Kirsten rat sarcoma (KRAS) protac compounds and uses thereof

Abstract

Provided herein are novel Kirsten Rat Sarcoma (KRAS) PROTAC compounds, pharmaceutical compositions and uses comprising the same, e.g., for targeting Kras mutant and non-mutant wild-type KRAS and are thus useful in the treatment of an abnormal cellular proliferation disease or disorder such as cancer.

Description

ARVN-174-PCT / / ARVN0174WO2KIRSTEN RAT SARCOMA (KRAS) PROTAC COMPOUNDS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONSThis application claims priority to U. S. Provisional Application Serial No. 63 / 779,256 filed March 27, 2025, the contents of which are incorporated herein by reference in their entireties.FIELD OF THE INVENTION

[0001] This application relates to novel Kirsten Rat Sarcoma (KRAS) PROTAC compounds, pharmaceutical compositions and uses comprising the same, e.g., for targeting Kras mutant and non-mutant wild-type KRAS and are thus useful in the treatment of an abnormal cellular proliferation disease or disorder such as cancer.BACKGROUND

[0002] The Kirsten rat sarcoma (KRAS) gene is an oncogene encoding KRAS, which is a small GTPase signal transduction protein. Ras proteins associate with the plasma membrane, and when GTP-bound, act as “on” switches in the transduction of extracellular signals to intracellular response, thereby regulating processes such as cell division. Following GTPase-activating proteins (GAPs) catalyzed hydrolysis of the y-phosphate, KRAS is deactivated from downstream effector pathways. Studies have revealed that KRAS alleles are distributed non-uniformly across different cancer types. Numerous activating or gain-of-function mutations of the KRAS gene are known, and in fact, KRAS is the most frequently mutated gene in cancer. Gain-of-function KRAS mutations are found in approximately 30% of all human cancers, including, e.g., pancreatic cancer (>80%), colon cancer (approximately 40-50%), lung cancer (approximately 30-50%), non-small cell lung cancer, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, and breast cancer. These activating mutations impair the ability of KRAS to switch between active and inactive states. The most common mutations observed in cancer occur most frequently at four codons: 12, 13, 61 or 146. In particular, mutation on codon 12 accounted for 72.2% of the mutations in the four hotspots, followed by codon 13 (9.8%), 61 (14.8%) and 146 (3.2%). The glycine at codon 12 can be transformed into six possible different amino acids (A, C, D, R, S and V). These mutations change the balance between active, GTP-bound KRAS and inactive, GDP-bound KRAS by either reducing GTP hydrolysis or enhancing GDP exchange for a new GTP. Key roles for mutant KRAS have been established in initiation,ARVN-174-PCT / / ARVN0174WO2maintenance, progression, and metastasis of various cancers, and mutations are frequently correlated with poor prognosis and increased resistance to chemotherapy and biological therapies, including, e.g., therapies that target epidermal growth factor receptor. However, despite its key role and high prevalence in cancer, there is an absence of effective therapies that directly target this oncogene, leading to it being considered “undruggable.”

[0003] Compounds that target KRAS activities are desirable and include traditional small molecule KRAS inhibitory compounds which generally aim to bind to a functional site and antagonize the target. The other class of compounds that target KRAS activities include proteolysis targeting chimeras (PROTACs), which are hetero-bifunctional molecules comprising a protein targeting moiety (PTM) and an E3 ubiquitin (Ub) ligase targeting moiety (ULM) joined together via a linker. The PTM recruits endogenous protein of interest such as Kras to the proximity of an E3 ubiquitin ligase, which induces the poly-ubiquitination of such protein of interest on the lysine residues, marking it for degradation by the various proteasome.

[0004] As a wide range of KRAS mutations and non-mutated wild-type KRAS occur in cancers, an ongoing need exists in the art for effective compounds that target the overexpression, aggregation, and / or overactivation of KRAS, particularly broad spectrum of KRAS variants.SUMMARY

[0005] Provided herein are novel PROTAC compounds, pharmaceutical compositions and uses comprising the same, e.g., for targeting KRAS mutant and non-mutant wild-type KRAS. Such compounds include those having the chemical structure of Formula I:PTM-L-ULM (I)comprising (i) a Kirsten Rat Sarcoma (KRAS) protein targeting moiety (PTM); (ii) a linker (L) comprising a chemical structure -O-CH2-((geminal halocyclopropyl)methyl-(optionally substituted heterocycloalkylene)); and (iii) a Cereblon E3 ubiquitin ligase targeting moiety (ULM), in free or salt form (Compound of Formula I). The PTM of Formula I is a KRAS protein targeting moiety, e.g., the KRAS PTM comprises a chemical structure oxa-6-azaspiro[3.5]nonane.

[0006] These PROTAC compounds, pharmaceutical compositions comprising these compounds, methods for their preparation, and methods of treating KRAS related conditions, including methods of treating abnormal cellular proliferation diseases or disorders such as cancer, using the disclosed compounds, are also included.ARVN-174-PCT / / ARVN0174WO2

[0007] Methods of treating conditions responsive to the modulation of KRAS using the disclosed PROTAC compounds, pharmaceutically acceptable salts, and compositions thereof are also included.

[0008] In a further embodiment, the compounds of the disclosure include compounds of Formula 1(A)’:KA)’in free or salt form, wherein:one of Zi and Z2 is O and the other is C(Ra)(Rb);X is =C(Ra)-, -C(Ra)(Rb)-, =N- or -N(Ra)-;Y is -N-, -C= or -C(Ra)-;each Raand Rb is independently H or Ci-4alkyl (e.g., methyl);Ri and R2 are independently halo (e.g. fluoro);R3 and R4 are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), Ci-4alkoxy (e.g., methoxy) or haloCi-4alkoxy;R12 and R13 are independently H or Ci-4alkyl (e.g., methyl); or R4 and R12 or R4 and R13 together with the carbons to which they are attached form a cyclic structure, for example, R4 and R12 or R4 and R13 together can form a two-atom bridge such as, for example, -O-CH2- resulting in formation of a heterocyclic structure, e.g., an oxazepine;Moiety A is a 4-12 membered heterocycloalkylene:Moiety B and C are independently abond,Ci-4alkylene (e.g.. methylene or ethylene),-OC(O)-,ARVN-174-PCT / / ARVN0174WO2-C(O)-Ci-4alkylene,-O-,C(0).-N(RX)-, wherein Rxis H or Ci-4alkyl (e.g., methyl);4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 7- azaspiro[3.5]nonanylene, 2,7-diazaspiro[3.5]nonanylene. 3,9- diazaspiro[5,5]undecanylene, 2-oxa-5,8-diazispiro[3.5]nonanylene, hexahydropyrrolo[3,4-c]pyrrolylene, 2,8-diazaspiro[4.5]decanylene, 1-oxa- 4,9-diazaspiro[5.5]undecanylene, 2,6-diazaspiro[3.3]heptanylene, pyrrolidinylene, azetidinylene, 2,5-diazabicyclo[2.2.1]heptanylene), or heteroarylene (e.g. pyridylene),wherein A, B and C are independently optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);Moiety D is selected from the following:wherein Rs, Re and R7 are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), C2-4alkynyl (e.g., ethynyl), C3-4cycloalkyl (e.g., cyclopropyl), Ci-4alkoxy (e.g.. methoxy), haloCi-4alkoxy (e.g., -O-C(F2)(H)), -OCH2-OP(O)(OH)2, -N(Ra)(Rb), -N(H)-C(O)CH3 or -N(H)-CH2CF3, wherein each Raand Re is independently H or Ci-4alkyl (e.g., methyl); andARVN-174-PCT / / ARVN0174WO2 ULM is selected from:O O O OULM-11 ULM-11-XARVN-174-PCT / / ARVN0174WO2ULM-15 ULM-16and wherein:Rs is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;R9 is H, halo (e.g., chloro or fluoro), OH, Ci-4alkyl or Ci-4alkoxy (e.g., methoxy orethoxy);ARVN-174-PCT / / ARVN0174WO2R10 is H or C1-4alkyl (e.g., methyl);RH is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy;Q1, Q10 and Q11 are independently C(O) or C(Ra)(Rb);Q7x is N(R7x) or C(Ra)(Rb); wherein R7x is H, C1-4alkyl (e.g., methyl, ethyl, propyl such as isopropyl) or C3-6aycloalkyl (e.g., cyclopropyl); Each of R11 and R11x is independently H, halo (e.g., chloro or fluoro);Q12 is O or CH2;Q14 is N(R14a), C(Ra)(Rb), wherein R14a is H, C1-4alkyl (e.g., methyl, ethyl, propyl such as isopropyl) or C3-6aycloalkyl (e.g., cyclopropyl);Q14x is N(R14ax) or C(Ra)(Rb), wherein R14ax is H, C1-4alkyl (e.g., methyl) or C3-6aycloalkyl (e.g., cyclopropyl);Q15 is N(R15a) or C(Ra)(Rb), wherein R15a is H, C1-4alkyl (e.g., methyl) or C3-5cycloalkyl (e.g., cyclopropyl);Q16 is C(O) or C(Ra)(Rb);Each of R10x, R11x, R12x and R13x is independently C1-4alkyl (e.g., methyl); R14b is H or C1-4alkyl (e.g., methyl);R14 is H or Ci-4alkyl (e.g., methyl);Ri4x is H or Ci-4alkyl (e.g., methyl);R15 is H or halo (e.g., fluoro);Each of R16b and R16c is H or C1-4alkyl (e.g., methyl);R16d is H or halo (e.g., fluoro);R16e is H or C1-4alkyl (e.g., methyl);R18 is H or C1-4alkyl (e.g., methyl);each Raand Rb is independently H or Ci-4alkyl (e.g., methyl); or-A-B-C together with the ULM forms the following structure:ARVN-174-PCT / / ARVN0174WO2Formula JRl7Formula Kx wherein each of RJx and Rkx is independently C1-4alkyl (e.g., methyl), R17 is H or halo (e.g., fluoro).

[0009] In a further embodiment, the compounds of the disclosure include compounds of Formula 1(A):KA)in free or salt form, wherein:one of Zi and Z2 is O and the other is C(Ra)(Rb);X is =C(Ra)-, -C(Ra)(Rb)-, =N- or -N(Ra)-;Y is -N-, -C= or -C(Ra)-;each Raand Rb is independently H or Ci-4alkyl (e.g., methyl);ARVN-174-PCT / / ARVN0174WO2Ri and R2 are independently halo (e.g. fluoro);R3 and R4 are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), C1-4alkoxy (e.g., methoxy) or haloC1-4alkoxy;R12 and R13 are independently H or Ci-4alkyl (e.g., methyl); or R4 and R12 or R4 and R13 together with the carbons to which they are attached form a cyclic structure, for example, R4 and R12 or R4 and R13 together can form a two-atom bridge such as, for example, -O-CH2- resulting in formation of a heterocyclic structure, e.g., an oxazepine;Moiety A is a 4-12 membered heterocycloalkylene;Moiety B and C are independently a bond, Ci-4alkylene (e.g., methylene or ethylene), -OC(O)-, -C(O)-Ci-4alkylene, -O-, a 4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 7-azaspiro[3.5]nonanylene, 2,7-diazaspiro[3.5]nonanylene, 3,9-diazaspiro[5,5]undecanylene, 2-oxa-5,8-diazispiro[3.5]nonanylene, hexahydropyrrolo[3,4-c]pyrrolylene, 2,8-diazaspiro[4.5]decanylene, l-oxa-4,9-diazaspiro[5.5]undecanylene, 2,6-diazaspiro[3.3]heptanylene. pyrrolidinylene, azetidinylene, 2,5-diazabicyclo[2.2.1]heptanylene), or a heteroarylene (e.g. pyridylene),wherein A, B and C are independently optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);Moiety D is selected from the following:wherein R5, Re and R7 are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), C2-4alkynyl (e.g., ethynyl), C3-4cycloalkyl (e.g., cyclopropyl), C1-4alkoxy (e.g., methoxy), haloC1-4alkoxy (e.g., -O-C(F2)(H)), -OCH2-OP(O)(OH)2, -N(Ra)(Rb), -N(H)-C(O)CH3 or -N(H)-CH2CF3, wherein each Ra and Rb is independently H or C1-4alkyl (e.g., methyl); andULM is selected from:ARVN-174-PCT / / ARVN0174WO2ULM-1 ULM-2 ULM-3ULM-12andULM-13wherein:R8 is H, halo (e.g., chloro or fluoro), C1-4alkyl (e.g., methyl), OH, or C1-4alkoxy;R9 is H, halo (e.g., chloro or fluoro), OH, Ci-4alkyl or Ci-4alkoxy (e.g., methoxy or ethoxy);Rio is H or Ci-4alkyl (e.g., methyl);ARVN-174-PCT / / ARVN0174WO2Rn is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy;Q1, Q10 and Q11 are independently C(O) or C(Ra)(Rb);Q2is N(Ra) or C(Ra)(Rb);Q12 is O or CH2;R14 is H or Ci-4alkyl (e.g.. methyl);R15 is H or halo (e.g., fluoro):each Raand Rb is independently H or Ci-4alkyl (e.g., methyl); or-A-B-C together with the ULM forms the following structure:Formula JorFormula Kwherein R17 is H or halo (e.g., fluoro).

[0010] In the second aspect, the disclosure provides pharmaceutical compositions comprising the compounds described herein (e.g., Formula I et seq. as disclosed herein), in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable excipient or earner (Composition I et seq.).

[0011] In the third aspect, the disclosure provides methods for the treatment or prophylaxis of a KRAS mediated disorder (such as an abnormal cellular proliferation disease or disorder, e.g., cancer) in a subject in need thereof (Method I), comprising administering to the subject an effective amount of any of the compounds disclosed herein (any of Formula I et seq.), in free or pharmaceutically acceptable salt form, or an effective amount of any of the pharmaceutical compositions disclosed herein (any of Composition I etseq.).

[0012] In the fourth aspect, the disclosure provides methods for the treatment of a KRAS mediated disorder (such as an abnormal cellular proliferation disease or disorder, e.g., cancer) in a subject in need thereof (Method I-A), comprising administering to the subject an effective amount of any of the compounds disclosed herein (any of Formula I et seq.), in free orARVN-174-PCT / / ARVN0174WO2pharmaceutically acceptable salt form, or an effective amount of any of the pharmaceutical compositions disclosed herein (any of Composition I et seq.).

[0013] In the fifth aspect, the disclosure provides methods of degrading a KRAS target protein in a cell (Method II) comprising contacting the cell with an effective amount of any of the compounds disclosed herein (any of Formula I et seq.) in free or pharmaceutically acceptable salt form or any of the pharmaceutical compositions disclosed herein (any of Composition I et seq) wherein the compound effectuates the degradation of the KRAS target protein.

[0014] In the sixth aspect, the disclosure provides any of the compounds disclosed herein (any of Formula I et seq.), in free or pharmaceutically acceptable salt form, or any of the pharmaceutical compositions disclosed herein (any of Composition I et seq.) for the manufacture of a medicament for the treatment or prophylaxis of a KRAS mediated disorder (Medicament I).

[0015] In the seventh aspect, the disclosure provides any of the compounds disclosed herein (any of Formula I et seq.), in free or pharmaceutically acceptable salt form, or any of the pharmaceutical compositions disclosed herein (any of Composition I et seq.) for the manufacture of a medicament for the treatment of a KRAS mediated disorder (Medicament I-A).

[0016] In the eighth aspect, the disclosure provides any of the compounds disclosed herein (any of Formula I et seq.), in free or pharmaceutically acceptable salt form, or any of the pharmaceutical compositions disclosed herein (any of Composition I et seq.) for the manufacture of a medicament or for use in the treatment or prophylaxis of a KRAS mediated disorder (e.g., any of Compound I et seq. or any of composition I et seq. for use in any of Method I or I-A et seq. or Medicament I or I-A et seq.).

[0017] In the ninth aspect, the disclosure provides any of the compounds disclosed herein (any of Formula I et seq.), in free or pharmaceutically acceptable salt form, or any of the pharmaceutical compositions disclosed herein (any of Composition I et seq.) for the manufacture of a medicament or for use in the treatment of a KRAS mediated disorder (e.g.. any of Compound I et seq. or any of composition I et seq. for use in any of Method I or I-A et seq. or Medicament I or I-A et seq.).

[0018] In another aspect, the disclosure also provides for a pharmaceutical combination, e.g., a kit, comprising a) a first agent which is a compound of the disclosure as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent. The kit can comprise instructions for its administration.ARVN-174-PCT / / ARVN0174WO2DETAILED DESCRIPTION

[0019] Provided herein are Kirsten Rat Sarcoma (KRAS) PROTAC compounds (e.g., compounds of Formula (I) or any disclosed herein) that target and degrade KRAS, including mutant KRAS and non-mutant wild- type KRAS, and are thus useful as a pharmaceutical composition and / or for the treatment of KRAS-related diseases or disorders, such as abnormal cellular proliferation, including cancer.

[0020] 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 this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0021] Unless defined otherwise, 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 well-known and commonly employed in the art.

[0022] The term “compound,” as used herein, unless otherwise indicated, refers to any specific chemical compound or genus of compounds disclosed herein and includes racemates, tautomers, regioisomers, geometric isomers, and where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers) thereof, as well as salts or pharmaceutically acceptable salts thereof where applicable, in context. Within its use in context, the term compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and / or optical isomers (including racemic mixtures) as well as specific enantiomers (R- or S-enantiomer) or enantiomerically enriched mixtures of disclosed compounds (e.g., wherein one enantiomer is in greater proportion than the other enantiomer, such as with greater than 50% enantiomeric excess (%ee), for example, 60-99.9% ee of one enantiomer over the other enantiomer, for example, greater or equal to than 80%, greater or equal to than 90%, greater or equal to 95%, greater or equal to 98%, greater than or equal to 99% or greater than or equal to 99.5% ee. Enantiomers and diastereomers may be isolated from racemic mixtures by any method known to those skilled in the art, including recrystallization from solvents in which oneARVN-174-PCT / / ARVN0174WO2stereoisomer is more soluble than the other, chiral column chromatography, chiral high performance liquid chromatography (HPLC). The term “compound” also refers, in context, to prodrug forms of the compound which has been modified to facilitate the administration and delivery of the compound to a site of activity. A prodrug form is a compound which converts in the body to a compound of the invention (Compounds of Formula I et seq.). For example, when a compound of the invention contains a hydroxy or carboxy substituent, these substituents may form physiologically hydrolysable and acceptable esters. As used herein, “physiologically hydrolysable and acceptable ester” means esters of the compounds of the invention which are hydrolysable under physiological conditions to yield acids (in the case of compounds of the invention which have hydroxy substituents) or alcohols (in the case of compounds of the invention which have carboxy substituents) which are themselves physiologically tolerable at doses to be administered. As will be appreciated, the term thus embraces conventional pharmaceutical prodrug forms. The term also refers to any specific chemical compound in which one or more atoms have been replaced with one or more different isotopes of the same element (e.g.. substitution of a hydrogen for a deuterium). It is noted that in describing the present compounds, numerous substituents and variables associated with same, among others, are described.

[0023] Specific compounds of the present invention may be identified in the present specification by chemical name and / or chemical structure. In the event of any conflict between the chemical name and chemical structure, the chemical structure will control.

[0024] As used herein, the articles “a” and “an” refer to one or to more than one (z.e., to 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, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0025] The term “administration” or the like as used herein refers to the providing a therapeutic agent to a subject. Multiple techniques of administering a therapeutic agent exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0026] The term “treat,” “treated,” “treating,” or “treatment” includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated. In certain embodiments, the treatment comprises alleviating, mitigating, ameliorating or delaying the onset of, inhibiting the progression of, reducing the severity of, and / or reducing theARVN-174-PCT / / ARVN0174WO2incidence of one or more symptoms of cancer. In another embodiment, treatment includes suppressing, inhibiting, delaying, mitigating or preventing the progression of cancer or cancer metastasis.

[0027] As used herein, the term “prevent” or “prevention” or “prophylaxis” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all the symptoms associated with the disorder or disease. In certain embodiment, prophylaxis or prevention of cancer includes preventing or delaying metastasis of the cancer.

[0028] As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[0029] As used herein, the term “subject” refers to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and marine mammals. In one embodiment, the subject is human. In another embodiment, the subject is a non-human subject, e.g., for veterinary use.

[0030] 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 provide the desired biological result or therapeutic benefit. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0031] As used herein, the term “pharmaceutically acceptable” refers to an attribute of a material, such as a carrier or diluent, which does not affect the biological activity or properties of the compound, and is relatively non-toxic. i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0032] As used herein, the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to 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 saltsARVN-174-PCT / / ARVN0174WO2of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The phrase “pharmaceutically acceptable salt” is not limited to a mono, or 1:1, salt. For example, “pharmaceutically acceptable salt” also includes bis-salts, such as a bis-hydrochloride salt. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences. 17th 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.

[0033] As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound useful within the disclosure with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0034] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the subject such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not injurious to the subject. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt: gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesameARVN-174-PCT / / ARVN0174WO2oil, 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; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; 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.

[0035] The term “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the present disclosure and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the compositions. Other additional ingredients that may be included in the pharmaceutical compositions are known in the art and described, for example, in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0036] As used herein, the term “alkyl,” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated {i.e., Ci -6 alkyl means an alkyl having one to six carbon atoms) and includes straight and branched chains.

[0037] The term “alkynyl” means a linear or branched hydrocarbon chain having the number of carbon atoms designated and having one or more carbon-carbon triple bonds that may occur at any stable point along the chain.

[0038] The term “alkylene” means a non-terminal, e.g., bivalent, saturated hydrocarbon having the number of carbon atoms designated. Similarly, “alkenylene” is a non-terminal, e.g., bivalent hydrocarbon having at least one carbon-carbon double bond and “alkynylene” is a nonterminal, e.g., bivalent hydrocarbon having at least one carbon-carbon triple bond.

[0039] The term “aryl” means any carbocyclic aromatic ring system, i.e., any aromatic ring system comprising only carbon atoms as ring atoms. This includes 6-membered monocyclic aryl ring systems and 9-membered or 10-membered fused bicyclic aryl ring systems, and larger fused ring systems, as long as such ring systems comprise at least one 6-membered aromatic carbocyclic ring (i.e., a benzene ring) within the fused ring system, and as long as no ring-atoms are heteroatoms. Thus, the term aryl includes, but is not limited to, phenyl, naphthyl.ARVN-174-PCT / / ARVN0174WO2

[0040] The term “arylene” means a non-terminal, e.g., bivalent aromatic ring system.

[0041] As used herein, the term “halo” or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.

[0042] As used herein, the term “cycloalkyl” means a non-aromatic carbocyclic system that is fully or partially saturated having 1 or more rings wherein the multicyclic rings may be fused, spiro or bridged. The term “fused” means that a second ring is present (z.e., attached or formed) by having two adjacent atoms in common (i.e., shared) with the first ring. Cycloalkyl also includes bicyclic structures that may be bridged or spirocyclic in nature with each individual ring within the bicycle varying from 3-8 atoms.

[0043] As used herein, the term “heterocycloalkyl” means a non-aromatic carbocyclic system containing one or more heteroatoms independently selected from N, O, and S and having 1 or more rings wherein the multicyclic rings may be fused, spiro or bridged, wherein fused is defined above. The term “heterocycloalkyl” includes unsaturated compounds such as dihydropyridinyl, dihydropyridazinyl, dihydropyrimidinyl, and dihydropyrazinyl.Heterocycloalkyl also includes bicyclic or multicyclic structures that may be fused, bridged or spirocyclic in nature with each individual ring within the bicycle varying from 3-8 atoms, and at least one ring containing 0, 1, or 2 N, O, or S atoms. The term “heterocyclo alkyl” includes cyclic esters (z'.e., lactones) and cyclic amides (i.e., lactams).

[0044] A x-membered heterocycloalkyl ring is a heterocycloalkyl group having x number of ring atoms and may be monocyclic or multicyclic (whether fused, spiro or bridged), wherein one or more e.g., 1, 2, or 3) ring atoms are independently selected from N. O, and S. Exemplary 4-12 membered ring heterocycloalkyls include piperidinyl, piperazinyl, morpholinyl but also 7-azaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 3,9-diazaspiro[5,5]undecanyl, 2-oxa-5,8-diazispiro[3.5]nonanyl, hexahydropyrrolo[3,4-c]pyrrolyl, 2,8-diazaspiro[4.5]decanyl, l-oxa-4,9-diazaspiro[5.5]undecanyl, 2,6-diazaspiro[3.3]heptanyl, pyrrolidinyl, azetidinyl, 2,5-diazabicyclo[2.2. l]heptanyl.

[0045] It is to be understood that if a cycloalkyl or heterocycloalkyl moiety may be bonded or otherwise attached to a designated moiety through differing ring atoms (z’.e., shown or described without denotation of a specific point of attachment), then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom.ARVN-174-PCT / / ARVN0174WO2

[0046] The terms “independently selected” or “each independently” are used herein to indicate that, for a variable which occurs in more than one location in a genus, the identity of the variable is determined separately in each instance. For example, if Rxappears as a substituent on two different atoms, the two instances of Rxmay be the same moiety, or different moieties. The same is true if a single atom is substituted with more than one instance of Rx. The identity of Rxin each instance is determined independently of the identity of the other(s).

[0047] The term “-O-CH2-((geminal halocyclopropyl)methyl-(optionally substituted heterocycloalkylene)” means a linking moiety, e.g.. that is bivalent, comprising the following general structure: -O-CH2-((2,2-dihalo-l-[optionally substituted heterocycloalkyl]methyl)cyclopropyl), in some embodiments, the heterocycloalkyl comprises a nitrogen hetero atom, wherein the nitrogen hetero atom is directly linked to the methyl group (marked with *) adjacent to the cyclopropyl, for example, having the following structure:wherein Ri and R2 are halo and moiety A is an optionally substituted heterocycloalkylene.

[0048] When a chemical structure comprising a stereocenter is marked with the term “OR” followed by an integer, it is intended that such “OR” designation encompasses compounds with either orientation at said stereocenter. Therefore, the “OR2” designation at the stereocenter in the exemplary Structure A below:Structure Aindicates that it encompasses either of the following structures:ARVN-174-PCT / / ARVN0174WO2or

[0049] When a chemical structure has two stereocenters that are marked with the term “OR” followed by the same integer, then said two stereocenters within the same chemical structure are intended to be synched and the structures with either orientation are intended.When a chemical structure has two stereocenters that are marked with the term “OR” followed by two different integers, then said two stereocenters within the chemical structure are independent of each other (i.e., not intended to be synched) and the structures with either orientation at each stereocenter are intended. For example, the exemplary Structure B below:comprising two stereocenters with the “OR2” designation on each are intended to encompass compounds with synched configurations such as the following configurations:ARVN-174-PCT / / ARVN0174WO2Likewise, the “0R1” designation at the carbon atom carrying the cyclopropyl and the “OR2” designations at the piperazine ring of Structure B are intended to encompass the structures with the following orientations:ARVN-174-PCT / / ARVN0174WO2

[0050] When a chemical structure comprises a stereocenter that is marked with the term “abs”, it is intended to cover a structure with the absolute configuration at said stereocenter as drawn. When a chemical structure is drawn with a wedge or hash bond without “abs”, it is intended to cover a structure with the absolute configuration at said stereocenter as drawn.

[0051] When a chemical structure has two stereocenters that are marked with the term followed by the same integer, then said two stereocenters within the same chemical structure are intended to be synched and a racemic mixture of the two orientations is intended. For example, the exemplary Structure below:is intended to cover a racemic mixture of:ARVN-174-PCT / / ARVN0174WO2Compounds of the present disclosure

