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 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-216-PCT / / ARVN0216WO2KIRSTEN RAT SARCOMA (KRAS) PROTAC COMPOUNDS AND USES THEREOFFIELD OF THE INVENTION

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

[0002] The Kirsten rat sarcoma (KRAS) gene is an oncogene encoding KRAS, which is a small GTPase signal transduction protein. Ras proteins associate with the plasma membrane, and when GTP-bound, act as “on” switches in the transduction of extracellular signals to intracellular response, thereby regulating processes such as cell division. Following GTPase-activating proteins (GAPs) catalyzed hydrolysis of the y-phosphate, KRAS is deactivated from downstream effector pathways. Studies have revealed that KRAS alleles are distributed non-uniformly across different cancer types. Numerous activating or gain-of-function mutations of the KRAS gene are known, and in fact, KRAS is the most frequently mutated gene in cancer. Gain-of-function KRAS mutations are found in approximately 30% of all human cancers, including, e.g., pancreatic cancer (>80%), colon cancer (approximately 40-50%), lung cancer (approximately 30-50%), non-small cell lung cancer, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, and breast cancer. These activating mutations impair the ability of KRAS to switch between active and inactive states. The most common mutations observed in cancer occur most frequently at four codons: 12, 13, 61 or 146. In particular, mutation on codon 12 accounted for 72.2% of the mutations in the four hotspots, followed by codon 13 (9.8%), 61 (14.8%) and 146 (3.2%). The glycine at codon 12 can be transformed into six possible different amino acids (A, C, D, R, S and V). These mutations change the balance between active, GTP-bound KRAS and inactive, GDP-bound KRAS by either reducing GTP hydrolysis or enhancing GDP exchange for a new GTP. Key roles for mutant KRAS have been established in initiation, 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 keyARVN-216-PCT / / ARVN0216WO2role 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 sproximity of an E3 ubiquitin ligase, which induces the poly-ubiquitination of such protein of interest on the lysine residues, marking it for degradation by the various proteasome.

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

[0005] Provided herein are novel 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. Such compounds include those having the chemical structure of Formula I:PTM-L-ULM (I)comprising (i) a Kirsten Rat Sarcoma (KRAS) protein targeting moiety (PTM); (ii) a linker (L) comprising a chemical structure -O-CH2-((geminal halocyclopropyl)methyl-(optionally substituted heterocycloalkylene)); and (iii) a Cereblon E3 ubiquitin ligase targeting moiety (ULM), in free or salt form (Compound of Formula I). The PTM of Formula I may be a KRAS protein targeting moiety, and in certain embodiment, the KRAS PTM comprises a chemical structure 6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl.

[0006] These PROTAC compounds, pharmaceutical compositions comprising these compounds, methods for their preparation, and methods of treating KRAS related conditions, including methods of treating abnormal cellular proliferation diseases or disorders such as cancer, using the disclosed compounds, are also included.ARVN-216-PCT / / ARVN0216WO2

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

[0008] In a further embodiment of the first aspect, the compounds of the present disclosure is a compound of Formula 1(A)’:in free or salt form, wherein:Ri and R2 are independently halo (e.g., fluoro);R3 is H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);Rzis H or Ci-4alkyl (e.g., methyl);Moiety A is a 4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 2-azabicyclo[2.2. l]heptanylene or 3,9-diazaspiro[5,5]undecanylene, hexahydropyrrolo [3,4-c] pyrrolylene);Each of moiety B and moiety C is independently a bond, C(O), S(O)2, O, Ci-4alkylene (e.g., methylene, ethylene or propylene for example prop-2-ylene), C3- ecycloalkylene (e.g., cyclopropylene) or a 4-12 membered heterocycloalkylene (e.g., piperazinylene, piperidinylene, diazepinylene or 2,7- diazaspir 0 [3.5 ] nonanylene);wherein each of moieties A, B and C is independently optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or -OCi-4alkyl (e.g., methoxy);Moiety D is an aryl or a 6-12 membered heterocycloalkyl, each optionally substituted with one or more hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), Ci-4haloalkyl (e.g., difluoromethyl), -OCi-4alkyl (e.g., methoxyl orARVN-216-PCT / / ARVN0216WO2ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl); andULM is selected from:ARVN-216-PCT / / ARVN0216WO2wherein:R4a is H or Ci-4alkyl (e.g., methyl);R4bis H or halo (e.g., fluoro):Rs is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;R9 is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy (e.g., methoxy);Riox is Ci-4alkyl (e.g., methyl);Qi, Q10 and Qu are independently C(O) or C(Ra)(Rb);Raand Rb are independently H or Ci-4alkyl (e.g., methyl);R11 is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy;Ri3x is Ci-4alkyl (e.g., methyl);Q12 is O;R14 is H or Ci-4alkyl (e.g., methyl);R15 is H, halo (e.g., fluoro). Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;Ri6 and Ris are independently H or Ci-4alkyl (e.g., methyl); or-A-B-C together with the ULM forms any of the following structure:Formula JorFormula Kwherein R17 is H, halo (e.g., fluoro), Ci-ralkyl (e.g., methyl), OH, or Ci-4alkoxy.

[0009] In still another further embodiment of the first aspect, the compound of the present disclosure is a compound of Formula 1(A):ARVN-216-PCT / / ARVN0216WO2in free or salt form, wherein:Ri and R2 are independently halo (e.g. fluoro);R3 is H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);Moiety A is a 4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 3.9-diazaspiro[5,5]undecanylene, or hexahydropyrrolo[3,4-c]pyrrolylene);Each of moiety B and moiety C is independently a bond, Ci-4alkylene (e.g., methylene), or a 4-12 membered heterocycloalkylene (e.g., piperazinylene, piperidinylene, or 2,7-diazaspiro[3.5]nonanylene);wherein each of moieties A, B and C is independently optionally substituted with one or more halo, hydroxy, Ci-4alkyl (e.g., methyl) or OCi-4alkyl (e.g., methoxy);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), Ci-4haloalkyl (e.g., difluoromethyl), - OCi-4alkyl (e.g., methoxyl or ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl); andULM is selected from:ARVN-216-PCT / / ARVN0216WO2ULM-12andULM-13wherein:Rs is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;R9 is H, halo (e.g.. chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;Qi and Q10 are independently C(O) or C(Ra)(Rb);Raand Rb are H;Q12 is O;R14 is H or Ci-4alkyl (e.g., methyl);R15 is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy; or Moieties -A-B-C together with the ULM forms any of the following structure:Formula J Formula K wherein R17 is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy.

[0010] 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 earner (Composition I et seq.).ARVN-216-PCT / / ARVN0216WO2

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

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

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

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

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

[0016] In the eighth aspect, the disclosure provides any of the compounds disclosed herein (any of Formula I et seq.), in free or pharmaceutically acceptable salt form, or any of the pharmaceutical compositions disclosed herein (any of Composition I et seq.) for the manufacture of a medicament or for use in the treatment or prophylaxis of a KRAS mediated disorder (e.g., any of Compound I et seq. or any of composition I et seq. for use in any of Method I or I-A et seq. or Medicament I or I-A et seq.).ARVN-216-PCT / / ARVN0216WO2

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

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

[0019] In still another aspect, the disclosure provides a compound of Formula Q-I:PTM-L-ULM (Q-I)comprising (i) a Kirsten Rat Sarcoma (KRAS) protein targeting moiety (PTM) comprising a chemical structure 6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl; (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), in free or salt form (Compound of Formula Q-I).

[0020] In a further embodiment, the compounds of Formula Q-I is a compound of Formula Q-I(A)’:Q-I(A)’in free or salt form, wherein:R3 is H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);Moiety A is a 4-12 membered heterocycloalkylene (e.g., a 6-membered heterocycloalkylene such as a piperidinylene or piperazinylene, or an 8-11 membered heterocycloalkylene such as a 3,9-diazaspiro[5,5]undecanylene);ARVN-216-PCT / / ARVN0216WO2Each of moiety B and moiety C is independently a bond, Ci-4alkylene (e.g., methylene), or a 4-12 membered heterocycloalkylene (e.g., piperazinylene, piperidinylene or 2,7-diazaspiro [3.5 ] nonany lene):wherein each of moieties A, B and C is independently optionally substituted with one or more, hydroxy, halo, Ci-4alkyl (e.g., methyl) or -OCi-4alkyl (e.g., methoxy);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) Ci-4haloalkyl (e.g., difluoromethyl), -OCi-4alkyl (e.g., methoxyl or ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl); and ULM is:wherein:Rs is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;R₉ is H, halo (e.g., chloro or fluoro), OH, C₁₋₄alkyl or C₁₋₄alkoxy (e.g., methoxy or ethoxy);Qi and Q10 are independently C(Ra)(Rb) or C=O;Riox is H or Ci-4alkyl (e.g., methyl);R14 is H or Ci-4alkyl (e.g., methyl);R15 is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy; andRaand Rb are independently H or Ci-4alkyl (e.g., methyl).

[0021] In a further embodiment, the compounds of the disclosure is a compound of Formula Q-I(A):ARVN-216-PCT / / ARVN0216WO2Q-I(A)in free or salt form, wherein:R3 is H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);Moiety A is a 4-12 membered heterocycloalkylene (e.g., piperidinylene or piperazinylene);Each of moiety B and moiety C is independently a bond. Ci-4alkylene (e.g., methylene), or a 4-12 membered heterocycloalkylene (e.g., piperazinylene, piperidinylene or 2,7-diazaspir 0 [3.5] nonanylene);wherein each of moieties A, B and C is independently optionally substituted with one or more, hydroxy, halo, Ci-4alkyl (e.g., methyl) or -OCi-4alkyl (e.g., methoxy);Moiety D is an aryl optionally substituted with one or more, hydroxy, halo (e.g. fluoro or chloro), C₁₋₄alkyl (e.g., methyl or ethyl) Ci-4haloalkyl (e.g., difluoromethyl), -OCi-4alkyl (e.g., methoxyl or ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl); and ULM is:wherein:R₈ is H, halo (e.g., chloro or fluoro), C₁₋₄alkyl (e.g., methyl), OH, or C₁₋₄alkoxy;R₉ is H, halo (e.g., chloro or fluoro), OH, C₁₋₄alkyl or C₁₋₄alkoxy (e.g., methoxy or ethoxy);Q₁ is C(Rₐ)(Rb) or C=O; andRₐ and Rbare H.

[0022] In another 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.).

[0023] In still another 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 theARVN-216-PCT / / ARVN0216WO2subject 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.).

[0024] In yet another 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.).

[0025] In another aspect, the disclosure provides methods of degrading a 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) wherein the compound effectuates the degradation of the KRAS target protein.

[0026] In another 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).

[0027] In another 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).

[0028] In another 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 el 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 Q-I-A et seq.).ARVN-216-PCT / / ARVN0216WO2

[0029] In another 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 et seq. or Medicament Q-I et seq.).

[0030] In another aspect, the disclosure also provides for a pharmaceutical combination, e.g.. a kit, comprising a) a first agent which is a compound of the disclosure as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent. The kit can comprise instructions for its administration.DETAILED DESCRIPTION

[0031] Provided herein are Kirsten Rat Sarcoma (KRAS) PROTAC compounds (e.g., compounds of Formula (I) or any disclosed herein) that target and degrade Kras, including mutant Kras and non-mutant wild-type KRAS, and are thus useful as a pharmaceutical composition and / or for the treatment of KRas-related diseases or disorders, such as abnormal cellular proliferation, including cancer.

[0032] 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.

[0033] 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.

[0034] The term “compound,” as used herein, unless otherwise indicated, refers to any specific chemical compound or genus of compounds disclosed herein and includes racemates, tautomers, regioisomers, geometric isomers, and where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers) thereof, as well as salts orARVN-216-PCT / / ARVN0216WO2pharmaceutically 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 et seq.). For example, when a compound of the invention contains a hydroxy or carboxy substituent, these substituents may form physiologically hydrolysable and acceptable esters. As used herein, “physiologically hydrolysable and acceptable ester” means esters of the compounds of the invention which are hydrolysable under physiological conditions to yield acids (in the case of compounds of the invention which have hydroxy substituents) or alcohols (in the case of compounds of the invention which have carboxy substituents) which are themselves physiologically tolerable at doses to be administered. As will be appreciated, the term thus embraces conventional pharmaceutical prodrug forms. The term also refers to any specific chemical compound in which one or more atoms have been replaced with one or more different isotopes of the same element (e.g., substitution of a hydrogen for a deuterium). It is noted that in describing the present compounds, numerous substituents and variables associated with same, among others, are described.

[0035] 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.

[0036] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means oneARVN-216-PCT / / ARVN0216WO2element 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] As used herein, the terms “effective amount.” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result or therapeutic benefit. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of aARVN-216-PCT / / ARVN0216WO2biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0043] 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.

[0044] 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.

[0045] As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound useful within the disclosure with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0046] As used herein, the term “pharmaceutically acceptable earner” means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler,ARVN-216-PCT / / ARVN0216WO2stabilizer, 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 corn 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.

[0047] 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.

[0048] As used herein, the term “alkyl,” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., Ci-6 alkyl means an alkyl having one to six carbon atoms) and includes straight and branched chains.ARVN-216-PCT / / ARVN0216WO2

[0049] 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.

[0050] 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.

[0051] The term “aryl” means any carbocyclic aromatic ring system, i.e.. any aromatic ring system comprising only carbon atoms as ring atoms. This includes 6-membered monocyclic aryl ring systems and 9-membered or 10-membered fused bicyclic aryl ring systems, and larger fused ring systems, as long as such ring systems comprise at least one 6-membered aromatic carbocyclic ring (i.e., a benzene ring) within the fused ring system, and as long as no ring-atoms are heteroatoms. Thus, the term aryl includes, but is not limited to, phenyl, naphthyl. The term aryl also includes tetrahydronaphthyl.

[0052] The term “arylene” means a non-terminal, e.g., bivalent aromatic ring system.

[0053] 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.

[0054] 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.

[0055] 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 atARVN-216-PCT / / ARVN0216WO2least one ring containing 0, 1, or 2 N, O, or S atoms. The term “heterocycloalkyl” includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams).

[0056] A x-membered heterocycloalkyl ring is a heterocycloalkyl group having x number of ring atoms and may be monocyclic or multicyclic (whether fused, spiro or bridged), wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 4-12 membered ring heterocycloalkyls include piperidinyl, piperazinyl, morpholinyl but also 7-azaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 3,9-diazaspiro[5,5]undecanyl, 2-oxa-5,8-diazispiro[3.5]nonanyl, hexahydropyrrolo[3,4-c]pyrrolyl, 2,8-diazaspiro[4.5]decanyl, l-oxa-4,9-diazaspiro[5.5]undecanyl, 2,6-diazaspiro[3.3]heptanyl, pyrrolidinyl, azetidinyl, 2,5-diazabicyclo[2.2.1]heptanyl. Heterocycloalkyl ring may include tetrahydroquinolinyl, for example, 1,2, 3,4- tetrahydroquinolinyl.

[0057] 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.

[0058] 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).

[0059] The term “-O-CH2-((geminal halocyclopropyl)methyl-(optionally substituted heterocycloalkylene)” means a bivalent moiety having the following general structure: -O-CH2-((2,2-dihalo-l -[optionally substituted heterocycloalk-l-yl]methyl)cyclopropyl)), in some embodiments, the heterocycloalk-l-yl comprises a nitrogen hetero atom, wherein the nitrogen hetero atom is directly linked to the cyclopropylmethyl, for example, having the following structure:ARVN-216-PCT / / ARVN0216WO2wherein are Ri and R2 are halo and moiety A is an optionally substituted heterocycloalkylene.

[0060] In some embodiments, the PTM of the present disclosure are numbered as follows:

[0061] 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 with all variable orientation at each stereocenter are intended. For example, the exemplary Structure B below:ARVN-216-PCT / / ARVN0216WO2comprising two stereocenters with the “OR3” designation on each stereocenter is intended to cover compounds with synched configurations such as any one of the following configurations:Likewise, the “OR2” designation at the carbon atom carrying the cyclopropyl and the “OR1” designations at the tetrahydronaphthyl ring of Structure B are intended to encompass the compounds with any one of the following orientations:ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2or

[0062] In the exemplary Structure Q-A below:ARVN-216-PCT / / ARVN0216WO2Structure Q-A,comprising two stereocenters wherein the “OR2” and “OR1” designation on each stereocenter is intended to cover compounds with any one of the following configurations:ARVN-216-PCT / / ARVN0216WO2or

[0063] When a chemical structure comprises a stereocenter that is marked with the term “abs”, it is intended to cover a structure with the absolute configuration at said stereocenter as drawn.Compounds of the present disclosure

