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-210-PCT / / ARVN0210WO2KIRSTEN RAT SARCOMA (KRAS) PROTAC COMPOUNDS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONSThis application claims priority to U. S. Provisional Application Serial No. 63 / 779,248 filed March 27, 2025, and U. S. Provisional Application Serial No. 63 / 779,241 the contents of each 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-ARVN-210-PCT / / ARVN0210WO2bound 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, maintenance, 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 PROTAC compounds, pharmaceutical compositions and uses comprising the same, e.g.. for targeting KRAS and non-mutant wild-type KRAS. Such compounds include those having the chemical structure:PTM-L-ULM (I)comprising (i) a Kirsten Rat Sarcoma (KRAS) protein targeting moiety (PTM) comprising a chemical structure oxa-6-azaspiro[3.5]nonane; (ii) a linker (L) comprising a chemical structure -O-CH2-((cyclopropyl)methyl-(optionally substituted heterocycloalkylene)); and (iii) a Cereblon E3 ubiquitin ligase targeting moiety (ULM), wherein the compound is a compound of Formula I:ARVN-210-PCT / / ARVN0210WO2in free or salt form, wherein:X is =C(Ra)-, -C(Ra)(Rb)-, =N-;Y is -N-, -C= or -C(Ra)-;Each of Raand Rbis independently H or C1-4alkyl (e.g., methyl) or Rais R4;Each of R3 and R4 is independently H, Ci-4alkyl (e.g., methyl), halo (e.g. fluoro or chloro), -OH or Ci-4alkoxy (e.g., methoxy);Moiety A is a 4-12 membered heterocycloalkylene and moiety B and C are independently a bond, Ci-4alkylene (e.g., methylene), -OC(O)-, -C(O)-Ci-4alkylene- (e.g., -C(O)CH2-), -Ci-4alkylene-C(O)- (e.g., -CH2-C(O)-), -O- or a 4-12 membered heterocycloalkylene (e.g., piperidinylene. piperazinylene, 7-azaspiro[3.5]nonanylene, 2,7-diazaspiro[3.5]nonanylene, 2-azaspiro[3.3]heptanylene, 3,9-diazaspiro[5,5]undecanylene, 2-oxa-5,8-diazispiro[3.5]nonanylene, 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 hexahydropyrrolo[3,4-c]pyrrolylene), wherein each of moieties A, B and C is independently optionally substituted with one or more halo (e.g.. fluoro or chloro), Ci-4alkyl (e.g., methyl), hydroxy, =0, or Ci-4alkoxy (e.g., methoxy);ARVN-210-PCT / / AR VN0210WO2Moiety D is:R5R6wherein each of Rs, Re and R7 is independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), C2-4alkynyl (e.g., ethynyl), -OC(O)OCi-4alkyl (e.g., -OC(O)OCH3 or -OC(O)OCH2CH3) or -N(Ra)(Rb), wherein each of Raand Rb is independently H or Ci-4alkyl (e.g., methyl);ULM is selected from:ARVN-210-PCT / / AR VN0210WO2ULM-11 ULM-9'wherein:R8is H, halo (e.g., chloro or fluoro) or C1-4alkyl (e.g., methyl);R9 is H, halo (e.g., chloro or fluoro) or Ci-4alkoxy (e.g., methoxy or ethoxy);R9X is halo (e.g., chloro or fluoro);Rio is H, halo (e.g., chloro) or Ci-4alkyl (e.g., methyl);R11 is H or Ci-4alkyl (e.g., methyl);E is a bond, N(Ra) or -C(O)N(Ra)-;Each of Qi, Q3 and Q10 is independently C(O) or C(Ra)(Rb);Q2is N(Ra) or C(Ra)(Rb);Qu is -O-;R14 is H or Ci-4alkyl (e.g., methyl);ARVN-210-PCT / / ARVN0210WO2Ris is H or halo (e.g., fluoro);Each of Raand Rbis independently H or C1-4alkyl (e.g., methyl),Provided that:a) when moiety A is an optionally substituted spiro-heterocycloalkylene and B is a bond or a methylene, then C is not an unsubstituted piperazinylene; orb) when moiety A is an optionally substituted spiro-heterocycloalkylene, B is a bond or a methylene and C is an unsubstituted piperazinylene, then R9 of ULM-1 is not H (e.g., R9 is e.g., halo); Rs and R9 of ULM-2 are not both fluoro; and Rn of ULM-3 is not H (e.g., Rn of ULM-3 is halo); andc) when moiety A is a piperidinylene optionally substituted with a fluoro or a methyl at the 4-position, B is a methylene, and C is an unsubstituted piperazinylene, then:R9 of ULM-1 is not H (e.g., R9 is e.g., halo) or Qi of ULM-1 is not C(Ra)(Rb) wherein Raand Rb are both H;Rs and R9 of ULM-2 are not both fluoro; andR11 of ULM-3 is not H (e.g., Rn of ULM-3 is halo);d) when A is unsubstituted morpholino, B is a methylene, and C is an unsubstituted piperazinylene, then Rs and R9 of ULM-2 are not both fluoro.

[0006] In the second aspect, the disclosure provides pharmaceutical compositions comprising the compounds described herein (Formula I et seq. as disclosed below), in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable excipient or carrier (Composition I et seq.).

[0007] 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 et seq.).

[0008] 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 effectiveARVN-210-PCT / / ARVN0210WO2amount 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 et seq.).

[0009] In the fifth aspect, the disclosure provides methods of degrading a 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.) or any of the pharmaceutical compositions disclosed herein (any of Composition I et seq).

[0010] 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).

[0011] 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).

[0012] 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.).

[0013] In the nineth 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 coagent. The kit can comprise instructions for its administration.

[0014] In the tenth aspect, the disclosure provides a compound of Formula Q-I:PTM-L-ULM (Q-I)comprising (i) a protein targeting moiety (PTM) comprising a chemical structure l-oxa-6-azaspiro[3.5]nonan-6-ylpyrido[4,3-d]pyrimidinyl; (ii) a linker (L) comprising a chemical structure optionally substituted oxymethyl-(Co-4alkyl)- (optionally substituted 4-12 memberedARVN-210-PCT / / ARVN0210WO2heterocycloalkylene); and (iii) a Cereblon E3 ubiquitin ligase targeting moiety (ULM), in free or salt form (PROTAC compounds of Formula Q-I or “Formula Q-I”).

[0015] In a further embodiment, the present disclosure provides compounds of Formula Q-I(A):’N- B N A O mQ-I(A)’in free or salt form, wherein:Each of Ri and R2 is independently H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy), or Ri and R2 together with the carbon to which they are attached form a 4-8 membered heterocycyl, wherein the heterocycyl is optionally substituted one or more halo (e.g. fluoro or chloro) or Ci-4alkyl (e.g., methyl).Each of R3 and R4 is independently H, C lkyl (e.g., methyl) or halo (e.g. fluoro or chloro);Each of m and n is independently 0, 1 or 2;Moiety A is a 4-12 membered heterocycloalkylene (e.g., pyrrolidinylene, piperidinylene, piperazinylene, hexahydro- 1-H-pyrrolizinylene or 3,9-diazaspiro[5,5]undecanylene);Moiety B is a bond or Ci-4alkylene (e.g., methylene)), wherein each carbon may be optionally replaced with O or C(O);Moiety C is:a bond;4-12 membered heterocycloalkylene (e.g., piperazinylene, piperidinylene, 3,9- diazaspiro [5,5] undecanylene);ARVN-210-PCT / / ARVN0210WO2(heterocycloalkylene)-O-(heterocycloalkylene);(cycloalkylene)-O-(cycloalkylene),wherein each of moieties A, B and C is independently optionally substituted with one or more halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), Ci ^alkoxy (e.g., methoxy) or CO;Moiety D is an aryl optionally substituted with one or more hydroxy, halo (e.g. fluoro or chloro). Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl);ULM is selected from:wherein:Rs is H, OH, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);R9 is H, OH, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);R11 is H, OH, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);Qi is C(O) or C(Ra)(Rb);Q2 is N(Ra) or C(Ra)(Rb); andEach of Raand Rb is independently H or Ci-4alkyl (e.g., methyl).

[0016] In the eleventh aspect, the disclosure provides pharmaceutical compositions comprising the compounds described herein (Formula Q-I et seq. as disclosed below), in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable excipient or carrier (Composition Q-I et seq.).

[0017] In the twelfth 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 Q-I), comprising administering to the subject an effective amount of any of the compounds disclosed herein (any of Formula Q-I et seq.),ARVN-210-PCT / / ARVN0210WO2in free or pharmaceutically acceptable salt form, or an effective amount of any of the pharmaceutical compositions disclosed herein (any of Composition Q-I et seq.).

[0018] In the thirteenth 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 Q-I- A), comprising administering to the subject an effective amount of any of the compounds disclosed herein (any of Formula Q-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 Q-I et seq.).

[0019] In the fourteenth aspect, the disclosure provides methods of degrading a KRAS target protein in a cell (Method Q-II) comprising contacting the cell with an effective amount of any of the compounds disclosed herein (any of Formula Q-I et seq.) in free or pharmaceutically acceptable salt form or any of the pharmaceutical compositions disclosed herein (any of Composition Q-I et seq).

[0020] In the fifteenth aspect, the disclosure provides any of the compounds disclosed herein (any of Formula Q-I et seq.), in free or pharmaceutically acceptable salt form, or any of the pharmaceutical compositions disclosed herein (any of Composition Q-I et seq.) for the manufacture of a medicament for the treatment or prophylaxis of a KRAS mediated disorder (Medicament Q-I).

[0021] In the sixteenth aspect, the disclosure provides any of the compounds disclosed herein (any of Formula Q-I et seq.), in free or pharmaceutically acceptable salt form, or any of the pharmaceutical compositions disclosed herein (any of Composition Q-I et seq.) for the manufacture of a medicament for the treatment of a KRAS mediated disorder (Medicament Q-I-A).

[0022] In the seventeenth aspect, the disclosure provides any of the compounds disclosed herein (any of Formula Q-I et seq.), in free or pharmaceutically acceptable salt form, or any of the pharmaceutical compositions disclosed herein (any of Composition Q-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 Q-I et seq. or any of composition Q-I et seq. for use in any of Method Q-I or Q-I-A et seq. or Medicament Q-I or Medicament Q-I-A et seq.).ARVN-210-PCT / / ARVN0210WO2

[0023] Tn the eighteenth aspect, the disclosure provides any of the compounds disclosed herein (any of Formula Q-I et seq.), in free or pharmaceutically acceptable salt form, or any of the pharmaceutical compositions disclosed herein (any of Composition Q-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 Q-I et seq. or any of composition Q-I et seq. for use in any of Method Q-I or Q-I-A et seq. or Medicament Q-I or Q-I-A et seq.).

[0024] In the nineteenth 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 coagent. The kit can comprise instructions for its administration.DETAILED DESCRIPTION

[0025] Provided herein are Kirsten Rat Sarcoma (KRAS) PROTAC compounds (e.g., compounds of Formula (I) or Q-I or any disclosed herein) that target and degrade Kras, particularly 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.

[0026] 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.

[0027] 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.

[0028] 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, includingARVN-210-PCT / / ARVN0210WO2optical 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 one stereoisomer 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 el 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.

[0029] 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.ARVN-210-PCT / / ARVN0210WO2

[0030] As used herein, the articles “a” and “an” refer to one or to more than one ( / ., 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.

[0031] 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.

[0032] 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 the incidence 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] As used herein, the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of anARVN-210-PCT / / ARVN0210WO2agent 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.

[0037] 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.

[0038] 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 salts of 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.

[0039] 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.ARVN-210-PCT / / ARVN0210WO2Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0040] As used herein, the term “pharmaceutically acceptable earner” 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, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; 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.

[0041] 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.ARVN-210-PCT / / ARVN0210WO2

[0042] 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 (z.e.. Ci-6 alkyl means an alkyl having one to six carbon atoms) and includes straight and branched chains.

[0043] 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.

[0044] 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.

[0045] The term “arylene” means a non-terminal, e.g., bivalent aromatic ring system.

[0046] 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.

[0047] 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 (i.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.

[0048] 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 (i.e., lactones) and cyclic amides (i.e.. lactams).ARVN-210-PCT / / ARVN0210WO2

[0049] 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 piperidinylene, piperazinylene, 7-azaspiro[3.5]nonanylene, 2,7-diazaspiro[3.5]nonanylene, 2-azaspiro[3.3]heptanylene, 3,9-diazaspiro[5.5]undecanylene. 2-oxa-5.8-diazispiro[3.5]nonanylene, 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. l]heptanylene or hexahydropyrrolo [3,4-c] pyrrolylene.

[0050] 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.

[0051] 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).

[0052] 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 the orientation as drawn at said stereocenter and compounds with the opposite orientation as drawn at said stereocenter. 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 compounds with the orientations as drawn at said stereocenter and compounds with the opposite orientation as drawn at said stereocenter 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 withARVN-210-PCT / / AR VN0210WO2all variable orientation at each stereocenter are intended. Therefore, the “OR2” and “OR3” designation at the stereocenters in the exemplary Structure A below:indicate that any one of the compounds with the following structures is covered:or

[0053] The term “oxymethyl-(Co-4alkyl)-(optionally substituted 4-12 membered heterocycloalkylene)” means a linking moiety, e.g., that is a bivalent moiety comprising the following general structure:RiR2wherein Ri and R2 are independently hydrogen or non-hydrogen, m and n are 0-4 and moiety A is an optionally substituted 4-12 membered heterocycloalkylene.

[0054] In some embodiments, the l-oxa-6-azaspiro[3.5]nonane of the PTM of the present disclosure are numbered as follows:ARVN-210-PCT / / ARVN0210WO2Compounds of the present disclosure

[0055] Provided herein are compounds of Formula I having the chemical structure:PTM-L-ULMcomprising (i) a Kirsten Rat Sarcoma (KRAS) protein targeting moiety (PTM) comprising a chemical structure oxa-6-azaspiro[3.5]nonane; (ii) a linker (L) comprising a chemical structure-0-CH2-((cyclopropyl)methyl-(optionally substituted heterocycloalkylene)); and (iii) a Cereblon E3 ubiquitin ligase targeting moiety (ULM), in free or salt form. Exemplary PROTAC compounds of the current disclosure include the following:1.1. The 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. The compound of Formula I or Formula 1.1, wherein the PTM targets or binds to KRAS mutant protein.1.3. The compound of Formula I or any of formulae 1.1-1.2, wherein the PTM targets or binds to KRAS G12A.1.4. The compound of Formula I or any of formulae 1.1-1.2, wherein the PTM targets or binds to KRAS G12C.1.5. The compound of Formula I or any of formulae 1.1-1.2, wherein the PTM targets or binds to KRAS G12D.ARVN-210-PCT / / ARVN0210WO21.6. The compound of Formula I or any of formulae 1.1 - 1.2, wherein the PTM targets or binds to KRAS G12R.1.7. The compound of Formula I or any of formulae 1.1-1.2, wherein PTM targets or binds to KRAS G12V.1.8. The compound of Formula I or formula 1.1-, wherein the PTM targets or binds to a nonmutant wild-type KRAS.1.9. The compound of Formula I or any of formulae 1.1-1.8, wherein the compound is a compound of Formula I:Iin free or salt form, wherein:X is =C(Ra)-, -C(Ra)(Rb)-, =N-;Y is -N-, -C= or -C(Ra)-;Each of Raand Rbis independently H or C1-4alkyl (e.g., methyl) or Rais R4;Each of R3 and R4 is independently H, Ci-4alkyl (e.g., methyl), halo (e.g. fluoro or chloro), -OH or Ci-4alkoxy (e.g., methoxy);Moiety A is a 4-12 membered heterocycloalkylene and moiety B and C are independently a bond, Ci-4alkylene (e.g.. methylene), -OC(O)-, -C(O)-Ci-4alkylene- (e.g., -C(O)CH2-), -Ci-4alkylene-C(O)- (e.g., -CH2-C(O)-), -O- or a 4-12 membered heterocycloalkylene (e.g.,ARVN-210-PCT / / AR VN0210WO2piperidinylene, piperazinylene, 7-azaspiro[3.5]nonanylene, 2,7-diazaspiro[3.5]nonanylene, 2-azaspiro[3.3]heptanylene, 3,9-diazaspiro[5,5]undecanylene, 2-oxa-5,8-diazispiro[3.5]nonanylene, 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), wherein each of moieties A, B and C is independently optionally substituted with one or more halo (e.g., fluoro or chloro). Ci-4alkyl (e.g., methyl), hydroxy, =0, or Ci-4alkoxy (e.g., methoxy);Moiety D is:R5R6wherein each of Rs, Re and R? is independently H, hydroxy, halo (e.g. fluoro or chloro). Ci-4alkyl (e.g., methyl or ethyl), C2-4alkynyl (e.g., ethynyl), -0C(0)0Ci-4alkyl (e.g., -OC(O)OCH3 or -OC(O)OCH2CH3) or -N(Ra)(Rb), wherein each of Raand Rb is independently H or Ci-4alkyl (e.g., methyl);ULM is selected from:ARVN-210-PCT / / ARVN0210WO2ULM-7 ULM-8ARVN-210-PCT / / AR VN0210WO2ULM-11 ULM-9'wherein:R8 is H, halo (e.g., chloro or fluoro) or Ci-4alkyl (e.g., methyl);R9 is H, halo (e.g., chloro or fluoro) or Ci-4alkoxy (e.g., methoxy or ethoxy);R9x is halo (e.g., chloro or fluoro);R10 is H, halo (e.g., chloro) or Ci-4alkyl (e.g., methyl);R11 is H or Ci-4alkyl (e.g., methyl);E is a bond, N(Ra) or -C(O)N(Ra)-;Each of Q1, Q3 and Q10 is independently C(O) or C(Ra)(Rb):Q2is N(Ra) or C(Ra)(Rb);Q11 is -O-;R14 is H or Ci-4alkyl (e.g., methyl);R15 is H or halo (e.g., fluoro);Each of Ra and Rb is independently H or Ci-4alkyl (e.g., methyl).Provided that:a) when moiety A is an optionally substituted spiro-heterocycloalkylene and B is a bond or a methylene, then C is not an unsubstituted piperazinylene; orARVN-210-PCT / / AR VN0210WO2b) when moiety A is an optionally substituted spiro-heterocycloalkylene, B is a bond or a methylene and C is an unsubstituted piperazinylene, then R9 of ULM-1 is not H (e.g., R9 is e.g., halo); Rs and R9 of ULM-2 are not both fluoro; and Rn of ULM-3 is not H (e.g., Rn of ULM-3 is halo); andc) when moiety A is a piperidinylene optionally substituted with a fluoro or a methyl at the 4-position, B is a methylene, and C is an unsubstituted piperazinylene, then:R9 of ULM-1 is not H (e.g., R9 is e.g., halo) or Q1 of ULM-1 is not C(Ra)(Rb) wherein Ra and Rb are both H;Rs and R9 of ULM-2 are not both fluoro; andRn of ULM-3 is not H (e.g., Rn of ULM-3 is halo);d) when A is unsubstituted morpholino, B is a methylene, and C is an unsubstituted piperazinylene, then Rs and R9 of ULM-2 are not both fluoro.1.10. Formula 1.9, wherein X is =C(Ra)-, -C(Ra)(Rb)- or =N-; and Y is -N-, -C= or -C(Ra)-. 1.11. Any of formulae 1.9-1.10, wherein X is =N- and Y is -C=.1.12. Any of formulae 1.9-1.11, wherein the compound is a compound of formula 1(A)Formula 1(A)1.13. Any of formulae 1.9-1.10, wherein Y is -N- and X is C(Ra)(Rb).1.14. Any of formulae 1.9-1.10, wherein the compound is a compound of formula 1(B):ARVN-210-PCT / / AR VN0210WO2, ULMCFormula 1(B)1.15. Any of formulae 1.9-1.10, wherein X is =C(Ra)- and Y is -C=.1.16. Any of formulae 1.9-1.10, wherein the compound is a compound of formula 1(C)1.17. Any of the foregoing formulae, wherein the compound is a compound of Formula I(A)-1:1.18. Any of the foregoing formulae, wherein the compound is a compound of Formula I(A)-2:ARVN-210-PCT / / ARVN0210WO2Formula I(A)-21.19. Any of formulae 1.9-1.18, wherein each of R3 and R4 is independently H, Ci-4alkyl (e.g., methyl), halo (e.g. fluoro or chloro), -OH or Ci-4alkoxy (e.g., methoxy).1.20. Any of formulae 1.9-1.19, wherein:R3 and R4 are independently H, Ci-4alkyl (e.g., methyl or halo (e.g. fluoro or chloro); D is Formula D-lD-lwherein R5 is H or hydroxy; Re is halo (e.g., fluoro or chloro); and R7 is Ci-4alkyl (e.g., methyl or ethyl) or C24alkynyl (e.g., ethynyl).1.21. Any of formulae 1.17-1.19, wherein:R3 and R4 are independently H, Ci-4alkyl (e.g., methyl or halo (e.g. fluoro or chloro); D is Formula D-l;Moiety A is a 4-12 membered heterocycloalkylene;Moiety B is independently a bond, Ci- alkylene (e.g., methylene), -OC(O)-, -C(O)-Ci- 4alkylene (e.g., -C(O)CH3), -Ci-4alkylene-C(O)- (e.g., -CH2-C(O)-), -O-; and moiety C is a 4-12 membered heterocycloalkylenewherein each of moiety A and C is optionally substituted with halo (e.g., fluoro or chloro), Ci-4alkyl (e.g., methyl), hydroxy, =0, or Ci-4alkoxy (e.g., methoxy).ARVN-210-PCT / / ARVN0210WO21.22. Any of formulae 1.9-1.21, wherein moiety B is Ci-4alkylene (e.g., methylene or ethylene).1.23. Any of formulae 1.9-1.21, wherein:Each of R3 and R4 is independently H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);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) or C2-4alkynyl (e.g., ethynyl);Moiety A is a 9-11 membered heterocycloalkylene (e.g., spiro-heterocycloalkylene), wherein moiety A is optionally substituted with halo (e.g., fluoro or chloro), Ci-4alkyl (e.g., methyl), hydroxy, =0, or Ci-4alkoxy (e.g., methoxy);Moiety B is a bond; andMoiety C is a bond.1.24. Any of formulae 1.9-1.23, wherein moiety A is optionally substituted with one or more halo (e.g., fluoro) or Ci-4alkyl (e.g., one methyl or two methyl groups).1.25. Any of formulae 1.9-1.23, wherein moiety A is substituted fluoro.1.26. Any of formulae 1.9-1.25, wherein moiety C is optionally substituted with one or more Ci-4alkyl (e.g., one methyl or two methyl groups).1.27. Any of formulae 1.9-1.26, wherein each of R3 and R4 is independently H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro).1.28. Any of formulae 1.9-1.27, wherein each of R3 and R4 is independently H.1.29. Any of formulae 1.9-1.28, wherein each of R3 and R4 is independently Ci-4alkyl (e.g., methyl).1.30. Any of formulae 1.9-1.28, wherein each of R3 and R4 is independently halo (e.g. fluoro or chloro).1.31. Any of formulae 1.9-1.30, wherein R3 is H.1.32. Any of formulae 1.9-1.30, wherein R3 is Ci-4alkyl (e.g., methyl).1.33. Any of formulae 1.9-1.30, wherein R3 is methyl.1.34. Any of formulae 1.9-1.30, wherein R3 is fluoro.1.35. Any of formulae 1.9-1.30, wherein R3 is chloro1.36. Any of formulae 1.9-1.35, wherein R4 is H.ARVN-210-PCT / / ARVN0210WO21.37. Any of formulae 1.9-1.35, wherein R4 is Ci-4alkyl (e.g., methyl).1.38. Any of formulae 1.9-1.35, wherein R4 is methyl.1.39. Any of formulae 1.9-1.35, wherein R4 is fluoro.1.40. Any of formulae 1.9-1.35, wherein R4 is chloro.1.41. Any of formulae 1.9-1.40, wherein moiety D is Formula D-l having the following structure:R1.42. Any of formulae 1.9-1.41, wherein each of Rs, Re and R7 is independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), C2-4alkynyl (e.g., ethynyl), - OC(O)OCi-4alkyl (e.g., -OC(O)OCH3 or -OC(O)OCH2CH3) or -N(Ra)(Rb), wherein each of Raand Rb is independently H or Ci-4alkyl (e.g., methyl).1.43. Any of formulae 1.9-1.42, wherein R5 is H, halo (e.g. fluoro or chloro), -OC(O)OCi- 4alkyl (e.g., -OC(O)OCH3 or -OC(O)OCH2CH3) or -N(Ra)(Rb), wherein each of Raand Rb is independently H or Ci-4alkyl (e.g., methyl).1.44. Any of formulae 1.9-1.43, wherein R5 is H.1.45. Any of the foregoing formulae 1.9-1.43, wherein R5 is hydroxy.1.46. Any of the foregoing formulae 1.9-1.43. wherein R5 is halo (e.g. fluoro or chloro).1.47. Any of the foregoing formulae 1.9-1.43, wherein R5 is chloro.1.48. Any of the foregoing formulae 1.9-1.43, wherein R5 is fluoro.1.49. Any of the foregoing formulae 1.9-1.43, wherein Rs is -OC(O)OCi-4alkyl (e.g., - OC(O)OCH3or -OC(O)OCH2CH3).1.50. Any of the foregoing formulae 1.9-1.43, wherein Rs is -N(Ra)(Rb).1.51. Any of the foregoing formulae 1.9-1.43, wherein Rs is haloCi-4alkoxy (e.g., -O- C(F2)(H)).1.52. Any of formulae 1.9-1.51, wherein each of Re and R7 is independently H, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).1.53. Any of formulae 1.9-1.52, wherein each of Re and R7 is independently H.ARVN-210-PCT / / ARVN0210WO21.54. Any of formulae 1.9-1.53, wherein each of Re and R? is independently halo (e.g. fluoro or chloro).1.55. Any of formulae 1.9-1.54, wherein Re is H.1.56. Any of formulae 1.9-1.54, wherein Re is halo (e.g. fluoro or chloro).1.57. Any of formulae 1.9-1.54, wherein Re fluoro.1.58. Any of formulae 1.9-1.54, wherein Re chloro.1.59. Any of formulae 1.9-1.58, wherein R? is Ci-4alkyl (e.g., methyl or ethyl).1.60. Any of formulae 1.9-1.59, wherein R? is ethyl.1.61. Any of formulae 1.9-1.58, wherein R? is C2-4alkynyl (e.g., ethynyl).1.62. Any of formulae 1.9-1.58, wherein R? is ethynyl.1.63. Any of formulae 1.9-1.62, wherein Raand Rb are independently H or Ci-4alkyl (e.g.. methyl) or Rais R4.1.64. Formula 1.63, wherein Raand Rb are both H.1.65. Formula 1.63, wherein the compound is Formula 1(C) wherein X is =C(Ra)- and Rais R4.1.66. Any of formulae 1.9-1.63, wherein Rais H and Rb is Ci-4alkyl (e.g., methyl).1.67. Any of formulae 1.9-1.63, wherein Rais H and Rb is methyl.1.68. Any of formulae 1.9-1.67, wherein moiety A is a 4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 7-azaspiro[3.5]nonanylene, 2,7- diazaspiro[3.5]nonanylene, 2-azaspiro[3.3]heptanylene, 3,9-diazaspiro[5.5]undecanylene, 2-oxa-5,8-diazispiro[3.5]nonanylene, 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 hexahydropyrrolo[3,4- c]pyrrolylene), wherein each of moieties A, B and C is independently optionally substituted with one or more halo (e.g., fluoro or chloro), Ci-4alkyl (e.g., methyl), hydroxy, =0, or Ci-4alkoxy (e.g.. methoxy).1.69. Any of formulae 1.9-1.68, 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).1.70. Any of formulae 1.9-1.69, wherein moiety A is a 4-11 membered heterocycloalkylene (e.g., 6-8 membered monocyclic- heterocycloalkylene, 8-10 membered fused-multicyclicARVN-210-PCT / / ARVN0210WO2heterocycloalkylene, 7-11 membered multicyclic spiro- heterocycloalkylene or 7-8 bridged heterocycloalkylene or any combination of fused- heterocycloalkylene, spiroheterocycloalkylene and / or bridged heterocycloalkylene).1.71. Any of formulae 1.9-1.70, wherein moiety A is a 6-11 membered heterocycloalkylene.1.72. Any of formulae 1.9-1.71, wherein moiety A is a 4-6 membered mono-cyclic heterocycloalkylene.1.73. Any of formulae 1.9-1.72, wherein moiety A is a piperidinylene.1.74. Any of formulae 1.9-1.72, wherein moiety A is a piperazinylene.1.75. Any of formulae 1.9-1.70, wherein moiety A is 4-membered heterocycloakylene (e.g., azetidinylene).1.76. Any of formulae 1.9-1.70, wherein moiety A is 5-membered heterocycloakylene (e.g., pyrrolidinylene).1.77. Any of formulae 1.9-1.70, wherein moiety A is a 7-11 membered multicyclic spiro- heterocycloakylene.1.78. Formula 1.77, wherein moiety A is 7-membered heterocycloakylene (e.g., 7-membered spiro-heterocycloakylene, for example, 2-azaspiro[3.3]heptanylene or 2,6- diazaspiro [3.3] heptanylene).1.79. Formula 1.77, wherein moiety A is an 8-membered heterocycloakylene (e.g., 8- membered fused-heterocycloakylene, for example, hexahydropyrrolo[3,4-c]pyrrolylene).1.80. Formula 1.77, wherein moiety A is a 9-membered heterocycloakylene (e.g., 9-membered spiro-heterocycloakylene, for example, 7-azaspiro[3.5]nonanylene, 2,7- diazaspiro[3.5]nonanylene, 2-oxa-5,8-diazispiro[3.5]nonanylene).1.81. Formula 1.77, wherein moiety A is a 7-azaspiro[3.5]nonanylene.1.82. Formula 1.77, wherein moiety A is an 10-membered heterocycloalkylene (e.g., 10- membered spiro-heterocycloakylene, for example, 2,8-diazaspiro[4.5]decenylene).1.83. Formula 1.77, wherein moiety A is an 11-membered heterocycloalkylene (e.g., 11- membered spiro-heterocycloakylene, for example, 3,9-diazaspiro[5,5]undecanylene or 1- oxa-4,9-diazaspiro[5.5]undecanylene).1.84. Any of formulae 1.9-1.70, wherein moiety A is an hexahydropyrrolo[3,4-c]pyrrolylene.1.85. Any of formulae 1.9-1.70, wherein moiety A is a bridged heterocycloalkylene.ARVN-210-PCT / / ARVN0210WO21.86. Formula 1.85, wherein moiety A is a 2,5-diazabicyclo[2.2.1]heptanylene.1.87. Any of formulae 1.9-1.86, wherein moiety A is optionally substituted with one or more halo, Ci-4alkyl (e.g.. methyl) or Ci-4alkoxy (e.g., methoxy).1.88. Any of formulae 1.9-1.87, wherein moiety A is unsubstituted.1.89. Any of formulae 1.9-1.87, wherein moiety A is substituted with one or more halo (e.g., fluoro).1.90. Any of formulae 1.9-1.87, wherein moiety A is substituted with one or more Ci-4alkyl (e.g., methyl).1.91. Any of formulae 1.9-1.87, wherein moiety A is a spiro-heterocycloakylene substituted with one or more halo (e.g., fluoro) and / or Ci-4alkyl (e.g., methyl).1.92. Any of formulae 1.9-1.87, wherein moiety A is substituted with one or more Ci-4alkoxy (e.g., methoxy).1.93. Any of formulae 1.9-1.87, wherein moiety A is piperidinylene substituted with one or more halo (e.g., fluoro).1.94. Any of formulae 1.9-1.87, wherein moiety A is piperidinylene substituted with one or more Ci-4alkyl (e.g., methyl).1.95. Any of formulae 1.9-1.87, wherein moiety A is piperidinylene substituted with one or more hydroxy or Ci-4alkoxy (e.g., methoxy).1.96. Any of formulae 1.9-1.87, wherein moiety A is piperidinylene substituted with hydroxy.1.97. Any of formulae 1.9-1.87, wherein moiety A is piperidinylene substituted with methoxy 1.98. Any of formulae 1.9-1.87, wherein moiety A is piperazinylene substituted with one or more Ci-4alkyl (e.g.. methyl).1.99. Any of formulae 1.9-1.98, wherein moiety A is selected from any of the following:ARVN-210-PCT / / AR VN0210WO21.100. Any of formulae 1.9-1.99, wherein moiety A is:1.101. Any of formulae 1.9-1.99, wherein moiety A is:1.102. Any of formulae 1.9-1.99, wherein moiety A is:1.103. Any of formulae 1.9-1.99, wherein moiety A is:ARVN-210-PCT / / ARVN0210WO21.104. Any of formulae 1.9-1.99, wherein moiety A is:1.105. Any of formulae 1.9-1.104, wherein each of moiety B and moiety C is independently a bond, Ci-4alkylene (e.g., methylene), -OC(O)-, -C(O)-Ci-4alkylene (e.g., -C(O)CH3), -Ci- 4alkylene-C(O)- (e.g., -CH2-C(O)-), -O- or a 4-12 membered heterocycloalkylene.1.106. Any of formulae 1.9-1.104, wherein each of moieties B and moiety C is independently a bond.1.107. Any of formulae 1.9-1.104, wherein moiety B is a bond.1.108. Any of formulae 1.9-1.104, wherein moiety B and moiety C are both a bond.1.109. Any of formulae 1.9-1.104, wherein each of moieties B and moiety C is independently Ci-4alkylene (e.g., methylene or ethylene).1.110. Any of formulae 1.9-1.104, wherein moiety B is ethylene.1.111. Any of formulae 1.9-1.104, wherein moiety B is methylene.1.112. Any of formulae 1.9-1.104, wherein moiety B is -OC(O)-.1.113. Any of formulae 1.9-1.104, wherein moiety B is -C(O)-Ci-4alkylene (e.g., -C(O)CH2-) or -Ci-4alkylene-C(O)- (e.g., -CH2-C(O)-).1.114. Any of formulae 1.9-1.104, wherein moiety B is -O-.1.115. Any of formulae 1.9- 1.114, wherein moiety B is a 4-12 membered heterocycloalkylene as described in any of formulae 1.68-1.104.1.116. Any of formulae 1.9-1.115, wherein moiety C is a 4-12 membered heterocycloalkylene as described in any of formulae 1.68-1.104.1.117. Any of formulae 1.9-1.116. wherein each of moiety B and moiety C is optionally substituted with one or more halo, Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy).ARVN-210-PCT / / AR VN0210WO21.118. Any of formulae 1.9- 1.116, wherein each of moiety B and moiety C is independently unsubstituted.1.119. Any of formulae 1.9-1.116. wherein each of moiety B and moiety C is independently substituted with one or more halo (e.g., fluoro).1.120. Any of formulae 1.9-1.116, wherein each of moiety B and moiety C is independently substituted with one or more Ci-4alkyl (e.g.. methyl).1.121. Any of formulae 1.9-1.116, wherein each of moiety B and moiety C is independently substituted with one or more Ci-4alkoxy (e.g., methoxy).1.122. Any of formulae 1.9-1.116, wherein moiety each of moiety A and moiety C is independently substituted with one or more Ci-4alkyl (e.g., methyl) and halo (e.g., fluoro).1.123. Any of formulae 1.9-1.122, wherein C is a 4-12 membered optionally substituted heterocycloalkylene selected from:ARVN-210-PCT / / AR VN0210WO21.124. Any of formulae 1.9-1.122, wherein moiety C is a bond.1.125. Any of formulae 1.9-1.26, wherein the ULM is selected from:ULM-7 ULM-8ARVN-210-PCT / / AR VN0210WO2ULM-11wherein:Rs is H, halo (e.g., chloro or fluoro) or Ci-4alkyl (e.g., methyl);R9 is H, halo (e.g.. chloro or fluoro) or Ci-4alkoxy (e.g., methoxy or ethoxy);Rio is H, halo (e.g., chloro) or Ci-4alkyl (e.g., methyl);R11 is H or Ci-4alkyl (e.g., methyl);E is a bond, N(Ra) or -C(O)N(Ra)-;Each of Qi, Q3 and Q10 is independently C(O) or C(Ra)(Rb);Q2 is N(Ra) or C(Ra)(Rb);Q11 is -O-;R14 is H or Ci-4alkyl (e.g., methyl);R15 is H or halo (e.g., fluoro):Each of Raand Rb is independently H or Ci-4alkyl (e.g., methyl).1.126. Any of formulae 1.9-1.125, wherein the ULM is ULM-1.1.127. Any of formulae 1.9-1.126, wherein Qi is C(O) or C(Ra)(Rb).1.128. Any of formulae 1.9-1.126, wherein Qi is C(O).1.129. Any of formulae 1.9-1.126, wherein Qi is C(Ra)(Rb).1.130. Any of formulae 1.9-1.125, wherein the ULM is ULM-2.ARVN-210-PCT / / ARVN0210WO21.131. formula 1.130, wherein E is a bond, N(Ra) or -C(O)N(Ra)-.1.132. formula 1.130 or 1.131, wherein E is a bond.1.133. formula 1.130 or 1.131, wherein E is N(Ra).1.134. formula 1.130 or 1.131, wherein E is -C(O)N(Ra)-.1.135. Any of formulae 1.9-1.125, wherein the ULM is ULM-6.1.136. Any of formulae 1.9-1.125. wherein the ULM is ULM-4.1.137. Any of formulae 1.9-1.136, wherein R10 is H, halo (e.g., chloro) or Ci-4alkyl (e.g., methyl).1.138. Any of formulae 1.9-1.137, wherein Rio is H.1.139. Any of formulae 1.9-1.137, wherein R10 is halo (e.g., chloro).1.140. Formula 1.136, wherein R is Ci-4alkyl (e.g., methyl).1.141. Any of formulae 1.9-1.125 wherein the ULM is ULM-3.1.142. Any of formulae 1.9-1.141, wherein Q2 is N(Ra) or C(Ra)(Rb).1.143. Any of formulae 1.9-1.141, wherein Q2 is N(Ra).1.144. Any of formulae 1.9-1.141, wherein Q2 is C(Ra)(Rb).1.145. Any of formulae 1.141-1.144, wherein Rn is H or Ci-4alkyl (e.g., methyl).1.146. Any of formulae 1.141-1.144, wherein Rn is H.1.147. Any of formulae 1.141-1.144, wherein Rn is C1-4alkyl (e.g., methyl).1.148. Any of formulae 1.9-1.125, wherein the ULM is ULM-5.1.149. Formula 1.148, wherein Qi is C(O) and Q3 is C(Ra)(Rb).1.150. Formula 1.148, wherein Q3 is C(O) and Qi is C(Ra)(Rb).1.151. Any of formulae 1.9-1.150. wherein the ULM is ULM-8.1.152. Any of formulae 1.9-1.150, wherein the ULM is ULM-91.153. Any of formulae 1.9-1.152, wherein Q2 is N(Ra) or C(Ra)(Rb).1.154. Any of formulae 1.9-1.153. wherein Q2 is N(Ra).1.155. Any of formulae 1.9-1.153, wherein Q2 is C(Ra)(Rb).1.156. Any of formulae 1.151-1.155, wherein Raand Rb are independently H.1.157. Any of formulae 1.151-1.156, wherein Raand Rb are independently Ci-4alkyl (e.g., methyl).1.158. Any of formulae 1.9-1.150, wherein the ULM is ULM-10.ARVN-210-PCT / / ARVN0210WO21.159. Any of formulae 1.9-1.158, wherein R14 is H or Ci-4alkyl (e.g., methyl).1.160. Any of formulae 1.9-1.159, wherein R14 is H.1.161. Any of formulae 1.9-1.159. wherein R is CiMalkyl (e.g., methyl).1.162. Any of formulae 1.9-1.150, wherein the ULM is ULM-11.1.163. Any of formulae 1.9-1.160, wherein R15 is H or halo (e.g., fluoro).1.164. Any of formulae 1.9-1.163. wherein Rs is H or halo (e.g., chloro or fluoro).1.165. Any of formulae 1.9-1.164, wherein Rs is H.1.166. Any of formulae 1.9-1.166, wherein Rs is halo (e.g., chloro or fluoro).1.167. Any of formulae 1.9-1.166, wherein R9 is H, halo (e.g., chloro or fluoro) or CiMalkoxy (e.g., methoxy or ethoxy).1.168. Any of formulae 1.9-1.166, wherein R9 is H.1.169. Any of formulae 1.9-1.166, wherein R9 is halo (e.g., chloro or fluoro).1.170. Any of formulae 1.9-1.166, wherein R9 is CiMalkoxy (e.g., methoxy or ethoxy).1.171. Any of formulae 1.9-1.170. wherein each of Raand Rb is independently H or CiMalkyl (e.g., methyl).1.172. Any of formulae 1.9-1.171, wherein each of Raand Rb is independently H.1.173. Any of formulae 1.9-1.171, wherein Raand Rb are both H.1.174. Any of formulae 1.9-1.171, wherein each of Raand Rb is independently Ci-4alkyl (e.g., methyl)1.175. Any of formulae 1.9-1.171, wherein Rais Ci alkyl (e.g., methyl).1.176. Any of formulae 1.9-1.175, wherein the ULM is ULM-8(a):ULM-8 (a).1.177. Any of formulae 1.9-1.175, wherein the ULM is ULM-8(b):ARVN-210-PCT / / AR VN0210WO2ULM-8(b)1.178. Any of formulae 1.9-1.175. wherein the ULM is:1.179. Any of formulae 1.9-1.175, wherein the ULM is ULM-9(a):ULM-9(a).1.180. Any of formulae 1.9-1.175. wherein the ULM is ULM-9(b):OOULM-9(b).1.181. Any of formulae 1.9-1.180, wherein the ULM is:ARVN-210-PCT / / AR VN0210WO2ARVN-210-PCT / / AR VN0210WO2rom the followingARVN-210-PCT / / ARVN0210W02 F F FF fFFF FARVN-210-PCT / / AR VN0210WO2rom the following:ARVN-210-PCT / / AR VN0210WO21.190. Any of formulae 1.9-1.187, wherein -A-B-C- is selected from the following:1.191. Any of formulae 1.9-1.187 wherein -A-B-C- is selected from the following:ARVN-210-PCT / / AR VN0210WO2rom the following:rom the following:ARVN-210-PCT / / AR VN0210WO21.194. Any of formulae 1.9-1.175, wherein -A-B-C- is selected from the following:1.195. Any of formulae 1.9-1.175, wherein -A-B-C- is selected from the following:1.196. Any of formulae 1.9-1.187, wherein -A-B-C- is selected from the following:1.197. Any of formulae 1.9-1.187, wherein -A-B-C- is selected from the following:ARVN-210-PCT / / AR VN0210WO21.198. Any of formulae 1.9-1.187, wherein -A-B-C- is selected from the following:1.199. Any of formulae 1.9-1.187, wherein -A-B-C- is selected from the following:1.200. Any of formulae 1.9-1.187, wherein -A-B-C- is the following:1.201. Any of formulae 1.9-1.187, wherein -A-B-C- is the following:1.202. Any of formulae 1.9-1.187, wherein -A-B-C- is the following:1.203. Any of formulae 1.9-1.187, wherein -A-B-C- is the following:1.204. Any of formulae 1.9-1.187, wherein -A-B-C- is the following:ARVN-210-PCT / / AR VN0210WO21.205. Any of formulae 1.9-1.204, wherein the ULM is selected from the following:5ARVN-210-PCT / / ARVN0210WO21.206. Any of formulae 1.9-1.205, wherein the compound is in free or pharmaceutically acceptable salt form.1.207. Any of the foregoing formulae, wherein the compound is in free form.1.208. Any of the foregoing formulae, wherein the compound is in salt form.1.209. Any of the foregoing formulae, wherein the compound is in pharmaceutically acceptable salt form.1.210. Any of the foregoing formulae, wherein the compound is in isotopic form (e.g, in deuterated form).1.211. 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).1.212. Any of the foregoing formulae, wherein the compound is in racemic form.1.213. Any of the foregoing formulae, wherein the compound degrades KRAS G12 mutations including KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, and KRAS G12V.1.214. Any of the foregoing formulae, wherein the compound degrades non-mutated wild-type KRAS.1.215. Any of the foregoing formulae, wherein the compound degrades KRAS G12D.1.216. Any of the foregoing formulae, wherein the compound degrades KRAS G12V.1.217. Any of the foregoing formulae, wherein the compound degrades KRAS G12C.ARVN-210-PCT / / ARVN0210WO21.218. Any of the foregoing formulae, wherein the compound degrades KRAS (wild-type or mutation KRAS) in cells carrying such KRAS (wild-type or mutation KRAS) at 24 hour with an DC50of less than 100nM, preferably less than 75nM, preferably less than 50nM, preferably less than 10nM, e.g., in an in vitro assay as described in Example 2 below. 1.219. Any of the foregoing formulae, wherein the compound degrades KRAS (wild-type or mutation KRAS)in cells carrying such KRAS (wild-type or mutation KRAS) 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.1.220. Any of the foregoing formulae, wherein KRAS mutant is a KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, and KRAS G12V.1.221. Any of the foregoing formulae, wherein KRAS mutant is a G 12V KRAS.1.222. Any of the foregoing formulae, wherein KRAS mutant is a G12D KRAS.1.223. Any of the foregoing formulae, wherein KRAS mutant is a G12C KRAS.1.224. Any of the foregoing formulae, wherein KRAS is a non-mutated wild-type KRAS.1.225. Any of the foregoing formulae, wherein -A-B-C is not:1.226. Any of the foregoing formulae, wherein -A-B-C is not:1.227. Any of the foregoing formulae, wherein -A-B-C is not:ARVN-210-PCT / / AR VN0210WO2ARVN-210-PCT / / AR VN0210WO21.232. Any of the foregoing formulae, wherein -A-B-C is:1.233. Any of the foregoing formulae, wherein the ULM is ULM-9’:wherein Rgxis halo (e.g., fluoro or chloro) and Q2 is N(Ra) or C(Ra)(Rb).1.234. Formula 1.232, wherein the ULM is selected from the following:ARVN-210-PCT / / AR VN0210WO2Any of the foregoing formulae, wherein the compound is selected from any of Compounds 1-151 of Tables 1-15, or Compounds 152-153 of Table 16, in free or salt form.ARVN-210-PCT / / ARVN0210WO2Table 1CompoundNo. StructureARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2Table 2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2Table 3ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2Table 4ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2Table 5ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2Table 7Compound No. Si rnct urcT Ni J Q 0Ill r i HIX JJ A’CMsXjQfTable 8Compound No. Structure’'JScZ-v > N112 ti r - A vi_..i In “ <? «.I.. LH >ARVN-210-PCT / / ARVN0210WO2Table 9Compound No. StructureARVN-210-PCT / / ARVN0210WO2Table 10ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2Table 11ARVN-210-PCT / / ARVN0210WO2Table 12ARVN-210-PCT / / ARVN0210WO2Table 13ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / AR VN0210WO2Table 15CompoundNumber Structure139HO,O.,140141 HO, 'SS-a'HARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2Table 16ARVN-210-PCT / / ARVN0210WO2