[0052] Provided herein are Kirsten Rat Sarcoma (KRAS) PROTAC compounds for targeting KRAS mutant and non-mutant wild-type KRAS. Such compounds include those having the chemical structure of Formula IPTM-L-ULM (I)comprising (i) a Kirsten Rat Sarcoma (KRAS) protein targeting moiety (PTM); (ii) a linker(L) comprising a chemical structure -O-CH2-((geminal halocyclopropyl)methyl-(optionally substituted heterocycloalkylene)); and (iii) a Cereblon E3 ubiquitin ligase targeting moiety (ULM), in free or salt form (Compounds of Formula I or “Formula I”). Exemplary compounds of Formula (I) include the following:ARVN-174-PCT / / ARVN0174WO21.1. Compound of Formula I, wherein the PTM targets or binds to KRAS protein, e.g., KRAS protein comprising a mutation compared to the wild-type (KRAS mutant protein), e.g., selected from G12A, G12C, G12D, G12R, G12V or a combination thereof.1.2. Compound of Formula I or 1.1, wherein the PTM targets or binds to KRAS mutant protein.1.3. Compound of Formula I or any of 1.1 or 1.2, wherein the PTM targets or binds to KRAS G12A.1.4. Compound of Formula I or any of 1.1 or 1.2, wherein the PTM targets or binds to KRAS G12C.1.5. Compound of Formula I or any of 1.1 or 1.2, wherein the PTM targets or binds to KRAS G12D.1.6. Compound of Formula I or any of 1.1 or 1.2, wherein the PTM targets or binds to KRAS G12R.1.7. Compound of Formula I or any of 1.1 or 1.2, wherein the PTM targets or binds to KRAS G12V.1.8. Compound of Formula I or formula 1.1, wherein the PTM targets or binds to a non-mutant wild-type KRAS.1.9. Compound of Formula I or any of 1.1-1.8, wherein the PTM comprises a chemical structure oxa-6-azaspiro[3.5]nonane.1.10. Compound of Formula I or any of 1.1-1.8, wherein the PTM comprises a chemical l-oxa-6-azaspiro[3.5]nonan-6-yl.1.11. Compound of Formula I or any of 1.1-1.10, wherein the PTM comprises a chemical structure 4-(l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-<f|pyrimidine.1.12. Compound of Formula I or any of 1.1-1.8, wherein the PTM comprises a chemical structure 2-oxa-6-azaspiro[3.5]nonan-6-yl.1.13. Compound of Formula I or any of 1.1 -1.8, or 1.12 wherein the PTM comprises a chemical structure 4-(2-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-nQpyrimidine.1.14. Compound of Formula I or any of 1.1-1.13, wherein the compound is a compound of Formula 1(A):ARVN-174-PCT / / ARVN0174WO2Formula 1(A)in free or salt form, wherein:one of Zi and Z2 is O and the other is C(Ra)(Rb);X is =C(Ra)-, -C(Ra)(Rb)-, =N- or -N(Ra)-;Y is -N-, -C= or -C(Ra)-;each Raand Rb is independently H or Ci-4alkyl (e.g., methyl);Ri and R2 are independently halo (e.g. fluoro);R3 and R4 are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), C1-4alkoxy (e.g., methoxy) or haloC1-4alkoxy;R12 and R13 are independently H or Ci-4alkyl (e.g., methyl); or R4 and R12 or R4 and R13 together with the carbons to which they are attached form a cyclic structure, for example, R4 and R12 or R4 and R13 together can form a two-atom bridge such as, for example, -O-CH2- resulting in formation of a heterocyclic structure, e.g., an oxazepine;Moiety A is a 4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 7-azaspiro[3.5]nonanylene, 2,7-diazaspiro[3.5]nonanylene, 3,9-diazaspiro[5,5]undecanylene), 2-oxa-5,8-diazispiro[3.5]nonanylene, hexahydropyrrolo[3,4-c]pyrrolylene, 2,8-diazaspiro[4.5]decanylene, l-oxa-4,9-diazaspiro[5.5]undecanylene, 2,6-diazaspiro[3.3]heptanylene, pyrrolidinylene, azetidinylene, 2,5-diazabicyclo[2.2.1]heptanylene);Moiety B and moiety C are independently a bond, Ci-4alkylene (e.g., methylene or ethylene), -OC(O)-, -C(O)-Ci-4alkylene, -O-, a 4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 7-azaspiro[3.5]nonanylene, 2,7-diazaspiro[3.5]nonanylene, 3,9-diazaspiro[5,5]undecanylene), 2-oxa-5,8-diazispiro[3.5]nonanylene, hexahydropyrrolo[3,4-c]pyrrolylene, 2,8-diazaspiro[4.5]decanylene, l-oxa-4,9-diazaspiro[5.5]undecanylene, 2,6-ARVN-174-PCT / / ARVN0174WO2diazaspiro[3.3]heptanylene, pyrrolidinylene, azetidinylene, 2,5-diazabicyclo[2.2.1]heptanylene), or a heteroarylene (e.g. pyridylene),wherein A, B and C are independently optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);Moiety D is selected from the following:wherein R5, Re and R7 are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci- 4alkyl (e.g., methyl or ethyl), C2-4alkynyl (e.g., ethynyl), C3-4cycloalkyl (e.g., cyclopropyl), Ci- 4alkoxy (e.g.. methoxy), haloCi-4alkoxy (e.g., -O-C(F2)(H)), -OCH2-OP(O)(OH)2, -N(Ra)(Rb), -N(H)-C(0)CH3 or -N(H)-CH2CF3, wherein each Raand Re is independently H or Ci-4alkyl (e.g., methyl); andULM is selected from:ULM-1 ULM-2 ULM-3ARVN-174-PCT / / ARVN0174WO2ULM-12 ULM-13wherein:Rs is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;R9 is H, halo (e.g.. chloro or fluoro), OH, Ci-4alkyl or Ci-4alkoxy (e.g., methoxy or ethoxy);Rio is H or Ci-4alkyl (e.g., methyl);R11 is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy;Qi, Q10 and Qu are independently C(O) or C(Ra)(Rb);Q2 is N(Ra) or C(Ra)(Rb); andARVN-174-PCT / / ARVN0174WO2Q12 is O or CH2;R14 is H or Ci-4alkyl (e.g., methyl);R15 is H or halo (e.g., fluoro): andeach Raand Rb is independently H or Ci-4alkyl (e.g., methyl), or-A-B-C together with the ULM forms the following structure:Formula J or wherein R17 is H or halo (e.g., fluoro).1.15. Compound of formula 1.14, wherein one of Zi and Z2 is O and the other is C(Ra)(Rb).1.16. Compound of formula 1.14, wherein Zi is O and Z2 is C(Ra)(Rb).1.17. Compound of formula 1.14, wherein Z2 is O and Zi is C(Ra)(Rb).1.18. Any of formulae 1.14-1.17, wherein X is =C(Ra)-, -C(Ra)(Rb)-, =N- or -N(Ra)-;and Y is -N-, -C= or -C(Ra)-;1.19. Any of formulae 1.14-1.18. wherein X is =N- and Y is -C=.1.20. Any of formulae 1.14-1.19, wherein the compound is a compound of formula 1(A)- 1ARVN-174-PCT / / ARVN0174WO21.21. Any of formulae 1.14-1.18. wherein Y is -N- and X is C(Ra)(Rb).1.22. Any of formulae 1.14-1.18, wherein the compound is a compound of formula I(A)-2:1.23. Any of formulae 1.14-1.22, wherein Ri and R2 are independently halo (e.g.fluoro).1.24. Any of formulae 1.14-1.22, wherein Ri and R2 are both fluoro.ARVN-174-PCT / / ARVN0174WO21.25. Any of formulae 1.14-1.24, wherein R3 and R4 are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), Ci-4alkoxy (e.g., methoxy) or haloCi-4alkoxy.1.26. Any of formulae 1.14-1.25, wherein R3 and R4 are independently H.1.27. Any of formulae 1.14-1.26, wherein R3 and R4 are independently hydroxy.1.28. Any of formulae 1.14-1.27. wherein R3 and R4 are independently Ci-4alkyl (e.g..methyl or ethyl).1.29. Any of formulae 1.14-1.28. wherein R3 and R4 are independently methyl.1.30. Any of formulae 1.14-1.29, wherein R3 and R4 are independently halo (e.g. fluoro or chloro).1.31. Any of formulae 1.14-1.30. wherein R3 is methyl.1.32. Any of formulae 1.14-1.30, wherein R3 is fluoro.1.33. Any of formulae 1.14-1.30, wherein R3 is chloro1.34. Any of formulae 1.14-1.33. wherein R4 is H.1.35. Any of formulae 1.14-1.33, wherein R4 is fluoro1.36. Any of formulae 1.14-1.33, wherein R4 is chloro.1.37. Any of formulae 1.14-1.33, wherein R4 is methyl.1.38. Any of formulae 1.14-1.33, wherein R3 and R4 are independently Ci-4alkoxy (e.g., methoxy) or haloCi-4alkoxy.1.39. Any of formulae 1.14-1.38, wherein R3 and R4 are independently Ci-4alkoxy (e.g., methoxy).1.40. Any of formulae 1.14-1.39. wherein R12 and R13 are independently H or Ci-4alkyl (e.g., methyl) or R4 and R12 or R4 and R13 together with the carbons to which they are attached form a cyclic structure, for example, R4 is Ci-4alkoxy (e.g., methoxy) and R4 and R12 or R4 and R13 together with the carbons to which they are attached form a heterocyclic structure, e.g., form a oxazepane.1.41. Any of formulae 1.14-1.40, wherein R13 is H.1.42. Any of formulae 1.14-1.41, wherein R12 is H.1.43. Any of formulae 1.14-1.40, wherein R4 and R12 together with the carbons to which they are attached form a cyclic structure.ARVN-174-PCT / / ARVN0174WO2Any of formulae 1.14-1.41, wherein R4 is Ci-4alkoxy (e.g., methoxy) and R4 and R12 together with the carbons to which they are attached form a heterocyclic structure, e.g., form a oxazepane.Any of formulae 1.14-1.44, wherein D is selected from the following:Any of formulae 1.14-1.45, wherein D is Formula D-lAny of formulae 1.14-1.45, wherein D is Formula D-l(a) having the following structure:D-l(a)Any of formulae 1.14-1.45, wherein D is Formula D-2.Any of formulae 1.14-1.45, wherein D is Formula D-3.Any of formulae 1.14-1.49, wherein R5, Re and R7 are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), C2-4alkynyl (e.g., ethynyl), C3-4cycloalkyl (e.g., cyclopropyl), Ci-4alkoxy (e.g., methoxy), haloCi-4alkoxy (e.g., -O-C(F2)(H)), -OCH2-OP(O)(OH)2 or -N(Ra)(Rb), wherein each Raand Rb is independently H or Ci-4alkyl (e.g., methyl).Any of formulae 1.14-1.50. wherein R5 is H, hydroxy, Ci-4alkoxy (e.g.. methoxy), haloCi.4alkoxy (e.g., -O-C(F2)(H)), -OCH2-OP(O)(OH)2 or -N(Ra)(Rb), wherein each Raand Rbis independently H or Ci-4alkyl (e.g., methyl).Any of the foregoing formulae 1.14.1-1.50, wherein R5 is H.Any of the foregoing formulae 1.14.1-1.50, wherein R5 is hydroxy.Any of the foregoing formulae 1.14-1.50, wherein R5 is -OCH2-OP(O)(OH)2. Any of the foregoing formulae 1.14-1.50, wherein R5 is -N(Ra)(Rb).ARVN-174-PCT / / ARVN0174WO21.56. Any of formulae 1.14-1.73, wherein each Raand Rb is independently H or Ci- 4alkyl (e.g., methyl).1.57. Any of formulae 1.14-1.56. wherein Raand Rb are both H.1.58. Any of the foregoing formulae 1.14-1.50, wherein Rs is haloCi-4alkoxy (e.g., -O- C(F2)(H)).1.59. Any of formulae 1.14-1.58. wherein Re and R? are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), C2-4alkynyl (e.g., ethynyl), C3-4cycloalkyl (e.g., cyclopropyl), Ci-4alkoxy (e.g., methoxy), haloCi-4alkoxy (e.g., -O-C(F2)(H)), -OCH2-OP(O)(OH)2or -N(Ra)(Rb).1.60. Any of formulae 1.14-1.59, wherein Re and R? are independently H, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), C2-4alkynyl (e.g.. ethynyl) or C3-4cycloalkyl (e.g., cyclopropyl).1.61. Any of formulae 1.14-1.60, wherein Re is H.1.62. Any of formulae 1.14-1.60. wherein Re is H or halo (e.g. fluoro or chloro).1.63. Any of formulae 1.14-1.62, wherein Re is halo (e.g. fluoro or chloro).1.64. Any of formulae 1.14-1.62, wherein Re fluoro.1.65. Any of formulae 1.14-1.62, wherein Re chloro.1.66. Any of formulae 1.14-1.65, wherein R? is H, Ci-4alkyl (e.g., methyl or ethyl), C2.4alkynyl (e.g., ethynyl) or C3-4cycloalkyl (e.g., cyclopropyl).1.67. Any of formulae 1.14-1.66, wherein R?is H, Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).1.68. Any of formulae 1.14-1.66. wherein R?is H.1.69. Any of formulae 1.14-1.66, wherein R?is Ci-4alkyl (e.g., methyl or ethyl).1.70. Any of formulae 1.14-1.66, wherein R is ethyl.1.71. Any of formulae 1.14-1.66. wherein R? is C2-4alkynyl (e.g., ethynyl).1.72. Any of formulae 1.14-1.66, wherein R?is ethynyl.1.73. Any of formulae 1.14-1.66. wherein R? is C3-4cycloalkyl (e.g., cyclopropyl). 1.74. Any of formulae 1.14-1.73, wherein moiety A is a 4-12 membered heterocycloalkylene and moiety B and moiety C are independently a bond, Ci- 4alkylene (e.g., methylene). -OC(O)-, -C(O)-Ci-4alkylene, -O-, a 4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 7-ARVN-174-PCT / / ARVN0174WO2azaspiro[3.5]nonanylene, 2,7-diazaspiro[3.5]nonanylene, 3,9-diazaspiro[5,5]undecanylene), 2-oxa-5,8-diazispiro[3.5]nonanylene, hexahydropyrrolo[3,4-c]pyrrolylene, 2,8-diazaspiro[4.5]decanylene, l-oxa-4,9-diazaspiro[5.5]undecanylene, 2,6-diazaspiro[3.3]heptanylene, pyrrolidinylene, azetidinylene, 2,5-diazabicyclo[2.2.1]heptanylene), or a heteroarylene (e.g. pyridylene), wherein moieties A, B and C are independently optionally substituted with one or more halo, Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy). Any of formulae 1.14-1.74, wherein moiety A is a 4-12 membered heterocycloalkylene (e.g., mono-heterocyclic, fused-heterocyclic, spiro-heterocyclic or bridged heterocyclic or any combination of fused-heterocyclic, spiro-heterocyclic and / or bridged heterocyclic)Any of formulae 1.14-1.74, wherein moiety A is a 4-11 membered heterocycloalkylene (e.g., 6-8 membered monocyclic-heterocyclic, 8-10 membered fused-multicyclic heterocyclic, 7-11 membered multicyclic spiro-heterocyclic or 7-8 bridged heterocyclic or any combination of fused-heterocyclic, spiro-heterocyclic and / or bridged heterocyclic).Any of formulae 1.14-1.74, wherein moiety A is a 6-11 membered heterocycloalkylene.Any of formulae 1.14-1.74, wherein moiety A is a 6-membered mono-cyclic heterocycloalkylene.Any of formulae 1.14-1.74, wherein moiety A is a piperidinylene.Any of formulae 1.14-1.74, wherein moiety A is a piperazinylene.Any of formulae 1.14-1.74, wherein moiety A is 4-membered heterocycloakylene (e.g., azetidinylene).Any of formulae 1.14-1.74, wherein moiety A is 5-membered heterocycloakylene (e.g., pyrrolidinylene).Any of formulae 1.14-1.74, wherein moiety A is 7-membered heterocycloakylene (e.g., 2,5-diazabicyclo[2.2.1]heptanylene or 2,6-diazaspiro[3.3]heptanylene). Any of formulae 1.14-1.74, wherein moiety A is a 2,5-diazabicyclo[2.2. l]heptanylene.ARVN-174-PCT / / ARVN0174WO2Any of formulae 1.14-1.74, wherein moiety A is an 8-membered heterocycloakylene (e.g., hexahydropyrrolo[3,4-c]pyrrolylene).Any of formulae 1.14-1.74, wherein moiety A is a 9-membered heterocycloakylene (e.g., 7-azaspiro[3.5]nonanylene, 2,7- diazaspiro[3.5]nonanylene, 2-oxa-5,8-diazispiro[3.5]nonanylene).Any of formulae 1.14-1.74, wherein moiety A is a 7-azaspiro[3.5]nonanylene. Any of formulae 1.14-1.74, wherein moiety A is an 10-membered heterocycloalkylene (e.g., 2,8-diazaspiro[4.5]decenylene).Any of formulae 1.14-1.74, wherein moiety A is an 11 -membered heterocycloalkylene (e.g., 3,9-diazaspiro[5,5]undecanylene or l-oxa-4,9- diazaspir o [5.5 ] undecanylene).Any of formulae 1.14-1.89, wherein moiety A is optionally substituted with one or more halo, Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy).Any of formulae 1.14-1.90. wherein A is unsubstituted.Any of formulae 1.14-1.90, wherein A is substituted with halo (e.g., fluoro). Any of formulae 1.14-1.90, wherein A is substituted with Ci-4alkyl (e.g., methyl). Any of formulae 1.14-1.90, wherein A is substituted with Ci-4alkoxy (e.g., methoxy).Any of formulae 1.14-1.94, wherein A is selected from any of the following:ARVN-174-PCT / / ARVN0174WO21.97. Any of formulae 1.14-1.95, wherein A is:1.98. Any of formulae 1.14-1.95, wherein A is:1.99. Any of formulae 1.14-1.95. wherein A is:1.100. Any of formulae 1.14-1.99, wherein moiety B and moiety C are independently a bond, Ci-4alkylene (e.g., methylene), -OC(O)-, -C(O)-Ci-4alkylene (e.g., - C(O)CH2-), -O-. a 4-12 membered heterocycloalkylene.1.101. Any of formulae 1.14-1.99, wherein moiety B and moiety C is a bond.1.102. Any of formulae 1.14-1.99, wherein moiety B is a bond.1.103. Any of formulae 1.14-1.99. wherein moiety B and moiety C are both a bond. 1.104. Any of formulae 1.14-1.99, wherein moiety B and moiety C are independently Ci- 4alkylene (e.g., methylene or ethylene).1.105. Any of formulae 1.14-1.99, wherein moiety B is ethylene.ARVN-174-PCT / / ARVN0174WO21.106. Any of formulae 1.14-1.99, wherein moiety B is methylene.1.107. Any of formulae 1.14-1.99, wherein moiety B is -OC(O)-.1.108. Any of formulae 1.14-1.99, wherein moiety B is -C(O)-Ci-4alkylene (e.g., - C(O)CH2-).1.109. Any of formulae 1.14-1.99, wherein moiety B is -O-.1.110. Any of formulae 1.14-1.109, wherein moiety C is a 4-12 membered heterocycloalkylene1.111. Any of formulae 1.14-1.110, wherein moiety B and moiety C are optionally substituted with one or more halo, Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy).1.112. Any of formulae 1.14-1.110, wherein moiety B and moiety C and independently unsubstituted.1.113. Any of formulae 1.14-1.110, wherein moiety B and moiety C and independently substituted with halo (e.g., fluoro).1.114. Any of formulae 1.14-1.110, wherein B and C and independently substituted with Ci-4alkyl (e.g., methyl).1.115. Any of formulae 1.14-1.110, wherein B and C and independently substituted with Ci-4alkoxy (e.g., methoxy).1.116. Any of formulae 1.111-1.115, wherein moiety C is independently substituted. 1.117. Any of formulae 1.14-1.110, wherein moiety C is a 4-12 membered heterocycloalkylene as described in any of formulae 1.75-1.99.1.118. Any of formulae 1.14-1.116, wherein C is a 4-12 membered heterocycloalkylene selected from:ARVN-174-PCT / / ARVN0174WO21.119. Any of formulae 1.14-1.99, wherein moiety C is a bond.1.120. Any of formulae 1.14-1.99. wherein moiety C is a heteroarylene (e.g. pyridylene).1.121. Any of the foregoing formulae, wherein the compound is a compound of Formula I(A)-3:Formula I(A)-31.122. Any of the foregoing formulae, wherein the compound is the compound of Formula I(A)-4:ARVN-174-PCT / / ARVN0174WO2Formula I(A)-4Any of the foregoing formulae, wherein the compound is a compound of Formula I(A)-4a:Any of the foregoing formulae, wherein the compound is a compound of Formula I(A)-4b:ARVN-174-PCT / / ARVN0174WO2Formula I(A)-4bAny of the foregoing formulae, wherein the compound is a compound of Formula I(A)-5:Formula I(A)-5Any of the foregoing formulae, wherein the compound is a compound of Formula I(A)-5a:ARVN-174-PCT / / ARVN0174WO2Formula I(A)-5aAny of the foregoing formulae, wherein the compound is a compound of Formula I(A)-5b:Formula I(A)-5bAny of formulae 1.121-1.127, wherein the compound is a compound of Formula I(A)-6:ARVN-174-PCT / / ARVN0174WO2Formula I(A)-61.129. Any of formulae 1.14-1.128, wherein:Ri and R2 are both fluoro;R3 is H, halo (e.g. fluoro or chloro) or Ci-4alkyl (e.g., methyl or ethyl); R4 is H or Ci-4alkyl (e.g., methyl);R12 and R13 are both H;D is Formula D-l, wherein R5 is H or hydroxy; Re is H or halo (e.g., fluoro or chloro): and R7 is H, Ci-4alkyl (e.g., methyl or ethyl), C2- 4alkynyl (e.g., ethynyl).1.130. Any of formulae 1.121-1.129, wherein R3 is Ci-4alkyl.1.131. Any of formulae 1.121-1.130, wherein R3 is methyl.1.132. Any of formulae 1.121-1.128, wherein R3 is halo (e.g. fluoro or chloro).1.133. Any of formulae 1.121-1.132, wherein R4 is Ci-4alkyl.1.134. Any of formulae 1.121-1.133, wherein R4 is methyl.1.135. Any of formulae 1.121-1.132, wherein R4 is H.1.136. Any of formula 1.119-1.135, wherein R5 is hydroxy.1.137. Any of formula 1.119-1.136, wherein Re is halo (e.g. fluoro or chloro).1.138. Any of formula 1.119-1.136, wherein Re fluoro.1.139. Any of formula 1.119-1.136, wherein Re chloro.1.140. Any of formula 1.119-1.139, wherein R7 is Ci-4alkyl (e.g., methyl or ethyl).1.141. Any of formula 1.119-1.139, wherein R?is ethyl.1.142. Any of formula 1.119-1.139, wherein R?is C2-4alkynyl (e.g., ethynyl).1.143. Any of formula 1.119-1.139, wherein R?is ethynyl.ARVN-174-PCT / / ARVN0174WO21.144. Any of formulae 1.14-1.143, wherein the ULM is selected from:ULM-12 ULM-13wherein:Rs is H or halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;ARVN-174-PCT / / ARVN0174WO2R9 is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy or Ci-alkoxy (e.g., methoxy or ethoxy);Rio is H or Ci-4alkyl (e.g., methyl);R11 is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci ^alkoxy;Qi, Q10 and Qu are independently C(O) or C(Ra)(Rb);Q2 is N(Ra) or C(Ra)(Rb);Q12 is O or CH2;R14 is H or Ci-4alkyl (e.g., methyl);R15 is H or halo (e.g., fluoro);each Raand Rb is independently H or Ci-4alkyl (e.g., methyl), or-A-B-C together with the ULM forms the following structure:Formula JorFormula K1.145. Any of formulae 1.14-1.144, wherein the ULM is ULM-1.1.146. Any of formulae 1.14-1.145, wherein Qi is C(O) or C(Ra)(Rb).1.147. Any of formulae 1.14-1.145, wherein Qi is C(O).1.148. Any of formulae 1.14-1.145, wherein Qi is C(Ra)(Rb).1.149. Any of formulae 1.14-1.144, wherein the ULM is ULM-2.1.150. Any of formulae 1.14-1.144, wherein the ULM is ULM-3.1.151. Any of formulae 1.14-1.144, wherein the ULM is ULM-4.1.152. Formula 1.151, wherein Rais H or Ci-4alkyl (e.g., methyl).1.153. Formula 1.151, wherein Rais H.1.154. Formula 1.151, wherein Rais Ci-4alkyl (e.g., methyl).1.155. Formula 1.151, wherein Rais methyl.1.156. Any of formulae 1.14-1.144, wherein the ULM is ULM-6.1.157. Formula 1.156, wherein Rio is H or Ci-4alkyl (e.g., methyl).ARVN-174-PCT / / ARVN0174WO21.158. Formula 1.156, wherein Rio is H.1.159. Formula 1.156, wherein Rio is Ci-4alkyl (e.g., methyl).1.160. Any of formulae 1.14-1.144, wherein the ULM is ULM-9.1.161. Any of formulae 1.14-1.144, wherein the ULM is ULM -7.1.162. Any of formulae 1.14-1.161, wherein Q2 is N(Ra) or C(Ra)(Rb).1.163. Any of formulae 1.14-1.161, wherein Q2 is N(Ra).1.164. Any of formulae 1.14-1.161, wherein Q2 is C(Ra)(Rb).1.165. Any of formulae 1.161-1.164, wherein Rn is H, halo (e.g., chloro or fluoro), Ci- 4alkyl (e.g., methyl) or Ci-4alkoxy.1.166. Any of formulae 1.161-1.164, wherein Rn is H.1.167. Any of formulae 1.161-1.164, wherein Rn is Cmalkyl (e.g.. methyl).1.168. Any of formulae 1.14-1.144, wherein the ULM is ULM-10.1.169. Formula 1.168, wherein Qw is C(O) or C(Ra)(Rb).1.170. Formula 1.168 or 1.169, wherein Qw is C(O).1.171. Formula 1.168 or 1.169, wherein Qw is C(Ra)(Rb).1.172. Formula 1.171, wherein Qw is Raand Rb are independently H or Cmalkyl (e.g., methyl).1.173. Formula 1.171, wherein Qw is Raand Rb are both H.1.174. Any of formula 1.168-1.173, wherein R14 is H or Cmalkyl (e.g., methyl).1.175. Any of formula 1.168-1.173, wherein R14 is H.1.176. Any of formula 1.168-1.173, wherein R14 is Cmalkyl (e.g., methyl).1.177. Any of formula 1.168-1.173, wherein R14 is methyl.1.178. Any of formula 1.168-1.177, wherein R15 is H or halo (e.g., fluoro).1.179. Formula 1.178, wherein R15 is H.1.180. Formula 1.178, wherein R15 is halo (e.g., fluoro).1.181. Any of formulae 1.14-1.144, wherein the ULM is ULM- 11.1.182. Formula 1.181, wherein R15 is H or halo (e.g., fluoro).1.183. Formula 1.181, wherein R15 is H.1.184. Formula 1.181, wherein R15 is fluoro.1.185. Any of formulae 1.14-1.144, wherein the ULM is ULM-12.1.186. Formula 1.185, wherein Q12 is Q12 is O or CH2.ARVN-174-PCT / / ARVN0174WO21.187. Formula 1.185, wherein Q12 is O.1.188. Formula 1.185, wherein Q12 is CH2.1.189. Any of formulae 1.14-1.144, wherein the ULM is ULM-13.1.190. Formula 1.189, wherein R15 is H or halo (e.g., fluoro).1.191. Formula 1.189, wherein R15 is H.1.192. Formula 1.189, wherein R15 is halo (e.g., fluoro).1.193. Any of formulae 1.14-1.192, wherein Rs is H or halo (e.g., chloro or fluoro), Ci- 4alkyl (e.g., methyl), OH, or Ci-4alkoxy.1.194. Any of formulae 1.14-1.193, wherein Rs is H or halo (e.g., chloro or fluoro), 1.195. Any of formulae 1.14-1.192, wherein Rs is H.1.196. Any of formulae 1.14-1.192, wherein Rs is halo (e.g., chloro or fluoro).1.197. Any of formulae 1.14-1.196, wherein R9 is H, halo (e.g., chloro or fluoro), OH, Ci-4alkyl or Ci-4alkoxy (e.g., methoxy or ethoxy).1.198. Any of formulae 1.14-1.197, wherein R9 is H, halo (e.g.. chloro or fluoro).1.199. Any of formulae 1.14-1.197, wherein R9 is H.1.200. Any of formulae 1.14-1.197, wherein R9 is halo (e.g., chloro or fluoro).1.201. Any of formulae 1.14-1.197, wherein R9 is Ci-4alkoxy (e.g., methoxy or ethoxy).1.202. Any of formulae 1.14-1.197, wherein R9 is methoxy or ethoxy.1.203. Any of formulae 1.14-1.197, wherein R9 is -OCD3 (wherein D is deuterium). 1.204. Any of formulae 1.14-1.203, wherein each Ra and Rb is independently H or C1-4alkyl (e.g., methyl).1.205. Any of formulae 1.14-1.203, wherein Raand Rb are independently H.1.206. Any of formulae 1.14-1.203, wherein Raand Rb are both H.1.207. Any of formulae 1.14-1.203, wherein Raand Rb are independently Ci-4alkyl (e.g., methyl).1.208. Any of formulae 1.14-1.207, wherein the ULM is elected from the following:1.209. Any of formulae 1.14- 1.207, wherein the ULM is elected from the following:ARVN-174-PCT / / ARVN0174WO2ULM-13-a ULM-13-brmulae 1.14- 1.207, wherein the ULM is elected from the following:ULM-12-a ULM-12-brmulae 1.14-1.210, wherein the ULM is elected from the following:ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2elected from the following:ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO21.213. Any of formulae 1.14-1.212, wherein -A-B-C- is selected from the following:ARVN-174-PCT / / AR VN0174 W025ARVN-174-PCT / / ARVN0174WO21.214. Any of formulae 1.14-1.213, wherein -A-B-C- is selected from the following:ARVN-174-PCT / / ARVN0174WO21.215. Any of formulae 1.14-1.214, wherein -A-B-C together with the UML forms the following:Formula J Formula K.1.216. Any of formulae 1.14-1.215, wherein the compound is in pharmaceutically acceptable salt form.1.217. Any of the foregoing formulae, wherein the compound is in free form.1.218. Any of the foregoing formulae, wherein the compound is in salt or pharmaceutically acceptable salt form.1.219. Any of the foregoing formulae, wherein the compound is in isotopic form (e.g, in deuterated form, in partially deuterated or fully deuterated form; e.g., wherein one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms, are replaced with deuterium).1.220. Any of the foregoing formulae, wherein the compound is in an enantiomerically or diastereomically enriched form (e.g., in greater than or equal to 75%, 85%, 90%, 95%, 99%, 99.9% enantiomeric excess of one form over the other form). 1.221. Any of the foregoing formulae, wherein the compound has improved oral bioavailability relative to conventional small molecule enzyme inhibitors and other KRAS PROTAC compounds.ARVN-174-PCT / / ARVN0174WO2Any of the foregoing formulae, wherein the compound degrades KRAS G12 mutations including KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, and KRAS G12V.Any of the foregoing formulae, wherein the compound degrades non-mutated wild-type KRAS.Any of the foregoing formulae, wherein the compound degrades KRAS G12D. Any of the foregoing formulae, wherein the compound degrades KRAS G12V. Any of the foregoing formulae, wherein the compound degrades KRAS wild-type or mutant) in cells carrying such KRAS (non-mutant wild-type or mutation) at 24 hour with an DCso of less than lOOnM, preferably less than 75nM, preferably less than 50nM, preferably less than lOnM, e.g.. in an in vitro assay as described in Example 2 below.Any of the foregoing formulae, wherein the compound degrades KRAS (wildtype or mutant) in cells carrying such KRAS (non-mutant wild-type or mutation) at 24 hour with an Dmaxvalue of at least 25 %, preferably greater than or equal to 50%, preferably greater than or equal to 70%, preferably greater than 70%, e.g., in an in vitro assay as described in Example 2 below.Any of the foregoing formulae, wherein KRAS mutant is a KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, and KRAS G12V.Any of the foregoing formulae, wherein KRAS mutant is a G 12V KRAS.Any of the foregoing formulae, wherein KRAS mutant is a G12D KRAS.Any of the foregoing formulae, wherein KRAS is a non-mutated wild-type KRAS.Any of the foregoing formulae, wherein the compound is selected from Compound numbers 1-211 of Table 1. in free or salt form:Table 1StructureARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2in free or salt form thereof.1.233. The Compound of Formula I or any of 1.1-1.13, wherein the compound is a compound of Formula 1(A)’:1(A)’in free or salt form, wherein:one of Zi and Z2 is O and the other is C(Ra)(Rb);X is =C(Ra)-, -C(Ra)(Rb)-, =N- or -N(Ra)-;Y is -N-, -C= or -C(Ra)-;each Raand Rb is independently H or Ci-4alkyl (e.g., methyl);Ri and R2 are independently halo (e.g. fluoro);R3 and R4 are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g.. methyl or ethyl), Ci-4alkoxy (e.g., methoxy) or haloCi-4alkoxy;ARVN-174-PCT / / ARVN0174WO2R12 and i? are independently H or Ci-4alkyl (e.g., methyl); or R4 and R12 or R4 and R13 together with the carbons to which they are attached form a cyclic structure, for example, R4 and R12 or R4 and R13 together can form a two-atom bridge such as, for example, -O-CH2- resulting in formation of a heterocyclic structure, e.g., an oxazepine;Moiety A is a 4-12 membered heterocycloalkylene:Moiety B and C are independently abond,Ci-4alkylene (e.g., methylene or ethylene),-OC(O)-,-C(O)-Ci-4alkylene,-O-,C(O),-N(Rx)-, wherein Rxis H or Ci-4alkyl (e.g., methyl);4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 7- azaspiro[3.5]nonanylene, 2,7-diazaspiro[3.5]nonanylene, 3,9- diazaspiro[5,5]undecanylene, 2-oxa-5,8-diazispiro[3.5]nonanylene, hexahydropyrrolo[3,4-c]pyrrolylene, 2,8-diazaspiro[4.5]decanylene, 1-oxa- 4,9-diazaspiro[5.5]undecanylene, 2,6-diazaspiro[3.3]heptanylene, pyiTolidinylene, azetidinylene, 2,5-diazabicyclo[2.2.1]heptanylene), or heteroarylene (e.g. pyridylene),wherein A, B and C are independently optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);Moiety D is selected from the following:ARVN-174-PCT / / ARVN0174WO2wherein Rs, Rg and R7 are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), C2-4alkynyl (e.g., ethynyl), C3-4cycloalkyl (e.g., cyclopropyl), Ci-4alkoxy (e.g.. methoxy), haloCi-4alkoxy (e.g., -O-C(F2)(H)), -OCH2-OP(O)(OH)2, -N(Ra)(Rb), -N(H)-C(O)CHs or -N(H)-CH2CF3, wherein each Raand Rb is independently H or Ci-4alkyl (e.g., methyl); andULM is selected from:ULM-1 ULM-2 ULM-3ARVN-174-PCT / / ARVN0174WO25ARVN-174-PCT / / ARVN0174WO2wherein:Rs is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;R9 is H, halo (e.g., chloro or fluoro), OH, Ci-4alkyl or Ci-4alkoxy (e.g., methoxy or ethoxy);R10 is H or C1-4alkyl (e.g., methyl);R11 is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy;Qi, Q10 and Qu are independently C(O) or C(Ra)(Rb);Q?x is N(R?x) or C(Ra)(Rb); wherein R?xis H, Ci-4alkyl (e.g., methyl) or C3 eaycloalkyl (e.g., cyclopropyl); Each of Rn and Rnxis independently H, halo (e.g., chloro or fluoro):Q12 is O or CH2;ARVN-174-PCT / / ARVN0174WO2Q14 is N(Ri4a), C(Ra)(Rb), wherein Ruais H, Ci-4alkyl (e.g., methyl, ethyl, propyl such as isopropyl) or Cs eaycloalkyl (e.g., cyclopropyl);Qi4x is N(Ri4ax) or C(Ra)(Rb). wherein Ri4ax is H, Ci-4alkyl (e.g., methyl) or C3- eaycloalkyl (e.g., cyclopropyl);Q15 is N(Ri5a) or C(Ra)(Rb), wherein Risais H, Ci-4alkyl (e.g., methyl) or Cs-scycloalkyl (e.g., cyclopropyl);Q16 is C(O) or C(Ra)(Rb);Each of Rio. Riix. Ri2 and Ri?xis independently Ci-4alkyl (e.g., methyl); Ri4b is H or Ci- 4alkyl (e.g., methyl);R14 is H or Ci-4alkyl (e.g., methyl);Ri4x is H or Ci-4alkyl (e.g., methyl);R15 is H or halo (e.g., fluoro);Each of R16b and R16c is H or C1-4alkyl (e.g., methyl);Ri6d is H or halo (e.g.. fluoro);Ri6c is H or Ci-4alkyl (e.g., methyl);Ris is H or Ci-4alkyl (e.g., methyl);each Raand Rb is independently H or Cn4alkyl (e.g., methyl); or-A-B-C together with the ULM forms the following structure:ARVN-174-PCT / / ARVN0174WO2wherein each of Rjxand Rkx is independently Ci-4alkyl (e.g., methyl), R17 is H or halo (e.g., fluoro).1.234. The Compound of Formula 1 or 1.233, wherein:Zi is O and Z2 is C(Ra)(Rb);Xis =N-;Y is -C=;Each of Raand Rb is independently H or Ci-4alkyl (e.g., methyl);R12 and R13 are both H.1.235. The Compound of Formula I or any of 1.233-1.234, wherein the compound is a Compound of Formula I(A)-4:ARVN-174-PCT / / ARVN0174WO2Formula I(A)-4The Compound of Formula I or any of 1.233-1.234, wherein the compound is a Compound of Formula I(A)-4a:The Compound of Formula I or any of 1.233-1.234, wherein the compound is a Compound of Formula I(A)-4b:Formula I(A)-4bThe Compound of Formula I or any of 1.233-1.234, wherein the compound is a Compound of Formula I(A)-5:ARVN-174-PCT / / ARVN0174WO2Formula I(A)-5The Compound of Formula I or any of 1.233-1.234, wherein the compound is a Compound of Formula I(A)-5a:Formula I(A)-5aThe Compound of Formula I or any of 1.233-1.234, wherein the compound is a Compound of Formula I(A)-5b:ARVN-174-PCT / / ARVN0174WO2Formula I(A)-5bThe Compound of Formula I or any of 1.233-1.240, wherein:Ri and R2 are independently halo (e.g. fluoro);R3 is H, halo (e.g. fluoro or chloro) or Ci-4alkyl (e.g., methyl or ethyl);R4 is H or Ci-4alkyl (e.g., methyl);Moiety A is:a 4-12 membered heterocycloalkylene (e.g., 6-membered heterocycloalkylene such as a piperidinylene):B is:a bond;Ci-4alkylene (e.g.. methylene);C(O), or-N(RX)-, wherein Rxis H or Ci-4alkyl (e.g., methyl);C is:a bond, ora 4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 7- azaspiro[3.5]nonanylene, 2,7-diazaspiro[3.5]nonanylene, 3,9- diazaspiro[5,5]undecanylene, 2-oxa-5,8-diazispiro[3.5]nonanylene, hexahydropyrrolo[3,4-c]pyrrolylene, 2,8-diazaspiro[4.5]decanylene, 1- oxa-4,9-diazaspiro[5.5]undecanylene, 2,6-diazaspiro[3.3]heptanylene, pyrrolidinylene, azetidinylene, 2,5-diazabicyclo[2.2.1]heptanylene), or a heteroarylene (e.g. pyridylene);ARVN-174-PCT / / ARVN0174WO2wherein A, B and C are independently optionally substituted with one or more halo or Ci-4alkyl (e.g., methyl); andMoiety D is D-l to D-5, wherein R5, Re and R7 are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) or C24alkynyl (e.g., ethynyl).The Compound of Formula I or any of 1.233-1.241, wherein:Ri and R2 are independently halo (e.g. fluoro);R3 is H, halo (e.g. fluoro or chloro) or Ci-4alkyl (e.g., methyl);R4 is H or Ci-4alkyl (e.g., methyl);Moiety A is a 4-12 membered heterocycloalkylene (e.g., 6-membered heterocycloalkylene such as a piperidinylene. 3,9- diazaspiro[5.5]undecanylene, 2-azabicyclo[2.2.1]heptanylene or 7- azaspiro [3.5] nonanylene);B is a bond;C is a Ci-4alkylene (e.g., methylene or ethylene);Moiety D is D-l or D4, wherein R5, Re and R7 are independently H, hydroxy, halo (e.g. fluoro or chloro), Cn4alkyl (e.g., methyl or ethyl) or C2- 4alkynyl (e.g., ethynyl).The Compound of Formula I or any of 1.233-1.240, wherein:Ri and R2 are independently halo (e.g. fluoro);R3 is halo (e.g. fluoro or chloro) or Ci-4alkyl (e.g., methyl or ethyl);R4 is H;Moiety A is a 4-12 membered heterocycloalkylene (e.g., 6-membered heterocycloalkylene such as a piperidinylene or piperazinylene);B is Ci-4alkylene (e.g., methylene);C is a 4-12 membered heterocycloalkylene (e.g., 6-membered heterocycloalkylene such as a piperidinylene or piperazinylene); wherein A, B and C are independently optionally substituted with one or more halo or Ci-4alkyl (e.g., methyl);Moiety D is D-l or D4, wherein R5 is hydroxy, Re is halo (e.g. fluoro or chloro) and R7 is Ci-4alkyl (e.g., ethyl) or C2-4alkynyl (e.g., ethynyl).ARVN-174-PCT / / ARVN0174WO2The Compound of Formula T or any of 1.233- 1.243, wherein the ULM is ULM- 1, ULM-6, ULM-7-X, ULM-10-X, ULM-ll-X, ULM-12-X, ULM-13-X, ULM- 14, ULM-15, ULM-16 or ULM-18.The Compound of Formula I or any of 1.233-1.243, wherein the ULM isARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2The Compound of Formula I or any of 1.233-1.245, wherein the compound is a compound as defined in any of formulae 1.1-1.232.The Compound of Formula I or any of 1.233-1.244, wherein the ULM is ULM- Ka):ULM-1(a)wherein:Qi, is C(O) or C(Ra)(Rb);each of Raand Rb is independently H or Ci-4alkyl (e.g., methyl);R8 is H, halo (e.g., chloro or fluoro), C1-4alkyl (e.g., methyl), OH, or C1-4alkoxy;R9 is H, halo (e.g., chloro or fluoro), OH, C1-4alkyl or C1-4alkoxy (e.g., methoxy orethoxy);The Compound of Formula I or any of 1.233-1.247, wherein ULM is ULM- 1(a), wherein Qi is C(Ra)(Rb) and each of Raand Rb is independently H or Ci-4alkyl (e.g., methyl), Rs is H and R9 is H or halo (e.g.. chloro or fluoro).The Compound of Formula I or any of 1.233-1.248, wherein ULM is ULM- 1(a), wherein Qi, is C(Ra)(Rb) and Raand Rb are both H.The Compound of Formula I or any of 1.233-1.249, wherein Rs is H and R9 is H.ARVN-174-PCT / / ARVN0174WO21.251. The Compound of Formula I or any of 1.233—1.249, wherein Rs is H and R9 is halo (e.g., chloro or fluoro).1.252. The Compound of Formula I or any of 1.233-1.244 or 1.247-1.249, wherein Rs is H and R9 is fluoro.1.253. The Compound of Formula I or any of 1.233-1.244 or 1.247-1.249, wherein the ULM is:O OF1.254. The Compound of Formula I or any of 1.233-1.244, wherein the ULM is ULM- 6(a):ULM-6(a)wherein Rio is H or Ci-4alkyl (e.g., methyl).1.255. The Compound of Formula I or any of 1.233-1.244, wherein ULM is ULM-7. 1.256. The Compound of Formula I or any of 1.233-1.244 or 1.255, wherein ULM isULM-7(a)1.257. The Compound of Formula I or any of 1.233-1.244 or 1.255, wherein ULM is ULM-7(b):ARVN-174-PCT / / ARVN0174WO2ULM-7(b)1.258. The Compound of Formula I or any of 1.233-1.244 or 1.255-1.257, wherein Q2 is C(Ra)(Rb) and Raand Rb are H and Rn is H or halo (e.g.. chloro or fluoro).1.259. The Compound of Formula I or any of 1.233-1.244 or 1.255-1.257, wherein Q2 is N(Ra), wherein Rais independently H, Ci-4alkyl (e.g., methyl).1.260. The Compound of Formula I or any of 1.233-1.244 or 1.255-1.257 or 1.259, wherein Q2 is N(Ra), wherein Rais H.1.261. The Compound of Formula I or any of 1.233-1.244 or 1.255-1.257 or 1.259, wherein Q2 is N(Ra), wherein Rais Ci-4alkyl (e.g., methyl).1.262. The Compound of Formula I or any of 1.233-1.244 or 1.255-1.257 or 1.259, wherein Q2 is N(Ra), wherein Rais methyl.1.263. The Compound of Formula I or any of 1.233-1.244, wherein the ULM is ULM-7- X:ULM-7-Xwherein Q?xis N(R?X) or C(Ra)(Rb); wherein R?x is H, Ci-4alkyl (e.g.. methyl) or Cs-eaycloalkyl (e.g., cyclopropyl); Each of Rn and Rnxis independently H, halo (e.g., chloro or fluoro).1.264. The Compound of Formula I or any of 1.233-1.244 or 1.255-1.257 or 1.259- 1.263, wherein Rn is H.1.265. The Compound of Formula I or any of 1.233-1.244 or 1.255-1.262, wherein Rn is halo (e.g., chloro or fluoro).ARVN-174-PCT / / ARVN0174WO2The Compound of Formula T or any of 1.233-1.244 or 1.255-1.262, wherein Rn is fluoro.The Compound of Formula I or any of 1.233-1.244 or 1.255-1.262, wherein the ULM is:FThe Compound of Formula I or any of 1.233-1.244, wherein ULM is ULM-7-X, wherein Q7 is N(R?x), wherein R?xis independently H, Ci-4alkyl (e.g., methyl). The compound of formula 1.268, wherein Rnxand Rn are both fluoro.The Compound of Formula I or any of 1.268-1.269, wherein Q?xis N(R?X) wherein R?xis methyl.The Compound of Formula I or any of 1.233-1.244 or 1.255-1.263, wherein0The Compound of Formula I or any of 1.268-1.270, wherein the ULM is:The Compound of Formula I or any of 1.233-1.244, wherein the ULM is ULM-ARVN-174-PCT / / ARVN0174WO2wherein:Qi4 is N(Ri4a), C(Ra)(Rb). wherein Ri4a is H, Ci-4alkyl (e.g., methyl, ethyl, propyl such as isopropyl) or Cs-eaycloalkyl (e.g., cyclopropyl);Ri4b is H or Ci-4alkyl (e.g., methyl);Ri4 is H or Ci-4alkyl (e.g., methyl).1.274. The Compound of Formula I or any of 1.233-1.244 or 1.273, wherein the ULM is ULM- 14(a).ULM-14(a)1.275. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.274, wherein the ULM is ULM- 14 or ULM- 14(a). wherein Q14 is C(Ra)(Rb), wherein Raand Rb is independently H or Ci-4alkyl (e.g., methyl).1.276. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.274, wherein the ULM is ULM- 14 or ULM-14(a), wherein Q14 is N(Ri4a), wherein Ri4a is H, Ci- 4alkyl (e.g., methyl, ethyl, propyl such as isopropyl) or Cs-eaycloalkyl (e.g., cyclopropyl).1.277. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.276, wherein the ULM is ULM-14 or ULM-14(a), wherein Q14 is N(Ri4a), wherein Rnais H.ARVN-174-PCT / / ARVN0174WO21.278. The Compound of Formula T or any of 1.233-1.244 or 1.273-1.276, wherein the ULM is ULM-14 or ULM-14(a), wherein QM is N(Ri4a), wherein Ri4a is Ci-4alkyl (e.g., methyl, ethyl, propyl such as isopropyl).1.279. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.276, wherein the ULM is ULM-14 or ULM-14(a), wherein Q14 is N(Ri4a). wherein Ri4a is methyl.1.280. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.276. wherein the ULM is ULM-14 or ULM-14(a), wherein Q14 is N(Ri4a), wherein Ri4a is ethyl. 1.281. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.276, wherein the ULM is ULM-14 or ULM-14(a), wherein Q14 is N(Ri4a), wherein Ri4 is propyl such as isopropyl.1.282. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.276, wherein the ULM is ULM-14 or ULM-14(a), wherein Q14 is N(Ri4a), wherein Ri4 is C3- eaycloalkyl (e.g., cyclopropyl).1.283. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.276. wherein the ULM is ULM-14 or ULM-14(a), wherein Q14 is N(Ri4a), wherein Ri4 is C3- eaycloalkyl (e.g., cyclopropyl).1.284. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.276, wherein the ULM is ULM-14 or ULM-14(a), wherein Q14 is N(Ri4a), wherein Ri4a is cyclopropyl.1.285. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.284, wherein the ULM is ULM-14 or ULM- 14(a), wherein Ri4b is H or Ci-4alkyl (e.g., methyl). 1.286. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.285, wherein the ULM is ULM-14 or ULM-14(a), wherein Ri4bis H.1.287. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.285, wherein the ULM is ULM-14 or ULM-14(a). wherein Ri4b is Ci-4alkyl (e.g., methyl).1.288. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.287, wherein the ULM is ULM-14 or ULM- 14(a), wherein R14 is H or Ci-4alkyl (e.g., methyl). 1.289. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.288, wherein the ULM is ULM-14 or ULM- 14(a), wherein Ri4is H.1.290. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.288, wherein the ULM is ULM-14 or ULM-14(a), wherein RI4is Ci-4alkyl (e.g., methyl).ARVN-174-PCT / / ARVN0174WO21.291. The Compound of Formula T or any of 1.233-1.244 or 1.273-1.288, wherein the ULM is ULM-14 or ULM- 14(a), wherein RM is methyl.1.292. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.291, wherein the ULM is ULM-14 or ULM-14(a), wherein R15 is H or halo (e.g., fluoro).1.293. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.292, wherein the ULM is ULM-14 or ULM- 14(a). wherein R15 is H.1.294. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.292, wherein the ULM is ULM-14 or ULM- 14(a), wherein R15 is halo (e.g., fluoro).1.295. The Compound of Formula I or any of 1.233-1.244 or 1.273-1.294, wherein the ULM is selected from the following:ARVN-174-PCT / / AR VN0174 WO25 1.296. The Compound of Formula I or any of 1.233-1.244, wherein the ULM is:ARVN-174-PCT / / ARVN0174WO2The Compound of Formula I or any of 1.233-1.244, wherein the ULM is:The Compound of Formula I or any of 1.233-1.294, wherein the ULM is selected from the following:The Compound of Formula I or any of 1.233-1.294, wherein the ULM is:The Compound of Formula I or any of 1.233-1.243, wherein the ULM is ULM-10-X.The Compound of Formula I or any of 1.233-1.243, wherein the ULM is ULM- 11-X.ARVN-174-PCT / / ARVN0174WO21.302. The Compound of Formula T or any of 1.233- 1.243, wherein the ULM is ULM- 12-X.1.303. The Compound of Formula I or any of 1.233-1.243, wherein the ULM is ULM- 13-X.1.304. The Compound of Formula I or any of 1.233-1.243, wherein the ULM is ULM- 15.1.305. The Compound of Formula I or any of 1.233-1.243, wherein the ULM is ULM- 16.1.306. The Compound of Formula I or any of 1.233-1.243, wherein the ULM is ULM- 18.1.307. The Compound of Formula I or any of 1.233-1.243, wherein -A-B-C together with the ULM forms the following structure.1.308. The Compound of Formula I or any of 1.233-1.243, wherein -A-B-C together with the ULM forms the following structure:1.309. The Compound of Formula I or any of 1.233-1.308, wherein Moiety D is formula D-l or D-4:ARVN-174-PCT / / ARVN0174WO2R5ReD-1 orD-4The Compound of Formula I or any of 1.233-1.309, wherein moiety D is formula D-l(a):D-l(a).The Compound of Formula I or any of 1.233-1.309, wherein Moiety D is formula D-4:R5R6D-4The Compound of Formula 1 or any of 1.233-1.309, wherein Moiety D is formula D-4(a):The Compound of Formula I or any of 1.233-1.308, wherein Moiety D is formula D-5.ARVN-174-PCT / / ARVN0174WO21.314. The Compound of Formula T or any of 1.233- 1.313, wherein Rs, Re and R? are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), C2-4alkynyl (e.g., ethynyl).1.315. The Compound of Formula I or any of 1.233-1.314, wherein Rs is H or hydroxy, Re is H or halo (e.g. fluoro or chloro) and, R? is H, Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).1.316. The Compound of Formula I or any of 1.233-1.315, wherein Rs is H or hydroxy, Re is H or halo (e.g. fluoro or chloro) and R? is H or Ci-4alkyl (e.g., methyl or ethyl).1.317. The Compound of Formula I or any of 1.233-1.315, wherein Rs is H or hydroxy, Re is H or halo (e.g. fluoro or chloro) and R? is H or C2-4alkynyl (e.g., ethynyl).1.318. The Compound of Formula I or any of 1.233-1.317, wherein Rs is hydroxy, Re is H or halo (e.g. fluoro or chloro) and R? is Ci-4alkyl (e.g., methyl or ethyl) or C2- 4alkynyl (e.g., ethynyl).1.319. The Compound of Formula I or any of 1.233-1.318, wherein R7 is H or Ci-4alkyl (e.g., methyl or ethyl).1.320. The Compound of Formula I or any of 1.233-1.318, wherein R7 is Ci-4alkyl (e.g., methyl or ethyl).1.321. The Compound of Formula I or any of 1.233-1.318, wherein Rs is hydroxy, Re is H and R7 is Ci-4alkyl (e.g., methyl or ethyl).1.322. The Compound of Formula I or any of 1.233-1.321, wherein Rs is hydroxy, Re is H and R7 is methyl.1.323. The Compound of Formula I or any of 1.233-1.321, wherein Rs is hydroxy, Re is H and R7 is ethyl.1.324. The Compound of Formula I or any of 1.233-1.323, wherein each stereocenter is optionally and independently in an enantiomerically or diastereomically enriched form (e.g., in greater than or equal to 75%, 85%, 90%, 95%, 99%, 99.9% enantiomeric excess of one form over the other form), for example, wherein each stereocenter is independently enantiomerically enriched in the R-form and in another embodiment, in the S-form, or in still another embodiment, in racemic form.ARVN-174-PCT / / ARVN0174WO21.325. The Compound of Formula T or any of 1.233- 1.324, wherein Moiety D is:HO1.326. The Compound of Formula I or any of 1.233-1.324, wherein Moiety D is:1.,1.327. The Compound of Formula I or any of 1.233-1.324, wherein Moiety D is:1.328. The Compound of Formula I or any of 1.233-1.327, wherein Moiety C is a heterocycloalkylene as described in any of formulae 1.75-1.99.1.329. The Compound of Formula I or any of 1.233-1.328, wherein Moiety C is a 6-7 membered heterocycloalkylene (e.g., piperidinylene or piperazinylene) optionally substituted with one or more Chalky I (e.g., methyl).1.330. The Compound of Formula I or any of 1.233-1.329, wherein Moiety C is a 7 membered heterocycloalkylene (e.g., 2,5-diazabicyclo[2.2.1]heptanylene).1.331. The Compound of Formula I or any of 1.233-1.329, wherein Moiety C is a 6 membered heterocycloalkylene (e.g., piperidinylene or piperazinylene) optionally substituted with one or more Ci-4alkyl (e.g.. methyl).1.332. The Compound of Formula I or any of 1.233-1.329, wherein Moiety C is a piperidinylene optionally substituted with one or more Ci-4alkyl (e.g., methyl). 1.333. The Compound of Formula I or any of 1.233-1.329, wherein Moiety C is a piperazinylene optionally substituted with one or more Ci-4alkyl (e.g., methyl).ARVN-174-PCT / / ARVN0174WO2The Compound of Formula 1 or any of 1.233- 1.333, wherein Moiety C is unsubstituted.The Compound of Formula I or any of 1.233-1.333, wherein Moiety C is substituted with one or more Ci-4alkyl (e.g., methyl).The Compound of Formula I or any of 1.233-1.333, wherein Moiety C is substituted with one or more methyl.The Compound of Formula I or any of 1.233-1.333, wherein Moiety C is substituted with two methyl.The Compound of Formula I or any of 1.233-1.333, wherein Moiety C isThe Compound of Formula I or any of 1.233-1.333, wherein Moiety C isThe Compound of Formula I or any of 1.233-1.333, wherein Moiety C is:The Compound of Formula I or any of 1.233-1.333, wherein Moiety C is:or2 / The Compound of Formula I or any of 1.233-1.333, wherein Moiety C isThe Compound of Formula I or any of 1.233-1.333, wherein Moiety C isARVN-174-PCT / / ARVN0174WO21.344. The Compound of Formula I or any of 1.233-1.333, wherein Moiety C is1.345. The Compound of Formula 1 or any of 1.233- 1.344, wherein Moiety A is described herein, e.g., in any of 1.74-1.99.1.346. The Compound of Formula I or any of 1.233-1.345, wherein Moiety A is:1.347. The Compound of Formula I or any of 1.233-1.345, wherein Moiety A is:1.348. The Compound of Formula I or any of 1.233-1.333, wherein Moiety C is:1.349.or. The Compound of Formula I or any of 1.233- 1.345, wherein Moiety A is:1.350. The Compound of Formula I or any of 1.233-1.345, wherein Moiety A is aARVN-174-PCT / / ARVN0174WO21.351. The Compound of Formula I or any of 1.233- 1.350, wherein Moiety B is a bond.1.352. The Compound of Formula I or any of 1.233-1.350, wherein Moiety B is C(O).1.353. The Compound of Formula I or any of 1.233-1.350, wherein Moiety B is -N(RX)-.wherein Rxis H or Ci-4alkyl (e.g., methyl).1.354. The Compound of Formula I or any of 1.233-1.350, wherein Moiety B is a Ci- 4alkylene (e.g., methylene).1.355. The Compound of Formula I or any of the foregoing wherein -A-B-C is:or2 oj- or2 1.356. The Compound of Formula I or any of the foregoing wherein -A-B-C is:ARVN-174-PCT / / ARVN0174WO2The Compound of Formula I or any of the foregoing wherein -A-B-C is:The Compound of Formula I or any of the foregoing wherein -A-B-C is:The Compound of Formula I or any of the foregoing wherein -A-B-C is:The Compound of Formula I or any of the foregoing wherein the compound is selected from any of the compound disclosed in Table 1-A, in free or salt form:ARVN-174-PCT / / ARVN0174WO2Table 1-AARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2Pharmaceutical C

[0053] The compounds of the present invention in free or a pharmaceutically acceptable salt thereof can be used as a therapeutically active substance, e.g. in the form of a pharmaceutical preparation or composition. The pharmaceutical preparations / compositions can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally. vaginally or via an implanted reservoir. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G.. eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds.. The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington’s Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins, 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Liquid dosage forms, injectable preparations, solid dispersion forms, solid dosage form, and dosage forms for topical or transdermal administration of the compounds, the pharmaceutically acceptable salts of the compounds, and the pharmaceutical compositions described herein are included herein. In one aspect, the compounds, the pharmaceutically acceptable salts of the compounds, and the pharmaceutical compositions described herein are administered orally.