[0064] Provided herein are Kirsten Rat Sarcoma (KRAS) PROTAC compounds for targeting KRAS mutant and non-mutant wild-type KRAS. Such compounds include those having the chemical structure of Formula IPTM-L-ULM (I)comprising (i) a Kirsten Rat Sarcoma (KRAS) protein targeting moiety (PTM); (ii) a linker (L) comprising a chemical structure -O-CH2-((geminal halocyclopropyl)methyl-(optionally substituted heterocycloalkylene)); and (iii) a Cereblon E3 ubiquitin ligase targeting moiety (ULM), in free or salt form (Compound of Formula I or “Formula I”). Exemplary compounds of Formula (I) include the following:1.1 Compound of Formula I, wherein the PTM targets or binds to KRAS protein, e.g., KRAS protein comprising a mutation compared to the wild-type (KRAS mutant protein), e.g, selected from G12A, G12C, G12D, G12R, G12V or a combination thereof.1.2 Compound of Formula I or 1.1, wherein the PTM targets or binds to KRAS mutantprotein.ARVN-216-PCT / / ARVN0216WO21.3 Compound of Formula I or any of 1.1 or 1.2, wherein the PTM targets or binds to KRAS G12A.1.4 Compound of Formula I or any of 1.1 or 1.2, wherein the PTM targets or binds to KRAS G12C.1.5 Compound of Formula I or any of 1.1 or 1.2, wherein the PTM targets or binds to KRAS G12R.1.6 Compound of Formula I or any of 1.1 -1.2, wherein the PTM targets or binds to KRAS G12D.1.7 Compound of Formula I or any of 1.1-1.2, wherein the PTM targets or binds to KRAS G12V.1.8 Compound of Formula I, wherein the PTM targets or binds to a non-mutant wild-type KRAS.1.9 Compound of Formula I or any of 1.1-1.8, wherein the PTM comprises a chemical structure 6.10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca- 1(19), 11,13, 15, 17-pentaen- 17-yl],1.10 Compound of Formula I or any of 1.1 -1.9, wherein the compound is a compound of Formula 1(A):ULMKA)in free or salt form, wherein:Ri and R2 are independently halo (e.g. fluoro);R3 is H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);Moiety A is a 4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 3,9-diazaspiro[5,5]undecanylene, or hexahydropyrrolo[3,4-c]pyrrolylene);ARVN-216-PCT / / ARVN0216WO2Each of moiety B and moiety C is independently a bond, Ci-4alkylene (e.g., methylene), or a 4-12 membered heterocycloalkylene (e.g., piperazinylene, piperidinylene or 2,7-diazaspiro [3.5 ] nonany lene);wherein each of moieties A, B and C is independently optionally substituted with one or more halo, hydroxy, Ci-4alkyl (e.g., methyl) or OCi-4alkyl (e.g., methoxy);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), Ci-4haloalkyl (e.g., difluoromethyl), -OCi-4alkyl (e.g., methoxyl or ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl); and ULM is selected from:ULM-12andULM-13 wherein:R₈ is H, halo (e.g., chloro or fluoro), C₁₋₄alkyl (e.g., methyl), OH, or C₁₋₄alkoxy;R9 is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;Qi and Q10 are independently C(O) or C(Ra)(Rb);Raand Rb are H;Q12 is O;R14 is H or Ci-4alkyl (e.g., methyl);R15 is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy; or Moieties -A-B-C together with the ULM forms any of the following structure:ARVN-216-PCT / / ARVN0216WO2Formula JorFormula Kwherein R17 is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy.1.11 Formula 1.10, wherein Ri and R2 are both halo (e.g. fluoro).1.12 Formula 1.10 or 1.11, wherein Ri and R2 are both fluoro.1.13 Formula I or any of formulae 1.10-1.12, wherein R3 is H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro).1.14 Formula I or any of formulae 1.10-1.13, wherein R3 is H or halo (fluoro or chloro).1.15 Formula I or any of formulae 1.10-1.13, wherein R3 is H.1.16 Formula I or any of formulae 1.10-1.13, wherein R3 is Ci-4alkyl (e.g., methyl).1.17 Formula I or any of formulae 1.10-1.13, wherein R3 is methyl.1.18 Formula I or any of formulae 1.10-1.13, wherein R3 is halo (e.g. fluoro or chloro).1.19 Formula I or any of formulae 1.10-1.18, wherein R3 is fluoro.1.20 Formula I or any of formulae 1.10-1.18, wherein R3 is chloro1.21 Formula I or any of formulae 1.10-1.20, wherein moiety D is aryl optionally substituted with hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).1.22 Formula I or any of formulae 1.10-1.20, wherein moiety D is Formula D-l:R4ReD-1wherein:ARVN-216-PCT / / ARVN0216WO2each of R4, Rs and Re is independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) Ci-4haloalkyl (e.g., difluoromethyl), -OCi-4alkyl (e.g., methoxyl or ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl).1.23 Formula I or any of formulae 1.10-1.22, wherein moiety D-l is Formula D-l(a) having the following structure:D-1(a)1.24 Formula I or any of formulae 1.10-1.23, wherein each of R4, Rs and Re is independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).1.25 Formula I or any of formulae 1.10-1.24, wherein R4is H.1.26 Formula I or any of the foregoing formulae 1.10-1.24, wherein R4is hydroxy.1.27 Formula I or any of formulae 1.10-1.26, wherein each of Rs and Re is independently H, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).1.28 Formula I or any of formulae 1.10-1.27, wherein each of Rs and Re is independently H.1.29 Formula I or any of formulae 1.10-1.28, wherein each of Rs and Re is independently halo (e.g. fluoro or chloro).1.30 Formula I or any of formulae 1.10-1.29, wherein Re is halo (e.g. fluoro or chloro).1.31 Formula I or any of formulae 1.10-1.29, wherein Re fluoro.1.32 Formula I or any of formulae 1.10-1.29, wherein Re chloro.1.33 Formula I or any of formulae 1.10-1.32, wherein Rs is Ci-4alkyl (e.g., methyl or ethyl).1.34 Formula I or any of formulae 1.10-1.33, wherein Rs is ethyl.1.35 Formula I or any of formulae 1.10-1.32, wherein Rs is C2-4alkynyl (e.g., ethynyl).1.36 Formula I or any of formulae 1.10-1.32, wherein Rs is ethynyl.1.37 Formula I or any of formulae 1.10-1.32, wherein Rs is ethynyl and Re is halo (e.g. fluoro or chloro)ARVN-216-PCT / / ARVN0216WO21.38 Formula I or any of formulae 1.10-1.32, wherein Rs is ethyl and Re is halo (e.g. fluoro or chloro).1.39 Formula I or any of formulae 1.10-1.38, wherein moiety A is a 4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 3,9- diazaspiro[5,5]undecanylene or hexahydropyrrolo[3,4-c]pyrrolylene).1.40 Formula I or any of formulae 1.10-1.39. wherein moiety A is a 4-11 membered heterocycloalkylene (e.g., mono-heterocyclic, fused-heterocyclic, spiro-heterocyclic). 1.41 Formula I or any of formulae 1.10-1.39, wherein moiety A is a 4-11 membered heterocycloalkylene (e.g., 5-6 membered mono-heterocyclic, 8-10 membered fused- multicyclic heterocyclic or 7-11 membered multicyclic spiro-heterocyclic).1.42 Formula I or any of formulae 1.10-1.39, wherein moiety A is a 6-11 membered heterocycloalkylene.1.43 Formula I or any of formulae 1.10-1.39, wherein moiety A is a 6-membered mono-cyclic heterocycloalkylene (e.g.. piperidinylene or piperazinylene).1.44 Formula I or any of formulae 1.10-1.39, wherein moiety A is a piperidinylene.1.45 Formula I or any of formulae 1.10-1.39, wherein moiety A is an 8-membered heterocycloakylene (e.g., hexahydropyrrolo[3,4-c]pyrrolylene).1.46 Formula I or any of formulae 1.10-1.39, wherein moiety A is an 11 -membered heterocycloalkylene (e.g.. 3,9-diazaspiro[5,5]undecanylene).1.47 Formula I or any of formulae 1.10-1.46, wherein A is optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or -OCi-4alkyl (e.g., methoxy).1.48 Formula I or any of formulae 1.10-1.46, wherein A is substituted with one or more halo or Ci-4alkyl (e.g., methyl).1.49 Formula I or any of formulae 1.10-1.46, wherein A is substituted with one or more halo.1.50 Formula I or any of formulae 1.10-1.46, wherein A is unsubstituted.1.51 Formula I or any of formulae 1.10-1.51, wherein A is selected from any of the following:1.52 Formula I or any of formulae 1.10-1.51, wherein A is:ARVN-216-PCT / / ARVN0216WO21.53 Formula I or any of formulae 1.10-1.51, wherein A is:1.54 Formula I or any of formulae 1.10-1.51, wherein A is:1.55 Formula I or any of formulae 1.10-1.54, wherein each of moiety B and moiety C is independently a bond, Ci-4alkylene (e.g., methylene) or a 4-12 membered heterocycloalkylene.1.56 Formula I or any of formulae 1.10-1.55, wherein each of moiety B and moiety C is independently a bond.1.57 Formula I or any of formulae 1.10-1.55, wherein moiety B is a bond.1.58 Formula I or any of formulae 1.10-1.55, wherein each of moiety B and moiety C are both a bond.1.59 Formula I or any of formulae 1.10-1.55, wherein moiety B is Ci-4alkylene (e.g., methylene).1.60 Formula I or any of formulae 1.10-1.55, wherein moiety B is methylene.1.61 Formula I or any of formulae 1.10-1.60, wherein moiety C is a 4-12 membered heterocycloalkylene (e.g., piperazinylene, piperidinylene, or 2,7- diazaspiro [3.5 ] nonanylene).1.62 Formula I or any of formulae 1.10-1.61, wherein moiety C is mono-heterocyclic, fused- heterocyclic or spiro-heterocyclic.1.63 Formula I or any of formulae 1.10-1.62, wherein moiety C is a 4-11 membered heterocycloalkylene (e.g.. 5-6 membered mono-heterocycloalkylene, 8-10 membered fused-multicyclic heterocycloalkylene or 7-11 membered spiro-heterocycloalkylene).ARVN-216-PCT / / ARVN0216WO21.64 Formula I or any of formulae 1.10-1.63, wherein moiety C is a 6-membered mono- heterocyclylene (e.g., piperazinylene or piperidinylene).1.65 Formula I or any of formulae 1.10-1.63, wherein moiety C is a piperazinylene.1.66 Formula I or any of formulae 1.10-1.63, wherein moiety C is a 9-membered multicyclic spiro- heterocycloalkylene.1.67 Formula I or any of formulae 1.101.63 or 1.66, wherein moiety C is 2,7- diazaspiro[3.5]nonanylene.1.68 Formula I or any of formulae 1.10-1.67, wherein moiety C is optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or -OCi-4alkyl (e.g., methoxy).1.69 Formula I or any of formulae 1.10-1.68, wherein moiety C is unsubstituted.1.70 Formula I or any of formulae 1.10-1.68, wherein moiety C is substituted with one or more Ci-4alkyl (e.g., methyl).1.71 Formula I or any of formulae 1.10-1.68, wherein moiety C is substituted with a methyl.1.72 Formula I or any of formulae 1.10-1.71, wherein moiety C is a 4-12 membered heterocycloalkylene selected from:1.73 Formula I or any of formulae 1.10-1.55, wherein moiety C is a bond.1.74 Formula I or any of the foregoing formulae, wherein the compound is a compound of Formula 1(A)- 1:ULMFormula 1(A)- 1ARVN-216-PCT / / ARVN0216WO21.75 Formula I or any of the foregoing formulae, wherein the compound is a compound of Formula 1(A)- 1(a):ULMFormula 1(A)- 1(a)1.76 Formula I or any of the foregoing formulae, wherein the compound is a compound of Formula 1(A)- 1(b):Formula 1(A)- 1(b)1.77 Formula I or any of formulae 1.74- 1.76, wherein:Ri and R2 are both halo (e.g., fluoro);R3 is H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);D is Formula D-l, wherein R4 is H or hydroxy; Re is H or halo (e.g., fluoro or chloro); and R5 is H, Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).1.78 Formula I or any of formulae 1.74-1.77, wherein R3 is H or halo (e.g. fluoro or chloro).1.79 Formula I or any of formulae 1.74-1.77, wherein R3 is H.1.80 Formula I or any of formulae 1.74-1.77, wherein R3 is halo (e.g. fluoro or chloro).1.81 Formula I or any of formulae 1.74-1.78, wherein R3 is fluoro.ARVN-216-PCT / / ARVN0216WO21.82 Formula I or any of formulae 1.74-1.78, wherein R3 is chloro.1.83 Formula I or any of formulae 1.74-1.82, wherein R4 is H.1.84 Formula I or any of formulae 1.74-1.82, wherein R4 is hydroxy.1.85 Formula I or any of formula 1.74-1.84, wherein Re is halo (e.g. fluoro or chloro).1.86 Formula I or any of formula 1.74-1.84, wherein Re fluoro.1.87 Formula I or any of formula 1.74-1.84, wherein Re chloro.1.88 Formula I or any of formula 1.74-1.87, wherein R5 is Ci-4alkyl (e.g., methyl or ethyl). 1.89 Formula I or any of formula 1.74-1.87, wherein R5 is ethyl.1.90 Formula I or any of formula 1.74-1.87, wherein Rs is C2-4alkynyl (e.g., ethynyl).1.91 Formula I or any of formula 1.74-1.87, wherein Rs is ethynyl.1.92 Formula I or any of formulae 1.10-1.91, wherein the ULM is selected from:wherein:Rs is H or halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;R9 is H, halo (e.g.. chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;Qi and Q10 are independently C(O) or C(Ra)(Rb); andRaand Rb are both H;Q12 is O;R14 is H or Ci-4alkyl (e.g., methyl);Ris is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy; or-A-B-C together with the ULM forms the following structure:ARVN-216-PCT / / ARVN0216WO2Formula J or Formula Kwherein Rn is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy.1.93 Formula I or any of formulae 1.10-1.92, wherein the ULM is ULM-1, whereinRs is H or halo (e.g., chloro or fluoro);R9 is H, halo (e.g., chloro or fluoro);Qi is C(Ra)(Rb);Raand Rb are both H.1.94 Formula I or any of formulae 1.10-1.93, wherein the ULM-1 is formula UML-l(a)R8 O ORgULM-1 (a)1.95 Formula I or any of formulae 1.10- 1.94, wherein Rs and R9 are independently H or halo (e.g., fluoro).1.96 Formula I or any of formulae 1.10-1.92, wherein the ULM is ULM-2, wherein:Rs is H or halo (e.g., chloro or fluoro);R9 is H, halo (e.g., chloro or fluoro);1.97 Formula 1.96, wherein the UML-2 is a UML-2(a):R8ULM-2(a)1.98 Formula I or any of formulae 1.10-1.92, wherein the ULM is ULM-10, wherein Q10 are independently C(O) or C(Ra)(Rb);ARVN-216-PCT / / ARVN0216WO2Raand Rb are H;Ri4 is H or Ci-4alkyl (e.g., methyl);Ris is H or halo (e.g., fluoro).1.99 Formula I or any of formulae 1.10-1.92 or 1.98, wherein the ULM is ULM-10, wherein Qio is C(Ra)(Rb);Raand Rb are H;Ri4 is H or Ci-4alkyl (e.g., methyl);Ris is H or halo (e.g., fluoro);1.100 Formula I or any of formulae 1.10-1.92 or 1.98-1.99, wherein the ULM is ULM-10, wherein:Ri4 is H or methyl; andRis is H or halo (e.g. fluoro).1.101 Formula I or any of formulae 1.10-1.92 or 1.98-1.99, wherein UML-10 is UML-10(a):R NH II I OR14ULM-10(a)1.102 Formula I or any of formulae 1.10-1.92 or 1.98-1.99, wherein UML-10 is UML-10(b):R O NH II Nf Q-io1.103 Formula I or any of formulae 1.10-1.92 or 1.98-1.102, wherein R14 is H.1.104 Formula I or any of formulae 1.10-1.92, wherein the ULM is ULM- 12, wherein:Q12 is O; andRis is H or halo (e.g., fluoro).1.105 Formula I or any of formulae 1.10-1.92 or 1.104, wherein the ULM is UML-12(a):ARVN-216-PCT / / ARVN0216WO2ULM-12(a)Formula I or any of formulae 1.10-1.92 or 1.104, wherein the ULM is UML-12(b):HULM-12(b)Formula I or any of formulae 1.10-1.92, wherein the ULM is ULM-13, wherein R15 is H or halo (e.g., fluoro).Formula I or any of formulae 1.10-1.92 or 1.107, wherein the ULM is ULM-13(a):ULM-13(a)Formula I or any of formulae 1.10-1.92 or 1.107, wherein the ULM is ULM-13-a or UML-13(b):ULM-13(b)Formula I or any of formulae 1.10-1.92 or 1.98-1.110, wherein R15 is H or halo (e.g., fluoro).Formula I or any of formulae 1.10-1.92 or 1.98-1.110, wherein Risis H.Formula I or any of formulae 1.10-1.92 or 1.98-1.110, wherein R15 is halo (.e.g., fluoro).ARVN-216-PCT / / ARVN0216WO21.113 Formula I or any of formulae 1.10-1.112, wherein Rs is H or halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy.1.114 Formula I or any of formulae 1.10-1.113, wherein Rs is H or halo (e.g.. chloro or fluoro).1.115 Formula I or any of formulae 1.10-1.113, wherein Rs is H.1.116 Formula I or any of formulae 1.10-1.113, wherein Rs is halo (e.g., chloro or fluoro). 1.117 Formula I or any of formulae 1.10-1.116, wherein R9 is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy.1.118 Formula I or any of formulae 1.10-1.116, wherein R9 is H or halo (e.g., chloro or fluoro).1.119 Formula I or any of formulae 1.10-1.116, wherein R9 is H.1.120 Formula I or any of formulae 1.10-1.116, wherein R9 is halo (e.g., chloro or fluoro). 1.121 Formula I or any of formulae 1.10-1.116, wherein Rs is H and R9 is halo (e.g., chloro or fluoro).1.122 Formula I or any of formulae 1.10-1.92, wherein:Rs is H or halo (e.g., chloro or fluoro);R9 is H or halo (e.g., chloro or fluoro);Qi is C(Ra)(Rb);Raand Rb are both H; andD is Formula D-l, wherein:R4 is H, or OH;Re is fluoro or chloro; andR5 is Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).1.123 Formula I or any of formulae 1.10-1.122, wherein the ULM is selected from:ARVN-216-PCT / / ARVN0216WO21.124 Formula I or any of formulae 1.10-1.123, wherein -A-B-C- is:1.126 Formula I or any of formulae 1.10-1.124, wherein -A-B-C- is:1.127 Formula I or any of formulae 1.10-1.124, wherein -A-B-C- is:ARVN-216-PCT / / ARVN0216WO21.128 Formula I or any of formulae 1.10-1.122 or 1.125, wherein -A-B-C together with the UML forms the following:OFormula J1.129 Formula I or any of formulae 1.10-1.122 or 1.125, wherein -A-B-C together with the UML forms the following:Formula Kwherein Ru is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy.1.130 Formula 1.129, wherein Rnis H.1.131 Formula 1.129, wherein Rnis halo (e.g., fluoro).1.132 Formula 1.129, wherein -A-B-C together with the UML forms the following:1.133 Formula I or any of formulae 1.10-1.132, wherein moiety D is Formula D-l or D-l(a), wherein R4 is hydroxy; Re is halo (e.g., fluoro or chloro); and R5 is Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).ARVN-216-PCT / / ARVN0216WO21.134 Formula I or any of the foregoing formulae, wherein the compound is in pharmaceutically acceptable salt form.1.135 Formula I or any of the foregoing formulae, wherein the compound is in free form.1.136 Formula I or any of the foregoing formulae, wherein the compound is in salt form.1.137 Formula I or any of the foregoing formulae, wherein the compound is in isotopic form (e.g, in deuterated form, in partially deuterated or fully deuterated form; e.g.. wherein one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms, are replaced with deuterium).1.138 Formula I or any of the foregoing formulae, wherein the compound is in an enantiomerically or diastereomically enriched form, for example the C-8 carbon of the PTM is, in some embodiments, enriched in the (S) form, and in other embodiments, enriched in the (R) form and / or the carbon carrying the cyclopropyl is, in some embodiments, enriched in the (R)-form, and in other embodiments, enriched in the (S) 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), or in still other embodiments, the C-8 of the PTM and / or the carbon carrying the cyclopropyl is / are in racemic form.1.139 Formula I or any of the foregoing formulae, wherein the compound has improved oral bioavailability relative to conventional small molecule KRAS inhibitors and other KRAS PROTAC compounds.1.140 Formula I or any of the foregoing formulae, wherein the compound degrades KRAS G12 mutations including KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, and KRAS G12V.1.141 Formula I or any of the foregoing formulae, wherein the compound degrades nonmutated wild-type KRAS1.142 Formula I or any of the foregoing formulae, wherein the compound degrades KRAS G12D.1.143 Formula I or any of the foregoing formulae, wherein the compound degrades KRAS G12V.1.144 Formula I or any of the foregoing formulae, wherein the compound degrades KRAS G12C.ARVN-216-PCT / / ARVN0216WO21.145 Formula I or any of the foregoing formulae, wherein the compound degrades KRAS (non-mutant wild type or mutant) in cells carrying such KRAS at 24 hour with an DC50 of 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.1.146 Formula I or any of the foregoing formulae, wherein the compound degrades KRAS (non-mutant wild-type or mutant KRAS) in cells carrying such KRAS wild-type or mutation at 24 hour with an Dmaxvalue of at least 25 %, preferably greater than or equal to 50%, preferably greater than or equal to 70%, preferably greater than 70%, e.g.. in an in vitro assay as described in Example 2 below.1.147 Formula I or any of the foregoing formulae, wherein KRAS mutant is a KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, and KRAS G12V.1.148 Formula I or any of the foregoing formulae, wherein KRAS mutant is a G 12V KRAS. 1.149 Formula I or any of the foregoing formulae, wherein KRAS mutant is a G12C KRAS. 1.150 Formula I or any of the foregoing formulae, wherein KRAS mutant is a G12D KRAS. 1.151 Formula I or any of the foregoing formulae, wherein KRAS is a non-mutated wild-type KRAS.1.152 Formula I or any of the foregoing formulae, wherein the compound is selected from compounds 1-26 of Table 1:ARVN-216-PCT / / ARVN0216WO2Table 1x d 4W y \ l-:pv p- —C / .,. A ( J )YyX 1- / O A T J rN 0 ’j y - / “YT IK' '°'X'Ci H” TXJQ Q1 J\ Y A" X1k i.lL $ *1. \?f' KX YK rYzV > 0- ' L y K Y A 4< IHI X v'0.. ( ) 0 CHO X J^XJU1Y,„X° XIX ^FUJJ?1 1vARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO21.153 Compound of Formula I or any of 1.1-1.9 or 1.134-1.151, wherein the compound is a compound of Formula 1(A)’:in free or salt form, wherein:Ri and R2 are independently halo (e.g., fluoro);R3 is H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);Rzis H or Ci-4alkyl (e.g., methyl);Moiety A is a 4- 12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 2-azabicyclo[2.2. l]heptanylene or 3,9-diazaspiro[5,5]undecanylene, hexahydropyrrolo [3,4-c] pyrrolylene);Each of moiety B and moiety C is independently a bond. C(O), S(O)2, O. Ci-4alkylene (e.g., methylene, ethylene or propylene for example prop-2-ylene), C3- ecycloalkylene (e.g., cyclopropylene) or a 4-12 membered heterocycloalkylene (e.g., piperazinylene, piperidinylene, diazepanylene or 2,7- diazaspir 0 [3.5 ] nonanylene);wherein each of moieties A, B and C is independently optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or -OCi-4alkyl (e.g., methoxy);ARVN-216-PCT / / ARVN0216WO2Moiety D is an aryl or a 6-12 membered heterocycloalkyl, each optionally substituted with one or more hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), Ci-4haloalkyl (e.g., difluoromethyl), -OCi-4alkyl (e.g., methoxyl or ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl); andULM is selected from:A R VN-216- P C 77 / A R VN0216 WO2ULM-12 ULM-13 ULM-13-Xwherein:R4a is H or Ci-4alkyl (e.g.. methyl);Rbis H or halo (e.g., fluoro);Rs is H or halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;R9 is H, halo (e.g.. chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy (e.g., methoxy);Riox is Ci-4alkyl (e.g., methyl);Qi, Q10 and Qu are independently C(O) or C(Ra)(Rb);Raand Rb are independently H or Ci-4alkyl (e.g., methyl);R11 is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy; Ri3Xis Ci-alkyl (e.g., methyl);Q12 is O;Ri4 is H or Ci-4alkyl (e.g., methyl);Ris is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;Ri6 and Rix are independently H or Ci-4alkyl (e.g., methyl); or-A-B-C together with the ULM forms any of the following structure:ARVN-216-PCT / / ARVN0216WO2Formula J or Formula Kwherein Rn is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy.The Compound of Formula I or 1.153, wherein the compound is a compound of Formula 1(A)’- 1:ULMFormula 1(A)’ -1The Compound of Formula I or any of 1.153-1.154, wherein the compound is a compound of Formula 1(A)’ -1(a)ARVN-216-PCT / / ARVN0216WO2Any of 1.153-1.156, wherein Rzis H.Any of 1.153-1.156, wherein Rzis Ci-4alkyl (e.g., methyl).Any of 1.153-1.156, wherein Rzis methyl.Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151 or 1.153- 1.159, wherein the ULM is selected from:ARVN-216-PCT / / ARVN0216WO2ULM-13-XRs is H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);Moiety A is a 6-11 membered heterocycloalkylene optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g.. methyl) or -OCi-4alkyl (e.g., methoxy);Moiety B is Ci-4alkylene (e.g., methylene); andMoiety C is a 4-12 membered heterocycloalkylene (e.g.. piperazinylene, piperidinylene, or 2,7-diazaspiro[3.5]nonanylene) optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or -OCi-4alkyl (e.g., methoxy).Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151 or 1.153- 1.161, wherein the ULM is selected from:ARVN-216-PCT / / ARVN0216WO2ULM-11ULM-151.163 Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151 or 1.153- 1.162, wherein the ULM is ULM-4A or ULM-4B:wherein R4a is H or Ci-4alkyl (e.g., methyl); and R4b is H or halo (e.g., fluoro). 1.164 Compound of formula 1.163, wherein R4a is Ci-4alkyl (e.g., methyl) and R4b is halo (e.g., fluoro).1.165 Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153- 1.162 or 1.163, wherein the ULM is:ARVN-216-PCT / / ARVN0216WO2Compound of formula 1.163, wherein R4a is and R4b are both H.Compound of Formula I or any of 1.10-1.91, 1.110-1.122. 1.124-1.151 or 1.153- 1.162, wherein the ULM is ULM-13-X:HULM-13-Xwherein R15 is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy; and Ri3x is Chalky! (e.g., methyl).Compound of 1.167, wherein R15 is halo (e.g., fluoro) and Ri3x is Ci-4alkyl (e.g., methyl).Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153- 1.162 or 1.167, wherein the ULM is:Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151 or 1.153- 1.162, wherein the ULM is ULM-18:ARVN-216-PCT / / ARVN0216WO2wherein Ris is H or Ci-4alkyl (e.g.. methyl).Compound of 1.170, wherein Ri8 is Ci-4alkyl (e.g., methyl).Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153- 1.162 or 1.170, wherein the ULM is:Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151 or 1.153- 1.162, wherein the ULM is ULM-10-X.wherein:Qio is C(O) or C(Ra)(Rb);Riox is Ci-4alkyl (e.g., methyl);Ri4 is H or Ci-4alkyl (e.g., methyl);R15 is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy; and Raand Rbare independently H or Ci-4alkyl (e.g., methyl).Compound of Formula I or any of 1.10-1.91, 1.110-1.122. 1.124-1.151 or 1.153-1.162, wherein the ULM is ULM-10-X:ARVN-216-PCT / / ARVN0216WO2Qio is C(O) or C(Ra)(Rb), wherein Raand Rb are independently H or Ci-4alkyl (e.g., methyl);Riox is Ci-4alkyl (e.g., methyl);Ri4 is H or Ci-4alkyl (e.g., methyl);R15 is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy (e.g., methoxy).Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153- 1.162 or 1.173-1.174, wherein the ULM is ULM-10-X and Qw is C(O).Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153- 1.162 or 1.173-1.175, wherein the ULM is ULM-10-X and Qio is C(Ra)(Rb). Any of 1.173-1.175, wherein Qio is C(Ra)(Rb), wherein Raand Rbare both H. Any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153-1.162 or 1.173-1.176, wherein the ULM is ULM-10-X and Riox is methyl.Any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153-1.162 or 1.173-1.178, wherein the ULM is ULM-10-X and RI4is H.Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153- 1.162 or 1.173-1.178, wherein the ULM is ULM-10-X and Ru is Ci-4alkyl (e.g.. methyl).Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153- 1.162 or 1.173-1.180, wherein the ULM is ULM-10-X and Ris is H.Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153- 1.162 or 1.173-1.180, wherein the ULM is ULM-10-X and Ris is halo (e.g., fluoro).Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153- 1.162 or 1.173-1.180, wherein R15 is Ci-4alkyl (e.g., methyl).ARVN-216-PCT / / ARVN0216WO2Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153- 1.162 or 1.173-1.183, wherein the ULM is selected from:Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153- 1.162, wherein the ULM is ULM-11:wherein: Qu is C(O) or C(Ra)(Rb); R15 is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy; Rie is H or Ci-4alkyl (e.g., methyl); andARVN-216-PCT / / ARVN0216WO2Raand Rbare independently H or Ci-4alkyl (e.g., methyl).1.186 Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151 or 1.153- 1.162, wherein the ULM is ULM-11:NHRI6Xr° }=0INl\k ) R-15ULM-11wherein:Qu is C(0) or C(Ra)(Rb), wherein Raand Rb are independently H or Ci-4alkyl (e.g., methyl);R15 is H or halo (e.g., fluoro);Ri6 is H or Ci-4alkyl (e.g., methyl).1.187 Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153- 1.162, or 1.185-1.186, wherein the ULM is ULM-11 and Qu is C(O).1.188 Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153- 1.162, or 1.185-1.186, wherein the ULM is ULM-11 and Qu is C(Ra)(Rb).1.189 Compound of 1.188, wherein Qu is C(Ra)(Rb), wherein Raand Rb are both H. 1.190 Compound of Formula I or any of 1.10-1.91, 1.110-1.122. 1.124-1.151, 1.153- 1.162, or 1.185-1.189, wherein the ULM is ULM-11 and R15 is H.1.191 Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153- 1.162, or 1.185-1.189, wherein the ULM is ULM-11 and R15 is halo (e.g., fluoro).1.192 Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153- 1.162, or 1.185-1.191, wherein the ULM is ULM-11 and Ri6 is H.1.193 Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, L153- 1.162, or 1.185-1.191, wherein the ULM is ULM-11 and Rie is Ci-4alkyl (e.g., methyl).1.194 Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153- 1.162, or 1.185-1.193, wherein the ULM is:ARVN-216-PCT / / ARVN0216WO2The Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153-1.162, wherein the ULM is ULM-1:ULM-1 The Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153-1.162, wherein the ULM is ULM-1:wherein:Rs is H, halo (e.g., chloro or fluoro) or Ci-4alkyl (e.g., methyl);R9 is H or 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) wherein Raand Rb are H or Ci-4alkyl (e.g., methyl). The Compound of Formula I or any of 1.10-1.91. 1.110-1.122, 1.124-1.151, 1.153-1.162 or 1.195-1.196, wherein the ULM is ULM-1 and Qi is C(O).The Compound of Formula I or any of any of 1.10-1.91, 1.110-1.122, 1.124- 1.151, 1.153-1.162 or 1.195-1.196, wherein the ULM is ULM-1 and Qi is C(Ra)(Rb) wherein Raand Rbare H.The Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153-1.162 or 1.195-1.198, wherein Rs and Rs are independently H.ARVN-216-PCT / / ARVN0216WO2The Compound of Formula T or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153-1.162 or 1.195-1.198, wherein Rs and Rs are independently Ci-4alkyl (e.g., methyl).The Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153-1.162 or 1.195-1.198, wherein Rs and Rs are independently methyl.The Compound of Formula I or any of 1.10-1.91. 1.110-1.122, 1.124-1.151, 1.153-1.162 or 1.195-1.201, wherein R9 is halo e.g., fluoro or chloro.The Compound of Formula I or any of 1.10-1.91. 1.110-1.122, 1.124-1.151, 1.153-1.162 or 1.195-1.201, wherein R9 is fluoro.The Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153-1.162 or 1.195-1.201, wherein R9 is chloro.The Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153-1.162 or 1.195-1.201, wherein Rs is H and R9 is halo e.g., fluoro or chloro. The Compound of Formula I or any of 1.10-1.91. 1.110-1.122, 1.124-1.151, 1.153-1.162 or 1.195-1.201, wherein Rs is Ci-4alkyl (e.g., methyl) and R9 is halo e.g., fluoro or chloro.The Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153-1.162 or 1.195-1.198, wherein Rs and R9 are both H.The Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153-1.162 or 1.195-1.198, wherein R9 is Ci-4alkoxy (e.g., methoxy);.The Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153-1.162 or 1.195-1.198, wherein Rs is H and R9 is Ci-4alkoxy (e.g., methoxy). The Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153-1.162 or 1.195-1.209, wherein the ULM is selected from any of the following:ARVN-216-PCT / / ARVN0216WO2The Compound of Formula I or any of 1.10-1.91, 1.110-1.122, 1.124-1.151, 1.153-1.162, wherein the ULM is selected from any of the following:The Compound of Formula I or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151, or 1.153-1.211, wherein Moiety D is:R4D-2 wherein R4, R5 and Re are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g.. methyl or ethyl), Ci-4haloalkyl (e.g., difluoromethyl), -OCi-4alkyl (e.g., methoxyl or ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl); and R?ais Ci-4alkyl (e.g., ethyl).ARVN-216-PCT / / ARVN0216WO21.213 The Compound of Formula T or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.212, wherein Moiety D is formula D-l.1.214 The Compound of Formula I or any of 1.10-1.20. 1.124-1.91, 1.110-1.122. 1.124- 1.151 or 1.153-1.212, wherein Moiety D is formula D-l(a):D-l (a)1.215 The Compound of Formula I or any of 1.10-1.20. 1.124-1.91, 1.110-1.122. 1.124- 1.151 or 1.153-1.212, wherein Moiety D is formula D-2:R4D-21.216 The Compound of Formula I or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.212 or 1.215, wherein Moiety D is formula D-2(a):R6D-2(a)1.217 The Compound of Formula l or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.216, wherein R4, R5 and Re are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).ARVN-216-PCT / / ARVN0216WO21.218 The Compound of Formula T or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.217, wherein R4 is H or hydroxy, Re is H or halo (e.g. fluoro or chloro) and Rs is H, Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).1.219 The Compound of Formula I or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.218, wherein R4 is H or hydroxy, Re is H or halo (e.g. fluoro or chloro) and R.s is H or Ci-4alkyl (e.g., methyl or ethyl).1.220 The Compound of Formula I or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.218, wherein R4 is H or hydroxy, Re is H or halo (e.g. fluoro or chloro) and Rs is H or C2-4alkynyl (e.g., ethynyl).1.221 The Compound of Formula I or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.220, wherein R4 is hydroxy, Re is H or halo (e.g. fluoro or chloro) and Rs is Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).1.222 The Compound of Formula I or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.221, wherein Rs is C2-4alkynyl (e.g., ethynyl).1.223 The Compound of Formula I or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.221, wherein Rs is Ci-4alkyl (e.g., methyl or ethyl).1.224 The Compound of Formula I or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.221, wherein R4 is hydroxy, Re is H and Rs is Ci-4alkyl (e.g., methyl or ethyl).1.225 The Compound of Formula I or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.221, wherein R4 is hydroxy, Re is H and Rs is methyl.1.226 The Compound of Formula I or any of 1.10-1.20. 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.221, wherein R4 is hydroxy, Re is H and Rs is ethyl.1.227 The Compound of Formula I or any of 1.153-1.226, wherein one or more of the stereo centers of the compound are independently in an enantiomerically or diastereomically enriched form (e.g., in greater than or equal to 75%, 85%, 90%, 95%, 99%, 99.9% enantiomeric excess of one form over the other form), for example, one or more stereocenters of the compound are independently enantiomerically enriched in the R-form and in another embodiment, one or more stereocenters of the compound are independently enriched in the S-form.ARVN-216-PCT / / ARVN0216WO21.228 The Compound of Formula T or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.227, wherein Moiety D is:1.229 The Compound of Formula I or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.227, wherein Moiety D is:HO1.230 The Compound of Formula I or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.227, wherein Moiety D is:1.231 The Compound of Formula I or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.227, wherein Moiety D is:1.232 The Compound of Formula I or any of 1.10-1.20. 1.124-1.91, 1.110-1.122. 1.124- 1.151 or 1.153-1.227, wherein Moiety D is:ARVN-216-PCT / / ARVN0216WO2The Compound of Formula T or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.227, wherein Moiety D is:The Compound of Formula I or any of 1.10-1.20. 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.227, wherein Moiety D is formula D-l.The Compound of Formula I or any of 1.10-1.20, 1.124-1.91, 1.110-1.122, 1.124- 1.151 or 1.153-1.227, herein Moiety D is:The Compound of Formula I or any of 1.153-1.235, wherein the compound is a compound of formula 1(A) ’-1(a):Formula 1(A)’- 1(a)The Compound of Formula I or any of 1.153-1.235, wherein the compound is a compound of Formula 1(A)’ -1(b):ARVN-216-PCT / / ARVN0216WO2C - ULMFormula 1(A)’- 1(b)The Compound of Formula I or any of 1.153-1.235, wherein the compound is a compound of formula 1(A)’ -1(a)’:The Compound of Formula I or any of 1.153-1.235, wherein the compound is a compound of Formula 1(A)’ -1(b)’:Formula 1(A)’ -1(b)’The Compound of Formula I or any of 1.10-1.38, 1.55-1.151 or 1.153-1.239, wherein Moiety A is a.6-9 membered heterocyclo alkylene optionally substitutedARVN-216-PCT / / ARVN0216WO2with one or more hydroxy, halo, Chalky I (e.g., methyl) or -OCi-4alkyl (e.g., methoxy.The Compound of Formula I or any of 1.10-1.38, 1.55-1.151 or 1.153-1.239, wherein Moiety A is 6-9 membered bridged heterocycloalkylene (e.g., 2- azabicyclo[2.2.1]heptanylene) optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g.. methyl) or -OCi-4alkyl (e.g.. methoxy).The Compound of Formula I or any of 1.10-1.38, 1.55-1.151 or 1.153-1.240, wherein Moiety A is a 6-membered monocyclic heterocycloalkylene (e.g., piperazinylene or pipiridinylene) optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or -OCi-4alkyl (e.g., methoxy).The Compound of Formula I or any of 1.10-1.38, 1.55-1.151 or 1.153-1.240, wherein Moiety A is a piperazinylene optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or -OCi-4alkyl (e.g., methoxy).The Compound of Formula I or any of 1.10-1.38, 1.55-1.151 or 1.153-1.240, wherein Moiety A is a pipiridinylene optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or -OCi-4alkyl (e.g., methoxy).The Compound of Formula I or any of 1.10-1.38, 1.55-1.151 or 1.153-1.244, wherein Moiety A is unsubstituted.The Compound of Formula I or any of 1.10-1.38, 1.55-1.151 or 1.153-1.244, wherein Moiety A is substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or -OCi-4alkyl (e.g., methoxy).The Compound of Formula I or any of 1.10-1.38, 1.55-1.151 or 1.153-1.244, wherein Moiety A is substituted with one or more halo or Ci-4alkyl (e.g., methyl). The Compound of Formula I or any of 1.10-1.38, 1.55-1.151 or 1.153-1.247, wherein Moiety A is:ARVN-216-PCT / / ARVN0216WO2The Compound of Formula I or any of 1.10-1.54, 1.61-1.151 or 1.153-1.248, wherein B is Ci-4alkylene (e.g., methylene, ethylene or propylene for example prop-2-ylene).The Compound of Formula I or any of 1.10-1.54, 1.61-1.151 or 1.153-1.248, wherein B is ethylene or propylene for example prop-2-ylene.The Compound of Formula I or any of 1.10-1.54, 1.61-1.151 or 1.153-1.248, wherein B is Cs-ecycloalkylene (e.g., cyclopropylene).The Compound of Formula I or any of 1.10-1.54, 1.61-1.151 or 1.153-1.248, wherein B is methylene.The Compound of Formula I or any of 1.10-1.54, 1.61-1.151 or 1.153-1.248, wherein B is C(O).The Compound of Formula I or any of 1.10-1.54, 1.61-1.151 or 1.153-1.248, wherein B is S(O)2.The Compound of Formula I or any of 1.10-1.54, 1.61-1.151 or 1.153-1.248, wherein B is O.The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.255, wherein C is a bond.The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.255, wherein C is a 6-7 membered heterocycloalkylene optionally substituted with one or more halo or Ci-4alkyl (e.g., methyl).The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.255, wherein C is a 7-membered heterocycloalkylene optionally substituted with one or more halo or Ci-4alkyl (e.g., methyl).The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.255, wherein C is a diazepanylene, optionally substituted with one or more halo or Ci-4alkyl (e.g., methyl).The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.255, wherein C is 6-membered heterocycloalkylene optionally substituted with one or more halo or Ci-4alkyl (e.g., methyl).ARVN-216-PCT / / ARVN0216WO21.261 The Compound of Formula T or any of 1.10-1.60, 1.74-1.151 or 1.153-1.255, wherein C is a piperazinylene optionally substituted with one or more halo or Ci- 4alkyl (e.g., methyl).1.262 The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.256, wherein C is a piperidinylene optionally substituted with one or more halo or Ci- 4alkyl (e.g., methyl).1.263 The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.262, wherein C is unsubstituted.1.264 The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.256, wherein C is substituted with one or more halo or Ci-4alkyl (e.g., methyl).1.265 The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.256, wherein C is substituted with one Ci-4alkyl (e.g., methyl).1.266 The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.256, wherein C is substituted with two Ci-4alkyl (e.g., methyl).1.267 The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.266, wherein C is selected from:f^N-|1.268 The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.267, wherein C is selected from:ARVN-216-PCT / / ARVN0216WO2The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.267, wherein C is:The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.267, wherein C is:The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.267, wherein C is:The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.267, wherein C is:The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.267, wherein C is:ARVN-216-PCT / / ARVN0216WO2The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.267, wherein C is:The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.267, wherein C is:The Compound of Formula I or any of 1.10-1.60, 1.74-1.151 or 1.153-1.267, wherein C is:The Compound of Formula I or any of 1.153-1.276, wherein -A-B-C- is as provided in Table 1 or Table 1-A.The Compound of Formula I or any of 1.153-1.276, wherein -A-B-C- is:ARVN-216-PCT / / ARVN0216WO25ARVN-216-PCT / / ARVN0216WO21.279 The Compound of Formula I or any of 1.153-1.278, wherein -A-B-C- is selected from:1.280 The Compound of Formula I or any of 1.153-1.268, wherein -A-B-C- is:1.281 The Compound of Formula I or any of 1.153-1.268, wherein -A-B-C- is:1.282 The Compound of Formula I or any of 1.153-1.268, wherein -A-B-C- is:1.283 The Compound of Formula I or any of 1.153-1.268, wherein -A-B-C- is:ARVN-216-PCT / / ARVN0216WO2The Compound of Formula I or any of 1.153-1.268, wherein -A-B-C- is:The Compound of Formula I or any of 1.153-1.284, wherein:Ri and R2 are independently halo (e.g., fluoro);R3 is Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);D is formula D-l(a)’:wherein:R4 is hydroxy, Rs is Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl); and Re is halo (e.g. fluoro or chloro);Moiety A is a 6-membered heterocycloalkylene;Moiety B is Ci-4alkylene (e.g., methylene);Moiety C is a 6-membered heterocycloalkylene, optionally substituted with one or more Ci-4alkyl (e.g., methyl).The Compound of Formula I or any of the foregoing wherein the compound is a compound selected from the following, in free or salt form:ARVN-216-PCT / / ARVN0216WO2Table 1-AARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2