[0056] Exemplary compounds of Formula Q-I include Q-I(A)’ or any of the following:Q.1.1. Compounds of Formula Q-I, wherein the PTM targets or binds to KRAS protein, e.g., wild-type KRAS or KRAS protein comprising a mutation compared to the wild-type (KRAS mutant protein), e.g, selected from G12A, G12C, G12D, G12R, G 12V or a combination thereof.Q.l.2. Compound of Formula Q-I or Q.1.1, wherein the PTM targets or binds to KRAS mutant protein.Q.l.3. Compound of Formula Q-I or any of Q.1.1 or Q.1.2, wherein the PTM targets or binds to KRAS G12A.Q.l.4. Compound of Formula Q-I or any of Q.1.1 or Q.1.2, wherein the PTM targets or binds to KRAS G12C.Q.l.5. Compound of Formula Q-I or any of Q.1.1 or Q.1.2, wherein the PTM targets or binds to KRAS G12D.Q.l.6. Compound of Formula Q-I or any of Q.1.1 or Q.1.2, wherein the PTM targets or binds to KRAS G12R.Q.1.7. Compound of Formula Q-I or any of Q.1.1 or Q.1.2, wherein the PTM targets or binds to KRAS G12V.Q.l.8. Compound of Formula Q-I or any of Q.1.1 or Q.1.2, wherein the PTM targets or binds to a non-mutant wild-type KRAS.Q.l.9. Compound of Formula Q-I or any of formulae Q.l.l-Q.1.8, wherein the compound is a compound of Formula Q-I(A):KA)ARVN-210-PCT / / ARVN0210WO2in free or salt form, wherein:Each of Ri and R2 is independently H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), or Ci-4alkoxy (e.g., methoxy), or Ri and R2 together with the carbon to which they are attached form a4-8 membered heterocycyl, where the heterocycyl is optionally substituted with one or more halo (e.g. fluoro or chloro) or Ci-4alkyl (e.g., methyl);Each of R3 and R4 is independently H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);Each of m and n is independently 0, 1 or 2;Moiety A is a 4-12 membered heterocycloalkylene (e.g., pyrrolidinylene, piperidinylene, piperazinylene, hexahydro- 1-H-pyrrolizinylene or 3,9- diazaspiro [5, 5 ] undecanylene);Moiety B is a bond, or Ci-4alkylene (e.g., methylene), wherein each carbon may be optionally replaced with O;Moiety C is:a bond;a 4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 3,9- diazaspiro [5,5] undecanylene, azetidinylene);a (heterocycloalky lene)-O-(heterocycloalkylene); ora (cycloalkylene)-O-(cycloalkylene),wherein each of moieties A, B and C is independently optionally substituted with one or more halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), Ci- 4alkoxy (e.g., methoxy), or CO;Moiety D is aryl optionally substituted with one or more hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g.. methyl or ethyl) or C2-4alkynyl (e.g., ethynyl): andULM is selected from:ARVN-210-PCT / / ARVN0210WO2wherein:Rs is H, OH, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);R9 is H, OH, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy or ethoxy);R11 is H, OH, halo (e.g., chloro or fluoro). Ci-4alkyl (e.g., methyl) or_Ci-4alkoxy (e.g., methoxy);Qi is C(O) or C(Ra)(Rb);Q2 is N(Ra) or C(Ra)(Rb);Each of Raand Rb is independently H or Ci-4alkyl (e.g., methyl).Q.1.10. Formula Q.1.9, wherein each of Ri and R2 is independently H, halo (e.g. chloro or fluoro), Ci-4alkyl (e.g., methyl), or C lkoxy (e.g., methoxy), or Ri and R2 together with the carbon to which they are attached form a 4-8 membered heterocycyl, where the heterocycyl is optionally substituted with one or more halo (e.g. fluoro or chloro) or Ci-4alkyl (e.g., methyl).Q.1.11. Any of formulae Q.1.9-Q.1.10, wherein each of Ri and R2 is independently H, or Ci-4alkyl (e.g.. methyl) or Ci-4alkoxy (e.g., methoxy), or Ri and R2 together with the carbon to which they are attached form a 4-8 membered heterocyclic structure, e.g., an oxetane.Q.1.12. Any of formulae Q.1.9-Q.1.10. wherein each of Ri and R2 is independently H. Q.1.13. Any of formulae Q.1.9-Q.1.12, wherein each of Ri and R2 is independently Ci- 4alkyl (e.g., methyl).Q.1.14. Any of formulae Q.1.9-Q.1.13, wherein each of Ri and R2 is independently Ci- 4alkoxy (e.g., methoxy).ARVN-210-PCT / / ARVN0210WO2Q.1.15. Any of formulae Q.1.9-Q.1.11, wherein each of Ri and R2 together with the carbon to which they are attached form a 4-8 membered heterocycyl wherein the heterocycyl is optionally substituted with one or more halo (e.g. fluoro or chloro) or Ci-4alkyl (e.g., methyl.Q.1.16. Any of formulae Q.1.9-Q.1.11, wherein each of Ri and R2 together with the carbon to which they are attached form a 4-6 membered heterocycyl. e.g., an oxetane.Q.1.17. Any of formulae Q.1.9-Q.1.11, wherein each of Ri and R2 together with the carbon to which they are attached form an oxetane.Q.1.18. Any of formulae Q.1.9-Q.1.12, wherein each of Ri and R2 are both H.Q.1.19. Any of formulae Q.1.9-Q.1.11. wherein each of Ri and R2are both Ci-4alkyl (e.g., methyl).Q.1.20. Any of formulae Q.1.9-Q.1.19, wherein m is 0, 1 or 2.Q.1.21. Any of formulae Q.1,9-Q.1.20. wherein m is 0.Q.1.22. Any of formulae Q.1,9-Q.1.20, wherein m is 1.Q.1.23. Any of formulae Q.1.9-Q.1.20, wherein m is 2.Q.1.24. Any of formulae Q.1.9-Q.1.23, wherein n is 0, 1 or 2.Q.1.25. Any of formulae Q.1.9-Q.1.24, wherein n is 0.Q.1.26. Any of formulae Q.1.9-Q.1.24, wherein n is 1.Q.1.27. Any of formulae Q.1.9-Q.1.24, wherein n is 2.Q.1.28. Any of formulae Q.1.9-Q.1.20, wherein m and n are both 0.Q.1.29. Any of formulae Q.1,9-Q.1.20. wherein m and n are both 1.Q.1.30. Any of formulae Q.1,9-Q.1.29, wherein each of R3 and R4 is independently H, Ci 4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro).Q.1.31. Any of formulae Q.1.9-Q.1.30. wherein each of R3 and R4 is independently H or halo (e.g. fluoro or chloro).Q.1.32. Any of formulae Q.1.9-Q.1.31, wherein each of R3 and R4 is independently H. Q.1.33. Any of formulae Q.1.9-Q.1.32, wherein each of R3 and R4 is independently Ci- 4alkyl (e.g., methyl).ARVN-210-PCT / / ARVN0210WO2Q.l.34. Any of formulae Q.1.9-Q.1.33, wherein each of R3 and R4 is independently halo (e.g. fluoro or chloro).Q.1.35. Any of formulae Q.l.9-Q.1.34, wherein R3 is H.Q.1.36. Any of formulae Q.l.9-Q.1.34, wherein R3 is Ci-4alkyl (e.g., methyl).Q.l.37. Any of formulae Q.l.9-Q.1.34, wherein R3 is methyl.Q.l.38. Any of formulae Q.l.9-Q.1.34, wherein R3 is fluoro.Q.l.39. Any of formulae Q.l.9-Q.1.34, wherein R3 is chloro.Q.l.40. Any of formulae Q.l.9-Q.1.39, wherein R4 is H.Q.1.41. Any of formulae Q.l.9-Q.1.39, wherein R4 is Ci-4alkyl (e.g., methyl).Q.l.42. Any of formulae Q.l.9-Q.1.39, wherein R4 is methyl.Q.1.43. Any of formulae Q.l.9-Q.1.39. wherein R4 is fluoro.Q.l.44. Any of formulae Q.l.9-Q.1.39, wherein R4 is chloro.Q.1.45. Any of formulae Q.l.9-Q.1.44, wherein R4 is H and R3 is halo (e.g., chloro or fluoro).Q.1.46. Any of formulae Q.l.9-Q.1.45, wherein moiety D is Formula D-l having the following structure:R5Rswherein each of R5, Re and R7 is independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl). Q.l.47. Any of formulae Q.l.9-Q.1.46, wherein D is Formula D-l (a):D-l(a)ARVN-210-PCT / / ARVN0210WO2Q.1.48. Any of formulae Q.1.9-Q.1.147, wherein each of Rs, Re and R7 is independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) or C2- 4alkynyl (e.g., ethynyl).Q.1.49. Any of formulae Q.1.9- Q.1.148, wherein Rs is H or hydroxy.Q.1.50. Any of formulae Q.1.9- Q.1.149 wherein Rs is H.Q.1.51. Any of the foregoing formulae Q.l.l-Q.1.149, wherein Rs is hydroxy.Q.1.52. Any of formulae Q.1.9-Q.1.51, wherein each of Re and R7 is independently H, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).Q.1.53. Any of formulae Q.1.9- Q.1.152, wherein each of Re and R7 is independently H. Q.1.54. Any of formulae Q.1,7-Q.1.53. wherein each of Re and R7 is independently halo (e.g. fluoro or chloro).Q.1.55. Any of formulae Q.1.7-Q-1.54 wherein Re is H.Q.1.56. Any of formulae Q.1.7-Q.1.54, wherein Re is halo (e.g. fluoro or chloro).Q.1.57. Any of formulae Q.1.7- Q.1.54, wherein Re fluoro.Q.1.58. Any of formulae Q.1.7- Q.1.54, wherein Re chloro.Q.1.59. Any of formulae Q.1.7- Q.1.58, wherein R?is Ci-4alkyl (e.g., methyl or ethyl). Q.1.60. Any of formulae Q.1.7- Q.1.58, wherein R?is ethyl.Q.1.61. Any of formulae Q.1.7- Q.1.58, wherein R?is C2-4alkynyl (e.g., ethynyl).Q.1.62. Any of formulae Q.1.7- Q.1.58, wherein R?is ethynyl.Q.1.63. Any of formulae Q.1.7- Q.1.58, wherein R?is H.Q.1.64. Any of formulae Q.1.7- Q.1.63, wherein moiety A is a 4-12 membered heterocycloalkylene (e.g., pyrrolidinylene, piperidinylene, piperazinylene, hexahydropyrrolo[3,4-c]pyrrolylene or 3,9-diazaspiro[5,5]undecanylene), wherein moiety A is optionally substituted with one or more halo and / or C lkyl (e.g., methyl).Q.1.65. Any of formulae Q.1.9-Q.1.64, 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 or bridged heterocyclic).ARVN-210-PCT / / ARVN0210WO2Q.1.66. Any of formulae Q-1.9-Q.1.65, wherein moiety A is a 4-11 membered heterocycloalkylene (e.g., 5-8 membered monocyclic- heterocycloalkylene, 8-10 membered fused-multicyclic heterocycloalkylene, 7-11 membered multicyclic spiro- heterocycloalkylene or 7-8 bridged heterocycloalkylene or any combination of fused- heterocycloalkylene, spiro- heterocycloalkylene or bridged heterocycloalkylene).Q.1.67. Any of formulae Q.1.9-Q.1.66, wherein moiety A is a 6-11 membered heterocycloalkylene.Q.1.68. Any of formulae Q.1.9-Q.1.67, wherein moiety A is a 4-6 membered mono-cyclic heterocycloalkylene.Q.1.69. Any of formulae Q.1.9-Q.1.68. wherein moiety A is a. 6 membered mono-cyclic heterocycloalkylene.Q.1.70. Any of formulae Q.1.9-Q.1.69, wherein moiety A is a piperidinylene.Q.1.71. Any of formulae Q.1.9-Q.1.66. wherein moiety A is 5-membered heterocycloakylene (e.g., pyrrolidinylene).Q.1.72. Any of formulae Q.1.9-Q.1.66 or Q.1.71, wherein moiety A is a pyrrolidinylene. Q.1.73. Any of formulae Q.1.9-Q.1.66, wherein moiety A is a 7-11 membered multicyclic spiro- or fused heterocycloakylene.Q.1.74. Any of formulae Q.1.9-Q.1.66 or Q.1.73, wherein moiety A is an 8-membered heterocycloakylene (e.g., 8-membered fused-heterocycloakylene, for example, hexahydropyrrolo [3,4-c] pyrrolylene).Q.1.75. Any of formulae Q.1.9-Q.1.66. wherein moiety A is an hexahydropyrrolo [3, 4- c]pyrrolylene.Q.1.76. Any of formulae Q.1.9-Q.1.66 or Q.1.73, wherein moiety A is an 11-membered heterocycloalkylene (e.g., 11-membered spiro-heterocycloakylene, for example.3,9-diazaspiro[5,5]undecanylene).Q.1.77. Any of formulae Q.1.9-Q.1.76, wherein moiety A is optionally substituted with one or more halo and / or Ci-4alkyl (e.g., methyl).Q.1.78. Any of formulae Q.1.9-Q.1.77, wherein moiety A is unsubstituted.ARVN-210-PCT / / ARVN0210WO2Q.l.79. Any of formulae Q.1.9-Q.1.77, wherein moiety A is substituted with one or more halo (e.g., fluoro).Q.l.80. Any of formulae Q.1.9-Q.1.77. wherein moiety A is substituted with one or more Ci-4alkyl (e.g., methyl).Q.l.81. Any of formulae Q.l.9-Q.1.77, wherein moiety A is piperidinylene substituted with one or more halo (e.g., fluoro).Q.l.82. Any of formulae Q.1.9-Q.1.77, wherein moiety A is piperidinylene substituted with one or more Ci-4alkyl (e.g., methyl).Q.l.83. Any of formulae Q.1.9-Q.1.77, wherein moiety A is pyrrolidinylene substituted with one or more Ci-4alkyl (e.g., methyl).Q.l.84. Any of formulae Q.1.9-Q.1.83. wherein moiety A is selected from any of the following:Q.l.85. Any of formulae Q.l.9-Q.1.84, wherein moiety A is:Q.l.87. Any of formulae Q.1.9-Q.1.84, wherein moiety A is:Q.1.88. Any of formulae Q.1.9-Q.1.87, wherein Moiety B is a bond or Ci-4alkylene (e.g., methylene), wherein each carbon may be optionally replaced with O.Q.1.89. Any of formulae Q.l.9-Q.1.88. wherein each of moieties B is a bond.ARVN-210-PCT / / ARVN0210WO2Q.1.90. Any of formulae Q.1.9-Q.1.88, wherein each of moieties B is Ci-4alkylene (e.g., methylene), wherein each carbon may be optionally replaced with O. Q.1.91. Any of formulae Q.1.9-Q.1.88. wherein each of moieties B is a Ci-4alkylene (e.g., methylene).Q.1.92. Any of formulae Q.1.9-Q.1.88, wherein moiety B is methylene.Q.1.93. Any of formulae Q.1.90-Q.1.92, wherein B is substituted with one or more halo (e.g. chloro or fluoro), Ci-4alkyl (e.g., methyl), Ci-4alkoxy (e.g., methoxy), or C(O).Q.1.94. Any of formulae Q.1.90-Q.1.93, wherein B is substituted with C(O).Q.1.95. Any of formulae Q.1.90-Q.1.93, wherein moiety B is -Ci-2alkylene-OC(O)- (e.g.,-CH2-O-C(O)-).Q.1.96. Any of formulae Q.1.90-Q.1.93, wherein B is -CH2-OC(O)-.Q.1.97. Any of formulae Q.1.9-Q.1.88, wherein B is unsubstituted.Q.1.98. Any of formulae Q.1.9-Q.1.97. wherein moiety C is:a bond;4-12 membered heterocycloalkylene (e.g., piperazinylene, piperidinylene, 3,9-diazaspiro[5,5]undecanylene);(heterocycloalkylene)-O-(heterocycloalkylene); or(cycloalkylene)-O-(cycloalkylene),Q.1.99. Any of formulae 1.9-Q.1.97, wherein moiety C is:a bond;4-12 membered heterocycloalkylene (e.g., piperazinylene. piperidinylene or 3,9-diazaspiro[5,5]undecanylene); or (heterocycloalkylene)-O-(heterocycloalkylene),wherein moiety C is optionally substituted with one or more halo and / or Ci-4alkyl (e.g., methyl). Q.1.100. Any of formulae Q.1.9-Q.1.99, wherein moiety C is a bond.Q.1.101. Any of formulae Q.1.9-Q.1.99, wherein moiety C is 4-12 membered heterocycloalkylene.Q.1.102. Any of formulae Q.1.9-Q.1.101, wherein moiety C is 4-membered heterocycloakylene (e.g., azetidinylene).ARVN-210-PCT / / ARVN0210WO2Q.1.103. Any of formulae Q.1.9-Q.1.101, wherein moiety C is a 6-membered heterocycloalkylene (e.g., piperazinylene or piperidinylene).Q.1.104. Any of formulae Q.1.9-Q.1.101, wherein moiety C is piperazinylene.Q.1.105. Any of formulae Q.1.9-Q.1.101, wherein moiety C is piperidinylene.Q.1.106. Any of formulae Q.1.9-Q.1.101, wherein moiety C is a 7-11-membered heterocycloalkylene (e.g., a 7-11 membered multicyclic spiro- heterocycloakylene).Q.1.107. Any of formulae Q.1.9-Q.1.99 or Q.1.106, wherein moiety C is 3,9- diazaspiro [5,5] undecanylene.Q.1.108. Any of formulae Q.1.9-Q.1.99 or Q.1.106, wherein moiety C is (heterocycloalkylene)-O-(heterocycloalkylene).Q.1.109. Any of formulae Q.1.9-Q.1.99, wherein moiety C is a (6-membered heterocycloalkylene)-O-(4-6 membered heterocycloalkylene).Q.1.110. Any of formulae Q.1.9-Q.1.99. wherein moiety C is (piperidinylene)-O- (azetidinylene)-.Q.1.111. Any of formulae Q.1.9-Q.1.99, wherein moiety B and moiety C are both a bond. Q.1.112. Any of formulae Q.1.9-Q.1.110, wherein moiety C is optionally substituted with one or more halo and / or Ci-4alkyl (e.g., methyl).Q.1.113. Any of formulae Q.1.9-Q.1.110, wherein moiety C is unsubstituted.Q.1.114. Any of formulae Q.1.9-Q.1.113, wherein C selected from:Q.1.115. Any of formulae Q.1.9-Q.1.114, wherein -O-CH2-[C(Ri)(R2)]m-(CH2)n-A-B-C- is selected from the following:ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2 Q.1.116. Any of formulae Q.1.9-Q.1.114, wherein -O-CH2-[C(Ri)(R2)]m-(CH2)n-A-B-C- isARVN-210-PCT / / AR VN0210WO2Q.1.117. Any of formulae Q.1.9-Q.1.114, wherein -O-CH2-[C(Ri)(R2)]m-(CH2)n-A-B-C- is selected from the following:Q.1.118. Any of the foregoing formulae, wherein the compound is a compound of Formula Q-I(A)-1:ARVN-210-PCT / / AR VN0210WO2~^ULMQ.1.119. Any of the foregoing formulae, wherein the compound is a compound of Formula Q-I(A)-2:^ULMCTQ.1.120. Any of formulae Q.1.9-Q.1.119, wherein:R3 and R4 are independently H, Ci-4alkyl (e.g., methyl or halo (e.g. fluoro or chloro);Moiety D is Formula D-l(a) wherein Rs is H or hydroxy; Re is halo (e.g., fluoro or chloro); and R7 is Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).Q.1.121. Any of formulae Q.1.9-Q.1.120, wherein the ULM is selected from:ARVN-210-PCT / / ARVN0210WO2wherein:Rs is H, OH halo (e.g., chloro or fluoro) Ci-4alkyl (e.g., methyl) or Ci- 4alkoxy (e.g., methoxy);R9 is H, OH, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci- 4alkoxy (e.g., methoxy or ethoxy);R11 is H, OH, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci- 4alkoxy (e.g., methoxy);Qi is C(O) or C(Ra)(Rb);Q2is N(Ra) or C(Ra)(Rb);Each of Raand Rb is independently H or Ci-4alkyl (e.g., methyl).Q.1.122. Any of formulae Q.1.9-Q.1.121, wherein:Rs is H or halo (e.g., chloro or fluoro);R9 is H, halo (e.g., chloro or fluoro) or Ci-4alkoxy (e.g., methoxy or ethoxy);R11 is H or Ci-4alkyl (e.g., methyl);Qi is C(O) or C(Ra)(Rb);Q2 is N(Ra) or C(Ra)(Rb);Each of Raand Rb is independently H or Ci-4alkyl (e.g., methyl).Q.1.123. Any of formulae Q.1.9-Q.1.122, wherein the ULM is ULM-1.Q.1.124. Any of formulae Q.1.9-Q.1.123, wherein Qi is C(O) or C(Ra)(Rb).Q.1.125. Any of formulae Q.1.9-Q.1.123, wherein Qi is C(O).Q.1.126. Any of formulae Q.1.9-Q.1.123, wherein Qi is C(Ra)(Rb).Q.1.127. Any of formulae Q.1.9-Q.1.126, wherein each of Raand Rb is independently H or Ci-4alkyl (e.g., methyl).Q.1.128. Any of formulae Q.1.9-Q.1.127, wherein each of Raand Rb is independently H.ARVN-210-PCT / / ARVN0210WO2Q.1.129. Any of formulae Q.1.9-Q.1.127, wherein each of Raand Rbis C1-4alkyl (e.g., methyl).Q.1.130. Any of formulae Q.1.9-Q.1.127, wherein both Raand Rbare H.Q.1.131. Any of formulae Q.1.9-Q.1.122, wherein the ULM is ULM-2.Q.1.132. formula Q.1.131, wherein Q2 is N(Ra) or C(Ra)(Rb).Q.1.133. formula Q.1.131 or Q.1.132, wherein Q2 is C(Ra)(Rb).Q.1.134. formula Q.1.131 or Q.1.132, wherein Q2 is N(Ra).Q.1.135. formula Q.1.134, wherein Ra is H or Ci-4alkyl (e.g., methyl).Q.1.136. formula Q.1.134, wherein Ra is H.Q.1.137. formula Q.1.134, wherein Ra is Ci-4alkyl (e.g., methyl).Q.1.138. Any of formulae Q.1.131 -Q.1.137, wherein Rn is H or Ci-4alkyl (e.g., methyl). Q.1.139. Any of formulae Q.1.131-Q.1.138, wherein Rn is H.Q.1.140. Any of formulae Q.1.131-Q.1.138, wherein Rn is C1-4alkyl (e.g., methyl).Q.1.141. Any of formulae Q.1.131-Q.1.138, wherein Rn is methyl.Q.1.142. Any of formulae Q.1.9-Q.1.141, wherein Rs is H or halo (e.g., chloro or fluoro). Q.1.143. Any of formulae Q.1.9-Q.1.142, wherein Rs is H.Q.1.144. Any of formulae Q.1.9-Q.1.141, wherein Rs is halo (e.g., chloro or fluoro).Q.1.145. Any of formulae Q.1.9-Q.1.144, wherein R9 is H, halo (e.g., chloro or fluoro). Q.1.146. Any of formulae Q.1.9-Q.1.145, wherein R9 is H.Q.1.147. Any of formulae Q.1.9-Q.1.145, wherein R9 is halo (e.g., chloro or fluoro).Q.1.148. Any of the foregoing formulae, wherein the compound is selected from any of Compounds 1-21 of Table 1, in free or salt form.Q.1.149. Any of the foregoing formulae, wherein the compound is in free or pharmaceutically acceptable salt form.Q.1.150. Any of the foregoing formulae, wherein the compound is in free form.Q.1.151. Any of the foregoing formulae, wherein the compound is in salt form.Q.1.152. Any of the foregoing formulae, wherein the compound is in pharmaceutically acceptable salt form.Q.1.153. Any of the foregoing formulae, wherein the compound is in isotopic form (e.g, in deuterated form).ARVN-210-PCT / / ARVN0210WO2Q.1.154. Any of the foregoing formulae, wherein the compound is in an enantiomerically or diastereomically enriched form, for example the C-4 carbon of the l-oxa-6- azaspiro[3.5]nonane moiety of the PTM is, in some embodiments, enriched in the (S) form, and in other embodiments, enriched in the (R) 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).Q.1.155. Any of the foregoing formulae, wherein the compound degrades KRAS G12 mutations including KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, and KRAS G12DV.Q.1.156. Any of the foregoing formulae, wherein the compound degrades non-mutated wild-type KRAS.Q.1.157. Any of the foregoing formulae, wherein the compound degrades KRAS G12D. Q.1.158. Any of the foregoing formulae, wherein the compound degrades KRAS G12V. Q.1.159. Any of the foregoing formulae, wherein the compound degrades KRAS (wildtype or mutant KRAS) in cells carrying such KRAS (wild-type or mutation) at 24 hour with an DC50of less than 100nM, preferably less than 75nM, preferably less than 50nM, preferably less than 10nM, e.g., in an in vitro assay as described in Example 2 below.Q.1.160. Any of the foregoing formulae, wherein the compound degrades KRAS (wildtype or mutant KRAS) in cells carrying such wild-type KRAS or KRAS mutation (e.g., in AsPC-cells or SW620 cells) at 24 hour with an Dmax value 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.Q.1.161. Any of the foregoing formulae, wherein KRAS mutant is a KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, and KRAS G12V.Q.1.162. Any of the foregoing formulae, wherein KRAS mutant is a G12V KRAS.Q.1.163. Any of the foregoing formulae, wherein KRAS mutant is a G12D KRAS.Q.1.164. Any of the foregoing formulae, wherein KRAS is a non-mutated wild-typeKRAS.ARVN-210-PCT / / ARVN0210WO2Q.l.165. Any of the foregoing formulae, wherein the compound is a compound of Formula Q-I(A)’:Q-I(A)’in free or salt form, wherein:Each of Ri and R2 is independently H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy), or Ri and R2 together with the carbon to which they are attached form a 4-8 membered heterocycyl. wherein the heterocycyl is optionally substituted one or more halo (e.g. fluoro or chloro) or Ci-4alkyl (e.g., methyl).Each of R3 and R4 is independently H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);Each of m and n is independently 0, 1 or 2;Moiety A is a 4-12 membered heterocycloalkylene (e.g., pyrrolidinylene, piperidinylene, piperazinylene, hexahydro- 1-H-pyrrolizinylene or 3,9-diazaspiro[5,5]undecanylene);Moiety B is a bond or Ci-4alkylene (e.g., methylene)), wherein each carbon may be optionally replaced with O or C(O);Moiety C is:a bond;4-12 membered heterocycloalkylene (e.g., piperazinylene, piperidinylene, 3,9- diazaspiro[5,5]undecanylene);(heterocycloalkylene)-O-(heterocycloalkylene);(cycloalkylene)-O-(cycloalkylene),wherein each of moieties A, B and C is independently optionally substituted with one or more halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), Ci-4alkoxy (e.g., methoxy) or CO;ARVN-210-PCT / / ARVN0210WO2Moiety D is an aryl optionally substituted with one or more hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl);ULM is selected from:ULM-1 andwherein:Rs is H, OH, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);R9 is H, OH, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);R11 is H, OH, halo (e.g., chloro or fluoro). Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);Qi is C(O) or C(Ra)(Rb);Q2is N(Ra) or C(Ra)(Rb); andEach of Raand Rbis independently H or Ci-4alkyl (e.g., methyl).Q.1.166. Any of the foregoing formulae, wherein the compound is a compound of Formula Q-I(A)’-1:Q.1.167. Any of the foregoing formulae, wherein the compound is a compound of Formula Q-I(A)’-2:ARVN-210-PCT / / ARVN0210WO2ULMcPharmaceutical

[0057] 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 pharmaceuticallyARVN-210-PCT / / ARVN0210WO2acceptable 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. In another aspect, the compounds, pharmaceutical compositions as described herein may be administered intravenously.