[0054] A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the pharmaceutical composition.

[0055] Therefore, provided herein are pharmaceutical compositions comprising a compound described herein (e.g.. any of formulae 1.1-1.232, in free or pharmaceuticallyARVN-174-PCT / / ARVN0174WO2acceptable salt form) in combination or association with a pharmaceutically acceptable carrier (Composition I).Methods of Treatment

[0056] This application also provides methods of treating or ameliorating a disease state or condition that is modulated or mediated through the target protein, i.e., KRAS, Therefore, provided herein are methods for the treatment or prophylaxis of a KRAS mediated disorder (such as an abnormal cellular proliferation disease or disorder, including cancer) in a subject in need thereof (Method I), comprising administering to the subject an effective amount of any of the compounds disclosed herein (any of Formula I or any of 1.1-1.232 or 1.233-1.360), in free or pharmaceutically acceptable salt form, or an effective amount of any of the pharmaceutical compositions disclosed herein. In another aspect, provided herein are methods for the treatment of a KRAS mediated disorder (such as an abnormal cellular proliferation disease or disorder, including cancer) in a subject in need thereof (Method I), comprising administering to the subject an effective amount of any of the compounds disclosed herein (any of Formula I or any of 1.1-1.232 or 1.233-1.360), in free or pharmaceutically acceptable salt form, or an effective amount of any of the pharmaceutical compositions disclosed herein. In certain embodiments, Method I includes the following:3.1. Method I, wherein the disease or disorder is an abnormal cellular proliferation disorder such as a tumor or cancer.3.2. Method I or 3.1, wherein the disease or disorder is KRAS-mediated cancer.3.3. Method I or any of 3.1-3.2, wherein the disease or disorder is mediated by a mutant form of KRAS.3.4. Method I or any of 3.1-3.3, wherein the disease or disorder is mediated by a G12A mutant KRAS.3.5. Method I or any of 3.1-3.3, wherein the disease or disorder is mediated by a G12C mutant KRAS.3.6. Method I or any of 3.1-3.3, wherein the disease or disorder is mediated by a G12D mutant KRAS.3.7. Method I or any of 3.1-3.3, wherein the disease or disorder is mediated by a G 12R mutant KRAS.ARVN-174-PCT / / ARVN0174WO23.8. Method I or any of 3.1-3.3, wherein the disease or disorder is mediated by a G12V mutant KRAS.3.9. Method I or any of 3.1-3.2, wherein the disease or disorder is mediated by nonmutant wild-type KRAS.3.10. Method I or any of 3.1-3.9, wherein the cancer is pancreatic cancer, pancreatic ductal adenocarcinoma, pancreatic adenosquamous carcinoma, pancreatic squamous cell carcinoma, acinar cell carcinoma, giant cell tumor, pancreatoblastoma, invasive intraductal papillary mucinous neoplasm, invasive mucinous cystic neoplasm, colorectal cancer, colorectal adenocarcinoma, colorectal squamous cell carcinoma, lung cancer, non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, large cell carcinoma, or small cell lung cancer.3.11. Method I or 3.1-3.10 wherein the cancer is pancreatic, colorectal or lung cancer.3.12. Method I or 3.1-3.10 wherein the cancer is pancreatic cancer.3.13. Method I or 3.1-3.10 wherein the cancer is a pancreatic ductal adenocarcinoma.3.14. Method I or 3.1-3.10 wherein the cancer is colorectal cancer.3.15. Method I or 3.1-3.10 wherein the cancer is lung cancer.3.16. Method I or 3.1-3.10 wherein the cancer is a non-small cell lung cancer.3.17. Method I or any of the foregoing methods, wherein the subject is a human subject.3.18. Method I or any of the foregoing methods, wherein the subject is a non-human subject.3.19. Method I or any of the foregoing methods, further comprising administering one or more anticancer agent.

[0057] According to the methods of treatment of the present disclosure, disorders are treated or prevented in a subject, such as a human or other animal, by administering to the subject a therapeutically effective amount of a compound of the disclosure, in such amounts and for such time as is necessary to achieve the desired result. The term “effective amount” of a compound of the disclosure, as used herein, means enough of the compound so as to decrease the symptoms of a disorder in a subject. As is well understood in the medical arts an effective amount of a compound of this disclosure will be at a reasonable benefit / risk ratio applicable to any medical treatment.ARVN-174-PCT / / ARVN0174WO2

[0058] In general, compounds of the disclosure will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. An effective amount may vary widely depending on the severity of the disease, the subject's previous or ongoing therapy, the age and relative health of the subject, the route of administration, the subject’s response to the drugs, the judgement of the treating physician, the potency of the compound used and other factors. An illustrative example of a dose for a subject is in the range of from about 0.001 mg to about 1000 mg of compound (per day, in single or divided dosage units (e.g., BID, TID, QID).

[0059] It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific inhibitory dose for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age. body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.Kits

[0060] Provided herein are kits comprising a compound capable of degrading KRAS selected from one or more compounds of disclosed herein, and instructions for use in treating a disorder associated with KRAS.

[0061] The disclosure provides a kit comprising a compound capable of degrading KRAS selected from a compound disclosed herein.

[0062] Also provided herein are kits comprising a compound disclosed herein for the treatment of any of the indications disclosed herein.

[0063] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are within the scope of this disclosure and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g.,ARVN-174-PCT / / ARVN0174WO2nitrogen atmosphere, and reducing / oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

[0064] It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

[0065] The following examples further illustrate aspects of the present disclosure.However, they are in no way a limitation of the teachings of the present disclosure as set forth.Methods of Making:

[0066] The compounds of the present disclosure may generally be prepared as follows:General synthetic Scheme 1:wherein R1-R7 are as defined herein.ARVN-174-PCT / / ARVN0174WO2General synthetic Scheme 2:wherein R1-R4 and moiety A and ULM are as defined herein and Linker is moiety B-C as defined herein.General synthetic Scheme 3:wherein R1-R4 and moiety A and ULM are as defined herein and moiety B and moiety C are both a bond.ARVN-174-PCT / / ARVN0174WO2General Synthetic Scheme 4wherein R1-R4 and moiety A and ULM are as defined herein and Linker is moiety B-C as defined herein.ARVN-174-PCT / / ARVN0174WO2General Synthetic Scheme 5wherein X is F and Z is haloARVN-174-PCT / / ARVN0174WO2 General Synthetic Scheme 6INT-7-E1 / E2INT-25 wherein R1-R7 are as defined herein.General Synthetic Scheme 7ARVN-174-PCT / / ARVN0174WO2INT-15 wherein R1-R4 and moiety A and ULM are as defined herein and Linker is moiety B-C as defined herein.General Synthetic Scheme 8wherein R1-R4 and moiety A and ULM are as defined herein and Linker is moiety B-C as defined herein.ARVN-174-PCT / / ARVN0174WO2General Synthetic Scheme 9Synthesis of 2-(3-(methoxymethoxy)-8-methyl-5,6,7,8-tetrahydronaphthalen-l -yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane:ARVN-174-PCT / / ARVN0174WO2OMe OMe OMe MeONH2’HCi N3S:Pd(OAc)-- - >. OH6H OAc INT-33 INT-34 1NT-35 1NT-36PtO?, H2(20 Psi)SNT-37 iNT-38 SNT-39Chiral SFCOMOM OMOM INT-40 (R)-INT-4Q (SHNT-40 (NT-41Step 1:OH OH^T-33 IHT-34

[0067] To a mixture of 6-hydroxytetralin-l-one (50 g, 308.29 mmol, 1 eq) and O-methylhydroxylamine;hydrochloride (38.62 g, 462.44 mmol, 35.1 mL, 1.5 eq) in acetonitrile (250 mL) was added pyridine (36.58 g, 462.44 mmol, 37.33 mL, 1.5 eq) in one portion at 20 °C under nitrogen. The mixture was stirred at 20 °C for 2 hours, then poured into ice-water (w / w = 1 / 1) (1000 mL) and stirred for 10 min. The aqueous phase was extracted with t-butyl methyl ether (1000 mL x 3). The combined organic phase was washed with brine (1000 mL x 2), driedARVN-174-PCT / / ARVN0174WO2with anhydrous sodium sulfate, filtered and concentrated in vacuum to afford (1E)-1-methoxyiminotetralin-6-ol (Intermediate 34, 52 g, crude) as a yellow solid.Step 2:OH OAcINT44 INT45

[0068] To a mixture of Intermediate 34 (50 g, 261.47 mmol, 1 eq) and triethylamine (52.92 g, 522.94 mmol, 72.8 mL, 2 eq) in t-butyl methyl ether (500 mL) was added acetyl chloride (24.63 g, 313.77 mmol, 22.3 mL, 1.2 eq) by dropwise addition at 0 °C under nitrogen. The mixture was stirred at 20 °C for 12 hours, then poured into ice-water (w / w = 1 / 1) (2000 mL) and stirred for 10 min. The aqueous phase was extracted with / -butyl methyl ether (1000 mL x 3). The combined organic phase was washed with brine (1000 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to afford [(1E)-1-methoxyiminotetralin-6-yl] acetate (Intermediate 35, 55 g, 235.79 mmol, 90% yield) as a yellow solid. 'H NMR (400 MHz, CDC13) 8: 8.01 (d, I = 8.4 Hz, 1H), 6.99 - 6.87 (m, 2H), 4.00 (s, 3H), 2.74 (q, J = 6.4 Hz, 4H), 2.31 (s, 3H), 1.87 (quin, J = 6.4 Hz, 2H)OMeNBS, PdtOAchOAcINT-35 1NT-36ARVN-174-PCT / / ARVN0174WO2

[0069] To a mixture of Intermediate 35 (55 g, 235.79 mmol, 1 eq) and 1-bromopyrrolidine-2, 5-dione (46.16 g, 259.36 mmol, 1.1 eq) in acetic acid (270 mL) was added palladium(ii) acetate (3.71 g, 16.51 mmol. 0.07 eq) in one portion at 35 °C under nitrogen. The mixture was stirred at 35 °C for 16 hours, then cooled to 20 °C. 10% sodium sulfite (220 mL) was added and the solid was formed and stirred for 1 h. Water (1000 mL) was added and the product was extracted with r-butyl methyl ether (2000 mL). The organic layer was washed with 15% sodium carbonate (1000 mL), saturated sodium bicarbonate solution (1000 mL), and brine (1000 mL x 2), then dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was triturated with heptane (IL) at 0 °C for 30 min. to afford [(1E)-8-bromo-l-methoxyimino-tetralin-6-yl] acetate (Intermediate 36, 55 g, 176.19 mmol, 74% yield) as a yellow solid. NMR (400 MHz, CDC13) 5: 7.32 (s, 1H), 6.91 (s, 1H), 4.05 (d. J = 1.2 Hz, 3H), 2.82 - 2.71 (m, 2H), 2.67 - 2.58 (m, 2H), 2.31 (d, J = 1.2 Hz, 3H), 1.79 (quin, J = 5.6 Hz, 2H).Step 4:OH INT-37

[0070] A mixture of Intermediate 36 (62 g, 198.62 mmol, 1 eq) and hydrogen chloride (2 M, 644.8 mL, 6.49 eq) in dioxane (650 mL) was heated to 100 °C and stirred for 3 hours, then cooled to 20 °C and concentrated under reduced pressure at 45 °C. The residue was filtered and the cake was dried under high vacuo. The cake was washed with water (1000 mL x 3) and dried under high vacuo to afford crude 8-bromo-6-hydroxy-tetralin-l-one (Intermediate 37, 45 g, 186.66 mmol, 93.98% yield) as a yellow solid, which was used in the next reaction without further purification.Step 5:ARVN-174-PCT / / ARVN0174WO2OH OMOMNT-37 I T-38

[0071] To a mixture of Intermediate 37 (65 g, 269.62 mmol, 1 eq) and dimethoxymethane (205.16 g, 2.7 mol. 239 mL, 10 eq) in ethyl acetate (320 mL) was added butylphosphonic anhydride (389 g, 539.24 mmol, 50% purity, 2 eq) in one portion at 50 °C under nitrogen. The mixture was stirred at 50 °C for 16 hours, then cooled to 20 °C and poured into ice-water (w / w = 1 / 1) (2000 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (lOOOmL x 3) and the combined organic phase was washed with 2 M potassium carbonate (2000 mL), brine (1000 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / l, 3 / 1) to afford 8-bromo-6-(methoxymethoxy)tetralin-l-one (Intermediate 38, 70 g, 245.50 mmol, 91% yield) as yellow solid.Step 6:QMOM OMOMINT-38 NT-39

[0072] To a mixture of methyl(triphenyl)phosphonium;iodide (170.12 g, 420.86 mmol, 2 eq) in tetrahydrofuran (600 mL) was added potassium te -butoxide (1 M, 526.1 mL, 2.5 eq) in one portion at 20°C under nitrogen. The mixture was stirred at 20 °C for 30 min, then Intermediate 38 (60 g, 210.43 mmol, 1 eq) was added at 20 °C. The mixture was stirred for 16 hours, then poured into ice-water (w / w = 1 / 1) (500 mL) and stirred for 5 min. The aqueousARVN-174-PCT / / ARVN0174WO2phase was extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with brine (300 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate= 100 / 1, 10 / 1) to afford 8-bromo-6-(methoxymethoxy)-l-methylene-tetralin (Intermediate 39, 42 g, 148.33 mmol, 70% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 5: 7.22 (d, J = 2.4 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 5.62 (s, 1H), 5.32 (d, J = 1.2 Hz, 1H), 5.17 (s, 2H), 3.50 (s, 3H), 2.73 (t, J - 6.4 Hz, 2H), 2.50 (t, J - 6.8 Hz, 2H), 1.86 (quin, J = 6.8 Hz, 2H)Step 7:PtCh, K? (20 Psi)~ MOMOM OMOMI N T-39 INT-40

[0073] To a solution of Intermediate 39 (14 g, 49.44 mmol, 1 eq) in THF (150 mL) was added platinum dioxide (7 g) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (20 psi) at 20 °C for 16 hours, then filtered. The filtrate was concentrated, and the crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=10:l) to afford the crude product. The crude product was further purified by prep-HPLC (heptane- ethyl alcohol; gradient: l%-5% to afford 8-bromo-6-(methoxymethoxy)-l- methyl-tetralin (Intermediate 40, 7 g, 24.55 mmol, 70% yield) as a white solid. 'H NMR (400 MHz, CDC13) 8: 7.03 (d, J = 1.9 Hz, 1H), 6.65 (s. 1H), 5.04 (s, 2H), 3.39 (s, 3H), 3.08 (dt, J = 3.6, 6.7 Hz, 1H), 2.71 - 2.60 (m, 2H), 1.86 - 1.73 (m, 1H), 1.72 - 1.60 (m, 3H), 1.14 (d, J = 7.0 Hz, 3H)Step 8:ARVN-174-PCT / / ARVN0174WO2Chiral SFC - >.OMOM OMOMI T-40 (RHNT-40 (SHN*M0

[0074] Intermediate 40 (7 g, 24.55 mmol, 1 eq) was separated by chrial SFC (isopropanol (0.1% NH3H2O) in CO2 from 10% to 10%) to afford (17?)-8-bromo-6-(methoxymethoxy)-l-methyl-tetralin (( / ^-Intermediate 40-E1, 2.8 g, 9.82 mmol, 40% yield) as a yellow oil and (15)-8-bromo-6-(methoxymethoxy)-l-methyl-tetralin ((S)-Intermediate 40-E2, 2.6 g, 9.12 mmol, 37. % yield) as a yellow oil.Step 9\OMOM OMOM(KHNT-40

[0075] To a mixture of ( )-Intermediate 40 (2.50 g, 8.77 mmol, 1 eq) and potassium acetate (3.01 g, 30.68 mmol, 3.5 eq) in toluene (50 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4.45 g, 17.53 mmol, 2 eq) and [l, T-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (641 mg, 0.88 mmol, 0.1 eq) in one portion at 108 °C under nitrogen. The mixture was stirred at 108 °C for 16 hours, then cooled to 20 °C and filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (0~8% ethyl acetate / hexanes) to afford 2-[(47?)-7-(methoxymethoxy) -4-methyl-tetralin-5-yl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane ((R)-Intermediate 41, 2.6 g, 7.83 mmol, 89% yield) as a yellow solid.NMR (400 MHz, CDC13) 8: 7.17 (d. J = 2.8 Hz, 1H). 6.73 (d, J = 2.8 Hz, 1H), 5.12 - 5.01 (m, 2H), 3.58 - 3.48 (m, 1H), 3.39 (s, 3H), 2.74 - 2.57 (m, 2H), 1.85 - 1.72 (m, 2H), 1.69 - 1.55 (m, 2H), 1.28 - 1.25 (m, 12H), 1.10 (d, J = 7.2 Hz, 3H).ARVN-174-PCT / / ARVN0174WO2EXAMPLES

[0076] 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, which are within the skill of the art.

[0077] The following examples further illustrate aspects of the present disclosure.However, they are in no way a limitation of the teachings of the present disclosure as set forth.AbbreviationscataCXium A Pd G3 mesylate[(di( 1 -adamantyl)-n-butylphosphine)-2-(2'-amino- 1,1'- biphenyl)] palladium(II)CS2CO3 cesium carbonateDCM dichloromethaneDess-Martin periodinane 1,1,1 -tris(acetyloxy)- 1, 1 -dihydro- 1,2-benziodoxol-3-( lH)-one DIEA N, N-DiisopropylethylamineDMA N, N-Dimethy lacetamideEtOAc ethyl acetateEtOH ethyl alcoholKI potassium iodideLiHMDS lithium bis(trimethylsilyl)amideMTBE methyl tert-butyl etherNaBH(OAc)3sodium triacetoxyborohydrideNa2COs sodium carbonateNaOAc sodium acetateNa2SO4sodium sulfateNH4CI ammonium chlorideARVN-174-PCT / / ARVN0174WO2rac-BINAP-Pd-G3 [2'-(amino-KA [ 1, 1 '-biphenyl] -2-yl -KC] [[2'- (diphenylphosphino)[ 1, 1 '-binaphthalen]-2-yl]diphenylphosphine- KP] (methanesulfonato-KO)- palladiumRuPhos Pd G4 [dicyclohexyl(2’,6'-diisopropoxy-2-biphenylyl)phosphine- KP] (methanesulf onatato-KO) [2 (methylamino-KA9-2-bipheny lyl- KC2] palladiumSPhos Pd G3 (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino- 1, 1 '-biphenyl)] palladium(II) methanesulfonateTBAF tetrabutylammonium fluorideTFA trifluoroacetic acidTHF tetrahydrofuranProceduresExample 1.1Exemplary synthesis of Compound 81:Step 1:CbzCl. TEADCM.-78- 25 °C, 3h

[0078] To a solution of 2,2-dimethylpiperazine (25.0 g, 219 mmol, 1 eq) in dichloromethane (250 mL) is added triethylamine (33.23 g, 328 mmol, 45.7 mL, 1.5 eq), and the resulting mixture is cooled to -78 °C. Benzyl chloroformate (31.2 mL, 219 mmol, 1 eq) is then added, and the reaction mixture is stirred at 25 °C for 3 h. The mixture is diluted with water (500 mL) and extracted with dichloromethane (300 mL x 2). The combined organic extract is washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (5%-30% acetonitrile in water (formic acid) over 20 min) to afford benzyl 3,3-dimethylpiperazine-l -carboxylate (19.5 g, 35%) as a colorless oil. LC / MS (ESI) m / z 249.0 [M+H]+; ’H NMR (400 MHz, CDCI3) <5: 7.41 - 7.28 (m, 5H), 5.15 (s, 2H), 3.44 (t, J= 5.2 Hz, 2H), 3.24 (s, 2H), 2.90 (s, 2H), 1.11 (s, 6H).Step 2:ARVN-174-PCT / / ARVN0174WO2DIEA, NaBH(OAc)3, Ti(i-PrOH)4DCM / i-PrOH, 25-40°C, 14.5 h

[0079] To a solution of benzyl 3,3-dimethylpiperazine-l -carboxylate (10 g, 40.27 mmol, 1 eq) in dichloromethane (100 mL) and dimethyl sulfoxide (100 mL) is added N, N-diisopropylethylamine (15.61 g, 121 mmol, 21 mL, 3 eq), and the resulting mixture is stirred at 25 °C for 0.5 h. tert-Butyl 4-formylpiperidine- 1 -carboxylate (8.59 g, 40.27 mmol, 1 eq) is then added, and the mixture is stirred at 40 °C for 2 h. Titanium (IV) isopropoxide (22.89 g, 80 mmol, 23.7 mL, 2 eq) and sodium triacetoxyborohydride (25.60 g, 121 mmol, 3 eq) are added at 25 °C, and the reaction mixture is stirred at 40 °C for 12 h. The mixture is diluted with water (500 mL), and the suspension is filtered. The filtrate is extracted with dichloromethane (500 mL x 2), and the combined organic extracts are washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (20%-50% acetonitrile in water (formic acid) over 20 min) to afford benzyl 4-((l-(z -butoxycarbonyl)piperidin-4-yl)methyl)-3,3-dimethylpiperazine-l-carboxylate (13.8 g, 76%) as a white solid. LC / MS (ESI) m / z 446.2 [M+H]+;JH NMR (400 MHz, CDCI3) 8: 7.44 - 7.28 (m, 5H), 5.14 (s, 2H), 4.21 - 4.01 (m. 2H), 3.49 (s, 2H). 3.19 (s, 2H), 2.67 (t, J = 12.0 Hz, 2H), 2.48 (s, 2H), 2.13 (d, J = 7.2 Hz, 2H), 1.73 (d, J= 11.8 Hz, 2H), 1.46 (s, 10H), 1.09 - 0.87 (m, 8H). Step 3: Boc^ '\ZXMxCbZ H2’Pd / Al2°3 BoC^ N | i - ►THF / MeOH, 60°C, 6 h

[0080] A solution of benzyl 4-((l-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-3,3-dimethylpiperazine- 1 -carboxylate (13.8 g, 31 mmol, 1 eq) in tetrahydrofuran (138 m ) and methanol (138 mL) is pumped to a fixed bed (FLR1, 20 mL volume, packed with granular catalyst 5% Pd / APCh (10 g), 1.5 mpa hydrogen back pressure regulator, 60 mL / min hydrogen flow rate) at 60 °C for 6 h. The eluent is collected and concentrated under reduced pressure to afford tert-butyl 4-((2,2-dimethylpiperazin-l-yl)methyl)piperidine-l -carboxylate (9.7 g, crude) as a white solid, which is used in the next step without further purification.1H NMR (400 MHz, CDC13) A- 4.09 (d, J = 4.0 Hz, 2H), 2.93 - 2.81 (m, 2H), 2.67 (t, J = 12.4 Hz, 2H), 2.58 (s, 2H),ARVN-174-PCT / / ARVN0174WO22.48 - 2.41 (m, 2H), 2.13 (d, J = 12 Hz, 2H), 1.74 (d, J= 12.4 Hz, 2H), 1.46 (s, 11H), 1.09 - 0.91 (m, 8H).Step 4:F FF / XZ SOCI2, MeOHFu X / 0H- 80 °C, 12 h X\ XO O

[0081] To a solution of 3,4-difluoro-2-methyl-benzoic acid (50.00 g, 290 mmol, 1 eq) in methanol (500 mL) is added thionyl chloride (63.2 mL, 3 eq drop wise, and the reaction mixture is stirred at 80 °C for 12 h. The mixture is poured into ice water (1 L) dropwise, and the resulting mixture is filtered. The filter cake is dissolved in ethyl acetate (10 mL), filtered and concentrated to afford methyl 3,4-difluoro-2-methyl-benzoate (51.00 g, 94%) as a white solid.JH NMR (400 MHz, CDC13) d: 7.74 - 7.68 (m, 1H), 7.08 - 6.99 (m, 1H), 3.90 (s, 3H), 2.60 - 2.53 (m, 3H).Step 5:F FFNBS, BPOf / Xz^Br XX A^X\ '- - DCE, 80 °C, 2 h V Jk / 0-o o

[0082] To a mixture of methyl 3,4-difluoro-2-methyl-benzoate (40.00 g, 215 mmol, 1 eq) in 1,2-dichloroethane (400 mL) are added / V-bromosuccinimide (57.37 g, 322 mmol, 1.5 eq) and benzoyl peroxide (520 mg, 2 mmol, 0.01 eq), and the reaction mixture is degassed and purged with nitrogen several times, then stirred at 80 °C for 2 h. The mixture is cooled to 20 °C, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 20:1) to afford methyl 2-(bromomethyl)3,4-difluoro-benzoate (51.00 g, 89%) as a colorless oil.JH NMR (400 MHz, CDCh) 3: 7.85-7.80 (m. 1H), 7.16-7.23 (m, 1H), 5.02 (d. J= 22 Hz, 2H), 3.96 (s, 3H).Step 6:ARVN-174-PCT / / ARVN0174WO2

[0083] To a mixture of methyl 2-(bromomethyl)-3,4-difluoro-benzoate (51.00 g, 192 mmol, 1 eq) and 3-aminopiperidine-2, 6-dione (33.25 g, 202 mmol, 1 eq, hydrochloride) in N, N-dimethylformamide (600 mL) is added N, N-di isopropylethylamine (100.5 mL, 3 eq), and the reaction mixture is stirred at 40 °C for 1 h, then at 110 °C for 12 h. The mixture is poured into water (800 mL) and the resulting mixture is filtered. The filter cake is dissolved in ethyl acetate (500 mL), filtered and concentrated to afford 3-(4,5-difluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (29.7 g, 55%) as a gray solid. NMR (400 MHz, DMSO-d6) δ: 11.02 (s, 1H), 7.66 -7.58 (m, 2H), 5.11 (dd, J = 5.2, 13.2 Hz, 1H), 4.66 - 4.59 (m, 1H), 4.49 - 4.42 (m, 1H), 2.97 -2.86 (m, 1H), 2.65 - 2.57 (m, 1H), 2.46 - 2.37 (m, 1H), 2.05 - 1.98 (m, 1H). Step 7:

[0084] To a solution of ze / 7-butyl 4-((2,2-dimethylpiperazin-l-yl)methyl)piperidine-l-carboxylate (4 g, 13 mmol, 1.5 eq) and 3-(4,5-difluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (2.40 g, 8.6 mmol, 1 eq) in dimethyl sulfoxide (40 mL) is added N,N-diisopropylethylamine (4.4 mL, 3 eq), and the reaction mixture is stirred at 130 °C for 12 h. The mixture is diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 2). The combined organic extracts are washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (10%-40% acetonitrile in water (formic acid) over 10 min) to afford / -butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-l-oxoisoindolin-5-yl)-2,2-dimethylpiperazin-l-yl)methyl)piperidine-l-carboxylate (1.87 g. 38%) as a yellow solid. LC / MS (ESI) m / z 572.3 [M+H]+; 'H NMR (400 MHz, DMSO-d6) δ: 10.98 (s, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.12 (t, J= 8.0 Hz, 1H), 5.07 (dd, J= 5.2, 13.2 Hz, 1H), 4.54 - 4.23 (m, 2H), 3.93 (d, J = 11.2 Hz. 2H), 3.10 (s, 2H), 2.96 - 2.83 (m, 3H), 2.69 - 2.55ARVN-174-PCT / / ARVN0174WO2(m, 5H), 2.47 - 2.37 (m, 1H), 2.17 (d, 7= 6.4 Hz, 2H), 2.01 - 1.93 (m, 1H), 1.70 (d, J = 12.4 Hz, 2H), 1.59 - 1.50 (m, 1H), 1.40 - 1.36 (m, 11H), 1.03 (s, 6H).Step 8:

[0085] A solution of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-l-oxoisoindolin-5-yl)-2,2-dimethylpiperazin-l-yl)methyl)piperidine-l-carboxylate (300 mg, 0.5 mmol, 1 eq) in HCl / dioxane (2 M, 10 mL) is stirred at 25 °C for 1 h, then concentrated under reduced pressure. The residue is triturated with petroleum ether (30 mL) to afford 3-(5-(3,3-dimethyl-4-(piperidin-4-ylmethyl)piperazin-l-yl)-4-fluoro-l-oxoisoindolin-2-yl)piperidine-2,6-dione (330 mg, 96%, HC1 salt) as a yellow solid. LC / MS (ESI) m / z: 472.2 [M+H]+.Step 9:

[0086] To a solution of 3-(5-(3,3-dimethyl-4-(piperidin-4-ylmethyl)piperazin-l-yl)-4-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (330 mg, 0.5 mmol, 1 eq, HC1 salt) and [(1S)-1- [[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl] methyl methanesulfonate (327 mg, 0.5 mmol, 0.9 eq) in A, A-dimethylformamide (7ARVN-174-PCT / / ARVN0174WO2L) are added potassium iodide (418 mg, 2.5 mmol, 5 eq) and sodium carbonate (267 mg, 2.5 mmol, 5 eq), and the reaction mixture is stirred at 90 °C for 12 h. The mixture is diluted with water (100 mL) and extracted with dichloromethane (100 mL x 2). The combined organic extracts are washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-TLC (dichloromethane / methanol = 10:1) to afford 3-(5-(4-((l-(((7?)-l-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-4-((S)-l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-^pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)methyl)-3,3-dimethylpiperazin-l-yl)-4- fluoro- l-oxoisoindolin-2-yl)piperidine-2, 6-dione (200 mg, 36%) as a yellow solid. LC / MS (ESI) m / z 1096.5 [M+H]+.Step 10:

[0087] To a solution of 3-(5-(4-((l-(((A)-l-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-4-((S)-l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-^pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)methyl)-3,3-dimethylpiperazin-l-yl)-4- fluoro- l-oxoisoindolin-2-yl)piperidine-2,6-dione (360 mg, 0.33 mmol, 1 eq) in dichloromethane (4 mL) is added trifluoro acetic acid (2 mL), and the mixture is stirred at 25 °C for 0.5 h. The mixture is diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane (30 mL x 2). The combined organic layers are washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (dichloromethane / methanol = 10:1), and the crude product is further purified by prep-HPLC (13%-43% acetonitrile in water (formic acid) over 2 min) to afford Compound 81 (98.2 mg,ARVN-174-PCT / / ARVN0174WO225%, trifluoroacetate salt) as a white solid. LC / MS (ESI) m / z 1052.6 [M+H]+; 'H NMR (400 MHz, DMSO-d6) δ: 10.98 (s, 1H), 9.97 (s, 1H), 9.26 (d, J= 6.4 Hz, 1H), 8.13 (s, 1H), 7.77 (dd, J = 6.0. 9.2 Hz, 1H). 7.47 (d, J= 8.4 Hz. 1H). 7.41 - 7.28 (m, 2H), 7.18 - 7.08 (m, 1H), 7.05 (dd, J = 2.4, 5.6 Hz, 1H), 5.07 (dd, 7= 5.2, 13.2 Hz, 1H), 4.79 - 4.13 (m, 8H), 3.98 - 3.76 (m, 1H), 3.59 - 3.43 (m. 2H), 3.19 - 2.99 (m, 3H), 2.98 - 2.74 (m, 5H), 2.73 - 2.55 (m, 4H), 2.47 - 2.29 (m, 5H), 2.26 - 2.04 (m. 4H), 2.03 - 1.93 (m, 2H). 1.92 - 1.80 (m, 3H), 1.79 - 1.62 (m. 3H), 1.59 - 1.22 (m, 3H), 1.00 (s, 6H), 0.79 - 0.68 (m, 3H).Example 1.2Exemplary synthesis of Compound 82:

[0088] Compound 82 is prepared in a manner analogous to Compound 81 starting from tert- butyl 4-((2,2-dimethylpiperazin-l-yl)methyl)piperidine-l-carboxylate and 3-(4-chloro-5-fhioro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione, as a white solid (TFA salt). LC / MS (ESI) m / z 1068.6 [M+H]+;NMR (400 MHz, DMSO-d6) δ: 10.99 (s, 1H). 9.98 (s, 1H), 9.26 (d, J = 6.0 Hz, 1H), 8.13 (s, 1H), 7.77 (dd, J = 6.0, 9.2 Hz, 1H), 7.66 (d, J= 7.6 Hz, 1H), 7.41 - 7.30 (m, 2H), 7.28 - 7.18 (m, 1H), 7.05 (dd, 7 = 2.4, 5.6 Hz, 1H), 5.10 (dd, 7 = 5.2, 13.2 Hz, 1H), 4.77 -4.15 (m, 8H), 3.98 - 3.75 (m, 1H), 3.59 - 3.43 (m, 2H), 3.19 - 2.99 (m, 3H), 2.99 - 2.72 (m, 5H), 2.71 - 2.53 (m, 4H), 2.47 - 2.27 (m, 5H), 2.25 - 2.05 (m, 4H), 2.04 - 1.94 (m, 2H), 1.94 - 1.79 (m, 4H), 1.78 - 1.66 (m, 2H), 1.64 - 1.24 (m. 3H), 1.15 - 0.89 (m, 6H). 0.74 (q, J =1.2 Hz. 3H).Example 1.3Exemplary synthesis of Compound 88:Step 1:Ruphos Pd G 3, Cs2CO3, dioxane, 100 °C, 12 h

[0089] A mixture of 5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)-4-fluoro-isoindolin-l-one (500 mg, 1 mmol, 1 eq), r -butyl (3S)-3-methylpiperazine-l -carboxylate (456 mg, 1.9 mmol, 2 eq, hydrochloride), Ruphos Pd G3 (93 mg, 0.1 mmol, 0.1 eq) and cesium carbonate (627 mg, 1.9 mmol, 2 eq) in dioxane (7 mL) is degassed and purged with nitrogen several times, then stirred atARVN-174-PCT / / ARVN0174WO2100 °C for 12 h under nitrogen atmosphere. The reaction mixture is diluted with water (200 mL) and extracted with ethyl acetate (100 mL). The organic phase is separated, washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (70%-100% acetonitrile in water (formic acid) over 18 min) to afford tert-butyl (3S)-4-[2-(2,6-dibenzyloxy-3-pyridyl)-4-fluoro-l-oxo-isoindolin-5-yl]-3-methyLpiperazine-l -carboxylate (1.95 g) as a brown solid. 'H NMR (400 MHz, CDCL) <5: 7.71 - 7.61 (m, 2H), 7.43 - 7.29 (m, 10H), 7.10 - 7.02 (m, 1H), 6.49 (d, J= 8.4 Hz, 1H), 5.41 (s, 2H), 5.34 (s, 2H), 4.77 (s, 2H), 4.04 - 3.78 (m, 1H), 3.77 - 3.67 (m, 1H), 3.61 - 3.51 (m, 2H), 3.31 (d, J = 9.2 Hz, 2H), 3.03 - 2.91 (m, 1H), 1.50 (s, 9H), 1.03 (d, 7= 6.4 Hz, 3H); LC / MS (ESI) wt / z:639.4 [M+H]+.Step 2:

[0090] To a solution of tert-butyl (35')-4-[2-(2,6-dibenzyloxy-3-pyridyl)-4-fluoro-l-oxo-isoindolin-5-yl]-3-methyl-piperazine-l-carboxylate (1.9 g, 3 mmol, 1 eq) in dichloromethane (6 mL) is added trifluoroacetic acid (3 mL, 13.23 eq), and the mixture is stirred at 20 °C for 0.5 h. The reaction mixture is concentrated under reduced pressure to afford (S)-2-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-5-(2-methylpiperazin-l-yl) isoindolin-l-one (1.9 g, crude, trifluoroacetate salt) as a brown oil, which is used in the next step directly. LC / MS (ESI) n? / -:539.2 [M+H]+.DIEA, NaBH(0Ac)3, Ti(i-PrO)4, DMSO,20 °C, 2 hARVN-174-PCT / / ARVN0174WO2

[0091] To a solution of 2-(2,6-dibenzyloxy-3-pyridyl)-4-fluoro-5-[(2S)-2-methylpiperazin-l-yl]isoindolin-l-one (1.85 g, 2.8 mmol, 1 eq, trifluoroacetate salt) in dimethyl sulfoxide (7 mL) are added diisopropylethylamine (0.5 mL, 1 eq), titanium(IV) isopropoxide (806 mg, 2.8 mmol, 0.8 mL, 1 eq) and tert-butyl 4-formylpiperidine- 1 -carboxylate (605 mg, 2.8 mmol, 1 eq), and the resulting mixture is stirred at 20 °C for 1 h. Sodium triacetoxyborohydride (1.8 g, 8.5 mmol, 3 eq) is then added, and the reaction mixture is stirred at 20 °C for 1 h. The mixture is concentrated under reduced pressure, and the residue is purified by prep-HPLC (32%-62% acetonitrile in water (formic acid) over 15 min) to afford: (1) tert-butyl 4-[[(35)-4-[2-(2-benzyloxy-6-hydroxy-3-pyridyl)-4-fluoro-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-yl]methyl]piperidine-l-carboxylate (1.05 g, 57%) as a pink solid LC / MS (ESI) m / z.' 646.5 [M+H]+; ’H NMR (400 MHz, DMSO-d6) δ 7.60 (d. J= 8.4 Hz, 1H), 7.52 - 7.43 (m, 3H), 7.43 -7.29 (m, 4H), 7.19 (t, J = 7.6 Hz, 1H), 6.21 (d, 7= 7.6 Hz, 1H), 4.78 (s, 2H), 3.93 (d, J = 11.6 Hz, 3H), 3.73 (d, J= 3.6 Hz, 1H), 3.28 - 3.21 (m, 3H), 2.97 (s, 1H), 2.83 - 2.60 (m, 4H), 2.38 -2.27 (m, 1H), 2.21 - 2.09 (m, 2H), 1.70 (d. J = 11.2 Hz, 3H). 1.40 - 1.38 (m, 9H), 1.01 (d. 7 = 6.4 Hz, 3H), 0.96 (d, 7= 11.6 Hz, 2H); and (2) tert-butyl 4-[[(3S)-4-[2-(2,6-dibenzyloxy-3-pyridyl)-4-fluoro-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-yl]methyl]piperidine-l-carboxylate (275 mg, 13%) as a brown oil. NMR (400 MHz, DMSO-d6) δ 7.76 (d, 7= 8.4 Hz, 1H), 7.51 (d, 7 = 8.0 Hz, 1H), 7.43 - 7.26 (m, 11H), 7.20 (t, 7 = 7.6 Hz, 1H), 6.54 (d, 7 = 8.4 Hz, 1H), 5.34 (s, 2H), 4.78 (s, 2H), 3.98 - 3.86 (m. 2H), 3.77 - 3.70 (m, 1H), 3.32 - 3.18 (m, 4H), 3.00 - 2.91 (m, 1H), 2.75 - 2.62 (m, 3H), 2.34 - 2.29 (m, 1H), 2.18 - 2.09 (m, 2H), 1.69 (d, 7= 11.2 Hz, 3H), 1.39 (s, 9H), 1.02 - 0.93 (m, 5H). Step 4:OBnOo o

[0092] To a solution of tert-butyl 4-[[(3S)-4-[2-(2-benzyloxy-6-hydroxy-3-pyridyl)-4-fluoro-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-yl]methyl]piperidine-l-carboxylate (865 mg.ARVN-174-PCT / / ARVN0174WO21 mmol, 1 eq) in tetrahydrofuran (20 mL) is added 10% palladium on activated carbon (142 mg, 0.1 mmol, 0.1 eq) under nitrogen atmosphere. The suspension is degassed and purged with hydrogen several times, and the mixture is stirred under hydrogen at 25 °C for 12 h. The reaction mixture is concentrated under reduced pressure to afford z -butyl 4-[[(3S)-4-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-yl] methyl] piperidine- 1-carboxylate (673 mg, crude) as a white solid, which is used in the next step directly.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 5.08 (dd, 7= 5.2, 13.2 Hz, 1H), 4.49 - 4.44 (m, 1H), 4.36 - 4.27 (m. 1H), 3.93 (d, J= 11.6 Hz, 3H), 3.72 (dd, J= 1.2, 2.4 Hz, 1H), 3.30 - 3.17 (m, 2H), 2.98 - 2.88 (m, 2H), 2.75 - 2.59 (m, 4H), 2.41 - 2.28 (m, 2H), 2.18 - 2.10 (m, 2H), 1.99 (s, 1H), 1.69 (d, J = 11.2 Hz, 3H), 1.39 (s, 9H), 1.02 -0.94 (m, 5H); LC / MS (ESI) m / z: 558.3 [M+H]+.Step 5:OBnO H2(50 Psi), Pd / C THF, 25 °C, 12 h0 O

[0093] To a solution of / erz-butyl 4-[[(3S)-4-[2-(2,6-dibenzyloxy-3-pyridyl)-4-fluoro-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-yl]methyl]piperidine-l-carboxylate (150 mg, 0.2 mmol, 1 eq) in tetrahydrofuran (10 mL) is added 10% palladium on activated carbon (21.69 mg, 0.02 mmol. 0.1 eq) under nitrogen atmosphere. The suspension is degassed and purged with hydrogen several times, and the mixture is stirred under hydrogen at 25 °C for 12 h. The reaction mixture is concentrated under reduced pressure to afford Zert-butyl 4-[[(3S)-4-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-yl] methyl] piperidine- 1-carboxylate (120 mg, crude) as a white solid, which is used in the next step directly. LC / MS (ESI) m / z 558.3 [M+H]+.Step 6:ARVN-174-PCT / / ARVN0174WO2

[0094] To a solution of tert-butyl 4-[[(3S)-4-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-yl]methyl]piperidine-l-carboxylate (673 mg, 1.21 mmol, 1 eq) in dichloromethane (4 mL) is added trifluoroacetic acid (2 mL, 22.31 eq), and the mixture is stirred at 20 °C for 0.5 h. The reaction mixture is concentrated under reduced pressure, and the residue is triturated with methyl tert-butyl ether (10 mL) at 20 °C for 12 h to afford 3-[4-fluoro-5-[(2S)-2-methyl-4-(4-piperidylmethyl)piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2,6-dione (817 mg, trifluoroacetate, crude) as a brown solid. ’H NMR (400 MHz, DMSO-<7>) d 11.01 (s, 1H), 8.78 - 8.63 (m, 1H), 8.55 - 8.37 (m, 1H), 7.58 (d, J= 6.8 Hz, 1H), 7.50 - 7.31 (m, 1H), 5.10 (dd, 7 = 4.4, 12.4 Hz, 1H), 4.59 - 4.48 (m, 1H), 4.44 - 4.30 (m, 1H), 3.36 - 3.26 (m, 4H), 3.07 (s, 2H), 2.95 - 2.82 (m. 4H). 2.60 (d, J= 17.2 Hz, 1H), 2.42 (dd, 7 = 4.0, 13.2 Hz, 1H). 2.17 (d, 7= 5.6 Hz, 1H), 2.01 - 1.86 (m, 3H), 1.44 - 1.34 (m, 3H), 1.10 (s, 5H); LC / MS (ESI) / n / z:458.1 [M+H]+.Step 7:

[0095] To a solution of 3-[4-fhioro-5-[(2S)-2-methyl-4-(4-piperidylmethyl)piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (119 mg, 0.2 mmol, 1.5 eq, trifluoroacetate salt) and [(lS)-l-[[7-[8-ethyl-7-fhroro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-ARVN-174-PCT / / ARVN0174WO2cyclopropyl]methyl methanesulfonate (100 mg, 0.1 mmol, 1 eq) in N,N-dimethylformamide (5 mL) are added potassium iodide (115 mg, 0.7 mmol, 5 eq) and sodium carbonate (73 mg, 0.7mmol. 5 eq), and the reaction mixture is stirred at 90 °C for 12 h. The mixture is diluted with water (50 mL) and extracted with ethyl acetate (70 mL). The organic extract is washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-TLC (dichloromethane / methanol = 10 / 1) to afford 3-[5-[(2S)-4-[[l-[[(17?)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]-2-methyl-piperazin-l-yl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (60 mg, 40 %) as a white solid. LC / MS (ESI) m / z. 1082.6 [M+H]+. Step 8.o

[0001] To a solution of 3-[5-[(2S)-4-[[l-[[(lR)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]-2-methyl-piperazin- l-yl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (50 mg, 0.05 mmol, 1 eq) in dichloromethane (1 mL) is added trifluoroacetic acid (1 mL, 291.37 eq), and the mixture is stirred at 20 °C for 0.5 h. The reaction mixture is diluted with saturated aqueous sodium bicarbonate solution (30 mL) and extracted with dichloromethane (80 mL). The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (13%-43% acetonitrile in water (formic acid) over 10 min) to afford Compound 88 (8 mg, 16%, formic acid salt) as a white solid. LC / MS (ESI) m / z'.1038.7 [M+H]+; *H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.96 (d, J= 1.6 Hz, 1H), 9.25 (d, J =ARVN-174-PCT / / ARVN0174WO25.2 Hz, 1H), 7.77 (dd, J = 6.0, 8.8 Hz, 1H), 7.47 (d, J= 8.4 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.21 -7.12 (m, 1H), 7.05 (t, J = 2.8 Hz, 1H), 5.12 - 5.04 (m, 1H), 4.67 (s, 1H), 4.55 - 4.27 (m, 7H), 3.98 - 3.76 (m. 1H), 3.75 - 3.63 (m, 1H). 3.57 - 3.46 (m, 1H), 2.95 - 2.88 (m, 2H), 2.84 - 2.75 (m, 2H), 2.69 - 2.65 (m, 1H), 2.32 (s, 8H), 2.16 - 2.05 (m, 4H), 2.01 - 1.93 (m, 3H), 1.88 - 1.80 (m, 3H), 1.75 - 1.70 (m, 1H), 1.67 - 1.58 (m, 2H), 1.49 - 1.42 (m, 2H). 1.28 - 1.19 (m, 4H), 0.97 (d, J = 6.0 Hz. 3H), 0.89 - 0.82 (m, 1H). 0.77 - 0.71 (m, 3H).Example 1.4Exemplary synthesis of Compound 90:Step 1:MS2O BocTEA, DCM

[0096] To a solution of tert-butyl (3?)-3-hydroxypyrrolidine-l -carboxylate (5.0 g, 27 mmol, 1.0 eq) in dichloromethane (50 mL) at 0 °C under nitrogen atmosphere is added triethylamine (811.15 mL, 3.0 eq) followed by methylsulfonyl methanesulfonate (6.98 g, 40 mmol, 1.5 eq) in dichloromethane (30 mL), and the reaction mixture is stirred at 25°C for 12 h under nitrogen atmosphere. The mixture is diluted with water (50 mL) and extracted with dichloromethane (30 mL x 3). The combined organic extract is washed with brine (30 mL x 3), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford tert-butyl (37?)-3-methylsulfonyloxypyrrolidine-l-carboxylate (7.08 g, crude) as a yellow oil, which is used in the next step directly. 'H NMR (400 MHz, CDCI3) 55.24 (br s, 1H), 3.71 - 3.42 (m, 4H), 3.03 (s, 3H), 2.35 - 2.05 (m, 2H), 1.45 (s, 9H).Step 2:DIEA

[0097] To a mixture of benzyl (2S)-2-methylpiperazine-l -carboxylate (1 g, 4 mmol, 1.0 eq) in diisopropylethylamine (3.72 mL, 5.0 eq is added tert-butyl (37?)-3-ARVN-174-PCT / / ARVN0174WO2methylsulfonyloxypyrrolidine-1 -carboxylate (3.96 g, 15 mmol, 3.5 eq), and the reaction mixture is stirred at 100 °C for 16 h. The mixture is cooled to 25 °C, diluted with water (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic extract is washed with brine (5 mL x 3), dried over anhydrous NaiSCU, filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography (0-21% ethyl acetate in petroleum ether) to afford benzyl (2S)-4-[(3S)-l- rt-butoxycarbonylpyrrolidin-3-yl]-2-methyl-piperazine-l-carboxylate (1.68 g, 91%) as a yellow oil. LC / MS (ESI) / z: 404.3 [M+H]+; 'H NMR (400 MHz, CDCI3) 87.27 (s, 5H), 5.13 (br s, 2H), 4.31 (br s, 1H). 3.90 (brd, 7= 11.6 Hz, 1H), 3.71 -3.43 (m, 2H), 3.34 - 3.23 (m, 1H), 3.19 - 2.99 (m, 2H), 2.88 - 2.52 (m, 3H), 2.20 (br dd, 7 = 2.9, 10.9 Hz, 1H), 2.11 - 2.02 (m, 2H), 1.75 (br s, 1H), 1.46 (s, 9H), 1.28 - 1.24 (m, 3H).Step 3:

[0098] Benzyl (25)-4-[(35)- l-rert-butoxycarbonylpyrrolidin-3-yl]-2-methyl-piperazine- 1-carboxylate (4.5 g, 11 mmol) is purified by SFC (25% i-PrOH (0.1%NH3H2O) in CO2). The first eluted fraction is obtained as benzyl (2S)-4-[(3S)-l- / -butoxycarbonylpyrrolidin-3-yl]-2-methyl-piperazine- 1 -carboxylate (2.2 g, 49%) as a colorless oil.JH NMR (400 MHz, CDCI3) 8 7.38 - 7.11 (m, 5H), 5.06 (s, 2H), 4.23 (br s, 1H), 3.82 (br d, J = 12.6 Hz, 1H), 3.49 (br t, J = 8.9 Hz, 2H), 3.20 (br s, 1H), 3.11 - 2.89 (m, 2H), 2.74 - 2.52 (m. 3H), 2.13 (br d. J = 8.4 Hz, 1H), 2.03 - 1.89 (m, 2H), 1.61 (br s, 1H), 1.38 (s, 9H), 1.18 (br d, J = 6.6 Hz, 3H). Fractions two is obtained as benzyl (2S)-4-[(3R)-l-tert-butoxycarbonylpyrrolidin-3-yl]-2-methyl-piperazine-l-carboxylate (1.4 g, 31.11%) as a colorless oil. 'H NMR (400 MHz, CDCI3) 87.36 - 7.15 (m, 5H), 5.06 (d, J = 2.8 Hz, 2H), 4.22 (br s, 1H), 3.84 (br d, J= 12.9 Hz, 1H), 3.61 - 3.38 (m, 2H), 3.24 -3.15 (m, 1H), 3.08 (br t, J = 12.1 Hz, 1H), 3.03 - 2.90 (m, 1H). 2.77 (brd, J= 10.1 Hz, 1H), 2.65 (brd, 7 = 6.5 Hz, 1H), 2.48 (brd, 7= 10.3 Hz, 1H), 2.16 (br s, 1H), 2.02 - 1.93 (m, 2H), 1.67 (br s, 1H), 1.38 (s, 9H), 1.22 - 1.15 (m, 3H).Step 4:ARVN-174-PCT / / ARVN0174WO2H2(30 psi), Pd / CBoc / fsA Boc 'N N-CbzEtOAc, 40°C, 15h

[0099] To a solution of benzyl (25')-4-[(3 / ?)-l-tert-butoxycarbonylpyrrolidin-3-yl]-2-methyl-piperazine- 1 -carboxylate (1,4 g, 3 mmol, 1.0 eq) in CH3OH (30 mL) is added 10% palladium on carbon (0.3 g) under argon atmosphere, and thesuspension is degassed and purged with hydrogen several times, then stirred under hydrogen (30 psi) at 40 °C for 12 h. The reaction mixture is then filtered and concentrated under reduced pressure to afford tert-butyl (3 / ?)-3-[(3S)-3-methylpiperazin-l-yl]pyrrolidine-l-carboxylate (0.9 g, crude) as a light yellow solid, which is used in the next step directly. 'H NMR (400 MHz, CDCI3) 53,73 - 3.48 (m, 2H), 3.31 - 3.20 (m, 1H), 3.13 - 3.04 (m, 1H), 3.01 - 2.82 (m, 4H), 2.81 - 2.68 (m, 2H), 2.15 - 2.03 (m, 2H), 1.81 - 1.66 (m, 2H), 1.45 (s, 9H), 1.05 (d, J= 6.3 Hz, 3H).Step 5:Boc0°> Boc... Bn XPhos Pd2(dba)3, Cs2CO3dioxane, 100°C, 16h

[0100] To a mixture of tert-butyl (3A)-3-[(3S)-3-methylpiperazin-l-yl]pyrrolidine-l-carboxylate (0.9 g, 3 mmol, 1.0 eq), 5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin- 1-one (1.68 g, 3 mmol, 1.0 eq), CS2CO3 (3.27 g, 10 mmol, 3.0 eq) and XPhos (318.54 mg, 0.7 mmol, 0.2 eq) in dioxane (30 mL) is added Pd2(dba)3 (305.9 mg, 0.3 mmol, 0.1 eq), and the reaction mixture is stirred at 100 °C for 12 h. The mixture is cooled to 25 °C, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-55% ethyl acetate in petroleum ether) to afford tert-butyl (3 / ?)-3-[(3 )-4-[2-(2,6-dibenzyloxy-3-pyridyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-yl]pyrrolidine-l -carboxylate (650 mg, 26.8%) as a gray solid, LC / MS (ESI) m / z 690.4 [M+H]+.Step 6:ARVN-174-PCT / / ARVN0174WO2Boc Boc H2(50 psi), Pd / C, Pd(OH)2 / C THF, 50°C, 15h 0 o o oBn

[0101] To a solution of tert-butyl (37?)-3-[(3S)-4-[2-(2,6-dibenzyloxy-3-pyridyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-yl]pyrrolidine-l-carboxylate (650 mg, 0.9 mmol, 1.0 eq) in EtOAc (10 mL) and THF (10 mL) are added 10% palladium on carbon (0.3 g) and 20% palladium hydroxide (0.3 g) under argon atmosphere. The suspension is degassed and purged with hydrogen several times, and the mixture is stirred under hydrogen (50 psi) at 50 °C for 12 h. The mixture is filtered through celite and concentrated under reduced pressure to afford tertbutyl (37?)-3-[(3S)-4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-y 1] pyrrolidine- 1 -carboxylate (470 mg, 97%) as an off-white solid. LC / MS (ESI) m / z 512.3 [M+H]+; ’H NMR (400 MHz, DMSO-tfc) 5 11.02 - 10.87 (m, 1H), 7.56 - 7.48 (m, 1H), 7.00 (br d, J= 5.0 Hz, 2H), 5.04 (dd, J= 5.0, 13.3 Hz, 1H), 4.35 - 4.26 (m, 1H), 4.22 - 4.17 (m, 1H), 3.62 - 3.57 (m, 1H), 3.56 - 3.46 (m, 2H), 3.45 - 3.38 (m, 1H), 3.24 - 3.13 (m. 1H), 3,06 - 2.93 (m, 3H), 2.81 - 2.75 (m, 1H), 2.70 - 2.53 (m, 3H), 2.41 - 2.30 (m, 2H), 2.17 - 2.02 (m, 2H), 1.99 - 1.90 (m, 1H), 1.78 - 1.74 (m, 1H), 1.44 - 1.38 (m, 9H), 1.08 - 1.02 (m, 3H).Step 7:BocNCS, TFA DCM / MeOH 40°C o o

[0102] To a solution of tert-butyl (3R)-3-[(3S)-4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-yl]pyrrolidine-l-carboxylate (0,4 g, 0.8 mmol, 1.0 eq) and N-chlorosuccinimide (114.84 mg, 0.86 mmol, 1.1 eq) in dichloromethane (10 mL) and CH3OH (1 mL) is added TFA (98.7 p. L, 1.7 eq), and the reaction mixture is stirred at 50 °C for 72 h. The mixture is diluted with water (10 mL) and extracted with dichloromethane (50 mL x 3). The combined organic extract is dried over NazSCL, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-10% CH3OH / dichloromethane).ARVN-174-PCT / / ARVN0174WO2The crude product is further purified by SFC (30% i-PrOH (0.1%NH4OH) in CO2) to afford tertbutyl (37?)-3-[(3S)-4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazin- 1-yl] pyrrolidine- 1 -carboxylate (130 mg, 30%) as a white solid. LC / MS (ESI) m / z 546.2 [M+H]+; 'H NMR (400 MHz, DMSO- e) 8 11.04 - 10.88 (m, 1H), 7.72 - 7.64 (m, 1H), 7.37 (br d, J = 8.1 Hz, 1H), 5.10 (br dd, J = 5.0, 13.3 Hz, 1H), 4.45 - 4.22 (m, 2H), 3.60 - 3.48 (m, 2H), 3.46 - 3.40 (m. 1H). 3.25 - 3.17 (m, 2H). 3.03 - 2.87 (m, 2H), 2.87 - 2.77 (m. 2H), 2.72 (br d, J= 3.0 Hz, 1H), 2.54 (s, 3H), 2.45 - 2.36 (m, 1H), 2.25 - 2.17 (m, 1H), 2.12 - 2.04 (m, 1H), 2.03 - 1.94 (m, 1H), 1.79 - 1.63 (m, 1H), 1.45 - 1.37 (m, 9H), 0.93 - 0.83 (m, 3H).Step 8:

[0103] To a solution of tert-butyl (37?)-3-[(3S)-4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-yl]pyrrolidine-l-carboxylate (130 mg, 238 pmol, 1.0 eq) in dichloromethane (5 mL) is added HCl / dioxane (2 M, 10 m, 84 eq), and the reaction mixture is stirred at 25 °C for 12 h. The mixture is concentrated under reduced pressure to afford 3-[4-chloro-5-[(25)-2-methyl-4-[(3R)-pyrrolidin-3-yl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (130 mg, crude, 2 HC1) as a white solid. LC / MS (ESI) m / z 446.1 [M+H]+.Step 9:ARVN-174-PCT / / ARVN0174WO2

[0104] To a solution of [(15)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl] methyl methanesulfonate (214 mg, 0.3 mmol, 1.25 eq) and 3-[4-chloro-5-[(2S)-2-methyl-4-[(37?)-pyrrolidin-3-yl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2,6-dione (106 mg, 0.2 mmol, 1.0 eq) in DMA (10 mL) are added Na2COs (126 mg, 1 mmol, 5.0 eq) and KI (197 mg, 1 mmol, 5.0 eq), and the reaction mixture is stirred at 90 °C for 12 h. The mixture is cooled to 25 °C and filtered. The filter cake is washed with ethyl acetate (100 mL), and the filtrate is diluted with water (50 mL). The organic layer is separated, and the aqueous layer is extracted with ethyl acetate (100 mL x 2). The combined organic extract is washed with brine (100 mL x 3), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-5% MeOH / DCM) to afford 3-[4-chloro-5-[(2. S 4-[(3 / J- 1 -[[(! / )-! -[[7-[8-ethyl-7-fliioro-3-(methoxymethoxy)- 1 -naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]pyrrolidin-3-yl]-2-methyl-piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2,6-dione (160 mg, 57%) as a light yellow solid. LC / MS (ESI) m / z 1071.0 [M+H]+.Step 10:ARVN-174-PCT / / ARVN0174WO2TFA / CH2CI2, rt, 2 h

[0105] To a solution of 3-[4-chloro-5-[(2S)-4-[(3R)-l-[[(lA)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(41S’)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]pyrrolidin-3-yl]-2-methyl-piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (160 mg, 149 pmol. 1.0 eq) in dichloromethane (6 mL) is added TFA (2 mL), and the reaction mixture is stirred at 25 °C for 2 h. The mixture is slowly poured into saturated NallCCL solution until pH reached 7 at 0 °C, then extracted with dichloromethane (50 mL x 3). The combined organic extract is washed with brine (50 mL x 2), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (4%-44% acetonitrile in water (formic acid) over 20.5 min) to afford Compound 90 (51.8 mg, 34%, formic acid salt) as a white solid. LC / MS (ESI) m / z: 1026.4 [M+H]+; *H NMR (400 MHz, DMSO-rf6) 5 11.04 - 10.91 (m, 1H), 10.00 - 9.87 (m, 1H), 9.23 (s, 1H), 8.21 - 8.11 (m. 1H), 7.82 - 7.72 (m, 1H), 7.69 - 7.56 (m, 1H), 7.40 - 7.27 (m, 3H), 7.11 - 6.91 (m, 1H), 5.14 - 5.03 (m, 1H), 4.74 - 4.58 (m, 1H), 4.57 - 4.43 (m, 1H), 4.43 - 4.29 (m, 4H), 4.29 - 4.24 (m, 1H), 4.23 - 4.10 (m, 1H), 3.97 - 3.77 (m, 1H), 3.59 - 3.46 (m, 2H), 3.20 - 3.10 (m. 2H), 2.97 - 2.75 (m, 3H). 2.75 - 2.63 (m, 5H), 2.62 - 2.53 (m. 4H), 2.44 - 2.37 (m, 4H), 2.18 - 2.06 (m, 3H), 2.02 - 1.95 (m, 1H), 1.93 - 1.78 (m, 4H), 1.75 - 1.62 (m, 2H), 1.57 - 1.48 (m, 1H), 0.86 - 0.78 (m, 3H), 0.76 - 0.67 (m, 3H).Example 1.5Exemplary synthesis of Compound 92:Step 1:ARVN-174-PCT / / ARVN0174WO2CH3I. t-BuOK, THF0 - 25 °C, 2 h

[0106] To a solution of 7-bromo-3-iodo- IH-indazole (4.5 g, 14 mmol, 1 eq) in tetrahydrofuran (45 mL) at 0 °C is added potassium tert-butylate (3.2 g, 28 mmol, 2.05 eq), and the resulting mixture is stirred for 1 h. Methyl iodide (1.6 mL, 1.82 eq) is then added at 0 °C, and the reaction mixture is warmed to 25 °C and stirred for 1 h. The mixture is diluted with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic extracts are washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (petroleum etherethyl acetate = 10:1) to afford 7-bromo-3-iodo-l -methylindazole (6.5 g, 69%) as a white solid. LC / MS (ESI) / n / z: 336.8 [M+H]+;]H NMR (400 MHz, DMSO-Je) 6: 7.68 (dd, J= 0.8, 7.2 Hz, 1H), 7.41 (dd, J= 0.8, 8.0 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 4.32 (s, 3H).Pd(PPh3)4, 2M K3PO4, dioxane, 90 °C, 12 h

[0107] A mixture of 7-bromo-3-iodo-l-methyl-indazole (6.0 g, 18 mmol, 1 eq), 2,6-dibenzyloxy- 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (12.63 g, 30 mmol, 1.7 eq), potassium phosphate (2 M, 77 mL, 8.6 eq) and tetrakis[triphenylphosphine]palladium(0) (1.03 g. 0.9 mmol. 0.05 eq) in dioxane (230 mL) is degassed and purged with nitrogen several times, then stirred at 90 °C for 12 h under nitrogen atmosphere. The reaction mixture is diluted with water (200 mL) and then extracted with ethyl acetate (100 mL x 2). The combined organic extracts are washed with brine (100 mL x 2), dried over sodium sulfate anhydrous, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (70%-90% acetonitrile in water (formic acid) over 45 min) to afford 7-bromo-3-(2,6-dibenzyloxy-3-ARVN-174-PCT / / ARVN0174WO2pyridyl)-! -methyl-indazole (5 g, 56%) as a pale yellow solid. LC / MS (ESI) m z 502.0 [M+H]+; *H NMR (400 MHz, DMSO-tfc) 3: 7.86 (d, J = 8.0 Hz, 1H), 7.71 - 7.58 (m, 2H), 7.53 - 7.45 (m, 2H), 7.42 - 7.19 (m, 9H), 6.92 (t, J = 8.0 Hz, 1H). 5.43 (s, 4H), 4.35 (s, 3H).Step 3:dioxane, 90 °C, 12 h

[0108] A mixture of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazole (4.5 g, 9 mmol, 1 eq), tert-butyl piperazine- 1 -carboxylate (3.8 g, 20 mmol, 2.27 eq), Ruphos Pd G3 (752 mg, 0.9 mmol, 0.1 eq) and cesium carbonate (8.79 g, 27 mmol, 3 eq) in dioxane (120 mL) is degassed and purged with nitrogen several times, then stirred at 90 °C for 12 h under nitrogen atmosphere. The reaction mixture is diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic extracts are washed with brine (200 mL x 3), dried over sodium sulfate anhydrous, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to afford tertbutyl 4-[3-(2,6-dibenzyloxy-3- pyridyl)-l-methyl-indazol-7-yl]piperazine-l-carboxylate (3 g, 55%) as a pale yellow solid. LC / MS (ESI) m / z 606.3 [M+H]+; 'H NMR (400 MHz, DMSO-tfc) A- 7.85 (d, J= 8.0 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.42 - 7.28 (m, 9H), 7.05 - 6.98 (m, 1H), 6.93 (t, J = 7.6 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 5.42 (d, J = 5.2 Hz, 4H), 4.32 (s, 3H), 4.06 - 3.91 (m, 2H), 3.26 - 3.10 (m, 4H), 2.80 - 2.61 (m, 2H), 1.43 (s, 9H).Step 4:

[0109] To a solution of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-7-yl]piperazine -1 -carboxylate (3 g, 5 mmol, 1 eq) in tetrahydrofuran (60 mL) are added 10% palladium on activated carbon (500 mg) and 20% palladium hydroxide on activated carbon (500 mg) under nitrogen atmosphere. The suspension is degassed and purged with hydrogen (3x), andARVN-174-PCT / / ARVN0174WO2the reaction mixture is stirred under hydrogen (50 psi) at 50 °C for 12 h. The mixture is filtered through a pad of celite, and the filtrate solution is concentrated under reduced pressure. The residue is purified by prep-HPLC (35%-65 % acetonitrile in water (formic acid) over 20 min) to afford / e / v-butyl 4-[3-(2,6-dioxo-3-piperidyl)- l-methyl-indazol-7-yl] piperazine- 1-carboxylate (700 mg, 33%) as a gray solid. LC / MS (ESI) nVz\ 428.2 [M+H]+; NMR (400 MHz, DMSO-d6) d: 10.88 (s. 1H), 7.47 - 7.37 (m, 1H).7.11 - 6.96 (m, 2H), 4.34 (d. J = 5.2 Hz, 1H), 4.25 (s, 3H), 4.10 - 3.89 (m, 2H), 3.23 - 2.98 (m, 5H), 2.74 - 2.61 (m, 3H), 2.34 - 2.27 (m, 1H), 2.20 - 2.10 (m, 1H), 1.48 - 1.37 (m, 9H). Step 5:DCM / TFA 25°C, 0.5h

[0110] To a solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl] piperazine- 1- carboxylate (650 mg, 1.5 mmol, 1 eq) in dichloromethane (3 mL) is added trifluoroacetic acid (1.5 mL, 13.28 eq), and the reaction mixture is stirred at 25°C for 0.5 h. The mixture is concentrated under reduced pressure to afford 3-(l-methyl-7-piperazin-l-yl-indazoL3-yl)piperidine-2, 6-dione (660 mg, crude, trifluoroacetate salt) as a yellow solid, which is used in the next step directly. LC / MS (ESI) m / z 328.1 [M+H]+.Step 6:DCM, DIEA, NaBH(OAc)30-25°C, 1 h

[0111] To a solution of 3-(l-methyl-7-piperazin-l-yl-indazol-3-yl)piperidine-2, 6-dione (660 mg, 1.5 mmol, 1 eq, trifluoroacetate salt) in dichloromethane (8 mL) are added N, N-diisopropylethylamine (0.2 mL, 1 eq) and tert-butyl 4-formylpiperidine- 1-carboxylate (380 mg, 1.8 mmol, 1.19 eq), and the resulting mixture is stirred at 25 °C for 10 minutes. Sodium triacetoxyborohydride (950 mg, 4.5 mmol, 3 eq) is then added at 0°C, and the reaction mixture is stirred at 25 °C for 45 minutes. The mixture is diluted with water (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic extracts are washed with brine (50 mL xARVN-174-PCT / / ARVN0174WO22), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to afford tert-butyl 4-[[4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]piperazin-l-yl]methyl]piperidine-l-carboxylate (500 mg, 63%) as a yellow solid. LC / MS (ESI) m / z'. 525.2 [M+H]+; NMR (400 MHz, DMSO-t / e)^; 10.88 (s, 1H), 7.39 (d, 7= 2.0, 6.8 Hz, 1H), 7.11 -6.91 (m, 2H), 4.33 (d. J = 4.8, 9.6 Hz, 1H), 4.23 (s. 3H), 3.99 - 3.85 (m, 2H). 3.19 - 3.00 (m, 2H), 3.00 - 2.76 (m, 4H), 2.75 - 2.58 (m, 4H), 2.40 - 2.11 (m, 6H), 1.79 - 1.62 (m, 3H), 1.39 (s, 9H), 1.06 - 0.90 (m, 2H). Step 7:DCMtTFA 25°C, 0.5 h

[0112] To a solution of tert-butyl 4-[[4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]piperazin-l-yl]methyl]piperidine-l-carboxylate (500 mg, 0.9 mmol, 1 eq) in dichloromethane (5 mL) is added trifluoro acetic acid (1.5 mL, 21.19 eq), and the mixture is stirred at 25 °C for 0.5 h. The mixture is concentrated under reduced pressure to afford 3-[l-methyL7-[4-(4-piperidylmethyl) piperazin- l-yl]indazol-3-yl]piperidine-2, 6-dione (500 mg, crude. trifluoroacetate salt) as a pale yellow solid, which is used in the next step directly. LC / MS (ESI) ni / z: 425.1 [M+H]+.Step 8:

[0113] To a solution of 3-[l-methyl-7-[4-(4-piperidylmethyl)piperazin-l-yl]indazol-3-yl] piperidine- 2,6-dione (450 mg, 0.8 mmol, 1 eq, trifluoroacetate salt). [( 15)- l-[[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (400 mg, 0.56 mmol, 0.7 eq) in A\A imethylformamide (7 mL) are added potassium iodide (693 mg, 4 mmol, 5 eq) and sodium carbonate (442 mg, 4 mmol, 5 eq), and the reaction mixture isARVN-174-PCT / / ARVN0174WO2stirred at 90°C for 12 h. The mixture is diluted with water (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic extracts are washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (18% -48% acetonitrile in water (formic acid) over 15 min) to afford 3-[7-[4-[[l-[[(lR)-l-[[7-[8-ethyl-7-fhioro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4- [(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]-l-methyl-indazol-3-yl]piperidine-2,6-dione (290 mg. 33%) as a brown solid. LC / MS (ESI) m / z 1049.4 [M+H]+; ‘H NMR (400 MHz, DMSO- e) 3 10.88 (s, 1H), 9.27 (d, J= 4.0 Hz, 1H), 7.90 (dd, J = 6.4, 9.2 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.30 - 7.21 (m, 1H), 7.08 - 6.96 (m, 2H), 5.38 - 5.30 (m, 2H), 4.78 - 4.27 (m, 7H), 4.23 (s, 3H). 3.97 - 3.80 (m, 1H), 3.57 - 3.47 (m, 1H), 3.22 - 3.07 (m. 3H), 3.07 - 2.70 (m, 7H), 2.67 - 2.61 (m, 2H), 2.54 (s, 3H), 2.45 - 2.24 (m, 7H), 2.22 - 2.08 (m, 4H), 2.06 - 1.80 (m, 5H), 1.79 - 1.39 (m, 5H), 1.33 - 0.96 (m, 2H), 0.80 - 0.71 (m, 3H).Step 9:

[0114] To a solution of 3-[7-[4-[[l-[[(lR)-l-[[7-[8-ethyl-7-fhioro-3-(methoxymethoxy)- 1-naphthyl]- 8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]-l-methyl-indazol-3-yl]piperidine-2, 6-dione (300 mg, 0.28 mmol. 1 eq) in dichloromethane (3 mL) is added trifluoroacetic acid (0.7 mL, 35.31 eq), and the reaction mixture is stirred at 25°C for 0.5 h. The mixture is concentrated under reduced pressure, and the residue is dissolved in dichloromethane (50 mL). The mixture is diluted with saturated sodium bicarbonate aqueous solution until pH reached 8, then extracted with dichloromethane (30 mL x 2). The combined organic extracts areARVN-174-PCT / / ARVN0174WO2washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (13%-43% acetonitrile in water (formic acid) over 10 min) to afford Compound 92 (91.6 mg, 26%. trifluoroacetate salt) as a colorless gum. LC / MS (ESI) m / z: 1005.7 [M+H]+;NMR (400 MHz, DMSO-^) b: 10.89 (s, 1H), 9.98 (s, 1H), 9.34 - 9.22 (m, 1H), 7.86 - 7.71 (m, 1H), 7.54 - 7.27 (m, 3H), 7.17 - 6.96 (m, 3H), 4.80 - 4.46 (m, 2H), 4.45 - 4.16 (m. 8H). 4.01 - 3.82 (m, 1H), 3.79 - 3.51 (m, 4H), 3.21 -2.98 (m, 5H), 2.93 - 2.73 (m, 2H), 2.70 - 2.60 (m, 2H), 2.42 - 2.27 (m, 7H), 2.25 - 2.06 (m, 6H), 2.04 - 1.79 (m, 5H), 1.79 - 1.66 (m, 2H), 1.64 - 1.33 (m, 2H), 1.32 - 1.05 (m, 1H), 0.81 - 0.63 (m, 3H).Example 1.6Exemplary synthesis of Compound 97:Pd(dppf)CI2, K2CO3, dioxane / H2O, 80 °C, 12h

[0115] To s solution of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (5 g, 12 mmol, 1 eq), l-bromo-4-iodobenzene (4.07 g, 14 mmol, 1.2 eq) and potassium carbonate (3.31 g, 24 mmol, 2 eq) in dioxane (50 mL) and water (10 mL) is added [l, T-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (876 mg, 1 mmol, 0.1 eq) under nitrogen, and the reaction mixture is stirred at 80 °C for 12 h. The mixture is diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic extracts are washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-4% ethyl acetate / petroleum ether) to afford 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (2.36 g, 44%) as a yellow solid. LC / MS (ESI) m / z: 446.1 [M+H]+.Step 2:ARVN-174-PCT / / ARVN0174WO2Pd2(dba)3, RuPhos, Cs2CO3Tol.,110°C, 12 h

[0116] To a mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (2.36 g, 5 mmol, 1 eq), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (2.69 g, 10 mmol, 2 eq) and cesium carbonate (3.45 g, 10 mmol, 2 eq) in toluene (30 mL) are added tris(dibenzylideneacetone)dipalladium(0) (242 mg, 0.26 mmol, 0.05 eq) and [2',6'-bis(propan-2-yloxy)-[l,l'-biphenyl]-2-yl]dicyclohexylphosphane (246 mg, 0.53 mmol, 0.1 eq) under nitrogen, and the reaction mixture is stirred at 110 °C for 12 h. The mixture is diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic extracts are washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-24% ethyl acetate / petroleum ether) to afford tert-butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.5 g. 45%) as a yellow solid. LC / MS (ESI) m / z 620.4 [M+H]+.Step 3:

[0117] To a solution of tert-butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3.9-diazaspiro[5.5]undecane-3-carboxylate (1.0 g, 1.6 mmol, 1 eq) in tetrahydrofuran (20 mL) is added 20% palladium hydroxide on activated carbon (400 mg, 0.57 mmol, 0.35 eq) under nitrogen, and the suspension is degassed and purged with hydrogen several times. The mixture is stirred under hydrogen (15 psi) at 25 °C for 12 h, then filtered, and the filtrate is concentrated under reduced pressure. The residue is triturated with 2-methoxy-2-methylpropane (30 mL) to afford tert-butyl 9-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (380 mg, 53%) as a white solid. LC / MS (ESI) m / z: 442.3 [M+H]+; 'H NMR (400ARVN-174-PCT / / ARVN0174WO2MHz, CDCh) 6: 7.96 (s, 1 H), 7.09 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 3.73 (dd, J = 5.2, 9.2 Hz, 1H), 3.47 - 3.37 (m, 4H), 3.22 - 3.13 (m, 4H), 2.76 - 2.59 (m, 2H), 2.34 - 2.16 (m, 2H), 1.66 (d, J = 5.8 Hz, 4H). 1.51 - 1.45 (m, 13H).Step 4:

[0118] To a solution of tert-butyl 9-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (680 mg, 1.5 mmol, 1 eq) in dichloromethane (7 mL) is added trifluoroacetic acid (3.5 mL, 30.60 eq), and the reaction mixture is stirred at 25 °C for 0.5 h. The mixture is concentrated under reduced pressure, and the residue is dissolved in isopropanol (2 mL) and diluted with N, ALdiisopropylethylamine until pH 8. The suspension is filtered, and the filter cake is dried to afford 3-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2, 6-dione (560 mg, 79%, trifluoroacetate salt) as a white solid, which is used in the next step directly. LC / MS (ESI) m / z'. 342.2 [M+H]+.Step 5:ARVN-174-PCT / / ARVN0174WO2

[0119] To a solution of 3-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione (200 mg, 0.44 mmol, 1.5 eq, trifluoroacetate salt) and ((5)-l-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-4-((5)-l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-6 / ]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate (211 mg, 0.29 mmol, 1 eq) in A(iV-dimethy 1 formamide (5 mL) are added potassium iodide (242 mg, 1.5 mmol, 5 eq) and sodium carbonate (155 mg, 1.5 mmol, 5 eq), and the reaction mixture is stirred at 90 °C for 12 h. The mixture is diluted with water (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic extracts are washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (25%-55% acetonitrile in water (formic acid) over 15 min) to afford 3-(4-(9-((( )-l-(((7-(8-ethyl-7-fhioro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-4-(( )-l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3- ]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2, 6-dione (147 mg, 51 %) as a pink solid. LC / MS (ESI) m / z 966.5 [M+H]+.ARVN-174-PCT / / ARVN0174WO2MOMO

[0120] To a solution of 3-(4-(9-(((R)-l-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-4-((5)-l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-<7]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2, 6-dione (147 mg, 0.15 mmol, 1 eq) in dichloromethane (3 mL) is added trifluoroacetic acid (1.5 mL, 132.71 eq), and the reaction mixture is stirred at 25 °C for 0.5 h. The mixture is diluted with dichloromethane (30 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL x 2) followed by brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (20%-50% acetonitrile in water (formic acid) over 10 min) to afford Compound 97 (51.9 mg, 31%, trifluoroacetate salt) as a white solid. LC / MS (ESI) m / z 922.6 [M+H]+;NMR (400 MHz, DMSO-dd) 3: 10.78 (s, 1H), 10.00 (s, 1H), 9.26 (s, 1H), 8.97 - 8.62 (m, 1H), 7.78 (dd, J = 6.0, 9.2 Hz. 1H), 7.40 - 7.30 (m, 2H), 7.10 - 6.97 (m, 3H), 6.88 (d. J = 7.6 Hz, 2H), 4.85 - 4.47 (m, 2H), 4.46 - 4.18 (m. 4H), 3.97 - 3.79 (m, 1H). 3.71 (dd, J = 4.8, 10.8 Hz. 1H), 3.61 - 3.39 (m, 5H), 3.33 - 3.16 (m, 2H), 3.10 (s, 4H), 2.63 (m, 1H), 2.45 - 2.29 (m, 5H), 2.21 - 2.05 (m, 4H), 2.05 - 1.80 (m, 5H), 1.71 (dd, J= 3.2, 7.6 Hz, 2H), 1.56 - 1.30 (m. 5H), 0.79 - 0.69 (m, 3H).Example 1.7Exemplary synthesis of Compound 98:Step I:ARVN-174-PCT / / ARVN0174WO2

[0121] To a solution of 3-[4-chloro-l-oxo-5-[8-(4-piperidylmethyl)-2-oxa-5.8-diazaspiro[3.5]nonan-5-yl]isoindolin-2-yl]piperidine-2, 6-dione (made in a manner analogous to intermediate 3-[4-chloro-5-[8-[(4-fluoro-4-piperidyl)methyl]-2-oxa-5,8-diazaspiro[3.5]nonan-5-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione, 303 mg, 0.4 mmol, 1.0 eq, 2TFA) in DMA (6 mL) are added Na2CO3(220 mg, 2 mmol, 5.0 eq), [(lS)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (300 mg, 0.4 mmol, 1.0 eq and KI (345 mg, 2 mmol, 5.0 eq), and the reaction mixture is stirred at 90°C for 16 h. The mixture is diluted with ethyl acetate (20 mL) and filtered. The filtrate solution is washed with saturated NH4CI solution(20 mL x 2), water (20 mL x2) and brine (20 mL), dried over NazSCU. filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography (0-5% methanol in dichloromethane) to afford 3-[4-chloro-5-[8-[[l-[[(17?)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]-2-oxa-5,8-diazaspiro[3.5]nonan-5-yl]- 1-oxo-isoindolin-2-yl]piperidine-2, 6-dione (224 mg, 45%) as light yellow solid. LC / MS (ESI) m / z 1126.0 [M+H]+.Step 2:ARVN-174-PCT / / ARVN0174WO2

[0122] To a solution of 3-[4-chloro-5-[8-[[l-[[(17?)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]-2-oxa-5,8-diazaspiro[3.5]nonan-5-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (224 mg, 0.2 mmol, 1.0 eq) in dichloromethane (6.9 mL) is added TFA (2.3 mL), and the reaction mixture is stirred at 20°C for 1 h. The mixture is slowly diluted with saturated NaHCCL solution until pH 8 followed by dichloromethane (20 mL). The resulting mixture is extracted with dichloromethane / methanol (V: V = 10:1, 22 mL x 3), and the combined organic extracts are washed with brine (20 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (2-42% acetonitrile in water (formic acid) over 20 min) to afford Compound 98 (120.4 mg, 54%, formic acid salt) as a light yellow solid. LC / MS (ESI) m / z'. 1082.5 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 5: 11.00 (s, 1H), 10.11 - 9.83 (m, 1H), 9.26 (d, J = 6.8 Hz, 1H), 8.15 (s, 1H), 7.78 (dd. J = 6.0, 9.2 Hz, 1H), 7.69 (d, J= 8.0 Hz, 1H), 7.41 - 7.27 (m, 3H), 7.08 -7.01 (m, 1H), 5.12 (dd, J= 5.2, 13.2 Hz, 1H), 4.74 - 4.61 (m, 1H), 4.58 - 4.17 (m, 12H), 3.98 - 3.78 (m, 1H), 3.60 - 3.49 (m, 1H), 3.11 - 3.01 (m, 1H), 2.96 - 2.75 (m, 5H), 2.73 - 2.56 (m, 2H), 2.48 - 2.43 (m, 2H), 2.42 - 2.30 (m, 5H), 2.20 - 2.10 (m, 4H), 2.04 - 1.96 (m, 2H), 1.93 - 1.78 (m, 4H), 1.77 - 1.60 (m, 3H), 1.58 - 1.44 (m, 2H), 1.13 - 0.89 (m, 2H), 0.79 - 0.72 (m, 3H).Example 1.8Exemplary synthesis of Compound 99:Step 1:ARVN-174-PCT / / ARVN0174WO2

[0123] To a solution of [(lS)-l-[[7-[8-ethyl-7-fhioro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl] methyl methanesulfonate (250 mg, 0.3 mmol, 1.0 eq, 2HC1) and 3-[4-chloro-5- [2,2-dimethyl-4-(4-piperidylmethyl)piperazin- 1 -yl] - 1 -oxo-isoindolin-2-yl]piperidine- 2, 6-dione (made in a manner analogous to intermediate 3-[4-chloro-5-[(2S)-2-methyl-4-[(37?)-pyrrolidin-3-yl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione, 231 mg, 0.47 mmol, 1.5 eq) in DMA (5 mL) are added Na2COs (167 mg, 1.6 mmol, 5.0 eq) and KI (261 mg, 1.6 mmol, 5.0 eq), and the reaction mixture is stirred at 90 °C for 16 h. The mixture is then diluted with ethyl acetate (60 mL) and filtered. The filtrate is washed with water (20 mL) and brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography (3% methanol in dichloromethane) to afford 3-[4-chloro-5-[4-[[l-[[(17?)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]-2,2-dimethyl-piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (250 mg, 64% purity, 46%) as a white solid. LC / MS (ESI) nVz 1112.5 [M+H]+.Step 2:ARVN-174-PCT / / ARVN0174WO2

[0124] To a solution of 3-[4-chloro-5-[4-[[l-[[(lA)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]-2,2-dimethyl-piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2,6-dione (250 mg, 0.2 mmol, 1.0 eq) in dichloromethane (6 mL) is added TFA (2 mL), and the reaction mixture is stirred at 25 °C for 0.5 h. The mixture is cooled to 0 °C, and diluted with saturated NaHCCh solution to adjust the pH to 7. The resulting mixture is extracted with dichloromethane (50 mL x 2), and the combined organic extract is dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by prep-HPLC (0%-40% acetonitrile in water (formic acid) over 20.5 min) to afford Compound 99 (94.7 mg, 38%, formic acid salt) as a yellow solid. LC / MS (ESI) m / z 1068.5 [M+H]+; 'H NMR (400 MHz, DMSO-rfc) 8 10.99 (s, 1H), 9.95 (s, 1H), 9.25 (d, J= 6.0 Hz, 1H), 7.77 (dd, 7 = 6.0, 9.2 Hz, 1H), 8.14 (s, 1H), 7.65 (d, 7 = 8.0 Hz, 1H), 7.53 (d.7 = 8.0 Hz, 1H), 7.38 - 7.32 (m, 2H), 7.05 (t, 7= 3.2 Hz, 1H), 5.10 (dd, 7 = 4.8, 13.2 Hz, 1H), 4.75 - 4.59 (m, 1H), 4.57 - 4.13 (m, 8H), 3.98 - 3.77 (m, 1H), 3.58 - 3.45 (m, 1H), 2.98 - 2.75 (m, 4H), 2.73 -2.68 (m, 2H), 2.64 - 2.56 (m, 2H), 2.45 - 2.48(m. 2H), 2.44 - 2.40 (m, 2H). 2.39 - 2.35 (m, 2H), 2.23 - 2.08 (m, 4H), 2.08 - 2.02 (m, 2H), 2.00 - 1.94 (m, 2H), 1.89 - 1.84 (m, 2H), 1.79 - 1.55 (m, 4H), 1.51 - 1.42 (m, 2H), 1.33 - 1.19 (m, 3H), 1.07 - 0.96 (m, 2H). 0.95 - 0.85 (m, 3H), 0.78 -0.72 (m, 3H).Example 1.9Exemplary synthesis of Compound 101:Step 1:FARVN-174-PCT / / ARVN0174WO2

