected from bladder cancer, colon cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, uterine cancer, ovarian cancer, testicular cancer, thyroid cancer, pineal cell tumor, carcinoma, carcinoma, ependymoma, ganglioglioma, ganglioneuroma, glioblastoma, glioma, leukemia, lymphoma, medulloblastoma, melanoma, meningioma, myeloma, nephroblastoma, neuroblastoma, neurofibroma, oligodendroglioma, peripheral neuroepithelioma, sarcoma, and schwannoma.

99. 99. The method of claim 98, wherein the carcinoma is a teratocarcinoma.

100. 99. The method of claim 98, wherein the tumor is an astrocytoma.

101. 99. 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. 99. The method of 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. 99. The method of claim 98, wherein the lymphoma is selected from Burkitt's 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. 99. The method of claim 98, wherein the nephroblastoma is Wilms' tumor.

105. 99. The method of claim 98, wherein the sarcoma is selected from carcinosarcoma, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, synovial sarcoma, and meningeal sarcoma.

106. 97. A method of degrading a target protein in a cell, comprising contacting the cell with an effective amount of a compound of any one of claims 1 to 95, or an effective amount of the pharmaceutical composition of claim 96, wherein the compound causes degradation of the target protein.

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