[0058] 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.

[0059] Therefore, provided herein are pharmaceutical compositions comprising a compound described herein (e.g., any of formulae 1.1-1.235, in free or pharmaceutically acceptable salt form) in combination or association with a pharmaceutically acceptable carrier (Composition I).

[0060] Also provided herein are pharmaceutical compositions comprising a compound of Formula Q-I or any of Q.l.l-Q.1.167, in free or pharmaceutically acceptable salt form) in combination or association with a pharmaceutically acceptable carrier (Composition Q-I).Methods of Treatment

[0061] 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 1.1-1.235 or 1.234-1.235), 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:ARVN-210-PCT / / ARVN0210WO23.1. 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 3.1-3.2, wherein the disease or disorder is mediated by a G12D mutant KRAS.3.5. Method I or any of 3.1-3.2, wherein the disease or disorder is mediated by a G12V mutant KRAS.3.6. Method I or any of 3.1-3.2, wherein the disease or disorder is mediated by a G12A mutant KRAS.3.7. Method I or any of 3.1-3.2, wherein the disease or disorder is mediated by a G12C mutant KRAS.3.8. Method I or any of 3.1-3.2, wherein the disease or disorder is mediated by a G12R mutant KRAS3.9. Method I or any of 3.1-3.2, wherein the disease or disorder is mediated by a G12V mutant KRAS.3.10. Method I or any of 3.1-3.9, wherein the disease or disorder is mediated by nonmutant wild-type KRAS.3.11. Method I or any of 3.1-3.10, 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.3.12. Method I or 3.1-3.11 wherein the cancer is pancreatic, colorectal or lung cancer.3.13. Method I or 3.1-3.11 wherein the cancer is pancreatic cancer.3.14. Method I or 3.1-3.11 wherein the cancer is a pancreatic ductal adenocarcinoma.ARVN-210-PCT / / ARVN0210WO23.15. Method I or 3.1-3.11 wherein the cancer is colorectal cancer.3.16. Method I or 3.1-3.11 wherein the cancer is lung cancer.3.17. Method I or 3.1-3.11 wherein the cancer is a non-small cell lung cancer.3.18. Method I or any of the foregoing methods, wherein the subject is a human subject.3.19. Method I or any of the foregoing methods, wherein the subject is a non-human subject.3.20. Method I or any of the foregoing methods, further comprising administering one or more anticancer agent.3.21. Method I or any of the foregoing methods, wherein the cancer is non-small cell lung cancer, for example, non-squamous non-small cell lung cancer or non- squamous colorectal cancer.

[0062] The disclosure also provides 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 Q-I). comprising administering to the subject an effective amount of any of the compounds of Formula Q-I or any of Q.l.l-Q.1.167), 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 Q-I- A), comprising administering to the subject an effective amount of any of the compounds of Formula Q-I or any of Q.l.l-Q.1.167), in free or pharmaceutically acceptable salt form, or an effective amount of any of the pharmaceutical compositions disclosed herein. In certain embodiments. Method Q-I includes the following.Q.3.1. Method I, wherein the disease or disorder is an abnormal cellular proliferation disorder such as a tumor or cancer.Q.3.2. Method I or 3.1, wherein the disease or disorder is KRAS-mediated cancer. Q.3.3. Method I or any of Q.3.1-3.2, wherein the disease or disorder is mediated by a mutant form of KRAS.Q.3.4. Method I or any of Q.3.1-Q.3.3, wherein the disease or disorder is mediated by a G12A mutant KRAS.ARVN-210-PCT / / ARVN0210WO2Q.3.5. Method I or any of Q.3.1-Q.3.3, wherein the disease or disorder is mediated by a G12C mutant KRAS.Q.3.6. Method I or any of Q.3.1-Q.3.3, wherein the disease or disorder is mediated by a G12D mutant KRAS.Q.3.7. Method I or any of Q.3.1-Q.3.3, wherein the disease or disorder is mediated by a G12R mutant KRAS.Q.3.8. Method I or any of Q.3.1-Q.3.3, wherein the disease or disorder is mediated by a G 12V mutant KRAS.Q.3.9. Method I or any of Q.3.1-Q.3.3, wherein the disease or disorder is mediated by non-mutant wild-type KRAS.Q.3.10. Method I or any of Q.3.1-Q.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.Q.3.11. Method I or Q.3.1-Q.3.10 wherein the cancer is pancreatic, colorectal or lung cancer.Q.3.12. Method I or Q.3.1-Q.3.10 wherein the cancer is pancreatic cancer.Q.3.13. Method I or Q.3.1-Q.3.10 wherein the cancer is a pancreatic ductal adenocarcinoma.Q.3.14. Method I or Q.3.1 -Q.3.10 wherein the cancer is colorectal cancer.Q.3.15. Method I or Q.3.1-Q.3.10 wherein the cancer is lung cancer.Q.3.16. Method I or Q.3.1-Q.3.10 wherein the cancer is a non-small cell lung cancer. Q.3.17. Method I or any of the foregoing methods, wherein the subject is a human subject.Q.3.18. Method I or any of the foregoing methods, wherein the subject is a non-human subject.ARVN-210-PCT / / ARVN0210WO2Q.3.19. Method I or any of the foregoing methods, further comprising administering one or more anticancer agent.Q.3.20. Method Q-I or any of the foregoing methods, wherein the cancer is non-small cell lung cancer, for example, non- squamous non-small cell lung cancer or non-squamous colorectal cancer.

[0063] 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.

[0064] 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).

[0065] 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 theARVN-210-PCT / / ARVN0210WO2treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.Kits

[0066] 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.

[0067] The disclosure provides a kit comprising a compound capable of degrading KRAS selected from a compound disclosed herein.

[0068] Also provided herein are kits comprising a compound disclosed herein for the treatment of any of the indications disclosed herein.

[0069] 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., nitrogen atmosphere, and reducing / oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

[0070] 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.

[0071] 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:

[0072] The compounds of the present disclosure may generally be prepared as follows:ARVN-210-PCT / / ARVN0210WO2 General synthetic Scheme 1:INT-3chiral separation(S)-INT-3wherein Linker is moieties -B-C and moiety A, ULM and R3-R4, are as defined herein.General synthetic Scheme 2:ARVN-210-PCT / / AR VN0210WO2wherein R3-R4 and moiety A and ULM are as defined herein and Linker is moiety B-C as defined herein.General synthetic Scheme 3:HR3(S)-INT-2 (S)-INT-3ARVN-210-PCT / / AR VN0210WO2I NT-4INT-5INT-6 wherein R3-R4 and moiety A and ULM are as defined herein and Linker is moiety B-C as defined herein.General Synthetic Scheme 4Cl ClINT-11MeMgBr, Fe(acac)2INT-15ARVN-210-PCT / / ARVN0210WO2(S)-INT-3General Synthetic Scheme 5INT-19 (S)-INT-19ARVN-210-PCT / / AR VN0210WO2wherein moiety A and ULM are as defined herein and Linker is moiety B-C as defined herein.General synthetic Scheme Q-l:General Synthetic Scheme Q-2ARVN-210-PCT / / ARVN0210WO2General Synthetic Scheme Q-3ARVN-210-PCT / / ARVN0210WO2General Synthetic Scheme Q-4ARVN-210-PCT / / ARVN0210WO2ARVN-210-PCT / / ARVN0210WO2EXAMPLES

[0073] 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.

[0074] 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.Example 1.1Exemplary synthesis of Compound 29: 3-{4-chloro-5-[(3R)-4-[(l-{[L({[7-(8-ethyL7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-4-[(4S)-l-oxa-6-azaspiro[3.5]nonan-6-yl]pyrido[4,3-d]pyrimidin-2-yljoxy }methyl)cyclopropyl]methyl } -4-fluoropiperidin-4-yl)methyl] -3-methylpiperazin- 1 -yl] - 1 -oxo-2,3-dihydro- lH-isoindol-2-yl }piperidine-2, 6-dioneStep 1:

[0075] A mixture of methyl 3-chloro-4-fluoro-benzoate (5.0 g, 26 mmol), tert-butyl (2R)-2-methylpiperazine-1-carboxylate (7.97 g, 40 mmol) and A, A-diisopropylethylamine (13.8 mL) in dimethyl sulfoxide (40 mL) was degassed and purged with nitrogen several times, then stirred at 130 °C for 12 h under nitrogen atmosphere. The mixture was diluted with water (600 mL) and extracted with dichloromethane (300 mL). The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 15 / 1) to afford tert-butyl (2R)-4-(2-chloro-4-methoxycarbonyl-phenyl)-2-methyl-piperazine-1-carboxylate (2 g, 20%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) d 7.87 (d, J = 2.0 Hz, 1H), 7.86 - 7.81 (m, 1H), 7.19 (d, J= 8.4 Hz, 1H), 4.28 - 4.16 (m, 1H), 3.90 - 3.75 (m, 4H), 3.34 - 3.26 (m, 2H), 3.22 - 3.11 (m, 1H), 2.81 - 2.63 (m, 2H), 1.41 (s, 9H), 1.28 (d, J= 6.8 Hz, 3H).ARVN-210-PCT / / ARVN0210WO2Step 2:

[0076] To a solution of tert-butyl (2R)-4-(2-chloro-4-methoxycarbonyl-phenyl)-2-methyl-piperazine- 1-carboxylate (14 g, 38 mmol) in tetrahydrofuran (40 mL), water (40 mL) and methanol (40 mL) was added lithium hydroxide monohydrate (7.96 g, 190 mmol), and the reaction mixture was stirred at 25 °C for 1 h. The mixture was diluted with saturated citric acid solution until pH 6, and the resulting mixture was extracted with ethyl acetate (200 mL x 2). The combined organic extract was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 4-[(3R)-4-tert-butoxycarbonyl-3-methyl-piperazin-l-yl]-3-chloro-benzoic acid (10.7 g, 79%) as a white solid, which was used in the next step directly. LC / MS (ESI) m / z: 355.2 [M+H]+; 'H NMR (400 MHz, DMSO-d ) d 7.87 (d, 7= 2.0 Hz, 1H), 7.86 - 7.81 (m. 1H), 7.19 (d, J= 8.4 Hz, 1H), 4.28 - 4.17 (m, 1H), 3.86 - 3.80 (m, 1H), 3.32 - 3.27 (m, 2H), 3.20 - 3.14 (m, 1H), 2.82 - 2.67 (m, 2H), 1.42 (s, 9H), 1.29 (d, 7= 6.8 Hz, 3H).Step 3:DMF, n-BuLi, THF, -70°C

[0077] To a solution of 4-[(3R)-4-tert-butoxycarbonyl-3-methyl-piperazin-l-yl]-3-chloro-benzoic acid (5.3 g, 15 mmol) in tetrahydrofuran (200 mL) at -70 °C was added n-butyllithium (2.5 M, 13.1 mL) dropwise under nitrogen atmosphere, and the reaction mixture was stirred at -70 °C for 3 h. Dimethylformamide (5.7 mL, 75 mmol) was added dropwise, and the reaction mixture was stirred at -70 °C for Ih. The mixture was diluted with saturated citric acid solution 200 mL and extracted with ethyl acetate (200 mL x 2). The combined organic extract was washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (40%-70%ARVN-210-PCT / / ARVN0210WO2acetonitrile in water (formic acid) over 20 min) to afford tert-butyl (2R)-4-(4-chloro-3-hydroxy-l-oxo-3H-isobenzofuran-5-yl)-2-methyl-piperazine-l-carboxylate (1.7 g, 29%) as a pale yellow solid. LC / MS (ESI) m / z 327.0 [M-C4H8+H]+; 'H NMR (400 MHz, DMSO-t / e) <58.20 (d, J= 8.8 Hz, 1H), 7.73 (dd, J = 1.2, 8.0 Hz, 1H), 7.33 (dd, 7 = 2.8, 8.0 Hz, 1H), 6.61 (d, 7= 8.8 Hz, 1H), 4.32 - 4.20 (m, 1H), 3.91 - 3.80 (m, 1H), 3.33 - 3.14 (m, 3H), 2.96 - 2.70 (m, 2H), 1.42 (s, 9H), 1.29 (d. 7 = 6.8 Hz, 3H).Step 4:o2-MePyBHs, NaOAc,AcOH / MeOH, 25 - 50“C, 13 h

[0078] To a solution of tert-butyl (2R)-4-(4-chloro-3-hydroxy-l-oxo-3H-isobenzofuran-5-yl)-2- methyl-piperazine-1 -carboxylate (3.4 g, 9 mmol) in methanol (40 mL) were added sodium acetate (1.46 g, 18 mmol), 3-aminopiperidine-2, 6-dione (2.19 g, 13 mmol, hydrochloride) and acetic acid (4 mL), and the resulting mixture was stirred at 25 °C for 1 h. 2-M ethylpyridine borane (1.90 g. 18 mmol) was then added, and the reaction mixture was stirred at 50 °C for 12 h. The mixture was filtered and concentrated, and the residue was triturated with ethyl acetate at 25 °C for 1 h to afford tert-butyl (2R)-4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-2-methyl-piperazine-l-carboxylate (3.4 g, 80%) as a blue solid. LC / MS (ESI) nt / z: 477.3 [M+H]+; 'H NMR (400 MHz, DMSO-tfc) d 10.99 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H). 5.10 (dd, J = 4.8, 13.2 Hz, 1H), 4.48 - 4.38 (m, 1H), 4.34 - 4.20 (m, 2H), 3.90 - 3.80 (m, 1H), 3.32 - 3.25 (m, 2H), 3.24 - 3.14 (m, 1H), 2.98 - 2.71 (m, 3H), 2.63 -2.55 (m, 1H), 2.48 - 2.36 (m, 1H), 2.11 - 1.94 (m, 1H), 1.42 (s, 9H), 1.31 (d, J = 6.8 Hz, 3H).Step 5:

[0079] To a mixture of tert-butyl (2R)-4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-2- methyl-piperazine-1 -carboxylate (0.80 g, 1.7 mmol) in dichloromethane (6ARVN-210-PCT / / ARVN0210WO2mL) was added trifluoroacetic acid (2 mL) and the reaction mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure, and the residue was triturated with acetonitrile / petroleum ether (V: V=1:1. 50 mL) for 0.5 h to afford 3-[4-chloro-5-[(3R)-3-methylpiperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (800 mg, 97%, trifluoroacetate salt) as a blue gum. LC / MS (ESI) m / z: 377.0 [M+H]+.Step 6:oNaBH3CN, DIEA, DCM / DMSO0-25 °C, 125 hF

[0080] To a solution of 3-[4-chloro-5-[(3R)-3-methylpiperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine -2,6-dione (0.8 g, 2 mmol, trifluoroacetate salt) in dichloromethane (8 mL) and dimethyl sulfoxide (8 mL) was added A / / V-diisopropylethylamine (0.8 m L), and the resulting mixture was stirred at 25 °C for 10 minutes, then cooled to 0 °C. L / v-Butyl 4-fluoro-4-formyl-piperidine- 1-carboxylate (700 mg, 3 mmol) and sodium cyanoborohydride (307 mg, 4.9 mmol) were then added, and the reaction mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic extracts were washed with brine (100 mL x 5), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (25%-55% acetonitrile in water (formic acid) over 17 min) to afford tert-butyl 4-[[(2R)-4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-2-methyl-piperazin-l-yl]methyl]-4-fluoro-piperidine- 1-carboxylate (200 mg, 20%) as a white solid. LC / MS (ESI) m / z 592.3 [M+H]+; 'H NMR (400 MHz, DMSO- fc) J 10.99 (s, 1H), 7.77 - 7.57 (m, 1H), 7.40 - 7.20 (m, 1H), 5.10 (dd, J = 4.8, 13.2 Hz, 1H), 4.49 - 4.37 (m, 1H), 4.34 - 4.22 (m. 1H), 3.94 - 3.66 (m, 3H), 3.12 - 2.77 (m, 7H), 2.63 - 2.57 (m, 1H), 2.45 - 2.36 (m, 1H), 2.06 - 1.53 (m, 6H), 1.48 - 1.31 (m, 12H), 1.26 (m, 3H).ARVN-210-PCT / / ARVN0210WO2

[0081] To a mixture of fert-butyl 4-fluoro-4-[[rac-(2R)-4-[4-chloro-2-(2,6-dioxo-3- piperidyl)- 1-oxo- isoindolin-5-yl]-2-methyl-piperazin-l-yl]methyl]piperidine-l-carboxylate (300 mg, 0.5 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 25 °C, and the reaction mixture was stirred for 10 minutes, then concentrated under reduced pressure. The residue was purified by prep-HPLC (0%-22% acetonitrile in water (trifluoroacetic acid) over 15 min) to afford 3-[4-chloro-l-oxo-5-[rac-(3R)-4-[(4-fluoro-4-piperidyl)methyl]-3-methyl- piperazin-l-yl]isoindolin-2-yl]piperidine-2, 6-dione (360 mg, 98%, trifluoroacetic acid salt) as a yellow solid. LC / MS (ESI) m / z 985.6 [M+H]+; ‘H NMR (400 MHz, DMSO-J6) 5 11.00 (s, 1H), 9.04 - 8.88 (m, 1H), 8.83 - 8.64 (m, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.3O (d, J = 8.4 Hz, 1H), 5.11 (dd, J = 4.8, 13.2 Hz, 1H), 4.50 - 4.37 (m, 1H), 4.30 - 4.23 (m, 1H), 4.18 - 4.05 (m, 2H), 3.50 - 3.26 (m, 6H), 3.23 - 2.95 (m, 6H), 2.94 - 2.85 (m. 1H), 2.64 - 2.55 (m, 1H), 2.48 - 2.36 (m, 1H), 2.31 - 2.19 (m, 1H), 2.17 - 2.07 (m, 1H), 2.05 - 1.78 (m, 3H), 1.48 - 1.18 (m, 3H).

[0082] [l-[[7-Chloro-8-fluoro-4-(l-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[4,3- d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (2.7 g) was purified by SFC (50% isopropanol (0.1%NH4OH) in carbon dioxide, isocratic elution). The first eluted fraction was assigned as [l-[[7-chloro-8-fluoro-4-[(4R)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3- d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (1.4 g, 35%) as a yellow solid. LC / MS (ESI) m / z 409.0 [M+H]+. The second eluted fraction was assigned as [l-[[7-chloro-8-fluoro-4-[(4S)-l- oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (1.1 g, 38%) as a yellow solid. LC / MS (ESI) m / z 409.1 [M+H]+.Step 9:ARVN-210-PCT / / ARVN0210WO2

[0083] To a solution of [l-[[7-chloro-8-fluoro-4-[rac-(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (2.8 g, 6.8 mmol) in dichloromethane (20 mL) was added l,l,l-tris(acetyloxy)-l,l-dihydro-l,2-benziodoxol-3-(lH)-one (5.8 g, 14 mmol), and the reaction mixture was stirred at 25 °C for 2 h. The mixture was diluted with saturated sodium bicarbonate solution (20 mL) and water (20 mL), then extracted with dichloromethane (40 mL x 3). The combined organic extract was washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column (0-42% THF in petroleum ether) to afford l-[[7-chloro-8-fluoro-4-[rac-(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropanecarbaldehyde (2.5 g, 90%) as a yellow solid. LC / MS (ESI) m / z: 407.1 [M+H]+;1H NMR (400 MHz, CDCI3) 89.21 (s, 1H), 9.00 (s, 1H), 4.72 (s, 2H), 4.64 - 4.51 (m, 2H), 4.39 (d, J = 13.2 Hz, 1H), 4.27 - 4.16 (m, 1H), 3.65 (d, 7= 13.2 Hz, 1H), 3.43 - 3.31 (m, 1H), 2.43 (t, 7=8.0 Hz, 2H), 2.34 - 2.21 (m, 1H), 2.05 - 1.97 (m, 1H), 1.88 - 1.76 (m, 2H), 1.40 -1.35 (m, 2H), 1.34 - 1.29 (m, 2H).Step 10:

[0084] To a mixture of l-[[7-chloro-8-fluoro-4-[rac-(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropanecarbaldehyde (5.1 g. 12 mmol) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-ol (3.96 g, 12 mmol) in dioxane (100 mL) and water (20 mL) were added K3PO4 (7.98 g, 38 mmol) and cataCXium A Pd G3 (912.9 mg, 1.3 mmol) under nitrogen atmosphere, and the reaction mixture was stirred atARVN-210-PCT / / AR VN0210WO285 °C for 16 h. The mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (400 mL). The combined organic extract was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (0-30% THF in dichloromethane) to afford l-[[7-(8-ethyl-7-fhioro-3-hydroxy-l-naphthyl)-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropanecarbaldehyde (4.0 g, 57%) as a yellow solid. LC / MS (ESI) m / z 561.1 [M+H]+; 'H NMR (400 MHz, CDC13) 89.29 - 9.13 (m, 2H), 7.97 - 7.72 (m, 1H), 7.55 - 7.45 (m, 1H), 7.18 (t, J = 9.2 Hz, 1H), 7.11 (t, 7= 2.4 Hz, 1H), 7.04 - 6.93 (m, 1H), 4.78 - 4.53 (m, 4H), 4.37 - 4.22 (m, 1H), 3.80 - 3.57 (m, 2H), 3.51 - 3.32 (m, 1H), 2.37 - 2.15 (m, 2H), 2.09 - 1.99 (m, 2H), 1.89 - 1.78 (m, 2H), 1.74 - 1.65 (m, 2H), 1.38 - 1.28 (m, 4H), 0.90 - 0.73 (m, 3H).Step 11:

[0085] To a solution of l-[[7-(8-ethyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropanecarbaldehyde (260 mg, 0.46 mmol) in dichloromethane (5 mL) and dimethyl sulfoxide (3 mL) was added N-methylmorpholine (0.3 mL), and the resulting mixtureARVN-210-PCT / / ARVN0210WO2was stirred at 25 °C for 0.5 h. 3-[4-Chloro-l-oxo-5-[rac-(3R)-4-[(4-fluoro-4-piperidyl)methyl]-3-methyl-piperazin-l-yl]isoindolin-2-yl]piperidine-2, 6-dione (360 mg, 0.49 mmol, trifluoroacetate) was then added, and the resulting mixture was stirred at 40 °C for 2 h, then cooled to 0 °C.Titanium(IV) isopropoxide (0.3 mL, 1 mmol) and sodium triacetoxyborohydride (317 mg, 1.5 mmol) were added, and the reaction mixture was stirred at 40 °C for 10 h. The mixture was diluted with water (50 mL) and extracted with 1 / 1 dichloromethane / tetrahydrofuran (100 mL x 2). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (20%-50% acetonitrile in water (formic acid) over 15 min) to afford 3-{4-chloro-5-[(3R)-4- [( 1 - { [ 1 -( { [7-(8-ethyL7-fluoro-3-hydroxynaphthalen- l-yl)-8-fluoro-4- [(4S)- 1 -oxa-6-azaspiro[3.5]nonan-6-yl]pyrido[4,3-d]pyrimidin-2-yl]oxy}methyl)cyclopropyl]methyl}-4-fluoropiperidin-4-yl)methyl]-3-methylpiperazin-l-yl]-l-oxo-2,3-dihydro-lH-isoindol-2-yl} piperidine- 2, 6-dione (193.9 mg, 36%, formic acid salt) as a white solid. LC / MS (ESI) m / z:. 1037.6 [M+H]+;NMR (400 MHz, DMSO-J6) 5 10.99 (s, 1H), 10.09 - 9.78 (m, 1H), 9.21 (d. J = 4.4 Hz, 1H), 8.14 (s, 1H), 7.75 (dd, J= 6.0, 8.8 Hz, 1H), 7.67 - 7.58 (m, 1H), 7.38 - 7.30 (m, 2H), 7.22 (d, 7= 8.4 Hz, 1H), 7.09 - 7.00 (m, 1H), 5.10 (dd, 7 = 4.8, 13.2 Hz, 1H), 4.54 - 4.16 (m, 8H), 3.94 - 3.76 (m, 1H), 3.53 - 3.47 (m, 1H), 3.17 - 2.86 (m, 6H), 2.80 - 2.57 (m, 6H), 2.46 -2.28 (m, 7H), 2.27 - 2.15 (m, 2H), 2.14 - 1.95 (m, 3H), 1.94 - 1.81 (m, 3H), 1.79 - 1.49 (m, 4H), 1.03 (d, 7 = 5.2 Hz, 3H), 0.80 - 0.70 (m, 3H), 0.69 - 0.62 (m. 2H), 0.49 - 0.33 (m, 2H).Example 1.2Exemplary synthesis of Compound 95: 3-(4-chloro-5-((5)-4-((l-((l-(((8-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-l-yl)-4-((S)-l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3- 7]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-4-fluoropiperidin-4-yl)methyl)-2-methylpiperazin- 1 -yl)- 1 -oxoisoindolin-2-yl)piperidine-2,6-dioneStep 1:Ruphos Pd G4, CS2CO3dioxane, 90 °C, 12 hARVN-210-PCT / / ARVN0210WO2

[0086] A mixture of terf-butyl (3S)-3-methylpiperazine- 1 -carboxylate (8.02 g, 40 mmol), methyl 4-bromo-2-cyanobenzoate (12.5 g, 52 mmol), Ruphos Pd G4 (3.41 g, 4 mmol) and cesium carbonate (39.15 g, 120 mmol) in dioxane (150 mL) was degassed and purged with nitrogen several times, then stirred at 90 °C for 12 h under nitrogen atmosphere. The mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0-12% ethyl acetate / petroleum ether) to afford tert-butyl (3S)-4-(3-cyano-4-methoxycarbonyl-phenyl)-3-methyl-piperazine-l- carboxylate (14.2 g, 98%) as a yellow solid. LC / MS (ESI) m / z 360.2 [M+H]+.Step 2:

[0087] To a solution of tert-butyl (3S)-4-(3-cyano-4-methoxycarbonyl-phenyl)-3-methyl-piperazine -1 -carboxylate (6.1 g, 17 mmol) in pyridine (90 mL) were added Raney-Ni (4.36 g, 51 mmol), acetic acid (45 mL) and sodium dihydrogen phosphate (10.18 g, 85 mmol) in water (22.5 mL), and the reaction mixture was stirred at 50 °C for 10 h. The mixture was cooled to 25 °C, filtered through celite, and washed with ethyl acetate (1000 mL). The filtrate was washed with brine (50 mL x 3). dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0-15% ethyl acetate / petroleum ether) to afford tert-butyl (3S)-4-(3-formyl-4-methoxycarbonyl-phenyl)-3-methyl-piperazine- 1 -carboxylate (6.06 g, 94%) as a yellow solid. LC / MS (ESI) m / z 363.2 [M+H]+.Step 3:

[0088] To a solution of tert-butyl (3S)-4-(3-formyl-4-methoxycarbonyl-phenyl)-3-methyl-piperazine- 1 -carboxylate (9.46 g, 26 mmol) in methanol (100 mL) was added sodiumARVN-210-PCT / / ARVN0210WO2acetate (6.42 g, 78 mmol), and the resulting mixture was stirred for 10 minutes. A solution of 3-aminopiperidine-2, 6-dione (6.44 g, 39 mmol, hydrochloride) in dichloromethane (100 mL) and acetic acid (14.9 mL) were added, and the mixture was stirred at 25 °C for 20 minutes. Sodium cyanoborohydride (4.92 g, 78 mmol) was then added, and the reaction mixture was stirred at 40 °C for 12 h. The mixture was diluted with water (100 mL) and extracted with dichloromethane (50 mL x 3). The combined organic extracts were washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ethyl acetate (80 mL) to afford / c / -bulyl (3S)-4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazine-l-carboxylate (6 g, 51%) as a white solid. LC / MS (ESI) m / z. 443.2 [M+H]+; 'H NMR(400 MHz, DMSO-6) 10.96 (s, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.06 - 6.97 (m, 2H), 5.05 (dd. J= 5.2, 13.2 Hz, 1H), 4.38 - 4.27 (m, 1H), 4.24 - 4.11 (m. 2H), 4.01 - 3.87 (m, 1H), 3.79 (d, J= 12.8 Hz, 1H), 3.48 (d, J = 8.2 Hz, 1H), 3.29 - 3.12 (m, 1H), 3.05 - 2.97 (m, 2H), 2.95 - 2.83 (m, 1H), 2.58 (d, J= 16.8 Hz, 1H), 2.36 (dq, J = 4.4, 13.2 Hz, 1H), 1.98 - 1.88 (m. 1H), 1.42 (s. 9H). 0.97 (d, J= 6.4 Hz. 3H).Step 4:NCS, DCM, / MeOH, TFA25 to 40 °C, 12 h

[0089] To a solution of tert-butyl (3S)-4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3-methyl- piperazine- 1 -carboxylate (2.0 g. 4.5 mmol) in dichloromethane (100 mL) and methanol (10 mL) at 25 °C were added trifluoroacetic acid (3.3 mL) and IV-chlorosuccinimide (724 mg, 5.4 mmol), and the reaction mixture was stirred at 40 °C for 12 h. The mixture was concentrated under reduced pressure, and the residue was triturated with ethyl acetate (20 mL) to afford tert-butyl (3S)-4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazine-1 -carboxylate (1.95 g, 90%) as a white solid. LC / MS (ESI) m / z 411.3 [M+H]+;1HNMR(400 MHz, DMSO-t / e) 5 11.00 (s, 1H), 7.67 (d, J= 8.1 Hz, 1H), 7.36 (d, J= 8.0 Hz, 1H), 5.11 (dd, J= 5.0, 13.2 Hz, 1H), 4.50 - 4.38 (m, 1H), 4.33 - 4.22 (m, 1H), 3.63 - 3.53 (m, 3H), 3.28 - 3.15 (m, 2H), 2.97 - 2.85 (m. 1H), 2.74 - 2.66 (m, 1H), 2.62 - 2.53 (m, 2H), 2.48 -2.42 (m, 1H), 2.04 - 1.94 (m, 1H), 1.43 (s, 9H), 0.85 (d, J= 6.2 Hz, 3H).ARVN-210-PCT / / ARVN0210WO2Step 5:HCI / Dioxane DCM, 25 °C, 0.25 h

[0090] To a solution of tert-butyl rac-(3S)-4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5- yl]-3-methyl-piperazine-l-carboxylate (500 mg, 1 mmol) in dichloromethane (5 mL) was added 2 M hydrochloric acid in dioxane (5 mL), and the reaction solution was stirred at 20 °C for 15 minutes. The mixture was concentrated under reduced pressure to afford 3-[4-chloro-1 -oxo-5- [rac-(2S)-2-methylpiperazin-l-yl] isoindolin-2-yl]piperidine-2, 6-dione (470 mg, crude, hydrochloride salt) as a white solid, which was used in the next step directly. LC / MS (ESI) m / z 377.1 [M+H]+.Step 6:o

[0091] To a solution of 3-[4-chloro-l-oxo-5-[rac-(2S)-2-methylpiperazin-l-yl]isoindolin- 2-yl] piperidine-2, 6-dione (470 mg, 1 mmol, hydrochloride) and terf-butyl 4-fluoro-4-formyl-piperidine-1 -carboxylate (241 mg, 1 mmol) in dimethyl sulfoxide (5 mL) were added sodium acetate (428 mg, 5 mmol) and acetic acid (0.3 mL, 5 mmol) followed by sodium triacetoxyborohydride (553 mg, 2.6 mmol), and the reaction mixture was stirred at 40 °C for 16 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic extract was washed with brine (30 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The mixture was triturated with methyl tert-butyl ether (15 mL) to afford tert-butyl 4-fluoro-4-[[rac-(3S)-4-[4-chloro-2-(2,6-dioxo-3-piperidyl)- 1-oxo- isoindolin-5-yl]-3-methylpiperazin-l-yl]methyl]piperidine-l -carboxylate (276 mg, 44%) as a white solid. LC / MS (ESI) m / z 592.2 [M+H]+.ARVN-210-PCT / / ARVN0210WO2Step 7:

[0092] To a solution of tert-butyl 4-fluoro-4-[[rac-(3S)-4-[4-chloro-2-(2,6-dioxo-3-piperidyl)- 1-oxo- isoindolin-5-yl]-3-methyl-piperazin-l-yl]methyl]piperidine-l-carboxylate (176 mg, 0.3 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1.5 mL, 20 mmol), and the reaction solution was stirred at 20 °C for 0.5 h. The solution was concentrated under reduced pressure, the residue was purified by prep-HPLC (0%-23% acetonitrile in water (formic acid) over 15 min) to afford 3-[4-chloro-1-oxo-5-[rac-(2S)-4-[(4-fluoro-4-piperidyl)methyl]- 2-methyl-piperazin-l-yl]isoindolin-2-yl]piperidine-2, 6-dione (100 mg, 40%, trifluoroacetic acid salt) as a white solid. LC / MS (ESI) m / z: 492.3 [M+H]+.Step 8:

[0093] To a solution of 2,4,7, 8-tetrachloropyrido[4,3-d]pyrimidine (6.8 g, 25 mmol, 1 eq) in dichloromethane (100 mL) were added A / -ethyl-A / -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 was stirred at -60 °C for 0.5 h. The mixture was diluted with water (100 mL) and extracted with dichloromethane (100 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 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-210-PCT / / ARVN0210WO2Step 9:

[0094] To a solution of 8-(2,7,8-trichloropyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5]nonane (9.0 g, 25 mmol) in acetonitrile (100 mL) were added 1,4-diazabicyclo[2.2.2]octane (0.5 mL, 5 mmol), [l-(hydroxymethyl)cyclopropyl]methanol (63.9 g, 626 mmol) and cesium carbonate (24.46 g, 75 mmol), and the reaction mixture was stirred at 50 °C for 2 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL). The combined organic extracts were washed with water (200 mL) followed by brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to afford [l-[[7.8-dichloro-4-(l-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (2 g, 19%) as a colorless oil. LC / MS (ESI) m / z 425.2 [M+H]+.Step 10:

[0095] (l-(((7,8-Dichloro-4-(l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol(16 g) was purified by SFC (45% isopropanol (0.1% NH3H2O) in carbon dioxide). The first eluted fraction was assigned as [l-[[7,8-dichloro-4-[rac-(4R)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (7.8 g) as a yellow solid.NMR (400 MHz, DMSO-cL) 3: 9.13 (s, 1H), 4.70 (t, J= 5.6 Hz, 1H), 4.46 - 4.34 (m, 5H), 4.25 - 4.13 (m, 1H), 3.88 - 3.80 (m, 1H), 3.49 - 3.39 (m, 3H), 2.49 - 2.41 (m. 1H), 2.40 - 2.32 (m, 1H). 2.17 - 2.06 (m, 1H), 1.93 -ARVN-210-PCT / / ARVN0210WO21.79 (m, 2H), 1.77 - 1.66 (m, 1H), 0.68 - 0.48 (m, 4H). The second eluted fraction was assigned as [l-[[7,8-dichloro-4-[rac-(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (7.4 g) as a white solid.!H NMR (400 MHz, DMSO-cfe) d: 9.15 (s, 1H), 4.72 (t, J = 5.6 Hz, 1H), 4.47 - 4.37 (m, 5H), 4.22 (d, J = 12.4 Hz, 1H), 3.91 - 3.85 (m, 1H), 3.51 - 3.42 (m, 3H), 2.51 - 2.35 (m, 2H), 2.18 - 2.10 (m, 1H), 1.95 - 1.70 (m, 3H), 0.68 -0.54 (m, 4H).