[0125] To a solution of 3-(4,5-difluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (3.0 g, 11 mmol, 1 eq and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (3.27 g, 13 mmol, 1.2 eq) in dimethyl sulfoxide (30 mL) is added / V, / V-diisopropylethylamine (9.3 mL, 5 eq), and the reaction mixture is stirred at 130 °C for 12 h. The mixture is diluted with water (200 mL) and extracted with 2 / 1 mixture of ethyl acetate / tetrahydrofuran (200 mL x 2). The combined organic extracts are washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is triturated with ethyl acetate (50 mL) to afford tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-l-oxoisoindolin-5-yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (3 g, 54%) as a white solid. LC / MS (ESI) m / z: 515.3 [M+H]+.Step 2:DCM / TFA 25°C, 30 min

[0126] To a solution of tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-l- oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (500 mg, 0.97 mmol, 1 eq) in dichloromethane (6 mL) is added trifluoroacetic acid (4.61 g, 40.39 mmol, 3 mL, 41.56 eq), and the reaction mixture is stirred at 25 °C for 0.5 h. The mixture is concentrated under reduced pressure. The residue is dissolved in isopropanol (2 mL) and diluted with N, N- diisopropylethylamine until pH 8. The suspension is filtered, and the filter cake is dried to afford 3-(4-fluoro-l-oxo-5-(3,9-diazaspiro[5.5]undecan-3-yl)isoindolin-2-yl)piperidine-2, 6-dione (476 mg, 92%, trifluoroacetate salt) as a white solid, which is used in the next step directly. LC / MS (ESI) m / z: 415.1 [M+H]+.Step 3:ARVN-174-PCT / / ARVN0174WO2

[0127] To a solution of 3-(4-fluoro-l-oxo-5-(3.9-diazaspiro[5.5]undecan-3-yl)isoindolin-2-yl)piperidine-2, 6-dione (476 mg, 0.9 mmol, 1.5 eq, trifluoroacetate salt) and [(15)- l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (432 mg, 0.6 mmol, 1 eq) in ^-dimethylformamide (10 mL) are added potassium iodide (498 mg, 3 mmol, 5 eq) and sodium carbonate (318 mg, 3 mmol, 5 eq), and the reaction mixture is stirred at 90 °C for 12 h. The mixture is diluted with water (100 mL) and extracted with dichloromethane (200 mL x 2). The combined organic extracts are washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (30%-60% acetonitrile in water (formic acid) over 15 min) to afford 3-(5-(9-(((7?)-l-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-4-((5)-l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-^pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (550 mg, 88%) as a white solid. LC / MS (ESI) m / z: 520.5 [M / 2+H]+. Step 4:ARVN-174-PCT / / ARVN0174WO2TFA / DCM, 25°C 30 min

[0128] To a solution of 3-(5-(9-((( / ?)-l-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-4-((S)-l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-fl pyrimidin-2-yl)oxy)methyl)-2,2-difiuorocyclopropyl)methyl)-3.9-diazaspiro[5.5]undecan-3-yl)-4-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (550 mg, 0.5 mmol, 1 eq) in dichloromethane (6 mL) is added trifluoroacetic acid (3 mL, 76.30 eq), and the reaction mixture is stirred at 25 °C for 30 min. The mixture is diluted with dichloromethane (30 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL x 2). The organic layer is further washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (25%-55% acetonitrile in water (formic acid) over 15 min). The crude product is further purified by silica gel chromatography (dichloromethane / methanol = 10:1) to afford Compound 101 (85.8 mg, 15%, formic acid salt) as a white solid. LC / MS (ESI) m / z: 995.6 [M+H]+;1H NMR (400 MHz, DMSO-J6) b: 10.98 (s, 1H), 9.96 (s, 1H), 9.25 (s, 1H), 8.15 (s, 1H), 7.77 (dd, J= 6.0, 9.2 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.39 - 7.32 (m, 2H), 7.15 (t, J = 8.0 Hz, 1H). 7.05 (d, J= 2.0 Hz. 1H). 5.07 (dd, J= 5.2, 13.2 Hz, 1H), 4.66 (t, J - 11.6 Hz, 1H), 4.57 - 4.11 (m, 7H), 3.97 - 3.78 (m, 1H), 3.58 - 3.40 (m, 1H), 3.07 (s, 4H), 2.98 - 2.84 (m, 1H), 2.79 - 2.64 (m, 1H), 2.58 (d, J = 16.8 Hz, 1H), 2.48 - 2.27 (m, 9H), 2.20 - 2.05 (m, 2H), 1.96 (dd, J = 5.2, 10.4 Hz, 1H), 1.92 - 1.77 (m, 3H), 1.76 - 1.66 (m, 1H), 1.59 - 1.33 (m, 9H), 0.81 - 0.68 (m, 3H).ARVN-174-PCT / / ARVN0174WO2Example 1.10Exemplary synthesis of Compound 104:Step 1:Boc

[0129] To a solution of 3-(6-fhioropyridin-3-yl)piperidine-2, 6-dione (1.5 g, 7 mmol, 1 eq) and tert-butyl piperazine- 1 -carboxylate (1.61 g, 8.7 mmol, 1.2 eq) in dimethyl sulfoxide (20 mL) is added A( / Cdiisopropylethylamine (6.2 mL, 5 eq), and the reaction mixture is stirred at 135 °C for 12 h. The mixture is diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic extracts are washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford tertbutyl 4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazine-l-carboxylate (700 mg, 25%) as a yellow solid. LC / MS (ESI) m / z 375.2 [M+H]+.Step 2:

[0130] To a solution of tert-butyl 4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazine-1-carboxylate (700 mg, 1.9 mmol, 1 eq) in dichloromethane (7 mL) is added trifluoroacetic acid (3.5 mL, 25.20 eq), and the reaction mixture is stirred at 25 °C for 0.5 h. The mixture is concentrated under reduced pressure to afford 3-(6-(piperazin-l-yl)pyridin-3-yl)piperidine-2,6-dione (700 mg, 96%, trifluoroacetate salt) as a brown oil, which is used in the next step directly. LC / MS (ESI) m / z 275.1 [M+H]+.Step 3:ARVN-174-PCT / / ARVN0174WO2DCM / i-PrOH, DIEA,NaBH(OAc)3, 25°C, 1 h

[0131] To a solution of 3-(6-(piperazin-l-yl)pyridin-3-yl)piperidine-2, 6-dione (700 mg, 1.8 mmol, 1 eq, trifluoroacetate salt) and tert-butyl 4-formylpiperidine-l -carboxylate (576 mg, 2.7 mmol, 1.5 eq) in dichloromethane (7 mL) and isopropanol (7 mL) is added N, N-diisopropylethylamine (0.6 mL, 2 eq), and the mixture is stirred at 25 °C for 15 minutes. Sodium triacetoxyborohydride (764 mg, 3.6 mmol, 2 eq) is then added, and the reaction mixture is stirred at 25 °C for 45 minute. The mixture is then diluted with water (100 mL) and extracted with dichloromethane (100 mL x 2). The combined organic extracts are washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is triturated with 2-methoxy-2-methylpropane (20 mL) to afford te -butyl 4-((4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-l-yl)methyl)piperidine-l -carboxylate (600 mg, 70%) as a white solid. LC / MS (ESI) m / z 472.3 [M+H]+;NMR (400 MHz, DMSO-tfc) 3: 10.82 (s, 1H), 7.99 (s, 1H), 7.45 (d. J = 1.2 Hz, 1H), 7.01 - 6.75 (m, 1H), 4.50 - 4.17 (m, 1H). 3.93 (d, J = 11.2 Hz, 2H), 3.76 (dd, J= 3.8, 11.8 Hz, 1H), 3.66 - 3.48 (m, 1H), 3.32 - 3.20 (m, 2H), 3.18 - 2.94 (m, 2H), 2.83 - 2.59 (m, 4H), 2.52 (d. J = 2.0 Hz, 2H), 2.49 - 2.30 (m, 2H), 2.19 (m, 2H), 2.01 - 1.92 (m, 1H), 1.72 (d, J= 12.4 Hz, 2H), 1.39 (s, 9H), 1.08 - 0.91 (m, 2H).Step 4:DCM / TFA 25°C, 30 min

[0132] To a solution of tert-butyl 4-((4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-l-yl)methyl)piperidine-l -carboxylate (767 mg, 1.6 mmol, 1 eq) in dichloromethane (8 mL) is added trifluoro acetic acid (4.0 mL, 33.41 eq), and the reaction mixture is stirred at 25 °C for 0.5 h. The mixture is concentrated under reduced pressure, and the residue is dissolved in isopropanol (2mL) and diluted with N,N-diisopropylethylamine until pH 8. The resulting mixture is purified by prep-HPLC (1%- 10% acetonitrile in water (formic acid) over 20 min). The crudeARVN-174-PCT / / ARVN0174WO2product is triturated with 2-methoxy-2-methylpropane (30 mL) to afford 3-(6-(4-(piperidin-4-ylmethyl)piperazin-l-yl)pyridin-3-yl)piperidine-2, 6-dione (652 mg, 96%, formic acid salt) as a white solid. LC / MS (ESI) m / z 372.1 [M+H]+.Step 5:

[0133] To a solution of 3-(6-(4-(piperidin-4-ylmethyl)piperazin-l-yl)pyridin-3-yl)piperidine-2, 6-dione (200 mg, 0.54 mmol, 1.5 eq) and [(lS)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (258 mg, 0.36 mmol, 1 eq) in A / imethylformamide (5 mL) are added sodium carbonate (190 mg, 1.79 mmol, 5 eq) and potassium iodide (297 mg, 1.79 mmol, 5 eq), and the reaction mixture is stirred at 90 °C for 12 h. The mixture is diluted with water (100 mL) and extracted with dichloromethane (100 mL x 2). The combined organic extracts are washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (13%-43% acetonitrile in water (formic acid) over 22 min) to afford 3-(6-(4-((l-(((7?)-l-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-4-((S)-l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-c(]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)methyl)piperazin-l-yl)pyridin-3-yl)piperidine-2,6-dione (130 mg, 36%) as a red solid. LC / MS (ESI) m / z. 996.5 [M+H]+.Step 6:ARVN-174-PCT / / ARVN0174WO2TFA / DCM, 25°C, 30 min

[0134] To a solution of 3-(6-(4-((l-(((R)-l-(((7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-4-((1S’)-l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3- 6 / ]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)methyl)piperazin- l-yl)pyridin-3-yl)piperidine-2, 6-dione (130 mg. 0.13 mmol, 1 eq) in dichloromethane (2 mL) is added trifluoroacetic acid (1 mL, 103.15 eq), and the reaction mixture is stirred at 25 °C for 0.5 h. The mixture is diluted with saturated sodium bicarbonate solution (50 mL) and extracted with dichloromethane (30 mL x 2). The combined organic extracts are washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (13%-43% acetonitrile in water (formic acid) over 10 min) to afford Compound 104 (11.2 mg, 7%, trifluoroacetate salt) as a pink solid. LC / MS (ESI) m / z 952.6 [M+H]+; 'H NMR (400 MHz, DMSO-rfc) 6: 10.82 (s, 1H), 9.97 (s, 1H), 9.25 (d,. / = 5.2 Hz, 1H), 8.13 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.77 (dd, J= 6.0, 9.2 Hz, 1H), 7.42 - 7.30 (m, 3H), 7.13 - 6.95 (m, 1H), 6.78 (d, J= 8.8 Hz, 1H), 4.72 - 4.14 (m, 6H), 3.97 - 3.78 (m, 1H), 3.73 (dd, J = 4.8, 12.2 Hz, 1H), 3.58 - 3.40 (m, 5H), 2.92 - 2.75 (m, 2H), 2.74 - 2.60 (m, 2H), 2.47 - 2.28 (m, 8H), 2.26 - 2.04 (m, 6H), 2.03 - 1.77 (m. 6H), 1.76 - 1.58 (m, 3H). 1.58 - 1.40 (m, 2H), 1.13 - 0.92 (m, 2H), 0.79 - 0.68 (m, 3H).Example 1.11Exemplary synthesis of Compound 107:ARVN-174-PCT / / ARVN0174WO2Step 1:

[0135] To a solution of [(lS)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl] methyl methanesulfonate (340 mg, 0.47 mmol, 1.0 eq) and 4-(dimethoxymethyl)piperidine (113 mg, 0.71 mmol, 1.5 eq) in DMA (5 mL) are added Na2COs (250 mg, 2.4 mmol, 5.0 eq) and KI (392 mg, 2.4 mmol, 5.0 eq), and the reaction mixture is stirred at 90 °C for 16 h. The mixture is diluted with saturated aqueous NH4CI solution (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic extracts is washed with water (40 mL x 3) and brine (40 mL), dried over anhydrous NazSCU. filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography (0-3% methanol in dichloromethane) to afford (4S)-8-[2-[[(lA)-l-[[4-(dimethoxymethyl)-l-piperidyl] methyl] -2, 2-difluoro-cyclopropyl] methoxy] -7 - [8 -ethyl-7-fluoro-3 -(methoxymethoxy)-l-naphthyl]-8-fhioro-pyrido[4,3-d]pyrimidin-4-yl]-l-oxa-8-azaspiro[3.5]nonane (300 mg, 81%) as a yellow solid. LC / MS (ESI) m / z. 784.8 [M+H]+.Step 2:

[0136] To a solution of (4 )-8-[2-[[(17?)-l-[[4-(dimethoxymethyl)-l-piperidyl]methyl]-2, 2-difluoro-cyclopropyl] methoxy]-7- [8-ethyl-7-fluoro-3- (methoxymethoxy)- 1 -naphthyl] - 8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-l-oxa-8-azaspiro[3.5]nonane (300 mg, 0.38 mmol, 1.0 eq) in dichloromethane (18 mL) is added TFA (6 mL), and the reaction mixture is stirred at 20°C for 0.5 h. The mixture is diluted with saturated aqueous NallCCh solution until pH reached 8-9, and the resulting mixture is extracted with dichloromethane (50 mL x 2). The combined organic extract is washed with brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentratedARVN-174-PCT / / ARVN0174WO2under reduced pressure. The crude product is purified by silica gel flash column chromatography (0-3% methanol in dichloromethane) to afford l-[[(17?)-l-[[7-(8-ethyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]piperidine-4-carbaldehyde (170 mg, 64%) as a yellow solid. LC / MS (ESI) m / z: 694.3 [M+H]+; 'H NMR (400MHz, CDCI3) 59.64 - 9.62 (m, 1H), 9.32 - 9.05 (m, 1H), 7.64 - 7.45 (m. 1H). 7.25 - 7.11 (m, 2H), 7.07 - 6.94 (m, 1H), 4.73 -4.38 (m, 4H), 3.59 - 3.25 (m, 2H), 3.11 - 2.69 (m, 3H), 2.59 - 2.39 (m, 3H), 2.35 - 2.12 (m, 5H), 2.11 - 2.06 (m, 1H), 2.04 - 2.02 (m, 1H), 1.96 - 1.73 (m, 4H), 1.69 - 1.49 (m, 6H), 0.87 - 0.82 (m.3H).Step 3:K2CO3, DMA, 90°C, 2 h

[0137] To a solution of l-[[(17?)-l-[[7-(8-ethyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-4-[(4R)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]piperidine-4-carbaldehyde (300 mg, 0.43 mmol, 1.0 eq) in DMA (6 mL) are added CS2CO3 (705 mg, 2 mmol, 5.0 eq) and ethyl 2-bromo-2,2-difluoro-acetate (877 mg, 4 mmol, 10.0 eq), and the reaction mixture is stirred at 90 °C for 2 h. The mixture is diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic extract is washed with water (20 mL x 3) and brine (20 mL), dried over anhydrous NaiSC, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (52%-92% acetonitrile in water (NH4HCO3) over 20 min). The crude fractions are concentrated under reduced pressure, and the residue is extracted with EtOAc (30 mL x 2). The combined organic extract is washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford l-[[(lA)-l-[[7-[3-(difluoromethoxy)-8-ethyl-7-fluoro-l-naphthyl]-8-fluoro-4-[(4A)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]piperidine-4-carbaldehyde (81 mg, 25%) as a yellow solid. LC / MS (ESI) / / z: 744.3 [M+H]+.Step 4:ARVN-174-PCT / / ARVN0174WO22-picoline borane, HOAc, NMM, DMSO, 50°C,48h

[0138] To a solution of l-[[(17?)-l-[[7-[3-(difluoromethoxy)-8-ethyl-7-fluoro-l-naphthyl]-8-fluoro-4-[(4. S')-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4.3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]piperidine-4-carbaldehyde (81 mg, 0.11 mmol, 1.0 eq) and 3-(4-chloro-l-oxo-5-piperazin-l-yl-isoindolin-2-yl)piperidine-2, 6-dione (71 mg, 0.16 mmol, 1.5 eq, 2 HC1) in DMSO (3 mL) is added NaOAc (36 mg, 0.44 mmol, 4.0 eq), followed by NaBH(OAc)3(92 mg, 0.44 mmol, 4.0 eq, and the reaction mixture is stirred at 40 °C for 16 h. The reaction mixture is suspended in saturated aqueous NaHCCh solution (10 mL) and then filtered. The filter cake is purified by prep-HPLC (2%-42% acetonitrile in water (formic acid) over 20 min) to afford Compound 107 (37.9 mg, 31%, 0.22 formic acid salt) as a white solid. LC / MS (ESI) zn / z: 1090.4 [M+H]+;1H NMR (400 MHz, DMSO-zfc) 8 10.99 (s, 1H), 9.28 - 9.27 (m, 1H), 8.16 - 8.05 (m. 1H), 7.96-7.95 (m, 1H), 7.66 - 7.56 (m. 1H), 7.62 - 7.20 (m, 4H). 5.13 -5.13 (m, 1H), 4.65 - 4.51 (m, 1H), 4.55 - 4.19 (m, 7H), 3.97 - 3.79 (m, 1H), 3.58 - 3.39 (m, 2H), 3.07 (s, 4H), 2.95 - 2.55 (m, 6H), 2.49 - 2.27 (m, 7H), 2.23 - 2.08 (m, 4H), 2.04 - 1.94 (m, 2H), 1.92 - 1.78 (m, 4H), 1.75 - 1.57 (m, 3H), 1.48 (s, 2H), 1.10 - 0.86 (m, 2H), 0.83 - 0.71 (m, 3H).Example 1.12Exemplary synthesis of Compound 108:Step 1:ARVN-174-PCT / / ARVN0174WO2Na2CO3, KI, DMF, 90°C 12h

[0139] To a solution of 3-[4-fluoro-l-oxo-5-[4-(4-piperidylmethyl)piperazin-l-yl]isoindolin-2-yl] piperidine-2, 6-dione (made in a manner analogous to intermediate 3-[ 1-methyl-7-[4-(4-piperidylmethyl) piperazin- l-yl]indazol-3-yl]piperidine-2, 6-dione (300 mg, 0.45 mmol, 1 eq, 2 trifluoroacetate salt) and [(lS)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (386 mg, 0.5 mmol, 1.2 eq) in / V. A'-dimethylformamide (5 mL) are added sodium carbonate (237 mg, 2 mmol, 5 eq) and potassium iodide (378 mg, 2.23 mmol. 5 eq), and the reaction mixture is stirred at 90 °C for 12 h. The mixture is diluted with water (80 mL) and extracted with dichloromethane (40 mL x 2). The combined organic extract is washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-TLC (dichloromethane:methanol = 10:1) to afford 3-[5-[4-[[l-[[(17?)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (307 mg, 64%) as a white solid. LC / MS (ESI) m / z 1068.5 [M+H]+.Step 2:ARVN-174-PCT / / ARVN0174WO2

[0140] To a solution of 3-[5-[4-[[l-[[(l / ?)-l-[[7-[8-ethyl-7-fhroro-3-(methoxymethoxy) -l-naphthyl]-8-fhioro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (307 mg, 0.29 mmol, 1 eq) in dichloromethane (3 mL) is added trifluoroacetic acid (1 mL, 46.84 eq), and the reaction mixture is stirred at 25 °C for 0.5 h. The mixture is diluted with saturated sodium bicarbonate solution to adjust the pH to 8, and the resulting mixture is extracted with dichloromethane (10 mL x 2). The combined organic extract is washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (12%-42% acetonitrile in water (formic acid) over 15 min) to afford Compound 108 (79.1 mg, 25%. formic acid salt) as a white solid. LC / MS (ESI) m / z 1025.5 [M+H]+; 'H NMR (400 MHz, DMSO-tfc) d: 10.98 (s, 1H), 9.95 ( s, 1H), 9.25 (d, J = 4.4 Hz, 1H), 7.77 (dd, J = 6.0, 9.2 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.40 - 7.30 (m, 2H), 7.13 ( t, J = 7.6 Hz, 1H), 7.05 ( d, J= 2.4 Hz, 1H), 5.07 (dd, J = 4.8, 13.2 Hz, 1H), 4.71 - 4.58 (m, 1H), 4.54 - 4.23 (m, 7H), 4.00 - 3.76 (m, 1H), 3.52 ( d, J= 8.0 Hz, 1H), 3.11 ( s, 4H). 2.89 ( d. J= 12.8 Hz, 1H), 2.81 ( d, J = 7.2 Hz, 2H). 2.73 - 2.64 (m, 1H), 2.58 ( d, J= 17.2 Hz, 1H), 2.48 - 2.43 (m, 4H), 2.43 - 2.30 (m, 5H), 2.11 ( d, J = 6.0 Hz, 4H), 2.00 - 1.92 (m, 2H), 1.90 - 1.76 (m, 4H), 1.75 - 1.57 (m, 3H), 1.46 ( d, J= 5.2 Hz, 2H), 1.08 -0.85 (m, 2H), 0.79 - 0.65 (m, 3H).Example 1.13Exemplary synthesis of Compound 112:Step 1:ARVN-174-PCT / / ARVN0174WO2O OPd-PEPPSI-IPent, Cs2CO3,dioxane, 100°C, 6 h

[0141] A mixture of 3-(5-bromo-4-methoxy-l-oxo-isoindolin-2-yl)piperidine-2, 6-dione (700 mg, 1.98 mmol, 1 eq), / erz-butyl piperazine- 1 -carboxylate (443 mg, 2 mmol, 1.2 eq), cesium carbonate (1.94 g, 6 mmol, 3 eq) and dichloro[l,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (193 mg, 0.20 mmol, 0.1 eq) in dioxane (10 mL) is degassed and purged with nitrogen several times, then stirred at 100 °C for 6 h under nitrogen atmosphere. The reaction mixture is diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic extract is washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford tertbutyl 4-[2-(2,6-dioxo-3-piperidyl)-4-methoxy-l-oxo-isoindolin-5-yl]piperazine-l-carboxylate (500 mg, 55%) as a yellow solid. LC / MS (ESI) m / z: 459.2 [M+H]+.Step 2:

[0142] To a solution of ZerZ-butyl 4-[2-(2,6-dioxo-3-piperidyl)-4-methoxy-l-oxo-isoindolin-5-yl] piperazine- 1 -carboxylate (585 mg, 1.3 mmol, 1 eq) in dichloromethane (6 mL) is added trifluoroacetic acid (3 mL, 31.65 eq). The mixture is stirred at 25 °C for 1 h, then concentrated under reduced pressure to afford 3-(4-methoxy-l-oxo-5 -piperazin- 1-yl-isoindolin- 2-yl) piperidine-2, 6-dione (600 mg, crude, trifluoroacetate salt) as a yellow gum, which is used in the next step directly. LC / MS (ESI) m / z: 359.1 [M+H]+.Step 3-6:

[0143] The final assembly of Compound 112 is analogous to step 3-6 of Compound 104, isolated as a white solid. LC / MS (ESI) m / z: 1036.4 [M+H]+; 'HNMR (400 MHz, DMSO-^) 3 10.97 (s, 1H), 10.37 - 9.67 (m, 1H), 9.25 (d, J= 5.3 Hz, 1H). 8.24 (s, 1H), 7.77 (dd, J = 6.0, 9.2 Hz, 1H), 7.41 - 7.31 (m, 3H), 7.08 - 7.01 (m, 2H), 5.06 (dd, J= 5.2, 13.2 Hz, 1H), 4.73 - 4.58 (m, 1H), 4.55 - 4.44 (m, 2H), 4.44 - 4.38 (m, 2H), 4.38 - 4.32 (m, 1H), 4.32 - 4.19 (m, 2H), 3.84 (s,ARVN-174-PCT / / ARVN0174WO23H), 3.59 - 3.48 (m, 1H), 3.40 (dd, J = 2.4, 10.0 Hz, 2H), 3.08 ( s, 4H), 2.95 - 2.85 (m, 1H), 2.84 - 2.74 (m, 2H), 2.73 - 2.64 (m, 1H), 2.60 ( d, J= 2.0 Hz, 1H), 2.54 ( s, 2H), 2.46 - 2.28 (m, 6H), 2.11 ( d, 7= 6.8 Hz, 4H), 2.01 - 1.92 (m. 2H), 1.91 - 1.77 (m, 4H), 1.76 - 1.56 (m, 3H), 1.47 ( s, 2H), 1.09 - 0.85 (m, 2H), 0.79 - 0.69 (m, 3H).Example 1.14Exemplary synthesis of Compound 128:Step 1:BnO5=N Bn - A NH - ►? I °\ >=N BnRuphos-Pd-G4Cs2CO3T f N ~ OBocdioxane, 100°C, 16hX—O

[0144] To a solution of tert-butyl 2,3-dimethylpiperazine-l -carboxylate (1.00 g, 4.7 mmol, 1 eq) and 5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-l-one (2.34 g, 4.7 mmol, 1 eq) in dioxane (20 mL) are added CS2CO3 (4.56 g, 14 mmol, 3.0 eq) and Ruphos Pd G4 (396.8 mg, 0.5 mmol, 0.1 eq) under nitrogen atmosphere, and the resulting mixture is degassed and purged with nitrogen three times, then stirred at 100 °C for 16 h. The reaction mixture is filtered, and the filtrate solution is concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography (0-20% ethyl acetate in petroleum ether) to afford tert-butyl-4- [2-(2,6-dibenzyloxy-3-pyridyl)-l-oxo-isoindolin-5-yl]-2,3-dimethyl-piperazine-l-carboxylate (6.1 g, 68%) as a yellow solid. LC / MS (ESI) m / z: 635.4 [M+H]+.Step 2:o

[0145] Terf-butyl-4-[2-(2,6-dibenzyloxy-3-pyridyl)-l-oxo-isoindolin-5-yl]-2,3-dimethyl-piperazine-1 -carboxylate (4.8 g) is purified by prep-SFC (50% EtOH (0.1%NH4OH) in CO2). The first eluted fraction is assigned to t<?rt-butyl-(2S,3R)-4-[2-(2,6-dibenzyloxy-3-pyridyl)-l- oxo-isoindolin-5-yl]-2,3-dimethyl-piperazine-l-carboxylate (2.38 g, 49%) as a yellow solid. LC / MS (ESI) m / z'. 635.4 [M+H]+. The second eluted fraction is assigned to tert-butyl-(2R,3S')-4-ARVN-174-PCT / / ARVN0174WO2[2-(2,6-dibenzyloxy-3-pyridyl)- 1 -oxo-isoindolin-5-yl]-2,3-dimethyl-piperazine- 1 -carboxylate (2.29 g, 47%) as a yellow solid. LC / MS (ESI) m / z'. 635.4 [M+H]+.Step 3:

[0146] To a solution of tert-butyl (25,3?)-4-[2-(2,6-dibenzyloxy-3-pyridyl)-l-oxo-isoindolin-5-yl]-2,3-dimethyl-piperazine-l-carboxylate (2.38 g, 3.8 mmol, 1 eq) in THF (110 mL) is added 20% palladium hydroxide (1 g, 7 mmol, 1.90 eq) under nitrogen atmosphere. The mixture is degassed and purged with hydrogen (3x), then heated to 75°C and stirred for 16 h under hydrogen (50 psi) atmosphere. The reaction mixture is filtered through celite, and the filtrate solution is concentrated under reduced pressure to afford tert-butyl-(02S,3 / ?)-4-[2-(2,6-dioxo-3-piperidyl)- 1 -oxo-isoindolin-5-yl] -2,3-dimethyl-piperazine- 1 -carboxylate ( 1.52 g, 78%, 88% purity) as a white solid. LC / MS (ESI) m / z 457.1 [M+H]+.Step 4:NCS, TFACH2CI2 / MeOH40°C, 48h

[0147] To a solution of tert-butyl (25',37?)-4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-2,3-dimethyl-piperazine-l-carboxylate (1.52 g, 3 mmol, 1 eq) in DCM (20 mL) and MeOH (2 mL) are added TFA (645 mg, 5.7 mmol, 1.7 eq) and A-chlorosuccinimide (497.9 mg, 3.7 mmol, 1.12 eq), and the reaction mixture is stirred at 40 °C for 48 h. The mixture is diluted with saturated sodium bicarbonate solution (40 mL) and extracted with dichloromethane (60 mL x 3). The combined organic extract is washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography (0-4% methanol in dichloromethane). The crude product is suspended in acetonitrile (20 mL) and stirred at 85 °C for 1.5 h, then filtered and dried to afford tert-butyl (2S,37?)-4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-2,3-dimethyl-piperazine- 1 -carboxylate (0.8 g, 47%) as a white solid. LC / MS (ESI) m / z 491.1 [M+H]+.ARVN-174-PCT / / ARVN0174WO2Step 5:o o HCI / dioxane35°C, 1h

[0148] A solution of tert-butyl (2S,3 / ?)-4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-2,3-dimethyl-piperazine-l-carboxylate (800 mg, 1.6 mmol, 1 eq) in HCI / dioxane (2 M, 30 mL, 36.82 eq) is stirred at 35 °C for 1 h. The mixture is suspended in petroleum ether (90 mL) and filtered. The filter cake is dried to afford 3-[4-chloro-5-[(2R,3S)-2,3-dimethylpiperazin- 1-yl]- l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (745 mg, 98%, 2HC1 salt) as a gray solid. LC / MS (ESI) m / z 391.0 [M+H]+.Step 6 - 9:

[0149] The final assembly of Compound 128 is analogous to step 3-6 of Compound 104, isolated as a yellow solid (formic acid salt). LC / MS (ESI) m / z: 535.2 [M / 2+H]+; ’H NMR (400 MHz, DMSO-t / e) 8 10.97 (s, 1H), 9.24 (d, 7= 8.4 Hz, 1H), 8.14 (s, 1H), 7.76 (dd, 7= 9.2, 6.0, Hz, 1H), 7.64 (d, 7= 8.0 Hz, 1H), 7.41 - 7.30 (m, 2H). 7.26 - 7.18 (m, 1H), 7.05 (t, 7= 3.2 Hz, 1H), 5.15 - 5.03 (m, 1H), 4.68 - 4.15 (m, 9H), 3.97 - 3.75 (m, 1H), 3.67 - 3.50 (m, 2H), 2.96 - 2.74 (m, 5H), 2.73 - 2.55 (m, 3H), 2.47 - 2.31 (m, 5H), 2.26 - 1.69 (m, 13H), 1.60 - 1.34 (m, 3H), 1.09 - 0.89 (m, 5H), 0.85 - 0.79 (m. 3H), 0.77 - 0.69 (m, 3H).Example 1.15Exemplary synthesis of Compound 129:Step 1:

[0150] To a mixture of l-benzylpiperidin-4-one (50.0 g, 264 mmol, 49 mL, 1.0 eq) and iV-diisopropylethylamine (41.0 g, 317 mmol, 1.2 eq) in dichloromethane (500 mL) is added ethyl 2-cyanoacetate (29.9 g, 264 mmol, 1.0 eq), and the reaction mixture is stirred at 25 °C for 7 days. The mixture is poured into iced water (500 mL), then extracted with dichloromethane (200ARVN-174-PCT / / ARVN0174WO2mL x 3). The combined organic extract is washed with brine (200 mL x 3), dried over NazSC, filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography (0-10% ethyl acetate in petroleum ether) to afford ethyl 2-(l-benzyl-4-piperidylidene)-2-cyano-acetate (51.2 g, 68%) as an orange solid. LC / MS (ESI) m / z:. 285.0 [M+H]+; NMR (400 MHz, CDCE) 87.41 - 7.23 (m. 5H), 4.27 (q, 7= 7.2 Hz, 2H), 3.55 (s, 2H), 3.15 (t, 7= 6.0 Hz. 2H), 2.82 - 2.76 (m, 2H). 2.68 - 2.54 (m, 4H), 1.34 (t, 7 = 7.2 Hz. 3H). Step 2:

[0151] To a solution of LiHMDS (1.0 M, 198 mL, 1.2 eq) in THF (300 mL) at -78 °C under nitrogen atmosphere is added acetone (10.56 g, 182 mmol, 1.1 eq slowly, and the resulting mixture is stirred at -78 °C for 40 minutes. A solution of ethyl 2-(l-benzyl-4-piperidylidene)-2-cyano-acetate (47.0 g, 165 mmol, 1.0 eq) in THF (200 mL) is then added, and the reaction mixture is stirred for 1 h at -78 °C, slowly warmed to 25 °C and stirred for 2 h. The mixture is diluted with saturated NH4CI (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic extract is washed with brine (300 mL x 2), dried over NazSCU, filtered. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel flash column chromatography (0-10% then up to 50% ethyl acetate in petroleum ether) to afford ethyl 2-(4-acetonyl-l-benzyl-4-piperidyl)-2-cyano-acetate (24.4 g, 43%) as an orange oil. LC / MS (ESI) m / z 343.3 [M+H]+; 'H NMR (400 MHz, CDCI3) 87.28 - 7.18 (m, 5H), 4.32 (s, 1H), 4.16 (q, 7= 7.2 Hz, 2H), 3.43 (s, 2H), 2.84 - 2.56 (m, 4H). 2.16 - 2.04 (m, 5H), 1.94 - 1.81 (m, 3H), 1.56 (s, 1H), 1.24 (t, J = 12 Hz, 3H).Step 3:1 1Bn BnARVN-174-PCT / / ARVN0174WO2

[0152] In a flow reactor are added ethyl 2-(4-acetonyl-l-benzyl-4-piperidyl)-2-cyano-acetate (24.4 g, 71 mmol, 1.0 eq), lithium chloride (4.53 g, 107 mmol, 1.5 eq) and water (3.85 mL, 214 mmol, 3.0 eq) in iV-methyl-2-pyrrolidone (400 mL). The flow rate of Pump 1 is adjusted to 2.75 mL / min for the above solution. The reaction mixture is collected after running at 185°C for 220 minutes. The reaction mixture is diluted with EtOAc (2 L), then washed with water (200 mL x 10) and brine (500 mL x 2). The organic layer is dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography (0-1% CH3OH in dichloromethane) to afford 2-(4-acetonyl-l-benzyl-4-piperidyl)acetonitrile (11.3 g, 59%) as an orange oil. LC / MS (ESI) m / z 271.0 [M+H]+;rH NMR (400 MHz, CDCI3) 87.33 - 7.25 (m, 5H), 3.51 (s, 2H), 2.75 (s, 2H), 2.66 (s, 2H), 2.49 - 2.35 (m, 4H), 2.17 (s, 3H), 1.70 (t, J= 5.6 Hz, 4H).Step 4:N HBn Bn

[0153] A solution of 2-(4-acetonyl-l-benzyl-4-piperidyl)acetonitrile (11.2 g, 41 mmol, 1.0 eq) in CH3OH (300 mL) is pumped into a fixed bed (loaded with granular catalyst Ni / AhCh (41.42 mmol, 5 mL, 14%) and heated to 80 °C) at 0.3 mL / min, and the flow rate of hydrogen is 30 mL / min (2.5 mpa). The reaction mixture is collected after 24 h, then concentrated under reduced pressure. The residue is purified by prep-HPLC (0-30% acetonitrile in water (HC1) over 25 min). The pure fractions are diluted with saturated aqueous NazCCL solution until pH 9, and the resulting mixture is extracted with 20 / ldichloromethane / CH3OH (1 L x 5). The combined organic extract is dried over NaiSO i. filtered and concentrated under reduced pressure to afford 3-benzyl-10-methyl-3,9-diazaspiro[5.5]undecane (3 g, 28%) as a yellow oil. LC / MS (ESI) m / .259.0 [M+H]+; 'H NMR (400 MHz, CDCI3) 87.39 - 7.18 (m, 5H), 3.50 (s, 2H), 2.91 - 2.73 (m, 3H), 2.48 - 2.32 (m, 4H), 1.75 -1.63 (m, 4H), 1.40 (t, J = 5.6 Hz, 2H), 1.18 (dt, J = 5.2, 12.8 Hz, 1H), 1.03 (d, J = 6.4 Hz, 3H), 0.93 - 0.78 (m, 1H).Step 5:ARVN-174-PCT / / ARVN0174WO2HCPhos Pd G3, Cs2CO3,dioxane, 100°C, 15hBn

[0154] To a mixture of 3-benzyl-10-methyl-3,9-diazaspiro[5.5]undecane (1.5 g, 5.8 mmol, 1.0 eq) and 5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-l-one (2.92 g, 5.8 mmol, 1.0 eq in dioxane (20 mL) are added CS2CO3 (5.68 g, 17 mmol. 3.0 eq) and CPhos Pd G3 (468.08 mg, 580 pmol, 0.1 eq) in a glovebox, and the reaction mixture is stirred at 100 °C in a sealed tube for 15 h. The mixture is cooled to 25 °C and filtered, and the filter cake is washed with EtOAc (50 mL). The filtrate is washed with water (20 mL x 3) and brine (20 mL x 3). The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography (0-40% THF in petroleum ether) to afford 5-(9-benzyl-4-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-2-(2,6-dibenzyloxy-3- pyridyl)isoindolin-l-one (2.8 g, 65%) as a brown solid. LC / MS (ESI) m / z 679.3 [M+H]+.Step 6:

[0155] Racemic 5-(9-benzyl-4-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-2-(2,6- dibenzyloxy-3-pyridyl)isoindolin-l-one (2.8 g) is purified by SFC (50% EtOH (0.1%NH4OH) in CO2). The first eluted fraction is assigned to 5-[(47?)-9-benzyl-4-methyl-3,9- diazaspiro[5.5]undecan-3-yl]-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-l-one (1.2 g, 43%) as a yellow solid. LC / MS (ESI) m / z 679.5 [M+H]+. The second fraction is assigned to 5-[(4S)-9- benzyl-4-methyl-3,9-diazaspiro[5.5]undecan-3-yl]-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-l- one (1.25 g, 45%) as a yellow solid. LC / MS (ESI) m / z: 679.5 [M+H]+.Step 7:ARVN-174-PCT / / ARVN0174WO2

[0156] To a solution of 5-[(4 )-9-benzyl-4-methyl-3,9-diazaspiro[5.5]undecan-3-yl]-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-l-one (1.2 g, 1.8 mmol, 1.0 eq), di-tert-butyl dicarbonate (463 mg, 2 mmol, 1.2 eq) and triethylamine (492 pL, 3.5 mmol, 2.0 eq) in THF (300 mL) are added 10% palladium on carbon (200 mg) and 20% palladium hydroxide (200 mg) in THF (50 mL), and the suspension is degassed and purged with hydrogen several times, then stirred under hydrogen (50 psi) at 60 °C for 15 h. The reaction mixture is filtered and washed with THF (lOOmL), and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography (0-55% THF in petroleum ether) to afford tert-butyl (4 / )-3-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-4-methyl-3,9-diazaspiro[5.5]undecane-9-carboxylate (823 mg, 91%) as a white solid. LC / MS (ESI) nV. 511.3 [M+H]+; 'H NMR (400 MHz, CDCh) 88.01 (s, 1H), 7.74 (d. J= 8.4 Hz, 1H), 6.99 (d. J= 8.4 Hz, 1H), 6.89 (s, 1H), 5.21 (dd, J = 5.2, 13.2 Hz, 1H), 4.48 - 4.20 (m, 2H), 3.83 - 3.70 (m, 1H), 3.61 - 3.43 (m, 2H), 3.42 -3.14 (m, 4H), 2.97 - 2.76 (m, 2H), 2.40 - 2.26 (m, 1H), 2.25 - 2.16 (m, 1H), 1.75 (dd, 7= 5.2, 13.8 Hz, 1H), 1.71 - 1.65 (m, 2H), 1.55 - 1.49 (m. 3H). 1.48 - 1.43 (m, 11H). 1.13 (d, J = 6.4 Hz.3H).Step 8 - 11:

[0157] The final assembly of Compound 129 is analogous to step 7-10 of Compound 90, isolated as a white solid. LC / MS (ESI) m / z: 1025.4 [M+H]+; 'H NMR (400 MHz, DMSO-tfc) 8 10.99 (s, 1H), 9.96 (s, 1H), 9.25 (s, 1H), 7.81 - 7.72 (m, 1H). 7.64 - 7.69 (m, 1H), 7.45 - 7.52 (m, 1H), 7.29 - 7.38 (m, 2H), 7.05 (s, 1H), 5.15 - 5.05 (m, 1H), 4.74 - 4.11 (m, 8H), 3.97 - 3.76 (m, 1H), 3.60 - 3.43 (m, 1H), 3.35 - 3.26 (m, 2H), 2.97 - 2.82 (m, 2H), 2.77 - 2.55 (m, 3H), 2.47 - 2.30 (m, 8H), 2.19 - 2.06 (m, 2H), 2.04 - 1.95 (m. 1H), 1.92 - 1.53 (m, 8H), 1.37 - 1.51 (m, 2H), 1.20 - 1.34 (m, 2H), 1.05 - 1.15 (m, 1H), 0.80 - 0.70 (m, 6H).Example 1.16Exemplary synthesis of Compound 131:Step 1:ci ClPMB(1 R,2R)-N1, N2-dimethylcyclohexane-1,2-diamineCui, Cs2CO3, dioxane, 80°C, 12 hARVN-174-PCT / / ARVN0174WO2

[0158] To a solution of 8-bromo-6-chloro-3-iodoimidazo[l,2-tz]pyridine (20 g, 56 mmol, 1 eq) and 3-(4-methoxybenzyl)dihydropyrimidine-2,4( lH,377)-dione (15.73 g, 67 mmol, 1.2 eq) in dioxane (300 mL) are added cuprous iodide (5.33 g, 28 mmol, 0.5 eq), (1R,2R)-N1 dimethylcyclohexane- 1,2-diamine (2.39 g, 17 mmol, 0.3 eq) and cesium carbonate (54.70 g, 168 mmol, 3 eq), and the reaction mixture is degassed and purged with nitrogen several times, then stirred at 80 °C for 12 h under nitrogen atmosphere. The reaction mixture is filtered and concentrated under reduced pressure, and the residue is purified by column chromatography (petroleum ether:ethyl acetate = 20 / 1 to 1 / 1) to afford l-(8-bromo-6-chloroimidazo[l,2-(z]pyridin-3-yl)-3-(4-methoxybenzyl) dihydropyrimidine-2, 4(1 / 7, 3 / / )-dione (13 g, 50%) as a yellow solid.Step 2:Cphos Pd G3, CS2CO390 °C, 12 h