[0065] Exemplary compounds of Formula Q-I include the following:Q-l.l. Compound of Formula Q-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.Q-1.2. Compound of Formula Q-I or Q- 1.1, wherein the PTM targets or binds to KRAS mutant protein.Q-1.3. Compound of Formula Q-I or any of Q-l.l-Q-1.2, wherein the PTM targets or binds to KRAS G12A.Q-1.4. Compound of Formula Q-I or any of Q-l.l-Q-1.2, wherein the PTM targets or binds to KRAS G12C.Q-1.5. Compound of Formula Q-I or any of Q-l.l-Q-1.2, wherein the PTM targets or binds to KRAS G12D.Q-1.6. Compound of Formula Q-I or any of Q-l.l-Q-1.2, wherein the PTM targets or binds to KRAS G12R.ARVN-216-PCT / / ARVN0216WO2Q-l.7. Compound of Formula Q-I or any of Q-l.l-Q-1.2, wherein the PTM targets or binds to KRAS G12V.Q-l.8. Compound of Formula Q-I or Q-l.l. wherein the PTM targets or binds to a nonmutant wild-type KRAS.Q-l.9. Compound of Formula Q-I or any of Q-l.l-Q-1.8, wherein the PTM comprises a chemical structure 6,10-dioxa-2,12,16,18- tetrazatetracy clo [9.7.1.02, 8.015, 19] nonadeca- 1(19), 11, 13, 15, 17 -pentaen- 17 -yl] optionally substituted.Q-l.10. Compound of Formula Q-I or any of Q-l.l -Q-l.9, wherein the compound is a compound of Formula Q-I(A):in free or salt form, wherein:R3 is H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);Moiety A is a 4-12 membered heterocycloalkylene (e.g., piperidinylene or piperazinylene);Each of moiety B and moiety C is independently a bond. Ci-4alkylene (e.g., methylene), or a 4- 12 membered heterocycloalkylene (e.g., piperazinylene, piperidinylene or 2,7-diazaspiro[3.5]nonanylene);wherein each of moieties A, B and C is independently optionally substituted with one or more halo, hydroxy, Ci-4alkyl (e.g., methyl) or OCi-4alkyl (e.g., methoxy); 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) Ci-4haloalkyl (e.g., difluoromethyl), -OCi-4alkyl (e.g., methoxyl or ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl); andULM is:ARVN-216-PCT / / ARVN0216WO2R9ULM-1wherein:R₈ is H, halo (e.g., chloro or fluoro), C₁₋₄alkyl (e.g., methyl), OH, or C₁₋₄alkoxy; R9 is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy; Q₁ is C(Rₐ)(Rb) or C=O; andRₐ and Rbare H.Q-l.l 1. Formula Q-I or Q- 1.10, wherein R3 is H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro).Q-1.12. Formula Q-I or any of formulae Q- 1.10-Q-l.l 1, wherein R3 is H.Q-l.l 3. Formula Q-I or any of formulae Q-l.l 0-Q-l.ll, wherein R3 is Ci-4alkyl (e.g.,methyl).Q-1.14. Formula Q-I or any of formulae Q-l.l 0-Q-l.ll, wherein R3 is methyl.Q-1.15. Formula Q-I or any of formulae Q- 1.10-Q-l.l 1, wherein R3 is halo (e.g. fluoro or chloro).Q-l.l 6. Formula Q-I or any of formulae Q-l.l 0-Q-l.ll, or formula 1.18, wherein R3 is fluoro.Q-1.17. Formula Q-I or any of formulae Q- 1.10-Q-l.l 1, or formula 1.18, wherein R3 is chloro.Q-1.18. Formula Q-I or any of formulae Q-l.10-Q-l.17, wherein D is aryl optionally substituted with one or more hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) Ci-4haloalkyl (e.g., difluoromethyl), -OCi-4alkyl (e.g., methoxyl or ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl).Q- 1.19. Formula Q-I or any of formulae Q-l.l 0-Q- 1.18, wherein 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).Q-1.20. Formula Q-I or any of formulae Q-l.l 0-Q- 1.18, wherein moiety D is Formula D-l:ARVN-216-PCT / / ARVN0216WO2R4D-1wherein:each of R4, Rs and Re is independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) Ci-4haloalkyl (e.g., difluoromethyl), -OCi-4alkyl (e.g., methoxyl or ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl).Q-1.21. Formula Q-I or any of formulae Q-l.10-Q-l.20, wherein moiety D is Formula D-l(a) having the following structure:D-1(a)Q-1.22. Formula Q-I or any of formulae Q-l.10-Q-l.21, wherein each of R4, R5 and Re is independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).Q-1.23. Formula Q-I or any of formulae Q-l.10-Q-l.22, wherein R4is H.Q-1.24. Formula Q-I or any of the formulae Q-l.10-Q-l.22, wherein R4 is hydroxy.Q-1.25. Formula Q-I or any of formulae Q-l.10-Q-l.24, wherein each of Rs and Re is independently H, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) or C2- 4alkynyl (e.g., ethynyl).Q-1.26. Formula Q-I or any of formulae Q-l.10-Q-l.25, wherein each of R5 and Re is independently H.ARVN-216-PCT / / ARVN0216WO2Q-1.27. Formula Q-T or any of formulae Q-l.10-Q-1.26, wherein each of Rs and Re is independently halo (e.g. fluoro or chloro).Q-l.28. Formula Q-I or any of formulae Q-l.10-Q-l.27, wherein Re is halo (e.g. fluoro or chloro).Q-l.29. Formula Q-I or any of formulae Q-l.10-Q-l.27, wherein Re fluoro.Q-l.30. Formula Q-I or any of formulae Q-l.10-Q-l.27, wherein Re chloro.Q-l.31. Formula Q-I or any of formulae Q-l.10-Q-l.30, wherein Rs is Ci-4alkyl (e.g., methyl or ethyl).Q-l.32. Formula Q-I or any of formulae Q-l.10-Q-l.31, wherein Rs is ethyl.Q-l.33. Formula Q-I or any of formulae Q-l.10-Q-l.30, wherein Rs is C2-4alkynyl (e.g., ethynyl).Q-l.34. Formula Q-I or any of formulae Q- 1.10-Q- 1.30, wherein Rs is ethynyl.Q-1.35. Formula Q-I or any of formulae Q- 1.10-Q- 1.34, wherein Rs is ethynyl and Re is halo (e.g. fluoro or chloro)Q- 1.36. Formula Q-I or any of formulae Q- 1.10-Q- 1.32, wherein Rs is ethyl and Re is halo (e.g. fluoro or chloro).Q-l.37. Formula Q-I or any of formulae Q- 1.10-Q- 1.36, wherein moiety A is a 4- 12membered heterocycloalkylene (e.g., piperidinylene, piperazinylene).Q-l.38. Formula Q-I or any of formulae Q-l.10-Q-l.37, wherein moiety A is a 4-12membered heterocycloalkylene (e.g., mono-heterocycloalkylene, fused- heterocycloalkylene, spiro-heterocycloalkylene).Q-l.39. Formula Q-I or any of formulae Q-l.10-Q-l.37, wherein moiety A is a 4-11membered heterocycloalkylene (e.g., 5-6 membered mono-heterocycloalkylene, 8-10 membered fused-multicyclic heterocycloalkylene or 7-11 membered multicyclic spiro- heterocycloalkylene).Q-l.40. Formula Q-I or any of formulae Q-l.10-Q-l.37, wherein moiety A is a 6-11membered heterocycloalkylene.Q-l.41. Formula Q-I or any of formulae Q- 1.10-Q- 1.37, wherein moiety A is a 6-membered mono-cyclic heterocycloalkylene.Q-1.42. Formula Q-I or any of formulae Q-l.10-Q-l.37, wherein moiety A is apiperidinylene.ARVN-216-PCT / / ARVN0216WO2Q-l.43. Formula Q-T or any of formulae Q-l.10-Q-l.42, wherein moiety A is optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or -OCi-4alkyl (e.g., methoxy).Q-l.44. Formula Q-I or any of formulae Q- 1.10-Q-l.43, wherein A is unsubstituted.Q-l.45. Formula Q-I or any of formulae Q-l.10-Q-l.43, wherein A is substituted with halo (e.g., fluoro).Q-l.46. Formula Q-I or any of formulae Q-l.10-Q-l.43, wherein A is substituted with fluoro. Q-l.47. Formula Q-I or any of formulae Q-l.10-Q-l.46, wherein A is:Q-l.48. Formula Q-I or any of formulae Q- 1.10-Q-l.47, wherein each of moiety B and moiety C is independently a bond, Ci-4alkylene (e.g., methylene) or a 4-12 membered heterocycloalkylene.Q-l.49. Formula Q-I or any of formulae Q- 1.10-Q-l.48, wherein each of moiety B and moiety C is independently a bond.Q-l.50. Formula Q-I or any of formulae Q-l.10-Q-l.48, wherein moiety B is a bond.Q-l.51. Formula Q-I or any of formulae Q- 1.10-Q-l.48, wherein each of moiety B and moiety C is both a bond.Q-l.52. Formula Q-I or any of formulae Q- 1.10-Q-l.48, wherein moiety B is Ci-4alkylene (e.g., methylene).Q-l.53. Formula Q-I or any of formulae Q-l.10-Q-l.48, wherein moiety B is methylene. Q-l.54. Formula Q-I or any of formulae Q-l.10-Q-l.53, wherein moiety C is a 4-12membered heterocycloalkyleneQ-l.55. Formula Q-I or any of formulae Q-l.10-Q-l.54, wherein moiety C is monoheterocycloalkylene, fused- heterocycloalkylene or spiro- heterocycloalkylene.Q-l.56. Formula Q-I or any of formulae Q-l.10-Q-l.55, wherein moiety C is a 4-11membered heterocycloalkylene (e.g., 5-6 membered mono-heterocycloalkylene. 8-10 membered fused-multicyclic heterocycloalkylene or 7-11 membered spiroheterocycloalkylene).ARVN-216-PCT / / ARVN0216WO2Q-l.57. Formula Q-T or any of formulae Q-l.10- Q-l.56, wherein moiety C is a 6-membered mono-heterocycloalkylene (piperazinylene or piperidinylene).Q-l.58. Formula Q-I or any of formulae Q-l.10-Q-l.56, wherein moiety C is a piperazinylene.Q-l.59. Formula Q-I or any of formulae Q-l.10-Q-l.56, wherein moiety C is a 7-11membered multicyclic spiro- heterocycloalkylene.Q-l.60. Formula Q-I or any of formulae Q-l.10-Q-l.56, wherein moiety C is a 9-membered multicyclic spiro- heterocycloalkylene.Q-l.61. Formula Q-I or any of formulae Q-l.10-Q-l.56, wherein moiety C is 2,7- diazaspiro [3.5] nonanylene.Q-l.62. Formula Q-I or any of formulae Q-l.10-Q-l.61, wherein moiety C is optionally substituted with one or more Ci-4alkyl (e.g., methyl).Q-l.63. Formula Q-I or any of formulae Q-l.10-Q-l.62, wherein moiety C is unsubstituted. Q-l.64. Formula Q-I or any of formulae Q-l.10-Q-l.62, wherein moiety C is substituted with one or more Ci-4alkyl (e.g., methyl).Q-l.65. Formula Q-I or any of formulae Q-l.10-Q-l.62, wherein moiety C is substituted with a methyl.Q-l.66. Formula Q-I or any of formulae Q-l.10-Q-l.65, wherein moiety C is a 4-12membered heterocycloalkylene selected from:Q-l.67. Formula Q-I or any of formulae Q-l.10-Q-l.48, wherein moiety C is a bond.Q-l.68. Formula Q-I or any of formulae Q-l.10-Q-l.48, wherein moiety B and moiety C are both a bond.Q-l.69. Formula Q-I or any of the foregoing formulae, wherein the compound is a compound of Formula 1(A)- 1:ARVN-216-PCT / / ARVN0216WO2Formula 1(A)- 1Q-1.70. Formula Q-I or any of formulae Q-l.10-Q-l.69, wherein:R3 is H or halo (e.g. fluoro or chloro);D is Formula D-l or D-l(a), wherein R4 is H or hydroxy; Re is H or halo (e.g., fluoro or chloro); and R5 is H, Ci-4alkyl (e.g., methyl or ethyl) or C2- 4alkynyl (e.g., ethynyl).Q-1.71. Formula Q-I or any of formulae Q-l.69-Q-l.70, wherein R3 is halo (e.g. fluoro or chloro).Q- 1.72. Formula Q-T or any of formulae Q- 1,69-Q- 1.71, wherein R3 is fluoro.Q-1.73. Formula Q-I or any of formulae Q-l.69-Q-l.71, wherein R3 is chloro.Q-1.74. Formula Q-I or any of formulae Q-l.69-Q-l.73, wherein R4 is H.Q- 1.75. Formula Q-I or any of formulae Q- 1,69-Q- 1.73, wherein R4 is hydroxy.Q-1.76. Formula Q-I or any of formula Q-l.69-Q-l.75, wherein Re is halo (e.g. fluoro or chloro).Q-1.77. Formula Q-I or any of formula Q-l.69-Q-l.76, wherein Re fluoro.Q-1.78. Formula Q-I or any of formula Q-l.69-Q-l.76, wherein Re chloro.Q-1.79. Formula Q-I or any of formula Q-l.69-Q-l.78, wherein Rs is Ci-4alkyl (e.g., methyl or ethyl).Q-1.80. Formula Q-I or any of formula Q-l.69-Q-l.79, wherein R is ethyl.Q-1.81. Formula Q-I or any of formula Q-l.69-Q-l.78, wherein Rs is C2-4alkynyl (e.g.,ethynyl).Q-1.82. Formula Q-I or any of formula Q-l.69-Q-l.78, wherein Rs is ethynyl.Q-1.83. Formula Q-I or any of formulae Q-l.10-Q-l.82, wherein the ULM is selected from:ARVN-216-PCT / / ARVN0216WO2wherein:Rs is H or halo (e.g., chloro or fluoro);R9 is H, halo (e.g., chloro or fluoro);Qi is C(Ra)(Rb); andRaand Rb are both H.Q-1.84. Formula Q-I or any of formulae Q-l.10-Q-l.83, wherein the ULM is ULM-1.Q-1.85. Formula Q-I or any of formulae Q-l.10-Q-l.84, wherein Rs is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy.Q-1.86. Formula Q-I or any of formulae Q-l.10-Q-l.84, wherein Rs is H or halo (e.g., chloro or fluoro).Q-1.87. Formula Q-I or any of formulae Q-l.10-Q-l.85, wherein Rs is H.Q-1.88. Formula Q-I or any of formulae Q-l.10-Q-l.85, wherein Rs is halo (e.g., chloro or fluoro).Q-1.89. Formula Q-I or any of formulae Q-l.10-Q-l.88, wherein R9 is H, halo (e.g., chloro or fluoro), OH, Ci-4alkyl or Ci-4alkoxy (e.g., methoxy or ethoxy).Q-1.90. Formula Q-I or any of formulae Q-l.10-Q-l.88, wherein R9 is H or halo (e.g., chloro or fluoro).Q-1.91. Formula Q-I or any of formulae Q-l.10-Q-l.88, wherein R9 is H.Q-1.92. Formula Q-I or any of formulae Q-l.10-Q-l.88, wherein R9 is halo (e.g., chloro or fluoro).Q-1.93. Formula Q-I or any of formulae Q-l.10-Q-l.87, wherein Rs is H and R9 is halo (e.g., chloro or fluoro).Q-1.94. Formula Q-I or any of formulae Q-l.10-Q-l.93, wherein the ULM is:ARVN-216-PCT / / ARVN0216WO2Q-1.95. Formula Q-I or any of formulae Q-l.10-Q-l.94, wherein -A-B-C- is:Q-1.96. Formula Q-I or any of formulae Q-1.10- Q-1.95, wherein -A-B-C- is:FQ-l.97. Formula Q-I or any of formulae Q-l.10-Q-l.95, wherein -A-B-C- is:FQ-1.98. Formula Q-I or any of formulae Q-l.10-Q-l.97, wherein D is Formula D-l(a).wherein R4 is hydroxy; Re is halo (e.g., fluoro or chloro); and R5 is Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).Q-1.99. Formula Q-I or any of the foregoing formulae, wherein the compound is in pharmaceutically acceptable salt form.Q-1.100. Formula Q-I or any of the foregoing formulae, wherein the compound is in free form. Q- 1.101. Formula Q-I or any of the foregoing formulae, wherein the compound is in salt form. Q- 1.102. Formula Q-I or any of the foregoing formulae, wherein the compound is in isotopic form (e.g, in deuterated form, in partially deuterated or fully deuterated form; e.g., wherein one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms, are replaced with deuterium).Q-l.103. Formula Q-I or any of the foregoing formulae, wherein the compound is in an enantiomerically or diastereomically enriched form, for example the C-8 carbon 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), or in still other embodiments, the C-8 of the PTM is in racemic form.ARVN-216-PCT / / ARVN0216WO2Q-1.104. Formula Q-T or any of the foregoing formulae, wherein the compound degrades KRAS G12 mutations including KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, and KRAS G12V.Q-1.105. Formula Q-I or any of the foregoing formulae, wherein the compound degrades nonmutated wild-type KRAS.Q-1.106. Formula Q-I or any of the foregoing formulae, wherein the compound degrades KRAS G12C.Q-1.107. Formula Q-I or any of the foregoing formulae, wherein the compound degrades KRAS G12D.Q-1.108. Formula Q-I or any of the foregoing formulae, wherein the compound KRAS G12V. Q-1.109. Formula Q-I or any of the foregoing formulae, wherein the compound degrades KRAS (non-mutant wild-type or mutant KRAS) in cells carrying such non-mutant wild-type KRAS or KRAS mutation at 24 hour with an DC50 of 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-1.110. Formula Q-I or any of the foregoing formulae, wherein the compound degrades KRAS (non-mutant wild-type or mutant KRAS) in cells carrying such KRAS (non- mutant wild-type or mutation) 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-1.111. Formula Q-I or any of the foregoing formulae, wherein KRAS mutant is a KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, and KRAS G12V.Q-1.112. Formula Q-I or any of the foregoing formulae, wherein KRAS mutant is a G 12V KRAS.Q-1.113. Formula Q-I or any of the foregoing formulae, wherein KRAS mutant is a G12D KRAS.Q-1.114. Formula Q-I or any of the foregoing formulae, wherein KRAS mutant is a G12C KRAS.Q-1.115. Formula Q-I or any of the foregoing formulae, wherein KRAS is a non-mutated wildtype KRAS.ARVN-216-PCT / / ARVN0216WO2Q-l.116. Formula Q-T or any of the foregoing formulae, wherein the compound is selected from Compounds No. Q-l to Q-4 of Table Q-l, in free or salt form.Table Q-lCompound Io i||iiiliiilli:!kr / t7’O 0oii £Q-l11J (0 V I1X j P1“1 f'Q-2 | MJ.iJ® V it....... ® Tf 0B o—Q-3 Yo. r ) / aas'TT 0 01 ® y-MHN C |tQ-4HO - zU. J'-'- A.sz-’x, s - / T TTb1 1 1 J ixx>Q-l.117. The Compound of Formula Q-I or any of Q-l.11.1-Q- 1.9 or Q-l.99-Q-l.115, wherein the compound is a compound of Formula Q-I(A)’:ARVN-216-PCT / / ARVN0216WO2KA)’in free or salt form, wherein:R3 is H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);Moiety A is a 4-12 membered heterocycloalkylene (e.g., a 6-membered heterocycloalkylene such as a piperidinylene or piperazinylene, or an 8- 11 membered heterocycloalkylene such as a 3,9-diazaspiro[5,5]undecanylene); Each of moiety B and moiety C is independently a bond, Ci-4alkylene (e.g., methylene), or a 4-12 membered heterocycloalkylene (e.g., piperazinylene, piperidinylene or 2,7 -diazaspiro [3.5 ] nonanylene);wherein each of moieties A, B and C is independently optionally substituted with one or more, hydroxy, halo, Ci-4alkyl (e.g., methyl) or -OCi-4alkyl (e.g.. methoxy); 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) Ci-4haloalkyl (e.g., difluoromethyl), - OCi-4alkyl (e.g., methoxyl or ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl); andULM is:ULM-1 andwherein:R₈ is H, halo (e.g., chloro or fluoro), C₁₋₄alkyl (e.g., methyl), OH, or C₁₋₄alkoxy;R9 is H, halo (e.g., chloro or fluoro), OH, Ci-4alkyl or Ci-4alkoxy (e.g., methoxy orethoxy);ARVN-216-PCT / / ARVN0216WO2Qi and Qio are independently C(Ra)(Rb) or C=O;Riox is H or Ci-4alkyl (e.g., methyl);Ri4 is H or Ci-4alkyl (e.g., methyl);R15 is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy; andRaand Rb are independently H or Ci-4alkyl (e.g., methyl).Q-1.118. The Compound of Formula Q-I or any of Q-l.l-Q-1.36, Q-l.48-Q-l.94, Q-l.98- Q-1.115 or Q- 1.117, wherein Moiety A is a 4-12 membered heterocycloalkylene (e.g., a 6-membered mono-cyclic heterocycloalkylene such as a piperidinylene or piperazinylene, or an 8-11 membered heterocycloalkylene such as a 3,9- diazaspiro[5,5]undecanylene), optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g.. methyl) or -OCi-4alkyl (e.g., methoxy).Q-l.l 19. The Compound of Formula Q-I or any of Q-l.l-Q-1.36, Q-l.48-Q-l.94, Q-l.98- Q-1.115 or Q-l.117-Q-l.118, wherein Moiety A is a piperidinylene or piperazinylene.Q-l.120. The Compound of Formula Q-I or any of Q-l.l-Q-1.36, Q-l.48-Q-l.94, Q-l.98- Q-1.115 or Q-l.l 17-Q- 1.118, wherein Moiety A is an 8-11 membered heterocycloalkylene such as a 3,9-diazaspiro[5,5]undecanylene.Q-l.121. The Compound of Formula Q-I or any of Q-l.l-Q-1.36, Q-l.48-Q-l.94, Q-l.98- Q-1.115 or Q-l.l 17-Q- 1.120 wherein Moiety A is selected from:Q-l.122. The Compound of Formula Q-I or any of Q-l.l-Q-1.47, Q-l.54-Q-l.94, Q-l.98- Q-1.115 or Q-l.l 17-Q- 1.121, wherein Moiety B is a Ci-4alkylene (e.g.. methylene).Q-l.123. The Compound of Formula Q-I or any of Q-l.l-Q-1.47, Q-l.54-Q-l.94, Q-l.98- Q-1.115 or Q-l.l 17-Q- 1.121, wherein Moiety B is a bond.Q-l.124. The Compound of Formula Q-I or any of Q-l.l-Q-1.53, Q-l.69-Q-l.94, Q-l.98- Q-1.115 or Q-l.l 17-Q- 1.123, wherein Moiety C is a bond.Q-l.125. The Compound of Formula Q-I or any of Q-l.l-Q-1.53, Q-l.69-Q-l.94, Q-l.98- Q-1.115 or Q-l.117-Q-l.123, wherein Moiety C is a piperidinylene.ARVN-216-PCT / / ARVN0216WO2Q- 1.126. The Compound of Formula Q-I or any of Q-l.l-Q-1.53, Q-l.69-Q-l.94, Q-1.98- Q-1.115 or Q-1.117-Q- 1.123, wherein Moiety C is a piperazinylene optionally substituted with one or more halo or Ci-4alkyl (e.g., methyl).Q-1.127. The Compound of Formula Q-I or any of Q-l.l-Q-1.53, Q-l.69-Q-l.94, Q-1.98- Q-1.115 or Q-l.117-Q-l.123, wherein Moiety C is selected from:Q-1.128. The Compound of Formula Q-I or any of Q-l.l-Q-1.36, Q-l.69-Q-l.94, Q-1.98- Q-1.115 or Q-l.l 17-Q- 1.127, wherein Moiety -A-B-C- is:Q-1.129. The Compound of Formula Q-I or any of Q-l.l-Q-1.82, Q-1.95-Q-1.115 or Q- 1.117-Q-L 128, wherein the ULM is ULM-1.Q-1.130. Compound of Formula Q-I or any of Q-l.l-Q-1.82, Q-1.95-Q- 1.115 or Q-l.l 17- Q-l.128, wherein the ULM is ULM-10:OULM-10wherein:Qio is C(O) or C(Ra)(Rb);Riox is H or Ci-4alkyl (e.g., methyl);Ri4 is H or Ci-4alkyl (e.g., methyl);ARVN-216-PCT / / ARVN0216WO2R15 is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy; and Raand Rb are independently H or Ci-4alkyl (e.g., methyl).Q-1.131. Compound of Formula Q-I or any of Q-l.l-Q-1.82, Q-l,95-Q-l.115 or Q-1.117- Q-1.128, or Q-l.130, wherein the ULM is ULM-10 and Qio is C(O).Q-l.132. Compound of Formula Q-I or any of Q-l.l-Q-1.82, Q-l,95-Q-l.115 or Q-l.117- Q-1.128. or Q-l.130, wherein the ULM is ULM-10 and Qio is C(Ra)(Rb).Q-1.133. Compound of Formula Q-I or any Q-l.l-Q-1.82, Q-1.95-Q-1.115 or Q-1.117-Q- 1.128, or Q-l.130-Q-l.132, wherein the ULM is ULM-10 and Riox is H or Ci- 4alkyl (e.g., methyl);Q-1.134. Compound of Formula Q-I or any of any Q-l.l-Q-1.82, Q- 1,95-Q-L 115 or Q- 1.117-Q-L 128, or Q-l.130-Q-l.132. wherein the ULM is ULM-10 and Rioxis H. Q-1.135. Compound of Formula Q-I or any of any Q-l.l-Q-1.82, Q-l.95-Q-l.115 or Q- 1.117-Q-L 128, or Q-l.130-Q-l.132, wherein the ULM is ULM-10 and Riox is Ci- 4alkyl (e.g., methyl).Q-1.136. Compound of Formula Q-I or any of any Q-l.l-Q-1.82, Q- 1,95-Q-L 115 or Q- 1.117-Q-l.128, or Q-l.130-Q-l.132, wherein the ULM is ULM-10 and Rioxis methyl.Q-1.137. Compound of Formula Q-I or any of Q-l.l-Q-1.82, Q-1.95-Q- 1.115 or Q-l.l 17- Q-l.128, or Q-l.130-Q-l.136, wherein the ULM is ULM-10 and Ri4 is H.Q-L 138. Compound of Formula Q-I or any of Q-l.l-Q-1.82, Q-l.95-Q-l.115 or Q-L 117- Q-1.128, or Q-l.130-Q-l.136, wherein the ULM is ULM-10 and Ri4 is Ci-4alkyl (e.g., methyl).Q-l.139. Compound of Formula Q-I or any of any Q-l.l-Q-1.82, Q- 1,95-Q-l.115 or Q- 1.117-Q-l.128, or Q-l.130-Q-l.138, wherein the ULM is ULM-10 and R15 is H. Q-1.140. Compound of Formula Q-I or any of Q-l.l-Q-1.82, Q-1.95-Q- 1.115 or Q-l.117- Q-l.128, or Q-l.130-Q-l.138, wherein the ULM is ULM-10 and R15 is halo (e.g., fluoro).Q-1.141. Compound of Formula Q-I or any of Q-l.l-Q-1.82, Q-l.95-Q-l.115 or Q-l.117- Q-l.128, or Q-l.130-Q-l.138, wherein R15 is Ci-4alkyl (e.g., methyl).Q-1.142. Compound of Formula Q-I or any of Q-l.l-Q-1.82, Q-l.95-Q-l.115 or Q-l.l 17- Q-l.128-Q- 1.141, wherein the ULM is selected from:ARVN-216-PCT / / ARVN0216WO2Q-l.143. Compound of Formula Q-I or any of Q-l.l-Q-1.97, Q-l.99-Q-l.115 or Q-l.117- Q-l.142, wherein Moiety D is:R4 R4Re R6D-1nrD-2wherein R4, R5 and Re are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), Ci-4haloalkyl (e.g., difluoromethyl), -OCi-4alkyl (e.g., methoxyl or ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl).Q-l.144. Compound of Formula Q-I or any of Q-l.l-Q-1.97, Q-l.99-Q-l.115 or Q-l.117- Q- 1.143, wherein Moiety D is formula D-2:R4R6D-2ARVN-216-PCT / / ARVN0216WO2Q-l.145. Compound of Formula Q-T or any of Q-l.l-Q-1.97, Q-l,99-Q-l.115 or Q-l.117- Q-1.143, wherein Moiety D is formula D-2(a):D-2(a)Q-l.146. Compound of Formula Q-I or any of Q-l.l-Q-1.97, Q-1.99-Q-1.115 or Q-l.117- Q-1.145, wherein R4, R5 and Re are independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g.. ethynyl).Q-l.147. Compound of Formula Q-I or any of Q-l.l-Q-1.97, Q-l.99-Q-l.115 or Q-l.117- Q-1.145, wherein R4 is H or hydroxy, Re is H or halo (e.g. fluoro or chloro) and, R5 is H, Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g.. ethynyl).Q-l.148. Compound of Formula Q-I or any of Q-l.l-Q-1.97, Q-l.99-Q-l.115 or Q-l.117- Q-1.145, wherein R4 is H or hydroxy, Re is H or halo (e.g. fluoro or chloro) and, R5 is H or Ci-4alkyl (e.g., methyl or ethyl).Q-l.149. Compound of Formula Q-I or any of Q-l.l-Q-1.97, Q-l.99-Q-l.115 or Q- 1.117- Q-1.145, wherein R4 is H or hydroxy, Re is H or halo (e.g. fluoro or chloro) and, Rs is H or C2-4alkynyl (e.g., ethynyl).Q-l.150. Compound of Formula Q-I or any of Q-l.l-Q-1.97, Q-l.99-Q-l.115 or Q-l.117- Q-1.145, wherein R4 is hydroxy, Re is H or halo (e.g. fluoro or chloro) and R5 is Ci-4alkyl (e.g., methyl or ethyl) or C2-4alkynyl (e.g., ethynyl).Q-l.151. Compound of Formula Q-I or any of Q-l.l-Q-1.97, Q-l.99-Q-l.115 or Q-l.117- Q-1.150, wherein R5 is C2-4alkynyl (e.g., ethynyl).Q-l.152. Compound of Formula Q-I or any Q-l.l-Q-1.97, Q-l.99-Q-l.115 orQ-1.117-Q- 1.150, wherein R5 is Ci-4alkyl (e.g., methyl or ethyl).Q-l.153. Compound of Formula Q-I or any of Q-l.l 17-Q-l.150, wherein R4 is hydroxy, Re is H and R5 is Ci-4alkyl (e.g., methyl or ethyl).Q-l.154. Compound of Formula Q-I or any of Q-l.l-Q-1.97, Q-1.99-Q- 1.115 or Q-l.117- Q-1.150, wherein R4 is hydroxy, Re is H and R5 is methyl.ARVN-216-PCT / / ARVN0216WO2Q-l.155. Compound of Formula Q-T or any of Q-l.l-Q-1.97, Q-l,99-Q-l.115 or Q-l.117- Q-1.150, wherein R4 is hydroxy, Re is H and R5 is ethyl.Q-l.156. Compound of Formula Q-I or any of Q-l.10-Q-l.155, wherein one or more of the stereo centers of the compound are independently in an enantiomeric ally or diastereomically enriched form (e.g., in greater than or equal to 75%, 85%, 90%, 95%. 99%. 99.9% enantiomeric excess of one form over the other form), for example, in one embodiment, one or more of the stereo centers of the compound are independently enantiomerically enriched in the R-form and in another embodiment, one or more of the stereo centers of the compound are independently in the S-form.Q-l.157. Compound of Formula Q-I or any of Q-l.l-Q-1.97, Q-l.99-Q-l.115 or Q-l.117- Q-1.156, wherein Moiety D is:Q-l.158. The Compound of Formula Q-I or any of the foregoing wherein the compound is a compound selected from the following, in free or salt form:Table Q-l-ACompoundStructureNo.J k abs X N O O y-NHQ-5 H JH >=° ""'OCT"- “TTiXOpARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2Pharmaceutical is

[0066] The compounds of the present invention in free or a pharmaceutically acceptable salt thereof can be used as a therapeutically active substance, e.g. in the form of a pharmaceutical preparation or composition. The pharmaceutical preparations / compositions can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G., eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed„ Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington’s Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins, 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Liquid dosage forms, injectable preparations, solid dispersion forms, solid dosage form, and dosage forms for topical or transdermal administration of the compounds, the pharmaceutically acceptable salts of the compounds, and the pharmaceutical compositions described herein are included herein. In one aspect, the compounds, the pharmaceutically acceptable salts of the compounds, and the pharmaceutical compositions described herein are administered orally.