[0096] To a solution of [l-[[7,8-dichloro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (7.40 g, 17 mmol) in dichloromethane (100 mL) were added tetrapropylammoniumperruthenate (1.22 g, 3.5 mmol) and Mmethylmorpholine-Moxide (4.6 mL, 43 mmol), and the reaction mixture was stirred at 25 °C for 1 h. The mixture was diluted with water (100 mL) and extracted with dichloromethane (100 mL). The combined organic extracts were washed with water (100 mL) followed by brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (dichloromethane / methanol = 10:1) to afford 1-[[7,8-dichloro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropanecarbaldehyde (5.9 g. 80%) as a white solid. MS (ESI) m / z. 423.2 [M+H]+.Step 12:ARVN-210-PCT / / ARVN0210WO2CataCXium A Pd G3, 1 5 M K3PO4,THF, 70 °C, 12 h

[0097] 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]cyclopropanecarbaldehyde (1.00 g, 2.4 mmol), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-ol (896 mg, 2.8 mmol), potassium phosphate (1.5 M, 3.2 mL) and cataCXium A Pd G3 (258 mg, 0.35 mmol) in tetrahydrofuran (10 mL) was degassed and purged with nitrogen several times, then stirred at 70 °C for 12 h under nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The combined organic extracts were washed with water (10 mL) followed by brine (lOmL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (35%-65% acetonitrile in water (formic acid) over 25 min) to afford l-[[8-chloro-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]cyclopropanecarbaldehyde (445 mg, 33%) as a yellow solid. LC / MS (ESI) m / z 577.2 [M+H]+.Step 13:

[0098] To a solution of 3-(4-chloro-5-((S)-4-((4-fluoropiperidin-4-yl)methyl)-2-methylpiperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione (430 mg, 0.6 mmol, trifluoroacetate) in dichloromethane (5 mL) and dimethyl sulfoxide (5 mL) was added N, N-diisopropylethylamine (0.3 mL), and the resulting mixture was stirred at 25 °C for 0.5 h. l-[[8-Chloro-7-(8-ethyl-7-fluoro-3-hydroxy-l-naphthyl)-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-ARVN-210-PCT / / ARVN0210WO2yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropanecarbaldehyde (310 mg, 0.5 mmol) was then added, and the reaction mixture was stirred at 40 °C for 2 h. Titanium(IV) isopropoxide (339 mg, 1 mmol, 0.3 mL) and sodium triacetoxyborohydride (379 mg, 1.8 mmol) were then added, and the reaction mixture was stirred at 40 °C for 12 h. The mixture was diluted with water (50 mL) and filtered, and the filtrate was extracted with dichloromethane (30 mL x 2). The combined organic extracts were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (20%-50% acetonitrile in water (formic acid) over 10 min) to afford 3-(4-chloro-5-((S)-4-((l-((l-(((8-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-l-yl)-4-((5)-l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-<f|pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-4-fhioropiperidin-4-yl)methyl)-2-methylpiperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (200 mg, 30%, formic acid salt) as an off-white solid. LC / MS (ESI) ni / 1054.2[M+H]+; NMR (400 MHz, DMSO-d6) 3: 10.99 (s. 1H), 10.19 - 9.62 (m. 1H), 9.29 (s, 1H), 8.17 (s, 1H), 7.75 (dd, J = 6.4, 8.8 Hz, 1H), 7.64 (d. J = 8.0 Hz, 1H), 7.38 - 7.27 (m, 3H), 6.96 (dd, J = 2.4, 5.6 Hz, 1H), 5.10 (dd, J= 5.2, 13.2 Hz, 1H), 4.52 - 4.11 (m, 8H), 3.98 - 3.77 (m, 1H), 3.61 - 3.51 (m, 2H), 3.24 - 3.20 (m, 1H), 2.97 - 2.84 (m, 1H), 2.79 - 2.54 (m, 8H). 2.47 - 2.28 (m, 7H), 2.20 (d, J = 7.6 Hz, 4H), 2.13 - 1.95 (m, 2H), 1.92 - 1.67 (m, 5H), 1.66 - 1.41 (m, 2H), 0.87 (d, J= 5.2 Hz, 3H), 0.76 (m, 3H), 0.67 (s, 2H), 0.43 (s, 2H).Example 1.3Exemplary synthesis of Compound 38: 3-[4-chloro-5-[4-[[l-[[l-[[7-(8-ethyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fhioro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4-fluoro-4-piperidyl]methyl]piperazin-l-yl]- 1-oxo-isoindolin-2-yl]piperidine-2, 6-dioneStep 1:(COCI)2, DMSO, CH2CI2Et3N, CH2CI2

[0099] To a solution of dimethyl sulfoxide (502 mg, 6 mmol) in anhydrous dichloromethane (5.0 mL) at -78°C was added a solution of oxalyl chloride (598 mg, 4.7 mmol) in anhydrous dichloromethane dropwise (2.0 mL) under nitrogen, and the resulting mixture wasARVN-210-PCT / / ARVN0210WO2stirred at -78°C for 20 minutes. tert-Butyl 4-fluoro-4-(hydroxymethyl)piperidine-l -carboxylate (500 mg, 2 mmol) in anhydrous dichloromethane (5.0 mL) was added dropwise, and the reaction mixture was stirred for 0.5 h. Triethylamine (2.17 g, 21 mmol) was then added dropwise, and the reaction mixture was stirred at -78 °C for 10 minutes. The mixture was diluted with water (10 mL) and extracted with dichloromethane (40 mL x 3). The combined organic extract was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford tertbutyl 4-fluoro-4-formyl-piperidine- 1 -carboxylate (550 mg, crude) as yellow oil, which was used directly in the next step.:H NMR (400MHz, CDCI3) 59.66 (d, J = 5.2 Hz, 1H), 4.06-3.96 (m, 2H), 3.05-2.92 (m, 2H), 1.84-1.71 (m, 4H), 1.39 (s, 9H).Step 2:NaOAc, NaBH(OAc)3,HOAC, CH2CI2,

[0100] To a solution of 3-(4-chloro-l-oxo-5-piperazin-l-yl-isoindolin-2-yl)piperidine- 2,6-dione (400 mg, 0.9 mmol, hydrochloride) and mrf-butyl 4-fhroro-4-formyl-piperidine-l-carboxylate (1.33 g, 4 mmol) in dichloromethane (4 mL) were added sodium triacetoxyborohydride (456 mg, 2 mmol), acetic acid (247 pL, 4 mmol) and sodium acetate (707 mg, 9 mmol), and the reaction mixture was stirred at 25 °C for 16 h. The mixture was diluted with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with dichloromethane (70 mL). The combined organic extract was washed with water (30 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% methanol in dichloromethane) to afford ferr-butyl 4-[[4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]piperazin-l-yl]methyl]-4-fluoro-piperidine-l -carboxylate (343 mg, 69%) as a white solid. LC / MS (ESI) m / z:578.1 [M+H]+; 'H NMR (400 MHz, CDCh) d 10.47 (s, 1H), 7.17 (d, J= 8.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 4.69-4.58 (m, 1H), 3.92-3.81 (m, 2H), 3.36 (brd, J = 10.8 Hz, 2H), 2.63-2.52 (m, 2H), 2.39-2.21 (m. 6H), 2.15-2.09 (m, 3H), 2.06 (br s, 3H), 1.98-1.85 (m. 1H), 1.71-1.61 (m, 1H), 1.49-1.37 (m, 2H), 1.19-1.03 (m, 2H), 0.96 (s, 9H).ARVN-210-PCT / / ARVN0210WO2Step 3:

[0101] To a solution of / er / -butyl 4-[[4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl] piperazin-l-yl]methyl]-4-fluoro-piperidine-l-carboxylate (600 mg, 1 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL), and the reaction solution was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (0%-20% acetonitrile in water (formic acid) over 15 min) to afford 3- [4-chloro-5 - [4- [(4-fluoro-4-piperidyl)methyl] piperazin- 1 -yl] - 1 -oxo-isoindolin-2-yl] piperidine-2, 6-dione (268 mg, 54%) as a white solid. LC / MS (ESI) m / z 478.2 [M+H]+.Step 4:

[0102] 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]cyclopropyl]methanol (3.00 g. 7.3 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.78 g, 7.7 mmol) and potassium phosphate (4.67 g. 22 mmol) in dioxane (30 mL) and water (3 mL) was added cataCXium A Pd G3 (534 mg, 0.7 mmol), and the reaction mixture was stirred at 90 °C for 12 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-80% ethyl acetate / petroleum ether) to afford l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-ARVN-210-PCT / / ARVN0210WO2azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropanemethanol (2 g, 45%) as a yellow solid. LC / MS (ESI) m / z 607.2 [M+H]+; 'H NMR (400 MHz, CDC13) 39.25 (d, J= 11.2 Hz, 1H), 7.68 (dd, 7 = 5.6. 8.8 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H). 7.26 - 7.21 (m, 2H), 5.29 (s, 2H), 4.69 - 4.49 (m, 4H), 4.42 - 4.25 (m, 2H), 4.03 - 3.86 (m, 1H), 3.69 (t, 7 = 13.2 Hz, 1H), 3.51 (d, 7 = 1.6 Hz, 4H), 3.48 - 3.32 (m, 2H), 2.58 - 2.42 (m, 3H), 2.38 - 2.27 (m. 1H), 2.26 - 2.15 (m, 1H). 2.14 - 2.05 (m, 1H), 1.94 - 1.77 (m. 2H), 0.85 (q, 7 = 7.2 Hz, 3H), 0.74 - 0.55 (m.4H).

[0103] To a solution of dimethylsulfoxide (0.6 mL, 8 mmol) in dichloromethane (20 mL) at -65 °C was added a solution of oxalyl chloride (0.4 mL, 5 mmol) in dichloromethane (20 mL) dropwise, and the resulting mixture was stirred at -65 °C for 30 minutes. A solution of 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]cyclopropanemethanol (2 g, 3 mmol) in dichloromethane (20 mL) was added dropwise, and the reaction mixture was stirred at -65 °C for 0.5 h. Triethylamine (2.3 mL, 16 mmol) was then added, and the reaction mixture was stirred at -65 °C for 0.5 h, then warmed to 25 °C and stirred for 1 h. The mixture was diluted with water (100 mL) and extracted with dichloromethane (100 mL x 2). The combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 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]cyclopropanecarbaldehyde (1.9 g, 95%) as a yellow solid, which was used in the next step without further purification. LC / MS (ESI) m / z 605.3 [M+H]+.Step 6:ARVN-210-PCT / / ARVN0210WO2

[0104] To a solution of 3-[4-chloro-5-[4-[(4-fluoro-4-piperidyl)methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (160 mg, 0.33 mmol) in dichloromethane (2 mL) and dimethyl sulfoxide (2 mL) were added N,N-diisopropylethylamine (0.1 mL, 0.7 mmol), 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]cyclopropanecarbaldehyde (202 mg, 0.33 mmol) and titanium(IV) isopropylate (0.1 mL, 0.5 mmol), and the resulting mixture was stirred at 40 °C for 4 h. Sodium triacetoxyborohydride (213 mg, 1 mmol) was then added, and the reaction mixture was stirred at 40 °C for 12 h. The mixture was diluted with water (30 mL) and extracted with dichloromethane (15 mL x 3). The combined organic extract was washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (dichloromethane / methanol = 10:1) to afford 3-[4-chloro-5-[4-[[l-[[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]cyclopropyl]methyl]-4- fluoro-4-piperidyl]methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (343 mg, 96%) as a white solid. LC / MS (ESI) m / z 1066.5 [M+H]+.Step 7:

[0105] To a solution of 3-[4-chloro-5-[4-[[l-[[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]cyclopropyl]methyl]-4-fluoro-4-piperidyl]methyl]piperazin-l-yl]-l-ARVN-210-PCT / / ARVN0210WO2oxo-isoindolin-2-yl]piperidine-2, 6-dione (343 mg, 0.3 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (2 mL), and the reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (12%-42% acetonitrile in water (formic acid) over 7 min) to afford 3-[4-chloro-5-[4-[[l-[[l-[[7- (8-ethyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8- yl]pyrido [4, 3-d] pyrimidin-2-yl] oxymethyl] cyclopropyl] methyl] -4-fluoro-4- piperidyl]methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (44.2 mg, 13%) as a white solid. LC / MS (ESI) m / z: 1022.5 [M+H]+;1HNMR(400 MHz, DMSO- e) d 10.97 (s, 1H), 9.93 (s, 1H), 9.21 (d, 7= 3.6 Hz, 1H), 8.14 (s, 1H), 7.76 (dd, J = 6.0, 9.2 Hz, 1H), 7.64 (d, 7 = 8.0 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.24 (d, 7= 8.4 Hz, 1H), 7.04 (t, 7= 3.2 Hz, 1H), 5.09 (dd, 7 = 5.2, 13.2 Hz, 1H), 4.53 - 4.22 (m. 8H). 3.63 - 3.46 (m, 1H), 3.10 - 2.85 (m, 6H), 2.73 - 2.58 (m, 8H), 2.38 - 2.27 (m, 5H), 2.26 - 2.15 (m, 3H), 2.15 - 2.05 (m, 2H), 2.02 - 1.96 (m, 1H), 1.92 - 1.50 (m, 8H), 0.78 - 0.70 (m, 3H), 0.66 (s, 2H), 0.46 - 0.39 (m, 2H).Example 1.4Exemplary synthesis of Compound 2: 3-[5-[7-[[l-[[l-[[7-(8-ethyl-7-fhroro-3-hydroxy-l- naphthyl)-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-fluoro-4-piperidyl]methyl]-2,7-diazaspiro[3.5]nonan-2-yl]- 4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione.

[0106] The title compound was prepared in a manner analogous to Example 1.1 (Compound 29), starting from methyl 3, 4-difluoro benzoate and tert-butyl 2,7- diazaspiro[3.5]nonane-7-carboxylate, isolated as a white solid (formic acid salt). LC / MS (ESI) m / z 1046.9 [M+H]+;NMR (400 MHz, DMSO-cfc) d 10.97 (s, 1H), 10.50 - 9.57 (m, 1H), 9.22 (d, J = 4.8 Hz, 1H), 8.14 (s, 1H), 7.76 (dd, J = 6.0, 9.2 Hz, 1H), 7.41 - 7.26 (m, 3H), 7.04 (t, J = 3.2 Hz, 1H), 6.58 (t, J= 8.0 Hz, 1H), 5.04 (dd, J= 5.2, 13.2 Hz, 1H), 4.54 - 4.12 (m, 8H), 3.92 -ARVN-210-PCT / / ARVN0210WO23.77 (m, 1H), 3.73 (s, 4H), 3.49 (s, 2H), 2.95 - 2.84 (m, 1H), 2.74 (s, 2H), 2.58 (d, J = 17.2 Hz, 1H), 2.47 - 2.31 (m, 11H), 2.24 (s, 2H), 2.18 - 2.06 (m, 2H), 1.94 (dd, J= 5.2, 10.0 Hz, 1H), 1.91 - 1.82 (m, 2H). 1.81 - 1.66 (m, 7H), 1.66 - 1.48 (m, 2H), 0.79 - 0.70 (m, 3H). 0.67 (s, 2H). 0.44 (s, 2H).Example 1.5Exemplary synthesis of Compound 61: 3-[4-chloro-5-[4-[[4-[[l-[[7-(8-ethyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl] oxymethyl]cyclopropyl]methyl]piperazin- 1 -yl]methyl] - 1 -piperidyl] - 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dioneStep 1:NaBH(OAc)3, DIEA, DCM / DMSO, 25 °C, 12h

[0107] To a mixture of l-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]piperidine-4- carbaldehyde (1.0 g. 2.6 mmol) and / ert-butyl piperazine- 1 -carboxylate (477 mg, 2.6 mmol) in dichloromethane (10 mL) and dimethyl sulfoxide (5 mL) was added N, N-diisopropylethylamine (33 mg, 0.25 mmol), and the mixture was stirred at 25 °C for 0.5 h.Sodium triacetoxyborohydride (1.63 g, 7.7 mmol) was then added, and the reaction mixture was stirred at 25 °C for 11.5 h. The mixture was suspended in water (20 mL), filtered and washed with ethyl acetate (100 mL) to afford tert-butyl 4-[[l-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-4- piperidy 1] methyl] piperazine- 1 -carboxylate (1.1 g, 76%) as a blue solid.LC / MS (ESI) m / z 560.4 [M+H]+; 'H NMR (400 MHz, DMSO-6) b 10.98 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 5.09 (dd, J = 5.2. 13.6 Hz, 1H). 4.46 - 4.36 (m, 1H), 4.31 -4.16 (m, 1H), 3.44 - 3.37 (m, 2H), 3.32 - 3.27 (m, 4H), 2.97 - 2.85 (m, 1H), 2.78 - 2.68 (m, 2H), 2.63 - 2.55 (m, 1H), 2.47 - 2.37 (m, 1H), 2.35 - 2.26 (m, 4H), 2.24 - 2.17 (m, 2H), 2.04 - 1.94 (m.1H), 1.88 - 1.79 (m, 2H), 1.75 - 1.63 (m. 1H). 1.39 (s, 9H), 1.36 - 1.24 (m, 2H).Step 2:ARVN-210-PCT / / ARVN0210WO2

[0108] To a solution of tert-butyl 4-[[l-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-4- piperidyl]methyl]piperazine-l-carboxylate (1.1 g, 2 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL), and the reaction mixture was stirred at 25 °C for 0.5 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (l%-20% acetonitrile in water (hydrochloric acid) over 10 min) to afford 3-[4-chloro-l-oxo-5-[4-(piperazin-l-ylmethyl)-l-piperidyl] isoindolin-2-yl]piperidine-2, 6-dione (500 mg, 47%, hydrochloride salt) as a white solid. LC / MS (ESI) m / z 460.2 [M+H]+;1H NMR (400 MHz, DMSO-63 11.29 (s, 1H), 10.97 (s, 1H), 9.70 - 9.53 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.28 (d, 7 = 8.0 Hz, 1H), 5.10 (dd, J = 4.8, 13.2 Hz, 1H), 4.47 - 4.36 (m, 1H), 4.31 - 4.18 (m, 1H), 3.82 - 3.69 (m, 1H), 3.64 - 3.49 (m, 4H), 3.46 - 3.36 (m, 4H), 3.35 - 3.03 (m, 4H), 2.97 - 2.85 (m, 1H). 2.81 - 2.70 (m, 2H), 2.65 - 2.52 (m, 1H), 2.48 - 2.38 (m.1 H), 2.11 - 1.90 (m, 4H), 1.50 - 1.35 (m, 2H).Step 3:

[0109] To a solution of 3-(4-chloro-l-oxo-5-(4-(piperazin-l-ylmethyl)piperidin-l-yl)isoindolin-2-yl) piperidine-2, 6-dione (200 mg, 0.37 mmol, hydrochloride) in dichloromethane (3 mL) and dimethyl sulfoxide (3 mL) was added N,N-diisopropylethylamine (0.4 mL, 2 mmol), and the resulting mixture was stirred at 25 °C for 0.5 h. 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]cyclopropanecarbaldehyde (249 mg, 0.4 mmol) was then added, and the resulting mixture was stirred at 40 °C for 2 h. Titanium(IV) isopropoxide (0.2 mL, 0.8 mmol) and sodium triacetoxyborohydride (238 mg, 1 mmol) were added at 25 °C, and the reaction mixture was stirred at 40 °C for 12 h. The mixture was suspended in water (50 mL) andARVN-210-PCT / / ARVN0210WO2filtered, and the filtrate was extracted with dichloromethane (30 mL x 2). The combined organic extracts were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (25%-55% acetonitrile in water (formic acid) over 15 min) to afford 3-[4-chloro-5-[4-[[4-[[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] cyclopropyl] methyl] piperazin- 1 -yl] methyl] - 1 -piperidyl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (230 mg, 58%) as a white solid. LC / MS (ESI) m / z 1048.5 [M+H]+.Step 4:

[0110] To a mixture of 3-[4-chloro-5-[4-[[4-[[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]cyclopropyl]methyl]piperazin-l-yl]methyl]-l-piperidyl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (1 g, 1 mmol) in dichloromethane (6 mL) at 0 °C was added trifluoroacetic acid (43 mL), and the reaction mixture was stirred for 2.5 h. The mixture was diluted with saturated sodium bicarbonate solution until pH 7, the resulting mixture was extracted with dichloromethane (30 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (20% - 50% acetonitrile in water (formic acid) over 20 min) to afford 3-[4-chloro-5-[4-[[4-[[l-[[7-(8-ethyl-7-fluoro-3- hydroxy-l-naphthyl)-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]piperazin-l-yl]methyl]-l-piperidyl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (591.6 mg, 56%, formic acid salt) as a white solid. LC / MS (ESI) m / z: 1004.5 [M+H]+;NMR (400 MHz, DMSO-6J: 10.99 (s, 1H), 9.96 (s, 1H), 9.22 (d, J= 2.8 Hz, 1H), 8.13 (s, 1H), 7.77 (dd, J = 6.0, 9.2 Hz, 1H), 7.64 (d, J= 8.0 Hz, 1H), 7.40 - 7.31 (m, 2H), 7.28 - 7.21 (m. 1H), 7.07 - 7.01 (m, 1H), 5.09 (dd, 7= 5.2, 13.2 Hz, 1H), 4.55 - 4.18 (m, 8H), 3.96 - 3.78 (m, 1H), 3.58 - 3.46 (m, 1H), 3.42 - 3.37 (m, 4H), 2.97 - 2.86 (m, 1H), 2.78 - 2.64 (m, 3H), 2.61 - 2.54 (m, 2H), 2.48 - 2.31 (m, 9H), 2.29 -ARVN-210-PCT / / ARVN0210WO22.20 (m, 2H), 2.17 - 2.08 (m, 2H), 2.06 - 1.61 (m, 8H), 1.36 - 1.21 (m, 2H), 0.81 - 0.62 (m, 5H), 0.46 (s, 2H).Example 1.6Exemplary synthesis of Compound 137: 3-(4-chloro-5-((R)-4-((l-((l-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-methyl-4-((S)-l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-4-fluoropiperidin-4-yl)methyl)-3-methylpiperazin- 1 -yl)- 1 -oxoisoindolin-2-yl)piperidine-2,6-dione.Step 1:

[0111] To a solution of 2,4,7-trichloro-8-methyl-pyrido[4,3-d]pyrimidine (2.3 g, 9 mmol) in dichloromethane (25 mL) were 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 was stirred at 0 °C for 1 h. The mixture was diluted with water (50 mL) and extracted with dichloromethane (3 x 30 mL). The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was 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]+; 'H NMR (400 MHz, DMSO-689.16 (s, 1H), 4.43 - 4.35 (m, 3H), 4.20 - 4.18 (m, 1H), 3.85 (d,. / = 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 2:ARVN-210-PCT / / ARVN0210WO2

[0112] 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 (1 g, 3 mmol) in N,N-dimethylacetamide (20 mL) were added cesium carbonate (2.88 g, 8.8 mmol) and [l-(hydroxymethyl)cyclopropyl]methanol (602.16 mg, 5.9 mmol), and the reaction mixture was stirred at 25 °C for 6 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC (30%-33% acetonitrile in water (0.225% trifluoroacetic acid) over 15 min) to afford (S)-(l-(((7-chloro-8-methyl-4-(l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (780 mg, 65%) as a yellow solid. LC / MS (ESI) m / z 405.2 [M+H]+; 'H NMR (400 MHz, DMSO-63 9.05 (s, 1H), 4.63 -4.53 (m, 2H), 4.51 (s, 2H), 4.36 (d. J= 13.2 Hz. 1H), 4.22 - 4.14 (m, 1H), 3.65 (d, J = 13.2 Hz, 1H), 3.53 (s, 2H), 3.42 - 3.32 (m, 1H), 2.61 (s, 3H), 2.43 (t, J= 7.6 Hz, 2H), 2.31 - 2.23 (m, 1H), 2.04 - 1.96 (m, 1H), 1.90 - 1.80 (m, 2H), 0.75 - 0.55 (m, 4H).Step 3:

[0113] To a solution of (S)-(l-(((7-chloro-8-methyl-4-(l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (780 mg, 1.9 mmol) in dichloromethane (10 mL) were added tetrapropylammoniumperruthenate (135.4 mg, 0.39 mmol) and 4-methyl-4-oxidomorpholin-4-ium (338.5 mg, 2.9 mmol), and the reaction mixture was stirred at 90 °C for 12 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0-50% ethyl acetate / petroleum ether) toARVN-210-PCT / / ARVN0210WO2afford (S)-l-(((7-chloro-8-methyl-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-l-carbaldehyde (530 mg, 68%) as a white solid. LC / MS (ESI) m / z 403.2 [M+H]+; 'H NMR (400 MHz, DMSO-6<5: 9.20 (s, 1H), 9.04 (s. 1H), 4.72 (s, 2H). 4.64 -4.51 (m, 2H), 4.30 (d, J = 13.2 Hz, 1H), 4.17 - 4.08 (m, 1H), 3.66 (d, J = 13.2 Hz, 1H), 3.44 -3.31 (m, 1H), 2.59 (s, 3H), 2.41 (t, J= 7.6 Hz, 2H), 2.29 - 2.19 (m, 1H), 2.04 - 1.94 (m, 1H), 1.89 - 1.72 (m. 2H), 1.41 - 1.36 (m, 2H). 1.35 - 1.29 (m, 2H).

[0114] To a solution of (S)-l-(((7-chloro-8-methyl-4-(l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-l-carbaldehyde (430 mg, 1.1 mmol) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-ol (674.93 mg, 2.1 mmol) in tetrahydrofuran (8 mL) were added potassium phosphate (1.5 M, 1.8 mL) and cataCXium A Pd G3 (77.7 mg, 0.11 mmol), and the reaction mixture was stirred at 75 °C for 16 h under nitrogen. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic extracts were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0-80% ethyl acetate / petroleum ether) to afford (S)-l-(((7-(8-ethyL7-fluoro-3-hydroxynaphthalen-l-yl)-8-methyl-4-(l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-l-carbaldehyde (330 mg, 56%) as a yellow solid. LC / MS (ESI) m / z 557.2 [M+H]+; 'H NMR (400 MHz, DMSO-63: 9.38 - 9.14 (m, 2H), 7.50 - 7.40 (m, 1H), 7.16 (t, J= 9.2 Hz. 1H), 6.95 (t, J= 2.4 Hz, 1H), 6.86 (dd, Ji = 2.4 Hz, Ji = 11.6 Hz. 1H), 4.77 -4.46 (m, 4H), 4.35 - 4.22 (m, 1H), 4.17 - 4.10 (m, 1H), 3.84 - 3.57 (m, 1H), 3.56 - 3.28 (m, 1H), 2.51 - 2.37 (m, 2H), 2.36 - 2.22 (m, 2H), 2.22 - 2.11 (m, 4H), 2.08 - 1.98 (m, 2H), 1.90 - 1.75 (m, 2H), 1.39 - 1.30 (m, 3H), 0.90 - 0.70 (m. 3H).ARVN-210-PCT / / ARVN0210WO2Step 5:

[0115] To a solution of (S)-l-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-methyl-4-(l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-l-carbaldehyde (176.8 mg, 0.36 mmol) in dichloromethane (3 mL) and dimethyl sulfoxide (3 mL) was added N,N-diisopropylethylamine (0.19 mL, 1 mmol), and the resulting mixture was stirred at 25 °C for 0.5 h. l-[[7-(8-Ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropanecarbaldehyde (200 mg, 0.36 mmol) and tetraisopropoxytitanium (0.32 mL, 1.1 mmol) were added, and the mixture was stirred at 25 °C for 2 h. Sodium triacetoxyborohydride (228.5 mg, 1.1 mmol) was then added, and the reaction mixture was stirred at 40 °C for 13.5 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2) and tetrahydrofuran (50 mL x 2). The combined organic extracts were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC (30%-33% acetonitrile in water (formic acid) over 15 min) to afford 3 - (4-chloro- 5 - ( (R) -4- (( 1 - (( 1 - (( (7 - ( 8 -ethyl-7 -fluor o- 3 -hydroxynaphthalen- 1 -y 1) - 8 -methyl-4-((S)-l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-4-fluoropiperidin-4-yl)methyl)-3-methylpiperazin- 1 -yl)- 1 -oxoisoindolin-2-yl)piperidine-2, 6-dione (134 mg, 36%, formic acid salt) as an off-white solid. LC / MS (ESI) m / z 1032.8 [M+H]+; 'H NMR (400 MHz, DMSO-6<5: 11.00 (s, 1H), 9.20 (s, 1H), 8.15 (s, 1H), 7.79 - 7.68 (m, 1H), 7.63 (d, J= 8.0 Hz, 1H), 7.31 (t, J= 9.2 Hz, 1H), 7.26 (d, J= 2.4 Hz, 1H), 7.21 (d, J= 8.4 Hz, 1H), 6.88 (dd, Ji = 2.4 Hz, J2=5.6 Hz. 1H). 5.10 (dd. Ji = 4.8 Hz, h =13.2 Hz, 1H), 4.52 - 4.12 (m, 8H), 4.08 - 3.88 (m, 1H), 3.88 - 3.55 (m, 1H), 3.36 - 3.29 (m, 1H), 3.18 - 3.08 (m, 2H), 3.06 - 2.99 (m, 1H), 2.97 - 2.85 (m, 2H). 2.79 - 2.62 (m, 5H), 2.47 - 2.30 (m. 6H), 2.28 - 2.06 (m, 8H). 2.05 - 1.45 (m, 9H), 1.03 (d. J= 5.2 Hz, 3H), 0.76 -0.57 (m, 5H), 0.44 (s, 2H).ARVN-210-PCT / / ARVN0210WO2Example 1.7Exemplary synthesis of Compound 136: 3-[4-chloro-5-[4-[[l-[[l-[[7-(8-ethyl-7-fluoro-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]cyclopropyl]methyl]-4-fLuoro-4-piperidyl]methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dioneStep 1:ci o ci ciNAJNHP0CI3>DI EArNAANCl MeCN, 90 °C, 2 h ClF F

[0116] 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 were added phosphorus oxychloride (16.6 mL, 179 mmol) and A / . N,N-diisopropylethylamine (18.7 mL, 107 mmol), and the reaction mixture was degassed and purged with nitrogen several times then stirred at 90 °C for 2 h. The mixture was cooled to room temperature, then poured into water (100 mL). The resulting mixture was 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 were washed with brine (80 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was 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:F

[0117] 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) were added N, N-diisopropylethylamine (13.2 mL, 76 mmol) and (4S)-l-oxa-8-azaspiro[3.5]nonane (4.81 g, 38ARVN-210-PCT / / ARVN0210WO2mmol), and the reaction mixture was stirred at 0 °C for 1 h. The mixture was concentrated under reduced pressure, and the residue was 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. 'H NMR (400 MHz, CDCh) 4.65 - 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:

[0118] A solution of (4S)-8-(5,7-dichloro-8-fluoro-2-methylsulfanyLpyrido[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) were simultaneously pumped to a flow reactor (FLRL 56.3 mL / min) at 18 °C for 0.33 min. The reaction mixture was 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 were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was 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, CDC13) d 4.59 - 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-210-PCT / / ARVN0210WO2

[0119] To a solution of (4S)-8-(7-chloro-8-fluoro-5-methyl-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5]nonane (3.0 g, 8 mmol) in dimethylformamide (30 mL) at 25 °C was added molecular sieves (3.0 g, 8 mmol), and the resulting mixture was stirred for 4 h. Oxone (15.0 g, 24 mmol) was added, and the reaction mixture was stirred at 25 °C for 12 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0-75% ethyl acetate / petroleum ether) to afford (4S)-8-(7-chloro- 8-fluoro-5-methyl-2-methylsulfonyl-pyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5]nonane (1.93 g, 59%) as light yellow solid. LC / MS (ESI) m / z: 401.1 [M+H]+; 'H NMR (400 MHz, CDCh) d: 4.55 (dd, J= 4.8, 6.0 Hz, 2H), 4.17 - 3.91 (m, 2H), 3.77 - 3.15 (m, 5H), 2.75 (d,. / = 8.4 Hz, 3H), 2.50 - 2.16 (m, 2H), 2.05 (s, 2H), 1.78 - 1.58 (m, 2H).