[0159] To a solution of l-(8-bromo-6-chloro-imidazo[l,2-a]pyridin-3-yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (2 g, 4 mmol, 1 eq), tert-butyl piperazine- 1 -carboxylate (803 mg, 4 mmol, 1 eq) and cesium carbonate (4.22 g, 13 mmol, 3 eq) in dioxane (30 mL) is added 2-methoxy-5-(3-methyl-l,2-oxazol-5-yl)- / V-(2,4,6-trimethylphenyl)benzene-l -sulfonamide (348 mg, 0.4 mmol, 0.1 eq) under nitrogen, and the reaction mixture is stirred at 90 °C for 12 h under nitrogen atmosphere. The mixture is diluted with water (20 mL) and the mixture is extracted with ethyl acetate (10 mL x 3). The combined organic extract is washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (30%-55% acetonitrile in water (TFA) over 20 min to afford tert-butyl 4-[6-chloro-3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-l-yl]imidazo[l,2-a]pyridin-8-yl]piperazine-l -carboxylate (500 mg, 20%) as a yellow solid. LC / MS (ESI) m / z 569.3 [M+H]+. Step 3:ARVN-174-PCT / / ARVN0174WO2

[0160] To a solution of tert-butyl 4-[6-chloro-3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-l-yl]imidazo[l,2-a]pyridin-8-yl]piperazine-l-carboxylate (90 mg, 0.16 mmol, 1 eq) in dichloromethane (2 mL) is added trifluoroacetic acid (1 mL, 85 eq), and the reaction mixture is stirred at 25 °C for 1 h. The mixture is concentrated under reduced pressure to afford l-(6-chloro-8-piperazin-l-yl-imidazo[l,2-a]pyridin-3-yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (90 mg, crude, trifluoroacetate salt) as a yellow oil, which is used in the next step directly. LC / MS (ESI) w / z: 469.2 [M+H]+.Step 4:

[0161] To a solution of l-(6-chloro-8-piperazin-l-yl-imidazo[l,2-a]pyridin-3-yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (160 mg, 0.34 mmol, 1 eq) in dichloromethane (2 mL) and dimethyl sulfoxide (2 mL) are added diisopropylethylamine (0.2 mL, 3 eq) and tert-butyl 4-formylpiperidine- 1 -carboxylate (94.60 mg, 0.4 mmol, 1.3 eq), followed by sodium triacetoxyborohydride (216 mg, 1 mmol, 3 eq), and the reaction mixture is stirred at 25 °C for 12 h. The mixture is diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic extract is washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by preparative TLC (petroleum etherethyl acetate = 1:1) to afford tert-butyl 4-[[4-[6-chloro-3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-l-yl]imidazo[l,2-a]pyridin-8-yl]piperazin-l-yl]methyl]piperidine-l-carboxylate (160 mg, 70%) as a white solid. LC / MS (ESI) mfr. 666.4 [M+H]+.ARVN-174-PCT / / ARVN0174WO2Step 5:TfOH / TFA60 °C, 0.5h

[0162] To a solution of tert-butyl 4-[[4-[6-chloro-3-[3-[(4-methoxyphenyl)methyl]-2,4- dioxo-hexahydropyrimidin- 1 - y 1] imidazo [ 1,2- a] pyridin- 8 - y 1] piper azin- 1 -yl] methyl] piperidine- 1 - carboxylate (160 mg, 0.2 mmol, 1 eq) in trifluoroacetic acid (3 mL) is added trifuoromethanesulfonic acid (0.5 mL, 23.53 eq), and the reaction mixture is stirred at 60 °C for 0.5 h. The mixture is concentrated under reduced pressure, and the residue is purified by prep- HPLC (1%- 10% acetonitrile in water (formic acid) over 10 min) to afford l-[6-chloro-8-[4-(4- piperidylmethyl)piperazin-l-yl]imidazo[l,2-a]pyridin-3-yl]hexahydropyrimidine-2, 4-dione (100 mg, 74%, trifluoroacetate salt) as a white solid. LC / MS (ESI) m / z 446.3 [M+H]+.Step 6:

[0163] To a mixture of l-[6-chloro-8-[4-(4-piperidylmethyl)piperazin-l-yl]imidazo[l,2- a]pyridin-3-yl]hexahydropyrimidine-2, 4-dione (100 mg, 0.18 mmol, 1 eq, trifluoroacetate salt) and [(15)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8- azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro- cyclopropyl] methyl methanesulfonate (128 mg, 0.18 mmol, 1 eq) in N,N-dimethylformamide (2 mL) are added potassium iodide (148 mg, 0.9 mmol, 5 eq) and sodium carbonate (94 mg, 0.9 mmol, 5 eq), and the reaction mixture is stirred at 90 °C for 16 h under nitrogen. The mixture is diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic extract is washed with brine (10 mL x 2), dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (15% -45 %ARVN-174-PCT / / ARVN0174WO2acetonitrile in water (formic acid) over 10 min) to afford 1-[6-chloro-8-[4-[[l-[[(l7?)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]imidazo[l,2-a]pyridin-3-yl]hexahydropyrimidine-2, 4-dione (50 mg, 26%) as a white solid. LC / MS (ESI) m / z 1070.5 [M+H]+;1H NMR (400 MHz, CDCl3) 8 9.25 (d. J = 2.3 Hz, 1H), 7.74 - 7.63 (m, 1H), 7.77 - 7.61 (m. 1H). 7.55 - 7.49 (m, 2H), 7.43 (s, 1H), 7.25 - 7.20 (m, 2H), 6.41 (s, 1H), 5.38 - 5.22 (m, 2H), 4.89 - 4.72 (m, 1H), 4.65 - 4.46 (m, 4H), 4.37 - 4.20 (m, 1H), 3.91 - 3.82 (m, 2H), 3.60 (s, 4H), 3.54 - 3.40 (m, 5H), 3.00 - 2.91 (m, 4H), 2.67 (s, 4H), 2.54 - 2.44 (m, 3H), 2.35 - 2.26 (m, 4H), 2.16 - 2.03 (m, 4H), 1.84 - 1.70 (m, 3H), 1.68 - 1.42 (m, 3H), 1.31 - 1.17 (m, 3H), 0.98 - 0.71 (m, 4H).Step 7:

[0164] To a solution of l-[6-chloro-8-[4-[[l-[[(17?)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]imidazo[l,2-a]pyridin-3-yl]hexahydropyrimidine-2, 4-dione (50 mg, 0.05 mmol, 1 eq) in dichloromethane (1 mL) is added trifluoroacetic acid (0.5 mL, 144 eq), and the reaction mixture is stirred at 25 °C for 20 min. The mixture is diluted with dichloromethane (10 mL), then suspended in water (20 mL), and filtered through diatomite. The filter cake is rinsed with tetrahydrofuran (100 mL), and the filtrate is diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic extract is washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. TheARVN-174-PCT / / ARVN0174WO2residue is purified by prep-HPLC (18%-38% acetonitrile in water (formic acid) over 10 min) to afford Compound 131 (22.9 mg, 43%, trifluoroacetate salt) as a white solid. LC / MS (ESI) m / .1026.6 [M+H]+;NMR (400 MHz, DMSO-J6) 3 10.64 (s, 1H), 9.96 (s. 1H), 9.27 (d, J= 10.5 Hz, 1H), 8.84 - 8.70 (m, 1H), 8.32 - 8.09 (m, 1H), 7.84 - 7.72 (m, 1H), 7.51 (s, 1H), 7.42 - 7.31 (m, 2H), 7.10 - 6.98 (m, 1H), 6.72 - 6.40 (m, 1H), 4.82 - 4.52 (m, 2H), 4.51 - 4.15 (m, 4H), 4.02 - 3.84 (m, 1H), 3.76 (d, J= 6.4 Hz, 2H). 3.67 - 3.47 (m, 4H), 3.45 - 3.33 (m. 2H), 3.24 (s. 3H). 3.18 - 2.95 (m, 2H), 2.94 - 2.72 (m, 3H), 2.71 - 2.60 (m, 1H), 2.54 (s, 3H), 2.45 - 2.28 (m, 4H), 2.25 - 2.04 (m, 4H), 2.03 - 1.77 (m, 5H), 1.76 - 1.58 (m, 2H), 1.53 - 1.37 (m, 1H), 1.28 - 0.92 (m.1H), 0.80 - 0.66 (m, 3H).Example 1.17Exemplary synthesis of Compound 139:Step 1:

[0165] To a solution of 3-[4-chloro-5-[(3 / ?)-3-methyl-4-(4-piperidylmethyl)piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (made in a manner analogous to intermediate 3- [4-chloro-5-[4-[(4-fluoro-4-piperidyl)methyl]-2,2-dimethyl-piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione, 253 mg, 0.5 mmol, 1.1 eq) and [(15)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-ARVN-174-PCT / / ARVN0174WO2d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (350 mg, 0.5 mmol, 1.0 eq) in DMF (5 mL) are added KI (403 mg, 2.4 mmol, 5.0 eq) and Na2C0a (257 mg, 2.4 mmol, 5.0 eq). The reaction mixture is stirred at 90 °C for 16 h. The mixture is then filtered, and the filtrate is diluted with saturated aqueous NH4CI solution (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic extract is washed with brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column (0-4% CH3OH in dichloromethane) to afford 3-[4-chloro-5-[(37?)-4-[[l-[[(17?)-l-[[7-[8-ethyl-7-fhioro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S')-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]-3-methyl-piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (210 mg, 38%) as a white solid. LC / MS (ESI) m / z 549.8 [M / 2+H]+. Step 2:

[0166] To a solution of 3-[4-chloro-5-[(3 / ?)-4-[[l-[[(17?)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]-3-methyl-piperazin- 1-yl]- l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (200 mg, 182 pmol, 1.0 eq) in dichloromethane (6 mL) is added TFA (2 mL), and the reaction mixture is stirred at 20 °C for 1 h. The mixture is diluted with saturated aqueous NaHCO? solution until pH 7, then extracted with dichloromethane (20 mL x 3). The combined organic extract is washed with brine (50 mL),ARVN-174-PCT / / ARVN0174WO2dried over anhydrous Na2SC>4, filtered and concentrated. The residue is purified by prep-HPLC (0%-40% acetonitrile in water (formic acid) over 20 min) to afford Compound 139 (86.2 mg, 43%, formic acid salt) as a white solid. LC / MS (ESI) m / z 1054.4 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 8 10.99 (s, 1H), 9.25 (d, J= 4.8 Hz, 1H), 8.14 (s, 1H), 7.77 (dd, J = 9.2, 6.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.39 - 7.31 (m, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 3.2 Hz, 1H), 5.10 (dd, 7= 13.2. 4.8 Hz, 1H). 4.72 - 4.57 (m, 1H), 4.53 - 4.46 (m. 1H), 4.45 - 4.15 (m. 6H). 3.97 - 3.79 (m, 1H), 3.59 - 3.48 (m, 1H), 3.24 - 3.13 (m, 3H), 2.97 - 2.55 (m, 9H), 2.47 - 2.28 (m, 7H), 2.19 - 2.08 (m, 2H), 2.01 - 1.66 (m, 9H), 1.62 - 1.36 (m, 3H). 1.04 - 0.96 (m, 4H), 0.79 -0.70 (m, 3H).Example 1.18Exemplary synthesis of Compound 142:Step 1:MOMO

[0167] To a solution of [(15)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]- 8-fluoro-4-[(4 )-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (made in a manner analogous to intermediate 3- [4-chloro-5-[4-[(4-fluoro-4-piperidyl)methyl]-2,2-dimethyl-piperazin-l-yl]-l-oxo-isoindolin-2-ARVN-174-PCT / / ARVN0174WO2yl]piperidine-2, 6-dione, 320 mg, 0.4 mmol, 1.0 eq) and 3-[4-chloro-5-[(2S,5 / ?)-2,5-dimethyl-4-(4-piperidylmethyl)piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (425 mg, 0.4 mmol, 1.0 eq, 4 TFA salt) in DMF (5 mL) are added Na2COs (142 mg, 1 mmol, 3.0 eq) and KI (221 mg, 1 mmol, 3.0 eq), and the reaction mixture is stirred at 90 °C for 2 h. The mixture is filtered and washed with ethyl acetate (60 mL). The filtrate is washed with saturated aqueous NH4CI solution (30 mL x 2), water (30 mL x 2) and brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column (0-5% CH3OH in dichloromethane) to afford 3-[4-chloro-5-[(25,57?)-4-[[l-[[(17?)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]-2,5-dimethyl-piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (340 mg, 67%) as a white solid. LC / MS (ESI) m / z 557.0 [M / 2+H]+.Step 2:TFA / CH2CI225°C, 30 min

[0168] To a solution of 3-[4-chloro-5-[(2S,5A)-4-[[l-[[(lA)- L[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl] oxymethyl] -2,2-difluoro-cyclopropyl] methyl] -4-piperidyl] methyl] -2,5 -dimethyl-piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (330 mg, 0.3 mmol, 1.0 eg) in dichloromethane (6 mL) is added TFA (2 mL), and the reaction mixture is stirred at 25 °C for 0.5 h. The mixture is concentrated under reduced pressure, and the residue is diluted with saturated aqueous NaHCCh solution (20 mL) and extracted with 10 / 1 dichloromethane / CFLOH (50 mL). The organic extract is dried over anhydrous NazSCU, filtered and concentrated underARVN-174-PCT / / ARVN0174WO2reduced pressure. The residue is purified by preparative HPLC (0%-40% acetonitrile in water (formic acid) over 20 min) to afford Compound 142 (118.5 mg, 35%, formic acid salt) as a white solid. LC / MS (ESI) m / z: 1068.4 [M+H]+; 'H NMR (400MHz. CD3OD) 89.30 (d, J = 6.8 Hz, 1H), 7.78 - 7.60 (m, 2H), 7.41 -7.39 (m, 1H), 7.33 - 7.20 (m, 2H), 7.09 (s, 1H), 5.21 - 5.10 (m, 1H), 4.84 - 4.71 (m, 2H), 4.69 - 4.35 (m, 7H), 3.81 (t,. / = 13.6 Hz, 1H), 3.51 - 3.37 (m, 3H), 3.36 - 3.33 (m. 1H), 3.20 - 3.07 (m, 2H). 2.99 - 2.75 (m, 5H), 2.61 - 2.42 (m. 7H), 2.39 - 2.28 (m 3H), 2.24 - 2.11 (m, 2H), 2.07 - 1.77 (m, 7H), 1.62 - 1.28 (m, 3H), 1.09 (d, 7 = 4.0 Hz, 3H), 0.91 - 0.89 (m. 3H), 0.82 (dt, J= 2.8, 7.2 Hz, 3H).Example 1.19Exemplary synthesis of Compound 145:Step 1:

[0169] To a solution of 8-bromo-6-methyl-imidazo[l,2-a]pyridine (6.0 g, 28 mmol, 1.0 eq) in DMF (60 mL) is added NIS (6.4 g, 28 mmol. 1.0 eq), and the reaction mixture is stirred at 25 °C for 2 h. The mixture is diluted with ethyl acetate (200 mL), and then washed with saturated Na2SC>3 solution (100 mL), water (50 mL x 2) and brine (50 mL). The organic phase is dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 8-bromo-3-iodo-6-methyLimidazo[l,2-a]pyridine (6.1 g, crude) as a brown solid, which is used in the next step directly. LC / MS (ESI) m / z 336.9 [M+H]+.Step 2:

[0170] To a mixture of 8-bromo-3-iodo-6-methyl-imidazo[l,2-a]pyridine (6.1 g. 18 mmol, 1.0 eq) and 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (4.2 g, 18 mmol, 1.0 eq) in DMF (80 mL) are added rac-(lS,2S)-A^l,2V2-dimethylcyclohexane-l,2-diamineARVN-174-PCT / / ARVN0174WO2(1.0 g, 7 mmol, 0.4 eq), CuT (689 mg, 3.6 mmol, 0.2 eq) and CS2CO3 (11.8 g, 36.21 mmol, 2.0 eq in a glovebox, and the reaction mixture is stirred at 70 °C for 16 h. The mixture is filtered and washed with ethyl acetate (100 mL). The filtrate is diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extract is washed with water (50 mL x 3) and brine (50 mL), dried over NazSCL, filtered and concentrated. The residue is purified by silica gel flash column chromatography (0-60% THF in petroleum ether) to afford l-(8-bromo-6-methyl-imidazo[l,2-a]pyridin-3-yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (2.8 g, 35%) as a yellow solid. LC / MS (ESI) m / z 445.0 [M+H]+; 'H NMR (400 MHz, DMSO-de) 58.12 (s, 1H), 7.64 - 7.54 (m, 2H), 7.26 (d, J = 8.8 Hz, 2H), 6.91 - 6.85 (m, 2H), 4.83 (s, 2H), 3.81 (s, 2H), 3.73 (s, 3H), 3.12 - 2.95 (m, 2H), 2.30 (s, 3H).Step 3;Pd-peppsi-ipent Cl-O-picoline, Cs2CO3, DMF, 100°C, 4h

[0171] To a solution of l-(8-bromo-6-methyl-imidazo[l,2-a]pyridin-3-yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (1.1 g, 2 mmol, 1.0 eq) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (946.8 mg, 3.7 mmol, 1.5 eq) in DMF (15 mL) are added CS2CO3 (2.43 g, 7 mmol, 3.0 eq) and dichloro[l,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(Il) (121 mg, 0.1 mmol, 0.05 eq) in a glovebox, and the reaction mixture is stirred at 100 °C under nitrogen for 4 h. The mixture is then cooled to room temperature and diluted with water (20 mL). The organic layer is separated, and the aqueous layer is extracted with ethyl acetate (30 mL x 3). The combined organic extract is washed with water (15 mL x 3) and brine (30 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column (0-33% THF in petroleum ether) to afford tert-butyl 9-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-l-yl]-6-methyl-imidazo[l,2-a]pyridin-8-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (1 g, 65%) as a gray solid. LC / MS (ESI) m / z 617.9 [M+H]+.Step 4:ARVN-174-PCT / / ARVN0174WO2

[0172] To a solution of / e / 7-butyl 9-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-l-yl]-6-methyl-imidazo[l,2-a]pyridin-8-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.0 g, 1.6 mmol, 1.0 eq) in TFA (6.0 mL) is added TfOH (1.0 mL, 11 mmol, 7 eq), and the reaction mixture is stirred at 70 °C for 5 h. The mixture is concentrated under pressure, and the residue is diluted with dichloromethane (10 mL) and water (10 mL). The pH of the mixture is adjusted to 8 by saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (25 mL x 3). The combined organic extracts are concentrated under reduced pressure, and the residue is triturated with THF (40 mL x 3) to afford 1 - [8-(3,9-diazaspiro[5.5]undecan-3-yl)-6-methyl-imidazo[l,2-a]pyridin-3-yl]hexahydropyrimidine-2,4-dione (642 mg, crude) as a yellow solid. LC / MS (ESI) m / z: 397.1 [M+H]+.Step 5-6:

[0173] The final assembly of Compound 145 is analogous to step 6-7 of Compound 131, isolated as a white solid. LC / MS (ESI) m / z. 977.4 [M+H]+; 'H NMR (400 MHz, DMSO- s) 5 10.61 (s, 1H), 9.25 (s, 1H), 8.14 (s, 1H), 7.77 (dd, J= 6.0, 8.8 Hz, 1H), 7.63 (s, 1H), 7.39 - 7.30 (m, 3H), 7.05 (s, 1H), 6.34 (s, 1H), 4.66 (t, J = 11.6 Hz, 1H), 4.58 - 4.11 (m, 6H), 3.93 - 3.82 (m, 1H), 3.72 (d, J = 5.6 Hz, 2H), 3.52 (d, J= 10.0 Hz, 2H), 3.41 - 3.35 (m, 2H), 2.95 - 2.64 (m, 4H), 2.47 - 2.32 (m, 8H), 2.23 (s. 3H), 2.17 - 2.07 (m, 2H), 1.91 - 1.70 (m, 4H), 1.57 - 1.39 (m, 9H), 0.79 - 0.71 (m. 3H).Example 1.20Exemplary synthesis of Compound 150:Step 1:ARVN-174-PCT / / ARVN0174WO2NaBH(OAc)3, NaOAc, DMSO, 40°C, 16hO

[0174] To a solution of 3-[4-chloro-5-[(25)-2-methylpiperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (2.5 g, 3 mmol, 1.0 eq, 2 HC1) in DMSO (20 mL) are added NaOAc (1.41 g, 17 mmol, 5.0 eq), tert-butyl 4-oxopiperidine-l -carboxylate (755 mg, 3.8 mmol, 1.1 eq) and NaBH(OAc)? (2.19 g, 10 mmol, 3.0 eq), and the reaction mixture is stirred at 40 °C for 16 h. The mixture is suspended in saturated aqueous NaHCCh solution (8 mL) and water (20 mL), then filtered and washed with water (250 mL). The filter cake is dissolved in dichloromethane:methanol (10:1, 70 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 4-[(3S)-4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-yl]piperidine-l-carboxylate (1.45 g, 75%) as a white solid. LC / MS (ESI) m / z 560.1 [M+H]+.Step 2:TFA / CH2CI225°C, 1h

[0175] To a solution of tert-butyl 4-[(35)-4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-yl]piperidine-l-carboxylate (450 mg, 0.8 mmol, 1.0 eq) in dichloromethane (3.0 mL) is added TFA (1.0 mL), and the reaction mixture is stirred at 25°C for 1 h. The mixture is concentrated under reduced pressure, and the residue is diluted with acetonitrile (8.0 mL) and water (8.0 mL), then lyophilized to afford 3-[4-chloro-5-[(2S)-2-methyl-4-(4-piperidyl)piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2,6-dione (580 mg, crude, 2.3 TFA salt) as a white solid. LC / MS (ESI) m / z: 460.0 [M+H]+.Step 3:ARVN-174-PCT / / ARVN0174WO2

[0176] To a solution of 3-[4-chloro-5-[(2S)-2-methyl-4-(4-piperidyl)piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (401 mg, 0.6 mmol, 1.0 eq, 2.3 TFA) and [(1 S)- 1 -[[7-[8-ethyl-7-fhioro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl] methyl methanesulfonate (400 mg, 0.6 mmol, 1.0 eq) in DMF (6.0 mL) are added KI (461 mg, 2.8 mmol, 5.0 eq) and NazCCL (295 mg, 2.8 mmol, 5.0 eq), and the reaction mixture is stirred at 90 °C for 35 minutes. The mixture is diluted with ethyl acetate (50 mL) and filtered. The filtrate is washed with NH4CI (20 mL x 2) and brine (30 mL), dried over NazSCU, filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column (0-3% methanol in dichloromethane) to afford 3-[4-chloro-5-[(2S)-4-[l-[[(17?)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]-2-methyl-piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (250 mg, 41%) as a yellow solid. LC / MS (ESI) mz. 1085.2 [M+H]+.Step 4:ARVN-174-PCT / / ARVN0174WO2Oo

[0177] To a solution of 3-[4-chloro-5-[(25)-4-[l-[[(lR)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]-2-methyl-piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (250 mg, 0.2 mmol, 1.0 eq in dichloromethane (3 mL) is added TFA (1.0 mL), and the reaction mixture is stirred at 25 °C for 40 min. The mixture is diluted with saturated aqueous NaHCCL solution (15 mL) and extracted with dichloromethane (30 mL x 3). The combined organic extract is washed with brine (30 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue is purified by preparative HPLC (4%-44% acetonitrile in water (formic acid) over 25 min) to afford Compound 150 (95.2 mg, 37%, formic acid salt) as a light yellow solid. LC / MS (ESI) m / z: 1040.9 [M+H]+; 'H NMR (400 MHz, CD3OD) 59.28 (d, J= 8.0 Hz, 1H), 7.74 (dd, J = 1.2, 8.0 Hz, 1H), 7.70 - 7.61 (m. 1H), 7.40 (dd. J = 2.4, 8.0 Hz, 1H), 7.33 - 7.28 (m, 1H). 7.27 - 7.18 (m, 1H), 7.12 - 7.00 (m, 1H), 5.21 - 5.09 (m, 1H), 4.80 - 4.34 (m, 8H), 3.84 - 3.66 (m, 1H), 3.58 (s, 1H), 3.51 - 3.36 (m, 1H), 3.29 - 2.98 (m, 6H), 2.97 - 2.69 (m, 5H). 2.68 - 2.38 (m, 6H), 2.37 - 2.25 (m, 2H), 2.24 - 1.88 (m, 7H), 1.88 - 1.59 (m. 4H), 1.50 - 1.35 (m, 1H), 1.02 - 0.87 (m, 3H), 0.86 - 0.69 (m, 3H).Example 1.21Exemplary synthesis of Compound 151:Step 1:

[0178] To a solution of 3-[4-chloro-5-[(25)-2-methylpiperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (made in a manner analogous to intermediate 3-[4-chloro-5-[(2S)-2-methyl-4-[(3R)-pyrrolidin-3-yl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2,6-dione, 955ARVN-174-PCT / / ARVN0174WO2mg, 2 mmol, 1.1 eq, 2 HC1) in DMSO (20 mL) are added NaOAc (788 mg, 9.6 mmol, 5.0 eq), tert-butyl 4-formylpiperidine-l -carboxylate (410 mg, 1.9 mmol, 1.0 eq) and NaBH(OAc)3 (1.02 g, 4.8 mmol, 2.5 eq), and the reaction mixture is stirred at 40 °C for 12 h. The mixture is diluted with saturated aqueous NaHCOs solution (15 mL) and water (50 mL), then filtered. The filter cake is dissolved in dichloromethane (50 mL), dried over NazSCU. filtered and concentrated under reduced pressure to afford tert-butyl 4-[[(35)-4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-yl]methyl]piperidine-l-carboxylate (775 mg, 53%) as a white solid, which is used into next step and need no further purification. LC / MS (ESI) m / z. 596.3 [M+Na]+.Step 6:

[0179] To a solution of tert-butyl 4-[[(3S)-4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-yl]methyl]piperidine-l-carboxylate (775 mg, 1 mmol, 1.0 eq) in dichloromethane (9.0 mL) is added TFA (3.0 mL), and the reaction mixture is stirred at 25 °C for 1 h. The mixture is concentrated under reduced pressure, and the residue is diluted with water (10 mL) and acetonitrile (10 mL), then lyophilized to afford 3-[4-chloro-5-[(2S')-2-methyl-4-(4-piperidylmethyl)piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (1.0 g, 98%, 2 TFA salt) as a white solid, which is used in the next step without further purification. LC / MS (ESI) m / z 474.1 [M+H]+.ARVN-174-PCT / / ARVN0174WO2Step 7:0Na2CO3, KI, DMF, 90°C, 1h

[0180] To a solution of 3-[4-chloro-5-[(2S)-2-methyl-4-(4-piperidylmethyl)piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (612 mg, 0.6 mmol, 1.1 eq, 2 TFA salt) and [(15)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (350 mg, 0.5 mmol, 1.0 eq) in DMF (15 mL) are added Na2CC>3 (154 mg, 1.7 mmol, 3.0 eq) and KI (403 mg, 2.8 mmol, 5.0 eq), and the reaction mixture is stirred at 90 °C for 1 h. The mixture is diluted with ethyl acetate (50 mL) and filtered. The filtrate is washed with saturated NH4CI solution (30 mL x 2), water (20 mL x 2) and brine (30 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography (0-5% methanol in dichloromethane) to afford 3-[4-chloro-5-[(25)-4-[[l-[[(17?)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]-2-methyl-piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (181 mg, 28%) as a yellow foam. LC / MS (ESI) m / z'.550.1 [M / 2+H]+.ARVN-174-PCT / / ARVN0174WO2

[0181] To a solution of 3-[4-chloro-5-[(25')-4-[[l-[[(17?)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]-2-methyl-piperazin- 1-yl]- l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (181 mg, 0.15 mmol, 1.0 eq) in dichloromethane (6.0 mL) is added TFA (2.0 mL), and the reaction mixture is stirred at 25 °C for 1 h. The mixture is diluted with saturated NaHCCh solution (20 mL) and extracted with dichloromethane / methanol (55 mL x 3, V: V = 10:1). The combined organic extract is washed with NaHCCh (20 mL) and brine (30 mL), dried over NazSCU, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC(2%-42% acetonitrile in water (formic acid) over 20.5 min) to afford Compound 151 (79.3 mg, 44%, formic acid salt) as a white solid. LC / MS (ESI) m / z 1054.4 [M+H]+;JH NMR (400 MHz, CD3OD) 39.29 (d, J = 8.0 Hz, 1H), 8.39 (s, 1H), 7.75 - 7.62 (m, 2H), 7.36 (d, J= 8.0 Hz, 1H), 7.31 (s, 1H), 7.28 - 7.21 (m, 1H), 7.09 (d, J= 2.4 Hz, 1H), 5.19 - 5.06 (m, 1H), 4.85 - 4.37 (m, 9H), 3.85 - 3.75 (m, 1H), 3.62 (s, 1H), 3.52 - 3.38 (m. 2H), 3.38 - 3.34 (m, 1H). 3.29 - 3.24 (m, 1H), 3.00 - 2.74 (m, 6H), 2.72 - 2.37 (m, 10H), 2.30 (d, J= 12.8 Hz, 1H), 2.24 - 2.10 (m, 2H), 2.08 - 1.77 (m, 7H), 1.67 - 1.53 (m, 1H), 1.52 - 1.26 (m, 2H), 0.98 - 0.87 (m, 3H), 0.87 - 0.75 (m, 3H).Example 1.22ARVN-174-PCT / / ARVN0174WO2Exemplary synthesis of Compound 154:Step 1:

[0182] To a solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (957 mg, 3.8 mmol, 1.0 eq) and 5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)-4-methoxy-isoindolin-l-one (2.0 g, 3.8 mmol, 1.0 eq) in dioxane (40 mL) are added CS2CO3 (2.45 g, 7.5 mmol, 2.0 eq) and dichloro[l,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (110 mg, 0.1 mmol, 0.03 eq), and the reaction mixture is stirred at 100 °C for 16 h under nitrogen atmosphere. The mixture is filtered and washed with ethyl acetate (70 mL). The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel flash column (0-22% THF in petroleum ether) to afford tert-butyl 9-[2-(2,6-dibenzyloxy-3-pyridyl)-4-methoxy-l-oxo-isoindolin-5-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.6 g, 60%) as a yellow oil. LC / MS (ESI) m / z 705.2 [M+H]+.Step 2:

[0183] To a solution of tert-butyl 9-[2-(2,6-dibenzyloxy-3-pyridyl)-4-methoxy-l-oxo-isoindolin-5-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.6 g, 2 mmol, 1.0 eq) in THF (20 mL) is added 20% palladium hydroxide (0.8 g, 1 mmol) in THF (10 mL) under argon atmosphere, and the resulting suspension is degassed and purged with hydrogen several times, then stirred under hydrogen atmosphere (50 psi) at 50 °C for 16 h. The reaction mixture is filtered and washed with THF (800 mL). The filtrate is concentrated under reduced pressure to afford tert-butyl 9-[2-(2,6-dioxo-3-piperidyl)-4-methoxy-l-oxo-isoindolin-5-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.26 g, crude) as a gray solid, which is used in the next step directly. LC / MS (ESI) m / z: 527.3 [M+H]+.ARVN-174-PCT / / ARVN0174WO2Step 3:

[0184] A mixture of / er / -butyl 9-[2-(2,6-dioxo-3-piperidyl)-4-methoxy-l-oxo-isoindolin-5-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.26 g, 2 mmol, 1.0 eq) in HCl / dioxane (2 M, 30 mL) is stirred at 32 °C for 2 h. The reaction mixture is suspended in petroleum ether (40 mL) and filtered, and the filter cake is dried to afford 3-[5-(3,9-diazaspiro[5.5]undecan-3-yl)-4-methoxy-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (1.53 g, crude, 2 HC1) as a white solid, which is used in the next step directly. LC / MS (ESI) m / :. 427.1 [M+H]+.Step 4:

[0185] To a solution of 3-[5-(3,9-diazaspiro[5.5]undecan-3-yl)-4-methoxy-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (285 mg, 0.5 mmol, 1.0 eq, 2 HC1) in DMF (6 mL) is added Na2CC>3 (257 mg, 2.4 mmol, 5.0 eq), followed by [(lS)-l-[[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-ARVN-174-PCT / / ARVN0174WO2d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (350 mg, 0.5 mmol, 1.0 eq) and KI (403 mg, 2.4 mmol, 5.0 eq), and the reaction mixture is stirred at 90 °C for 16 h. The mixture is filtered and washed with ethyl acetate (30 mL). The filtrate solution is diluted with saturated aqueous NH4CI solution (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic extract is washed with water (40 mL x 4) and brine (40 mL), dried over Na2SO4. filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column (0-4% methanol in dichloromethane) to afford 3-[5-[9-[[(lS)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S')-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-3,9-diazaspiro[5.5]undecan-3-yl]-4-methoxy-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (310 mg, 61%) as a yellow solid. LC / MS (ESI) m / z 526.5 [M / 2+H]+.

[0186] To a solution of 3-[5-[9-[[(lS)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-3,9-diazaspiro[5.5]undecan-3-yl]-4-methoxy-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (300 mg, 0.3 mmol, 1.0 eq) in dichloromethane (18 mL) is added TFA (6 mL), and the reaction mixture is stirred at 25 °C for 40 minutes. TheARVN-174-PCT / / ARVN0174WO2mixture is diluted with saturated aqueous NaHCCh solution (30 mL) and extracted with 10 / 1 dichloromethane / CHsOH (20 mL x 3). The combined organic extract is washed with water (30 mL x 2) and brine (40 mL), dried over NazSCL, filtered and concentrated under reduced pressure The residue is purified by prep-HPLC (8%-48% acetonitrile in water (formic acid) over 20.5 min) to afford Compound 154 (133.7 mg, 44%, formic acid salt) as a white solid. LC / MS (ESI) m / z'. 1007.5 [M+H]+;NMR (400 MHz. DMSO-rfd) 8 10.96 (s, 1H), 9.24 (s, 1H), 7.83 - 7.72 (m, 1H), 7.39 - 7.30 (m, 3H), 7.12 - 6.98 (m, 2H), 5.11 - 4.99 (m, 1H), 4.67 (t, J= 12.4 Hz, 1H), 4.59 - 4.02 (m, 8H), 3.90 - 3.96 (m, 1H), 3.83 (s, 3H), 3.43 - 3.31 (m, 4H), 2.97 - 3.08 (m. 4H), 2.94 - 2.86 (m, 1H), 2.73 (t, J= 13.6 Hz, 1H), 2.54 - 2.62 (m, 1H), 2.45 - 2.31 (m, 8H), 2.18 - 2.06 (m, 2H), 2.00 - 1.77 (m, 4H), 1.76 - 1.67 (m, 1H), 1.48 - 1.55 (m, 4H), 1.40 - 1.43 (m, 2H), 0.84 - 0.64 (m, 3H).Example 1.23Exemplary synthesis of Compound 161:Step 1:

[0187] To a solution of [(lS)-l-[[7-[8-ethyL7-fhroro-3-(methoxymethoxy)-l-naphthyl]- 8-fluoro-4-[(4 )-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2- difluoro-cyclopropyl] methyl methanesulfonate (1.5 g, 2 mmol, 1.0 eq and 3-[4-chloro-5-(3,9- diazaspiro[5.5]undecan-3-yl)-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (made in a mannerARVN-174-PCT / / ARVN0174WO2analogous to intermediate 3-[4-chloro-5-[(25')-2-methyl-4-[(3 / ?)-pyrrolidin-3-yl]piperazin-l-yl]- l-oxo-isoindolin-2-yl]piperidine-2, 6-dione, 1.26 g, 2.5 mmol, 1.2 eq, 2 HC1) in DMA (30 mL) are added NazCCh (662 mg, 6 mmol. 3.0 eq) and KI (1.73 g, 10 mmol, 5.0 eq), and the reaction mixture is stirred at 90°C under nitrogen atmosphere for 16 h. The mixture is diluted with ethyl acetate (50 mL) and filtered. The filtrate is washed with saturated aqueous NH4CI solution (30 mL x 2), water (30 mL x 2), brine (20 mL), then dried over Na2SC>4. filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography (0-3% methanol in dichloromethane) to afford 3-[4-chloro-5-[9-[[(lA)-l-[[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3- d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-3,9-diazaspiro[5.5]undecan-3- yl]-l-oxo-isoindolin-2-yl]piperidine-2,6-dione (1.8 g. 89% purity, 73%) as light yellow solid. LC / MS (ESI) m / z 1055.3 [M+H]+.TFA / CH2CI2, 20°C, 50 min

[0188] To a solution of 3-[4-chloro-5-[9-[[(lA)-l-[[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3- d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-3,9-diazaspiro[5.5]undecan-3- yl]-l-oxo-isoindolin-2-yl]piperidine-2,6-dione (1.8 g, 1.7 mmol. 1.0 eq) in dichloromethane (54 mL) is added TFA (18 mL), and the reaction mixture is stirred at 20 °C for 50 minutes. The mixture is diluted slowly with saturated aqueous NaHCCh solution to reach pH 8 followed byARVN-174-PCT / / ARVN0174WO2dichloromethane (30 mL). The resulting mixture is extracted with 10 / 1 dichloromethane / CHsOH (33 mL x 3), and the combined organic extracts are washed with brine (30 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography (0-3% methanol in dichloromethane). The crude product is further purified by prep-HPLC (18-58% acetonitrile in water (formic acid) over 20 min) to afford Compound 161 (1251.6 mg, 2 batches combined, 29%, formic acid salt) as white solid. LC / MS (ESI) m / z 1011.4 [M+H]+; 'H NMR (400 MHz, CD3OD) 8: 9.29 (d, 7 = 10.8 Hz, 1H), 8.39 (s, 1H), 7.72 - 7.64 (m, 2H), 7.31 (d, J= 2.8 Hz, 1H), 7.29 - 7.22 (m, 2H), 7.08 (d, J= 2.4 Hz, 1H), 5.13 (dd, 7 = 5.2, 13.2 Hz, 1H), 4.85 - 4.37 (m, 9H), 3.82 (t, J= 13.2 Hz, 1H), 3.53 - 3.38 (m, 1H), 3.29 - 3.18 (m, 1H), 3.16 - 3.06 (m, 4H), 3.01 - 2.73 (m, 7H), 2.58 - 2.43 (m, 4H), 2.35 -2.27 (m, 1H), 2.25 - 2.12 (m, 2H), 2.10 - 1.91 (m. 2H), 1.86 - 1.77 (m, 2H). 1.75 - 1.66 (m, 7H), 1.62 - 1.52 (m, 1H), 0.82 (dt, J = 3.2, 7.2 Hz, 3H).Example 1.24Exemplary synthesis of Compound 163:o Na2CO3, KI, DMF, 90°C, 16h

[0189] A solution of 3-[3-methyl-2-oxo-4-[4-(4-piperidylmethyl)piperazin-l-yl]benzimidazol-l-yl]piperidine-2, 6-dione (made in a manner analogous to intermediate 3-[4-[4-[(4-fluoro-4-piperidyl)methyl]piperazin-l-yl]-3-methyl-2-oxo-benzimidazol-l-yl]piperidine-2,6-dione (297 mg, 2 HC1, 0.4 mmol, 1.0 eq) and Na2CO3(132 mg, 1.2 mmol, 3.0 eq) in DMF (9.0ARVN-174-PCT / / ARVN0174WO2mL) is stirred for 5 minutes at 90 °C. [(lS)-l-[[7-[8-Ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (300 mg, 0.4 mmol, 1.0 eq) and KI (345 mg, 2 mmol, 5.0 eq) are then added, and the reaction mixture is stirred at 90 °C for 16 h under nitrogen atmosphere. The mixture is cooled to room temperature, diluted with ethyl acetate (80 mL) and filtered. The filtrate is washed with water (15 mL x 4), brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography (0-3% methanol in dichloromethane) to afford 3-[4-[4-[[l-[[(l )-l-[[7-[8-ethyl-7-fhroro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]-3-methyl-2-oxo-benzimidazol-l-yl]piperidine-2, 6-dione (230 mg, 47%) as a yellow solid. LC / MS (ESI) in / -;.1065.4 [M+H]+.Step 2:

[0190] To a solution of 3-[4-[4-[[l-[[(17?)-l-[[7-[8-ethyl-7-fhioro-3-(methoxymethoxy)- l-naphthyl]-8-fluoro-4-[(4. S')-l-oxa-8-azaspiro[3.5]nonari-8-yl]pyrido[4,3-d]pyrimidiri-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]-3-methyl-2-oxo-benzimidazol-l-yl]piperidine-2, 6-dione (220 mg, 0.2 mmol, 1.0 eq) in dichloromethane (6.0 mL) is added TFA (3.0 mL), and the reaction mixture is stirred at 25 °C for 0.5 h. The mixture is diluted with saturated aqueous NaHCCh solution until pH 8-9. and extracted with 10 / 2 dichloromethane / CHsOH (30 mL x 3). The combined organic extract is washed with brine (15ARVN-174-PCT / / ARVN0174WO2mL x2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (0%-40% acetonitrile in water (formic acid) over 25 min) to afford Compound 163 (78 mg, 34%, 2 formic acid salt). LC / MS (ESI) m / z 1021.5 [M+H]+; 'H NMR (400 MHz, CD3OD) 89.29 (d, J= 8.8 Hz, 1H), 7.68 - 7.65 (m, 1H), 7.33 - 7.20 (m, 2H), 7.12 - 6.90 (m, 4H), 5.34 - 5.31 (m, 1H), 4.83 - 4.72 (m, 2H). 4.71 - 4.41 (m, 5H), 3.81 (t, J = 13.2 Hz, 1H), 3.73 (s. 3H), 3.53 - 3.38 (m, 2H). 3.22 - 3.01 (m, 6H), 2.99 - 2.39 (m. 14H), 2.31 (d, 7- 13.2 Hz, 1H), 2.26 - 2.11 (m, 2H), 2.09 - 1.77 (m, 7H), 1.61 - 1.55 (m, 1H), 1.54 - 1.34 (m, 2H), 0.84 - 0.79 (m, 3H).Example 1.25Exemplary synthesis of Compound 169:

[0191] Compound 169 is prepared in a manner analogous to Compound 151, obtained as a white solid. LC / MS (ESI) m / z: 1040.4 [M+H]+;NMR (400 MHz, DMSO-( / 6) 8 10.98 (s, 1H), 9.94 (s, 1H), 9.25 (d. J= 4.0 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.64 (d. J= 8.0 Hz, 1H), 7.39 -7.31 (m, 2H), 7.25 (d, 7= 8.4 Hz, 1H), 7.05 (t, 7= 2.8 Hz, 1H), 5.14 - 5.05 (m, 1H), 4.71 - 4.58 (m, 1H), 4.54 - 4.18 (m, 7H), 3.97 - 3.79 (m, 1H), 3.59 - 3.33 (m, 2H), 3.06 (s, 4H), 2.96 - 2.85 (m, 1H), 2.84 - 2.74 (m, 2H), 2.73 - 2.52 (m, 3H), 2.48 - 2.29 (m, 7H), 2.18 - 2.07 (m, 4H), 2.03 -1.93 (m, 2H), 1.92 - 1.78 (m, 4H), 1.76 - 1.69 (m, 1H), 1.68 - 1.56 (m, 2H), 1.40 - 1.53 (m, 2H), 1.08 - 0.86 (m, 2H), 0.80 - 0.70 (m, 3H).Example 1.26Exemplary synthesis of Compound 124:Step 1:Cs2CO3, DMA, 25°C, 1hARVN-174-PCT / / ARVN0174WO2

[0192] To a solution of (4S)-8-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5]nonane (1.5 g, 4.37 mmol, 1.0 eq) and [2,2-difluoro-l-(hydroxymethyl)cyclopropyl]methanol (1.2 g, 8.74 mmol, 2.0 eq) in DMA (30 mL) is added CS2CO3 (4.3 g, 13 mmol, 3.0 eq), and the reaction mixture is stirred at 25 °C for 1 h. The mixture is diluted with ethyl acetate (30 mL x 3) and filtered. The filtrate is washed with water (30 mL x 4) and brine (50 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. Purification by silica gel flash column chromatography (0-25% tetrahydrofuran in petroleum ether) afforded [l-[[7-chloro-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (960 mg, 64 %) as a yellow solid. LC / MS (ESI) m / z: 445.1 [M+H]+.Step 2:

[0193] To a solution of [l-[[7-chloro-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (1.2 g, 2.7 mmol, 1.0 eq) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-naphthyl]ethynyl-triisopropyl-silane (1.38 g, 2.7 mmol, 1.0 eq) in dioxane (20 mL) and H2O (4 mL) are added cataCXium A Pd G3 (196.5 mg, 270 pmol, 0.1 eq) and K3PO4 (1.72 g, 8 mmol, 3.0 eq), and the reaction mixture is stirred at 90 °C for 12 h under nitrogen atmosphere. The mixture is filtered, and the filtrate is concentrated under reduced pressure. The resulting material is diluted with water (40 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extract is washed with brine (50 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel flash column (0-100% ethyl acetate in petroleum ether) to afford to afford[2,2-difluoro-l-[[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (1.3 g, 60%) as a yellow solid. LC / MS (ESI) m / z 795.1 [M+H]+.ARVN-174-PCT / / ARVN0174WO2Step 3:

[0194] [2,2-Difluoro-l-[[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-l-naphthyl]-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3- d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (1.3 g) is purified by SFC (30% i-PrOH (0.1%NH3H2O) in CO2). The first eluted fraction is assigned as [(17?)-2,2-difluoro-l-[[8-fluoro- 7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]-4-[(45)-l-oxa-8- azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (0.72 g, 54%) as a light yellow solid. LC / MS (ESI) m / z 795.1 [M+H]+. The second eluted fraction is assigned as [(15 2,2-difluoro-l-[[8-fhioro-7-[7-fhioro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3- d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (0.68 g, 50%) as a light yellow solid. LC / MS (ESI) m / z: 795.1 [M+H]+.