[0067] 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,ARVN-216-PCT / / ARVN0216WO2body 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.

[0068] Therefore, provided herein are pharmaceutical compositions comprising a compound described herein. Therefore, provided herein are pharmaceutical compositions comprising a compound described herein (e.g., Formula I or any of formulae 1.1-1.152 or 1.153-1.286, in free or pharmaceutically acceptable salt form) in combination or association with a pharmaceutically acceptable carrier (Composition I).

[0069] Also provided herein are pharmaceutical compositions comprising a compound of Formula Q-I or any of Q-l.l-Q-1.16 or Q-1.17-Q- 1.158, in free or pharmaceutically acceptable salt form) in combination or association with a pharmaceutically acceptable carrier (Composition Q-i).Methods of Treatment

[0070] 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 1.1-1.152 or 1.153-1.286), in free or pharmaceutically acceptable salt form, or an effective amount of any of the pharmaceutical compositions disclosed herein. In another aspect, provided herein are methods for the treatment of a KRAS mediated disorder (such as an abnormal cellular proliferation disease or disorder, including cancer) in a subject in need thereof (Method I-A), comprising administering to the subject an effective amount of any of the compounds disclosed herein (any of Formula I or any of 1.1-1.152 or 1.153-1.286), in free or pharmaceutically acceptable salt form, or an effective amount of any of the pharmaceutical compositions disclosed herein. In certain embodiments, Method I includes the following:3.1. Method I or I-A, wherein the disease or disorder is an abnormal cellular proliferation disorder such as a tumor or cancer.ARVN-216-PCT / / ARVN0216WO23.2. Method I or I-A or 3.1, wherein the disease or disorder is KRAS-mediated cancer.3.3. Method I or I-A 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 I-A, or any of methods 3.1-3.3, wherein the disease or disorder is mediated by a G12A mutant KRAS.3.5. Method I or I-A or any of methods 3.1-3.3, wherein the disease or disorder is mediated by a G12C mutant KRAS.3.6. Method I or I-A or any of methods 3.1-3.3, wherein the disease or disorder is mediated by a G12D mutant KRAS.3.7. Method I or I-A or any of methods 3.1-3.3, wherein the disease or disorder is mediated by a G12R mutant KRAS.3.8. Method I or I-A or any of methods 3.1-3.3, wherein the disease or disorder is mediated by a G 12V mutant KRAS.3.9. Method I or I-A or any of methods 3.1-3.2, wherein the disease or disorder is mediated by non-mutant wild-type KRAS.3.10. Method I or I-A or any of 3.1-3.9, wherein the cancer is pancreatic cancer, pancreatic ductal adenocarcinoma, pancreatic adenosquamous carcinoma, pancreatic squamous cell carcinoma, acinar cell carcinoma, giant cell tumor, pancreatoblastoma, invasive intraductal papillary mucinous neoplasm, invasive mucinous cystic neoplasm, colorectal cancer, colorectal adenocarcinoma, colorectal squamous cell carcinoma, lung cancer, non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, large cell carcinoma, or small cell lung cancer.3.11. Method I or 3.1-3.10, wherein the cancer is pancreatic, colorectal or lung cancer.3.12. Method I or 3.1-3.10, wherein the cancer is pancreatic cancer.3.13. Method I or 3.1-3.10, wherein the cancer is a pancreatic ductal adenocarcinoma.3.14. Method I or 3.1-3.10, wherein the cancer is colorectal cancer.3.15. Method I or 3.1-3.10, wherein the cancer is lung cancer.3.16. Method I or 3.1-3.10, wherein the cancer is a non-small cell lung cancer.3.17. Method I or any of the foregoing methods, wherein the subject is a human subject.ARVN-216-PCT / / ARVN0216WO23.18. Method I or any of the foregoing methods, wherein the subject is a non-human subject.3.19. Method I or any of the foregoing methods, further comprising administering one or more anticancer agent.3.20. 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.

[0071] 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-1.16 or Q-1.17-Q-1.158), 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-1.16 or Q-l.17-Q-l.158), 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 Q-I, wherein the disease or disorder is an abnormal cellular proliferation disorder such as a tumor or cancer.Q-3.2. Method Q-I or Q-3.1, wherein the disease or disorder is KRAS-mediated cancer. Q-3.3. Method Q-I or any of Q-3. l-Q-3.2, wherein the disease or disorder is mediated by a mutant form of KRAS.Q-3.4. Method Q-I or any of Q-3. l-Q-3.2, wherein the disease or disorder is mediated by a G12A mutant KRAS.Q-3.5. Method Q-I or any of Q-3. l-Q-3.2, wherein the disease or disorder is mediated by a G12C mutant KRASQ-3.6. Method Q-I or any of Q-3. l-Q-3.2, wherein the disease or disorder is mediated by a G12D mutant KRAS.ARVN-216-PCT / / ARVN0216WO2Q-3.7. Method Q-I or any of Q-3.1 -Q-3.2, wherein the disease or disorder is mediated a G12R mutant KRAS.Q-3.8. Method Q-I or any of Q-3. l-Q-3.2, wherein the disease or disorder is mediated a G12V mutant KRAS.Q-3.9. Method Q-I or any of Q-3. l-Q-3.2, wherein the disease or disorder is mediated by non-mutant wild-type KRAS.Q-3.10. Method Q-I or Q-3. l-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 Q-I or Q-3.l-Q-3.10 wherein the cancer is pancreatic, colorectal or lung cancer.Q-3.12. Method Q-I or Q-3.l-Q-3.10 wherein the cancer is pancreatic cancer.Q-3.13. Method Q-I or Q-3. l-Q-3.10 wherein the cancer is a pancreatic ductal adenocarcinoma.Q-3.14. Method Q-I or Q-3. l-Q-3.10 wherein the cancer is colorectal cancer.Q-3.15. Method Q-I or Q-3. l-Q-3.10 wherein the cancer is lung cancer.Q-3.16. Method Q-I or Q-3. l-Q-3.10 wherein the cancer is a non-small cell lung cancer. Q-3.17. Method Q-I or any of the foregoing methods, wherein the subject is a human subject.Q-3.18. Method Q-I or any of the foregoing methods, wherein the subject is a non-human subjectQ-3.19. Method Q-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.ARVN-216-PCT / / ARVN0216WO2

[0072] 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.

[0073] 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).

[0074] It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific inhibitory dose for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age. body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.Kits

[0075] 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.ARVN-216-PCT / / ARVN0216WO2

[0076] The disclosure provides a kit comprising a compound capable of degrading KRAS selected from a compound disclosed herein.

[0077] Also provided herein are kits comprising a compound disclosed herein for the treatment of any of the indications disclosed herein.

[0078] 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.

[0079] 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.

[0080] 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:

[0081] The compounds of the present disclosure may generally be prepared as follows:Synthesis of INT-30 o o o K2CO3F F INT-1 INT-2 INT-3ARVN-216-PCT / / ARVN0216WO2General Synthetic Scheme 1INT-4 INT-5 INT-6 X = F, ClARVN-216-PCT / / ARVN0216WO2General Synthetic Scheme 2MsCI, TEAHNWhereinrepresents moiety A as defined herein and linker is moieites -B-C and ULM is a ubiquitin E3 ligase.ARVN-216-PCT / / ARVN0216WO2HCI / DioxaneINT-17whereinrepresents moiety A as defined herein and linker is moieties -B-C and ULM is a ubiquitin E3 ligase.General Synthetic SchemeARVN-216-PCT / / ARVN0216WO2wherein A as defined herein and linker is moieties -B-C and ULM is a ubiquitin E3 ligase.ARVN-216-PCT / / ARVN0216WO2EXAMPLES

[0082] 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.

[0083] 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.Synthetic ProceduresAbbreviations:cataCXium A Pd G3 mesylate[(di( 1 -adamantyl)-n-butylphosphine)-2-(2'-amino- 1,1'- biphenyl)] palladium(II)EtOAc ethyl acetaten-BuLi n-butyl lithiumprep-HPLC preparative high performance liquid chromatography RuPhos Pd G3 (2-Dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)[2-(2'- amino- 1, 1 '-biphenyl)]palladium(II) methanesulfonateSFC Supercritical fluid chromatographyXPhos Pd G2 Chloro(2-dicyclohexylphosphino-2',4’,6'-triisopropyl-l, T- biphenyl) [2-(2 '-amino- 1, 1 '-biphenyl)]palladium(II)Example 1.1Exemplary synthesis of Compound No. 1: 3-[5-[4-[[l-[[(lR)-l-[[(8S)-13-(8-ethyl-7-fhioro-3-hydroxy- 1 -naphthyl)- 14- fluoro-6, 10-dioxa-2, 12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),11.13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluorocyclopropyl] methyl] -4-piperidyl] methyl] piperazin- 1 -yl] -4-fluoro- 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dioneStep 1:ARVN-216-PCT / / ARVN0216WO2BnO2-picoline boraneAcOH / MeOH25-50°C, 13h

[0084] To a solution of 5-bromo-4-fluoro-3-hydroxy-3H-isobenzofuran-l-one (900 mg, 3.6 mmol) in acetic acid (9 mL) and methanol (9 mL) is added 2,6-dibenzyloxypyridin-3-amine (1.12 g, 3.6 mmol). The mixture is stirred at 25 °C for 0.5 h, followed by the addition of 2-methylpyridine borane (779.4 mg, 7.3 mmol). The reaction mixture is stirred at 50 °C for 12 h, then diluted with sodium bicarbonate until pH 8, the resulting mixture is extracted with dichloromethane (20 mL x 3), and the combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-40% ethyl acetate / petroleum ether) to afford 5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)-4-fluoro-isoindolin-l-one (1.3 g, 69%) as a white solid. MS (ESI) m / z 519.0 [M+H]+;NMR (400 MHz, CDC13) d: 7.74 - 7.66 (m, 2H), 7.64 - 7.59 (m, 1H), 7.45 - 7.28 (m, 10H), 6.51 (d, J = 8.4 Hz, 1H), 5.41 (s, 2H), 5.35 (s, 2H), 4.82 (s, 2H).Step 2:

[0085] A mixture of 5-bromo-2-(2,6-dibenzyloxy-3-pyridyl)-4-fluoro-isoindolin-l-one (10 g, 19 mmol), tert-butyl 4-(piperazin-l-ylmethyl)piperidine-l -carboxylate (6.55 g, 23 mmol), cesium carbonate (18.82 g, 58 mmol) and Xphos Pd G2 (1.51 g, 1.9 mmol) in dioxane (100 mL) is degassed and purged with nitrogen several times, and then the mixture is stirred at 100 °C for 12 h under nitrogen atmosphere. The mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase is washed with brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (40-80% ethyl acetate / petroleum ether). The crudeARVN-216-PCT / / ARVN0216WO2product is purified by prep-HPLC (40%-60% acetonitrile in water (formic acid) over 15 min) to afford tert-butyl 4-[[4-[2-(2,6-dibenzyloxy-3-pyridyl)-4-fluoro-l-oxo-isoindolin-5-yl]piperazin- l-yl]methyl]piperidine-l-carboxylate (7.6 g, 55%) as a yellow solid. MS (ESI) m / z722.3 [M+H]+; NMR (400MHz, DMSO-tfc) 3: 7.76 (d, J= 8.4 Hz, 1H), 7.51 (d, J= 8.0 Hz, 1H), 7.46 - 7.26 (m, 10H), 7.16 (t,. / = 7.6 Hz, 1H), 6.54 (d,. / = 8.4 Hz, 1H), 5.44 - 5.30 (m, 4H), 4.77 (s. 2H). 3.97 - 3.85 (m, 2H), 3.44 - 3.39 (m, 2H), 3.34 (s. 2H). 3.18 - 3.08 (m, 4H). 2.79 - 2.62 (m, 2H), 2.18 (d, J- 6.4 Hz, 2H), 1.77 - 1.61 (m, 3H), 1.39 (s, 9H), 1.02 - 0.85 (m, 2H).Step 3:Pd / C, Pd(OH)2H2(50 psi) THF 40 °C, 12h

[0086] To a solution of tert-butyl 4-[[4-[2-(2,6-dibenzyloxy-3-pyridyl)-4-fluoro-l-oxo-isoindolin-5-yl]piperazin-l-yl]methyl]piperidine-l-carboxylate (7.6 g, 10 mmol) in tetrahydrofuran (80 mL) is added 10% palladium on carbon (0.76 g) and 20% palladium hydroxide (0.76 g) under nitrogen. The suspension is degassed and purged with hydrogen several times. The mixture is stirred at 40 °C under hydrogen (50 psi) for 12 h, then filtered and concentrated under reduced pressure. The crude product is triturated with dichloromethane at 25 °C for 20 min, filtered and dried to afford tert-butyl 4-[[4-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-l- oxo-isoindolin-5-yl]piperazin-l-yl]methyl]piperidine-l-carboxylate (4.2 g, 73%) as a gray solid. MS (EST) m / z544.3 [M+H]+; 'H NMR (400MHz, DMSO-6) 3 10.97 (s, 1H), 7.55 - 7.43 (m, 1H), 7.15 (t, J = 8.0 Hz, 1H), 5.11 - 5.00 (m, 1H), 4.60 - 4.23 (m, 2H), 4.00 - 3.83 (m, 2H), 3.65 - 3.55 (m, 3H), 3.18 - 3.07 (m, 4H), 2.97 - 2.82 (m. 1H), 2.80 - 2.65 (m, 2H), 2.64 - 2.55 (m, 2H), 2.46 - 2.34 (m, 1H), 2.23 - 2.17 (m, 2H), 2.05 - 1.91 (m, 1H), 1.73 - 1.64 (m, 3H), 1.39 (s, 9H), 1.02 - 1.91 (m, 2H).Step 4:ARVN-216-PCT / / ARVN0216WO2

[0087] To a solution of tert-butyl 4-[[4-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-l-oxo-isoindolin-5-yl]piperazin-l-yl]methyl]piperidine-l-carboxylate (4.1 g, 7 mmol) in dichloromethane (40 mL) is added trifluoroacetic acid (20 mL). The mixture is stirred at 25 °C for 0.5 h, then concentrated under reduced pressure. The residue is diluted with acetonitrile (30 mL), and N, / V-diisopropylethylamine is added to adjust the pH to 8. The mixture is filtered and concentrated under reduced pressure to afford 3-[4-fluoro-l-oxo-5-[4-(4-piperidylmethyl)piperazin-l-yl]isoindolin-2-yl]piperidine-2, 6-dione (4.75 g, crude, 2 TFA salt) as a gray solid. MS (ESI) m / z 444.3 [M+H]+; ‘H NMR (400MHz, DMSO-6): 10.98 (s, 1H), 8.70 - 8.07 (m, 3H), 7.48 (d, 7= 8.0 Hz, 1H), 7.16 (t, 7= 8.0 Hz, 1H), 5.11 -5.01 (m, 1H), 4.55 -4.23 (m, 2H), 3.69 - 3.53 (m, 2H), 3.33 - 3.23 (m, 4H), 3.20 - 3.02 (m, 6H), 2.92 - 2.80 (m, 3H), 2.64 - 2.58 (m, 1H), 2.44 - 2.35 (m, 1H). 2.25 - 2.15 (m, 2H), 2.02 - 1.94 (m, 1H), 1.91 - 1.81 (m.3H).Step 5:

[0088] A mixture of 5,7-dichloro-8-fhioro-2-methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one (8.50 g, 30 mmol) and tert-butyl (3 / ?)-3-(hydroxymethyl)-l,4-oxazepane-4-carboxylate (7.02 g, 30 mmol) in tetrahydrofuran (210 mL) is cooled to -5°C, and sodium hydride (4.86 g, 121 mmol, 60%) is added slowly under nitrogen. The mixture is stirred at -5°C for 2 h, then 25°C for 12 h under nitrogen. The reaction mixture is slowly quenched with saturated ammonium chloride solution (100 mL), and the mixture is extracted with ethyl acetate / methanol (10:1, 100 mL x 3). The combined organic phase is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl (3S)-3-[(7-chloro-8-fluoro-2-methylsulfanyl-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)oxymethyl]-l,4-oxazepane-4-carboxylateARVN-216-PCT / / ARVN0216WO2(14.4 g, crude) as a light yellow solid, which is used in the next step directly. MS (ESI) m / z 375.0 [M-100+H]+.

[0089] To a solution of tert-butyl (3S)-3-[(7-chloro-8-fluoro-2-methylsulfanyl-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)oxymethyl]-l,4-oxazepane-4-carboxylate (14.4 g, 30 mmol) in dichloromethane (60 mL) is added 2 M hydrochloric acid in dioxane (60 mL). The mixture is stirred at 25 °C for 2 h, then concentrated under reduced pressure. The residue is diluted with water (200 mL) and 2 M aqueous hydrochloric acid solution is added to adjust the pH to 2. The mixture is extracted with ethyl acetate (100 mL x 2), and the aqueous layer is separated and freeze-dried to afford 7-chloro-8-fluoro-2-methylsulfanyl-5-[[(3S)-l,4-oxazepan-3-yl]methoxy]-3H-pyrido[4,3-d]pyrimidin-4-one (11 g, 72%. 82% purity, HC1 salt) as a white solid, which is used in the next step directly. MS (ESI) m / z 375.0 [M+H]+.Step 7:F

[0090] To a solution of 7-chloro-8-fluoro-2-methylsulfanyl-5-[[(3S)-l,4-oxazepan-3-yl]methoxy]-3H-pyrido[4,3-d]pyrimidin-4-one (11 g, 22 mmol, hydrochloride) and N, N-diisopropylethylamine (38.2 mL) in toluene (275 mL) is added phosphorus oxychloride (8.18 mL, 88 mmol) at 0°C, and the mixture is stirred at 25°C for 2 h. The mixture is poured into water (300 mL), and sodium carbonate solid is added to adjust the pH to 7-8. The mixture is extractedARVN-216-PCT / / ARVN0216WO2with EtOAc (200 mL x 2), the combined organic phase is washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (petroleum ether:ethyl acetate = 10:1 to 0:1). The crude product is purified by preparative HPLC (35%-60% acetonitrile in water (formic acid) over 20 min) to afford (8S)-13-chloro-14-fluoro-17-methylsulfanyl-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02, 8.015, 19]nonadeca-l(19), 11.13, 15, 17-pentaene (4.1 g, 50%) as a light yellow solid. MS (ESI) m / z 356.9 [M+H]+;NMR (400MHz, DMSO-6) 8: 5.02- 4.96 (m, 1H), 4.69 - 4.65 (m, 1H), 4.52 (d, J = 13.2 Hz, 1H), 4.31 - 4.27 (m, 1H), 4.10 - 4.06 (m, 1H), 3.88 - 3.83 (m, 1H), 3.60 - 3.54 (m, 1H), 3.42 - 3.37 (m, 2H), 2.53 (s, 3H), 2.00 - 1.83 (m, 2H).Step 8:

[0091] To a solution of (8S)-13-chloro-14-fluoro-17-methylsulfanyl-6,10-dioxa- 2, 12, 16, 18-tetrazatetracyclo[9.7.1.02, 8.015, 19]nonadeca- 1(19), 11, 13, 15, 17-pentaene (3.6 g, 10 mmol) in N,N-dimethylformamide (40 mL) is added 4A molecular sieves (3.6 g, 1.4 mmol), the mixture is stirred for 4 h, and Oxone (15.51 g, 25 mmol) is added. The reaction mixture is stirred at 25 °C for 12 h, filtered, and the filter cake is washed with ethyl acetate (200 mL). The filtrate solution is washed with saturated aqueous sodium sulfite solution (60 mL x 2), and concentrated under reduced pressure to afford (85)-13-chloro-14-fluoro-17-methylsulfonyl-6,10-dioxa-2, 12, 16, 18-tetrazatetracyclo[9.7.1.02, 8.015, 19]nonadeca- 1(19), 11, 13.15, 17-pentaene (3.7 g, 88%) as a light yellow solid, which is used in the next step directly. MS (ESI) m / z 388.9 [M+H]+; NMR (400MHz, DMSO-nfe) 6: 5.01- 4.95 (m, 1H), 4.77 - 4.73 (m, 1H), 4.63 - 4.57 (m, 1H), 4.43 -4.39 (m, 1H), 4.14 - 4.10 (m, 1H), 3.90 - 3.84 (m, 1H), 3.65 - 3.59 (m, 1H), 3.53 - 3.48 (m, 2H), 3.39 (s, 3H), 2.01 - 1.88 (m, 2H).Step 9:ARVN-216-PCT / / ARVN0216WO2diglyme, 180°C, 5h

[0092] To a solution of 2-methylenepropane-l,3-diyl diacetate (20.0 g, 116 mmol) in 1-methoxy-2-(2-methoxyethoxy)ethane (200 mL) is dropwise added sodium 2-chloro-2,2-difluoroacetate (88.55 g, 581 mmol) in l-methoxy-2-(2-methoxyethoxy)ethane (200 mL) over 4 h at 180 °C, and the solution is stirred at 180 °C for 1 h. The reaction mixture is cooled to room temperature and diluted with water (1000 mL). The mixture is extracted with petroleum ether (1000 mL x 3), and the combined organic layers are washed with water (1000 mL x 4) and brine (1000 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (2,2-difluorocyclopropane-l,l-diyl)bis(methylene) diacetate (28 g, crude) as a black oil, which is used in the next step directly. 'H NMR (400 MHz, CDCls-d) d: 4.30 (m, 2H), 4.11 (d. J = 12.0 Hz. 2H), 2.09 (s, 6H), 1.47 (t, J= 8.8 Hz, 2H).Step 10:K2CO3, MeOH,25°C, 12h

[0093] To a solution of (2,2-difluorocyclopropane-l,l-diyl)bis(methylene)diacetate (28.0 g, 126 mmol) in methanol (250 mL) is added potassium carbonate (34.83 g, 252 mmol), and the mixture is stirred at 25 °C for 12 h. The reaction mixture is filtered, the filtrate solution is diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 4). The combined organic layers are washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (0-69% ethyl acetate / petroleum ether) to afford (2,2-difluorocyclopropane-l,l-diyl)dimethanol (4.3 g, 24%) as a yellow solid. *H NMR (400 MHz, DMSO-d6) 6: 4.78 (d, J= 2.4 Hz, 2H), 3.51 (d, J = 1.6 Hz, 4H), 1.29 (t, J= 8.8 Hz. 2H).Step 11:ARVN-216-PCT / / ARVN0216WO2Cs2CO3, DMAc, 25 °C, 1 h

[0094] To a solution of (85)-13-chloro-14-fluoro-17-methylsulfonyl-6.10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaene (3.7 g, 9.5 mmol) in N,N-dimethylacetamide (80 mL) are added cesium carbonate (9.30 g, 28 mmol) and [2,2-difluoro-l-(hydroxymethyl)cyclopropyl]methanol (2.63 g, 19 mmol). The mixture is stirred at 25 °C for 1 h, then diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2).The combined organic phase is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 0:1) to afford [l-[[(8S)-13-chloro-14-fluoro-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),11.13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (3 g, 70%) as a white solid. MS (ESI) m / z 447.0 [M+H]+; NMR (400MHz, DMSO-d6) 5: 5.09 (t, J= 5.6 Hz, 1H), 4.99- 4.92 (m, 1H), 4.69 - 4.65 (m, 1H), 4.60 (d, J = 11.6 Hz, 1H), 4.50 (d, J = 13.2 Hz, 1H), 4.42 (d, J = 11.6 Hz, 1H), 4.31 - 4.27 (m, 1H), 4.09 - 4.05 (m, 1H), 3.88 - 3.83 (m, 1H), 3.60 - 3.54 (m, 3H), 3.44 - 3.41 (m, 2H), 2.01 - 1.94 (m, 1H), 1.89 - 1.83 (m, 1H), 1.73 - 1.66 (m, 1H), 1.59 - 1.52 (m. 1H).Step 12:

[0095] To a solution of [l-[[(8S)-13-chloro-14-fluoro-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]-2.2-ARVN-216-PCT / / ARVN0216WO2difluoro-cyclopropyl]methanol (1.00 g, 2 mmol) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.61 g, 4.5 mmol) in tetrahydrofuran (20 mL) is added potassium phosphate (1.5 M, 4.5 mL) and CataCXium A Pd G3 (163 mg, 0.23 mmol) at 25°C. The mixture is stirred at 70°C for 12 h under nitrogen, then diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 0:1) to afford [l-[[(85)-13-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-14-fluoro-6,10-dioxa-2,12, 16,18-tetrazatetracyclo[9.7.1.02, 8.015, 19]nonadeca-l(19),l 1,13, 15,17-pentaen-17-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (3.4 g, 78%) as white solid. MS (ESI) m / z 645.2 [M+H]+; 'H NMR (400MHz, CDCh). 5: 7.67 - 7.63 (m. 1H). 7.48 (d, J= 2.0 Hz. 1H), 7.27 - 7.20 (m, 2H), 5.30 - 5.22 (m, 3H), 4.86 - 4.79 (m, 1H), 4.70 - 4.45 (m, 3H), 4.23 - 4.00 (m, 4H), 3.86 - 3.62 (m. 3H), 3.51 (s, 4H), 3.43 - 3.32 (m, 1H), 2.61 - 2.21 (m, 3H), 2.05 - 2.02 (m, 1H), 1.56 - 1.37 (m, 2H). 0.95 - 0.90 (m, 3H).Step 13:ARVN-216-PCT / / ARVN0216WO2

[0096] [l-[[(8S)H3-[8-ethyl-7Tluoro-3-(methoxymethoxy)-l -naphthyl]- 14-fluoro-6, 10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl] oxymethyl] -2,2-difluoro-cyclopropyl] methanol (3.4 g) is purified by SFC (40% acetonitrile / isopropanol (0.1% ammonium hydroxide) in carbon dioxide, isocratic elution mode). The first eluted fraction is assigned as [(lR)-l-[[(8S)-13-[8-ethyl-7-fluoro-3-(methoxymethoxy)- l-naphthyl]-14-fluoro-6,10-dioxa-2,12,16.18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca- l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (1.55 g, 45%) as a light yellow solid. MS (ESI) m / z: 645.1 [M+H]+:NMR (400MHz, CDC13) 5: 7.67 - 7.63 (m, 1H), 7.48 (d, 7= 2.0 Hz, 1H), 7.27 - 7.20 (m, 2H), 5.31 - 5.22 (m, 3H), 4.86 -4.77 (m, 1H), 4.71 - 4.46 (m, 3H), 4.25 - 4.19 (m, 1H), 4.14 - 4.07 (m, 1H), 4.06 - 4.00 (m, 1H), 3.86 - 3.62 (m, 3H), 3.54 - 3.48 (m, 4H), 3.43 - 3.32 (m, 1H), 2.61 - 2.23 (m. 3H), 2.08 - 2.02 (m, 1H), 1.56 - 1.37 (m, 2H), 0.95 - 0.91 (m, 3H). The second eluted fraction is assigned as [(1 )-1-[[(8S)-13-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-14-fluoro-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),11.13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (1.6 g, 47%) as a light yellow solid. MS (ESI) m / z: 645.2 [M+H]+; NMR (400MHz, CDCI3) 8: 7.67 - 7.63 (m, 1H), 7.48 (s, 1H), 7.29 - 7.20 (m. 2H), 5.30 - 5.22 (m, 3H), 4.86 - 4.77 (m, 1H), 4.69 - 4.46 (m, 3H), 4.23 - 4.19 (m, 1H), 4.13 - 4.07 (m, 1H), 4.06 - 3.99 (m, 1H), 3.85 - 3.64 (m, 3H), 3.54 - 3.48 (m, 4H), 3.41 - 3.31 (m, 1H), 2.56 - 2.20 (m, 3H), 2.06 - 1.99 (m, 1H), 1.56 - 1.39 (m, 2H), 0.95 - 0.90 (m. 3H).OMs