[0120] To a solution of (4S)-8-(7-chloro-8-fluoro-5-methyl-2-methylsulfonyl-pyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro[3.5]nonane (1.9 g, 4.7 mmol) and [1-(hydroxymethyl)cyclopropyl] methanol (968 mg, 9.5 mmol) in N,N-dimethylacetamide (40 mL) was added cesium carbonate (4.63 g, 14 mmol), and the reaction mixture was stirred at 25 °C for 12 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (50%-65% acetonitrile in water (0.225% trifluoroacetic acid) over 10 min) to afford [l-[[7-chloro-8-fluoro-5-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (1.25 g, 62%) as light yellow solid. LC / MS (ESI) m / z 423.1 [M+H]+.ARVN-210-PCT / / ARVN0210WO2

[0121] To a solution of [l-[[7-chloro-8-fluoro-5-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (1.2 g, 2.8 mmol) in dichloromethane (12 mL) were added tetrapropylammoniumperruthenate (200 mg, 0.6 mmol) and 4-methyl-4-oxidomorpholin-4-ium (0.45 mL, 4 mmol), and the reaction mixture was stirred at 25 °C for 1 h. The mixture was diluted with water (30 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic extracts were washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0-85% ethyl acetate / petroleum ether) to afford l-[[7-chloro-8-fluoro-5-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2yl]oxymethyl]cyclopropanecar-baldehyde (900 mg, 75%) as white solid. LC / MS (ESI) m / z: 421.1[M+H]+; 'll NMR (400 MHz, CDC13) <5: 9.20 (s, 1H), 4.79 - 4.62 (m, 2H), 4.56 - 4.47 (m.1H), 4.43 - 4.19 (m, 1H), 4.08 - 3.95 (m. 1H). 3.85 - 3.46 (m, 2H), 3.43 - 3.12 (m, 1H), 2.75 (d. J = 20.0 Hz, 3H), 2.41 - 2.22 (m, 2H), 2.15 - 1.98 (m, 2H), 1.88 (dd, J - 2.4, 4.0 Hz, 1H), 1.77 -1.66 (m, 1H), 1.41 - 1.29 (m, 4H).Step 7:

[0122] To a solution of l-[[7-chloro-8-fhroro-5-methyl-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropanecarbaldehyde (380 mg, 0.9 mmol) and 5-ethyL6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-ARVN-210-PCT / / ARVN0210WO22-ol (571 mg, 1.8 mmol) in THF (6 mL) were added cataCXium A Pd G3 (66 mg, 0.09 mmol) and potassium phosphate (1.5 M, 1.50 mL), and the reaction mixture was stirred at 75°C for 12 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0-95% ethyl acetate / petroleum ether) to afford l-[[7-(8-ethyl-7-fluoro-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]cyclopropanecarbaldehyde (198 mg, 38%) as light yellow solid. LC / MS (ESI) m / z 575.2 [M+H]+; 'H NMR (400 MHz, CDCh) A 9.20 - 9.12 (m, 1H), 7.55 - 7.46 (m, 1H), 7.21 -7.14 (m, 1H), 7.12 (s, 1H), 7.09 - 7.02 (m, 1H), 4.82 - 4.60 (m, 2H), 4.60 - 4.32 (m, 2H), 4.08 -3.96 (m, 1H), 3.94 - 3.76 (m, 1H), 3.74 - 3.49 (m. 1H), 3.39 - 3.07 (m, 1H). 2.83 (s, 3H), 2.48 -2.33 (m, 2H), 2.28 - 2.13 (m, 2H), 2.05 - 1.92 (m, 2H), 1.87 - 1.62 (m, 2H), 1.42 - 1.27 (m, 5H), 0.85 (t, J = 7.2 Hz, 2H).Step 8:

[0123] To a solution of 3-[4-chloro-5-[4-[(4-fluoro-4-piperidyl)methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (150 mg, 0.3 mmol) in dimethyl sulfoxide (3 mL) and dichloromethane (3 mL) was added iV-diisopropylethylamine (0.16 mL, 0.9 mmol), and the resulting mixture was stirred at 25 °C for 0.5 h. l-[[7-(8-Ethyl-7-fluoro-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]cyclopropanecarbaldehyde (180 mg, 0.3 mmol) and tetraisopropoxytitanium (0.28 mL, 0.9 mmol) were added, and the resulting mixture was stirred at 25 °C for 2 h. Sodium triacetoxyborohydride (200 mg, 0.9 mmol) was then added, and the reaction mixture was stirred at 40 °C for 12.5 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate / THF (2 x 50 mL). The combined organic extracts were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified byARVN-210-PCT / / ARVN0210WO2prep-HPLC (35%-45% acetonitrile in water (0.03% formic acid) over 15 min) to afford 3-[4-chloro-5-[4-[[l-[[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]cyclopropyl]methyl]-4-fluoro-4-piperidyl]methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (120.6 mg, 37%, formic acid salt) as white solid. LC / MS (ESI) m / z 1036.4 [M+H]+; 'H NMR (400 MHz, DMSO-6) <5: 11.00 (s, 1H). 7.75 (dd, J= 6.0. 8.8 Hz, 1H). 7.64 (d, J= 8.0 Hz. 1H), 7.37 - 7.29 (m, 2H), 7.24 (d, J = 8.4 Hz, 1H), 7.15 - 6.97 (m, 1H), 5.10 (dd, J= 5.2, 13.2 Hz, 1H), 4.44 -4.17 (m, 6H), 4.00 - 3.78 (m, 2H), 3.21 - 3.11 (m, 1H), 3.05 (s, 4H). 2.97 - 2.83 (m, 1H), 2.73 -2.58 (m, 11H), 2.48 - 2.41 (m, 2H), 2.41 - 2.13 (m, 8H), 2.09 - 1.71 (m, 7H), 1.69 - 1.50 (m, 3H), 0.76 (t, J= 7.2 Hz, 3H), 0.65 (s, 2H), 0.42 (s, 2H).Example 1.8Exemplary synthesis of Compound 102: 3-[4-[4-[[l-[[l-[[7-(8-ethyl-7-fluoro-3-hydroxy-l-naphthyl)-4-[rac-(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]-6.8-dihydro-5H-pyrido[3.4-d]pyrimidin- 2-yl]oxymethyl]cyclopropyl]methyl]-4-fluoro-4-piperidyl]methyl]piperazin-l-yl]-3-methyl-2-oxo-benzimidazol-l-yl]piperidine-2, 6-dioneStep 1:

[0124] To a solution of benzyl 2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (10 g, 30 mmol) in dichloromethane (100 mL) were added N, N-diisopropylethylamine (20.6 mL, 118 mmol) and l-oxa-8-azaspiro[3.5]nonane (3.8 g, 30 mmol), and the reaction mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (0-20% THF in petroleum ether) to afford benzyl 2-chloro-4-(l-oxa-8-azaspiro[3.5]nonan-8-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (9.4 g, 74%) as a white solid. LC / MS (ESI) m / z 428.9 [M+H]+; 'H NMR (400 MHz, CDC13) 87.37 (s, 5H), 5.19 (s, 2H), 4.70 - 4.47 (m. 4H), 3.85 (d, J= 13.2 Hz, 1H), 3.75 - 3.66 (m, 1H), 3.59 (s, 2H), 3.39 (d, J = 13.2 Hz, 1H), 3.18 - 3.08ARVN-210-PCT / / ARVN0210WO2(m, 1H), 2.91 - 2.58 (m, 2H), 2.39 (t, 7= 7.6 Hz, 2H), 2.18 - 2.06 (m, 1H), 1.96 - 1.73 (m, 2H), 1.66 (s, 1H).Step 2:

[0125] To a solution of benzyl 2-chloro-4-(l-oxa-8-azaspiro[3.5]nonan-8-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (9.4 g, 22 mmol) and [1 -[[tert-butyl (dimethyl) silyl] oxymethyl] cyclopropyl] methanol (9.5 g, 44 mmol) in toluene (200 mL) were added CS2CO3 (21.42 g, 66 mmol), RuPhos (2.1 g, 4.4 mmol) and Pd2(dba)3 (2.0 g, 2 mmol), and the reaction mixture was stirred at 95 °C for 16 h under nitrogen. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-20% ethyl acetate in petroleum ether) to afford benzyl 2-[[l-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopropyl]methoxy]-4-(l-oxa-8-azaspiro[3.5]nonan-8-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (11.6 g, 87%) as a yellow oil. LC / MS (ESI) m / z 609.5 [M+H]+.

[0126] To a solution of 2-[[l -[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopropyl]methoxy]-4-(l-oxa-8-azaspiro[3.5]nonan-8-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (11.6 g, 19 mmol) in ethyl acetate (100 mL) was added 10% palladium on carbon (2.3 g), and the resulting mixture was degassed and purged with hydrogen several times, then stirred at 25 °C under hydrogen (15 psi) for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purifiedARVN-210-PCT / / ARVN0210WO2by silica gel flash chromatography (0-4% methanol in dichloromethane) to afford rcrt-butyl-dimethyl-[[l-[[4-(l-oxa-8-azaspiro[3.5]nonan-8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methoxy] silane (7.4 g, 82%) as a dark brown oil. LC / MS (ESI) m / z 475.3 [M+H]+; 'H NMR (400 MHz, CDC13) 54.58 - 4.49 (m, 2H), 4.20 (d, J= 2.8 Hz, 2H), 3.98 (s, 2H), 3.65 (s, 2H). 3.64 - 3.46 (m, 2H), 3.40 - 3.17 (m, 2H), 3.15 - 3.02 (m, 2H), 2.77 - 2.68 (m, 2H), 2.61 (s. 1H), 2.38 (J= 4.8, 7.6 Hz, 2H), 2.08 - 1.96 (m. 1H). 1.91 - 1.80 (m, 2H), 1.65 (d, J= 3.2 Hz, 1H), 0.86 (s, 9H), 0.56 (d, J= 1.2 Hz, 4H), 0.01 (s, 6H).OTBS

[0127] tert-Butyl-dimethyl-[[l-[[4-(l-oxa-8-azaspiro[3.5]nonan-8-yl)-5, 6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methoxy]silane (5 g) was purified by SFC (50% isopropanol (0.1%NH3H2O) in carbon dioxide, isocratic elution mode). The first eluted fraction was assigned as / -butyl-dimethyl-[[l-[[4-[(4R)-l-oxa-8-azaspiro[3.5]nonan-8-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methoxy]silane (2.3 g, 46%) as a dark brown oil. LC / MS (ESI) m / z: 475.2 [M+H]+. The second eluted fraction was assigned as / er / -butyl-dimethyl-[[l-[[4-[(4S)- l-oxa-8-azaspiro[3.5]nonan-8-yl]-5, 6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methoxy] silane (2.3 g, 46%) as a black brown oil. LC / MS (ESI) m / z: 475.1 [M+H]+.Step 5:

[0128] To a solution of / -butyl-dimethyl-[[l-[[4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl] -5,6,7.8-tetrahydropyrido [3,4-d]pyrimidin-2-yl] oxymethyl] cyclopropyl] methoxy] silane (500ARVN-210-PCT / / ARVN0210WO2mg, 1 mmol) and [8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]trifluoromethanesulfonate (443 mg, 1.2 mmol) in toluene (10 mL) were added molecular sieves (200 mg), CS2CO3 (1.0 g, 3.16 mmol) and rac-BINAP-Pd-G3 (104 mg, 0.11 mmol) in a glove box, and the reaction mixture was stirred at 110 °C under nitrogen for 15 h. The mixture was filtered and washed with ethyl acetate (60 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-7% tetrahydrofuran in petroleum ether) to afford tert-butyl-[[l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methoxy]-dimethyl-silane (297 mg, 40%) as a black oil. LC / MS (ESI) m / z 707.4 [M+H]+; 'H NMR (400 MHz, CDCI3) 87.62 - 7.50 (m, 1H), 7.24 - 7.16 (m, 2H), 7.03 (t, J = 2.8 Hz, 1H). 5.27 (s, 2H), 4.61 - 4.50 (m, 2H), 4.22 (s. 2H), 3.95 - 3.71 (m, 2H), 3.67 (s, 2H), 3.53 (s, 3H), 3.51 - 3.34 (m, 4H), 3.20 - 2.99 (m, 3H), 2.75 - 2.59 (m, 1H), 2.32 (d, J = 3.2 Hz, 2H), 1.98 - 1.88 (m, 1H), 1.84 - 1.76 (m, 1H), 1.64 - 1.55 (m, 4H), 1.13 (dt, J= 4.0, 7.2 Hz, 3H), 0.87 (s, 9H), 0.57 (s. 4H), 0.02 (d, 7= 0.8 Hz, 6H).Step 6:

[0129] To a solution of terLbutyl-[[l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methoxy]-dimethyl-silane (560 mg, 0.8 mmol) in THF (6 mL) was added TBAF (1 M, 1.6 mL), and the reaction mixture was stirred at 25 °C for 2 h. The mixture was diluted with ethyl acetate (80 mL) and washed with water (20 mL x 5) followed by brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-3% methanol in dichloromethane) to afford [l-[[7-[8-ethyL7-fhroro-3-(methoxymethoxy)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]-6,8-dihydro-5H-pyrido[3.4-d]pyrimidin-2-ARVN-210-PCT / / ARVN0210WO2yl]oxymethyl]cyclopropyl]methanol (403 mg, 86%) as a yellow oil. LC / MS (ESI) m / z 593.3 [M+H]+.Step 7:

[0130] To a solution of [l-[[7-[8-ethyl-7-fhioro-3-(methoxymethoxy)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (403 mg, 0.68 mmol) in dichloromethane (10 mL) were added TPAP (48 mg, 0.14 mmol) and NMO (119 mg, 1.02 mmol), and the reaction mixture was stirred at 25 °C for 1 h. The mixture was diluted with dichloromethane (20 mL) and washed with water (20 mL x 2) followed by brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-33% tetrahydrofuran in 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]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]cyclopropanecarbaldehyde (306 mg, 76%) as a yellow oil. LC / MS (ESI) m / z 591.4 [M+H]+; NMR (400 MHz. CDCh) 59.18 (d. J = 1.6 Hz, 1H), 7.57 (dd, J = 5.6, 8.8 Hz, 1H), 7.24 - 7.16 (m, 2H), 7.03 (d, J= 1.6 Hz, 1H), 5.27 (s, 2H), 4.63 -4.49 (m, 4H), 4.33 - 4.15 (m, 1H), 3.87 - 3.68 (m, 2H), 3.53 (s, 3H), 3.50 - 3.32 (m, 4H), 3.19 -3.03 (m, 2H), 2.76 - 2.59 (m, 1H), 2.55 - 2.31 (m. 2H), 2.03 - 1.93 (m, 1H), 1.89 - 1.79 (m, 1H), 1.65 - 1.54 (m, 4H), 1.35 - 1.25 (m, 4H), 1.13 (dt, J= 3.2, 7.2 Hz, 3H).Step 8:ARVN-210-PCT / / ARVN0210WO2

[0131] To a solution of 3-[4-[4-[(4-fluoro-4-piperidyl)methyl]piperazin-l-yl]-3-methyl- 2-oxo-benzimidazol-l-yl]piperidine-2, 6-dione (326.0 mg, 0.7 mmol) in DMSO (10 mL) were added NaOAc (278.0 mg, 3.4 mmol), l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]- 4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2- yl]oxymethyl]cyclopropanecarbaldehyde (360 mg, 0.6 mmol) and sodium triacetoxyborohydride (430.0 mg, 2 mmol), and the mixture was stirred at 40 °C for 60 h. 2-Methylpyridine borane (217.0 mg, 2 mmol) was added, and the reaction mixture was stirred at 40 °C for 2 h. The mixture was quenched with saturated sodium bicarbonate solution (10 mL), then diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic extract was washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% methanol in dichloromethane) to afford 3-[4-[4-[[l-[[l-[[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-l-naphthyl]-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]-6,8-dihydro-5H- pyrido [3,4-d]pyrimidin-2-yl] oxymethyl] cyclopropyl] methyl] -4-fluoro-4- piperidyl]methyl]piperazin-l-yl]-3-methyl-2-oxo-benzimidazol-l-yl]piperidine-2, 6-dione (540 mg, 86%) as a yellow solid. LC / MS (ESI) m / z 517.4 [M / 2+H]+.Step 9:

[0132] A solution of 3-[4-[4-[[l-[[l-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l- naphthyl]-4-[rac-(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin- 2-yl]oxymethyl]cyclopropyl]methyl]-4-fluoro-4-piperidyl]methyl]piperazin-l-yl]-3-methyl-2-ARVN-210-PCT / / ARVN0210WO2oxo-benzimidazol-l-yl]piperidine-2, 6-dione (90 mg, 0.09 mmol) in 4 / 1 dichloromethane / TFA (5 mL) was stirred at 25 °C for 20 minutes. This reaction was repeated in 5 additional batches using the same above condition. The 6 batches were combined and diluted with saturated sodium bicarbonate solution until pH 8-9, then extracted with dichloromethane (50 mL x 2). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-5% methanol in dichloromethane). The crude product was further purified by prep-HPLC (2%-42% acetonitrile in water (formic acid) over 25 min) to afford 3-[4-[4-[[ l-[[ 1-[[7-(8-ethyl-7-fluoro-3-hydroxy-l-naphthyl)-4-[rac-(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4-fluoro-4-piperidyl]methyl]piperazin-l-yl]-3-methyl-2-oxo-benzimidazol-l-yl]piperidine-2, 6-dione (76.3 mg, 14%, formic acid salt) as a white solid. LC / MS (ESI) m / z 989.5 [M+H]+; 'H NMR (400 MHz, CD3OD) 87.55 - 7.41 (m, 1H), 7.12 (t, J = 9.2 Hz, 1H), 7.07 - 7.01 (m, 1H), 6.99 - 6.93 (m, 3H), 6.89 (d. J = 7.6 Hz, 1H), 5.32 (dd, J= 5.6. 12.4 Hz. 1H), 4.63 - 4.49 (m, 5H). 4.36 -4.24 (m, 2H), 4.13 - 4.05 (m, 1H), 3.81 - 3.64 (m, 5H), 3.63 - 3.34 (m, 6H), 3.21 - 3.12 (m, 2H), 2.98 - 2.86 (m, 7H), 2.82 - 2.76 (m, 2H), 2.68 - 2.41 (m, 9H), 2.16 (dt,. / = 5.2, 10.8 Hz, 2H), 2.08 - 1.88 (m, 4H), 1.88 - 1.58 (m, 4H), 1.12 (t, J = 7.2 Hz, 3H), 0.73 (s, 2H), 0.55 (s, 2H).Example 1.9Exemplary synthesis of Compound 41:Step 1:

[0133] To a solution of 6-(2,7-dichloro-8-fhroropyrido[4,3-d]pyrimidin-4-yl)-l-oxa-6-azaspiro[3.5] nonane (10.7 g, 31.18 mmol, 1 eq) and cyclopropane- 1,1-diyldimethanol (95.53 g, 935.36 mmol, 30 eq) in 2V,iV-dimethylacetamide (110 mL) was added cesium carbonate (11.17 g, 34.30 mmol, 1.1 eq). The mixture was stirred at 30 °C for 2 h. The residue was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 2). The combined organic layersARVN-210-PCT / / ARVN0210WO2were washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (mobile phase: [water(FA)-ACN];gradient:20%-50% B over 21 min) to afford (l-(((7-chloro-8-fluoro-4-(l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d] pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (6.4 g, 15.65 mmol, 50% yield) as a white solid. LCMS (ESI) m / z: 409.1 [M+l] +

[0134] This material was further purified by SFC (column: DAICEL CHIRALPAK AS 250mm x 30mm, I. D., lOum); isopropanol (0.1% NH3H2O) in CO2 from 45% to 45%; Flow rate: 150 mL / min; Wavelength: 220 nm) to afford two compounds.

[0135] Peak 1: Compound (R)-(l-(((7-chloro-8-fluoro-4-(l-oxa-6-azaspiro[3.5]nonan -6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (3.2 g, 7.83 mmol, 50% yield) was obtained as a white solid. 'H NMR (400 MHz, CDC13) 8: 9.01 (s, 1H), 4.62 - 4.54 (m, 2H), 4.49 (s, 2H), 4.45 (br d, J = 13.2 Hz, 1H), 4.31 - 4.22 (m, 1H), 3.70 (t, J = 6.8 Hz, 1H), 3.64 (d, J = 13.6 Hz, 1H), 3.45 (d, J = 6.8 Hz, 2H), 3.41 - 3.31 (m, 1H), 2.44 (t, J = 7.6 Hz, 2H), 2.35 - 2.26 (m, 1H), 2.10 - 1.97 (m, 1H), 1.90 - 1.73 (m, 2H), 0.72 - 0.60 (m, 4H).

[0136] Peak 2: Compound (5)-(l-(((7-chloro-8-fluoro-4-(l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl) cyclopropyl)methanol (2.9 g, 7.09 mmol, 45% yield) was obtained as a white solid.1H NMR (400 MHz, CDC13) 8: 9.02 (s, 1H), 4.66 - 4.53 (m, 2H), 4.50 (s, 2H), 4.45 (d, J = 13.2 Hz, 1H). 4.32 - 4.21 (m, 1H), 3.72 - 3.66 (m. 1H), 3.64 (d, J = 13.2 Hz, 1H), 3.45 (d, J = 6.9 Hz, 2H), 3.37 (ddd, J = 2.8, 10.4, 13.2 Hz, 1H), 2.44 (t, J = 7.6 Hz, 2H), 2.35 - 2.24 (m, 1H), 2.11 - 1.97 (m, 1H), 1.91 - 1.74 (m, 2H), 0.74 - 0.59 (m, 4H).Step 2:ARVN-210-PCT / / ARVN0210WO2

[0137] To a solution of (S)-(l-(((7-chloro-8-fluoro-4-(l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (2.9 g, 7.09 mmol, 1 eq), ((2-fhioro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethynyl) triisopropylsilane (3.82 g, 7.45 mmol, 1.05 eq) and potassium phosphate (4.52 g, 21.28 mmol, 3 eq) in dioxane (30 mL) and water (3 mL) was added [2-(2-aminophenyl)phenyl] palladium(l+);bis(l-adamantyl)-butyl-phosphane;methanesulfonate (516 mg, 0.7 mmol, 0.1 eq) under nitrogen. The mixture was stirred at 90 °C for 12 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (0-45% ethyl acetate / petroleum ether) to afford (S)-(l-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl silyl)ethynyl)naphthalen-l-yl)-4-(l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (2.91 g, 3.83 mmol, 54% yield) as a brown solid. LCMS (ESI) ni / z 759.5[M+l] +. NMR (400 MHz, CDC13) 8: 9.46 - 8.96 (m, 1H), 7.79 (dd, J = 5.6, 9.2 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.37 - 7.28 (m, 2H), 5.36 - 5.24 (m, 2H).

[0138] 5.05 (dd, J = 12.4. 15.6 Hz. 1H), 4.69 - 4.53 (m, 2H). 4.36 - 4.21 (m, 2H), 3.92 (t, J = 11.6 Hz, 1H), 3.86 - 3.69 (m, 2H), 3.67 - 3.54 (m, 1H), 3.51 (d, J = 0.8 Hz, 3H), 3.47 - 3.31 (m, 1H), 3.13 (ddd, J = 4.0, 8.0. 12.0 Hz, 1H), 2.51 - 2.42 (m, 2H), 2.33 - 2.21 (m, 1H), 2.04 - 1.93 (m, 1H), 1.89 - 1.76 (m, 2H), 0.95 - 0.83 (m. 18H), 0.75 - 0.62 (m. 4H). 0.61 - 0.54 (m, 3H).Step 3:ARVN-210-PCT / / ARVN0210WO2(COCI)2, DMSO, TEA

[0139] To a solution of oxalyl dichloride (727 mg, 5.73 mmol, 0.5 mL, 1.5 eq) in dichloromethane (20 mL) was added dropwise to a solution of dimethyl sulfoxide (746 mg, 9.55 mmol, 0.7 mL, 2.5 eq) in dichloromethane (20 mL) at -65 °C. The mixture was stirred at same temperature for 30 min, and then a solution of (S)-(l-(((8-fluoro-7-(7-fluoro-3-(methoxy methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-4-(l-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d] pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (2.9 g, 3.82 mmol, 1 eq) in dichloromethane (20 mL) was added dropwise. The mixture was stirred at -65 °C for 30 min before an addition of triethylamine (1.93 g, 19.10 mmol, 2.7 mL, 5 eq). The resulting mixture was stirred at the same temperature for 30 min and warmed to 25 °C for 1 h. The mixture was diluted with water (100 mL) and extracted with dichloromethane (100 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (0-54% ethyl acetate / petroleum ether) to afford (5)-l-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-4-(l-oxa-6-azaspiro[3.5] nonan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-l-carbaldehyde (1.84 g. 2.43 mmol, 63% yield) as a yellow solid. LCMS (ESI) m / z 757.3 [M+l] +. ‘H NMR (400 MHz, DMSO-d6) 6: 9.37 - 9.10 (m, 1H), 8.94 (s, 1H), 8.10 (dd, J = 6.0, 9.2 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.56 (t, J = 8.8 Hz, 1H), 7.35 (dd, J = 2.4, 11.6 Hz, 1H), 5.36 (s, 2H), 4.61 -4.42 (m, 4H), 4.41 - 4.32 (m, 1H), 4.32 - 4.20 (m. 1H). 3.75 (br d. J = 13.6 Hz. 1H), 3.43 (s. 3H).2.47 - 2.31 (m, 2H), 2.21 - 2.05 (m, 1H), 1.94 - 1.64 (m, 4H), 1.41 - 1.33 (m, 2H), 1.33 - 1.24 (m, 2H), 0.91 - 0.72 (m, 18H), 0.50 (quind, J = 7.6, 10.0 Hz, 3H).Step 4:ARVN-210-PCT / / ARVN0210WO2o oF

[0140] To a solution of 3-(4-chloro-l-oxo-5-piperazin-l-yl-isoindolin-2-yl)piperidine-2, 6-dione (400 mg, 0.84 mmol, 1 eq, trifluoroacetate) in dichloromethane (6 mL) and methanol (6 mL) were added A-diisopropylethylamine (325 mg, 2.52 mmol, 0.4 mL, 3 eq) and tert-butyl 4-fhroro-4-formyl-piperidine-l -carboxylate (904 mg, 3.91 mmol, 4.66 eq). The reaction mixture was stirred for 0.5 h, then sodium cyanoborohydride (105 mg, 1.68 mmol, 2 eq) was added. The mixture was stirred at 25 °C for 1.5 h, then was poured into water (40 mL) and stirred for 2 min. The aqueous phase was extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The resulting residue was purified by prep-TLC (dichloromethane / methanol = 10 / 1) to afford tert-butyl 4-[[4-[4-chloro-2-(2,6-dioxo-3-piperidyl)- 1 -oxo-isoindolin-5-yl]piperazin- 1 -yl] methyl] -4-fluoro-piperidine- 1 -carboxylate (480 mg, 0.83 mmol, 99% yield) as a white solid. LCMS (ESI) m / z 578.2 [M+l]+.Step 5:TFA / DCM

[0141] To a solution of tert-butyl 4-[[4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl] piperazin- l-yl]methyl]-4-fluoro-piperidine-l-carboxylate (600 mg, 1.04 mmol, 1 eq) in dichloromethane (6 mL) was added trifluoroacetic acid (3.07 g. 26.92 mmol, 2 mL, 25.94 eq). The mixture was stirred at 25 °C for 1 h, then concentrated under reduced pressure at 45 °C. The resulting residue was purified by prep-HPLC (mobile phase: [water(FA)-ACN]; gradient:0%-20% B over 15 min) to afford 3-[4-chloro -5-[4-[(4-fluoro-4-piperidyl)methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (268 mg, 0.56 mmol, 54% yield) as a white solid. LCMS (ESI) m / z: 478.2 [M+l]+.ARVN-210-PCT / / ARVN0210WO2

[0142] To a solution of 3-[4-chloro-5-[4-[(4-fluoro-4-piperidyl)methyl]piperazin-l-yl]-l-oxo- isoindolin-2-yl]piperidine-2, 6-dione (770 mg, 1.09 mmol, 1 eq, 2 trifluoroacetate) in dichloromethane (10 mL) and dimethyl sulfoxide (6 mL) was added JV-methy 1 morpholine (441 mg, 4.36 mmol, 0.5 mL, 4 eq). The reaction mixture was stirred at 25 °C for 0.5 h. 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]cyclopropanecarbaldehyde (600 mg, 0.79 mmol, 7.27e-l eq) was added to the mixture at 25 °C. The mixture was stirred at 40°C for 2 h. Tetraisopropyl orthotitanate (619 mg, 2.18 mmol, 0.6 mL, 2 eq) and sodium triacetoxyborohydride (693 mg, 3.27 mmol, 3 eq) was added to the mixture at 0 °C. The reaction mixture was stirred at 40 °C for 10 h. The reaction mixture was quenched by addition of water (50 mL), and then extracted with dichloromethane 100 mL (50 mL x 2). The combined organic layers were washed with saturated aqueous sodium chloride 500 mL (100 mL x 5), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude 3- [4-chloro-5-[4-[[4-fluoro-l-[[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]methyl]-4-piperidyl]methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (500 mg, 0.34 mmol, 31% yield, 84% purity) as a yellow solid, which was used directly in the next reaction without further purification. LCMS (ESI) m / z 436.3 [M+l],Step 7:ARVN-210-PCT / / ARVN0210WO2

[0143] To a solution of 3-[4-chloro-5-[4-[[4-fluoro-l-[[l-[[8-fluoro-7-[7-fluoro-3-(methoxymethoxy) -8-(2-triisopropylsilylethynyl)-l-naphthyl]-4-[rac-(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 (500 mg, 0.41 mmol, 1 eq) in dimethyl sulfoxide (5 mL) was added cesium fluoride (1.3 g, 8.56 mmol, 20.86 eq). The mixture was stirred at 25 °C for 12hr. The reaction mixture was filtered and the filtrate was quenched by the addition of water (50 mL). The aqueous layer was extracted with dichloromethane 90 mL (30 mL x 3) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (dichloromethane: methanol = 10:1) to afford 3-[4-chloro-5-[4-[[l-[[l-[[7-[8-ethynyl-7- fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[rac-(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4- fluoro-4-piperidyl]methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (320 mg, 0.30 mmol, 73% yield) as a yellow solid. LCMS (ESI) m / z 1062.5 [M+l] +. 'H NMR (400 MHz, DMSO-d6) 8: 10.99 (s, 1H), 9.22 - 9.06 (m, 1H), 8.13 - 8.06 (m, 1H), 7.78 - 7.69 (m, 1H), 7.68 -7.60 (m, 1H), 7.58 - 7.49 (m, 1H), 7.43 - 7.35 (m, 1H), 7.28 - 7.20 (m, 1H). 5.37 (s, 2H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 4.52 - 4.15 (m, 8H), 3.92 - 3.81 (m, 1H), 3.43 (d, J = 1.4 Hz, 3H), 3.12 - 2.98 (m, 4H), 2.79 - 2.59 (m, 7H), 2.54 (s, 4H), 2.49 - 2.28 (m, 6H), 2.25 - 2.09 (m, 3H), 1.95 - 1.52 (m, 8H), 0.72 - 0.60 (m, 2H). 0.50 - 0.30 (m, 2H).Step 8:

[0144] A mixture of 3-[4-chloro-5-[4-[[l-[[l-[[7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)-l-naphthyl]-8-fluoro-4-[rac-(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido [43-d] pyrimidin-2-yl] oxymethyl] cyclopropyl] methyl] -4-fluoro-4-piperidyl]methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (320 mg, 0.30 mmol, 1 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (1.23 g, 10.77 mmol, 0.8 mL, 35.76 eq) at 0 °C and stirred for 2.5 h. The reaction mixture was concentrated under reducedARVN-210-PCT / / ARVN0210WO2pressure. The resulting residue was purified by prep-HPLC (mobile phase: [water(FA)-ACN];gradient:15%-45% B over 15 min) to afford 3-[4-chloro-5-[4-[[l-[[l-[[7-(8-ethynyl-7-fluoro-3-hydroxy- l-naphthyl)-8-fluoro-4-[rac-(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4-fluoro-4-piperidyl]methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (79.6 mg, 0.07 mmol, 24% yield, 98% purity, formate) as a yellow solid. LCMS (ESI) m / z 560.4 [M+l] +. 'H NMR (400 MHz. DMSO-d6) 8: 10.99 (s.1H), 10.17 (s, 1H), 9.23 - 9.08 (m, 1H), 8.13 (s, 1H), 8.02 - 7.93 (m, 1H), 7.64 (d, J - 8.4 Hz,lH), 7.46 (t, J = 9.2 Hz, 1H), 7.41 - 7.37 (m. 1H), 7.28 - 7.17 (m, 2H), 5.10 (dd, J = 5.2, 13.6 Hz, 1H), 4.51 - 4.12 (m, 8H), 3.99 (s, 1H), 3.91 - 3.78 (m, 1H), 3.52 - 3.36 (m, 2H), 3.36 - 3.33 (m, 4H), 3.11 - 2.99 (m, 4H), 2.96 - 2.82 (m, 2H), 2.70 - 2.63 (m, 4H), 2.62 - 2.56 (m, 2H), 2.48 -2.30 (m, 4H), 2.19 - 2.07 (m, 1H), 2.04 - 1.62 (m. 8H), 0.83 - 0.65 (m, 2H), 0.63 - 0.41 (m, 2H).Example 1.10Exemplary synthesis of Compound 91:Step 1:

[0145] To a solution of 5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-l-one (4 g, 7.98 mmol, 1.0 eq) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (2 g, 7.98 mmol, 1.0 eq) in dioxane (40 mL) were added CS2CO3 (7.80 g, 23.93 mmol, 3.0 eq) and XPhos (761 mg, 1.60 mmol, 0.2 eq). Pd2(dba)3 (731 mg, 0.798 mmol, 0.1 eq). The mixture was stirred at 100°C for 16 hours under N2 atmosphere. The reaction mixture was filtered, and the cake was washed with ethyl acetate (50 mL). The filtrate was diluted with water (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (0-30% THF in petroleum ether) to afford tert-butyl 9-[2-(2,6-dibenzyloxy-3-ARVN-210-PCT / / ARVN0210WO2pyridyl)-! -oxo-isoindolin-5-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (4.3 g, 6.37 mmol, 77.07% yield) as a brown solid. LCMS (ESI) mz 675.8 [M+l]+. 'H NMR (400 MHz, CDC13) 8 = 7.77 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H). 7.43 - 7.28 (m, 10H). 7.04 - 6.87 (m, 2H), 6.48 (d, J = 8.4 Hz, 1H), 5.40 (s, 2H), 5.34 (s, 2H), 4.69 (s, 2H), 3.47 - 3.39 (m, 4H), 3.37 - 3.29 (m, 4H), 1.66 (s, 4H), 1.50 (d, J = 5.6 Hz, 4H), 1.48 (s, 9H).Step 2:

[0146] To a reaction mixture of tert-butyl 9-[2-(2,6-dibenzyloxy-3-pyridyl)-l-oxo-isoindolin-5-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (4.3 g, 6.37 mmol, 1.0 eq) in THF (40 mb) was added Pd(OH)2 (2.3 g, 3.19 mmol, 20% purity, 0.5 eq). The mixture was stirred at 50 °C for 16 hours under H2 (50 psi) atmosphere. The reaction mixture was filtered and the cake was washed with THF (300 mL), filtered and concentrated under reduced pressure to afford tertbutyl 9-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (2.6 g, 4.97 mmol, 78.06% yield) as a yellow solid. LCMS (ESI) m / ~. 497.2 [M+l]+.Step 3:O

[0147] To a solution of tert-butyl 9-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (2.6 g, 4.97 mmol, 1.0 eq) in MeOH (4 mL) and DCM (40 mL) were added NCS (664 mg, 4.97 mmol, 1.0 eq) and TFA (628 pL, 8.46 mmol, 1.7 eq), the mixture was stirred at 40 °C for 16 hours. The reaction mixture was diluted with water (50 mL), then extracted with dichloromethane (50 mL x 3). The combined organic layer wasARVN-210-PCT / / ARVN0210WO2washed with brine (40 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica get chromatorgrpahy (0-48% THF in petroleum ether) to afford a residue, which was triturated with ethanol: dichloromethane (41 mL * 2, V: V = 40: 1) under 40 °C for 2 hours. Solid material was collected by filtration and dried under reduced pressure to give tert-butyl 9-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3.9-diazaspiro[5.5]undecane-3-carboxylate (820 mg, 1.54 mmol, 31.05% yield) as a white solid. LCMS (ESI) m / z 531.1 [M+l]+.Step 4:

[0148] To a solution of tert-butyl 9-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (820 mg, 1.54 mmol, 1.0 eq) in DCM (6 mL) was added HCl / dioxane (4 M, 6 mL). The mixture was stirred at 25 °C for 10 min. The reaction mixture was diluted with petroleum ether (20 mL x 2), and solid material was precipitated. The solid material was collected by filtration and dried under reduced pressure to afford 3-[4-chloro-5-(3,9-diazaspiro[5.5]undecan-3-yl)-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (1.24 g, 1.53 mmol, 98.82% yield, 2HC1) as a white solid. LCMS (ESI) m / z 431.2 [M+l]+.