[0195] To a solution of [(l / ?)-2,2-difluoro-l-[[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)- 8-(2-triisopropylsilylethynyl)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-ARVN-174-PCT / / ARVN0174WO2d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (0.7 g, 0.9 mmol, 1.0 eq) in dichloromethane (10 mL) at 0 °C are added triethylamine (368 pL, 3.0 eq) and methylsulfonyl methanesulfonate (199.41 mg, 1 mmol, 1.3 eq), and the reaction mixture is stirred at 20 °C for 1 h under nitrogen atmosphere. The mixture is diluted with water (40 mL) at 25 °C for 5 minutes, then extracted with dichloromethane (30 mL x 3). The combined organic extract is washed with brine (40 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to afford [(15)-2.2-difluoro- l-[[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]-4-[(4S)- l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl methanesulfonate (0.77 g, 91%) as a yellow solid. LC / MS (ESI) m / z: 873.4 [M+H]+.Step 5:

[0196] To a solution of [(LS')-2.2-difliioro-l-[[8-fliioro-7-[7-flLioro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl methanesulfonate (0.76 g, 870.52 pmol, 1.0 eq) and 3-[4-chloro-l-oxo-5-[4-(4-piperidylmethyl)piperazin-l-yl]isoindolin-2-yl]piperidine-2,6-dione (495.63 mg, 870.52 pmol, 1.0 eq, 3 HC1) in DMF (30 mL) are added KI (722.54 mg, 4 mmol, 5.0 eq) and Na2COs (922.66 mg, 8.71 mmol, 10.0 eq), and the reaction mixture is stirred at 90 °C for 16 h. The mixture is filtered, then diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts are washed with brine (50 mL x 4), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-10% methanol in dichloromethane ether) to afford 3-[4-chloro-5-ARVN-174-PCT / / ARVN0174WO2[4-[[1-[[(l / ?)-2,2-difluoro-l-[[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]piperazin- 1-yl]- 1-oxo-isoindolin-2-yl]piperidine-2, 6-dione (0.7 g, 58%, 89% purity) as a yellow solid. LC / MS (ESI) m / z 619.1 [M / 2+H]+.Step 6:

[0197] To a solution of 3-[4-chloro-5-[4-[[l-[[(l / ?)-2,2-difluoro-l-[[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (0.7 g, 565.93 pmol, 1.0 eq) in THF (10 mL) is added TBAF (1 M, 1.70 mL, 3.0 eq), and the reaction mixture is stirred at 20 °C for 1 h. The mixture is filtered, and water (30 mL) is added. The resulting mixture is extracted with EtOAc (40 mL x 3), and the combined organic extracts are washed with brine (40 mL x 4), dried over Na2SC>4, filtered and concentrated under reduced pressure to afford 3-[4-chloro-5-[4-[[l-[[(17?)-l-[[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (600 mg, 68%. 69% purity) as a yellow solid. LC / MS (ESI) m / z. 541.0 [M / 2+1]+.Step 7:ARVN-174-PCT / / ARVN0174WO2

[0198] To a solution of 3-[4-chloro-5-[4-[[l-[[(17?)-l-[[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(45')-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (0.6 g, 555.27 pmol, 1.0 eq) in dichloromethane (12 mL) is added TFA (6.14 g, 53.85 mmol. 4 mL, 97.0 eq), and the reaction mixture is stirred at 25 °C for 0.5 h. The mixture is diluted with saturated aqueous NaHCCL (60 mL), then extracted with 10 / 1 dichloromethane / CEhOH (30 mL x 3). The combined organic extract is washed with brine (40 mL), dried over NarSCL. filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-10% CH3OH in dichloromethane) followed by prep-HPLC (0%-34% acetonitrile in water (formic acid) over 20 min) to afford Compound 124 (160 mg, 28%) as a yellow solid. LC / MS (ESI) m / z 1036.3 [M+H]+; ‘H NMR (400 MHz, DMSO-rfc) 8: 10.99 (s, 1H), 10.66 - 9.52 (m, 1H), 9.25 - 9.07 (m, 1H), 8.15 (s, 1H), 8.02 - 7.92 (m, 1H), 7.65 (d. 7= 8.1 Hz, 1H), 7.47 (t, 7= 9.0 Hz, 1H), 7.41 (d, 7= 2.0 Hz, 1H), 7.31 - 7.18 (m, 2H), 5.18 - 5.03 (m, 1H), 4.67 - 4.55 (m, 1H), 4.51 - 4.35 (m, 5H), 4.34 - 4.11 (m, 3H), 4.02 (s, 1H), 3.94 - 3.80 (m, 2H), 3.07 (br s, 4H), 2.96 - 2.79 (m, 4H), 2.70 (br d, 7 = 12.1 Hz, 1H), 2.59 (br d, 7= 17.1 Hz, 1H), 2.48 - 2.32 (m, 5H), 2.20 - 2.10 (m, 3H). 2.05 - 1.72 (m, 8H), 1.66 (br s, 2H), 1.50 (br s, 2H), 1.12 - 0.98 (m, 2H).Example 1.27Exemplary synthesis of Compound 87:Compound 87 is prepared in a manner analogous to Compound 81, isolated as a white solid.ARVN-174-PCT / / ARVN0174WO2

[0199] LC / MS (ESI) m / z 1011.4 [M+H]+; 'HNMR (400 MHz, DMSO-7s) / ) 10.99 (s, 1H), 10.15 - 9.85 (m, 1H), 9.31 (d, J = 5.6 Hz, 1H), 7.76 (dd, J= 6.0, 9.2 Hz, 1H), 7.45 (d, 7 = 8.0 Hz, 1H), 7.37 - 7.28 (m. 2H), 7.15 (t, 7 = 8.0 Hz, 1H), 6.98 - 6.92 (m. 1H), 5.07 (dd. 7 = 4.8, 13.2 Hz, 1H), 4.85 - 4.68 (m, 1H), 4.55 - 4.35 (m, 4H), 4.34 - 4.10 (m, 3H), 4.00 - 3.81 (m, 1H), 3.63 - 3.49 (m, 1H), 3.06 ( s, 4H), 2.96 - 2.83 (m, 1H), 2.72 ( d, 7= 9.2 Hz, 1H), 2.60 ( d, 7= 3.2 Hz, 1H), 2.45 - 2.32 (m. 7H). 2.21 ( d. 7= 6.8 Hz, 3H). 2.00 - 1.93 (m, 1H), 1.91 - 1.77 (m. 3H), 1.77 - 1.66 (m, 1H), 1.50 ( s, 5H), 1.44 - 1.20 (m, 5H), 0.77 (m, 7- 4.8, 7.2 Hz, 3H).Example 1.28Exemplary synthesis of Compound 96:Step 1:

[0200] To a solution of 2,4,7, 8-tetrachloropyrido[4,3-d]pyrimidine (6.8 g, 25 mmol, 1 eq) in dichloromethane (100 mL) are added N-ethyl- / V-propan-2-ylpropan-2-amine (16.34 g, 126 mmol, 22.02 mL, 5 eq) and l-oxa-8-azaspiro[3.5]nonane oxalic acid (3.05 g, 8.9 mmol, 0.35 eq), and the reaction mixture is stirred at -60 °C for 0.5 h. The mixture is diluted with water (100 mL) and extracted with dichloromethane (100 mL). The combined organic extracts are washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to afford 8-(2,7,8-trichloropyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5]nonane (9 g, 99%) as a yellow solid. LC / MS (ESI) m / z 361.0 [M+H]+.ARVN-174-PCT / / ARVN0174WO2

[0201] 8-(2,7,8-trichloropyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5]nonane (8.97 g) is purified by chiraLSFC (42% isopropyl alcohol in CO2). The first eluted fraction is assigned as (4R)-8-(2,7,8-trichloropyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5]nonane (4.4 g, 99%) as a yellow solid. The second eluted fraction as assigned as (4S)-8-(2,7,8-trichloropyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5]nonane (4.4 g, 99%) as a yellow solid.Step 2:

[0202] To a solution of (4S)-8-(2,7,8-trichloropyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5] nonane (4.33 g, 12 mmol, 1 eq) and [2,2-difluoro-l- (hydroxymethyl)cyclopropyl]methanol (3.33 g, 24 mmol, 2 eq) in 2V,iV-dimethylacetamide (80 mL) is added cesium carbonate (11.77 g, 36 mmol, 3 eq), and the reaction mixture is stirred at 25 °C for 1 h. The mixture is diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic extract is washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by prep-HPLC (31%-61% acetonitrile in water (formic acid) over 20 min) to afford [l-[[7,8-dichloro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl] methanol (3.19 g, 56%) as an off-white solid. LC / MS (ESI) m / z'. 461.1 [M+H]+; ’H NMR (400 MHz, DMSO-rfc) d 9.11 (d,.7= 1.2 Hz, 1H), 5.09 (t,. / = 5.6 Hz, 1H), 4.63 ( d,. / = 11.6 Hz, 1H), 4.45 ( d, J = 12.0 Hz, 1H), 4.41 - 4.32 (m, 3H), 4.17 ( d, J = 13.6 Hz, 1H), 3.83 (dd. J = 6.0, 13.2 Hz, 1H), 3.65 - 3.53 (m, 2H), 3.46 - 3.37 (m. 1H), 2.46 - 2.38 (m, 1H), 2.36 -2.29 (m, 1H), 2.07 (s, 1H), 1.84 ( d, J= 9.6 Hz, 2H), 1.77 - 1.64 (m, 2H), 1.60 - 1.51 (m, 1H).Step 3:ARVN-174-PCT / / ARVN0174WO2

[0203] A mixture of [l-[[7,8-dichloro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d] pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (2 g, 4 mmol, 1 eq), 2- [ 8 - ethyl -7 -fluoro-3 -(methoxymethoxy)- 1 -naphthyl] -4,4,5,5 -tetramethyl- 1,3,2-dioxaborolane (2.34 g, 6.5 mmol. 1.5 eq), potassium phosphate (1.5 M, 8.7 mL, 3 eq and cataCXium A Pd G3 (315 mg, 0.4 mmol, 0.1 eq) in dioxane (20 mL) is degassed and purged with nitrogen several times, then stirred at 80 °C for 12 h under nitrogen atmosphere. The mixture is cooled to 25 °C, diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic extract is washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by prep-HPLC (50%-70% acetonitrile in water (formic acid) over 20 min) to afford [l-[[8-chloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (857 mg, 30%) as a yellow solid. LC / MS (ESI) m / z 659.2 [M+H]+.

[0204] To a solution of [l-[[8-chloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-4-[(4S’)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (907 mg, 1.4 mmol, 1 eq) and trimethylamine (0.6 mL, 3 eq) in dichloromethane (10 mL) at 0 °C is added methanesulfonyl chloride (540 mg, 4.7 mmol, 0.4 mL,ARVN-174-PCT / / ARVN0174WO23.4 eq), and the reaction mixture is stirred at 25 °C for 1 h. The mixture is diluted with water (30 mL) and extracted with dichloromethane (30 mL x 2). The combined extracta are washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford [l-[[8-chloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl] methyl methanesulfonate (1.0 g, crude) as a yellow solid, which is used in the next step directly. LC / MS (ESI) m / z. 737.2 [M+H]+Step 5:

[0205] To a solution of 3-[5-(3,9-diazaspiro[5.5]undecan-3-yl)-4-methoxy-l-oxo-isoindolin-2-yl] piperidine-2, 6-dione (174 mg, 0.4 mmol, 1.5 eq) in N,N-dimethylformamide (5 mL) are added sodium carbonate (144 mg, 1.3 mmol. 5 eq), [l-[[8-chloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (200 mg, 0.27 mmol, 1 eq) and potassium iodide (225 mg, 1.4 mmol, 5 eq), and the reaction mixture is stirred at 90 °C for 3.5 h. The mixture is diluted with water (50 mL) and extracted with dichloromethane (40 mL x 2). The combined organic extract is washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-TLC (dichloromethane:methanol = 10:1) to afford 3-[5-[9-[[l-[[8-chloro-7-[8-ethyl-7-fluoro-3-ARVN-174-PCT / / ARVN0174WO2(methoxymethoxy)-l-naphthyl]-4-[(41S’)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-3,9-diazaspiro[5.5]undecan-3-yl]-4-methoxy-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (241 mg, 83%) as a white solid.LC / MS (ESI) m / z 1067.4 [M+H]+.Step 6:

[0206] To a solution of 3-[5-[9-[[l-[[8-chloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)- 1-naphthyl] -4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-3,9-diazaspiro[5.5]undecan-3-yl]-4-methoxy-l-oxo-isoindolin- 2-yl]piperidine-2, 6-dione (241 mg, 0.23 mmol, 1 eq) in dichloromethane (2 mL) is added trifluoroacetic acid (2 mL), and the reaction mixture is stirred at 25 °C for 0.5 h. The mixture is diluted with saturated sodium bicarbonate solution until pH 8, stirred for 2 minutes, and extracted with dichloromethane (10 mL x 2). The combined organic extract is washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (25%-55% acetonitrile in water (formic acid) over 15 min) to afford Compound 96 (69.5 mg, 28%, formic acid salt) as an off-white solid. LC / MS (ESI) m / z 1023.4 [M+H]+; 'H NMR (400 MHz, DMSO-rfc) 3 10.97 (s, 1H), 10.07 - 9.77 (m, 1H), 9.31 (d, J= 5.6 Hz, 1H), 8.16 (s, 1H), 7.76 (dd, J = 6.0, 9.2 Hz, 1H), 7.39 - 7.28 (m, 3H), 7.07 (d. J= 8.0 Hz, 1H). 6.96 (dd, J= 2.4. 6.4 Hz. 1H). 5.05 (dd, J= 5.2, 13.2 Hz, 1H), 4.84 - 4.66 (m, 1H), 4.47 ( d, J = 15.6 Hz, 2H), 4.43 - 4.35 (m, 2H), 4.34 - 4.25 (m, 2H), 4.24 - 4.09ARVN-174-PCT / / ARVN0174WO2(m, 1H), 4.02 - 3.86 (m, 1H), 3.84 (s, 3H), 3.54 ( dd, J= 3.6, 8.4 Hz, 1H), 3.11 - 2.97 (m, 4H), 2.95 - 2.83 (m, 1H), 2.80 - 2.65 (m, 1H), 2.58 ( d, J= 16.4 Hz, 1H), 2.46 - 2.27 (m, 8H). 2.22 ( d, 7= 7.0 Hz, 2H), 2.15 - 2.03 (m, 1H). 2.01 - 1.77 (m, 4H), 1.76 - 1.66 (m, 1H), 1.52 ( s, 5H), 1.40 ( s, 4H), 0.83 - 0.72 (m, 3H).Example 1.29Exemplary synthesis of Compound 105:

[0207] Compound 105 is prepared in a manner analogous to Compound 90, isolated as a white solid (formic acid salt). LC / MS (ESI) m / z: 1070.6 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 5 10.99 (s, 1H), 9.37 - 9.24 (m, 1H), 8.29 - 8.19 (m, 1H), 7.81 - 7.72 (m, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.39 - 7.26 (m. 3H), 7.03 - 6.92 (m, 1H). 5.14 - 5.04 (m, 1H), 4.85 (d. J = 6.8 Hz, 1H), 4.58 - 4.36 (m, 4H), 4.34 - 4.26 (m, 2H), 4.25 - 4.11 (m, 1H), 4.00 - 3.80 (m, 1H), 3.63 - 3.48 (m, 3H), 2.97 - 2.82 (m, 2H), 2.80 - 2.65 (m, 4H), 2.63 - 2.53 (m, 3H). 2.45 - 2.36 (m, 4H), 2.35 -2.28 (m, 1H), 2.26 - 2.16 (m, 3H), 2.15 - 2.04 (m. 3H), 2.02 - 1.92 (m, 2H), 1.91 - 1.77 (m, 4H), 1.76 - 1.68 (m, 1H), 1.67 - 1.56 (m, 2H), 1.53 - 1.38 (m, 2H), 1.06 - 0.90 (m, 2H), 0.87 (d, J = 5.8 Hz, 3H), 0.80 - 0.72 (m, 3H).Example 1.31Exemplary synthesis of Compound 176Step 1:

[0208] To a solution of l,2,3-trifhroro-5-nitro-benzene (20 g, 113 mmol) in N, N-dimethylformamide (300 mL) are added diisopropylethylamine (39.3 mL, 226 mmol) and tertbutyl (3S)-3-(hydroxymethyl)piperazine-l-carboxylate (29.3 g, 135 mmol), and the reaction mixture is stirred at 80 °C for 12 h. The mixture is concentrated under reduced pressure, and the residue is diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). TheARVN-174-PCT / / ARVN0174WO2combined organic extracts are washed with brine (200 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (l%-4% ethanol (0.1% ammonium hydroxide) in heptane over 13 min) to afford tert-butyl (3S)-4-(2,6-difluoro-4-nitro-phenyl)-3-(hydroxymethyl)piperazine-l-carboxylate (20.4 g, 48%) as a yellow solid. LC / MS (ESI) m / z = 274.3 [M-C5H8O2+H]+; 'H NMR (400 MHz, DMSO-t / 6) 88.00 - 7.94 (m, 2H), 4.78 - 4.62 (m. 1H). 3.83 (d, J = 12.8 Hz, 2H), 3.55 - 3.45 (m, 4H), 3.28 - 3.19 (m. 1H).3.11 (d, J = 12.4 Hz, 1H), 3.08 - 2.91 (m, 1H), 1.41 (s, 9H).Step 2:

[0209] To a solution of tert-butyl (3S)-4-(2,6-difluoro-4-nitro-phenyl)-3- (hydroxymethyl)piperazine-l -carboxylate (12 g, 32 mmol) in / V,7V-dimethylformamide (150 mL) is added cesium carbonate (12.6 g, 39 mmol), and the reaction mixture is stirred at 100 °C for 12 h. The mixture is filtered, and the filter cake is washed with ethyl acetate (3 x 100 mL). The filtrate is concentrated under reduced pressure to afford tert-butyl (4aS)-10-fluoro-8-nitro-2,4,4a,5-tetrahydro-lH-pyrazino[2,l-c][l,4]benzoxazine-3-carboxylate (11.3 g, crude) as a yellow solid, which is used in the next step without further purification. LC / MS (ESI) m / z 254.3 [M-C5H8O2+H]+; NMR (400 MHz. CDC13) 87.69 - 7.46 (m, 2H), 4.33 - 4.18 (m. 2H). 4.13 -3.92 (m, 3H), 3.45 - 3.32 (m, 1H), 3.08 (d, J= 9.2 Hz, 2H), 2.94 - 2.82 (m, 1H), 1.49 (s, 9H).Step 3:NO2O NH21%Pt / C, H2(1.5 MPa) N THF / MeOH, 50°C, 2 h.. J BocBoc

[0210] A solution of tert-butyl (4aS)-10-fluoro-8-nitro-2,4,4a,5-tetrahydro-lH-pyrazino[2,l-c][l,4]benzoxazine-3-carboxylate (15 g, 42 mmol) in tetrahydrofuran (200 mL) and methanol (100 mL) is pumped to a fixed bed (FLR1, 30 mL volume, packed with granular catalyst 1% platinum on carbon (15 g), 1.5 mpa hydrogen back pressure regulator, 20 mL / minARVN-174-PCT / / ARVN0174WO2hydrogen flow rate) at 50 °C for 2 h. The reaction mixture is collected and concentrated under reduced pressure to afford tert-butyl (4aS)-8-amino-10-fluoro-2,4,4a,5-tetrahydro-lH-pyrazino[2,l-c][l,4]benzoxazine-3-carboxylate (13.7 g, crude) as a brown solid. Which is used in the next step without further purification. LC / MS (ESI) m / z = 323.3 [M+H]+;1H NMR (400 MHz, CDCh) 86.16 - 5.97 (m, 2H), 4.15 - 4.00 (m. 2H), 3.76 - 3.59 (m, 2H), 3.58 - 3.46 (m, 2H), 3.39 - 3.26 (m, 1H), 3.20 - 3.07 (m. 1H). 3.05 - 2.95 (m, 1H), 1.54 - 1.42 (m, 9H).Step 4:

[0211] To a mixture of dibromocopper (2.1 mL, 45 mmol) and te -butyl nitrite (13.3 mL, 112 mmol) in acetonitrile (140 mL) at 0 °C is added a solution of tert-butyl (4aS)-8-amino-10-fluoro-2,4,4a,5-tetrahydro-lH-pyrazino[2,l-c][l,4]benzoxazine-3-carboxylate (14.5 g, 45 mmol) in acetonitrile (50 mL) drop wise, and the reaction mixture is stirred at 0 °C for 1 h, then stirred at 25 °C for 4 h. The mixture is concentrated under reduced pressure, and the residue is purified by flash silica gel chromatography (0-14% ethyl acetate / petroleum ether) to afford tert-butyl (4aS)-8-bromo-10-fluoro-2,4,4a,5-tetrahydro-lH-pyrazino[2,l-c][l,4]benzoxazine-3-carboxylate (9.2 g, 53%) as a yellow oil. LC / MS (ESI) m / z'. 387.0 [M+H]+;NMR (400 MHz, CDCh) 56.91 -6.70 (m, 2H). 4.23 - 4.09 (m, 1H), 3.98 (dd, J= 8.8, 10.8 Hz, 1H), 3.91 - 3.66 (m, 3H), 3.42 - 3.28 (m, 1H), 3.16 (d. J= 5.6 Hz, 2H), 2.97 (t, J= 8.8 Hz. 1H), 1.55 - 1.42 (m, 9H).Step 5:

[0212] A mixture of tert-butyl (4aS)-8-bromo-10-fluoro-2,4,4a,5-tetrahydro-lH-pyrazino[2,l-c][l,4]benzoxazine-3-carboxylate (9.5 g, 25 mmol), 2,6-dibenzyloxy-3-(4,4,5,5-ARVN-174-PCT / / ARVN0174WO2tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyridine (11.26 g, 27 mmol), [1, T-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.80 g, 2.5 mmol) and potassium carbonate (10.17 g, 74 mmol) in dioxane (100 mL) and water (20 mL) is degassed and purged with nitrogen several times, then stirred at 80 °C for 12 h under nitrogen. The reaction mixture is diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic extracts are washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-12% ethyl acetate / petroleum ether) to afford tert-butyl (4aS)-8-(2,6-dibenzyloxy-3-pyridyl)-10-fluoro-2,4,4a,5-tetrahydro-lH-pyrazino[2,l-c][l,4]benzoxazine-3-carboxylate (11.8 g, 78%) as a yellow oil. LC / MS (ESI) m / z 598.2 [M+H]+; 'H NMR (400 MHz, CDC13) 87.56 (d, J= 8.0 Hz, 1H), 7.47 - 7.28 (m. 10H), 6.96 (dd,7=2.0. 14.4 Hz. 1H), 6.91 - 6.83 (m, 1H). 6.45 (d, 7= 8.1 Hz, 1H), 5.45 (s, 2H), 5.35 (s, 2H), 4.19 (dd, 7= 2.4, 10.8 Hz, 1H), 4.02 (dd, 7= 8.7, 10.8 Hz, 1H), 3.95 - 3.74 (m, 3H), 3.40 - 3.29 (m. 1H), 3.28 - 3.17 (m, 1H), 3.13 (dd, 7= 1.4, 2.4 Hz, 1H), 3.06 - 2.93 (m, 1H), 1.50 (s, 9H).Step 6:

[0213] To a solution of tert-butyl (4aS)-8-(2,6-dibenzyloxy-3-pyridyl)-10-fluoro-2,4,4a,5-tetrahydro-lH-pyrazino[2,l-c][l,4]benzoxazine-3-carboxylate (9.8 g, 16 mmol) in tetrahydrofuran (200 mL) are added 10% palladium on carbon (2 g) and 10% palladium hydroxide (2 g) under nitrogen atmosphere, and the resulting suspension is degassed and purged with hydrogen several times, then stirred under hydrogen (50 psi) at 50 °C for 12 h. The mixture is filtered and concentrated under reduced pressure, and the residue is triturated with ethyl acetate (20 mL) at 25 °C for 30 minutes to afford tert-butyl (4aS)-8-(2,6-dioxo-3-piperidyl)-10-fluoro-2,4,4a,5-tetrahydro-lH-pyrazino[2,l-c][l,4]benzoxazine-3-carboxylate (6.7 g, 95%) as a white solid. LC / MS (ESI) m / z: 320.1[M-C5H8O2+H]+; NMR (400 MHz, DMSO-rf6) 5 10.79 (s, 1H), 6.62 (d, J= 14.0 Hz. 1H), 6.53 (s, 1H). 4.25 (d, J = 10.4 Hz, 1H), 4.01 - 3.87 (m. 1H), 3.81 - 3.69 (m, 2H), 3.63 (br dd, J= 6.0, 8.8 Hz, 2H), 3.29 - 3.19 (m, 1H), 3.10 (d, J = 5.6 Hz, 2H), 2.96 -ARVN-174-PCT / / ARVN0174WO22.86 (m, 1H), 2.69 - 2.53 (m, 2H), 2.17 (dq, J = 4.0, 12.0 Hz, 1H), 2.03 - 1.91 (m, 1H), 1.41 (s, 9H).Step 7:

[0214] To a solution of terLbutyl (4aS)-8-(2,6-dioxo-3-piperidyl)-10-fluoro-2,4,4a,5-tetrahydro-lH-pyrazino[2,l-c][l,4]benzoxazine-3-carboxylate (6.7 g, 16 mmol) in dichloromethane (60 mL) is added trifluoroacetic acid (11 mL), and the reaction mixture is stirred at 25 °C for 0.5 h. The mixture is concentrated under reduced pressure to afford 3-[(4aS)-10-fluoro-l,2,3,4,4a,5-hexahydropyrazino[2,l-c][l,4]benzoxazin-8-yl]piperidine-2,6-dione (6.9 g, crude, trifluoroacetic acid) as a yellow oil, which is used in the next step without further purification. LC / MS (ESI) m / z 320.0 [M+H]+.Step 8:

[0215] To a solution of 2,4,7-trichloro-8-methyl-pyrido[4,3-d]pyrimidine (2.3 g, 9 mmol) in dichloromethane (25 mL) are added N, N-diisopropylethylamine (2.4 mL, 14 mmol) and (4S)-l-oxa-8-azaspiro[3.5]nonane (1.41 g, 11 mmol), and the reaction mixture is stirred at 0 °C for 1 h. The mixture is diluted with water (50 mL) and extracted with dichloromethane (3 x 30 mL). The organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-20% ethyl acetate / petroleum ether) to afford (4S)-8-(2,7-dichloro-8-methyl-pyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5]nonane (2.3 g, 73%) as a white solid. LC / MS (ESI) m / z: 339.0 [M+H]+; ’HARVN-174-PCT / / ARVN0174WO2NMR (400 MHz, DMSO-d6) 89.16 (s, 1H), 4.43 - 4.35 (m, 3H), 4.20 - 4.18 (m, 1H), 3.85 (d, J = 13.2 Hz, 1H), 3.48 - 3.39 (m, 1H), 2.50 - 2.48 (m, 3H), 2.47 - 2.40 (m, 1H), 2.38 - 2.28 (m, 1H), 2.15 - 2.06 (m. 1H), 1.92 - 1.76 (m, 2H). 1.72 - 1.63 (m, 1H).Step 9:

[0216] To a solution of (4S)-8-(2,7-dichloro-8-methyl-pyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5]nonane (3.3 g, 9.7 mmol) in -dimethylacetamide (35 mL) are added cesium carbonate (9.51 g, 29 mmol) and [2,2-difluoro-l-(hydroxymethyl)cyclopropyl]methanol (2.69 g, 19 mmol), and the reaction mixture is stirred at 25 °C for 1 h. The mixture is diluted with water (50 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic extracts are washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-55% ethyl acetate / petroleum ether) to afford [l-[[7-chloro-8-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (2 g, 47%) as a white solid. LC / MS (ESI) m / z. 441.1 [M+H]+; 'll NMR (400 MHz, DMSO-tZ6) 89.01 (s, 1H), 5.11 (t. J = 5.6 Hz, 1H), 4.62 - 4.61 (m. 1H), 4.44 - 4.42 (m, 1H), 4.37 - 4.35 (m. 2H), 4.31 - 4.30 (m, 1H), 4.12 - 4.11 (m, 1H), 3.77 (dd, J = 4.4, 13.4 Hz, 1H), 3.59 (d, J = 4.4 Hz, 2H), 2.49 (s, 3H), 2.44 - 2.29 (m, 2H), 2.13 - 2.04 (m, 1H), 1.87 - 1.76 (m, 2H), 1.73 - 1.62 (m, 2H), 1.56 - 1.54 (m, 1H).Step 10:ARVN-174-PCT / / ARVN0174WO2

[0217] To a solution of [l-[[7-chloro-8-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (1.9 g, 4 mmol) in dimethylformamide (20 mL) are added imidazole (733 mg, 11 mmol) and chloro(triisopropyl)silane (1.1 mL, 5.2 mmol), and the reaction mixture is stirred at 25 °C for 12 h. The mixture is diluted with water (50 mL) and extracted with dichloromethane (3 x 30 mL). The organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-25% ethyl acetate / petroleum ether) to afford [l-[[7-chloro-8-methyL4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methoxy-triisopropyl-silane (2 g, 78%) as a white solid. LC / MS (ESI) m / z 597.2 [M+H]+; 'H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 4.66 - 4.53 (m, 2H), 4.36 (t, J = 7.6 Hz, 2H), 4.31 - 4.24 (m, 1H), 4.10 (s, 1H), 3.96 - 3.95 (m. 1H). 3.87 - 3.74 (m, 2H), 3.31 - 3.24 (m, 1H), 2.48 (s, 3H), 2.40 - 2.29 (m, 2H), 2.12 - 2.01 (m, 1H), 1.88 - 1.75 (m, 3H), 1.69 - 1.57 (m, 2H), 1.03 - 0.98 (m, 3H), 0.96 - 0.93 (m, 18H).

[0218] [l-[[7-Chloro-8-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methoxy-triisopropyl-silane (2 g) is purified by SFC (12% isopropanol 0.1%NH3H2O) in carbon dioxide, isocratic elution mode). The first eluted fraction is assigned as [(lS)-l-[[7-chloro-8-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methoxy-triisopropyl- silane (800 mg, 40%) as a white solid. LC / MS (ESI)597.2ARVN-174-PCT / / ARVN0174WO2[M+H]+. The second eluted fraction is assigned as [(lR)-l-[[7-chloro-8-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methoxy-triisopropyl-silane (990 mg, 48%) as a white solid. LC / MS (ESI) m / z 634.4 [M+H]+.Step 12:

[0219] To a solution of [(lR)-l-[[7-chloro-8-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methoxy-triisopropyl-silane (590 mg, 1 mmol) in tetrahydrofuran (7 mL) are added 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (712 mg, 2 mmol), SPhos Pd G3 (77.1 mg, 99 pmol) and potassium phosphate (1.5 M, 2 mL) under nitrogen, and the reaction mixture is stirred at 60 °C for 12 h. The mixture is filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford [(lR)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methoxy-triisopropylsilane (600 mg, 76%) as a white solid. LC / MS (ESI) m / z 795.4 [M+H]+; 'H NMR (400 MHz, DMSO-rfc) 8 9.23 (d, 7 - 4.4 Hz, 1H), 7.89 - 7.77 (m, 1H), 7.61 (d, 7 = 2.4 Hz. 1H), 7.41 (t, 7 = 9.2 Hz. 1H), 7.07 (d, 7 = 2.4 Hz, 1H), 5.37 - 5.31 (m, 2H), 4.76 - 4.47 (m, 2H), 4.44 - 4.15 (m, 4H), 3.99 - 3.90 (m, 3H), 3.85 - 3.73 (m, 2H), 3.61 - 3.51 (m, 1H), 3.42 (s, 3H), 2.35 (s, 2H), 2.17 (s, 5H), 2.12 - 2.02 (m, 1H), 1.95 -1.75 (m, 3H), 1.74 - 1.56 (m, 2H), 1.03 (s, 1H), 0.97 - 0.92 (m, 18H), 0.69 (t. 7 = 7.2 Hz, 3H).Step 13:ARVN-174-PCT / / ARVN0174WO2

[0220] To a solution of [(lR)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8- methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2- difluoro-cyclopropyl]methoxy-triisopropyl-silane (750 mg, 0.9 mmol) in dimethylsulfoxide (8 mL) is added triethylamine trihydrofluoride (3.1 mL, 19 mmol), and the reaction mixture is stirred at 25 °C for 12 h. The mixture is diluted with water (50 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic extracts are washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford [(1S)- l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-methyL4-[(4S)-l-oxa-8- azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro- cyclopropyl]methanol (590 mg, 98%) as a white solid. LC / MS (ESI) m / z 639.3 [M+H]+; 'H NMR (400 MHz, DMSO- d) 89.23 (s, 1H), 7.89 - 7.87 (m, 1H), 7.61 (d, J= 2.4 Hz, 1H), 7.42 - 7.40 (m, 1H), 7.09 - 7.07 (m, 1H), 5.38 - 5.29 (m, 2H), 5.11 - 5.09 (m. 1H), 4.64 - 4.62 (m, 1H). 4.47 - 4.22 (m, 4H), 4.12 - 4.10 (m, 4H), 3.97 - 3.76 (m, 1H), 3.63-3.61 (m, 2H), 3.33 - 3.27 (m, 2H), 2.35 (t, J= 8.0 Hz, 2H), 2.19 (s, 5H), 1.95 - 1.79 (m, 2H), 1.76 - 1.65 (m, 2H), 1.60 - 1.51 (m, 1H), 0.71- 0.69 (m, 3H).ARVN-174-PCT / / ARVN0174WO2

[0221] To a solution of [(lS)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl] methanol (300 mg, 0.47 mmol) and triethylamine (0.20 mL, 1.4 mmol) in dichloromethane (3 mL) at 0 °C is added methanesulfonyl chloride (0.20 mL, 2.6 mmol), and the reaction mixture is stirred at 25 °C for 1 h. The mixture is diluted with water (20 mL) and extracted with dichloromethane (30 mL x 2). The combined organic extracts are washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford [(lR)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl] methyl methanesulfonate (340 mg, crude) as a yellow oil, which is used in the next step without further purification. LC / MS (ESI) m / z'. 717.2 [M+H]+.Step 15:

[0222] To a solution of [(lR)-1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (250 mg, 0.35 mmol) and 3-[(4aS)-10-fluoro-3-(4-ARVN-174-PCT / / ARVN0174WO2piperidylmethyl)-2,4,4a,5-tetrahydro-lH-pyrazino[2,l-c][l,4]benzoxazin-8-yl]piperidine-2,6-dione (189 mg, 0.45 mmol) in dimethyl sulfoxide (5 mL) are added N,N-diisopropylethylamine (0.30 mL, 1.7 mmol) and potassium iodide (290 mg, 1.7 mmol), and the reaction mixture is stirred at 100 °C for 3 h. The mixture is poured into ice- water (20 mL), and the resulting suspension is filtered. The filter cake is purified by prep-TLC (SiO2, 1 / 2 dichloromethane / CH3OH) to afford 3-[(4aS)-3-[[l-[[(lS)-l-[[7-[8-ethyl-7-fhioro-3-(methoxymethoxy)-l-naphthyl]-8-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]- 10-fluoro-2,4,4a,5-tetrahydro- lH-pyrazino[2, 1-c][l,4]benzoxazin-8-yl]piperidine-2, 6-dione (180 mg, 49%) as a brown solid. LC / MS (ESI) m / z = 1037.5 [M+H]+; 'H NMR (400 MHz, CDC13) 89.28 (d, J = 6.4 Hz, 1H), 7.90 (s, 1H), 7.68 (dd, J = 5.6. 9.0 Hz, 1H), 7.51 - 7.43 (m, 1H), 7.26 - 7.21 (m, 1H). 7.08 (t, J= 2.8 Hz. 1H), 6.61 - 6.34 (m, 2H), 5.38 - 5.22 (m, 2H), 4.88 - 4.52 (m, 4H), 4.46 - 4.30 (m, 1H), 4.25 - 4.00 (m, 3H), 3.85 -3.69 (m, 2H), 3.64 (dd, J= 5.2, 9.6 Hz, 1H), 3.52 (d, J= 1.6 Hz, 3H), 3.49 - 3.39 (m, 1H), 3.23 (d, J= 2.4 Hz, 1H), 3.14 - 2.98 (m. 2H), 2.96 - 2.81 (m. 2H). 2.78 - 2.56 (m, 4H). 2.51 - 2.41 (m, 2H), 2.40 - 1.96 (m, 16H), 1.96 - 1.73 (m, 4H), 1.52 - 1.39 (m, 1H), 1.32 - 1.04 (m, 3H), 1.02 - 0.88 (m, 1H), 0.86 - 0.75 (m, 3H).Step 16:

[0223] To a solution of 3-[(4aS)-3-[[l-[[(lS)- l-[[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-l-naphthyl]-8-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-ARVN-174-PCT / / ARVN0174WO2d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]-10-fluoro-2,4,4a,5-tetrahydro-lH-pyrazino[2,l-c][l,4]benzoxazin-8-yl]piperidine-2,6-dione (180 mg, 0.2 mmol) in dichloromethane (3 mL) is added trifluoroacetic acid (1.5 mL) at 0 °C, and the reaction mixture is stirred at 25 °C for 1 h. The mixture is diluted with saturated sodium bicarbonate solution until pH 7-8, and the resulting mixture is extracted with dichloromethane (50 mL x 3). The combined organic extracts are washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by reverse phase HPLC (30% acetonitrile in water (0.3% formic acid) over 17 min) to afford Compound 176 (121.4 mg, 70%) as a white solid. LC / MS (ESI) m / z = 993.8 [M+l]+; 'H NMR (400 MHz, DMSO-rfe) 8 10.79 (s, 1H), 10.12 - 9.66 (m, 1H), 9.23 (s, 1H), 7.74 (dd, J= 6.0, 9.2 Hz, 1H), 7.47 - 7.17 (m, 2H), 6.89 (dd, J = 2.8, 5.6 Hz, 1H), 6.58 (dd, J = 2.0, 14.0 Hz, 1H). 6.50 (s, 1H), 4.79 - 4.58 (m, 1H), 4.54 -4.33 (m, 3H), 4.30 - 4.20 (m, 1H), 4.18 - 4.10 (m, 1H), 4.09 - 3.88 (m, 2H), 3.83 - 3.50 (m, 3H), 3.14 - 3.04 (m, 1H), 2.95 (t, J = 9.2 Hz, 1H), 2.85 - 2.69 (m, 3H), 2.68 - 2.56 (m. 4H), 2.42 - 2.24 (m, 5H), 2.23 - 2.07 (m, 8H). 2.04 (d, J = 5.6 Hz, 2H). 1.99 - 1.68 (m. 7H), 1.65 - 1.54 (m, 2H), 1.53 - 1.36 (m, 2H), 1.04 - 0.82 (m, 2H), 0.70 (dt, J= 2.8, 7.2 Hz, 3H).Example 1.32Exemplary synthesis of Compound 53Step 1:

[0224] To a solution of methyl 4-amino-6-chloro-pyridine-3-carboxylate (2.0 g, 11 mmol) in tetrahydrofuran (20 mL) is added 2, 2, 2-trichloroacetyl isocyanate (1.53 mL, 13 mmol), and the reaction mixture is stirred at 25 °C for 0.5 h. The mixture is concentrated under reduced pressure, and the residue is triturated with 2-methoxy-2-methylpropane (10 mL) to afford methyl 6-chloro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate (4.13 g, crude) as a white solid, which is used directly in the next step.ARVN-174-PCT / / ARVN0174WO2Step 2:

[0225] To a solution of methyl 6-chloro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate (4.13 g, 12 mmol) in methanol (20 mL) is added ammonia / methanol (7 M, 8.50 mL), and the reaction mixture is stirred at 25 °C for 1 h. The mixture is filtered, and the filter cake is triturated with 2-methoxy-2-methylpropane (10 mL) to afford 7-chloro-lH-pyrido[4,3-d]pyrimidine-2, 4-dione (2.3 g, 98%) as a white solid.1H NMR (400 MHz, DMSO-rfc) d 8.70 - 8.55 (m, 1H), 6.95 (d. J = 7.2 Hz, 1H).Step 3:Cl POCI3DIEA, MeCN 90 °C, 24 h