[0097] To a solution of [(lR)-l-[[(85)-13-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-14-fluoro-6,10-dioxa-2, 12, 16.18-tetrazatetracyclo[9.7.1.02, 8.015, 19]nonadeca- l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (250 mg, 0.4 mmol) and triethylamine (160 μL) in dichloromethane (5 mL) is drop wise addedARVN-216-PCT / / ARVN0216WO2methanesulfonyl chloride (350 μL) at 0°C under nitrogen. The mixture is stirred at 25 °C for 1 h, then diluted with water (20 mL) and extracted with dichloromethane (30 mL x 2). The combined organic layers are washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford [( IS)- 1 -[[(8S)- 13-[8-ethyl-7-fhioro-3-(methoxymethoxy)-l-naphthyl]-14-fluoro-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),11.13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (280 mg, crude) as a light yellow oil, which is used in the next step directly. MS (ESI) m / z: 723.1 [M+H]+.Step 15:

[0098] A mixture of 3-[4-fluoro-l-oxo-5-[4-(4-piperidylmethyl)piperazin-l-yl]isoindolin-2-yl]piperidine-2, 6-dione (240 mg, 0.43 mmol, 1.73 eq, trifluoroacetate), [(1S)-1-[[(8S)-13-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-14-fluoro-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),11.13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (180 mg, 0.25 mmol), sodium carbonate (264 mg 2.5 mmol) and potassium iodide (331 mg, 2 mmol) in A, A-dimethylformamide (7 mL) is stirredARVN-216-PCT / / ARVN0216WO2at 90 °C for 12 h. The reaction mixture suspended in water (10 mL), filtered to obtain an off-white solid. The above solid is dissolved in dichloromethane (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1) to afford 3-[5-[4-[[l -[[( 17?)- 1 - [[(8S)-13-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-14-fluoro-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),11.13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluorocyclopropyl] methyl] -4-piperidyl] methyl] piperazin- 1 -yl] -4-fluoro- 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dione (170 mg, 64%) as an off-white solid. MS (ESI) m / z 1070.7 [M+H]+.Step 16:

[0099] To a solution of 3-[5-[4-[[l-[[(17?)- l-[[(8S)-13-[8-ethyl-7-fluoro-3-(methoxymethoxy)- 1 - naphthyl]- 14-fluoro-6, 10-dioxa-2, 12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (170 mg, 0.2 mmol) in dichloromethane (2 mL) is added 2 M hydrochloride in dioxane (2 mL) at 25 °C and stirred for 10 min. The reaction mixture is suspended in methyl r -butyl ether (20 mL) and filtered. The filter cake is purified by prep-HPLC (10%-40% acetonitrile in water (0.225% formic acid) over 15 min) to afford 3-[5-[4-[[l-ARVN-216-PCT / / ARVN0216WO2[[( 1 R)- 1 - [[(8S)- 13-(8-ethyl-7-fluoro-3-hydroxy- 1 -naphthyl)- 14-fluoro-6, 10-dioxa-2, 12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluorocyclopropyl] methyl] -4-piperidyl] methyl] piperazin- 1 -yl] -4-fluoro- 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dione (124.9 mg, 73%, formate salt) as a white solid. MS (ESI) m / z: 1026.6 [M+H]+; NMR (400 MHz, DMSO-dy 5: 10.99 (s, 1H), 10.11 - 9.69 (m, 1H), 8.14 (s, 1H), 7.75 (dd, J = 6.0, 9.2 Hz, 1H), 7.48 (d. J = 8.0 Hz, 1H). 7.38 - 7.29 (m, 2H), 7.14 (t, J = 8.0 Hz, 1H), 7.07 - 6.97 (m, 1H), 5.13 - 4.95 (m, 2H), 4.70 - 4.28 (m, 7H), 4.16 - 4.08 (m, 1H), 3.96 -3.86 (m, 1H), 3.71 - 3.39 (m, 5H), 3.12 (s, 4H), 2.94 - 2.54 (m, 8H), 2.43 - 2.39 (m, 2H), 2.25 -1.77 (m, 9H), 1.70 - 1.64 (m, 2H), 1.53 - 1.47 (m, 2H), 1.14 - 0.95 (m, 2H), 0.85 - 0.79 (m, 3H).Example 1.2Exemplary synthesis of Compound 4: 3-[5-[(2S)-4-[[l-[[(lR)-l-[[(8S)-13-(8-ethyl-7-fluoro-3-hydroxy- 1 -naphthyl)- 14-fluoro-6, 10-dioxa-2, 12,16,18-tetrazatetracyclo[9.7.1.02'8.015 19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]-2,2-difhioro-cyclopropyl]methyl]-4-piperidyl]methyl] -2-methyl-piperazin- 1 -yl] -4-fluoro- 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dioneStep 1:

[0100] A mixture of t -butyl (3 )-3-methylpiperazine-l -carboxylate (9.45 g, 47 mmol), methyl 4-bromo-3-fluoro-benzoate (10 g, 43 mmol), cesium carbonate (41.94 g, 129 mmol) and RuPhos Pd G3 (2.87 g, 3.4 mmol) in dioxane (100 mL) is degassed and purged with nitrogen several times. The reaction mixture is stirred at 100 °C for 12 h, then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1). The crude product is purified by prep-HPLC (55%-85% acetonitrile in water (formic acid) over 20 min) to afford fert-butyl (3S)-4-(2-fluoro-4-methoxycarbonyl-phenyl)-3-methyl-piperazine-1 -carboxylate (10 g, 66%) as a light yellow gum. MS (ESI) m / z'. 353.4ARVN-216-PCT / / ARVN0216WO2[M+H]+;1H NMR (400 MHz, CDC13) b: 7.75 (dd, J = 2.0, 8.4 Hz, 1 H), 7.68 (dd, J = 2.0, 13.6 Hz, 1H), 6.91 (t, J= 8.4 Hz, 1H), 4.07 - 3.93 (m, 1H), 3.89 (s, 3H), 3.87 - 3.77 (m, 1H), 3.67 (td, 7= 2.0, 13.2 Hz, 1H), 3.44 (dd.7 = 3.6, 13.2 Hz, 1H), 3.37 - 3.15 (m, 2H), 3.01 (brdd, 7= 3.6, 8.4 Hz, 1H), 1.49 (s, 9H), 1.03 (d, 7 = 6.4 Hz, 3H).Step 2:LiOH, THF / MeOH / H2O 25 °C, 1 h

[0101] To a solution of tert-butyl (3S)-4-(2-fhroro-4-methoxycarbonyl-phenyl)-3-methyl-piperazine -1 -carboxylate (20 g, 57 mmol) in methanol (50 mL), tetrahydrofuran (50 mL) and water (50 mL) is added lithium hydroxide (11.91 g, 284 mmol). The reaction mixture is stirred at 25 °C for 1 h, then concentrated under reduced pressure. The residue is diluted with water (50 mL), the pH is adjusted to 5 by citric acid, and the resulting mixture is extracted with ethyl acetate (60 mL x 3). The combined organic layer is washed with brine (40 mL x 3). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated to afford 4-[(2S)-4-tert-butoxycarbonyl-2-methyl-piperazin-l-yl]-3-fluoro- benzoic acid (15.3 g, 79%) as a light yellow solid. MS (ESI) m / z 339.2 [M+H]+; 'H NMR (400 MHz, DMSO-tfc) 3 7.68 (dd, J= 2.0, 8.4 Hz, 1H), 7.57 (dd, J= 2.0. 13.6 Hz. 1H), 7.09 (t. J= 8.8 Hz, 1H), 3.91 - 3.72 (m, 2H), 3.65 - 3.54 (m.1H), 3.27 - 3.06 (m, 3H), 3.05 - 2.92 (m, 1H), 1.42 (s, 9H), 0.93 (d, 7= 6.4 Hz, 3H).Step 3:

[0102] To a mixture of 4-[(2S)-4-tert-butoxycarbonyl-2-methyl-piperazin-l-yl]-3-fluoro-benzoic acid (16 g, 47 mmol) in tetrahydrofuran (320 mL) is dropwise added n-BuLi (2.5 M, 43.5 mL) at -70 °C and stirred at -70 °C for 1 h under nitrogen. Then / V-dimethylformamideARVN-216-PCT / / ARVN0216WO2(19 mL) is added at -70 °C and stirred for 1 h under nitrogen. The reaction mixture is quenched by citric acid (300 mL) and stirred for 2 min. The resulting mixture is extracted with ethyl acetate (300 mL x 3). The combined organic phase is washed with brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (40%-70% acetonitrile in water (formic acid) over 20 min) to afford tertbutyl (3S)-4-(4-fluoro-3-hydroxy-l-oxo-3H-isobenzofuran-5-yl)-3-methyl-piperazine-l-carboxylate (15.2 g, 87%) as a white solid. MS (ESI) nVz 389.2 [M+Na]+; 'H NMR (400 MHz, DMSO-de) 3 8.23 (br s. 1H), 7.60 - 7.49 (m, 1H). 7.30 - 7.20 (m, 1H), 6.71 (s, 1H), 3.84 (br dd, J= 3.2, 6.4 Hz, 2H), 3.63 (br d, J= 13.2 Hz, 1H), 3.34 - 3.22 (m, 2H), 3.18 - 2.97 (m, 2H), 1.52 -1.37 (m, 9H), 1.06 - 0.89 (m, 3H).Step 4:

[0103] To a mixture of 3-aminopiperidine-2, 6-dione (8.19 g, 50 mmol, hydrochloride) in methanol (150 mL) are added sodium acetate (10.21 g, 124 mmol), tert-butyl (3S)-4-(4-fluoro-3-hydroxy- 1 -oxo-3H-isobenzofuran-5-yl)-3-methyl-piperazine- 1 -carboxylate (15.2 g, 41 mmol) and acetic acid (15 mL). The mixture is stirred at 25 °C for 1 h, then 2-methylpyridine borane (8.87 g, 83 mmol) is added, and the mixture is stirred at 50 °C for 12 h before the addition of 2-methylpyridine borane (4.44 g, 41 mmol). The reaction mixture is stirred at 50 °C for 12 h, then filtered and concentrated to afford 4-[(21S')-4-t rt-butoxycarbonyl-2-methyl-piperazin-l-yl]-2-[[(2,6-dioxo- 3-piperidyl)amino]methyl]-3-fluoro-benzoic acid (13.6 g, 68%) as a gray solid. MS (ESI) m / z 479.3 [M+H]+.ARVN-216-PCT / / ARVN0216WO2

[0104] To a solution of 4-[(2S)-4-t rt-butoxycarbonyl-2-methyl-piperazin-l-yl]-2-[[(2,6-dioxo-3- piperidyl)amino]methyl]-3-fluoro-benzoic acid (12.6 g, 26 mmol) and N, N-diisopropylethylamine (13.8 mL, 79 mmol) in A( / V-dimethylformamide (130 mL) is added O- -azabenzotriazol-l-yl)- A; A / \ / \'7!-tetramethyliironiiim hexafluorophosphate (10.01 g, 26 mmol) at 0 °C. The mixture is stirred at 25 °C for 0.5 h. The mixture is diluted with tetrahydrofuran / ethyl acetate (v / v = 1 / 1, 600 mL) and washed with brine (80 mL x 3). The organic layer is filtered and the filtered cake is collected. The filtrate solution is concentrated, the residue is triturated with t-butyl methyl ether (30 mL), filtered and the filtered cake is collected. The combined solid is dried in vacuo to afford tert-butyl (35)-4-[2-(2,6-dioxo-3- piperidyl)-4-fluoro-l-oxo-isoindolin-5-yl]-3-methyLpiperazine-l-carboxylate (10.09 g, 83%) as a gray solid. MS (ESI) ni / z 461.2 [M+H]+; ’H NMR (400 MHz, DMSO-(fc) d 10.99 (s. 1H), 7.49 (d, J= 8.0 Hz, 1H), 7.20 (s. 1H), 5.07 (dd, J = 5.2, 13.2 Hz, 1H), 4.60 - 4.43 (m, 1H), 4.40 - 4.29 (m, 1H), 3.87 - 3.64 (m, 2H), 3.56 - 3.40 (m, 2H), 3.28 - 3.13 (m, 2H), 3.02 - 2.90 (m, 2H), 2.59 (br d, J= 17.6 Hz, 1H), 2.48 -2.34 (m, 1H), 2.08 - 1.92 (m, 1H), 1.42 (s. 9H), 0.92 (d, J = 6.4 Hz, 3H).Step 6:O O TFA / DCM 25 °C, 2 h

[0105] To a solution of tert-butyl (3, S')-4-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-l-oxo-isoindolin-5 -yl]-3-methyl-piperazine-l-carboxylate (5.49 g, 12 mmol) in dichloromethane (50 mL) is added trifluoroacetic acid (10 mL). The mixture is stirred at 25 °C for 2 h, then concentrated under reduced pressure to afford 3-[4-fluoro-5-[(2S)-2-methylpiperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (5.7 g. crude, trifluoroacetate salt) as a brown gum, which is used in the next step directly. MS (ESI) m / ~ 361.1 [M+H]+.DIEA, NaBH(OAc)3, DCM / i-PrOH25°C, 12 5 hARVN-216-PCT / / ARVN0216WO2

[0106] To a solution of 3-[4-fluoro-5-[(2S)-2-methylpiperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (5.7 g, 12 mmol, trifluoroacetate) in dichloromethane (55 mL) and isopropanol (55 mL) are added. AMiisopropylethylamine (6.3 mL, 36 mmol) and tert-butyl 4-formylpiperidine- 1 -carboxylate (2.82 g, 13 mmol). The mixture is stirred at 25 °C for 0.5 h, then sodium triacetoxyborohydride (7.64 g, 36 mmol) is added, and the reaction mixture is stirred at 25 °C for 12 h. The mixture is diluted with water (100 mL) and extracted with dichloromethane (100 mL x 2). The combined organic layer is dried over anhydrous sodium sulfate, filtered and concentrated. The residue is triturated with t-butyl methyl ether (80 mL) to afford tert-butyl 4- [[(3S)-4-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-l-oxo-isoindolin-5-yl]-3-methyl-piperazin-l-yl]methyl]piperidine-l-carboxylate (6.05 g, 90%) as a gray solid. MS (ESI) m / z:. 558.2 [M+H]+; ’H NMR (400 MHz. DMSO_d6) d: 10.97 (s, 1H), 7.48 (br d. J = 5.2 Hz, 1H), 7.20 (br d, J= 3.6 Hz, 1H), 5.07 (br dd, J = 4.8, 13.2 Hz, 1H), 4.54 - 4.44 (m, 1H), 4.38 - 4.24 (m, 1H), 3.92 (br d, J = 12.8 Hz, 2H), 3.83 - 3.54 (m, 2H), 3.27 - 3.18 (m, 1H), 3.13 (ddd, J= 4.0, 7.2, 10.8 Hz, 1H), 2.90 (ddd, J = 5.2, 12.8. 18.4 Hz. 2H), 2.80 - 2.65 (m, 2H). 2.63 - 2.55 (m, 2H), 2.47 - 2.30 (m.3H), 2.23 - 2.09 (m, 1H), 2.04 - 1.94 (m, 1H), 1.70 (brd, J = 11.6 Hz, 3H), 1.39 (s, 9H), 1.29 - 1.19 (m, 3H), 0.99 (br s, 3H).Step 8:o o

[0107] To a solution of tert-butyl 4-[[(3S)-4-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-l-oxo-isoindolin-5- yl]-3-methyl-piperazin-l-yl]methyl]piperidine-l-carboxylate (6.05 g, 11 mmol) in dichloromethane (60 mL) is added trifluoroacetic acid (10 mL). The reaction solution is stirred at 25 °C for 1 h, then concentrated under reduced pressure. The residue is diluted with acetonitrile (60 mL) and basified with,2V-diisopropylethylamine until pH 8-9. The resulting mixture is filtered and the filtered cake is dried to afford 3-[4-fluoro-5-[(2S)-2-methyl-4-(4-piperidylmethyl) piperazin- l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (4.58 g, 92%) as a gray solid. ’H NMR (400 MHz. DMSO-O d 11.19 - 10.66 (m, 1H), 7.49 (d. J= 8.0 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 5.07 (dd, J= 5.2, 13.2 Hz, 1H), 4.64 - 4.45 (m, 1H), 4.32 (dd, J = 3.6, 16.8 Hz, 1H), 3.78 - 3.68 (m, 1H), 3.28 (br s, 3H), 3.02 - 2.78 (m, 5H), 2.71 - 2.55 (m, 2H), 2.46ARVN-216-PCT / / ARVN0216WO2- 2.29 (m, 3H), 2.24 - 2.10 (m, 2H), 1.99 (brdd, 7= 5.2, 11.2 Hz, 1H), 1.91 - 1.77 (m, 3H), 1.35 - 1.18 (m, 2H), 1.12 (br d, 7= 6.0 Hz, 1H), 1.01 (d, 7= 6.4 Hz, 3H).Step 9:MOMOMOMO

[0108] To a mixture of [(lS)-l-[[(85)-13-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-14- fluoro-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02’8.015 19]nonadeca- 1(19), 11, 13, 15, 17 -pentaen- 17 -yl] oxymethyl] -2, 2-difluoro-cyclopropyl] methyl methanesulfonate (660 mg, 0.9 mmol) and 3-[4-fluoro-5-[(2S)-2-methyl-4-(4-piperidylmethyl)piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (626 mg, 1.4 mmol) in A; N,N-dimethylformamide (13 mL) are added sodium carbonate (484 mg, 4.6 mmol) and potassium iodide (758 mg, 4.6 mmol), and the mixture is stirred at 90 °C for 12 h. The reaction mixture is cooled to 0 °C. suspended in water (30 mL) and filtered. The filtered cake is purified by flash silica gel chromatography (0- 10% methanol / dichloromethane) to afford 3-[5-[(2 )-4-[[l-[[(lR)-l-[[(8S)-13-[8-ethyl-7-fluoro-3-(methoxymethoxy)- 1-naphthyl]- 14-fluoro-6, 10-dioxa-2, 12, 16, 18-tetrazatetracyclo[9.7.1.02’8.015 19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]-2,2-difhioro-cyclopropyl]methyl]-4-piperidyl]methyl] -2-methyl-piperazin- 1 -yl] -4-fluoro- 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dione (790 mg, 79%) as a light yellow solid. MS (ESI) m / z 1084.6 [M+H]+; 'H NMR (400 MHz, CDC13) <5: 8.36 (d, J = 7.6 Hz, 1H), 7.64 (dd, J = 6.0, 9.2ARVN-216-PCT / / ARVN0216WO2Hz, 1H), 7.59 (d, 7= 8.4 Hz, 1H), 7.48 (dd, J= 1.2, 2.4 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.21 - 7.17 (m, 1H), 7.08 (t, J = 6.8 Hz, 1H), 5.30 (s, 2H), 5.29 - 5.24 (m, 2H), 5.24 - 5.15 (m, 2H), 4.78 (d, J = 11.6 Hz, 1H), 4.74 - 4.56 (m, 3H), 4.52 - 4.44 (m, 2H). 4.40 - 4.30 (m, 1H), 4.22 (ddd, 7 = 3.6, 8.4, 12.4 Hz, 1H), 4.12 - 4.00 (m, 2H), 3.87 - 3.70 (m, 3H), 3.50 (s, 3H), 3.47 - 3.25 (m, 3H), 3.11 - 2.98 (m, 3H), 2.92 - 2.80 (m, 2H), 2.72 - 2.55 (m, 3H), 2.50 - 2.32 (m, 6H), 2.23 - 2.15 (m.4H), 1.78 (dd, 7= 15.2, 18.4 Hz, 2H), 1.68 - 1.50 (m. 2H). 1.38 - 1.29 (m, 2H), 1.04 (d, 7= 6.4 Hz, 3H), 0.97 - 0.86 (m, 3H).Step 10:

[0109] To a mixture of 3-[5-[(2S)-4-[[l-[[(17?)-l-[[(8S)-13-[8-ethyl-7-fluoro-3-(methoxymethoxy)- 1 - naphthyl]- 14-fluoro-6, 10-dioxa-2, 12, 16,18-tetrazatetracyclo[9.7.1.02’8.015 19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl] -2-methyl-piperazin- 1 -yl] -4-fluoro- 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dione (790 mg, 0.7 mmol) in dichloromethane (15 mL) is added 2 M hydrochloric acid in dioxane (15 mL), and the mixture is stirred at 25 °C for 1 h. The reaction mixture is suspended in petroleum ether (15 mL) and filtered. The filtered cake is dissolved with dimethyl sulfoxide (7 mL) and basified with / V-diisopropylethylamine. then purified by prep-ARVN-216-PCT / / ARVN0216WO2HPLC (15%-45% acetonitrile in water (0.225% formic acid) over 15 min) to afford 3-[5-[(2S)-4-[[l-[[(lR)-l-[[(8S)-13-(8-ethyl-7-fluoro-3-hydroxy-l-naphthyl)-14-fluoro-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02’8.015 19]nonadeca-l(19).ll,13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl]-2-methyl-piperazin-l-yl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (357.7 mg, 45%, formate salt) as an off-white solid. MS (ESI) m / z 1041.8 [M+H]+;NMR (400 MHz, DMSO-rfc) <5: 10.99 (s, 1H). 9.96 (d, J = 10.8 Hz, 1H), 8.13 (s, 1H), 7.75 (dd, 7= 6.0, 8.8 Hz, 1H), 7.49 (d, 7= 8.0 Hz, 1H), 7.39 - 7.28 (m, 2H), 7.23 - 7.11 (m, 1H), 7.09 - 6.91 (m, 1H), 5.15 - 4.96 (m, 2H), 4.68 (dd, 7 = 3.6, 13.2 Hz, 2H), 4.59 - 4.50 (m, 2H), 4.49 - 4.27 (m, 4H), 4.17 - 4.07 (m, 1H), 3.95 - 3.86 (m, 1H), 3.78 - 3.62 (m, 2H), 3.61 - 3.53 (m, 1H), 3.51 - 3.44 (m, 2H), 3.28 - 3.17 (m, 2H), 3.00 -2.83 (m, 4H), 2.69 - 2.61 (m, 4H), 2.43 (dd, 7= 10.0, 14.4 Hz, 3H), 2.34 - 2.26 (m, 2H). 2.25 -2.14 (m, 2H), 2.08 - 1.95 (m, 3H), 1.93 - 1.64 (m, 5H), 1.35 - 1.12 (m, 2H), 0.98 (s, 3H), 0.82 (td, 7= 7.2, 11.6 Hz, 3H).Example 1.3Exemplary synthesis of Compound 46:Step 1:NH2PhCHO, NaBH4NHBn7- ►7EtOH, 0-25 °C, 2 h

[0110] To a solution of (35)-3-aminobutan-l-ol (5 g, 56.09 mmol, 1 eq) in ethanol (80 mL) was added benzaldehyde (5.95 g, 56.09 mmol, 5.7 mL, 1 eq) at 25 °C and stirred for 1 h. Then sodium borohydride (2.16 g, 57.09 mmol, 1.02 eq) was added slowly at 0 °C. The mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was quenched with ammonium chloride solution (20 mL) and diluted with water (20 mL). Then extracted with dichloromethane (60 mL x 3). The combined organic layers were washed with brine (40 mL), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was used into next step without further purification. Compound (3S)-3-(benzylamino)butan-l-ol (8.5 g, 47.42 mmol, 85% yield) was obtained as a light yellow oil. LCMS (ESI) m / z 180.2 [M+l] +; 1H NMR: (400 MHz, CDCh-d^. 7.35 - 7.26 (m, 5H), 3.93 -3.85 (m, 2H), 3.84 - 3.75 (m, 2H), 3.07 - 2.94 (m, 1H), 1.79 - 1.73 (m, 1H), 1.62 - 1.51 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H).ARVN-216-PCT / / ARVN0216WO2Step 2:OH NaBH(OAc)3, toluene35-105 °C, 15 h OH

[0111] To a solution of (3S)-3-(benzylamino)butan-l-ol (0.5 g, 2.79 mmol, 1 eq) in toluene (10 mL) was added oxetan-3-one (241 mg, 3.35 mmol, 1.2 eq) and stirred at 105 °C for 3 h. Then the mixture was cooled to 35 °C, sodium triacetoxyborohydride (1.18 g, 5.58 mmol, 2 eq) was added at 35 °C and stirred for 12 h. The reaction mixture was quenched by sodium bicarbonate solution (10 mL) and water (10 mL), and then extracted with ethyl acetate (20 mL*2). The combined organic layers were washed with brine (10 mL), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was used into next step without further purification. Compound (35)-3-[benzyl(oxetan-3-yl)amino]butan-l-ol (0.5 g, 2.12 mmol, 76% yield) was obtained as a colorless oil. LCMS (ESI) m / z 236.2 [M+l] +.Step 3:

[0112] A mixture of (3S)-3-[benzyl(oxetan-3-yl)amino]butan-l-ol (9 g, 38.25 mmol, 1 eq) and dibutyl hydrogen phosphate (9.65 g, 45.89 mmol, 1.2 eq) in toluene (100 mL) was stirred at 110 °C for 12 h. The reaction mixture was quenched by addition sodium bicarbonate solution (80 mL), and then extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (80 mL), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was used into next step without further purification. Compound [(5S)-4-benzyl-5-methyl-1,4-oxazepan-3-yl]methanol (8.6 g, crude) was obtained as a light yellow oil.Step 4:ARVN-216-PCT / / ARVN0216WO2Bn Bn Bn

[0113] The residue was purified by chiral SFC(column: DAICEL CHIRALPAK IG(250mm*50mm,10um);mobile phase: [CO2-MeOH(0.2% NH3*H2O)]; B%:35%, isocratic elution mode). Compound [(3S,5S)-4-benzyl-5-methyl-1,4-oxazepan-3-yl]methanol (5.3 g, 22.52 mmol, 59% yield) was obtained as a colorless oil. MS (ESI) m / z'. 236.1 [M+l] +; 1H NMR: (400 MHz. MeOD-d4) 5: 7.43 - 7.33 (m. 2H). 7.29 (t, J = 7.6 Hz, 2H), 7.24 - 7.16 (m, 1H), 4.07 (dd. J = 5.2, 12.8 Hz, 1H), 4.01 - 3.88 (m, 2H), 3.74 - 3.58 (m, 3H), 3.43 - 3.32 (m, 3H), 3.01 - 2.88 (m, 1H), 2.04 - 1.90 (m, 1H), 1.81 - 1.67 (m, 1H), 1.25 (d, J = 6.8 Hz, 3H).