[0149] 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]cyclopropyl]methanol (500 mg, 1.22 mmol, 1.0 eq)ARVN-210-PCT / / ARVN0210WO2and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1 -naphthyl]-4, 4,5, 5-tetramethyl- 1,3,2-dioxaborolane (485 mg, 1.35 mmol, 1.1 eq) in dioxane (10 mL) and H2O (2 mL) were added CataCXium Pd G3 (89 mg, 0.12 mmol, 0.1 eq) and K3PO4 (779 mg, 3.67 mmol, 3.0 eq). The mixture was stirred at 80°C under N2 for 16 hours. The mixture was dried over Na2SC>4 and then filtered. The filter cake was washed with ethyl acetate (20 mL) and the combined organic layer was concentrated under pressure. The residue was purified by flash silica gel chromatography (0-35 % THF in petroleum ether), then re-purified by prep-HPLC [30-70 % acetonitrile in water (FA)] to afford [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]cyclopropyl]methanol (290 mg, 96% purity, 0.46 mmol, 37.53% yield) as white solid. LCMS (ESI) / z 607.1 [M+H]+, tR = 0.683 min.MOMO

[0150] To a solution of [l-[[7-[8-ethyl-7-fhioro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-4-[(4R)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methanol (290 mg, 0.48 mmol, 1.0 eq) in DCM (6 mL) was added Dess-Martin periodinane (406 mg, 0.96 mmol, 2.0 eq). The mixture was stirred at 25 °C for 1 hour then quenched by sat. aq. NaHCCL (20 mL) and then extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SC>4, filtered and concentrated under pressure. The resulting residue was purified by flash silica gel chromatogrpahy (0-45 % ethyl acetate in petroleum ether) to afford 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]cyclopropanecarbaldehyde (251.9 mg, 90% purity, 0.37 mmol, 78.44% yield) as yellow solid. LCMS (ESI) m / z: 605.3 [M+H]+.ARVN-210-PCT / / ARVN0210WO2Step 7:

[0151] To a solution of 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]cyclopropanecarbaldehyde (450 mg, 0.744 mmol, 1.0 eq), 3-[4-chloro-5-(3,9- diazaspiro[5.5]undecan-3-yl)-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (405 mg, 0.749 mmol, 1.01 eq, 3HC1) in DMSO (10.0 mL) were added NaOAc (366 mg, 4.47 mmol, 6.0 eq) and NaBH(OAc)3 (394 mg, 1.86 mmol, 2.5 eq). The mixture was stirred at 40 °C for 24 hours, then quenched with NaHCCh solution (10.0 mL), diluted with dichloromethane (40 mL), and washed with water (30 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (30 mL x 3). The combined organic layer was washed with water (15 mL x 3) and brine (20 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (0-5% methanol in dichloromethane) to afford 3-[4-chloro-5-[9-[[l-[[7-[8-ethyl-7-fhioro-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] cyclopropyl] methyl] -3,9-diazaspiro[5,5]undecan-3-yl] - 1 -oxo-isoindolin-2- yl]piperidine-2, 6-dione (567 mg, 0.548 mmol, 73.68% yield) as a yellow foam. LCMS (ESI) m / z: 510.4 [M / 2+H]+.ARVN-210-PCT / / ARVN0210WO2

[0152] To a solution of 3-[4-chloro-5-[9-[[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]cyclopropyl]methyl]-3,9-diazaspiro[5.5]undecan-3-yl]-l-oxo-isoindolin-2-yl] piperidine- 2, 6-dione (567 mg, 0.548 mmol, 1 eq) in DCM (30 mL) was added TFA (10 mL, 134.62 mmol, 265.5 eq). The mixture was stirred at 25 °C for 20 minutes, then quenched by saturated Na2COs solution (50 mL) to pH ~ 8. The mixture was diluted with water (20 mL) and extracted with dichloromethane / methanol (165 mL, V: V = 10: 1). The combined organic layer was washed with brine (20 mL), dried over NaiSCL. filtered and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC [gradient 8%-48% acetonitrile in water (FA)] to afford 3-[4-chloro-5-[9-[[l-[[7-(8-ethyl-7-fhioro-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]cyclopropyl]methyl]-3,9-diazaspiro[5.5]undecan-3-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (275.6 mg, 99.36% purity, 268.06 pmol, 52.86% yield, FA) as a yellow solid. LCMS (ESI) m / z 975.7 [M+H]+. ’H NMR (400MHz. DMSO-d6) 8 = 10.98 (s, 1H), 9.22 (d, J = 1.2 Hz, 1H), 8.17 (s, 1H), 7.77 (dd, J = 6.0, 9.2 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.39 -7.30 (m, 2H), 7.27 (d, J = 8.4 Hz, 1H), 7.04 (t. J = 2.8 Hz, 1H), 5.09 (dd, J = 5.2, 13.6 Hz, 1H), 4.52 - 4.29 (m, 6H), 4.27 - 4.10 (m, 2H), 3.96 - 3.79 (m, 1H), 3.56 - 3.50 (m, 1H), 3.01 - 2.93 (m, 4H), 2.94 - 2.85 (m, 1H), 2.60 - 2.56 (m, 1H), 2.47 - 2.29 (m, 10H), 2.20 - 2.06 (m, 2H), 2.02 -1.95 (m, 1H), 1.94 - 1.79 (m, 2H), 1.77 - 1.66 (m, 1H), 1.63 - 1.36 (m, 8H), 0.81 - 0.62 (m, 5H), 0.43 (s, 2H).Example 1.11Exemplary synthesis of Compound 118:Step 1:DMSO, DIEA120 °C, 12 hARVN-210-PCT / / ARVN0210WO2

[0153] To a solution of methyl 3-chloro-4- fluoro-benzoate (30 g, 159.08 mmol, 1 eq) and tert-butyl piperazine- 1 -carboxylate (35.55 g, 190.90 mmol, 1.2 eq) in dimethylsulfoxide (300 mL) was added diisopropylethylamine (61.68 g, 477.24 mmol, 83 mL, 3 eq) at 20 °C, then the mixture was stirred for 12 h at 120 °C. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with saturated brine (300 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = from 10 / 1 to 3 / 1) to afford tert-butyl 4-(2-chloro-4-methoxycarbonyL phenyl)piperazine-l -carboxylate (33 g, 93.00 mmol, 58% yield) as a yellow oil. LCMS (ESI) m / z 355.2 [M+l]+Step 2:

[0154] To a solution of tert-butyl 4-(2-chloro-4-methoxycarbonyl-phenyl)piperazine-l-carboxylate (33 g, 93.00 mmol, 1 eq) in tetrahydrofuran (300 mL) and water (60 mL) was added lithium hydroxide (19.51 g, 465.01 mmol, 5 eq) at 20 °C, then the mixture was stirred for 12 h at 20 °C. The reaction mixture was adjusted pH to 4-5 with citric acid solution (500 mL) and the mixture was extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with brine (100 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with MTBE (300 mL). The resultant precipitate solid was collected by filtration and dried in vacuo to afford 4-(4- / erz-butoxycarbonylpiperazin-l-yl)-3-chloro-benzoic acid (31 g, 90.96 mmol, 98% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-de) 3 12.70 (s, 1H), 7.87 (d, 7 = 2.0 Hz, 1H), 7.86 - 7.81 (m, 1H), 7.21 (d, 7 = 8.4 Hz, 1H), 3.52 - 3.45 (m, 4H), 3.05 - 3.00 (m, 4H). 1.42 (s, 9H).Step 3:ARVN-210-PCT / / ARVN0210WO2

[0155] To a solution of 4-(4-ter / -butoxycarbonylpiperazin-l-yl)-3-chloro-benzoic acid (8.3 g, 24.35 mmol, 1 eq) in tetrahydrofuran (240 mL) was added dropwise / 7-butyl lithium (2.5 M, 20 mL, 2.03 eq) at -75 °C and maintained at -75 °C for 3 h. Then A imethylformamide (4.34 g, 59.38 mmol, 4.5 mL, 2.44 eq) was added dropwise at -75 °C, and the mixture was stirred at this temperature for 1 h under nitrogen. The reaction mixture was quenched with saturated ammonium chloride solution (150 mL) and the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with brine (150 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (mobile phase: [water(TFA)-ACN];gradient:35%-65% B over 20 min) to afford tert-butyl 4-(4-chloro-3-hydroxy-l-oxo-3H-isobenzofuran-5-yl)piperazine-l -carboxylate (2 g, 5.42 mmol, 22% yield) was obtained as a yellow solid. LCMS (ESI) m / z 369.0 [M+l]+. 'H NMR: (400 MHz, DMSO-de) d: 8.18 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.61 (s, 1H), 3.55 - 3.47 (m, 4H), 3.15 - 3.00 (m, 4H), 1.43 (s. 9H).Step 4:O O2-MePyBH3, NaOAc, AcOH / MeOH, 25 - 40°C, 12.5 h

[0156] To a solution of 3-aminopiperidine-2, 6-dione (4.02 g, 24.40 mmol, 1.5 eq, hydrochloride) in methanol (60 mL) was added sodium acetate (2.67 g, 32.54 mmol, 2 eq), then acetic acid (6 mL) and tert-butyl 4-(4-chloro-3-hydroxy-l-oxo-3H-isobenzofuran-5-yl)piperazine-l- carboxylate (6 g, 16.27 mmol, 1 eq) were added to the mixture and the mixture was stirred for 0.5 h at 25 °C. Borane;2-methylpyridine (3.48 g, 32.54 mmol, 2 eq) was added to the mixture and the mixture was stirred for 12 h at 40 °C. The resultant precipitate solid was collected by filtration, washed with methanol (10 mL x 3) and dried in vacuo to afford tert-butylARVN-210-PCT / / ARVN0210WO24-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]piperazine-1 -carboxylate (6.2 g, 13.39 mmol, 82 % yield) as a gray solid. LCMS (ESI) m / z: 463.1 [M+l]+. NMR: (400 MHz, DMSO-tZ^; 10.97 (s. 1H), 7.66 (d, J= 8.4 Hz, 1H), 7.29 (d, J= 8.0 Hz, 1H), 5.10 (dd, J = 5.2, 13.2 Hz, 1H), 4.49 - 4.36 (m, 1H), 4.31 - 4.22 (m, 1H), 3.55 - 3.45 (m, 4H), 3.08 - 3.00 (m, 4H), 2.97 - 2.84 (m, 1H), 2.68 - 2.56 (m, 1H), 2.47 - 2.38 (m, 1H), 2.04 - 1.94 (m, 1H), 1.43 (s, 9H).Step 5:O O TFA / DCM 25 °C, 0.5 h

[0157] To a solution of tert-butyl 4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin- 5-yl] piperazine- 1 -carboxylate (5 g, 10.80 mmol, 1 eq) in dichloromethane (50 mL) was added trifluoroacetic acid (23.03 g, 201.93 mmol, 15 mL, 18.70 eq). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound 3- (4-chloro-l-oxo-5-piperazin-l-yl-isoindolin-2-yl) piperidine-2, 6-dione (5.1 g, 10.70 mmol, 99% yield, trifluoroacetate) was obtained as an off-white solid. LCMS:, MS (ESI) ni z 363.1 [M+l]+Step 6: Preparation of tert-butyl 4-[[4-[4-chloro-2-(2,6-dioxo-3-piperidyl) -l-oxo-isoindolin-5-yl]piperazin- 1 -yl] methyl] -4-hydroxy-piperidine- 1 -carboxylateStep 6:o oDIEA, DMSO, 90-110 °C, 16 h

[0158] A mixture of 3-(4-chloro-l-oxo-5-piperazin-l-yl-isoindolin-2-yl)piperidine-2,6-dione (220 mg, 0.46 mmol, 1 eq, trifluoroacetate), tert-butyl l-oxa-6-azaspiro[2.5]octane-6-carboxylate (196 mg, 0.92 mmol, 2 eq), A, A-diisopropylethylamine (238 mg, 1.85 mmol, 0.3ARVN-210-PCT / / ARVN0210WO2mL, 4 eq) in dimethyl sulfoxide (5 mL) was degassed and purged with nitrogen 3 times. The mixture was stirred at 90 °C for 16h under nitrogen atmosphere, then stirred at 110 °C for another 12h. The mixture was diluted with ethyl acetate (100 mL), washed with water (200 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The resulting residue was purified by prep-HPLC (mobile phase: [water(FA)-ACN]; gradient:5%-35% B over 15 min) to afford tert-butyl 4-[[4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl] piperazin-1-yl]methyl] -4-hydroxy-piperidine- 1 -carboxylate (120 mg, 0.20 mmol, 45 % yield) was obtained as a pale yellow solid. LCMS (ESI) m / z 576.2 [M+l]+. 'H NMR: (400 MHz, DMSO-d6) 5: 10.98 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 4.48 - 4.36 (m, 1H), 4.32 - 4.16 (m, 2H), 3.72 - 3.49 (m, 2H), 3.22 - 2.99 (m, 6H), 2.96 - 2.85 (m, 1H), 2.81 - 2.63 (m, 4H), 2.63 - 2.56 (m. 1H), 2.47 - 2.38 (m, 1H), 2.38 - 2.25 (m, 2H), 2.02 -1.97 (m, 1H), 1.53 - 1.42 (m, 4H), 1.39 (s, 9H).Step 7:OH

[0159] A mixture of / ert-butyl 4-[[4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl] piperazin- 1-yl] methyl] -4-hydroxy-piperidine- 1 -carboxylate (350 mg, 0.61 mmol, 1 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (1.07 g, 9.42 mmol, 0.7 mL, 15.51 eq) at 0 °C and stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with petroleum ether (50 mL) for 0.5 h to afford 3-[4-chloro-5-[4-[(4-hydroxy-4-piperidyl)methyl]piperazin-l-yl]-l-oxo-isoindolin -2-yl]piperidine-2, 6-dione (350 mg, 0.59 mmol, 97% yield, trifluoroacetate) as a yellow gum.LCMS (ESI) m / z 476.3 [M+l]+

[0160] The preparation of 3-(4-chloro-5-{4-[(l-{[l-({[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-4-[(4S)-l-oxa-6-azaspiro[3.5]nonan-6-yl]pyrido[4,3-d]pyrimidin-2-yl]oxy }methyl)cyclopropyl] methyl } -4-hydroxypiperidin-4-yl)methyl]piperazin- 1-yl}-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione was prepared in analogous fashionARVN-210-PCT / / ARVN0210WO2as described in General Synthetic Scheme 2. LCMS (ESI) m / ~ 460.2 [M+l]+.NMR: (400 MHz, DMSO-Je) 6: 10.98 (s, 1H), 10.14 - 9.77 (m, 1H), 9.23 (d, 7= 5.2 Hz, 1H), 8.14 (s, 1H), 7.76 (dd, 7= 6.0, 8.8 Hz, 1H), 7.69 - 7.57 (m, 1H), 7.42 - 7.28 (m, 2H). 7.26 - 7.16 (m, 1H), 7.10 - 6.99 (m, 1H), 5.10 (dd, 7= 5.2, 13.2 Hz, 1H), 4.59 - 4.12 (m, 9H), 3.97 - 3.80 (m, 1H), 3.53 -3.45 (m, 2H), 3.10 - 3.00 (m, 4H), 2.97 - 2.81 (m, 3H), 2.75 - 2.56 (m, 8H). 2.46 - 2.26 (m, 6H), 2.17 - 2.05 (m. 2H), 2.04 - 1.94 (m, 1H). 1.94 - 1.80 (m, 2H), 1.78 - 1.49 (m. 5H), 0.82 - 0.64 (m, 5H), 0.61 - 0.47 (m, 2H).Example 1.12Exemplary synthesis of Compound 119:Step 1HATU, DIEA]DMF,25°C]1h o o

[0161] To a mixture of 3-(4-chloro-l-oxo-5-piperazin-l-yl-isoindolin-2-yl)piperidine-2, 6-dione (500 mg, 1.38 mmol, 1 eq), A / / V-diisopropylethylamine (356 mg, 2.76 mmol, 2 eq) and 2-( l-t -butoxycarbonyl-4-hydroxy-4-piperidyl)acetic acid (357 mg, 1.38 mmol, 1 eq) in N, N-dimethylformamide (5 mL) was added o-(7-azabenzotriazol-l-yl)-^, / V, A^', ^'-tetramethyluronium hexafluorophosphate (786 mg, 2.07 mmol, 1.5 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 1 h. To the mixture was added ice-water (w / w = 1 / 1) (40 mL) and stirred for 30 min. Some precipitate was formed, the cake was collected by filtration and dried under high vacuo at 50 °C, to afford / er / -butyl 4-[2-[4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]piperazin-l-yl]-2-oxo-ethyl]-4-hydroxy-piperidine-l-carboxylate (750 mg, 1.24 mmol, 90% yield) as yellow solid.Step 2: Preparation of 3-[4-chloro-5-[4-[2-(4-hydroxy-4-piperidyl)acetyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dioneARVN-210-PCT / / ARVN0210WO20 o

[0162] A mixture of tert-butyl 4-[2-[4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo- isoindolin-5 -yl] piperazin- 1 -yl] -2-oxo-ethyl] -4-hydroxy-piperidine- 1 -carboxylate (750 mg, 1.24 mmol, 1 eq) and trifluoro acetic acid (2 mL) in dichloromethane (8 mL) was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure at 30 °C to afford crude 3-[4-chloro-5- [4-[2-(4-hydroxy-4-piperidyl)acetyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (750 mg, crude, trifluoroacetate) as yellow solid. LCMS (ESI) m / z 504.1 [M+l]+. 'HNMR: (400 MHz, DMSO-d6) 8: 11.03 (s, 1H), 8.64 - 8.46 (m, 1H), 8.43 - 8.14 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.32 (d, 7 = 8.0 Hz, 1H), 5.15 (dd, 7= 5.2, 13.2 Hz, 1H), 4.55 - 4.38 (m, 1H), 4.32 (d, J = 17.2 Hz, 1H), 3.71 - 3.63 (m, 3H), 3.22 - 3.13 (m, 5H), 3.01 - 2.88 (m, 1H), 2.63 - 2.58 (m, 1H), 2.52 - 2.46 (m, 1H), 2.13 - 2.00 (m, 1H), 1.93 - 1.77 (m, 4H), 1.36 - 1.28 (m, 6H).

[0163] The preparation of 3-(4-chloro-5-{4-[2-(l-{[l-({[7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoro-4-[(4S)-l-oxa-6-azaspiro[3.5]nonan-6-yl]pyrido[4,3- d]pyrimidin-2-yl]oxy}methyl)cyclopropyl]methyl}-4-hydroxypiperidin-4-yl)acetyl]piperazin-l- yl}-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione was prepared in analogous fashion as described in General Synthetic Scheme 1. LCMS (ESI) m / z: 1048.5 [M+l]+. 'HNMR: (400 MHz. DMSO-d6)5: 11.01 (s, 1H), 10.11 - 9.81 (m, 1H), 9.23 (d. 7 = 4.0 Hz, 1H), 8.15 (s, 1H), 7.77 (dd, J= 6.4, 8.8 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.42 - 7.31 (m, 2H), 7.26 (d, J = 8.4 Hz, 1H), 7.05 (s, 1H), 5.12 (dd, J = 4.8, 13.2 Hz, 1H), 4.85 (d, 7= 2.4 Hz, 1H), 4.61 - 4.15 (m, 8H).3.98 - 3.79 (m, 1H), 3.69 (s, 4H), 3.58 - 3.37 (m, 4H), 3.14 - 3.00 (m, 4H), 2.98 - 2.76 (m, 3H), 2.69 - 2.56 (m, 4H), 2.47 - 2.29 (m, 4H), 2.20 - 2.05 (m, 2H), 2.04 - 1.95 (m, 1H), 1.94 - 1.81 (m, 2H), 1.74 - 1.56 (m, 4H), 0.84 - 0.64 (m. 5H), 0.53 (s, 2H).Example 1.13Exemplary synthesis of Compound 112:ARVN-210-PCT / / ARVN0210WO2 / BnFe, NH4CI oEtOH

[0164] To a solution of 2,6-dibenzyloxy-3-nitro-pyridine (44.5 g, 132.31 mmol, 1.0 eq) in EtOH (400 mL) and water (40 mL) was added Fe (51.7 g, 926.14 mmol, 7.0 eq) and NH4CI (141 g, 2.65 mol, 20 eq). The mixture was stirred at 85°C for 16 hours. The mixture was filtered and diluted with water (300 mL), then extracted with ethyl acetate (300 mL x 3). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated to give 2,6-dibenzyloxypyridin-3-amine (40.53 g, crude) as an oil. LCMS (ESI) m / z: 307.1 [M+H]+’H NMR: (400 MHz, DMSO-68: 7.45 - 7.28 (m, 10H). 6.98 (d, J= 8.0 Hz, 1H). 6.23 (d, J = 8.0 Hz, 1H), 5.34 (s, 2H), 5.18 (s, 2H), 4.48 - 4.34 (m, 2H).Step 2: Preparation of 5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-l-oneOBn

[0165] To a solution of 2,6-dibenzyloxypyridin-3-amine (40.5 g, 105.84 mmol, 1.5 eq) and methyl 4-bromo-2-(bromomethyl)benzoate (21.7 g, 70.56 mmol, 1.0 eq) in DMA (800 mL) were added. The mixture was stirred at 125 °C for 12 hours, then DIEA (25 mL, 141.12 mmol, 2.0 eq) was added and the resulting suspension was stirred at 125 °C for 12 hours. The reaction mixture was diluted with water (300 mL) and EtOAc (300 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (300 mL x 2). The organic layers were combined and washed with water (200 mL x 2), brine (300 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (0-15 % ethyl acetate in petroleum ether) to afford 5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-l-one (31 g, 82% purity, 50.70 mmol, 71.86% yield) as a red solid. LCMS (ESI) m / z: 502.8 [M+H]+ARVN-210-PCT / / ARVN0210WO2Boc.XPhos, Pd2(dba)3, Cs2CO3,dioxane, 100°C, 16h

[0166] To a solution of 5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)isoindolin-l-one (10 g, 19.95 mmol, 1.0 eq) and tert-butyl (3S)-3-methylpiperazine-l -carboxylate (3.99 g, 19.95 mmol, 1.0 eq) in dioxane (100 mL) was added CS2CO3 (19.5 g, 59.84 mmol, 3.0 eq), XPhos (1.9 g, 3.99 mmol, 0.2 eq) and Pd2(dba)s (1.83 g, 1.99 mmol, 0.1 eq). The mixture was stirred at 100 °C for 16 hours under N2. The reaction mixture was filtered, the cake was washed with ethyl acetate (100 mL), then the filtrate was diluted with water (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (150 mL x 2). The combined organic layer was washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (0-25% THF in petroleum ether) to afford terf-butyl (3S)-4-[2-(2,6-dibenzyloxy-3-pyridyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazine-l-carboxylate (6.86 g, 9.52 mmol, 47.73% yield). LCMS (ESI) m / z: 621.4 [M+H]+Step 4:

[0167] To Pd(OH)2 / C (3.43 g, 5.53 mmol, 20% purity. 0.5 eq), Pd / C (3.43 g, 3.23 mmol, 10% purity, 2.92e-l eq) in bottle was added THF (150 mL) carefully at 25°C under Ar. Then a solution of tert-butyl (3S)-4-[2-(2,6-dibenzyloxy-3-pyridyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazine-1 -carboxylate (6.86 g. 11.05 mmol, 1.0 eq) in THF (150 mL) was added at 25°C under Ar. The suspension was degassed and purged with H2 three times, then stirred under H2 (50 Psi) at 50°C for 16 hours. The mixture was filtered and washed with THF / methanol / dichloromethane (450 mL, V: V: V= 1: 1: 1). The filtrate was concentrated under reduced pressure to afford crude fert-butyl (3S)-4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-ARVN-210-PCT / / ARVN0210WO2yl]-3-methyl-piperazine-l -carboxylate (6.28 g, 8.71 mmol, 98.88% yield) which was used directly in the next step without further purification- LCMS (ESI) m / z:. 443.2 [M+H]+Step 5:NCS, TFACH2CI2 / MeOH40°C, 16h

[0168] To a solution of tert-butyl (35')-4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazine-l-carboxylate (6.28 g, 8.71 mmol. 1.0 eq) in CH2Q2 (60 mL) / MeOH (6.0 mL) was added TFA (1.27 mL, 14.8 mmol, 1.7 eq) and NCS (1.61 g, 9.58 mmol, 1.1 eq). The mixture was stirred at 40 °C for 16 hours under N2. The mixture was quenched with saturated NaHCCh solution (30 mL). The mixture was diluted with water (50 mL) and extracted with dichloromethane / methanol (55 mL x 4, V: V = 10: 1). The combined organic layer was washed with brine (70 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (0-44%, then up to 100% THF in petroleum ether) to afford the crude product, which was triturated with acetonitrile (20 mL) at 60°C for 2 hours and concentrated to afford tert-butyl (35)-4-[4-chloro-2- (2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazine-l-carboxylate (2.33 g, 4.54 mmol, 45.16% yield). LCMS (ESI) m / z 477.2 [M+H]+Step 6HCI / dioxane 40°C, 1h

[0169] A reaction mixture of tert-butyl (3S)-4-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-3-methyl-piperazine-l-carboxylate (2.33 g, 4.54 mmol, 1.0 eq) in HCI / dioxane (36.6 mL, 2 M, 15 eq) was stirred at 40 °C for 1 hour. The reaction mixture was diluted with petroleum ether (30 mL x 2), and the solid material was collected by filtration and dried under reduced pressure to afford 3-[4-chloro-5-[(25)-2-methylpiperazin-l-yl]-1-oxo-isoindolin-2-ARVN-210-PCT / / ARVN0210WO2yl]piperidine-2, 6-dione (3.5 g, 4.82 mmol, 98.76% yield, 2HC1) which was used into next step without further purification. LCMS (ESI) m / z: 377.1 [M+H]+Step 7NaBH(OAc)3, NaOAc, DMSO, 40°C, 16h

[0170] To a solution of 3-[4-chloro-5-[(2S)-2-methylpiperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (2.5 g, 3.45 mmol, 1.0 eq, 2HC1) in DMSO (20 mL) was added NaOAc (1.41 g, 17.23 mmol, 5.0 eq), then tert-butyl 4-oxopiperidine- 1 -carboxylate (755 mg, 3.79 mmol, 1.1 eq) and NaBH(OAc)3(2.19 g, 10.34 mmol, 3.0 eq) were added. The mixture was stirred at 40 °C for 16 hours, then quenched with sat. aq. NaHCO3(8 mL) and diluted with water (20 mL). The solid material was precipitated and the reaction mixture was filtered, and the cake was washed with water (250 mL). The solid was dissolved with 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, 2.59 mmol. 75.12% yield) LCMS (ESI) m / z: 560.2 [M+l]+Step 8:

[0171] 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]piperidine-l-carboxylate (400 mg, 0.714 mmol, 1.0 eq) in HCl / dioxane (2 M, 8 mL) was stirred at 35 °C for 1 hour. The reaction mixture was diluted with petroleum ether (40 mL x 2), and the solid material was precipitated. The solid was collected by filtration and dried under reduced pressure to afford 3-[4-chloro-5-[(2S)-2-methyl-4-ARVN-210-PCT / / ARVN0210WO2(4-piperidyl)piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (400 mg, crude, 2HC1). LCMS (ESI) m / z 460.0 [M+l]+

[0172] The preparation of 3-{4-chloro-5-[(2S)-4-(l-{ [l-({ [7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-4-[(45)-l-oxa-6-azaspiro[3.5]nonan-6-yl]pyrido[4,3-d]pyrimidin-2-yl] oxy } methyl)cyclopropyl] methyl } piperidin-4-yl)-2-methylpiperazin- 1 -yl] - 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione was prepared in analogous fashion as described in General Synthetic Scheme 1. LCMS (ESI) m / z 1004.4 [M+l]+.JH NMR: (400 MHz, DMSO) 8 = 11.00 (s, 1H), 9.22 (d, J = 5.2 Hz, 1H), 7.80 - 7.73 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.39 - 7.29 (m, 3H), 7.05 (t, J = 2.8 Hz, 1H), 5.14 - 5.06 (m, 1H), 4.53 - 4.21 (m, 8H), 3.95 - 3.78 (m, 1H), 3.51 (s. 2H). 3.19 (s, 1H), 3.06 (s, 2H), 2.98 - 2.84 (m, 1H), 2.76 (s. 1H). 2.70 - 2.53 (m, 4H), 2.47 - 2.21 (m, 8H), 2.16 - 2.05 (m, 2H), 2.03 - 1.82 (m, 5H), 1.81 - 1.66 (m, 3H), 1.31 - 1.46 (m, 2H), 0.81 - 0.89 (m, 3H), 0.79 - 0.71 (m, 3H). 0.65 - 0.70 (m, 2H), 0.39 -0.48 (m, 2H).Example 1.14Exemplary synthesis of Compound 139:Step 1:CbzOsuTHF / H2O, NaHCO3, 25°C, 12 h

[0173] To a solution of 1- (tert-butyl) 3-methyl piperazine- 1,3-dicarboxylate (17 g, 69.59 mmol, 1 eq) and benzyl (2,5-dioxopyrrolidin-l-yl) carbonate (26.01 g, 104.39 mmol, 1.5 eq in tetrahydrofuran (100 mL) and water (100 m ) was added sodium bicarbonate (29.23 g, 13.54 mmol, 5 eq). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched with water (500 mL) and the mixture was extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with brine (200 mLx 3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to afford crude 1 -benzyl 4- (tert-butyl) 2-methyl piperazine- 1, 2, 4-tricarboxylate, (26 g), which was used into next step directly. 'HNMR: (400ARVN-210-PCT / / ARVN0210WO2MHz, CDCh) 7.41 - 7.33 (m, 5H), 5.22 - 5.13 (m, 2H), 4.83 - 4.52 (m, 2H), 4.13 - 3.87 (m, 2H), 3.77 - 3.68 (m, 3H), 3.41 - 3.21 (m, 1H), 3.09 (d, J= 13.2 Hz, 1H), 2.85 (s, 1H), 1.45 (s, 9H).Step 2:LiHMDS, MeITHF,-78-20°C,12 h

[0174] To a solution of 1-benzyl 4-(tert-butyl) 2-methyl piperazine- 1, 2, 4-tricarboxylate (10 g, 26.43 mmol, 1 eq) in tetrahydrofuran (200 mL) was added lithium bis(trimethylsilyl)amide in 1.0 M tetrahydrofuran (1 M, 105.70 mL, 4 eq) at -78 °C. The mixture was stirred at -78 °C for 2 h, then iodomethane (11.25 g, 79.28 mmol, 4.94 mL, 3 eq) was added at -78 °C. The resulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched by addition a saturated aqueous solution of ammonium chloride at 0°C, then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The resulting residue was purified by silica gel column chromatography (pether / ethyl acetate=10 / l to 5 / 1) to afford 1-benzyl 4- (tert-butyl) 2-methyl 2-methylpiperazine-1,2,4-tricarboxylate (7.8 g, 19.88 mmol, 75% yield). LCMS (ESI) m / z 293.2 [M-56]+.1H NMR: (400 MHz, CDCl3) d: 7.39 - 7.33 (m, 5H), 5.21 - 5.04 (m, 2H), 4.03 - 3.32 (m, 9H). 1.54 (s, 3H), 1.45 (s, 8H).Flow Chemistry

[0175] Solution 1: 1-benzyl 4-(tert-butyl) 2-methyl 2-methylpiperazine- 1,2,4-tricarboxylate (5 g, 12.74 mmol, 1 eq) } in tetrahydrofuran (50 mL) and methanol (50 mL). The fixed bed (volume 5 mL) was completely packed with granular catalyst 5% palladium onARVN-210-PCT / / ARVN0210WO2aluminum oxide. The hydrogen back pressure regulator was adjusted to 1.0 MPa, and the flow rate of hydrogen was 30 mL / min. Then solution 1 was pumped to the fixed bed (0.3 mL / min, 50 °C). The reaction mixture was collected from the reactor output and concentrated in vacuum to afford crude 1 -(terf-butyl) 3-methyl 3-methylpiperazine-l,3-dicarboxylate (2.2g, 8.52 mmol, 66% yield) was obtained. 'HNMR: (400 MHz, DMSO-d6) δ 4.16 (d,. / = 12.0 Hz, 1H), 3.70 -3.58 (m, 4H), 2.83 - 2.58 (m, 5H), 1.38 - 1.36 (m. 9H). 1.13 (s, 3H).Step 4:ISolution 1: 1 -(tert-butyl) 3-methyl 3-methylpiperazine-l,3-dicarboxylate (6 g, 23.23 mmol, 1 eq) in THF (54 mL).Solution 2: lithium aluminum hydride (2.5 M in THF, 11.15 mL, 1.2 eq)

[0176] Solution 1 (9.3 mL / min) and solution 2 (1.7 mL / min) were pumped to the flow reactor (60 mL, 0 °C) for a residence time of 5 minutes. The mixture was collected with a bottle (quenched by water / sodium hydroxide / water=l: 1:3 at 0 °C) and concentrated in vacuum to afford crude tert-butyl 3-(hydroxymethyl)-3-methyl-piperazine-l-carboxylate (5.3 g), which was used directly in the next reaction without further purification.Step 5:Im, SOCl2DCM, -50-15 °C, 13 h

[0177] To a solution of imidazole (2.31 g, 33. mmol, 6 eq) in dichloromethane (20 mL) was added the solution of thionyl chloride (1.01 g, 8.47 mmol, 0.61 mL, 1.5 eq) in dichloromethane (4 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture wasARVN-210-PCT / / ARVN0210WO2stirred at 20 °C for 3 hours. To the above mixture was added the solution of tert- butyl 3-(hydroxymethyl)-3-methyl-piperazine-l -carboxylate (1.3 g, 5.64 mmol, 1 eq) in dichloromethane (4 mL) dropwise under nitrogen atmosphere. The resulting mixture was stirred at 15 °C for 10 hours. The reaction mixture was quenched with water (20 mL) and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. To afford crude tert-butyl 3a-methyl-l-oxo-3,4,6,7-tetrahydrooxathiazolo[3,4-a]pyrazine-5-carboxylat (1.5 g), which was used directly in the next reaction without further purification.NaIO4, RuCl3ACN / EA / H2O, 0-25°C, 3 h

[0178] To a solution of tert-butyl 3a-methyl-l-oxo-3,4,6,7-tetrahydrooxathiazolo[3,4-a]pyrazine-5-carboxylate (1.5 g, 5.43 mmol, 1 eq) in acetonitrile (5 mL) and ethyl acetate (5 mL) was added sodium periodate (1.51 g, 7.06 mmol, 0.39 mL, 1.3 eq) and ruthenium trichloride (22 mg, 0.11 mmol, 0.1 mL, 0.02 eq) in water (10 mL) at 0°C. The mixture was stirred at 20°C for 3 hours. The reaction mixture was filtered, and the filter was quenched by 10 mL saturated sodium sulfite aqueous solution, then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine 20 mL, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford crude tert-butyl 3a-methyl-1,1-dioxo-3, 4,6,7-tetrahydrooxathiazolo[3,4-a]pyrazine-5-carboxylate (800 mg, 2.74 mmol, 50% yield) which was used directly in the next reaction without further purification.1H NMR: (400 MHz, CDCl3) δ: 4.37 - 4.32 (m, 1H), 4.31 - 4.26 (m, 1H), 3.85 (d, J = 2.0 Hz, 1H), 3.51 (dd, J= 1.2, 10.4 Hz, 1H), 3.31 - 3.22 (m, 2H), 2.98 - 2.86 (m, 1H), 2.32 - 2.20 (m, 1H). 1.48 (s, 9H), 1.41 (s, 3H).Step 7:HMTA, TFA,110 °C, 12 hARVN-210-PCT / / ARVN0210WO2

[0179] To a solution of methyl 4-bromo-3-hydroxy-benzoate (20 g, 86.56 mmol, 1 eq) in trifluoroacetic acid (200 mL) was added hexamethylenetetraamine (55.27 g, 394.26 mmol, 4.55 eq). The mixture was stirred at 110 °C for 12 hr. The mixture was cooled to 20 °C, quenched with hydrochloric acid solution 2N in water (500 mL), and yellow precipitate was observed. The mixture was stirred for 10 min, before additional water (250 mL) was added, and the reaction mixture was stirred for further 1 hr. The mixture was filtered, and the filter cake was dissolved in dichloromethane, filtered over celite, dried over anhydrous sodium sulfate and concentrated in vacuo to afford methyl 4-bromo-2-formyl-3-hydroxy-benzoate (19 g, 73.34 mmol. 85% yield). 'HNMR: (400 MHz, DMSO-63: 12.06 (s, 1H), 10.38 (s, 1H), 8.00 (d, J= 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 3.87 (s, 3H).Step 8:OBnborane;2-methylpyridineAcOH, MeOH, 25 °C, 12 h O

[0180] To a solution of methyl 4-bromo-2-formyl-3-hydroxy-benzoate (18.2 g, 70.26 mmol, 1 eq) in acetic acid (200 mL) and methanol (200 mL) was added 2,6-dibenzyloxypyridin-3-amine (21.52 g, 70.26 mmol, 1 eq). The mixture was stirred at 25 °C for 0.5 h, then borane;2-methylpyridine (15.03 g, 140.51 mmol, 2 eq) was added, the mixture was stirred at 25 °C for 11.5 h. The reaction was poured into water (400 mL), then the precipitate was filtered and dried to give a crude product. The crude product was triturated with (petroleum ether: ethyl acetate =3:1, 100 mL), and then the reaction mixture was filtered, and the filter cake was concentrated under vacuum to afford 5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)-4-hydroxy-isoindolin-l-one (29 g. 56.05 mmol, 80% yield). LCMS (ESI) m / z 957.5 [M+l]+.JHNMR: (400 MHz. DMSO-d6) d 10.55 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.67 (d, J= 8.0 Hz, 1H), 7.42 - 7.26 (m, 10H), 7.18 (d, J = 8.0 Hz, 1H), 6.55 (d, J= 8.4 Hz, 1H), 5.41 (s, 2H), 5.34 (s. 2H), 4.73 (s, 2H).Step 9:ARVN-210-PCT / / AR VN0210WO2

[0181] To a solution of tert-butyl 5-amino-4-(5-bromo-4-hydroxy-l-oxo-isoindolin-2-yl)-5-oxo-pentanoate (1.7 g, 5.8 mmol. 1 eq) and 5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)-4-hydroxy-isoindolin-l-one (1.5 g, 52.9 mmol, 1 eq) in acetonitrile (15 mL) was added potassium carbonate (1.2 g, 8.7 mmol, 3 eq). The mixture was stirred at 60 °C for 15 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuum to afford crude 2-[[5-bromo-2-(2, 6-dibenzyloxy-3-pyridyl)-l-oxo-isoindolin-4-yl] oxymethyl] -4-tert-butoxycarbonyl-2-methyl-piperazine-1 -sulfonic acid (2.3 g, crude), which was used directly in the next reaction without further purification.