[0226] To a solution of 7-chloro-lH-pyrido[4,3-d]pyrimidine-2, 4-dione (2.2 g, 11 mmol) in acetonitrile (20 mL) at 0 °C are dropwise added phosphorus oxychloride (5.2 mL, 56 mmol) and N,N-diisopropylethylamine (5.8 mL, 33 mmol), and the reaction mixture is stirred at 90 °C for 24 h, then distilled to remove most of phosphorus oxychloride. The remaining mixture is diluted with saturated sodium bicarbonate solution until pH 7-8. Water (50 mL) is added, and the mixture is extracted with dichloromethane (50 mL x 3). The combined organic extracts are washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (10-20% ethyl acetate / petroleum ether) to afford 2,4,7-trichloropyrido[4,3-d]pyrimidine (1.25 g, 48%) as a white solid. LC / MS (ESI) m / z 233.9 [M+H]+.Step 4:ARVN-174-PCT / / ARVN0174WO2

[0227] To a solution of 2,4,7-trichloropyrido[4,3-d]pyrimidine (1.18 g, 5 mmol) in dichloromethane (10 mL) at 0 °C are added N,N-diisopropylethylamine (1.31 mL, 7.6 mmol) and (S)-l-oxa-6-azaspiro[3.5]nonane (640 mg, 5 mmol), and the reaction mixture is stirred at 0 °C for 1 h. The mixture is concentrated under reduced pressure, and the residue is purified by flash silica gel chromatography (15-30% ethyl acetate / petroleum ether) to afford (S)-6-(2.7-dichloropyrido[4,3-d]pyrimidin-4-yl)-l-oxa-6-azaspiro[3.5]nonane (1.6 g, 97%) as ayellow solid. LC / MS (ESI) m / z 325.0 [M+H]+; H NMR (400 MHz, DMSO-rf6) δ 9.31 (s, 1H), 7.68 (s, 1H), 4.48 - 4.34 (m, 3H), 4.30 - 4.14 (m, 1H). 3.86 (d, J = 13.2 Hz, 1H), 3.48 - 3.40 (m, 1H), 2.48 - 2.41 (m, 1H), 2.37 - 2.29 (m, 1H), 2.14 - 2.06 (m, 1H), 1.92 - 1.64 (m, 3H).Step 5:

[0228] To a solution of (4S)-8-(2,7-dichloropyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5]nonane (1.59 g, 4.9 mmol) and [2,2-difluoro-l-(hydroxymethyl)cyclopropyl]methanol (1.35 g, 9.8 mmol) in N-dimethylacetamide (10 mL) is added cesium carbonate (4.78 g, 15 mmol), and the reaction mixture is stirred at 25 °C for 1 h. The mixture is diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic extracts are washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (25%-30% acetonitrile in water (trifluoroacetic acid) over 10 min) to afford [l-[[7-chloro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl] methanol (1.44 g, 69%) as a white solid. LC / MS (ESI) m / z 427.2 [M+H]+; H NMRARVN-174-PCT / / ARVN0174WO2(400 MHz, DMSO-d6) δ: 9.20 - 9.10 (m, 1H), 7.49 (s, 1H), 5.08 (t, J= 5.6 Hz, 1H), 4.55 (d, J = 11.6 Hz, 1H), 4.44 - 4.27 (m, 4H), 4.14 (d, 7 = 12.8 Hz, 1H), 3.79 (dd, 7 = 4.8, 13.6 Hz, 1H), 3.59 (d, 7= 5.2 Hz, 2H), 3.43 - 3.38 (m. 1H). 2.43 - 2.27 (m, 2H), 2.12 - 2.04 (m, 1H), 1.90 - 1.74 (m, 2H), 1.71 - 1.63 (m, 2H), 1.60 - 1.48 (m, 1H).Step 6:

[0229] A mixture of [l-[[7-chloro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (1.44 g, 3.4 mmol), 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.43 g, 6.8 mmol), potassium phosphate (1.5 M, 6.8 mL) and cataCXium A Pd G3 (246 mg, 0.34 mmol) in tetrahydrofuran (20 mL) is degassed and purged with nitrogen several times, then stirred at 70 °C for 12 h under nitrogen atmosphere. The reaction mixture is diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic extracts are washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (45-55% ethyl acetate / petroleum ether) to afford [l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl] methanol (1.9 g, 84%) as a yellow solid. LC / MS (ESI) m / z 625.3 [M+H]+Step 7:ARVN-174-PCT / / ARVN0174WO2

[0230] [l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl] methanol (1.9 g) is purified by SFC (52% isopropanol (0.1%ammonium hydroxide) in carbon dioxide, isocratic elution mode). The first eluted fraction is assigned as [( 1R)- 1 -[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (1 g, 42%) as a white solid. LC / MS (ESI) m / z 625.3 [M+H]+. The second eluted fraction is assigned as [(IS)- 1-[[7-[8-ethyl-7-fhioro-3-(methoxymethoxy)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (1 g, 43%) as a white solid. LC / MS (ESI) m / z 625.3 [M+H]+.Step 8:

[0231] To a solution of [(lR)-l-[[7-[8-ethyl-7-fhroro-3-(methoxymethoxy)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-ARVN-174-PCT / / ARVN0174WO2cyclopropyl]methanol (630 mg, 1 mmol) in dichloromethane (10 mL) at 0 °C under nitrogen is added trimethylamine (421 pL, 3 mmol) followed by methanesulfonyl chloride (0.18 mL, 2 mmol), and the reaction mixture is stirred at 25 °C for 1 h. The mixture is diluted with water (30 mL) and extracted with dichloromethane (20 mL x 3). The combined organic extracts are washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford [(lS)-l-[[7-[8-ethyL7-fhioro-3-(methoxymethoxy)-l-naphthyl]-4-[(4S)-l-oxa- 8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro- cyclopropyl] methyl methanesulfonate (840 mg, crude) as yellow oil. LC / MS (ESI) m / z 703.2 [M+H]+.Step 9:

[0232] To a solution of [(lS)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-4- [(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro- cyclopropyl] methyl methanesulfonate (150 mg, 0.2 mmol) and 3-[4-fluoro-l-oxo-5-[4-(4- piperidylmethyl)piperazin-l-yl]isoindolin-2-yl]piperidine-2, 6-dione (119 mg, 0.2 mmol, trifluoroacetate) in / V. A imethylformamide (4 mL) are added potassium iodide (177 mg, 1.1 mmol) and sodium carbonate (113mg, 1.1 mmol), and the reaction mixture is stirred at 90 °C for 12 h. The mixture is diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic extracts are washed with brine (20 mL x 3). dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-TLCARVN-174-PCT / / ARVN0174WO2(dichloromethane / ethyl acetate / methanol = 3 / 3 / 1) to afford 3-[5-[4-[[l-[[(lR)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (50 mg, 18%) as a yellow solid. LC / MS (ESI) m / z: 1050.5 [M+H]+.Step 10:

[0233] To a solution of 3-[5-[4-[[l-[[(lR)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-4-[(4R)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]piperazin- 1 -yl] -4-fluoro- 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dione (45 mg, 0.04 mmol) in dichloromethane (1 mL) is added trifluoroacetic acid (0.5 mL), and the reaction mixture is stirred at 25 °C for 0.5 h. The mixture is diluted with tetrahydrofuran (5 mL) and dichloromethane (20 mL), washed with saturated sodium bicarbonate solution (30 mL x 3). dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-TLC (dichloromethane / methanol = 10 / 1). The crude fractions are diluted with acetonitrile (2 mL), formic acid (0.1 mL) and water (30 mL), then lyophilized to afford Compound 53 3-[5-[4-[[l-[[(lR)-l-[[7-(8-ethyl-7-fluoro-3-hydroxy-l-naphthyl)-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difhioro-cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (15 mg, 31%, formic acid salt) as a white solid. LC / MS (ESI) m / z 1006.5ARVN-174-PCT / / ARVN0174WO2[M+H]+; NMR (400 MHz, DMSO-d6) d 10.97 (s, 1H), 9.99 - 9.78 (m, 1H), 9.35 (s, 1H), 8.13 (s, 1H), 7.80 - 7.70 (m, 1H), 7.52 (s, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.33 (t, J= 9.6 Hz, 1H), 7.27 (d, 7= 2.4 Hz, 1H), 7.13 (t. J= 8.0 Hz, 1H), 7.04 - 6.97 (m, 1H). 5.06 (dd, Ji = 4.8, J2=13.2 Hz, 1H), 4.67 - 4.55 (m, 1H), 4.52 - 4.27 (m, 6H), 4.15 - 3.77 (m, 2H), 3.15 - 3.05 (m, 4H), 2.96 - 2.76 (m, 4H), 2.63 - 2.52 (m, 4H), 2.47 - 2.34 (m, 6H), 2.17 - 2.06 (m, 4H), 2.03 - 1.82 (m, 6H), 1.80 -1.61 (m, 4H), 1.53 - 1.43 (m, 2H), 1.10 - 0.91 (m. 2H). 0.78 (t. J = 6.4 Hz, 3H).Example 1.33Exemplary synthesis of Compound 4Step 1:

[0234] To a mixture of 5,7-dichloro-8-fluoro-2-methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one (10 g, 36 mmol) in acetonitrile (100 mL) at 0 °C are added phosphorus oxychloride (16.6 mL, 179 mmol) and N,N-diisopropylethylamine (18.7 mL, 107 mmol), and the reaction mixture is degassed and purged with nitrogen several times then stirred at 90 °C for 2 h. The mixture is cooled to room temperature, then poured into water (100 mL). The resulting mixture is diluted with saturated sodium bicarbonate solution to adjust the pH to 7-8, and extracted with dichloromethane (100 mL x 3). The combined organic extracts are washed with brine (80 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is triturated with ethyl acetate (40 mL) to afford 4,5,7-trichloro-8-fluoro-2-methylsulfanyL pyrido[4,3-d]pyrimidine (11.3 g, crude) as a yellow solid. LC / MS (ESI) m / z 299.8 [M+H]+. Step 2:ARVN-174-PCT / / ARVN0174WO2

[0235] To a solution of 4,5,7-trichloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidine (11.3 g, 38 mmol) in dichloromethane (100 mL) are added A, A-diisopropylethylamine (13.2 mL, 76 mmol) and (4S)-l-oxa-8-azaspiro[3.5]nonane (4.81 g, 38 mmol), and the reaction mixture is stirred at 0 °C for 1 h. The mixture is concentrated under reduced pressure, and the residue is purified by flash silica gel chromatography (15-20% ethyl acetate / petroleum ether) to afford (4S)-8-(5,7-dichloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5]nonane (12 g, 81%) as a white solid.NMR (400 MHz, CDCL) 34.65 - 4.18 (m, 3H), 3.90 - 3.65 (m, 2H), 3.52 - 3.07 (m, 1H), 2.62 (s, 3H), 2.41 - 2.24 (m, 2H), 2.21 - 1.87 (m, 3H), 1.85 - 1.66 (m, 1H).Step 3:

[0236] A solution of (4S)-8-(5,7-dichloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5]nonane (12 g, 61 mmol) and iron(III) acetylacetonate (0.54 g, 3.1 mmol) in tetrahydrofuran (240 mL) and a solution of methylmagnesium bromide (3 M, 40.8 mL, 122 mmol) in tetrahydrofuran (240 mL) are simultaneously pumped to a flow reactor (FLR1, 56.3 mL / min) at 18 °C for 0.33 min. The reaction mixture is poured into saturated ammonium chloride solution (1000 mL) at 0 °C, diluted with water (100 mL), and extracted with ethyl acetate (500 mL x 3). The combined organic extracts are washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (15-30% ethyl acetate / petroleum ether) to afford (4S)-8-(7-chloro-8-fluoro-5-methyl-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5]nonane (11.8 g, 52%) as a yellow solid. 'H NMR (400 MHz, CDCh) 44.59 - 4.47 (m, 1H), 4.43 - 4.19 (m, 1H), 4.09 - 3.53 (m, 3H), 3.45 - 3.09 (m, 1H), 2.73 (m, 3H), 2.63 (s, 3H), 2.40 - 2.23 (m, 2H), 2.04 - 1.79 (m, 3H), 1.76 - 1.64 (m, 1H).Step 4:ARVN-174-PCT / / ARVN0174WO2

[0237] A mixture of (4S)-8-(7-chloro-8-fluoro-5-methyL2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5]nonane (960 mg, 2.6 mmol), 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.13 g, 3.1 mmol), potassium phosphate (1.5 M, 5.21 mL) and cataCXium A Pd G3 (190 mg, 0.26 mmol) in tetrahydrofuran (10 mL) is degassed and purged with nitrogen several times, then stirred at 70 °C for 12 h under nitrogen atmosphere. The mixture is diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic extracts are washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (30-35%ethyl acetate / petroleum ether) to afford (4S)-8-[7-[8-ethyL7-fhroro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-5-methyl-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl]-l-oxa-8-azaspiro[3.5]nonane (2.29 g, 78%) as a yellow solid. LC / MS (ESI) m / z: 567.2 [M+H]+.Step 5:

[0238] To a solution of (4S)-8-[7-[8-ethyL7-fhroro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-5-methyL2-methylsulfanyLpyrido[4,3-d]pyrimidin-4-yl]-l-oxa-8-azaspiro[3.5]nonane (2.28 g, 4 mmol) in A, A-dimethylformamide (30 mL) is added 4A molecular sieves (2.28 g) at 25 °C, and the resulting mixture is stirred for 4 h. Potassium peroxymonosulfate (7.44 g, 44 mmol) is then added, and the reaction mixture is stirred at 25 °C for 12 h. The mixture is filtered, and theARVN-174-PCT / / ARVN0174WO2filtrate is concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (30-50% ethyl acetate / petroleum ether) to afford (4S)-8-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-5-methyl-2-methylsulfonyl-pyrido[4,3-d]pyrimidin-4-yl]-l-oxa-8-azaspiro[3.5]nonane (1.45 g, 60%) as a yellow solid. LC / MS (ESI) m / z 599.2 [M+H]+.Cs2CO3, DMAc, 25 °C, 1 h

[0239] To a solution of (4S)-8-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fhioro-5-methyl-2-methylsulfonyl-pyrido[4,3-d]pyrimidin-4-yl]-l-oxa-8-azaspiro[3.5]nonane (1.45 g. 2.4 mmol) in A(A imethylacetamide (10 mL) are added cesium carbonate (2.37 g, 7.3 mmol) and [2,2-difluoro-l-(hydroxymethyl)cyclopropyl]methanol (669 mg, 4.8 mmol), and the reaction mixture is stirred at 25 °C for 1 h. The mixture is diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic extracts are washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (50%-70% acetonitrile in water (trifluoroacetic acid) over 10 min) followed by flash silica gel chromatography (40-50% ethyl acetate / petroleum ether) to afford [l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-5-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl] methanol (850 mg, 53%) as a white solid. LC / MS (ESI) m / z 657.2 [M+H]+.Step 7:ARVN-174-PCT / / ARVN0174WO2

[0240] [ 1 - [[7- [8-ethyl-7-fluoro-3-(methoxymethoxy)- 1 -naphthyl]-8-fluoro-5-methyl-4- [(4R)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl] methanol (850 mg) is purified by SFC (45% isopropanol / acetonitrile (4:1, 0.1% ammonium hydroxide) in carbon dioxide, isocratic elution mode). The first eluted fraction is assigned as [(lR)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-5-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl] methanol (410 mg, 48%) as a white solid. LC / MS (ESI) m / z 657.2 [M+H]+;!H NMR (400 MHz, CDC13) 57.69 - 7.66 (m, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.36 - 7.28 (m, 1H). 7.26 - 7.21 (m, 1H), 5.37 - 5.23 (m, 2H), 4.97 - 3.86 (m, 6H), 3.83 - 3.62 (m, 3H), 3.53 (s, 3H), 3.45 - 3.08 (m, 1H), 2.83 (d, J = 8.4 Hz, 3H), 2.51 - 2.03 (m, 8H). 1.82 - 1.75 (m, 1H), 1.57 - 1.41 (m, 2H), 0.95 - 0.79 (m, 3H). The second eluted fraction is assigned as [(lS)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-5-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (400 mg, 47%) as a yellow solid. LC / MS (ESI) m / z: 657.2 [M+H]+; 'H NMR (400 MHz, CDCI3) 5: 7.69 - 7.66 (m, 1H), 7.52 (d, J= 2.4 Hz, 1H), 7.33 (s, 1H), 7.25 - 7.22 (m, 1H), 5.31 - 5.28 (m, 2H), 4.85 - 4.10 (m, 6H), 3.99 - 3.83 (m, 1H). 3.79 - 3.64 (m, 3H), 3.53 (s. 3H), 3.43 - 3.15 (m, 1H), 2.83 (d. J = 8.4 Hz, 3H), 2.48 - 2.08 (m, 6H), 1.86 - 1.69 (m, 2H), 1.54 - 1.40 (m, 2H), 0.87 (t, J= 6.8 Hz, 3H).Step 8:ARVN-174-PCT / / ARVN0174WO2

[0241] To a solution of [(lR)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-5-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (600 mg, 0.9 mmol) in dichloromethane (10 mL) are added triethylamine (636 pL, 4.6 mmol) and methylsulfonyl methanesulfonate (477 mg, 2.7 mmol), and the reaction mixture is stirred at 25 °C for 1 h. The mixture is diluted with water (30 mL) and extracted with dichloromethane (20 mL x 3). The combined organic extracts are washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford [(lS)-l-[[7-[8-ethyl-7-fhroro-3-(methoxymethoxy)-l-naphthyl]- 8-fluoro-5-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (730 mg, crude) as a yellow solid, which is used in the next step directly. LC / MS (ESI) m / z 735.3 [M+H]+.Step 9:ARVN-174-PCT / / ARVN0174WO2

[0242] To a solution of [(1 S)-1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-5-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (350 mg, 0.5 mmol) and 3-[4-fluoro-5-[(2S)-2-methyl-4-(4-piperidylmethyl)piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2,6-dione (327 mg, 0.6 mmol, trifluoroacetate) in N,N-dimethylformamide (5 mL) are added sodium carbonate (252.4 mg, 2.4 mmol) and potassium iodide (395 mg, 2.4 mmol), and the reaction mixture is stirred at 90 °C for 12 h. The mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by prep-HPLC (10%-40% acetonitrile in water (formic acid) over 10 min) to afford 3-[5-[(2S)-4-[[l-[[(lR)-l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-5-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]-2-methyl-piperazin-l-yl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (370 mg, 70%) as a white solid. LC / MS (ESI) m / z 1096.6 [M+H]+.Step 10:TFA / DCM, anisole

[0243] To a solution of 3-[5-[(2S)-4-[[l-[[(lR)-l-[[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-l-naphthyl]-8-fluoro-5-rnethyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]-2-methyl-piperazin-l-yl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (360 mg, 0.33 mmol) and anisole (0.60 mL, 5.5 mmol) in dichloromethane (4 mL) is addedARVN-174-PCT / / ARVN0174WO2trifluoroacetic acid (2 mL), and the reaction mixture is stirred at 25 °C for 1 h. The mixture is diluted with tetrahydrofuran (5 mL) and dichloromethane (20 mL), then washed with saturated sodium bicarbonate solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (30%-40% acetonitrile in water (formic acid) over 10 min) to afford Compound 43-[5-[(2S)-4-[[l-[[(lR)-l-[[7-(8-ethyL 7-fhioro-3-hydroxy-l-naphthyl)-8-fluoro-5-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]-2-methyl-piperazin-l-yl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (215 mg, 60%, formic acid salt) as a white solid. LC / MS (ESI) m / z 1052.4 [M+H]+; H NMR (400 MHz, DMSO-dd) 10.98 (s, 1H), 10.26 - 9.71 (m, 1H), 8.11 (s, 1H), 7.85 - 7.70 (m, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.40 - 7.30 (m, 2H), 7.23 - 6.97 (m, 2H), 5.07 (dd, Ji = 5.2, J2=13.2 Hz, 1H), 4.68 - 4.28 (m, 5H), 4.24 - 3.88 (m, 2H), 3.83 - 3.64 (m, 3H), 3.28 - 3.14 (m, 4H), 2.98 - 2.73 (m, 5H), 2.68 (s, 3H), 2.62 - 2.57(m, 2H), 2.45 - 2.25 (m, 8H), 2.11 - 1.75 (m. 10H), 1.70 - 1.60 (m, 3H), 1.54 - 1.39 (m. 2H), 0.97 (d, J= 6.4 Hz, 3H), 0.76 (t, J = 6.8 Hz, 3H).Example 1.34Exemplary synthesis of Compound 200:Step 1:Im, SOCI2 DCM, -50-15 °C, 15 h

[0244] To a solution of imidazole (3.78 g, 55 mmol, 6 eq) in dichloromethane (20 mL) is added a solution of thionyl chloride (1.65 g, 14 mmol, 1.01 mL, 1.5 eq) in dichloromethane (10 mL) dropwise at -50 °C under nitrogen atmosphere. The resulting mixture is stirred at -50 °C for 3 h. To the above mixture is added dropwise a solution of tert-butyl (35)-3-(hydroxymethyl)piperazine-l -carboxylate (2 g, 9 mmol, 1 eq) in dichloromethane (10 mL) under nitrogen atmosphere. The mixture is stirred at 15 °C for 12 h. The reaction mixture is diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase is washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated underARVN-174-PCT / / ARVN0174WO2reduced pressure to afford / c / v-butyl (3aS)-l-oxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate (1.88 g, 42%, 55% purity) as a white solid, which is used in the next step directly.NalO4, RUCI3ACN / EA / H2O, 0-25°C, 3 h

[0245] To a solution of tert-butyl (3aS)-l-oxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3.4-a]pyrazine-5-carboxylate (1 g, 2 mmol, 1 eq) in acetonitrile (5 mL) and ethyl acetate (5 mL) are added sodium periodate (582 mg, 2.73 mmol, 0.15 mL, 1.3 eq) and ruthenium trichloride (8 mg, 0.04 mmol. 0.1 mL, 0.02 eq) in water (10 mL) at 0°C. The mixture is stirred at 20°C for 3 h. The reaction mixture is filtered, and the filtrate is diluted with saturated sodium sulfite solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers are washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford t -butyl (3aS)-l,l-dioxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate (600 mg, crude) as a black solid, which is used in the next step directly. 'll NMR (400 MHz. CDCh-d) 8: 4.64 (dd, J = 6.4. 8.0 Hz, 1H), 4.31 - 4.07 (m. 3H), 3.68 - 3.59 (m, 1H), 3.45 (d, J = 11.2 Hz, 1H), 3.13 (s, 1H), 2.96 (dt, J= 3.2, 11.2 Hz, 2H), 1.47 (s, 9H).Step 3:

[0246] To a solution of methyl 4-bromo-3-hydroxy-benzoate (4.0 g, 17 mmol, 1 eq) in trifluoroacetic acid (50 mL) is added hexamethylenetetramine (9.87 g, 70 mmol, 4.07 eq). The mixture is stirred at 110 °C for 12 h. The reaction mixture is cooled to 20 °C, diluted with 2M aqueous hydrochloric acid solution (250 mL) and stirred for 10 min. Water (250 mL) is added, and the mixture is stirred for 1 h. The mixture is filtered, and the filter cake is dissolved in dichloromethane, filtered over celite, dried over anhydrous sodium sulfate and concentrated underARVN-174-PCT / / ARVN0174WO2reduced pressure to afford methyl 4-bromo-2-formyl-3-hydroxy-benzoate (3.3 g, 73%) as a yellow solid, which is used in the next step directly.Step 4:o

[0247] To a solution of methyl 4-bromo-2-formyl-3-hydroxy-benzoate (5.0 g, 19 mmol, 1 eq) and tert-butyl (4S)-4,5-diamino-5-oxo-pentanoate hydrochloride (4.84 g, 20 mmol, 1.05 eq) in methanol (70 mL) are added ^-diisopropylethylamine (2.62 g, 20 mmol. 3.53 mL, 1.05 eq), acetic acid (1.66 mL, 1.5 eq) and sodium cyanoborohydride (2.43 g, 38.6 mmol, 2 eq\, the mixture is stirred at 20 °C for 4.5 h. The reaction mixture is diluted with water (150 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=l / 3 to 0 / 1) to afford tert-butyl (4S)-5-amino-4-(5-bromo-4-hydroxy-l-oxo-isoindolin-2-yl)-5-oxo-pentanoate (6.8 g, 85%) as a yellow solid.!H NMR (400 MHz, DMSO- d) 3: 7.62 (s, 1H), 7.60 - 7.59 (m, 1H), 7.20(s, 1H), 7.10 (d, J = 8 Hz, 2H), 4.73 - 4.69 (m, 1H), 4.58 (d, J= 17.6 Hz, 1H), 4.39 (d,. / = 17.6 Hz, 1H), 2.19 - 2.13 (m, 3H), 2.02 - 1.95 (m. 1H), 1.31 (s, 9H).K2CO3, ACN, 60 °C 15 h

[0248] To a solution of tert-butyl (45)-5-amino-4-(5-bromo-4-hydroxy-l-oxo-isoindolin- 2-yl)-5-oxo-pentanoate (1.62 g, 5.8 mmol, 1 eq) in acetonitrile (20 mL) is added potassiumARVN-174-PCT / / ARVN0174WO2carbonate (2.41 g, 17 mmol, 3 eq), and the mixture is stirred at 60 °C for 15 h. The reaction mixture is filtered and washed with dichloromethane (50 mL). The filtrate is concentrated under reduced pressure. The reside is diluted with dichloromethane (36 mL) and -toluene sulphonic acid (2.21 g, 2 eq) is added, and the resulting solution is stirred for 3.5 h. The mixture is diluted with saturated aqueous sodium bicarbonate so...

Claims

1. ARVN-174-PCT / / ARVN0174WO2CLAIMS1. A compound having the chemical structure of Formula I:PTM-L-ULM (I)comprising (i) a Kirsten Rat Sarcoma (KRAS) protein targeting moiety (PTM); (ii) a linker (L) comprising a chemical structure-O-CH2-((geminal dihalocyclopropyl)methyl- (optionally substituted heterocycloalkylene)); and (iii) a Cereblon E3 ubiquitin ligase targeting moiety (ULM), in free or salt form.

2. The compound of claim 1, wherein the PTM comprises an optionally substitutedoxa-6- azaspiro[3.5]nonane.

3. The compound of claim 1 or 2, wherein the compound is a compound of Formula 1(A)’:KA)’in free or salt form, wherein:one of Zi and Z2 is O and the other is C(Ra)(Rb);X is =C(Ra)-, -C(Ra)(Rb)-, =N- or -N(Ra)-;Y is -N-, -C= or -C(Ra)-;each Raand Rb is independently H or Ci-4alkyl (e.g., methyl);Ri and R2 are independently halo (e.g. fluoro);R3 and R4 are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g.. methyl or ethyl), Ci-4alkoxy (e.g., methoxy) or haloCi-4alkoxy;ARVN-174-PCT / / ARVN0174WO2R12 and i? are independently H or Ci-4alkyl (e.g., methyl); or R4 and R12 or R4 and R13 together with the carbons to which they are attached form a cyclic structure, for example, R4 and R12 or R4 and R13 together can form a two-atom bridge such as, for example, -O-CH2- resulting in formation of a heterocyclic structure, e.g., an oxazepine;Moiety A is a 4-12 membered heterocycloalkylene:Moiety B and C are independently abond,Ci-4alkylene (e.g., methylene or ethylene),-OC(O)-,-C(O)-Ci-4alkylene,-O-,C(O),-N(Rx)-, wherein Rxis H or Ci-4alkyl (e.g., methyl);4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 7- azaspiro[3.5]nonanylene, 2,7-diazaspiro[3.5]nonanylene, 3,9- diazaspiro[5,5]undecanylene, 2-oxa-5,8-diazispiro[3.5]nonanylene, hexahydropyrrolo[3,4-c]pyrrolylene, 2,8-diazaspiro[4.5]decanylene, 1-oxa- 4,9-diazaspiro[5.5]undecanylene, 2,6-diazaspiro[3.3]heptanylene, pyiTolidinylene, azetidinylene, 2,5-diazabicyclo[2.2.1]heptanylene), or heteroarylene (e.g. pyridylene),wherein A, B and C are independently optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);Moiety D is selected from the following:ARVN-174-PCT / / ARVN0174WO2R5Re D-1wherein R5, Re and R7 are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci- 4alkyl (e.g., methyl or ethyl), C2-4alkynyl (e.g., ethynyl), C3-4cycloalkyl (e.g., cyclopropyl), Ci- 4alkoxy (e.g., methoxy), haloCi-4alkoxy (e.g., -O-C(F2)(H)), -OCH2-OP(O)(OH)2, -N(Ra)(Rb), -N(H)-C(O)CH3 or -N(H)-CH2CF3, wherein each Raand Rb is independently H or Ci-4alkyl (e.g., methyl); andULM is selected from:ULM-1ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ULM-15 ULM-16wherein:Rs is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;R9 is H, halo (e.g., chloro or fluoro), OH, Ci-4alkyl or Ci-4alkoxy (e.g., methoxy orethoxy);ARVN-174-PCT / / ARVN0174WO2R10 is H or C1-4alkyl (e.g., methyl);RH is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy;Q1, Q10 and Q11 are independently C(O) or C(Ra)(Rb);Q7x is N(R7x) or C(Ra)(Rb); wherein R7x is H, C1-4alkyl (e.g., methyl, ethyl, propyl such as isopropyl) or C3-6aycloalkyl (e.g., cyclopropyl); Each of R11 and R11x is independently H, halo (e.g., chloro or fluoro);Q12 is O or CH2;Q14 is N(R14a), C(Ra)(Rb), wherein R14a is H, C1-4alkyl (e.g., methyl, ethyl, propyl such as isopropyl) or C3-6aycloalkyl (e.g., cyclopropyl);Q14x is N(R14ax) or C(Ra)(Rb), wherein R14ax is H, C1-4alkyl (e.g., methyl) or C3-6aycloalkyl (e.g., cyclopropyl);Q15 is N(R15a) or C(Ra)(Rb), wherein R15a is H, C1-4alkyl (e.g., methyl) or C3-5cycloalkyl (e.g., cyclopropyl);Q16 is C(O) or C(Ra)(Rb);Each of R10x, R11x, R12x and R13x is independently C1-4alkyl (e.g., methyl); R14b is H or C1-4alkyl (e.g., methyl);R14 is H or Ci-4alkyl (e.g., methyl);Ri4x is H or Ci-4alkyl (e.g., methyl);R15 is H or halo (e.g., fluoro);Each of R16b and R16c is H or C1-4alkyl (e.g., methyl);R16d is H or halo (e.g., fluoro);R16e is H or C1-4alkyl (e.g., methyl);R18 is H or C1-4alkyl (e.g., methyl);each Raand Rb is independently H or Ci-4alkyl (e.g., methyl); or-A-B-C together with the ULM forms the following structure:ARVN-174-PCT / / ARVN0174WO2Formula JFormula K wherein each of Rjxand Rkx is independently C lkyl (e.g., methyl), R17 is H or halo (e.g., fluoro).

4. The compound of claim 1, 2 or 3, wherein the compound is a compound of Formula 1(A):KA)in free or salt form, wherein:one of Zi and Z2 is O and the other is C(Ra)(Rb);X is =C(Ra)-, -C(Ra)(Rb)-, =N- or -N(Ra)-;Y is -N-, -C= or -C(Ra)-;ARVN-174-PCT / / ARVN0174WO2each Raand Rb is independently H or Ci-4alkyl (e.g., methyl);Ri and R2 are independently halo (e.g. fluoro);R3 and R4 are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g.. methyl or ethyl), Ci-4alkoxy (e.g., methoxy) or haloCi-4alkoxy;R12 and R13 are independently H or Ci-4alkyl (e.g., methyl); or R4 and R12 or R4 and R13 together with the carbons to which they are attached form a cyclic structure, for example, R4 and R12 or R4 and R13 together can form a two-atom bridge such as, for example, -O-CH2- resulting in formation of a heterocyclic structure, e.g., an oxazepine;Moiety A is a 4-12 membered heterocycloalkylene;Moiety B and C are independently a bond, Ci-4alkylene (e.g., methylene), -OC(O)-, -C(O)-Ci-4alkylene, -O-, a 4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 7-azaspiro[3.5]nonanylene, 2,7-diazaspiro[3.5]nonanylene, 3,9-diazaspiro[5,5]undecanylene, 2-oxa-5,8-diazispiro[3.5]nonanylene, hexahydropyrrolo[3,4-c]pyrrolylene, 2,8-diazaspiro[4.5]decanylene, l-oxa-4,9-diazaspiro[5.5]undecanylene. 2,6-diazaspiro[3.3]heptanylene, pyrrolidinylene, azetidinylene, 2,5-diazabicyclo[2.

2. l]heptanylene), or a heteroarylene (e.g. pyridylene),wherein A, B and C are independently optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);Moiety D is selected from the following:wherein R5, Re and R7 are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci- 4alkyl (e.g.. methyl or ethyl), C2-4alkynyl (e.g., ethynyl), C3-4cycloalkyl (e.g., cyclopropyl), Ci-4alkoxy (e.g., methoxy), haloCi-4alkoxy (e.g., -O-C(F2)(H)), -OCH2-OP(O)(OH)2, -N(Ra)(Rb), -N(H)-C(0)CH3 or -N(H)-CH2CF3, wherein each Raand Rb is independently H or Ci-4alkyl (e.g., methyl); andULM is selected from:ARVN-174-PCT / / ARVN0174WO2wherein:Rs is H, halo (e.g., chloro or fluoro), -OH, Ci-4alkoxy or Ci-4alkyl (e.g., methyl);ARVN-174-PCT / / ARVN0174WO2Rg is H, halo (e.g., chloro or fluoro), -OH, Ci-4alkyl or Ci-4 lkoxy (e.g., methoxy or ethoxy);Rio is H or Ci-4alkyl (e.g., methyl);Rn is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), or Ci-4alkoxy;Q1, Q10 and Q11 are independently C(O) or C(Ra)(Rb);Q2is N(Ra) or C(Ra)(Rb);Q12 is O or CH2;R14 is H or Ci-4alkyl (e.g., methyl);R15 is H or halo (e.g., fluoro);each Raand Rbis independently H or Ci-4alkyl (e.g., methyl); or-A-B-C together with the ULM forms the following structure:Formula J Formula K wherein R17 is H or halo (e.g., fluoro).

5. The compound according to any of claims 1-4, wherein the compound is a compound of Formula 1(A)- 1:ARVN-174-PCT / / ARVN0174WO2Formula I(A)-2in free or salt form, wherein Zi, Z2, Ra, Rb Ri, R2, R3. R4, R12, R13, Moiety A, B, C, D, ULM, are as defined in any of claims 3-4.

6. The compound according to any of claims 1-5, wherein the compound is a compound of Formula I(A)-3:ARVN-174-PCT / / ARVN0174WO2KA)-3in free or salt form, wherein Ri, R2, R3, R4, R12, R13, Moiety A, B, C, D, ULM, are as defined in any of claims 3-4.

7. The compound according to any of claims 1-6, wherein the compound is a compound of Formula I(A)-4:Formula I(A)-4,in free or salt form, wherein Ri, R2, R3, R4, R12, R13, Moiety A, B, C, D, ULM, are as defined in any of claims 3-4.ARVN-174-PCT / / ARVN0174WO28. The compound according to any of claims 1-6, wherein the compound is a compound of Formula I(A)-5:Formula I(A)-5in free or salt form, wherein Ri, R2, R3, R4, R12, R13, Moiety A, B, C, D, ULM, are as defined in any of claims 3-4.

9. The compound according to any of claims 3-8, wherein moiety A is selected from:ARVN-174-PCT / / ARVN0174WO210. The compound according to any of claims 3-9, wherein:B is:a bond;Ci-4alkylene (e.g., methylene);C(O), or-N(Rx)-, wherein Rxis H or Ci-4alkyl (e.g., methyl);C is:a bond, ora 4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 7- azaspiro[3.5]nonanylene. 2,7-diazaspiro[3.5]nonanylene, 3.9- diazaspiro[5,5]undecanylene, 2-oxa-5,8-diazispiro[3.5]nonanylene, hexahydropyrrolo[3,4-c]pyrrolylene, 2,8-diazaspiro[4.5]decanylene, 1- oxa-4,9-diazaspiro[5.5]undecanylene, 2,6-diazaspiro[3.3]heptanylene, pyrrolidinylene, azetidinylene, 2,5-diazabicyclo[2.2.1]heptanylene), or a heteroarylene (e.g. pyridylene);wherein A, B and C are independently optionally substituted with one or more halo or Ci-4alkyl (e.g., methyl); andARVN-174-PCT / / ARVN0174WO2Moiety D is D-l to D-5, wherein R5, Re and R7 are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g.. ethynyl).

11. The compound according to any of claims 3-9, wherein moiety B is Ci-4alkylene (e.g., methylene) and moiety C is a 6-membered heterocycloalkylene optionally substituted with one or more Ci-4alkyl (e.g., methyl).

12. The compound according to any of claims 3-11, wherein -A-B-C- is selected from the following:or2 of or2ARVN-174-PCT / / ARVN0174WO213. The compound according to any of claims 3-11, wherein -A-B-C- is selected from the following:ARVN-174-PCT / / ARVN0174WO25ARVN-174-PCT / / ARVN0174WO214. The compound according to any of claims 3-13, wherein:Ri and R2 are both fluoro;R3 is H, halo (e.g. fluoro or chloro) or Ci-4alkyl (e.g., methyl or ethyl);R4 is H or Ci-4alkyl (e.g., methyl);R12 is H;D is Formula D-l, wherein R5 is H or hydroxy; Re is halo (e.g., fluoro or chloro); and R7 is Ci-4alkyl (e.g., methyl or ethyl), C2-4alkynyl (e.g., ethynyl).

15. The compound according to any of claims 3-13, wherein the compound is a compound of Formula I(A)-5, in free or salt form, wherein:Ri and R2 are independently halo (e.g. fluoro);R3 is halo (e.g. fluoro or chloro);R4is H;R12 and R13 are both H;Moiety D is formula D-l (a):ARVN-174-PCT / / ARVN0174WO2D-1(a)wherein: Rs is H or hydroxy; Re is H or halo (e.g. fluoro or chloro); and R? is H or Ci-4alkyl (e.g.. methyl or ethyl);Moiety A is a 6-membered heterocycloalkylene (e.g., piperidinylene or piperazinylene) optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);Moiety B is a Ci-4alkylene (e.g., methylene); andMoiety C is a 6-membered heterocycloalkylene (e.g., piperidinylene or piperazinylene) optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy).

16. The compound according to any of claims 3-15, wherein the ULM is ULM-1, wherein:Rs is H;R9 is H or halo (e.g., chloro or fluoro):Qi is C(O) or C(Ra)(Rb), wherein each Raand Rb is independently H or Ci-4alkyl (e.g., methyl).

17. The compound according to any of claims 3-15, wherein the ULM is ULM-2.

18. The compound according to any of claims 3-15, wherein the ULM is ULM-3.

19. The compound according to any of claims 3-15, wherein the ULM is ULM-4.

20. The compound according to any of claims 3-15, wherein the ULM is ULM-5.

21. The compound according to any of claims 3-15, wherein the ULM is ULM-6.

22. The compound according to any of claims 3-15, wherein the ULM is ULM-7-X, wherein:Q?x is N(R?x) or C(Ra)(Rb); wherein R?xis H, Ci-4alkyl (e.g., methyl, ethyl, propyl such as isopropyl) or C3-6cycloalkyl (e.g., cyclopropyl); Each of Rn and RHXis independently H, halo (e.g., chloro or fluoro).ARVN-174-PCT / / ARVN0174WO223. The compound according to any of claims 3-15, wherein the ULM is ULM-8.

24. The compound according to any of claims 3-15, wherein the ULM is ULM-9.

25. The compound according to any of claims 3-15, wherein the ULM is ULM-ll-X or ULM-10:0 0.ULM-10wherein:Qio is C(Ra)(Rb);Ri4 is H or Ci-4alkyl (e.g., methyl); andR15 is H or halo (e.g., fluoro).

26. The compound according to any of claims 3-15, wherein the ULM is ULM-11 or ULM- 11-X.

27. The compound according to any of claims 3-15, wherein the ULM is ULM- 12 or ULM- 12-X.

28. The compound according to any of claims 3-15, wherein the ULM is ULM- 13 or ULM- 13-X.

29. The compound according to any of claims 3-15, wherein the ULM is ULM- 14 or ULM- 14-X.

30. The compound according to any of claims 3-29, wherein the ULM is selected from:ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO25ARVN-174-PCT / / ARVN0174WO25 31. The compound according to any of claims 3-29, wherein the ULM is selected from:ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2ARVN-174-PCT / / ARVN0174WO2H32. The compound according to any of claims 3-29, wherein -A-B-C together with the ULM forms the following structureARVN-174-PCT / / ARVN0174WO2O or33. The compound according to any of claims 1-32, wherein the compound is selected from Compounds 1-211 of Table 1, Compounds 212-251 of Table 1-A and Compounds 252- 360 of Table 1-B, in free or salt form.

34. A pharmaceutical composition comprising the compound according to any one of claims 1-33, in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable carrier.

35. A method for the treatment or prophylaxis of a KRAS mediated disorder (such as an abnormal cellular proliferation disease or disorder, e.g., cancer) in a subject in need thereof, comprising administering to the subject an effective amount of any of the compound according to any one of claims 1-33, in free or pharmaceutically acceptable salt form, or the pharmaceutical composition according to claim 34.

36. A method for the treatment of a KRAS mediated disorder (such as an abnormal cellular proliferation disease or disorder, e.g., cancer) in a subject in need thereof, comprising administering to the subject an effective amount of any of the compound according to any one of claims 1-33, in free or pharmaceutically acceptable salt form, or the pharmaceutical composition according to claim 34.

37. The method according to claim 35 or 36, wherein the KRAS-mediated disease or disorder is cancer.ARVN-174-PCT / / ARVN0174WO238. The method according to claim 37, wherein the cancer is selected from pancreatic cancer, pancreatic ductal adenocarcinoma, pancreatic adenosquamous carcinoma, pancreatic squamous cell carcinoma, acinar cell carcinoma, giant cell tumor, pancreatoblastoma, invasive intraductal papillary mucinous neoplasm, invasive mucinous cystic neoplasm, colorectal cancer, colorectal adenocarcinoma, colorectal squamous cell carcinoma, lung cancer, non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and small cell lung cancer.

39. The method according to claim 37, wherein the cancer is pancreatic cancer, colorectal cancer, or lung cancer.

40. The method according to claim 37. wherein the cancer is pancreatic cancer.

41. The method according to claim 37. wherein the cancer is colorectal cancer.

42. The method according to claim 37, wherein the cancer is lung cancer.

43. The method according to claim 37, wherein the cancer is pancreatic ductal adenocarcinoma.

44. The method according to claim 37. wherein the cancer is non-small cell lung cancer.

45. A method of degrading a KRAS target protein in a cell comprising contacting the cell with an effective amount of the compound according to any one of claims 1-33, in free or salt form, or the pharmaceutical composition of claim 34, wherein the compound effectuates the degradation of the KRAS target protein.

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