[0114] Compound [(3R,5S)-4-benzyl-5-methyl-l,4-oxazepan-3-yl]methanol (2.7 g, 11.47 mmol, 30% yield) was obtained as a colorless oil. LCMS (ESI) m / z'. 236.1 [M+l] +; ’H NMR: (400 MHz, Me()D-d4) 5: 7.40 (d, J = 7.2 Hz, 2H), 7.28 (t, J = 7.2 Hz, 2H), 7.24 - 7.13 (m, 1H), 3.99 - 3.74 (m, 5H), 3.73 - 3.64 (m, 1H), 3.47 - 3.32 (m, 2H), 3.28 - 3.12 (m, 2H), 2.01 - E87 (m, 1H), 1.84 - 1.68 (m, 1H), 1.13 (d, J = 3.2 Hz, 3H).Step 5:Pd(OH)2, H2(15 Psi)HO7' N MeOH HO7' ABn 30 °C, 16 h H

[0115] To a solution of [3R,5S)-4-benzyl-5-methyl-l,4-oxazepan-3-yl]methanol (2.7 g, 11.47 mmol, 1 eq) in methanol (50 mL) was added palladium hydroxide on activated carbon catalyst (0.9 g, 20% purity) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 Psi) at 30 °C for 16 h. The reaction mixture was filtered, and the filter was concentrated to give a residue which was used into next step without further purification. Compound [(3,5S)-5-methyl-l,4- oxazepan-3-yl]methanol (1.6 g, 11.02 mmol, 96% yield) was obtained as a colorless oil. 'H NMR:400 MHz, DMSO-d6) 5: 4.78 - 4.53 (m, 1H), 3.74 - 3.57 (m, 3H), 3.26 - 3.10 (m, 3H), 2.96 - 2.76 (m, 2H), 1.83 - 1.68 (m, 1H), 1.51 - 1.41 (m, 1H), 1.05 (d, J = 6.4 Hz, 3H).ARVN-216-PCT / / ARVN0216WO2Step 6:Cl OH Cl ClPOCI3, DIEACI^ i ^ LN ILS / - 0-110 °C, 12 h JL L JLS / F F

[0116] To a solution of phosphorus oxychloride (19.16 g, 124.95 mmol, 5 eq) was added 5,7-dichloro-8-fluoro-2-methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one (7 g, 24.99 mmol, 1 eq) in 5 portions at 25 °C under nitrogen. Then A, A-diisopropylethylamine (9.69 g, 74.97 mmol.3 eq) was added dropwise slowly at 0 °C. The mixture was heated to 110 °C and stirred for 12 h under nitrogen. After the mixture was cooled down to a room temperature and the reaction mixture was poured slowly into water (100 mL) and adjusted to pH 8 by sodium bicarbonate solution. Then it was extracted with dichloromethane (100 mL x 3). All combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrate in vacuum to give a residue. The residue was triturated with methyl tert-butyl ether (50 mL), then filtered to obtain a brown solid. Compound 4,5,7-trichloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-rf]pyrimidine (2.8 g, 9.38 mmol, 38% yield) was obtained as a brown solid.Step 7:DIEA, ACN0-25 °C, 3 h

[0117] To a solution of [(3A,55)-5-methyl-l,4-oxazepan-3-yl]methanol (350 mg, 2.41 mmol, 1.03 eq) in dichloromethane (30 mL) was added 4,5,7-trichloro-8-fluoro-2-methylsulfanyl-pyrido [4,3-<7]pyrimidine (700 mg, 2.34 mmol, 1 eq) and N, N-diisopropylethylamine (1.21 g, 9.38 mmol, 4 eq) at 0 °C. The mixture was warmed to 25 °C and stirred for 3 h. The reaction mixture was diluted with water (10 mL), and then extracted with dichloromethane (20 mL x 2). The combined organic layers were washed with brine (10 mL),ARVN-216-PCT / / ARVN0216WO2dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1). Compound [(3 / ?,55)-4-(5,7-dichloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-<7]pyrimidin-4-yl)-5-methyl-l,4-oxazepan-3-yl]methanol (0.6 g, 1.47 mmol, 63% yield) was obtained as a brown solid.DBU, ACN50 °C, 12 h

[0118] To a solution of [(37?,5S)-4-(5,7-dichloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-(f| pyrimidin-4-yl)-5-methyl-l,4-oxazepan-3-yl]methanol (0.5 g, 1.23 mmol, 1 eq) in acetonitrile (10 mL) was added l,8-diazabicyclo[5.4.0]undec-7-ene (561 mg, 3.68 mmol, 3 eq) and stirred at 50 °C for 12 h. The reaction mixture was quenched by the addition of water (10 mL) and then extracted with ethyl acetate (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 to give a residue. The residue was dissolved in methanol (5 mL) and then triturated with methyl tert-butyl ether (30 mL), then filtered obtain a light yellow solid. Compound (35,85)-13-chloro- 14-fluoro-3-methyl- 17-methylsulfanyl-6, 10-dioxa-2, 12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaene (350 mg, 0.94 mmol, 77% yield) was obtained as a light yellow solid. LCMS (ESI) m / z 371.0 [M+l] +.Step 9:4A MS, oxoneDMF, 25 °C, 16 hFARVN-216-PCT / / ARVN0216WO2

[0119] To a solution of (3S,8S)-13-chloro-14-fluoro-3-methyl-17-methylsulfanyl-6,10-dioxa- 2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaene (1.4 g, 3.78 mmol, 1 eq) in N,N-dimethylformamide (20 mL) was added 4A molecular sieve (1.4 g) at 25 °C and stirred for 4 h. Then potassium bisulfate complex salt (6.96 g, 11.33 mmol, 3 eq) was added at 25 °C and stirred for 12 h. The mixture was filtered, the filter cake was washed with ethyl acetate (150 mL) and the combined organic phase was washed with saturated aqueous sodium sulfite (30 mL*2). Then the organic phase was evaporated under reduced pressure to give a residue which was used directly in the next step without further purification. Compound (3S,8S)-13-chloro-14-fhioro-3-methyl-17-methylsulfonyl-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaene (1.3 g, 3.23 mmol, 85% yield) was obtained as a light yellow solid. LCMS (ESI) m / z 403.1 [M+l] +.Step 10:Cs2CO3, DMF, 25 °C, 1 h

[0120] To a solution of (35,8S)-13-chloro-14-fluoro-3-methyl-17-methylsulfonyl-6,10-dioxa- 2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaene (450 mg, 1.12 mmol, 1 eq) and [2,2-difhioro-l-(hydroxymethyl)cyclopropyl]methanol (309 mg, 2.23 mmol, 2 eq) in N,N-dimethylacetamide (8 mL) was added cesium carbonate (1.09 g. 3.35 mmol, 3 eq) at 25 °C and stirred for 1 h. The residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (dichloromethane / methanol = 100 / 1 to 30 / 1). Compound [l-[[(3S,8S)-13-chloro-14-fluoro-3-methyl-6,10-dioxa-2, 12, 16,18-tetraza tetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluorocyclopropyl] methanol (500 mg, 1.08 mmol, 97% yield) was obtained as a light yellow oil. LCMS (ESI) m / z: 461.1 [M+l] +.ARVN-216-PCT / / ARVN0216WO2TIPSCI, DMAPDIEA, DCM25 °C, 2 h

[0121] To a solution of [l-[[(35,85)-13-chloro-14-fluoro-3-methyl-6.10-dioxa-2,12,16,18- tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluoro- yclopropyl] methanol (500 mg, 1.08 mmol, 1 eq) in dichloromethane (15 mL) was added / V-diisopropylethylamine (351 mg, 2.71 mmol, 2.5 eq), N, N-dimethylpyridin-4-amine (530 mg, 4.34 mmol, 4 eq) and chloro(triisopropyl)silane (628 mg, 3.25 mmol. 3 eq) at 25 °C and stirred for 2 h. The residue was diluted with water (10 mL) and extracted with dichloromethane (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (dichloromethane / methanol = 100 / 1). Compound [l-[[(35,85)-13-chloro-14-fluoro-3-methyl-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluorocyclopropyl]methoxy-triisopropyl-silane (0.6 g, 0.97 mmol, 90% yield) was obtained as a light yellow oil. The residue was purified by prep-HPLC (mobile phase:[water(0.225% formic acid)-acetonitrile]; gradient:70%-100% B over 20.0 min). Compound [1-[[(35,85)- 13-chloro- 14-fluoro-3-methyl-6, 10-dioxa-2, 12,16,18-tetrazatetracyclo[9.7.1.02, 8.015, 19]nonadeca-l (19), 11, 13,15, 17-pentaen-17-yl]oxymethyl]-2, 2-difhiorocyclopropyl]methoxy-triisopropyl-silane (950 mg, 1.54 mmol, 53% yield) was obtained as a white solid. LCMS (ESI) m / z 617.3 [M+l] +.JH NMR: (400 MHz, CDCh-d) 5: 4.71 - 4.50 (m, 3H), 4.43 - 4.20 (m, 3H), 4.15 - 3.99 (m, 3H), 3.85 (t, J = 11.2 Hz, 1H), 3.66 - 3.62 (m, 1H), 3.33 - 3.20 (m, 1H), 2.55 - 2.41 (m, 1H). 2.18 - 2.05 (m, 1H), 1.79 (d. J = 6.8 Hz, 3H). 1.57 - 1.51 (m, 1H), 1.43 - 1.33 (m, 1H), 1.13 - 0.97 (m, 21H).Step 12:ARVN-216-PCT / / ARVN0216WO2

[0122] The residue was separated by chiral SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10um); mobile phase: [CO2-EtOH(0.1% NH3*H2O)]; B%:30%, isocratic elution mode). Compound [(15)-l-[[(3S,8S)-13-chloro-14-fluoro-3-methyl-6,10- dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02, 8.015, 19]nonadeca- 1(19), 11.13,15, 17-pentaen-17-yl]oxymethyl]-2,2-difluorocyclopropyl]methoxy-triisopropyl-silane (400 mg, 0.65 mmol, 42% yield) was obtained as a colorless oil. LCMS (ESI) m / z 617.4 [M+l] +.

[0123] Compound [(17?)-l-[[(3S,85)-13-chloro-14-fluoro-3-methyl- 6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13.15,17-pentaen-17-yl]oxymethyl]-2,2-difluorocyclopropyl]methoxy-triisopropyl-silane (350 mg, 0.57 mmol, 37% yield) was obtained as a white solid, confirmed by LCMS and SFC. LCMS (ESI) m / z'. 617.4 [M+l] +.Step 13:CataCXium A Pd G3, K2CO3, dioxane / H2O, 70 °C, 12 h

[0124] A mixture of [(15)-l-[[(3.85)-13-chloro-14-fluoro-3-methyl-6.10-dioxa-2,12,16,18- tetrazatetracyclo[9.7.1.02’8.015 19]nonadeca-l(19), 11, 13,15, 17-pentaen-17-yl]oxymethyl]-2,2-difluorocyclopropyl]methoxy-triisopropyl-silane (500 mg, 0.81 mmol, 1 eq), 2-[(4S)-7-(methoxymethoxy)-4-methyltetralin-5-yl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (538 mg, 1.62 mmol, 2 eq), [2-(2-aminophenyl)phenyl]palladium(l+);bis(l-adamantyl)-butyl-phosphane:methanesulfonate (59 mg, 0.081 mmol, O.leq) and potassium phosphate (1.5 M, 1.62ARVN-216-PCT / / ARVN0216WO2mL, 3 eq) in tetrahydrofuran (8 mL) was stirred at 70 °C for 12 hours under nitrogen. The residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1). Compound [(lS)-2,2-difhioro-l-[[(3.8S)-14-fluoro-13-[(4S)-7-(methoxymethoxy)-4-methyl-tetralin-5-yl]-3-methyl- 6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02’8.015 19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]cyclopropyl]methoxy-triisopropyl-silane (590 mg, 0.74 mmol, 92% yield) was obtained as a light yellow solid. LCMS (ESI) / z:787.6 [M+l]+.

[0125] To a solution of [(15)-2,2-difluoro-l-[[(35,85)-14-fluoro-13-[(4S)-7- (methoxymethoxy)-4- methyl-tetralin-5-yl]-3-methyl-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015 19]nonadeca-l(19), 11, 13.15, 17-pentaen-17-yl]oxymethyl]cyclopropyl]methoxy-triisopropyl-silane (590 mg, 0.74 mmol, 1 eq) in dimethylsulfoxide (5 mL) was added triethylamine trihydrofluoride (2.42 g, 14.99 mmol, 20 eq) at 25 °C and stirred for 12 h. The reaction mixture was quenched by addition water (60 mL) at 25 °C, then filtered and concentrated under reduced pressure to give a residue. The residue was used into next step without further purification. Compound [(17?)-2,2-difhroro-l-[[(3S,8S)-14-fluoro-13-[(4S)-7-(methoxymethoxy)-4-methyl-tetralin-5-yl]-3-methyl-6.10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02’8.015 19]nonadeca-l(19), 11, 13,15, 17-pentaen-17-yl]oxymethyl]cyclopropyl]methanol (470 mg, 0.74 mmol, 98% yield) was obtained as a yellow oil. LCMS (ESI) m / z 631.3 [M+l]+.Step 15:ARVN-216-PCT / / ARVN0216WO2

[0126] To a solution of [(17?)-2,2-difhioro-l-[[(3S,8S)-14-fhioro-13-[(4S)-7-(methoxymethoxy)-4- methyl-tetralin-5-yl]-3-methyl-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02’8.015 19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl] cyclopropyl] methanol (470 mg, 0.74 mmol, 1 eq) in dichloromethane (5 mL) was added triethylamine (377 mg, 3.73 mmol, 5 eq) and methylsulfonyl methanesulfonate (389 mg, 2.24 mmol, 3 eq) 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 to give a residue which was used into next step without further purification. Compound [(lS)-2,2-difhroro-l-[[(3S,8S)-14-fhroro-13- [(4S)-7-(methoxymethoxy)-4-methyl-tetralin-5-yl]-3-methyl-6, 10-dioxa-2, 12,16,18-tetrazatetracyclo[9.7.1.02,8.015 19]nonadeca-l(19), 11, 13,15, 17-pentaen- 17-yl] oxymethyl]cyclopropyl]methyl methanesulfonate (500 mg, 0.70 mmol, 94% yield) was obtained as an yellow solid. LCMS (ESI) m / z 709.4 [M+l]+.Step 16:

[0127] A mixture of [(lS)-2,2-difluoro-l-[[(3S,8S)-14-fluoro-13-[(4S')-7-(methoxymethoxy)-4- methyl-tetralin-5-yl]-3-methyl-6,10-dioxa-2,12,16,18-tetrazatetracyclo [9.7.1.02’^ 015■19] nonadeca- 1 ( 19), 11, 13, 15, 17 -pentaen - 17-yl] oxymethyl] cyclopropyl] methyl methanesulfonate (200 mg, 0.28 mmol, 1 eq), 3-[4-fluoro-l-oxo-5-[4-(4-piperidylmethyl)piperazin-l-yl] isoindolin-2-yl]piperidine-2,6-dione (236 mg, 0.42 mmol, 1.5 eq, trifluoroacetate), sodium carbonate (149 mg, 1.41 mmol, 5 eq) an potassiumARVN-216-PCT / / ARVN0216WO2iodide (234 mg, 1.41 mmol, 5 eq) in A / N,N-dimethylformamide (7 mL) was stirred at 90 °C for 12 hours. The reaction mixture was added water (10 mL), filtered to obtain an off-white solid. Then it was dissolved in dichloromethane (50 mL), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1). Compound 3-[5-[4-[[l-[[( 17?)-2,2-difhioro-l-[[(3S.8S)-14-fluoro-13-[(4 )-7- (methoxymethoxy)-4-methyl-tetralin-5-yl]-3-methyl-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02’8.015 19]nonadeca-l(19),ll,13,15,17-pentaen- 17 -yl] oxymethyl]cyclopropyl]methyl] -4-piperidyl] methyl] piperazin- 1 -yl] -4- fluoro- 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dione (190 mg, 0.18 mmol, 71% yield) was obtained as a yellow solid. LCMS (ESI) m / z 1056.9 [M]+.Step 17:

[0128] To a solution of 3-[5-[4-[[l-[[(17?)-2,2-difluoro-l-[[(35,85)-14-fluoro-13-[(45)-7-(methoxymethoxy)-4-methyltetralin-5-yl]-3-methyl-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02'8.015 19]nonadeca-l(19), 11, 13,15, 17-pentaen-17-yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (230 mg, 0.21 mmol, 1 eq) in dichloromethane (24 mL) was added hydrochloride / dioxane (2 M, 0.1 mL, 1 eq) at 25 °C and stirred for 15 min. To the reaction mixture was added methyl tert-butyl ether (20 mL) to give a precipitate. The mixture was filtered to obtain a light yellow solid. The residue was purified by prep-HPLC (mobile phase:[water(0.225% formic acid)-acetonitrile]; gradient:9%-39% B over 15.0 min). Compound 3-[5- [4-[[l-[[(17?)-2,2-difLuoro-l-[[(35,8S')-14-fluoro-13-[(4A)-7-hydroxy-4-methyl-tetralin-5-yl]-3-methyl-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02’8.015 19]nonadeca-l(19),ll,13,15,17-pentaen- 17 -yl] oxymethyl]cyclopropyl]methyl] -4-piperidyl] methyl] piperazin- 1 -yl] -4- fluoro- 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dione (98.1 mg, 0.09 mmol, 42% yield, 100% purity, formate) was obtained as a white solid. LCMS (ESI) m / z 1012.6 [M+l]+. 'll NMR (400 MHz, DMSO-d6) 8: 11.04 - 10.92 (m, 1H), 8.18 - 8.13 (m. 1H), 7.55 - 7.40 (m, 1H), 7.22 - 7.05 (m, 1H), 6.61 -6.39 (m, 2H), 5.16 - 5.00 (m, 1H), 4.65 - 4.39 (m, 6H), 4.34 - 4.21 (m, 2H), 4.20 - 4.11 (m, 1H),ARVN-216-PCT / / ARVN0216WO24.00 - 3.88 (m, 1H), 3.68 - 3.55 (m, 2H), 3.17 - 3.04 (m, 6H), 2.97 - 2.86 (m, 2H), 2.84 - 2.77 (m, 2H), 2.75 - 2.64 (m, 4H), 2.60 (d, J = 16.0 Hz, 3H), 2.42 - 2.31 (m, 3H), 2.16 - 2.04 (m, 3H), 2.03 - 1.92 (m, 3H), 1.84 (d, J = 4.8 Hz, 1H), 1.83 - 1.60 (m. 10H), 1.58 - 1.41 (m. 3H), 0.83 -0.71 (m, 3H).Example 1.4Exemplary synthesis of Compound 21:Step 1:^OHIm, SOCI2DOM, -50-15 °C, 15 h

[0129] To a solution of imidazole (3.78 g. 55.48 mmol, 6 eq) in dichloromethane (20 mL) was added the solution of thionyl chloride (1.65 g, 13.87 mmol, 1.01 mL, 1.5 eq) in dichloromethane (10 mL) dropwise at -50 °C under nitrogen atmosphere. The resulting mixture was stirred at -50 °C for 3 hours. To the above mixture was added the solution of tert-butyl (37?)-3-(hydroxymethyl)piperazine-l-carboxylate (2.00 g, 9.25 mmol, 1 eq) in dichloromethane (10 mL) dropwise under nitrogen atmosphere. The resulting mixture was stirred at 15 °C for 12 hours. The reaction mixture was quenched with water (100 mL) and the mixture was extracted with ethyl acetate (100 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 used into next step directly. Compound tert-butyl (3a / ?)-l-oxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate (2.4 g, crude) was obtained as a yellow solid.Step 2:NalO4, RUCI3ACN / EA / H2O, 0-25°C, 3 h

[0130] To a solution of tert-butyl (3a7?)-l-oxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate (2.4 g, 9.15 mmol. 1 eq) in acetonitrile (10 mL) and ethyl acetate (10 mL) was added sodium periodate (2.54 g, 11.89 mmol, 1.3eq) and ruthenium trichloride (37.96 mg, 0.18mmol, 0.02 eq) in water (10 mL) at 0°C. The mixture was stirred at 20 °C for 3 hours.ARVN-216-PCT / / ARVN0216WO2The reaction mixture was filtered and the filtrate was quenched by 20 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 give a residue. The residue was used into next step directly.Compound tert-butyl (3a / ?)-l,l-dioxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate (2.45 g, 8.80 mmol, 96.22% yield) was obtained as a black solid.Step 3:

[0131] To a solution of tert-butyl (47?)-5-amino-4-(5-bromo-4-hydroxy-l-oxo-isoindolin-2-yl)-5-oxo-pentanoate (3.4 g, 8.23mmol, 1 eq) in acetonitrile (40 mL) was added potassium carbonate (2.40 g, 8.64 mmol, 1.05 eq)) and the mixture was stirred at 60 °C for 15 hours. The reaction mixture was filtered and the filter cake was washed with dichloromethane (50 mL). The organic layer was concentrated in vacuum to give a residue. The residue was diluted with dichloromethane (36 mL) again, - toluene sulphonic acid (2.83 g, 2 eq) was added to the resulting solution and stirred for 3.5 hours, then saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with dichloromethane (20 mLx3). The combined organic layers were washed with brine (10 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (mobile phase: [water(FA)-ACN]; gradient: 18%-48% B over 18min). Compound tert-butyl (37?)-3-[[5-bromo-2-[( l )-4-tert-butoxy- 1 -carbamoyl-4-oxo-butyl] - 1 -oxo-isoindolin-4-yl] oxymethyl] piperazine- 1 -carboxylate (1.9 g, 3.11mmol, 37.76% yield) was obtained as a yellow solid.Step 4:ARVN-216-PCT / / ARVN0216WO2Pd(OAc)2, Bl NAP, K2CO3Tol., 100 °C, 12h

[0132] A mixture of tert-butyl (37?)-3-[[5-bromo-2-[(15)-4-tert-butoxy-l-carbamoyl-4-oxo-butyl]-l-oxo-isoindolin-4-yl]oxymethyl]piperazine-l-carboxylate (1.8 g, 2.94 mmol, 1 eq), potassium carbonate (1.22 g, 8.83 mmol, 3 eq), palladium(II) acetate (26.43 mg, 0.11 mmol, 0.04 eq) and 2,2'-bis(diphenylphosphino)-l,r-binaphthalene (128 mg, 0.21 mmol, 0.07 eq) in toluene (15 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 100 °C for 12 hours under nitrogen atmosphere. The reaction mixture was filtered and the filter cake was washed with dichloromethane (20 mLx3). The combined organic layers were washed with brine (10 mLx3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane / methanol=l / 0 / 0 / 0 to 0 / 0 / 1 / 0). Compound tert-butyl (77?)-13-[(1 )-4-tert-butoxy- 1 -carbamoyl-4-oxo-butyl]- 14-oxo-9-oxa-2,5,13-triazatetracyclo[8.7.0.02’7.011 15]heptadeca-l(17),10.15-triene-5-carboxylate (1.3 g, 1.25 mmol, 43% yield) was obtained as a black solid. LCMS (ESI) m z 531.4 [M+l]+.

[0133] To a solution of tert-butyl (77?)-13-[(lS)-4-tert-butoxy-l-carbamoyl-4-oxo-butyl]- 14-oxo-9-oxa-2,5,13-triazatetracyclo[8.7.0.02,7.011 15]heptadeca-l(17),10,15-triene-5-carboxylate (670 mg, 1.26 mmol, 1 eq) in acetonitrile (10 mL) was added [(l,4S)-7,7-dimethyl-2-oxo-norbornan-l-yl] methanesulfonic acid (893 mg, 3.85 mmol, 3 eq). The mixture was stirred at 80ARVN-216-PCT / / ARVN0216WO2°C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue, which was used into next step directly. Compound (35)-3-[(77?)-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 (449 mg, 1.26 mmol, 99.78% yield) was obtained as a white solid. LCMS (ESI) m / z 357.2[M+1]+.Step 6:DIEA, AcOH, NaBH(OAc)3, DCM / DMSO 25°C, 1.5 h

[0134] To a solution of (3S)-3-[(77?)-14-oxo-9-oxa-2,5,13-triazatetracyclo[8.7.0.02’7.011 15]heptadeca-l(10),l 1(15), 16-trien-13-yl]piperidine-2, 6-dione (250 mg, 0.70 mmol, 1 eq) in dichloromethane (3 mL) and isopropanol (1 mL) was added N, N-diisopropylethylamine (271 mg, 2.10 mmol, 0.03 mL, 3 eq) to pH>7, then added acetic acid (42 mg, 0.70 mmol, 0.04 mL, 1 eq) to pH=5. tert-Butyl 4-formylpiperidine- 1 -carboxylate (300 mg, 1.41 mmol, 1.12 eq) was added and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (534 mg, 2.52 mmol, 2 eq) was added at 0°C and the mixture was stirred at 25 °C for 1 hour. The residue was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative thin layer silica gel chromatograph (dichloromethane / methanol-IO / l). Compound tert-butyl 4-[[(77?)-13-[(3S)-2,6-dioxo-3-piperidyl]-14-oxo-9-oxa-2,5,13-triazatetracyclo[8.7.0.02’7.011 13]heptadeca-l(10),ll(15),16-trien-5-yl]methyl]piperidine-l -carboxylate (320 mg, 0.58 mmol, 46% yield) was obtained as a white oil. LCMS (ESI) m / z: 554.2 [M+l]+Step 7o oARVN-216-PCT / / ARVN0216WO2

[0135] To a solution of tert-butyl 4-[[(77?)-13-[(35)-2,6-dioxo-3-piperidyl]-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]piperidine-l-carboxylate (320 mg, 0.58 mmol, 1 eq) in dichloromethane (2 mb) was added trifluoroacetic acid (1 mL). The mixture was stirred at 20 °C for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (mobile phase: [water(FA)-ACN]; gradient: l%-23% B over 15 min).). Compound (35)-3-[(77?)-14-oxo-5-(4-piperidylmethyl)-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 (283 mg, 0.41 mmol, 71% yield, trifluoroacetate) was obtained as a white solid. LCMS (ESI) m / z. 454.2 [M+l]+.JH NMR: (400 MHz, DMSO-d6) 6: 10.95 (s, 1H), 8.68 (br s, 1H), 8.55 - 8.35 (m, 1H), 7.24 (br d, J= 8.1 Hz, 1H), 7.13 (br d, 7= 8.0 Hz, 1H), 5.13 - 4.95 (m. 1H), 4.40 (br d, 7= 9.5 Hz, 1H), 4.32 - 4.23 (m, 1H), 4.20 - 4.02 (m, 3H), 3.31 (br d, 7= 11.4 Hz, 8H), 2.98 - 2.77 (m, 5H), 2.60 (br s, 1H), 2.45 -2.36 (m, 1H), 2.15 - 2.02 (m, 1H), 2.01 - 1.81 (m, 3H), 1.44 - 1.22 (m, 2H).The rest of the molecule was prepared according to General Synthetic Scheme 2.Example 1.5cataCXium A Pd G3 mesylate[(di(l-adamantyl)-n-butylphosphine)-2-(2'-amino-l, T-biphenyl)]palladium(II)CS2CO3 cesium carbonateDCM dichloromethaneDess-Martin periodinane 1,1,1 -tris(acetyloxy)- 1, 1 -dihydro- 1,2-benziodoxol-3-( lH)-oneDIEA N, N-DiisopropylethylamineDMA N, N-DimethylacetamideDMF N, N-Dimcthyl formamideEtOAc ethyl acetateEtOH ethyl alcoholKI potassium iodideLiHMDS lithium bis(trimethylsilyl)amideMTBE methyl re -butyl etherNaBH(OAc)3 sodium triacctoxyborohydridcNa2CC>3 sodium carbonateARVN-216-PCT / / ARVN0216WO2NaOAc sodium acetateNa? SO4 sodium sulfateNH4CI ammonium chloriderac-BINAP-Pd-G3 [2'-(amino-K2V)[ 1, 1 '-biphenyl] -2-yl-KC] [[2'-(diphenylphosphino)[ 1, 1 '-binaphlhalen |- 2-yl]diphenylphosphine-KP](methanesulfonato-KO)- palladiumRuPhos Pd G4 [dicyclohexyl(2',6'-diisopropoxy-2-biphenylyl)phosphine-KP](methanesulfonatato- K(9)[2'-(methylamino-KA)-2-biphenylyl-KC2]palladiumSPhos Pd G3 (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-l,l'-biphenyl)]palladium(II) methanesulfonateTBAF tetrabutylammonium fluorideTFA trifluoroacetic acidTHF tetrahydrofuranSynthesis of Intermediate 25Step I:INT-18

[0136] To a mixture of 6-hydroxytetralin-l-one (50 g, 308.29 mmol, 1 eq) and O-methylhydroxylamine;hydrochloride (38.62 g, 462.44 mmol, 35.1 mL, 1.5 eq) in acetonitrile (250 mL) was added pyridine (36.58 g, 462.44 mmol, 37.33 mL, 1.5 eq) in one portion at 20 °C under nitrogen. The mixture was stirred at 20 °C for 2 hours, then poured into ice-water (w / w = 1 / 1) (1000 mL) and stirred for 10 min. The aqueous phase was extracted with / -butyl methyl ether (1000 mL x 3). The combined organic phase was washed with brine (1000 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to afford (1E)-1-methoxyiminotetralin-6-ol (Intermediate 18, 52 g, crude) as a yellow solid.Step 2:ARVN-216-PCT / / ARVN0216WO2OMe OMei iOH OAcINT-18 INT-19

[0137] To a mixture of Intermediate 18 (50 g, 261.47 mmol, 1 eq) and triethylamine (52.92 g, 522.94 mmol, 72.8 mL, 2 eq) in t-butyl methyl ether (500 mL) was added acetyl chloride (24.63 g, 313.77 mmol, 22.3 mL, 1.2 eq) by dropwise addition at 0 °C under nitrogen. The mixture was stirred at 20 °C for 12 hours, then poured into ice-water (w / w = 1 / 1) (2000 mL) and stirred for 10 min. The aqueous phase was extracted with / -butyl methyl ether (1000 mL x 3). The combined organic phase was washed with brine (1000 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to afford [(lE)-l-methoxyiminotetralin-6-yl] acetate (Intermediate 19, 55 g, 235.79 mmol, 90% yield) as a yellow solid.]H NMR (400 MHz, CDC13) 5: 8.01 (d, J = 8.4 Hz, 1H), 6.99 - 6.87 (m, 2H), 4.00 (s, 3H), 2.74 (q, J = 6.4 Hz, 4H), 2.31 (s, 3H), 1.87 (quin, J = 6.4 Hz, 2H)Step 3:OMe OMei iOAc OAcINT-19 I NT-20

[0138] To a mixture of Intermediate 19 (55 g, 235.79 mmol, 1 eq) and 1-bromopyrrolidine-2, 5-dione (46.16 g, 259.36 mmol, 1.1 eq) in acetic acid (270 mL) was added palladium(ii) acetate (3.71 g, 16.51 mmol, 0.07 eq) in one portion at 35 °C under nitrogen. The mixture was stirred at 35 °C for 16 hours, then cooled to 20 °C. 10% sodium sulfite (220 mL) was added and the solid was formed and stirred for 1 h. Water (1000 mL) was added and the product was extracted with / -butyl methyl ether (2000 mL). The organic layer was washed with 15% sodium carbonate (1000 mL), saturated sodium bicarbonate solution (1000 mL), and brine (1000 mL x 2). then dried with anhydrous sodium sulfate, filtered and concentrated underARVN-216-PCT / / ARVN0216WO2vacuum. The crude product was triturated with heptane (1L) at 0 °C for 30 min. to afford [(1 E)-8-bromo-l-methoxyimino-tetralin-6-yl] acetate (Intermediate 20, 55 g, 176.19 mmol, 74% yield) as a yellow solid. 'H NMR (400 MHz, CDC13) 5: 7.32 (s. 1H), 6.91 (s, 1H). 4.05 (d, J = 1.2 Hz, 3H), 2.82 - 2.71 (m, 2H), 2.67 - 2.58 (m, 2H), 2.31 (d, J = 1.2 Hz, 3H), 1.79 (quin, J = 5.6 Hz, 2H).Step 4:OAcINT-21INT-20

[0139] A mixture of Intermediate 20 (62 g, 198.62 mmol, 1 eq) and hydrogen chloride (2 M, 644.8 mL, 6.49 eq) in dioxane (650 mL) was heated to 100 °C and stirred for 3 hours, then cooled to 20 °C and concentrated under reduced pressure at 45 °C. The residue was filtered and the cake was dried under high vacuo. The cake was washed with water (1000 mL x 3) and dried under high vacuo to afford crude 8-bromo-6-hydroxy-tetralin-l-one (Intermediate 21, 45 g, 186.66 mmol, 93.98% yield) as a yellow solid, which was used in the next reaction without further purification.Step 5:INT-21 INT-22

[0140] To a mixture of Intermediate 21 (65 g, 269.62 mmol, 1 eq) and dimethoxymethane (205.16 g, 2.7 mol. 239 mL, 10 eq) in ethyl acetate (320 mL) was added butylphosphonic anhydride (389 g, 539.24 mmol, 50% purity, 2 eq) in one portion at 50 °C under nitrogen. The mixture was stirred at 50 °C for 16 hours, then cooled to 20 °C and pouredARVN-216-PCT / / ARVN0216WO2into ice-water (w / w = 1 / 1) (2000 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (lOOOmL x 3) and the combined organic phase was washed with 2 M potassium carbonate (2000 mL), brine (1000 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / l, 3 / 1) to afford 8-bromo-6-(methoxymethoxy)tetralin-l-one (Intermediate 22, 70 g, 245.50 mmol, 91% yield) as yellow solid.Step 6:OMOM OMOMINT-22 INT-23