[0182] To a solution of 2-[[5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)-l-oxo-isoindolin-4-yl]oxymethyl]-4-tert-butoxycarbonyl-2-methyl-piperazine-l-sulfonic acid (4.6 g, 5.68 mmol. 1 eq) in dichloromethane (30 mL) was added 4-methylbenzenesulfonic acid (0.98 g, 5.68 mmol, 1 eq). The mixture was stirred at 25 °C for 2 hours. Water (60 mL) was added, and the reaction mixture was extracted with ethyl dichloromethane (100 mL x 3). The combined organic layers were washed with brine (50 mLx 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The resulting residue was purified by flash silica gel chromatographyARVN-210-PCT / / ARVN0210WO2(0-11% methanol / dichloromethane) to afford crude tert-butyl 3-[[5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)-1-oxo-isoindolin-4-yl]oxymethyl]-3-methyl-piperazine-1-carboxylate (4.1 g). LCMS(ESI) m / z 731.2 [M+2]+. 'H NMR: (400 MHz, DMSO-d6) d: 7.81 (dd, J= 8.0, 16.8 Hz, 2H).7.49 - 7.31 (m, 10H), 7.08 (d, J = 7.6 Hz, 1H), 6.57 (d, J= 8.0 Hz, 1H), 5.38 (d, J = 15.2 Hz,4H), 4.95 (s, 2H), 4.20 (s, 2H), 3.60 - 3.53 (m, 2H), 3.12 (s, 2H), 2.27 (s, 2H), 1.38 (s, 3H), 1.32(s. 9H).Step 11:o o

[0183] A mixture of tert- butyl 3-[[5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)-l-oxo-isoindolin-4-yl]oxymethyl]-3-methyl-piperazine-l-carboxylate (4 g, 5.48 mmol, 1 eq), cesium carbonate (2.68 g, 8.22 mmol, 1.5 eq), L3-bis[2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-l-ium-2-ide;3-chloropyridine;dichloropalladium (533 mg, 0.54 mmol, 0.1 eq) indioxane (50 mL) was degassed and purged with nitrogen for 3 times, and then the mixture wasstirred at 100 °C for 12 hours under nitrogen atmosphere. Water (50 mL) was added, and thereaction mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layerswere washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The resulting residue was purified by flash silica gelchromatography (0-50% ethyl acetate / petroleum ether) to afford Zerf-butyl 13-(2,6-dibenzyloxy-3-pyridyl)-7-methyl-14-oxo-9-oxa-2,5,13-triazatetracyclo[8.7.0.02’7.011,15] heptadeca- 1(10), 11(15), 16-triene-5 -carboxylate (3.15 g, 4.86 mmol, 88% yield) was obtained. LCMS (ESI) m / z 649.3 [M+l]+

[0184] / - Butyl 13-(2,6-dibenzyloxy-3-pyridyl)-7-methyl-14-oxo-9-oxa-2,5,13-triazatetracyclo[8.7.0.02’7.011 15]heptadeca-l(10),ll(15),16-triene-5-carboxylate (3 g, 4.62 mmol,1 eq) was purified by prep-SFC (column: DAICEL CHIRALPAK IK(250mm*25mm,10um);mobile phase: [CO2-EtOH: ACN=4:l (0.1% NH3H2O)]; B%:43%,isocratic elution mode).ARVN-210-PCT / / ARVN0210WO2

[0185] Compound tert-butyl (7S)-13-(2,6-dibenzyloxy-3-pyridyl)-7-methyl-14-oxo-9-oxa-2,5,13-triazatetracyclo[8.7.0.02’7. 011 15]heptadeca-l(10).ll(15).16-triene-5-carboxylate (1.2 g, 1.85 mmol, 40 % yield, ee% value:98.45%) was obtained as a yellow solid.

[0186] Compound tert-butyl (7R)-13-(2,6-dibenzyloxy-3-pyridyl)-7-methyl-14-oxo-9-oxa-2,5,13-triazatetracyclo[8.7.0.02’7.011 15]heptadeca-l(10),ll(15),16-triene-5-carboxylate (1.2 g, 1.85 mmol, 40 % yield ee% value:98.81%) was obtained as a white solid.Step 12:o o o o

[0187] A solution of tert-butyl (77?)-13-(2,6-dioxo-3-piperidyl)-7-methyl-14-oxo-9-oxa-2,5,13-triazatetracyclo[8.7.0.02,7.011,15]heptadeca-l(10),ll(15),16-triene-5-carboxylate (1.2 g, 1.85 mmol, 1 eq) in dichloromethane (8 mL) was added to trifluoroacetic acid (6.14 g, 53.83 mmol, 4 mL, 29 eq). The mixture was stirred at 25 °C for 30 minutes. The reaction mixture was concentrated in vacuum. The resulting residue was dissolved in dichloromethane / iso-propanol (5 / 1, 10 mL) and A, A-diisopropylethylamine (0.5 mL) was added. The mixture was triturated with petroleum ether (50 mL). The clear solution was removed and the precipitate was concentrated under reduced pressure to afford crude 3- [(77?) -7-methyl-14-oxo-9-oxa-2,5,13-triazatetracyclo[8.7.0.02,7.011,15]heptadeca-l (10), 11(15), 16-trien-13-yl]piperidine-2, 6-dione (800 mg, 1.65 mmol, 89% yield, trifluoroacetate) as a white solid, which was used directly in the next reaction without further purification. LCMS (ESI) m / 371.2[M+1] +. 'H NMR (400 MHz, DMSO-d6) 8: 10.94 (s, 1H), 7.22 - 7.16 (m. 1H). 6.89 (d, J = 8.4 Hz, 1H), 5.03 (dd. J = 4.8, 13.2 Hz, 1H), 4.33 - 4.23 (m, 1H), 4.14 - 4.07 (m, 1H), 3.93 (d, J = 9.6 Hz, 1H), 3.61 - 3.53 (m, 3H), 3.17 - 3.07 (m, 2H), 2.93 - 2.77 (m, 4H), 2.62 - 2.54 (m, 2H), 2.00 - 1.90 (m, 1H), 1.21 (d, J = 4.4 Hz, 3H).Step 13:ARVN-210-PCT / / ARVN0210WO20 oDIEA, AcOH, NaBH(OAc)3, DCM, 25 °C, 3 h

[0188] To a solution of 3-[(7 / ?)-7-methyl-14-oxo-9-oxa-2,5,13- triazatetracyclo[8.7.0.02,7.011,15] heptadeca-l(10),ll(15),16-trien-13-yl]piperidine-2, 6-dione (400 mg, 0.83 mmol, 1 eq, trifluoroacetate) in dichloromethane (15 mL) was added N, N- diisopropylethylamine (320 mg, 2.48 mmol, 3 eq) and tert-butyl 4-fhroro-4-formyl-piperidine-l- carboxylate (600 mg, 2.59 mmol, 3.14 eq) at 25 °C and stirred for 2 h. Then acetic acid (99 mg, 1.65 mmol, 2 eq) and sodium triacetoxyborohydride (438 mg, 2.06 mmol, 2.5 eq) were added at 25 °C and stirred for 1 h. The reaction mixture was quenched by addition of water (10 mL) and then extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to afford tert-butyl 4-[[(7R)-13-(2,6-dioxo-3- piperidyl)-7-methyl-14-oxo-9-oxa-2,5,13- triazatetracyclo[8.7.0.02,7.011,15]heptadeca- 1(10), 11(15), 16-trien-5-yl]methyl]-4-fluoro-piperidine-l-carboxylate (300 mg, 0.51 mmol, 62% yield). LCMS (ESI) m / z 586.4 [M+l]+Step 14:o o TFA / DCM25 °C, 0.5 h

[0189] To a solution of tert-butyl 4-[[(7 / ?)-13-(2,6-dioxo-3-piperidyl)-7-methyl-14-oxo- 9-oxa- 2,5,13-triazatetracyclo[8.7.0.02,7.011,15]heptadeca-l(10),ll(15),16-trien-5-yl]methyl]-4- fluoro-piperidine- 1 -carboxylate (300 mg, 0.51 mmol. 1 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL, 26.28 eq) at 25 °C and stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in dichloromethane / isopropanol (1 / 1, 4 mL) and added A / tV-diisopropylethylamine (2 mL), then triturated with petroleum ether (30 mL). The clear solution was removed and theARVN-210-PCT / / ARVN0210WO2remaining precipitate was concentrated under reduced pressure to afford 3-[(77?)-5-[(4-fluoro-4-piperidyl)methyl]-7-methyl-14-oxo-9-oxa-2,5,13-triazatetracyclo[8.7.0.02,7.011,15]heptadeca-1(10).11(15).16-trien-13-yl]piperidine-2, 6-dione (200 mg, 0.33 mmol, 65% yield, trifluoroacetate). LCMS (ESI) m / z 486.3 [M+l]+

[0190] The preparation of 3-[(7 *)-5-[(l-{ [ 1 -({ [7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-4-[(4S)-l-oxa-6-azaspiro[3.5]nonan-6-yl]pyrido[4,3-d] pyrimidin-2-yl] oxy } methyl)cyclopropyl] methyl } -4-fluoropiperidin-4-yl)methyl] -7-methyl- 14-oxo-9-oxa-2,5,13-triazatetracyclo[8.7.0.02,7.011,15]heptadeca-l(10),ll(15),16-trien-13-yl]piperidine-2, 6-dione was prepared in analogous fashion as described in General Synthetic Scheme 1. LCMS (ESI) m / z 643.4 [M+l]+.1H NMR: (400 MHz, CDCh-d) d: 9.29 (d, J = 11.6 Hz, 1H), 7.69 (dd, J = 6.0, 9.2 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.27 - 7.22 (m, 2H), 5.30 (d, J = 1.2 Hz, 2H), 4.92 - 4.76 (m, 1H), 4.71 - 4.52 (m, 4H), 4.46 - 4.30 (m, 1H), 3.81 - 3.62 (m, 3H), 3.52 (d. J = 2.0 Hz, 3H), 3.47 - 3.35 (m, 1H), 2.58 - 2.44 (m. 3H). 2.39 - 2.30 (m, 1H), 2.26 -2.15 (m, 1H), 2.13 - 2.07 (m, 1H), 1.94 - 1.81 (m, 2H), 1.80 - 1.57 (m, 1H), 1.57 - 1.37 (m, 2H), 0.86 (q, J = 7.6 Hz, 3H).

[0191] Using the methods disclosed or similarly disclosed herein, the following Compounds of Formula I were made:CompoundSynthesisNo.1 Analogous to Example 1.4 (Compound 2)2 Example 1.43 Analogous to Example 1.1 (Compound 29)4 Analogous to Example 1.1 (Compound 29)5 Analogous to Example 1.1 (Compound 29)6 Analogous to Example 1.1 (Compound 29)ARVN-210-PCT / / ARVN0210WO2Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Example 1.1Analogous to Example 1.1 (Compound 29)ARVN-210-PCT / / ARVN0210WO2Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Analogous to Example 1.1 (Compound 29)Example 1.3Example 1.9Analogous to Example 1.9 (Compound 41)Analogous to Example 1.9 (Compound 41)Analogous to Example 1.9 (Compound 41)Analogous to Example 1.9 (Compound 41)Analogous to Example 1.9 (Compound 41)Analogous to Example 1.9 (Compound 41)Analogous to Example 1.9 (Compound 41)General Scheme 2Analogous to Example 1.5 (Compound 61)Analogous to Example 1.5 (Compound 61)Analogous to Example 1.5 (Compound 61)Analogous to Example 1.5 (Compound 61)Analogous to Example 1.5 (Compound 61)Analogous to Example 1.5 (Compound 61)Analogous to Example 1.5 (Compound 61)ARVN-210-PCT / / ARVN0210WO2Analogous to Example 1.5 (Compound 61)Analogous to Example 1.5 (Compound 61)Analogous to Example 1.5 (Compound 61)Analogous to Example 1.5 (Compound 61)Example 1.5Analogous to Example 1.5 (Compound 61)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)ARVN-210-PCT / / ARVN0210WO2Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.10 (Compound 91)Example 1.10Analogous to Example 1.5 (Compound 61)Analogous to Example 1.2 (Compound 95)Example 1.2Analogous to Example 1.2 (Compound 95)Analogous to Example 1.2 (Compound 95)Analogous to Example 1.2 (Compound 95)Analogous to Example 1.2 (Compound 95)Analogous to Example 1.2 (Compound 95)Analogous to Example 1.2 (Compound 95)Example 1.8Analogous to Example 1.8 (Compound 102)Analogous to Example 1.3 (Compound 38)Analogous to Example 1.8 (Compound 102)Analogous to Example 1.8 (Compound 102)Analogous to Example 1.3 (Compound 38)Analogous to Example 1.8 (Compound 102)Analogous to Example 1.8 (Compound 102)ARVN-210-PCT / / ARVN0210WO2Analogous to Example 1.3 (Compound 38)Analogous to Example 1.3 (Compound 38)Example 1.13Analogous to Example 1.13 (Compound 112)Analogous to Example 1.13 (Compound 112)Analogous to Example 1.13 (Compound 112)Analogous to Example 1.3 (Compound 38)Analogous to Example 1.3 (Compound 38)Example 1.11Example 1.12Analogous to Example 1.5 (Compound 61)Analogous to Example 1.5 (Compound 61)Analogous to Example 1.5 (Compound 61)Analogous to Example 1.5 (Compound 61)Analogous to Example 1.5 (Compound 61)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.5 (Compound 61)Analogous to Example 1.5 (Compound 61)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.5 (Compound 61)Analogous to Example 1.5 (Compound 61)Analogous to Example 1.10 (Compound 91)Analogous to Example 1.5 (Compound 61)Analogous to Example 1.2 (Compound 95)ARVN-210-PCT / / AR VN0210WO2135 Analogous to Example 1.2 (Compound 95)136 Example 1.7137 Example 1.6138 Analogous to Example 1.7 (Compound 136)139 Example 1.14140 Analogous to Example 1.14 (Compound 139) 141 Analogous to Example 1.14 (Compound 139) 142 Analogous to Example 1.14 (Compound 139) 143 Analogous to Example 1.14 (Compound 139) 144 Analogous to Example 1.14 (Compound 139) 145 Analogous to Example 1.14 (Compound 139) 146 Analogous to Example 1.14 (Compound 139) 147 Analogous to Example 1.14 (Compound 139) 148 Analogous to Example 1.14 (Compound 139) 149 Analogous to Example 1.14 (Compound 139) 150 Analogous to Example 1.14 (Compound 139) 151 Analogous to Example 1.14 (Compound 139) 152 Analogous to Example 1.14 (Compound 139) 153 Analogous to Example 1.14 (Compound 139)Example Q-l.lExemplary synthesis of Compound Q-4:Step 1:ARVN-210-PCT / / ARVN0210WO2~. O —Br'' —rA / _ A\l0—o LMC ' bz N ', OCbz

[0192] To a solution of Ol-benzyl O2-methyl (25)-pyrrolidine-l,2-dicarboxylate (100 g, 379.81 mmol, 1 eq) in tetrahydrofuran (200 mL) was added lithium bis(trimethylsilyl)amide (1 M, 460 mL, 1.21 eq) at -78 °C for 1 h. Then 4-bromobut-l-ene (102 g, 755.54 mmol, 77 mL, 1.99 eq) was added in one portion at 20 °C. The mixture was stirred at 20 °C for 12 h, then poured into water (500 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (500 mL x 3) and the combined organic phase was washed with brine (500 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The resulting residue was purified by flash silica gel chromatography (0-18% ethyl acetate / petroleum ether) to afford (91 -benzyl O2-methyl 2-but-3-enylpyrrolidine-l,2-dicarboxylate (80 g, 252.06 mmol, 66% yield) as a colorless oil.Step 2:

[0193] To a solution of 01 -benzyl O2-methyl 2-but-3-enylpyrrolidine-l,2-dicarboxylate (80 g, 252.06 mmol, 1 eq) in dichloromethane (800 mL) was added 3-chloroperoxybenzoic acid (60.03 g, 347.85 mmol, 1.38 eq) at 10 °C in several portions under nitrogen, during which the temperature was maintained below 20 °C. Then the mixture was stirred at 20 °C for 16 h.Saturated aqueous sodium thiosulfate (1000 mL) was added, and the mixture was stirred at 25 °C for another 2 hours. The mixture was extracted with dichloromethane (1000 mL x 2) and the combined organic phase was washed with saturated sodium bicarbonate solution (2000 mL x 2), brine (2000 mL), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuum and the resulting residue was purified by flash silica gel chromatographyARVN-210-PCT / / ARVN0210WO2(0-25% ethyl acetate / petroleum ether) to afford 01 -benzyl O2-methyl 2-[2-(oxiran-2-yl)ethyl]pyrrolidine-l,2-dicarboxylate (84 g, 251.97 mmol, 99% yield) as a colorless oil.Step 3:HOH2, Pd / C / ''''T* ^°vVNoCbz

[0194] To a solution of Ol-benzyl 02-methyl 2-[2-(oxiran-2-yl)ethyl]pyrrolidine-l,2-dicarboxylate (340 g, 1.02 mol. 1 eq) in methanol (5000 mL) was added palladium on activated carbon catalyst (100 g, 5% purity) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (IMpa) at 25 °C for 48 hours. The reaction mixture was filtered and the filtrate was concentrated at 45 °C to afford crude methyl 3-(hydroxymethyl)-l,2,3,5,6,7- hexahydropyrrolizine-8-carboxylate (220 g) as a colorless oil.JH NMR (400 MHz, CDC13) 5: 3.88 - 3.78 (m, 2H), 3.71 (d, J = 12.4 Hz, 6H), 3.61 - 3.47 (m, 3H), 3.39 (dd, J = 3.2, 10.8 Hz, 1H), 3.21 - 3.12 (m, 1H), 3.10 - 3.03 (m, 1H), 2.98 - 2.91 (m, 1H), 2.79 - 2.65 (m, 2H), 2.56 (td, J = 4.8, 12.8 Hz, 1H), 2.37 - 2.14 (m, 3H), 1.92 - 1.76 (m, 8H), 1.91 - 1.75 (m, 1H). 1.73 - 1.60 (m, 3H)TBDPSO TBDPSCI, imidazole

[0195] To a solution of methyl 3-(hydroxymethyl)-l,2, 3,5,6, 7-hexahydropyrrolizine-8-carboxylate (10 g, 50.19 mmol, 1 eq) in dichloromethane (100 mL) was added imidazole (4.44 g, 65.25 mmol, 1.3 eq) and tert-butylchlorodiphenylsilane (16.55 g, 60.23 mmol, 15.5 mL, 1.2 eq) at 0 °C. Then the mixture was stirred at 25 °C for 16 h. The mixture was poured into water (50 mL) and stirred for 2 min. The aqueous phase was extracted with dichloromethane (50 mL x 2) and the combined organic phase was washed with brine (50 mL x 2), dried with anhydrousARVN-210-PCT / / ARVN0210WO2sodium sulfate, filtered and concentrated in vacuum. The resulting residue was purified by flash silica gel chromatography (0-75% ethyl acetate / petroleum ether gradient @ 120 mL / min) to afford methyl 3-[[tert-butyl(diphenyl)silyl]oxymethyl]-l,2,3.5,6,7-hexahydropyrrolizine- 8-carboxylate (4 g, 9.14 mmol, 18% yield) as a colorless oil and methyl 3-[[tert-butyl(diphenyl)silyl]oxymethyl]-l,2,3,5,6,7-hexahydropyrrolizine-8- carboxylate (3.6 g, 8.23 mmol, 16.39% yield) methyl 3-[[tert-butyl(diphenyl) silyl]oxymethyl]-l, 2,3.5.6.7-hexahydropyrrolizine-8-carboxylate (4 g, 9.14 mmol, 18% yield) as a white solid. LCMS (ESI) m / z 438.3 [M +1] +Step 5:TBDPSO TBDPSO TBDPSO TBDPSO LIAIH4SFC AV'' -A M * HO " HO VN * HOKVNOo> A; " U AJ

[0196] To a mixture of methyl 3-[[tert-butyl(diphenyl)silyl]oxymethyl]-l,2,3,5,6,7-hexahydropyrrolizine-8-carboxylate (63 g, 143.95 mmol, 1 eq) in tetrahydrofuran (640 mL) was added lithium aluminium tetrahydride (5.46 g. 143.95 mmol, 1. eq) in portion at 0 °C under nitrogen. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched by water (5.5 mL), 15% aqueous solution of sodium hydroxide (5.5 mL), water (16.5 mL) and then and then diluted with ethyl acetate (300 mL). The resulting suspension dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane:methanol= 100 / 1. 10 / 1), then repurified by prep-HPLC (mobile phase: [water(FA)-ACN]; B%: 30%-51%,20min) to afford [3-[[tert-butyl (diphenyl) silyl] oxymethyl]-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (46 g, 112.30 mmol, 78% yield) as a yellow oil.

[0197] [3-[[tert-butyl(diphenyl)silyl]oxymethyl]-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (70 g. 170.88 mmol. 1 eq) was purified by SFC (column: DAICEL CHIRALPAK OX 250x30mm, I. D., 10 um; mobile phase: isopropanol (0.1% NH3H2O) in CO2 from 40% to 40%; flow rate: 70 mL / min) to afford two compoundsARVN-210-PCT / / ARVN0210WO2

[0198] Peak 1: [(3 / ?,8S)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]- 1, 2, 3, 5,6,7-hexahydropyrrolizin-8-yl]methanol (33.6 g, 82.02 mmol, 48% yield); brown oil. 'H NMR (400 MHz. DMSO-d6) 8: 7.72 - 7.61 (m, 4H), 7.47 - 7.39 (m, 6H), 4.59 - 4.20 (m. 1H), 3.52 (br dd, J = 1.6, 12.8 Hz, 2H), 3.16 - 2.95 (m, 2H), 2.82 (br d, J = 2.0 Hz, 2H), 2.65 - 2.55 (m, 1H), 1.97 -1.83 (m, 2H), 1.81 - 1.63 (m, 3H), 1.60 - 1.30 (m, 3H), 0.99 (s, 9H)

[0199] Peak 2: [(3S,8R)-3-[[terLbutyl(diphenyl)silyl]oxymethyl]-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (26.6 g, 64.94 mmol, 38% yield); brown oil. ’H NMR (400 MHz, DMSO-d6) 5: 7.70 - 7.61 (m, 4H), 7.49 - 7.40 (m, 6H), 3.60 - 3.55 (m, 1H), 3.49 (br s, 1H), 3.12 - 3.01 (m, 2H), 2.94 - 2.81 (m, 2H), 2.70 - 2.65 (m, 1H), 1.97 - 1.84 (m, 2H), 1.80 -1.64 (m, 3H), 1.60 - 1.50 (m, 1H), 1.50 - 1.35 (m. 2H), 0.99 (s, 9H)

[0200] To a mixture of [(35,8R)-3-[[terLbutyl(diphenyl)silyl]oxymethyl]-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (4.5 g, 10.93 mmol, 1.5 eq) in tetrahydrofuran (50 mL) was cooled to 0 °C and lithium tert-butoxide (1 M, 22 mL, 3.0 eq) was added at 20 °C under nitrogen. Then the mixture was stirred at 20 °C for 15 min. To the resulting mixture was added (45)-8-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-l-oxa-8-azaspiro [3.5]nonane (2.5 g, 7.28 mmol, 1 eq) and the reaction was warmed to 50 °C for 6 h. Ice-water (10 mL) was added at 0 °C and the mixture was stirred for 15 min under nitrogen, then extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (50 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The resulting residue was purified by prep-HPLC (mobile phase: [water(FA)-ACN];gradient:40%-70% B over 17 min ) to afford ter -butyl-[[(3S,8R)-8-[[7-chloro-8-fluoro-4-[(45')-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-ARVN-210-PCT / / ARVN0210WO2d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-3-yl]methoxy]-diphenyl-silane (1.5 g, 2.09 mmol, 28% yield) as yellow oil. LCMS (ESI) m / t: 716.3 [M+l] +Step 7:

[0201] To a mixture of tert-butyl-[[(35,87?)-8-[[7-chloro-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-l,2,3,5,6,7-hexahydropyrrolizin-3-yl]methoxy]-diphenyl-silane (1.5 g, 2.09 mmol, 1 eq), 2-(8- ethyl-7-fluoro-l-naphthyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (942 mg, 3.14 mmol, 1.5 eq) and potassium phosphate (1.5 M, 4.2 mL, 3 eq) in tetrahydrofuran (30 mL) was added methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-l, T-biphenyl-2-yl)palladium(II) (228 mg, 0.3 mmol, 0.15 eq) under nitrogen. The mixture was stirred at 70 °C for 12 h, then diluted with ethyl acetate (50mL), washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=l / l, 0 / 1) to afford / c / -biityl-[[(3. S'.8A,)-8-[[7-(8-ethyl-7-fluoro- l-naphthyl)-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-l,2,3,5,6,7-hexahydropyrrolizin-3-yl]methoxy]-diphenyl-silane (1.4 g, 1.64 mmol, 78% yield) as yellow oil. LCMS (ESI) m / z: 854.4 [M+l]Step 8:ARVN-210-PCT / / ARVN0210WO2

[0202] To a mixture of tert-butyl-[[(3S,8A)-8-[[7-(8-ethyl-7-fluoro-l-naphthyl) -8-fluoro- 4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-l,2,3,5,6,7- hexahydropyrrolizin-3-yl]methoxy]-diphenyl-silane (1.4 g, 1.64 mmol, 1 eq) inA^V- dimethylformamide (15 mL) was added cesium fluoride (2.5 g, 16.39 mmol, 10 eq) and the mixture was stirred at 50 °C for 6 h under nitrogen. The reaction mixture was diluted with ethyl acetate (50 mL), washed with a saturated aqueous solution of ammonium chloride (20 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The resulting residue was purified by prep-HPLC (mobile phase: [water(FA)-ACN]; gradient: 25%-55% B over 15 min ) to afford [(31S’,87?)-8-[[7-(8-ethyl-7-fluoro-l-naphthyl)-8-fluoro-4-[(45)-l-oxa-8- azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-l,2,3, 5,6,7- hexahydropyrrolizin-3-yl]methanol(0.4 g, 0.68 mmol, 41% yield) as yellow solid. LCMS (ESI) m / z 616.3 [M+l] +Step 9:

[0203] To a solution of [(3,8 )-8-[[7-(8-ethyl-7-fhroro-l-naphthyl)-8-fluoro-4-[(4S)-l- oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-l,2,3,5,6,7- hexahydropyr rolizin- 3 -yl] methanol (75 mg, 0.12 mmol, leq) and (4-nitrophenyl) carbonochloridate (42 mg, 0.2 mmol, 1.7 eq) in tetrahydrofuran (5 mL) was added triethylamineARVN-210-PCT / / ARVN0210WO2(62 mg, 0.6 mmol, 5 eq) and dimethylaminopyridine (1 mg, 0.01 mmol, 0.1 eq). The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to afford crude [(35,8?)-8-[[7-(8-ethyl-7-fluoro-l-naphthyl)-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido [4,3-d]pyrimidin-2-yl]oxymethyl]-l,2,3,5,6,7-hexahydropyrrolizin-3-yl]methyl (4-nitrophenyl) carbonate (95 mg, 0.12 mmol, 99% yield) as a yellow solid, which was used directly in the next reaction without further purification. LCMS (ESI) m / z 781.3 [M+l]+Step 10:

[0204] To a solution of 3-[3-methyl-2-oxo-4-[3-(4-piperidyloxy)azetidin-l-yl]benzimidazol-l-yl]piperidine-2,6-dione(147 mg, 0.28 mmol, 2 eq, trifluoroacetate) and [(35,8R)-8-[[7-(8-ethyL7-fluoro-l-naphthyl)-8-fluoro-4-[(45)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrim idin-2-yl]oxymethyl]-l,2,3,5,6,7-hexahydropyrrolizin-3-yl]methyl (4-nitrophenyl) carbonate (95 mg, 0.1 mmol, 1 eq) in tetrahydrofuran (5 mL) was added triethylamine (37 mg, 0.36 mmol, 3 eq). The mixture was stirred at 25 °C for 2 h, then diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate filtered and concentrated under reduced. The resulting residue was purified by prep-HPLC (mobile phase: [water(FA)-ACN]; gradient:28%-58% B over 10 min) to afford [(35. 87f)-8-[[7-(8-ethyl-7-fluoro-l-naphthyl)-8-fluoro-4-(l-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyr rolizin-3-yl] methyl 4-[l-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl] azetidin-3-yl] oxypiperidine- 1 -carboxylate (23.5 mg, 0.02 mmol, 18% yield, 98% purity) as a white solid. LCMS (ESI) n z 1055.6 [M+l]+. 'H NMR (400MHz, DMSO-d6) 8: 11.08 (s, 1H), 9.23 (d, J = 6.4 Hz, 1H), 8.20 - 7.92 (m, 2H), 7.64 - 7.40 (m, 3H).7.03 - 6.90 (m, 1H), 6.83 - 6.57 (m, 2H), 5.32 (dd, J = 5.2, 12.4 Hz, 1H), 4.45 - 3.63 (m, 14H), 3.54 (s, 6H), 3.14 - 2.83 (m, 6H), 2.43 - 2.32 (m, 3H), 2.23 - 1.53 (m, 18H), 1.41 - 1.18 (m, 3H), 0.76 (q, J = 7.2 Hz, 3H)ARVN-210-PCT / / ARVN0210WO2Example Q-1.2Exemplary synthesis of Compound Q-9:Step 1:

[0205] To a solution of (4S)-8-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl) -1-oxa-8-azaspiro[3.5]nonane (500 mg, 1.46 mmol, 1 eq) and [3-(hydroxymethyl)oxetan-3-yl]methanol (2.58 g. 21.85 mmol, 15 eq) in / V-dimethylacetamide (10 mL) was added cesium carbonate (1.42 g, 4.37 mmol, 3 eq). The mixture was stirred at 30 °C for 2h. The mixture was cooled to 25 °C, then quenched by water (80 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (80 mL x 2). The combined organic phase was washed with brine (30 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The resulting residue was purified by prep-HPLC (mobile phase: [water(FA)-ACN]; gradient:20%-50% B over 15 min) to afford [3-[[7-chloro-8-fluoro-4-[(4 )-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido [4,3-d]pyrimidin-2-yl]oxymethyl]oxetan-3-yl]methanol (280 mg, 0.66 mmol, 45% yield) as a colorless oil. LCMS (ESI) m / z: 425.1 [M+l]+Step 2:ARVN-210-PCT / / ARVN0210WO2

[0206] A mixture of [3-[[7-chloro-8-fluoro-4-[(45')-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido [4,3-d]pyrimidin-2-yl]oxymethyl]oxetan-3-yl]methanol (150 mg, 0.35 mmol, 1 eq), 2-[8-ethyL7-fhioro-3-(methoxymethoxy)-l-naphthyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (190.77 mg, 0.53 mmol, 1.5 eq), potassium phosphate (1.5 M, 0.7 mL, 3 eq), methanesulfonato(diadamantyl-n-butylphosphino)-2’-amino-l,l’-biphenyl-2-yl)palladium(II) (26 mg, 0.04 mmol, 0.1 eq) in dioxane (6 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 100 °C for 5 h under nitrogen atmosphere. The mixture was poured into water (50 mL) and filtered, and the filtrate was collected. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (30 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The resulting residue was purified by prep-TLC (dichloromethane: methanol = 10:1) to afford [3-[[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]oxetan-3-yl]methanol (195 mg, 0.31 mmol. 89% yield) was a yellow solid. LCMS (ESI) m / z: 623.7 [M+l]+

[0207] To a solution of [3-[[7-[8-ethyL7-fhioro-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]oxetan-3-yl]methanol (100 mg, 0.16 mmol, 1 eq) in dichloromethane (3 mL) was added Dess-Martin periodinane (136 mg, 0.32 mmol, 0.1 mL, 2 eq) and sodium bicarbonate (40 mg, 0.48 mmol, 3 eq). The mixture was stirred at 25 °C for 2h. The mixture was poured into sodium thiosulfate saturated solution (20 mL), sodium bicarbonate solution (20 mL) and water (20 mL) and stirred for 5 min. The aqueous phase was extracted with dichloromethane (30 mL x 2). The combined organic phase was washed with brine (30 mL x 2), dried with anhydrous sodium sulfate, filteredARVN-210-PCT / / ARVN0210WO2and concentrated in vacuum. The resulting residue was purified by prep-TLC (dichloromethane: methanol = 10:1) to afford 3-[[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]oxetane-3-carbaldehyde (55 mg, 0.09 mmol, 55 % yield) as a white solid. LCMS (ESI) m / z: 621.5 [M+l]+

[0208] To a solution of 3-[[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]oxetane-3-carbaldehyde (55 mg, 0.09 mmol, 1 eq) in dichloromethane (2 mL) and dimethylsulfoxide (2 mL) was added diisopropylethylamine (23 mg, 0.18 mmol, 0.1 mL, 2 eq), 3- [4-chloro-5 - [4- [(4-fluoro-4-piperidyl)methyl] piperazin- 1 -yl] - 1 -oxo-isoindolin-2-yl] piperidine-2, 6-dione (63 mg, 0.09 mmol, 1 eq, 2 trifluoroacetate) and titanium(IV) isopropylate (38 mg, 0.13 mmol, 0.1 mL, 1.5 eq) was added and the mixture was stirred at 25 °C for 2 h. Sodium triacetoxyborohydride (56 mg, 0.27 mmol, 3 eq) was added and the mixture was stirred at 40 °C for 10 h, then cooled to 25 °C. The mixture was poured into water (50 mL) and the residue was filtered and the filtrate was collected. The aqueous phase was extracted with dichloromethane (20 mL x 2). The combined organic phase was washed with brine (30 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The resulting residue was purified by prep-TLC (dichloromethane: methanol = 10:1) to afford 3-[4-chloro-5-[4-[[l-[[3- [[7-[8-ethyl-7-fhioro-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]oxetan-3-yl]methyl]-4-fluoro-4-piperidyl]methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (70 mg, 0.06 mmol, 73% yield) as a white solid. LCMS (ESI) m / z: 1082.6 [M+l]+Step 5:ARVN-210-PCT / / ARVN0210WO2

[0209] To a solution of 3-[4-chloro-5-[4-[[l-[[3-[[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)- l-naphthyl]-8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3 J]nonan-8-yl]pyrido[4, 3-d]pyrimidin-2-yl]oxymethyl]oxetan-3-yl]methyl]-4-fluoro-4-piperidyl]methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (147 mg, 0.14 mmol, 1 eq) in dichloromethane (1.5 mL) was added trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL, 99.14 eq). The mixture was stirred at 0 °C for 15min. To the mixture was added saturated sodioum bicarbonate solution to adjust pH to 8, and stirred for 2 min. The aqueous phase was extracted with dichloromethane (10 mL x 2). The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The resulting residue was purified by prep-HPLC (mobile phase: [water(FA)-ACN]; gradient: 15%-45% B over 9 min) to afford 3-[4-chloro-5-[4-[[l-[[3-[[7-(8-ethyL7-fhioro-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]oxetan-3-yl]methyl]-4-fluoro-4-piperidyl]methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (45.4 mg, 0.04 mmol, 32% yield, 98 % purity) as a white solid. LCMS (ESI) m / z; 1038.5 [M+l] +. 'HNMR (400 MHz, DMSO-d6) 5: 10.99 (s, 1H), 10.09 - 9.83 (m, 1H), 9.24 (d, J = 6.8 Hz, 1H), 7.75 (dd, J = 6.0, 9.2 Hz. 1H). 7.64 (d, J = 8.0 Hz, 1H), 7.38 - 7.29 (m, 2H). 7.22 (d, J = 8.4 Hz. 1H), 7.05 (t, J = 3.2 Hz, 1H), 5.10 (dd, J = 5.2, 13.2 Hz, 1H), 4.73 - 4.63 (m, 2H), 4.52 ( d, J = 6.0 Hz, 2H), 4.44 - 4.40 (m, 3H), 4.40 - 4.29 (m, 3H), 4.25 ( d, J = 17.2 Hz, 1H), 3.98 - 3.79 (m, 1H), 3.57 -3.38 (m, 1H), 3.02 ( s. 4H). 2.95 - 2.85 (m, 1H). 2.80 - 2.72 (m, 2H), 2.63 ( s, 5H). 2.47 ( s, 2H), 2.44 - 2.32 (m, 7H), 2.30 - 2.21 (m, 2H), 2.17 - 2.05 (m, 2H), 2.04 - 1.94 (m, 1H), 1.92 - 1.83 (m, 2H), 1.75 ( d. J = 9.6 Hz, 3H), 1.67 - 1.47 (m, 2H), 0.79 - 0.68 (m. 3H)Example Q-1.3Exemplary synthesis of Compound Q-17:Step 1:ARVN-210-PCT / / ARVN0210WO2

[0210] To a solution of dimethyl sulfoxide (177 mg, 2.27 mmol, 8 eq) in dichloromethane (5 mL) was added a solution of oxalyl chloride (216 mg, 1.71 mmol. 6 eq) in dichloromethane (5 mL) at -60 °C dropwise under nitrogen. After stirred at the temperature for 10 min, [(3S,8 / ?)-8-[[7-(8-ethyl-7-fluoro-l-naphthyl)-8-fluoro-4-[(4S)-l-oxa-8- azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-l,2,3,5,6,7- hexahydropyrrolizin-3-yl]methanol (175 mg, 0.28 mmol, 1 eq) in dichloromethane (5 mL) was added dropwise and stirred for 20 min, then triethylamine (862 mg, 8.53 mmol, 30 eq) was added and stirred at -75 °C for 15 min. The reaction mixture was quenched by addition of sat sodium bicarbonate (10 mL), and then extracted with dichloromethane (40 mL x 3). The combined organic layers was washed with brine (40 mL), dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to afford crude (3S,87?)-8-[[7-(8-ethyl-7-fhioro-l-naphthyl)- 8-fluoro-4-[(4S)-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]- l,2,3,5,6,7-hexahydropyrrolizine-3-carbaldehyde (160 mg, 0.22 mmol, 79% yield, 87% purity) as a yellow solid, which was used directly in the next reaction without further purification.LCMS (ESI) m / z 632.3 [M+18] +

[0211] To a solution of (3S,87?)-8-[[7-(8-ethyl-7-fhioro-l-naphthyl)-8-fhioro-4-[(4S)-l- oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-l,2,3,5,6,7-ARVN-210-PCT / / ARVN0210WO2hexahydropyrrolizine-3-carbaldehyde (60 mg, 0.01 mmol, 1 eq) and 3-(4-chloro-l-oxo-5-piperazin-l-yl-isoindolin-2-yl)piperidine-2, 6-dione (60 mg, 0.12 mmol, 1.3 eq) in dichloromethane (3 mL) was added sodium triacetoxyborohydride (41 mg, 0.19 mmol, 2 eq) and triethylamine (29 mg, 0.29 mmol, 3 eq). The mixture was stirred at 20 °C for 2 h. The resulting product was dissolved in dichloromethane (3 mL) and filtered. The filtrate was concentrated and the resulting residue was purified by prep-HPLC (mobile phase: [water (FA)-ACN]; gradient: 25%-45% B over 10 min) to afford 3-[4-chloro-5-[4-[[(3S,87?)-8-[[7-(8-ethyl-7-fluoro-l-naphthyl)-8-fluoro-4-[(4S')-l-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-l,2,3,5,6,7-hexahydropyrrolizin-3-yl]methyl]piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (10 mg, 0.01 mmol, 10% yield, 97% purity) as a white solid. LCMS (ESI) m / z: 960.6 [M+l] +. 'H NMR (400 MHz, DMSO-d6) 5: 10.97 (s. 1H), 9.23 (d, J = 4.8 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 8.07 - 7.98 (m, 1H), 7.65 - 7.55 (m, 2H), 7.53 - 7.43 (m, 2H), 7.24 (dd, J = 4.8, 7.6 Hz, 1H), 5.14 - 5.05 (m, 1H), 4.44 - 4.35 (m, 3H), 4.30 - 4.21 (m, 2H), 4.18 -4.13 (m, 1H), 4.09 - 4.03 (m, 1H), 4.02 - 3.90 (m. 1H), 3.88 - 3.80 (m, 1H), 3.54 - 3.48 (m, 1H), 3.09 - 3.01 (m, 4H), 2.94 - 2.83 (m, 4H), 2.67 (d, J = 2.0 Hz, 2H), 2.57 (d, J = 7.2 Hz, 5H), 2.46 -2.41 (m, 2H), 2.39 - 2.30 (m, 3H), 2.20 (s, 1H), 2.10 (d, J = 12.4 Hz, 1H), 2.03 - 1.93 (m, 3H), 1.89 - 1.79 (m, 4H), 1.74 - 1.58 (m, 3H), 1.27 - 1.20 (m, 1H), 0.81 - 0.74 (m, 3H).Example 2: Biological AssaysReagentsAsPC-1 (CRL-1682) cells are purchased from ATCC and are homozygous for the G12D mutation in KRAS. AsPC-1 cells are cultured in GIBCO RPMI-1640 (ThermoFisher Scientific, catalog# 61870-036, with Glutamax, no HEPES, no Na Pyruvate) supplemented with 10% FBS (ThermoFisher Scientific, catalog# 2060357) and IX Penicillin- Streptomycin (ThermoFisher Scientific, catalog# 15140122, 10000 U / ml, 100X). For degradation assays, 384 well plates are used. Alamar blue is purchased from ThermoFisher Scientific (A50101) and used according to manufacturer instructions. The Nano-Gio® HiBiT Lytic Detection System and Nano-Gio® HiBiT Blotting System are purchased from Promega (#N3050 and #N2410) and used according to manufacturer instructions.ARVN-210-PCT / / ARVN0210WO2To create the AsPC-1 HiBiT-KRAS G12D cell line, CRISPR-Cas9 is used to insert the HiBiT tag onto the N-terminus of one or more of the endogenous KRAS alleles. See Schwinn, M. K. et al. (2018) CRIS PR-mediated tagging of endogenous proteins with a luminescent peptide, ACS Chem. Biol. 13(2), 467-474. After knock-in of the tag, individual clones are isolated by single cell dilution and screened for HiBiT insertion by PCR. A clone is identified that contained the desired HiBiT-KRASG12D sequence at one allele while the remaining two KRAS G12D alleles are untagged. This clone is used in further studies.HiBiT degradation assays (G12C, G12D, G12V, WT)NCI-H1299 HiBiT-KRasWT cells, SW1573E6 HiBiT-KRasG12C, AsPC-1 HiBiT-KRasG12D cells, or SW620 HiBiT-KRasG12V cells are plated in the appropriate cell media at 9000, 12,000, or 15,000 cells / well depending on the cell line in 384 well plates (Corning #3770). Compounds of the present disclosure and positive controls are diluted in the appropriate cell media and applied to the plated cells resulting in a final concentration titration of 10 pM to 508 pM in 0.5% DMSO. Gambogic acid is used as a positive control for cytotoxicity and titrated from 10 pM to 78 nM. All assays are performed in triplicate. Cells are treated with compounds for 24 hr at 37 °C in an incubator containing 5% CO2. Following treatment, alamar blue is used to determine if any compounds led to a loss in cell viability after 24 hr. The 10X alamar blue reagent is added to a final concentration of IX as recommended by the manufacturer and cells are returned to the incubator for 4 hr. Plates are then allowed to equilibrate to RT and fluorescence is measured using a Perkin-Elmer EnVision. After completion of the fluorescence read, the liquid from each well is removed and the cells are washed with PBS. The Nano-Gio® HiBiT detection reagent is prepared according to the manufacturer’s instructions and added to each well after the PBS wash is removed. Following incubation at room temperature for 45 min, the luminescence is read using the ultra- sensitive luminescence aperture on the Envision instrument.Data analysisFluorescence values from the alamar blue treatment are normalized to the DMSO-only control for each compound titration. HiBiT luminescence is normalized to the DMSO-onlyARVN-210-PCT / / AR VN0210WO2control and the fractional HiBiT signal is plotted versus the log of the PROTAC concentration and fit to a 4-parameter dose-response model to obtain the concentration of the compound that leads to half maximal degradation (DC50) as well as the maximum degradation observed (Dmax, conventionally expressed as a percentage of control).Degradation data is presented below in Table 1-A through 15- A.Results. The compounds of the disclosure are made and tested for degradation of KRAS-G12D in AsPC-1 cells, KRAS G12V in SW620 cells, KRAS G12C in HiBiT. SW1573E6 cells and KR AS WT inHiBiT_NCI-H1299 cells, at 24h and the results are provided below in tables 1-A through 15-A below:DCso'. A, B, C. or D. According to the code, A represents a DC50 value <10 nM; B represents a DC50 value >10 nM and <50 nM; C represents a DC50 value >50 nM and <100 nM; D represents an DC50 value >100 nM.Dmax. A, B, C, or D. According to the code, A represents a Dmaxvalue >70%; B represents a Dmax value >50% and <70%; C represents a Dmaxvalue >25% and <50%; D represents a Dmaxvalue <25%.Table 1Compoun Degradation- Degradation- Degradation- Degradation- Degradation- Degradation- Degradation Degradation d KRasG12D- KRasG12D- KRasG12C- KRasG12C- KRasG12V- KRasG12V- _KRasWT- _KRasWT- numb DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) er1 B A A B B B A A2 B A A B A B A A3 A A A B A B A A4 A A A A A A A5 A A A C A B A A6 A A A B A B A A7 B A A B B C A A8 B A A B B A A A9 B A B C B C A A10 B A B A B A A A11 A B A C A B A A12 A A A B A B A A13 B A A B B A A A14 A A A B A B A A15 A A A B A B A A16 A A A B A B A A< < < o < < < < < < < < < < < < < < < < << < < qq < < < < < < < < < < < < < < <pq pq o PP < < < pq pq < pq < pq < pq < pq pq pq < pq< < < Q < pq < < < < < < < < pq < < < < < << m o < Q pq qq pq pq < qq qq O pq O < pq O qq < pq< < < < qq < qq < < < < < < < < pq < < < < < << < pq < Q < < < < < < < < pq < pq < < pq < < << < < < Q pq pq < < < < < < pq pq O < < pq pq < <oo O\ 1— 1 CM cc in o OO •—— - -H O\ o H CM cc in o CX)CM CM CM CM CM CM CM CM cc cc cc cn cc cc ccTable 2-ADegraComp dationDegradation- Degradation- Degradation- Degradation- Degradation- Degradation Degradation ound KRasKRasG12D KRasG12C KRasG12C KRasG12V KRasG12V _KRasWT _KRasWT numb G12DDmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) er DC50(nM)41 A A A C A B A A 42 A A A C A C A A 43 A A A c A B A A 44 A B A c A C A A 45 D D D D D B D 46 D C D D D47 B B B C B C A A48 D D D DTable 3- ACompDegradation- Degradation- Degradation- Degradation- Degradation- Degradation- Degradatio Degradation oundKRasG12D KRasG12D KRasG12C KRasG12C KRasG12V KRasG12V n_KRasW _KRasWT numbDC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) er49 A A A B A B A A 50 D C D D B C51 A B A C A C A A52 A A A B A B A A 53 A A A B A B A A 54 B B A A A B A A 55 A A A C A B A A 56 A A A B A B A A 57 D B B C C B B A 58 A B A C A C A A 59 B B A C B B A A 60 A A A B A B A A 61 A A A B A B A A62 D C D D DTable 4-ADegradatioDegrad atio Degradatio Degradatio Degradation Degradation- Degradation- Degradation Cmpd. n n n_KRasGl n_KRasWKRasG12 KRasG12C KRasG12V _KRasWT number KRasG12D KRasG12C 2V TD Dmax (%) Dmax (%) Dmax (%) DC50 (nM) DC50 (nM) DC50 (nM) DC50 (nM)Dmax (%)67 A A A B A B A A 68 A A A B A B A A 69 A B A C A C A A 70 A A A A A A A A 71 A A A A A A A A 72 A A A B A B A A 73 A A A B A B A A 74 B A A B A B A A75 A A A B A B A A76 D D C D C D B B 77 A A A A A B A A 78 D C B D B D B C 79 B A A B A B A A 80 B B A C B C A B 81 A A A B A B A A 82 A A A B A C A A 83 B A A A A A A A 84 A A A B A B A A 85 A A A A A B A A 86 A A A C A B A A 87 A A A B A B A A 88 B B A C A C A A 89 A A A C A B A A 90 C B C C B C A B 91 A A A A A B A A92 A A A B A B A ATable 5-ACompoun Degradation- Degradation- Degradation- Degradation- Degradation- Degradation- Degradation Degradation d KRasG12D KRasG12D KRasG12C KRasG12C KRasG12V KRasG12V _KRasWT _KRasWT numb DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) er93 B A A C B B A A 95 B A B B B B A A96 A A A B A B A A97 D D D D B D 98 D D D D B C 99 A A A C A B A A 100 D D D D B C101 A A A B A B A ATable 6-ADegradatioComp Degradatio Degradatio Degradation Degradatio Degradatio Degradatio n_KRasGl Degradationound n_KRasGl n_KRasGl _KRasG12 n_KRasGl n_KRasGl n_KRasW 2D _KRasWTnumbe 2D 2C C 2V 2V T DC50 DC50 (nM) r Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) Dmax (%) (nM)102 B A B B B B A A 103 C B B C B B A A 104 B B A C B C A A 105 C B B C B C A A 106 D C C D B D B A 107 C C D B D B C 108 D C B D C D B A 109 D D C D D B B110 D D D D DTable 7-ACom Degradation- Degradation- Degradation- Degradation- Degradation- Degradation- Degradation Degradation poun KRasG12D KRasG12D KRasG12C KRasG12C KRasG12V KRasG12V _KRasWT _KRasWTd DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%)number111 B C B D B D B CTable 8- ACompoun Degradation- Degradation- Degradation- Degradation- Degradation- Degradation- Degradation Degradation d KRasG12D KRasG12D KRasG12C KRasG12C KRasG12V KRasG12V _KRasWT _KRasWT numb DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) er112 A A A A A A A A 113 A A A B A B A A 114 A A A B A B A A115 C C C C C C B ATable 9-ACompoun Degradation- Degradation- Degradation- Degradation- Degradation- Degradation- Degradation Degradation d KRasG12D KRasG12D KRasG12C KRasG12C KRasG12V KRasG12V _KRasWT _KRasWT numb DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) er116 A A A A A A A A 117 A A A B A B A A 118 A A A B A B A A119 B A B C B C A ATable 10- ACompDegradatio Degradation Degradati oun Degradation- Degradation Degradation- Degradation_K Degradation- n_KRasGl _KRasG12 on_KRas d KRasG12D _KRasG12D KRasG12C RasG12V KRasWT2C V WT nu DC50 (nM) Dmax (%) Dmax (%) Dmax (%) DC50 (nM)DC50 (nM) DC50 (nM) Dmax (%) mber120 A A A A A A A A 121 B A A B A B A A 122 B C C D B D B A 123 D D C D D B D124 D D B D D B BTable 11-AComp Degradatio Degradatio Degradatio Degradatio Degradatio Degradation Degradation- Degradation- ound n_KRasGl n_KRasGl n_KRasGl n_KRasGl n_KRasGl _KRasWT- KRasG12C KRasWTnumb 2D 2D 2C 2V 2V HiBiT_NCI Dmax (%) DC50 (nM)er DC50 (nM) Dmax (%) DC50 (nM) DC50 (nM) Dmax (%) Dmax (%) 125 A A A B A B A A126 A A A B A B A ATable 12- ACompoun Degradation- Degradation- Degradation- Degradation- Degradation- Degradation- Degradation Degradation d KRasG12D KRasG12D KRasG12C KRasG12C KRasG12V KRasG12V _KRasWT _KRasWT numb DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) er127 A A A B A B A A 128 A A A B A C A A129 B B A B B B A ATable 13-ACompoun Degradation- Degradation- Degradation- Degradation- Degradation- Degradation- Degradation Degradation d KRasG12D KRasG12D KRasG12C KRasG12C KRasG12V KRasG12V _KRasWT _KRasWT numb DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) er131 A B A B A C A A 132 D C D D C C 133 D D D D D D134 C D D D DTable 14- ACom Degradation- Degradation- Degradation- Degradation- Degradation Degradation Degradation- Degradation- poun KRasG12D KRasG12D KRasG12V KRasG12V _KRasWT _KRasWT KRasG12C KRasG12C d No. DC 50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) DC50 (nM) Dmax (%) 135 A A A B A A A C 136 A B A C A A A C 137 B A B B A A B c138 B B B C A A B cTable 15- ADegradation Degradation Degradation Degradation Degradation Degradation Compound _KRasG12 _KRasG12 _KRasG12 _KRasG12 _KRasG12 _KRasG12 Number DDC50 D Dmax VDC50 V CDC50 C(nM) (%) (nM) Dmax (%) (nM) Dmax (%)139 A A A A A B140 A A A A A A141 A A A B142 A A A B143 A A A B144 B B B C145 B A B B146 A B A C147 A A A C148 A B A C149 B B A D150 B B A C151 A B A B152 A A A A A B153 A B A C A C10

[0212] Using the methods disclosed or similarly disclosed herein, the following Compounds of Formula Q-I were made and the degradation activities were measured:Table Q-lCompound StructureNo.r-oSr'HO. Av. A(A-.-~ iSche llj Xh_ A A A B A BQ-l me 2<5 kA,S 12 KRA (11)234 DC50 (M)nS12 KRA (11)D% ()maxS2 KRA (11VC D50 (M)nS12 KRA (1VD% ()maxS12 KRA (1CDC5M0 ()nSCA12 KR (1D% ()maxh Sitnessyr'QSche B C C DQ-2 me 2KVYV N';k'o c>r'^ '’x'Y"'v3? o!<v. IL F ’Xz^xz^- V-'-A y™NHT il. \ p! N--< )"" OWx.7orq>*f8fea 1I;Sche B B B CQ-3 me 2''N'x''''Ox^y"'X"'NX'" Y'" ’''I F QU, 1. £ k„> ’•'x. -A ^--NHY lr \ H 1 N-- / > CUv < Yo.--Q*»q3ta 1Y Exam c D D pie Q-4 YfY,-., „ L.. / / ’'I 9z-s A X A -A * W P> V " ".., N.VA.<■ 'sy' s-yN- 'O' / ; rfctsjQ-l.l 1=,.< L F <4t>sN O 0 lxX.L YvY-x**1'^2 •Y o Sc he B B B BQ-5:.;r)!f X |,1 ^N-{ AO me 2 ' VVV'SN '■ 'O'z‘ '■'X''"' N '"^""s A 'N' " Y" / >- -NHIL J. F ' ■' 1,, L, N. J Cl OLC? ’.-'QA’A.. o., N.nV T T. Sche Q-6 N-.. A N ( A / \ lA A 'A! ^ D Dme 3 LA. i; ' o0::-" A.„0\ X.»"*T»fas I'N ".-...C~'7 " N- Z~ A. / A "- Z, z... Sche Q-7 N-'V 'N / <" T v B B C CA. 1 A rz^.o-z A me 3 Z- Y vy / — A »,.*z -:• NHIj J )■■; N O 0 < I<y.z- ■.r_0O'—-' \ 'Y V'N \: J\ \ ‘‘e. P '"'N ' Sche Q-8 N P" N / -< i B C Dme 3 O'r'-QZ' N ' p O Exam Q-9 s As V-NH B B B C pie r^ Q-1,2HOY~i.- \ / i Is >< zT1Y civ”” / YV\0o 'C> n / / f-'1 Z< 1 Sche D DQ-10 V, A-Z Dz'K> S, \ ' me 3 Z T" 'N „.. ZZ!• 1 J O6* V%Oz\ / <\ v^labs y '.j. > 1 ' KZX-N ’" Z Sche D DQ-l l Z / . V. zK ( \CSme 3. A. A A., Z-K / \ z° z|f 7 VN° 0x><>''' " TSche D DQ-12 me 3W)' S> Z■ '--•■•• z*~x X* &■ - 0 H» 'VN^Or Lj. $ >?r-q%I'--7w&.ri I s..•-- •N / ~5„ Sche Q- 3 4 > A D D1 me 3A, <■ r'r ' « _jt V safes O - / (X T 'N' '°' 0-"' ° \ 2'\*yU 'V~N.,njt / rf 'l / s.. *''' Sche N’ J ’<■■' ~ JQ- 4 > o D D1 me 2N^'Y^'N (.-s Ax Ax K,-K. ZT’\ N: ■. 'M ass£ \ j0 °%.-NoA / T'**’**T*st>y:c, Sche C D DQ-15N -...-, V*.k N X ( " V \ ~Zme 2.-x X A- A X, C~\! i i,-■ N"a‘W'f'■^.. X XpHCK,.. Q9 Z T'nZ X;■Vjis.5 # \.dSche " M"' ZX DQ-16 1. x" K Ci c c me 2N.._ < >--x Xx X- X i ''■3tosH CKS, N.S,. OO 'f' Tn&. X Jr'9........ / _ N ' ”■■W*“T»bs j / / Exam N '..->. \ c D D pie Q-17 X Z-N Ci*r v T --? Q-1.3 JOx X K. / > \a<5* N~~ / f''' 'z' 'X ’fcZ "'c' -••'-"*•ML J \.. J>51-1.-. XMO. Sche D DQ-18 TO ZXl'TXr^ me 2 / T " ' VH aL \ / ('... oo(.X / \ H“...1X" "n " B t- a\ \ (Q>, _^ ' '" ■zz »,6L ci(^. Sche Q-19 '\ Z~' A A A B! i me 2 A4 Q" X.^X i07'zQ \>V / XO. r J'N"N ''N Sche Q 20 HO D D- me 2 i::..? T oS| \ k A A >-»WHX., AF’ | J V< >=o.- t v«w>: z''~'~'‘,<ZN*"'!N V-. / A>•~~ / Sche A " N" "1,Q-21 N'- Y"' 'N t ’ Cl A A B Bme 2 HO Jx A J-k C \3i5SN •■•••■- 'V N 'O’ •>-*■"'■A < j.-'xF

[0213] The disclosed subject matter is not to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[0214] All references (e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) is specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.

Claims

CLAIMS1. A compound having the chemical structure:PTM-L-ULMcomprising (i) a Kirsten Rat Sarcoma (KRAS) protein targeting moiety (PTM) comprising an oxa-6-azaspiro[3.5]nonane moiety; (ii) a linker (L) comprising a -O-CH2- (cyclopropyl)methyl-heterocycloalkylene moiety; and (iii) a Cereblon E3 ubiquitin ligase targeting moiety (ULM), wherein the compound is a compound of Formula I:R,D ) IJ R3in free or salt form, wherein:X is =C(Ra)-, -C(Ra)(Rb)-, or =N-;Y is -N-, -C= or -C(Ra)-;Each of Raand Rbis independently H or C1-4alkyl (e.g., methyl) or Rais R4;Each of R3 and R4 is independently H, Ci-4alkyl (e.g., methyl), halo (e.g. fluoro or chloro), -OH or Ci-4alkoxy (e.g., methoxy);Moiety A is a 4-12 membered heterocycloalkylene and moiety B and C are independently a bond, Ci-4alkylene (e.g., methylene), -OC(O)-, -C(O)-Ci-4alkylene- (e.g., -C(O)CH2-), -Ci- 4alkylene-C(O)- (e.g., -CH2-C(O)-), -O- or a 4-12 membered heterocycloalkylene (e.g., piperidinylene. piperazinylene, 7-azaspiro[3.5]nonanylene, 2,7-diazaspiro[3.5]nonanylene, 2-azaspiro[3.3]heptanylene, 3,9-diazaspiro[5,5]undecanylene, 2-oxa-5,8-diazispiro[3.5]nonanylene, 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 hexahydropyrrolo[3,4-c]pyrrolylene), wherein each of moieties A, B and C is independently optionally substituted with one or more halo (e.g. fluoro or chloro). Ci-4alkyl (e.g., methyl), hydroxy, =0. or Ci-4alkoxy (e.g.. methoxy);Moiety D is:R5wherein each of Rs, Re and R? is independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), C2-4alkynyl (e.g.. ethynyl), -0C(0)0Ci-4alkyl (e.g., -0C(0)0CH3 or -OC(O)OCH2CH3) or -N(Ra)(Rb), wherein each of Raand Rb is independently H or Ci-4alkyl (e.g., methyl);ULM is selected from:ULM-8ULM-11 ULM-9' wherein:Rs is H, halo (e.g., chloro or fluoro, or Ci-4alkyl (e.g., methyl);R9 is H, halo (e.g., chloro or fluoro) or Ci-4alkoxy (e.g., methoxy or ethoxy); R9X is halo (e.g., chloro or fluoro);Rio is H, halo (e.g., chloro) or Ci-4alkyl (e.g., methyl);R11 is H or Ci-4alkyl (e.g., methyl);E is a bond, N(Ra) or -C(O)N(Ra)-;Each of Qi, Q3 and Q10 is independently C(O) or C(Ra)(Rb);Q2is N(Ra) or C(Ra)(Rb);Q11 is -O-;R14 is H or Ci-4alkyl (e.g., methyl);Ris is H or halo (e.g., fluoro);Each of Raand Rbis independently H or C1-4alkyl (e.g., methyl),Provided that:a) when moiety A is an optionally substituted spiro-heterocycloalkylene and B is a bond or a methylene, then C is not an unsubstituted piperazinylene; orb) when moiety A is an optionally substituted spiro-heterocycloalkylene, B is a bond or a methylene and C is an unsubstituted piperazinylene, then R9 of ULM-1 is not H (e.g., R9 is e.g., halo); Rs and R9 of ULM-2 are not both fluoro; and Rn of ULM-3 is not H (e.g., Rn of ULM-3 is halo); andc) when moiety A is a piperidinylene optionally substituted with a fluoro or a methyl at the 4-position, B is a methylene, and C is an unsubstituted piperazinylene, then:R9 of ULM-1 is not H (e.g., R9 is e.g., halo) or Qi of ULM-1 is not C(Ra)(Rb) wherein Raand Rb are both H;Rs and R9 of ULM-2 are not both fluoro; andRn of ULM-3 is not H (e.g.. Rn of ULM-3 is halo);d) when A is unsubstituted morpholino, B is a methylene, and C is an unsubstituted piperazinylene, then Rs and R9 of ULM-2 are not both fluoro.

2. The compound according to claims 1 or 2, wherein the compound is a compound of Formula 1(A), 1(B), or 1(C):Formula 1(A)OFormula 1(B)in free or salt form.

3. The compound according to any of claims 1-2, wherein the compound is a compound of Formula 1(A)- 1:Formula 1(A)- 1in free or salt form.

4. The compound according to any of claims 1-2, wherein the compound is a compound of Formula I(A)-2:Formula I(A)-2in free or salt form.

5. The compound according to any of claims 1-4, wherein moiety A is selected from:

6. The compound according to any of claims 1-5, wherein each of moiety B and moiety C is independently a bond, Ci-4alkylene (e.g., methylene), -OC(O)-, -C(O)-Ci-4alkylene (e.g., -C(O)CH3), -Ci-4alkylene-C(O)- (e.g., -CH2-C(O)-), -O- or a 4-12 membered heterocycloalkylene.

7. The compound according to any of claims 1-6, wherein B is a Ci-4alkylene (e.g., methylene).

8. The compound according to any of claims 1-7, wherein C is wherein C is a 4-12 membered optionally substituted heterocycloalkylene.

9. The compound according to any of claims 1-8, wherein C is selected from:.

010. The compound according to any of claims 1-9, wherein -A-B-C- is selected from theO11. The compound according to any of claims 1-10, wherein:R3 and R4 are independently H or halo (e.g. fluoro or chloro);D is Formula D-l:wherein R5 is H or hydroxy; Re is halo (e.g., fluoro or chloro); and R7 is Cwalkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).

12. The compound according to any of claims 1-11, wherein the ULM is selected from ULM-1, ULM-2, ULM-3, ULM-4, ULM-5, ULM-6, ULM-7, ULM-8, ULM-9, ULM-10 and ULM-11.

13. The compound according to any of claims 1-11, wherein the ULM is ULM-9 or ULM-9’.

14. The compound according to any of claims 1-11, wherein the ULM is ULM-10.

15. The compound according to any of claims 1-14, wherein the compound is selected from any of Compounds 1-151 of Tables 1-15 or Compound 152 or 153 of Table 16, in free or salt form.

16. A pharmaceutical composition comprising the compound according to any one of claims 1-15, in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable earner.

17. 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 1-15, in free or pharmaceutically acceptable salt form, or the pharmaceutical composition according to claim 16.

18. 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 1-15, in free or pharmaceutically acceptable salt form, or the pharmaceutical composition according to claim 16.

19. The method according to claim 17 or 18, wherein the KRAS-mediated disease or disorder is cancer.

20. The method according to claim 19. 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.

21. The method according to any one of claims 19 or 20, wherein the cancer is pancreatic cancer, colorectal cancer, or lung cancer.

22. The method according to any one of claims 19 or 20, wherein the cancer is non-small cell lung cancer, for example, non-squamous non-small cell lung cancer or non-squamous colorectal cancer.

23. The method according to any one of claims 19 or 20, wherein the cancer is pancreatic ductal adenocarcinoma.

24. 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 1-15, in free or salt form, or the pharmaceutical composition of claim 16, wherein the compound effectuates the degradation of the KRAS target protein.

25. A compound of formula Q-I(A)’:Jn \ Am \KA)in free or salt form, wherein:Each of Ri and R2 is independently H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g..methyl), or Ci-4alkoxy (e.g., methoxy), or Ri and R2 together with the carbon to which they are attached form a4-8 membered heterocycyl, where the heterocycyl is optionally substituted with one or more halo (e.g. fluoro or chloro) or Ci-4alkyl (e.g., methyl);Each of R3 and R4 is independently H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);Each of m and n is independently 0, 1 or 2;Moiety A is a 4-12 membered heterocycloalkylene (e.g., pyrrolidinylene, piperidinylene, piperazinylene, hexahydro- 1-H-pyrrolizinylene or 3,9- diazaspiro [5, 5 ] undec anylene);Moiety B is a bond, or Ci-4alkylene (e.g., methylene), wherein each carbon may be optionally replaced with O;Moiety C is:a bond;a 4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 3,9- diazaspiro [5,5] undecanylene, azetidinylene);a (heterocycloalkylene)-O-(heterocycloalkylene); ora (cycloalkylene)-O-(cycloalkylene),wherein each of moieties A, B and C is independently optionally substituted with one or more halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), Ci- 4alkoxy (e.g., methoxy), or CO;Moiety D is aryl optionally substituted with one or more hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl): andULM is selected from:Rs is H, OH, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g.. methyl) or Ci-4alkoxy (e.g., methoxy);R9 is H, OH, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy or ethoxy);R11 is H, OH, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or_Ci-4alkoxy (e.g., methoxy);Qi is C(0) or C(Ra)(Rb);Q2is N(Ra) or C(Ra)(Rb);Each of Raand Rn is independently H or Ci-4alkyl (e.g., methyl).

26. The compound of claim 25, wherein the compound is a compound of formula Q-I(A):Q-I(A)in free or salt form, wherein:Each of Ri and R2is independently H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy), or Ri and R2together with the carbon to which they are attached form a 4-8 membered heterocycyl. wherein the heterocycyl is optionally substituted one or more halo (e.g. fluoro or chloro) or Ci-4alkyl (e.g., methyl).Each of R3 and R4 is independently H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);Each of m and n is independently 0, 1 or 2;Moiety A is a 4-12 membered heterocycloalkylene (e.g., pyrrolidinylene, piperidinylene, piperazinylene, hexahydro- 1-H-pyrrolizinylene or 3,9-diazaspiro[5,5]undecanylene);Moiety B is a bond or Ci-4alkylene (e.g., methylene)), wherein each carbon may be optionally replaced with O;Moiety C is:a bond;4-12 membered heterocycloalkylene (e.g., piperazinylene. piperidinylene, 3.9- diazaspiro[5,5]undecanylene);(heterocycloalkylene)-O-(heterocycloalkylene);(cycloalkylene)-O-(cycloalkylene),wherein each of moieties A, B and C is independently optionally substituted with one or more halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), Ci-4alkoxy (e.g., methoxy) or CO;Moiety D is an aryl optionally substituted with one or more hydroxy, halo (e.g. fluoro or chloro). Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl);ULM is selected from:wherein:Rs is H, OH, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);R9 is H, OH, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);R11 is H, OH, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy (e.g., methoxy);Qi is C(O) or C(Ra)(Rb);Q2 is N(Ra) or C(Ra)(Rb); andEach of Raand Rb is independently H or Ci-4alkyl (e.g., methyl).

27. The compound according to claim 25 or 26, wherein the compound is selected from Compounds Q-l to Q-21 of Table Q-l, in free or salt form.

28. A pharmaceutical composition comprising the compound according to any one of claims 25-27, in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable carrier.

29. 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 25-27, in free or pharmaceutically acceptable salt form, or the pharmaceutical composition according to claim 28.

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