[0141] To a mixture of methyl(triphenyl)phosphonium;iodide (170.12 g, 420.86 mmol, 2 eq) in tetrahydrofuran (600 mL) was added potassium tert-butoxide (1 M, 526.1 mL, 2.5 eq) in one portion at 20°C under nitrogen. The mixture was stirred at 20 °C for 30 min, then Intermediate 22 (60 g, 210.43 mmol, 1 eq) was added at 20 °C. The mixture was stirred for 16 hours, then poured into ice-water (w / w = 1 / 1) (500 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with brine (300 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate= 100 / 1, 10 / 1) to afford 8-bromo-6-(methoxymethoxy)-l-methylene-tetralin (Intermediate 23, 42 g, 148.33 mmol, 70% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 8: 7.22 (d, J = 2.4 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 5.62 (s, 1H), 5.32 (d, J = 1.2 Hz, 1H), 5.17 (s, 2H), 3.50 (s, 3H), 2.73 (t, J = 6.4 Hz, 2H), 2.50 (t, J = 6.8 Hz, 2H), 1.86 (quin, J = 6.8 Hz, 2H)Step 7:ARVN-216-PCT / / ARVN0216WO2I NT-23 I NT-24

[0142] To a solution of Intermediate 23 (14 g, 49.44 mmol, 1 eq) in THF (150 mL) was added platinum dioxide (7 g) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (20 psi) at 20 °C for 16 hours, then filtered. The filtrate was concentrated, and the crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=10:l) to afford the crude product. The crude product was further purified by prep-HPLC (heptane- ethyl alcohol; gradient: l%-5% to afford 8-bromo-6-(methoxymethoxy)-l- methyl-tetralin (Intermediate 24, 7 g, 24.55 mmol, 70% yield) as a white solid. 'H NMR (400 MHz, CDC13) 8: 7.03 (d, J = 1.9 Hz, 1H), 6.65 (s, 1H), 5.04 (s, 2H), 3.39 (s, 3H), 3.08 (dt, J = 3.6, 6.7 Hz, 1H), 2.71 - 2.60 (m, 2H), 1.86 - 1.73 (m, 1H), 1.72 - 1.60 (m, 3H), 1.14 (d, J = 7.0 Hz, 3H)Step 8:OMOM OMOM OMOMINT-24 INT-24-E1 INT-24-E2

[0143] Intermediate 24 (7 g, 24.55 mmol, 1 eq) was separated by chrial SFC (isopropanol (0.1% NH3H2O) in CO2 from 10% to 10%) to afford (lR)-8-bromo-6-(methoxymethoxy)-l -methyl-tetralin (Intermediate 24-E1, 2.8 g. 9.82 mmol, 40% yield) as a yellow oil and ( I. S')-8-bromo-6-(methoxymethoxy)- 1 -methyl-tetralin (Intermediate 24-E2, 2.6 g, 9.12 mmol, 37. % yield) as a yellow oil.Step 9:ARVN-216-PCT / / ARVN0216WO2BPD, Pd(dppf)CI2, KOAcOMOM OMOMINT-24-E2 INT-25-E2

[0144] To a mixture of Intermediate 24-E2 (2.50 g, 8.77 mmol, 1 eq) and potassium acetate (3.01 g, 30.68 mmol, 3.5 eq) in toluene (50 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4.45 g, 17.53 mmol, 2 eq) and [l, T-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (641 mg, 0.88 mmol, 0.1 eq) in one portion at 108 °C under nitrogen. The mixture was stirred at 108 °C for 16 hours, then cooled to 20 °C and filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (0~8% ethyl acetate / hexanes) to afford 2-[(4 )-7-(methoxymethoxy) -4-methyl-tetralin-5-yl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Intermediate 25-E2, 2.6 g, 7.83 mmol, 89% yield) as a yellow solid. 'H NMR (400 MHz, CDC13) 5: 7.17 (d, J = 2.8 Hz, 1H), 6.73 (d, J = 2.8 Hz. 1H). 5.12 - 5.01 (m, 2H), 3.58 - 3.48 (m, 1H), 3.39 (s. 3H), 2.74 - 2.57 (m, 2H), 1.85 - 1.72 (m, 2H), 1.69 - 1.55 (m, 2H), 1.28 - 1.25 (m, 12H), 1.10 (d, J = 7.2 Hz, 3H)Example 1.5Exemplary synthesis of Compound No. 61: 3-[5-[4-[[l-[[(lR)-2,2-difhioro-l-[[(8S>14-tluoro-13-[(4R)-7-hydroxy-4-methyl-tetralin-5-yl]-5,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]-4-fluoro- 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dioneStep 1:ARVN-216-PCT / / ARVN0216WO2OMOMINT-25-E1INT-26-E1

[0145] To a mixture of [l-[[(85)-13-chloro-14-fluoro-6,10-dioxa-2, 12, 16,18-tetrazatetracyclo [9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (Intermediate 9, 1.5 g, 3.36 mmol, 1 eq) and 2-[(4R)-7-(methoxymethoxy)-4-methyl- tetralin-5-yl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Intermediate 25-E1, 1.45 g, 4.36 mmol, 1.3 eq), and potassium phosphate (1.5 M, 6.7 mL, 3 eq) in THF (40 mL) was added CataCXium A Pd G3 (244 mg, 0.33 mmol, 0.1 eq) in one portion at 75 °C under nitrogen. The mixture was stirred at 75 °C for 16 hours, then cooled to 20 °C and poured into ice- water (w / w = 1 / 1) (100 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL x 3), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / l, 0 / 1) to afford crude product which was was further purified by prep-HPLC (mobile phase: [water(0.225% formic acid)-acetonitrile];gradient:35%-65% B) to afford [2,2-difluoro-l-[[(8S)-14-fhioro-13-[(4R)-7-(methoxymethoxy)-4- methyltetralin-5-yl]-6,10-dioxa-2,12,16.18-tetrazatetracy clo [9.7.1.02,8.015,19] nonadeca- 1(19), 11, 13, 15, 17 -pentaen- 17 -yl]oxymethyl] cyclopropyl] methanol (Intermediate 26-E1, 1.2 g, 1.95 mmol, 58% yield) as a yellow solid.Step 2:ARVN-216-PCT / / ARVN0216WO2

[0146] Intermediate 26-E1 (1.20 g. 1.95 mmol, 1 eq) was separated by chrial SFC SFC (Mobile phase: isopropanol (0.1% NH3H2O) in CO2 from 35% to 35% to afford [( 17?)-2,2-difluoro-l-[[(8S)-14-fluoro-13-[(4R)-7-(methoxymethoxy)-4-methyl-tetralin-5-yl]-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl] cyclopropyl] methanol (Intermediate 26-E1E1, 570 mg, 0.92 mmol, 47% yield) and [(lS)-2,2-difhioro-l-[[(8S)-14-fhioro-13-[(4R)-7-(methoxymethoxy)-4-methyl- tetralin-5-yl]-6,10-dioxa-2, 12,16, 18-tetrazatetracyclo[9.7.1.02,8.015, 19]nonadeca-l(l 9), 11,13,15,17-pentaen-17-yl]oxymethyl]cyclopropyl]methanol (Intermediate 26-E1E2, 580 mg, 0.94 mmol, 48% yield) obtained as a white solid.

[0147] To a solution of Intermediate 26-E1E1 (570 mg, 0.92 mmol, 1 eq) and triethylamine (359 mg, 2.72 mmol, 0.48 mL, 3 eq) in DCM (10 mL) was added methylsulfonyl methanesulfonate (483 mg, 2.72 mmol, 3 eq) at 0 °C. The reaction was stirred at 25 °C for 1 h, then water (20 mL) was added and the aqueous phase was extracted with DCM (20 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to get the residue. The residue was purified by flash silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford [(15)-2,2-difluoro- l-[[(8S)-14-fhroro-13-[(4S)-7-(methoxymethoxy)-4-methyl-tetralin-5-yl]-6, 10-dioxa-2.12,16,18-tetrazatetracy clo [9.7.1.02,8.015,19] nonadeca- 1(19), 11, 13, 15, 17 -pentaen- 17 -ARVN-216-PCT / / ARVN0216WO2yl]oxymethyl]cyclopropyl]methyl methanesulfonate (Intermediate 27-E1 El, 610 mg, 0.88 mmol, 94% yield) was obtained as a light yellow solid. LCMS (ESI) m / z 659.4 [M+l]+Step 4:

[0148] To a solution of Intermediate 27-E1E1 (300 mg, 0.43 mmol, 1 eq) in N, N-dimethylformamide (5 mL) was added sodium carbonate (184 mg, 1.87 mmol. 4 eq). The reaction was stirred at 90 °C for 3 h, then cooled to 0 °C. Water (30 mL) was added and the mixture was stirred at 0 °C for 5 min. The mixture was filtered and the filtered cake was dissolved with DCM (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography (0-12% methanol / dichloromethane) to afford 3-[5-[4-[[l-[[(lA)-2,2-difluoro-l-[[(8S)-14-fluoro-13-[(47?)-7-(methoxymethoxy)-4-methyl-tetralin-5-yl]-5,10-dioxa-2,12,16,18-tetrazatetracy clo [9.7.1.02,8.015,19] nonadeca- 1(19), 11, 13, 15, 17 -pentaen- 17 -yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (Intermediate 30, 300 mg, 0.28 mmol, 66% yield) as a yellow solid. LCMS (ESI) m / z 1042.6 [M] +Step 5:

[0149] To a solution of Intermediate 30 (300 mg, 0.28 mmol, 1 eq) in DCM (5 mL) was added hydrogen chloride / dioxane (2 M, 5 mL, 28.17 eq). The reaction was stirred at 25 °C for 15 minutes, then diluted with petroleum ether (20 mL) and filtered. The filter cake was dissolved with DMSO (3 mL) and basified by the addition of M. V-diisopropylethylamine. The residue was purified by prep-HPLC (mobile phase: [water(0.225% formic acid)-ARVN-216-PCT / / ARVN0216WO2acetonitrile];gradient:5%-35% B) to afford 3-[5-[4-[[l-[[(lR)-2,2-difluoro-l-[[(8S)-14-fluoro- 13-[(4R)-7-hydroxy-4-methyl-tetralin-5-yl] -5, 10-dioxa-2, 12,16,18-tetrazatetracy clo [9,7,1,02,8.015,19] nonadeca- 1(19), 11.13, 15, 17 -pentaen- 17 -yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]piperazin-l-yl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (Compound 61, 149.9 mg, 0.14 mmol, 48% yield, 98% purity, formate) as a white solid. LCMS (ESI) m / z 998.8 [M]+. 'H NMR (400 MHz, DMSO-d6) 8: 10.97 (s, 1H), 9.24 (d, J - 4.8 Hz, 1H), 8.13 (s, 1H), 7.76 (dd, J = 6.0, 9.2 Hz, 1H), 7.46 (d, J - 8.0 Hz, 1H), 7.40 - 7.30 (m. 2H), 7.16 (t. J = 7.6 Hz, 1H), 7.04 (t, J = 3.2 Hz, 1H), 5.06 (dd, J = 5.2, 13.2 Hz, 1H), 4.73 - 4.57 (m, 1H), 4.55 - 4.44 (m, 2H), 4.43 - 4.34 (m, 2H), 4.34 - 4.25 (m, 2H), 4.24 - 4.08 (m, 1H), 3.92 (d, J = 13.6 Hz, 1H), 3.80 (d, J = 13.6 Hz, 1H), 3.74 - 3.63 (m, 2H), 2.96 - 2.87 (m, 2H), 2.87 - 2.65 (m. 4H), 2.63 - 2.54 (m, 2H), 2.44 - 2.24 (m, 8H), 2.18 -2.01 (m, 4H), 1.97 (dd, J = 5.2, 10.4 Hz, 2H), 1.91 - 1.76 (m, 4H), 1.75 - 1.55 (m, 3H), 1.46 (d, J = 1.6 Hz, 2H), 1.13 - 0.84 (m, 5H), 0.79 - 0.64 (m, 3H)Example 1.6Exemplary synthesis of Compound No. 67: 3-[5-[(2S)-4-[[l-[[l-[[(8S)-13-(l-ethyl-6-hydroxy-3.4-dihydro-2H-quinolin-8-yl)-14-fluoro-6, 10-dioxa-2, 12,16,18-tetrazatetracyclo [9.7.1.02, 8.015, 19] nonadeca- 1(19), 11, 13, 15, 17 -pentaen- 17 -yl ] oxymethyl ] -2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl] -2-methyl -piperazin- 1 -yl] -4-fluoro- 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dioneStep I:TIPSO^.( |1 TIPSCI, Et3N p ||| DMAP, DCM, 25 °C, 12 h |l|IHINT-31

[0150] To a solution of 1.2,3,4-tetrahydroquinolin-6-ol (10 g, 67.03 mmol. 1 eq) and triethylamine (20.35 g, 201.09 mmol, 3 eq) in THF (100 mL) was added / V-dimethylpyridin-4-amine (4.09 g, 33.51 mmol, 0.5 eq) and chlorotris(propan-2-yl)silane (19.38 g, 100.54 mmol, 1.5 eq) at 25 °C. The mixture was stirred for 12 h at 25 °C. then quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The resultingARVN-216-PCT / / ARVN0216WO2residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 100 / 1 to 10 / 1) to afford triisopropyl(l,2,3,4-tetrahydroquinolin-6-yloxy)silane (Intermediate 31, 20.6 g, crude) as a yellow oil. LCMS (ESI) m / z 306.2 [M+l] +Step 2:TIPSO TIPSO BrNBS, MeCN0-25°C, 2 h NHINT-31 INT-32

[0151] To a solution of Intermediate 31 (17.6 g. 57.60 mmol, 1 eq) in acetonitrile (200 mL) was added 1 -bromopyrrolidine-2, 5-dione (11.28 g, 63.37 mmol, 1.1 eq) at 0 °C. The mixture was stirred for 2 h at 25 °C, then quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = from 100 / 1 to 5 / 1) to afford (8-bromo-l,2,3,4-tetrahydroquinolin-6-yl)oxy-triisopropyl-silane (Intermediate 32, 6.8 g, 17.69 mmol, 31% yield) as a yellow oil. 'H NMR (400 MHz, CDC13) 8: 6.84 (d, J = 2.4 Hz, 1H), 6.52 - 6.47 (m, 1H), 3.37 - 3.31 (m, 2H). 2.75 - 2.70 (m, 2H), 1.95 - 1.87 (m, 2H), 1.70 - 1.50 (m, 1H), 1.25 - 1.15 (m, 3H), 1.06 (s, 18H).

[0152] To a solution of Intermediate 32 (6.8 g, 17.69 mmol, 1 eq) and acetaldehyde (3.90 g, 35.38 mmol, 2 eq) in methanol (80 mL) and acetic acid (8 mL) was added borane;2-methylpyridine (5.68 g, 53.07 mmol, 3 eq) at 25 °C. The mixture was stirred for 12 h at 25 °C, then concentrated in vacuo. The residue was purified by prep-HPLC [H2O(0.225% FA)-ACN]: 70%-100% B] to afford (8-bromo-l-ethyl-3.4-dihydro-2H-quinolin-6-yl)oxy-triisopropyl-silaneARVN-216-PCT / / ARVN0216WO2(Intermediate 33, 4.7 g, 11.39 mmol, 64% yield) as a yellow oil. LCMS (ESI) m / z 412.1 [M+l]+Step 4:CsFDMF 25 °C, 2 hINT-33 INT-34

[0153] To a solution of Intermediate 33 (4.4 g, 10.67 mmol, 1 eq) in DMF (50 mL) was added cesium fluoride (32.41 g, 213.34 mmol, 20 eq) at 25 °C. The mixture was stirred for 2 h at 25 °C, then quenched with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (200 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10 / 1 to 3 / 1) to afford 8-bromo-l-ethyl-3,4-dihydro-2H-quinolin-6-ol (Intermediate 34, 2.7 g, 10.54 mmol. 99% yield) was obtained as a yellow oil.MOMBr. DIEADCM 25 °C, 12 hINT-35

[0154] To a solution of Intermediate 34 (2.7 g, 10.54 mmol, 1 eq) and DIEA (4.09 g, 31.62 mmol, 3 eq) in DCM (30 mL) was added bromo(methoxy)methane (2.63 g, 21.08 mmol, 2 eq) at 25 °C. The mixture was stirred for 12 h at 25 °C, then quenched with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10 / 1 to 5 / 1) to afford 8-bromo-l-ethyl-6-(methoxymethoxy)-3,4-dihydro-2H-quinoline (Intermediate 35, 2.7 g, 8.99 mmol, 85% yield) as a yellow oil. ’H NMR: 400 MHz, CDC138: 7.15 (d. J = 2.8 Hz,ARVN-216-PCT / / ARVN0216WO21H), 6.71 (d, J = 2.8 Hz, 1H), 5.09 (s, 2H), 3.48 (s, 3H), 3.11 - 3.04 (m, 2H), 2.98 - 2.91 (m, 2H), 2.81 - 2.70 (m, 2H), 1.82 - 1.72 (m, 2H), 1.07 - 1.05 (m, 3H).Step 6:

[0155] To a solution of Intermediate 9 (3 g, 6.71 mmol, 1 eq), A imethylpyridin-4-amine (3.28 g, 26.86 mmol, 4 eq) and triethylamine (2.04 g, 20.14 mmol, 3 eq) in DCM (50 mL) was added chlorotris(propan-2-yl)silane (3.24 g, 16.79 mmol, 2.5 eq) at 0 °C. The mixture was stirred for 2 h at 25 °C, then quenched with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10 / 1 to 0 / 1) to afford [l-[[(87?)-14-chloro-15-fluoro-6,ll-dioxa-2,13,17,19-tetrazatetracyclo[10.7. L02,8.016,20]icosa-l(20).12,14,16,18-pentaen-18-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (Intermediate 36, 380 mg, 0.82 mmol, 83% yield) as a yellow solid. LCMS (ESI) m / z 461.1[M+1] +Step 7:

[0156] A mixture of Intermediate 36 (3.8 g, 6.30 mmol, 1 eq), tributyl(tributylstannyl)stannane (8.36 g, 14.41 mmol, 2.29 eq) and ditert-butyl(cyclopenta-l,4-ARVN-216-PCT / / ARVN0216WO2dien-l-yl)phosphane;dichloropalladium;iron (820 mg, 1.26 mmol, 0.2 eq) in dioxane (80 mL) was degassed and purged with nitrogen 3 times, then stirred at 100 °C for 12 hr under nitrogen atmosphere. The reaction mixture was concentrated in vacuo and the resulting residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 100 / 1 to 5 / 1) to afford [2,2-difluoro-l-[[(8S)-14-fluoro-13-tributylstannyl-6,10-dioxa-2,12,16,18-tetrazatetracy clo [9.7.1.02,8.015,19] nonadeca- 1(19), 11.13, 15, 17 -pentaen- 17 -yl] oxymethyl] cyclopropyl]methoxy-triisopropyl-silane (Intermediate 37, 2.4 g, 2.80 mmol, 44% yield) was obtained as a yellow oil. LCMS (ESI) m / z: 859.4 [M+l] +Step 8:INT-36 CataCXium A Pd G3, CsF toluene, 100 °C, 12h

[0157] A mixture of Intermediate 37 (1.21 g, 4.02 mmol, 1.5 eq), Intermediate 37 (2.3 g, 2.68 mmol, 1 eq), CataCXium A Pd G3 (195 mg, 0.27 mmol, 0.1 eq) and cesium fluoride (1.22 g, 8.04 mmol, 3 eq) in toluene (40 mL) was degassed and purged with nitrogen 3 times, then stirred at 100 °C for 12 hr under nitrogen atmosphere. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 to 1 / 1) to afford [l-[[(8S)-13-[l-ethyl-6-(methoxymethoxy)-3,4-dihydro-2H-quinolin-8-yl]-14-fluoro-6, 10-dioxa-2, 12, 16,18-tetrazatetracyclo[9.7.1.02,8.015,19] nonadeca- 1(19), 11, 13, 15, 17 -pentaen- 17-yl] oxymethyl] -2, 2-difluoro-cyclopropyl]methoxy-triisopropyl-silane (Intermediate 38, 800 mg, 1.02 mmol, 38% yield) as a yellow oil. LCMS: (ESI) m / z 788.4 [M+l] +Step 9:ARVN-216-PCT / / AR VN0216WO2MOMO

[0158] To a solution of Intermediate 38 (800 mg, 1.02 mmol, 1 eq) in DMF (10 mL) was added cesium fluoride (3.08 g, 20.31 mmol, 20 eq), and then the mixture was stirred at 25 °C for 2 hr. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by preparative TLC (petroleum ether: ethyl acetate = 0: 1, Rf = 0.19) to afford [1-[[(8S)-13-[1-ethyl-6-(methoxymethoxy)-3,4-di hydro-2 / 7-quinol in-8-yl] - 14-fluoro-6, 10-dioxa-2, 12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methanol (Intermediate 39, 540 mg, 0.85 mmol, 84% yield) as a yellow oil. LCMS (ESI) m / z 632.3[M+l] +. NMR (400 MHz. CDC13) 8: 6.91 (d, J = 2.8 Hz. 1H), 6.78 (d, J = 2.4 Hz, 1H), 5.25 - 5.17 (m, 1H), 5.11 (s, 2H), 4.76 - 4.65 (m, 3H), 4.40 - 4.32 (m, 1H), 4.25 - 4.20 (m, 1H), 4.10 - 3.98 (m, 2H), 3.85 - 3.75 (m, 1H). 3.70 - 3.60 (m, 2H), 3.46 (s, 3H), 3.44 - 3.29 (m, 2H), 3.13 - 3.05 (m, 2H), 2.80 - 2.75 (m, 2H), 2.70 - 2.65 (m, 2H), 2.31 -2.20 (m, 1H), 1.85 - 1.76 (m, 2H), 1.70 - 1.60 (m, 2H), 1.55 - 1.46 (m, 1H), 1.44 - 1.37 (m, 1H), 0.61 (t, J = 6.8 Hz. 3H).Ms2O. TEA DCM, 25°C, 2 h MOMOARVN-216-PCT / / ARVN0216WO2

[0159] To a solution of Intermediate 39 (540 mg, 0.95 mmol, 1 eq) and triethylamine (432 mg, 4.27 mmol, 5 eq) in DCM (10 mL) was added methylsulfonyl methanesulfonate (447 mg, 2.56 mmol, 3 eq). The mixture was stirred at 25 °C for 2 hr, then concentrated in vacuo. The resulting residue was purified by preparative TLC (petroleum ether: ethyl acetate = 0: 1, Rf = 0.53) to afford [l-[[(8S)-13-[l-ethyl-6-(methoxymethoxy)-3,4-dihydro-2H-quinolin-8-yl]-14-fluoro-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015.19]nonadeca-l(19),ll,13,15.17-pentaen-17-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl methanesulfonate (Intermediate 40, 450 mg, 0.63 mmol, 74% yield) was obtained as a yellow oil. LCMS (ESI) m / z: 710.2 [M+l] +Step 11:

[0160] To a solution of Intermediate 40 (300 mg, 0.42 mmol, 1 eq) and 3-[4-fluoro-5-[(2S)-2-methyl-4-(4-piperidylmethyl)piperazin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (362 mg, 0.63 mmol, 1.5 eq, trifluoroacetate) in DMF (10 mL) was added potassium iodide (350 mg, 2.11 mmol, 5 eq) and sodium carbonate (224 mg, 2.11 mmol. 5 eq). The mixture was stirred at 90 °C for 2 hr, then quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 2) and the combined organic phase was extracted with brine (10 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by preparative TLC (dichloromethane: methanol = 10: 1, Rf = 0.30) to afford 3-[5-[(2S)-4-[[l-[[l-[[(8S)-13-[l-ethyl-6-(methoxymethoxy)-3.4-dihydro-2H-quinolin-8-yl] - 14-fluoro-6, 10-dioxa-2, 12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-1(19), 11, 13, 15, 17 -pentaen- 17 -yl] oxymethyl] -2, 2-difluoro-cyclopropyl] methyl] -4-piperidyl]methyl]-2-methyl-piperazin-l-yl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (Intermediate 41, 380 mg, 0.35 mmol, 84% yield) was obtained as a yellow solid. LCMS (ESI) nVz 1071.5 [M+l]+Step 12:ARVN-216-PCT / / ARVN0216WO2

[0161] To a solution of Intermediate 41 (380 mg, 0.35 mmol, 1 eq) in DCM (4 mL) was added hydrogen chloride solution in dioxane (2 M, 22.55 eq). The mixture was stirred at 25 °C for 0.5 h, then concentrated in vacuo. The resulting residue was purified by prep-HPLC [H2O(0.225% FA)-ACN];gradient:5%-35% B] to afford 3-[5-[(25)-4-[[l-[[l-[[(85)-13-(l-ethyl-6-hydroxy-3,4-dihydro-2H-quinolin-8-yl)- 14-fluoro-6, 10-dioxa-2, 12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]-2,2-difluoro-cyclopropyl]methyl]-4-piperidyl]methyl] -2-methyl-piperazin- 1 -yl] -4-fluoro- 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dione (Compound 67, 279.4 mg, 0.26 mmol, 72% yield, 98% purity, formate) as a yellow solid. LCMS (ESI) m / z'. 1027.5 [M+l] +. 'H NMR (400 MHz, DMSO-d6) 8: 10.98 (s, 1H), 8.13 (s, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.52 - 6.45 (m, 2H), 5.07 (dd, J = 5.2, 13.2 Hz, 1H), 5.02 - 4.95 (m, 1H), 4.69 - 4.63 (m, 1H), 4.61-4.54 (m, 1H), 4.52- 4.48 (m, 1H), 4.47 - 4.42 (m, 2H), 4.36 - 4.26 (m, 2H), 4.18 - 4.07(m, 1H), 3.95 - 3.85 (m, 1H), 3.74 - 3.68 (m, 1H), 3.60 - 3.53 (m, 2H), 3.27 - 3.19 (m, 3H), 2.96 - 2.89 (m, 4H), 2.88 - 2.78 (m, 3H), 2.72 - 2.66 (m, 3H), 2.62 - 2.55 (m, 2H), 2.44 - 2.33 (m, 4H), 2.32 - 2.25 (m, 1H), 2.13 - 1.94 (m, 5H), 1.92 - 1.84 (m, 2H), 1.82 - 1.74 (m, 1H), 1.71 - 1.61 (m, 4H), 1.52 - 1.42 (m. 2H). 1.09 - 0.92 (m, 5H), 0.43 (d, J = 6.8 Hz, 3H).Using the methods disclosed or similarly disclosed herein, Compounds 1-155 were made:Compound Synthesis1 Example 1.1Analogous2 to Example 1.4(Compound 21)Analogous3 to Example 1.4(Compound 21)ARVN-216-PCT / / ARVN0216WO2Example 1.2Analogousto Example 1.4(Compound 21)Analogousto Example 1.4(Compound 21)Scheme 3Scheme 3Analogousto Example 1.4(Compound 21)Scheme 2Scheme 3Scheme 3Scheme 3Scheme 2Analogousto Example 1.4(Compound 21)Scheme 2Scheme 2Scheme 2Scheme 2Scheme 2Example 1.4ARVN-216-PCT / / ARVN0216WO2Analogousto Example 1.4(Compound 21)Scheme 2Scheme 3Scheme 2Scheme 21 H NMR (400 MHz, DMSO-d6) 6: 11.01 (s, 1 H), 9.27 (s, 1 H), 8.14 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 6.54 (d, J = 8.6 Hz, 2H), 5.17 - 4.95 (m, 2H), 4.74 - 4.57 (m, 2H), 4.56 - 4.42 (m, 3H), 4.41 - 4.26 (m, 2H), 4.14 (dd, J = 3.2, 11.6 Hz, 1H), 3.98 - 3.84 (m, 1H), 3.65 - 3.45 (m, 4H), 3.10 - 2.84 (m, 7H), 2.77 - 2.54 (m, 7H), 2.47 - 2.30 (m, 3H), 2.15 - 1.58 (m, 15H), 1.38 - 0.96 (m, 7H), 0.58 - 0.38 (m, 3H)1 H NMR (400 MHz, DMSO-d6) 5: 11.01 (s, 1 H), 9.27 (s, 1 H), 8.14 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.29 - 7.07 (m, 1H), 6.54 (d, J = 9.3 Hz, 2H), 5.09 (dd, J = 4.9, 13.2 Hz, 1H), 5.04 - 4.95 (m, 1 H), 4.79 - 4.58 (m, 2H), 4.57 - 4.46 (m, 2H), 4.44 - 4.29 (m, 3H), 4.14 (dd, J = 3.5, 12.0 Hz, 1H), 4.00 - 3.85 (m, 1H), 3.66 - 3.52 (m, 2H), 3.48 - 3.35 (m, 6H), 3.12 - 2.82 (m, 6H), 2.79 - 2.66 (m, 3H), 2.60 (d, J = 16.4 Hz, 4H), 2.48 - 2.31 (m, 2H), 2.12 - 1.54 (m, 13H), 1.48 - 0.90 (m, 7H), 0.47 (t, J = 7.3 Hz, 3H)1 H NMR (400 MHz, DMSO-d6) 5: 10.98 (s, 1 H), 9.40 - 9.08 (m, 1H), 6.98 (s, 1H), 6.55 (d, J = 2.4 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 5.11 - 4.94 (m, 2H), 4.69 - 4.36 (m, 5H), 4.35 - 4.28 (m, 1H), 4.27 - 4.05 (m, 3H), 3.99 - 3.84 (m, 2H), 3.61 - Scheme 43.55 (m, 1 H), 3.50 - 3.41 (m, 4H), 3.13 - 3.07 (m, 1H), 2.95 - 2.79 (m, 3H), 2.76 - 2.67 (m, 3H), 2.60 - 2.56 (m, 1H), 2.46 - 2.31 (m, 6H), 2.07 - 1.72 (m, 10H), 1.69 - 1.43 (m, 6H), 1.12 - 0.93 (m, 5H), 0.77 (d, J = 7.2 Hz, 3H)1 H NMR (400 MHz, DMSO-d6) 6: 11.00 (s, 1 H), 9.26 (s, 1 H), 8.14 (s, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.26 - 7.10 (m, 1H), 6.55 (d, J = 2.4 Hz, 1 H), 6.50 (d, J = 2.4 Hz, 1 H), 5.09 (dd, J = 5.0, 13.2 Hz, 1H), 5.05 - 4.97 (m, 1H), 4.73 - 4.58 (m, 2H), 4.52 (s, 1H), 4.50 - 4.43 (m, 2H), 4.39 - 4.29 (m, 2H), 4.11(dd, J = 3.8, 12.0 Hz, 1H), 3.96 - 3.87 (m, 1H), 3.57 (dd, J =ARVN-216-PCT / / ARVN0216WO210.2, 11.8 Hz, 1 H), 3.48 - 3.34 (m, 7H), 3.20 - 2.85 (m, 6H), 2.82 - 2.65 (m, 5H), 2.60 (d, J = 16.8 Hz, 2H), 2.42 (dq, J = 4.6, 13.2 Hz, 2H), 2.07 - 1.81 (m, 6H), 1.80 - 1.49 (m, 7H), 1.38 - 0.96 (m, 7H), 0.47 (t, J = 7.3 Hz, 3H)1H NMR (400 MHz, DMSO-d6) 6: 10.98 (s, 1H), 9.23 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.20 - 7.12 (m, 1H), 6.54 (d, J = 2.4 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 5.11 - 5.05 (m, 1 H), 5.03 - 4.96 (m, 1H), 4.69 - 4.61 (m, 1H), 4.59 - 4.43 (m, 4H), 4.36 - 4.27 (m, 2H), 4.12 - 4.05 (m, 1H), 3.92 - 3.84 (m, 1H), 3.69 - Scheme 43.55 (m, 5H), 3.48 - 3.38 (m, 2H), 3.16 - 3.05 (m, 5H), 2.93 - 2.81 (m, 3H), 2.75 - 2.67 (m, 3H), 2.63 - 2.55 (m, 2H), 2.44 - 2.35 (m, 2H), 2.10 - 1.94 (m, 4H), 1.93 - 1.86 (m, 1H), 1.83 - 1.71 (m, 3H), 1.69 - 1.63 (m, 1 H), 1.62 - 1.45 (m, 6H), 0.76 (d, J = 7.2 Hz, 3H)1 H NMR (400 MHz, DMSO-d6) 5: 10.93 (s, 1 H), 9.58 - 8.93 (m, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1 H), 6.46 (d, J = 2.4 Hz, 1 H), 5.08 - 4.92 (m, 2H), 4.69 - 4.56 (m, 2H), 4.54 - 4.41 (m, 2H), 4.36 - 4.22 Scheme 4 (m, 2H), 4.19 - 4.01 (m, 3H), 3.98 - 3.82 (m, 2H), 3.66 - 3.45 (m, 3H), 3.17 - 2.97 (m, 4H), 2.95 - 2.79 (m, 3H), 2.76 - 2.66 (m, 3H), 2.57 (d, J = 17.6 Hz, 1H), 2.45 - 2.26 (m, 4H), 2.16 (d, J = 7.2 Hz, 2H), 2.06 - 1.92 (m, 3H), 1.91 (s, 2H), 1.84 - 1.71 (m, 4H), 1.70 - 1.47 (m, 4H), 1.47 - 1.36 (m, 1 H), 1 1H NMR (400 MHz, DMSO-d6) 6: 10.94 (s, 1H), 9.40 - 9.04 (m, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1 H), 5.12 - 4.92 (m, 2H), 4.70 - 4.61 (m, 1 H), 4.61 - 4.55 (m, 1 H), 4.54 - 4.45 (m, 2H), 4.35 - 4.23 (m, 2H), 4.16 - 4.04 (m, 3H), 3.92 - 3.81 Scheme 4 (m, 2H), 3.63 - 3.52 (m, 2H), 3.50 - 3.36 (m, 3H), 3.08 (d, J =4.4 Hz, 1H), 2.96 - 2.78 (m, 3H), 2.77 - 2.67 (m, 4H), 2.57 (d, J = 18.4 Hz, 1H), 2.48 - 2.31 (m, 3H), 2.26 (dd, J = 3.6, 6.0 Hz, 1 H), 2.07 - 1.85 (m, 5H), 1.85 (s, 6H), 1.70 - 1.61 (m, 1H), 1.60 - 1.37 (m, 4H), 1.16 (d, J = 5.2 Hz, 3H), 1.12 - 0.89 (m, 5H), 0.77 (d, J = 7.2 Hz, 3H)1H NMR (400 MHz, DMSO-d6) 8: 10.99 (s, 1H), 9.44 - 9.06 (m, 1H), 8.14 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.56 - 6.53 (m, 1H), 6.47 - 6.44 (m, 1H), 5.13 - 5.05 (m, Scheme 4 1H), 5.03 - 4.94 (m, 1H), 4.70 - 4.55 (m, 2H), 4.54 - 4.37 (m,3H), 4.35 - 4.29 (m, 1H), 4.28 - 4.20 (m, 1H), 4.12 - 4.04 (m, 1H), 3.92 - 3.82 (m, 1H), 3.62 - 3.54 (m, 2H), 3.22 - 3.14 (m, 3H), 3.13 - 3.04 (m, 2H), 2.95 - 2.80 (m, 5H), 2.78 - 2.64 (m, 4 H), 2.62 - 2.55 (m, 1H), 2.47 - 2.28 (m, 4H), 2.05 - 1.94 (m,ARVN-216-PCT / / ARVN0216WO24H), 1.93 - 1.85 (m, 2H), 1.84 - 1.69 (m, 4H), 1.68 - 1.42 (m, 5H), 1.13 - 0.90 (m, 5H), 0.77 (d, J = 7.2 Hz, 3H)1 H NMR (400 MHz, DMSO-d6) 6: 10.94 (s, 1 H), 9.47 - 8.97 (m, 1H), 8.15 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 5.09 - 4.92 (m, 2H), 4.69 - 4.55 (m, 2H), 4.54 - 4.41 (m, 2H), 4.38 - 4.21 (m, 3H), 4.16 - 4.04 (m, 2H), 4.03 - 3.94 (m 1H), Scheme 4 3.91 - 3.82 (m, 1 H), 3.61 - 3.52 (m, 2H), 3.48 - 3.40 (m, 2H),3.22 - 3.17 (m, 1H), 3.13 - 3.05 (m, 1H), 2.95 - 2.78 (m, 5H), 2.76 - 2.65 (m, 3H), 2.61 - 2.53 (m, 1H), 2.46 - 2.31 (m, 2H), 2.15 - 1.92 (m, 7H), 1.91 - 1.83 (m, 2H), 1.82 - 1.70 (m, 3H), 1.69 - 1.58 (m, 3H), 1.57 - 1.40 (m, 3H), 1.25 - 1.14 (m, 3H), 1.08 - 0.92 (m, 2H), 0.76 (d, J = 7.2 Hz, 3H).1H NMR (400 MHz, DMSO-d6) 8: 10.94 (s, 1H), 9.43 - 9.01 (m, 1H), 8.14 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1 H), 6.54 (d, J - 2.4 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1 H), 5.09 - 4.92 (m, 2H), 4.69 - 4.55 (m, 2H), 4.54 - 4.42 (m, 2H), 4.38 - 4.22 (m, 3H), 4.16 - 4.04 (m, 2H), 4.03 - 3.95 (m, 1H), 3.91 - 3.82 Scheme 4 (m, 1H), 3.61 - 3.51 (m, 2H), 3.49 - 3.41 (m, 2H), 3.22 - 3.18 (m, 1H), 3.12 - 3.05 (m, 1H), 2.95 - 2.78 (m, 5H), 2.76 - 2.65 (m, 3H), 2.61 - 2.53 (m, 1H), 2.45 - 2.31 (m, 2H), 2.16 - 1.92 (m, 7H), 1.91 - 1.83 (m, 2H), 1.82 - 1.70 (m, 3H), 1.69 - 1.59 (m, 3H), 1.57 - 1.41 (m, 3H), 1.24 - 1.15 (m, 3H), 1.08 - 0.94 (m, 2H), 0.76(d, J = 6.8 Hz, 3H)1 H NMR (400 MHz, DMSO-d6) 6: 10.44 (s, 1 H), 9.39 - 9.09 (m, 1H), 6.54 (d, J = 2.4 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 5.02 - 4.94 (m, 1 H), 4.68 - 4.62 (m, 1 H), 4.59 ( d, J = 10.8 Hz, 1H), 4.51 (d, J = 13.2 Hz, 1H), 4.44 ( d, J = 10.4 Hz, 1H), 4.35 - 4.26 (m, 1H), 4.08 (dd, J = 3.6, 12.0 Hz, 1 H), 3.92 - Scheme 4 3.83 (m, 1 H), 3.79 (d, J = 11.6 Hz, 2H), 3.61 - 3.53 (m, 3H),3.49 - 3.43 (m, 3H), 3.09 ( d, J = 3.2 Hz, 2H), 2.89 ( t, J = 12.0 Hz, 2H), 2.75 - 2.65 (m, 5H), 2.47 - 2.21 (m, 8H), 2.07 (d, J = 6.4 Hz, 2H), 1.96 (s, 3H), 1.93 - 1.84 (m, 1 H), 1.80 - 1.63 (m, 7H), 1.58 - 1.46 (m, 2H), 1.14 - 1.01 (m, 2H), 0.76 (d, J = 7.2 Hz, 3H)1 H NMR (400 MHz, DMSO-d6) 6: 10.93 (s, 1 H), 9.46 - 8.94 (m, 1H), 8.16 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), Scheme 4 5.09 - 4.93 (m, 2H), 4.69 - 4.58 (m, 1H), 4.49 (d, J = 13.2 Hz,1H), 4.34 - 4.24 (m, 4H), 4.16 - 4.05 (m, 3H), 3.91 - 3.82 (m, 2H), 3.61 - 3.53 (m, 2H), 3.48 - 3.40 (m, 2H), 3.12 - 3.05 (m, 1H), 3.00 - 2.93 (m, 1H), 2.92 - 2.81 (m, 2H), 2.77 - 2.67 (m,5H), 2.64 - 2.53 (m, 2H), 2.48 - 2.39 (m, 2H), 2.37 - 2.33 (m,ARVN-216-PCT / / ARVN0216WO22H), 2.30 - 2.18 (m, 3H), 2.01 - 1.91 (m, 3H), 1.89 - 1.78 (m, 3H), 1.77 - 1.59 (m, 5H), 1.57 - 1.50 (m, 1 H), 1.20 (d, J = 6.0 Hz, 3H), 0.75 (d, J = 7.2 Hz, 3H), 0.65 (s, 2H), 0.43 (s, 2H) 1 H NMR (400 MHz, DMSO-d6) 6: 10.98 (s, 1 H), 9.67 - 8.91 (m, 1H), 8.19 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1 H), 6.54 (d, J = 2.4 Hz, 1 H), 6.45 (d, J = 2.4 Hz, 1 H), 5.06 (dd, J = 5.2, 13.2 Hz, 1 H), 5.03 - 4.94 (m, 1 H), 4.71 - 4.57 (m, 2H), 4.56 - 4.42 (m, 3H), 4.36 - 4.25 (m, 2H), 4.08 Scheme 4 (dd, J = 4.0, 12.0 Hz, 1H), 3.88 (td, J = 4.8, 12.4 Hz, 1 H),3.58 (dd, J = 10.2, 12.0 Hz, 1H), 3.48 - 3.42 (m, 2H), 3.39 - 3.34 (m, 2H), 3.08 (s, 4H), 2.97 - 2.83 (m, 1 H), 2.79 - 2.66 (m, 3H), 2.63 - 2.55 (m, 1 H), 2.44 - 2.33 (m, 5H), 2.07 - 1.93 (m, 2H), 1.92 - 1.72 (m, 4H), 1.71 - 1.62 (m, 1 H), 1.58 - 1.38 (m, 10H), 0.77 (d, J = 7.2 Hz, 3H)1 H NMR (400 MHz, DMSO-d6) 5: 10.95 (s, 1 H), 9.69 - 8.64 (m, 1H), 8.18 (s, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1 H), 6.54 (s, 1 H), 6.46 (d, J = 2.0 Hz, 1 H), 5.08 - 4.96 (m, 2H), 4.67 - 4.57 (m, 2H), 4.53 - 4.44 (m, 2H), 4.34 - 4.26 (m, 2H), 4.16 (s, 1H), 4.08 (d, J = 10.0 Hz, 2H), 3.99 (dd, J = 5.6, 9.2 Hz, 1H), 3.90 - 3.85 (m, 1H), 3.66 - 3.54 (m, 4H), Scheme 43.10 (d, J = 0.8 Hz, 2H), 2.97 - 2.86 (m, 2H), 2.82 (d, J = 9.6 Hz, 3H), 2.71 (s, 3H), 2.61 - 2.53 (m, 3H), 2.42 - 2.32 (m, 2H), 2.19 - 2.09 (m, 3H), 2.05 - 1.94 (m, 4H), 1.87 (d, J = 10.8 Hz, 2H), 1.78 - 1.73 (m, 2H), 1.68 - 1.62 (m, 2H), 1.56 - 1.43 (m, 3H), 1.11 (t, J = 4.8 Hz, 3H), 1.04 (d, J = 5.6 Hz, 4H), 0.76 (d, J = 7.0 Hz, 3H)1H NMR (400 MHz, DMSO-d6) 5:10.96 (S, 1 H), 9.52 - 8.94 (m, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1 H), 5.10 - 4.96 (m, 2H), 4.70 - 4.43 (m, 4H), 4.37 - 4.27(m, 2H), 4.20 - 4.07 Scheme 4 (m, 3H), 4.02 - 3.98 (m, 1 H), 3.92 - 3.85 (m, 1 H), 3.68 - 3.54 (m, 3H), 3.12 - 3.08 (m, 1 H), 2.93 - 2.78 (m, 4H), 2.75 - 2.66 (m, 3H), 2.63 - 2.54 (m, 2H), 2.43 - 2.32 (m, 2H), 2.22 - 1.83 (m, 10H), 1.82 - 1.63 (m, 6H), 1.58 - 1.43 (m, 3H), 1.12 (t, J = 5.2 Hz, 3H), 1.08 - 0.96 (m, 5H), 0.77 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO-d6):5: 10.94 (s, 1H), 9.76 - 8.85 (m, 1H), 8.16 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1 H), 6.54 (s, 1 H), 6.46 (d, J = 1.6 Hz, 1 H), 5.06 - 4.94 (m, 2H), 4.69 - 4.57 (m, 2H), 4.53 - 4.43 (m, 2H), 4.28 (dd, J Scheme 4 = 8.4, 16.9 Hz, 2H), 4.15 - 4.05 (m, 3H), 3.87 (t, J = 9.2 Hz,2H), 3.61 - 3.55 (m, 2H), 3.45 (dt, J = 3.2, 8.0 Hz, 2H), 3.37 - 3.32 (m, 2H), 3.09 (d, J = 5.2 Hz, 1H), 2.90 - 2.78 (m, 5H), 2.73 - 2.64 (m, 4H), 2.59 (s, 1H), 2.41 - 2.32 (m, 2H), 2.10 (d, J = 8.4 Hz, 1 H), 2.04 (d, J = 5.6 Hz, 2H), 1.96 (d, J = 10.4 Hz,2H), 1.91 - 1.84 (m, 2H), 1.80 - 1.75 (m, 2H), 1.69 (d, J =ARVN-216-PCT / / ARVN0216WO210.6 Hz, 2H), 1.64 (d, J = 2.8 Hz, 2H), 1.57 - 1.53 (m, 1H), 1.51 - 1.43 (m, 2H), 1.18 (d, J = 4.8 Hz, 3H), 1.07 - 0.97 (m, 2H), 0.76 (d, J = 6.8 Hz, 3H1H NMR (400 MHz, DMSO-d6) 6: 10.94 (s, 1H), 8.17 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1 H), 6.54 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 5.08 - 4.94 (m, 2H), 4.69 - 4.60 (m, 1H), 4.50 (d, J = 13.2 Hz, 1H), 4.34 - 4.24 (m, 4H), 4.16 - 4.03 (m, 3H), 3.92 - 3.82 (m, 2H), 3.62 - 3.53 (m, Scheme 4 2H), 3.48 - 3.30 (m, 3H), 3.09 (d, J = 5.2 Hz, 1 H), 3.03 - 2.95 (m, 2H), 2.93 - 2.79 (m, 3H), 2.73 - 2.65 (m, 2H), 2.57 (d, J = 17.2 Hz, 1H), 2.43 - 2.26 (m, 3H), 2.18 - 2.02 (m, 3H), 2.00 - 1.84 (m, 5H), 1.79 - 1.61 (m, 6H), 1.58 - 1.47 (m, 2H), 1.20 - 1.05 (m, 5H), 0.76 (d, J = 7.2 Hz, 3H), 0.65 (s, 2H), 0.43 (s, 2H).1H NMR (400 MHz, DMSO-d6) 6: 10.94 (s, 1H), 8.15 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.54 - 6.45 (m, 2H), 5.06 - 4.97 (m, 2H), 4.66 - 4.61 (m, 1H), 4.49 (d, J = 13.2 Hz, 1H), 4.35 - 4.24 (m, 4H), 4.16 - 4.04 (m, 3H), 3.91 - 3.81 Scheme 4 (m, 2H), 3.60 - 3.53 (m, 2H), 3.46 - 3.41 (m, 2H), 3.09 (s, 1 H),3.00 - 2.93 (m, 1H), 2.92 - 2.81 (m, 2H), 2.77 - 2.64 (m, 5H), 2.64 - 2.51 (m, 2H), 2.47 - 2.19 (m, 7H), 2.05 - 1.91 (m, 3H), 1.89 - 1.78 (m, 3H), 1.77 - 1.57 (m, 4H), 1.55 (br s, 1H), 1.28 - 1.14 (m, 3H), 0.75 (d, J = 7.2 Hz, 3H), 0.64 (s, 2H), 0.43 (s, 2H).1H NMR (400 MHz, DMSO-d6) 6: 11.04 - 10.92 (m, 1 H), 8.18 - 8.13 (m, 1H), 7.55 - 7.40 (m, 1H), 7.22 - 7.05 (m, 1H), 6.61 - 6.39 (m, 2H), 5.16 - 5.00 (m, 1H), 4.65 - 4.39 (m, 6H), 4.34 - 4.21 (m, 2H), 4.20 - 4.11 (m, 1 H), 4.00 - 3.88 (m, 1H), 3.68 - Example 1.3 3.55 (m, 2H), 3.17 - 3.04 (m, 6H), 2.97 - 2.86 (m, 2H), 2.84 - 2.77 (m, 2H), 2.75 - 2.64 (m, 4H), 2.60 (d, J = 16.0 Hz, 3H), 2.42 - 2.31 (m, 3H), 2.16 - 2.04 (m, 3H), 2.03 - 1.92 (m, 3H), 1.84 (d, J = 4.8 Hz, 1 H), 1.83 - 1.60 (m, 10H), 1.58 - 1.41 (m, 3H), 0.83 - 0.71 (m, 3H)1H NMR (400 MHz, DMSO-d6) 6: 10.98 (s, 1H), 9.23(s, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 1.6 Hz, 1H), 5.07 (dd, J = 5.2, 13.2Hz, 1H), Analogous 4.63 - 4.53 (m, 2H), 4.52 - 4.44 (m, 3H), 4.42 - 4.32 (m, 2H), to Example 1.3 4.31 - 4.26 (m, 1H), 4.16 (dd, J == 3.2, 12.0 Hz, 1H), 3.98 - 3.90 (Compound 46) (m, 1H), 3.75 - 3.67 (m, 1H), 3.59 (d, J = 11.6 Hz, 1H), 3.27 - 3.19 (m, 3H), 3.11 - 3.06 (m, 1 H), 2.96 - 2.87 (m, 2H), 2.84 - 2.76 (m, 2H), 2.74 - 2.67 (m, 3H), 2.62 - 2.55 (m, 2H), 2.46 - 2.30 (m, 6H), 2.12 - 1.95 (m, 5H), 1.89 - 1.73 (m, 4H), 1.70 (d, JARVN-216-PCT / / ARVN0216WO2= 6.8 Hz, 4H), 1.66 - 1.59 (m, 2H), 1.57 - 1.43 (m, 3H), 1.04 - 0.93 (m, 5H), 0.76 (d, J = 6.8 Hz, 3H)1H NMR (400 MHz, DMSO-d6) 6:10.99 (s, 1H), 9.89 - 8.75 (m, 1 H), 8.15 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.54 (s, 1H), 6.45 (d, J = 1.6 Hz, 1H), 5.07 (dd, J = 4.8, 13.2 Analogous Hz, 1H), 4.66 - 4.42 (m, 5H), 4.37 - 4.25 (m, 3H), 4.16 - 4.12 to Example 1.3 (m, 1H), 3.98 - 3.90 (m, 1H), 3.72 - 3.68 (m, 1H), 3.56 (t, J = (Compound 46) 11.2 Hz, 1H), 3.38 - 3.31 (m, 1H), 3.27 - 3.23 (m, 1H), 3.10 - 3.06 (m, 1H), 2.96 - 2.80 (m, 4H), 2.73 - 2.56 (m, 5H), 2.45 - 2.25 (m, 6H), 2.09 - 1.87 (m, 6H), 1.83 - 1.62 (m, 9H), 1.58 - 1.43 (m, 3H), 1.10 - 0.91 (m, 5H), 0.77 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, DMSO-d6) 6: 10.99 (s, 1H), 9.82 - 8.67 (m, 1H), 8.14 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.54 (s, 1H), 6.45 (d, J = 2.0 Hz, 1H), 5.07 (dd, J = 4.8, 13.2 Analogous Hz, 1H), 4.66 - 4.40 (m, 5H), 4.33 - 4.27 (m, 3H), 4.15 - 4.13 to Example 1.3 (m, 1H), 3.96 - 3.92 (m, 1H), 3.71 - 3.69 (m, 1H), 3.56 (t, J = (Compound 46) 11.2. Hz, 1H), 3.39 - 3.32 (m, 1H), 3.27 - 3.23 (m, 1H), 3.09 - 3.07 (m, 1H), 2.97 - 2.79 (m, 4H), 2.75 - 2.56 (m, 5 H ), 2.46 - 2.25 (m, 6H), 2.12 - 1.85 (m, 6H), 1.82 - 1.59 (m, 9H), 1.57 - 1.41 (m, 3H), 1.08 - 0.92 (m, 5H), 0.77 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO-d6) 5:10.98 (S, 1 H), 9.80 - 8.63 (m, 1H), 8.21 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.62 - 6.36 (m, 2H), 5.07 (dd, J = 5.2, 13.2 Hz, 1H), 4.61 - 4.52 (m, 2H), 4.51 - 4.35 (m, 4H), 4.34 - 4.24 (m, 2H), Analogous 4.16 (dd, J = 3.6, 12.0 Hz, 1H), 3.94 (dd, J = 5.2, 12.8 Hz,1H), 3.63 - 3.57 (m, 1H), 3.41 - 3.31 (m, 3H), 3.11 (s, 4H), to Example 1.32.94 - 2.86 (m, 1H), 2.80 (d, J = 10.4 Hz, 2H), 2.74 - 2.66 (m, (Compound 46) 3H), 2.58 (d, J = 16.4 Hz, 2H), 2.47 (s, 3H), 2.41 - 2.35 (m,2H), 2.10 (d, J = 6.4 Hz, 2H), 2.05 - 1.93 (m, 3H), 1.92 - 1.84 (m, 1 H), 1.83 - 1.73 (m, 3H), 1.70 (d, J = 6.8 Hz, 3H), 1.64 (d, J = 4.0 Hz, 3H), 1.58 - 1.43 (m, 3H), 1.07 - 0.91 (m, 2H), 0.76 (d, J = 7.2 Hz, 3H)1 H NMR (400 MHz, DMSO-d6) 6: 10.98 (s, 1 H), 9.69 - 8.84 (m, 1H), 8.20 (S, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.66 - 6.37 (m, 2H), 5.07 (dd, J = 5.2, 13.2 Hz, 1H), Analogous 4.63 - 4.53 (m, 2H), 4.52 - 4.36 (m, 4H), 4.35 - 4.25 (m, 2H), to Example 1.3 4.20 - 4.12 (m, 1H), 3.94 (dd, J = 5.2, 11.6 Hz, 1 H), 3.74 - (Compound 46) 3.67 (m, 1 H), 3.60 (t, J = 11.6 Hz, 1 H), 3.52 - 3.31 (m, 3H),3.30 - 3.18 (m, 2H), 3.11 - 3.05 (m, 1H), 2.96 - 2.87 (m, 2H), 2.80 (d, J = 10.0 Hz, 2H), 2.74 - 2.65 (m, 3H), 2.59 (d, J = 14.4 Hz, 2H), 2.54 - 2.51 (m, 1H), 2.49 - 2.34 (m, 5H), 2.34 -2.28 (m, 1 H), 2.06 (t, J = 6.0 Hz, 2H), 2.01 - 1.95 (m, 2H),ARVN-216-PCT / / ARVN0216WO21.91 - 1.83 (m, 1 H), 1.79 - 1.74 (m, 2H), 1.70 (d, J = 6.4 Hz, 3H), 1.67 - 1.62 (m, 2H), 1.58 - 1.52 (m, 1 H), 1.52 - 1.40 (m, 2H), 1.02 (s, 1 H), 0.98 (d, J = 6.4 Hz, 3H), 0.76 (d, J = 7.2 Hz, 3H)1 H NMR (400 MHz, DMSO-d6) 6: 10.98 (s, 1 H), 9.40 - 9.01 (m, 1H), 8.14 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1 H), 6.54 (d, J = 2.4 Hz, 1 H), 6.46 (d, J = 2.4 Hz, 1 H), 5.07 (dd, J = 5.2, 13.2 Hz, 1 H), 5.02 - 4.92 (m, 1 H), 4.69 - 4.56 (m, 2H), 4.52 - 4.41 (m, 3H), 4.37 - 4.25 (m, 2H), 4.11 (dd, J = 4.0, 12.0 Hz, 1H), 3.92 - 3.84 (m, 1H), 3.74 - 3.61 (m, Scheme 42H), 3.52 - 3.44 (m, 2H), 3.10 - 3.03 (m, 1H), 2.97 - 2.88 (m, 2H), 2.87 - 2.74 (m, 3H), 2.73 - 2.64 (m, 3H), 2.59 (d, J = 16.0 Hz, 2H), 2.46 - 2.36 (m, 4H), 2.33 - 2.25 (m, 1H), 2.13 - 1.93 (m, 5H), 1.92 - 1.84 (m, 2H), 1.82 - 1.72 (m, 3H), 1.65 (d, J = 10.8 Hz, 3H), 1.60 - 1.42 (m, 3H), 1.13 - 0.94 (m, 5H), 0.77 (d, J = 6.8 Hz, 3H)1 H NMR (400 MHz, DMSO-d6) 6: 10.98 (s, 1 H), 9.52 - 8.81 (m, 1H), 8.14 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1 H), 6.54 (d, J = 2.4 Hz, 1 H), 6.46 (d, J = 2.0 Hz, 1 H), 5.07 (dd, J = 5.2, 13.2 Hz, 1 H), 5.02 - 4.91 (m, 1 H), 4.69 - 4.58 (m, 2H), 4.54 - 4.41 (m, 3H), 4.36 - 4.27 (m, 2H), 4.11 (dd, J = 3.6, 12.0 Hz, 1H), 3.93 - 3.83 (m, 1 H), 3.74 - 3.62 (m, Scheme 42H), 3.47 (td, J = 4.0, 8.4 Hz, 2H), 3.07 (d, J = 5.2 Hz, 1H), 2.99 - 2.89 (m, 2H), 2.81 (d, J = 9.2 Hz, 3H), 2.75 - 2.65 (m, 3H), 2.62 - 2.54 (m, 2H), 2.47 - 2.34 (m, 4H), 2.33 - 2.24 (m, 1H), 2.13 - 1.94 (m, 5H), 1.88 (d, J = 12.0 Hz, 2H), 1.82 - 1.71 (m, 3H), 1.71 - 1.59 (m, 3H), 1.57 - 1.41 (m, 3H), 1.11 - 0.89 (m, 5H), 0.77 (d, J = 6.8 Hz, 3H)1H NMR (400 MHz, DMSO-d6) 6: 10.99 (s, 1H), 8.32 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.55 (d, J = 2.1 Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 5.14 - 4.96 (m, 2H), 4.71 - 4.57 (m, 2H), 4.56 - 4.43 (m, 3H), 4.39 - 4.26 (m, 2H), 4.10 (dd, J = 3.6, 12.0 Hz, 1H), 3.92 - 3.84 (m, 1H), 3.69 (d, J Scheme 4 = 10.9 Hz, 2H), 3.29 - 3.22 (m, 2H), 3.15 - 3.05 (m, 2H), 2.98 - 2.89 (m, 2H), 2.87 - 2.78 (m, 2H), 2.75 - 2.66 (m, 3H), 2.63 - 2.54 (m, 3H), 2.44 - 2.38 (m, 3H), 2.31 (dd, J = 6.9, 12.3 Hz, 1H), 2.12 - 2.05 (m, 2H), 2.03 - 1.84 (m, 5H), 1.82 - 1.73 (m, 3H), 1.67 (d, J = 8.5 Hz, 3H), 1.60 - 1.44 (m, 3H), 1.12 - 0.95 (m, 5H), 0.77 (d, J = 7.0 Hz, 3H)1H NMR (400 MHz, DMSO-d6) 6: 10.99 (s, 1H), 8.29 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.55 (d, J = Scheme 4 2.0 Hz, 1H), 6.47 (s, 1H), 5.08 (dd, J = 4.8, 13.2 Hz, 1H),5.03 - 4.95 (m, 1 H), 4.69 - 4.57 (m, 2H), 4.55 - 4.42 (m, 3H), 4.39 - 4.26 (m, 2H), 4.15 - 4.05 (m, 1H), 3.89 (dd, J = 5.2,12.4 Hz, 1H), 3.71 (d, J = 4.2 Hz, 1H), 3.30 - 3.20 (m, 2H),ARVN-216-PCT / / ARVN0216WO23.10 (s, 2H), 2.97 - 2.90 (m, 2H), 2.82 (d, J = 9.6 Hz, 2H), 2.77 - 2.66 (m, 4H), 2.63 - 2.55 (m, 3H), 2.48 - 2.32 (m, 5H), 2.10 - 1.95 (m, 5H), 1.92 - 1.85 (m, 2H), 1.82 - 1.73 (m, 3H), 1.66 (s, 3H), 1.59 - 1.44 (m, 3H), 0.99 (d, J = 6.0 Hz, 5H), 0.77 (d, J = 7.0 Hz, 3H)1H NMR (400 MHz, DMSO-d6) 6: 10.99 (s, 1H), 9.38 - 9.11 (m, 1H), 8.15 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1 H), 6.55 (d, J = 2.4 Hz, 1 H), 6.46 (d, J = 2.4 Hz, 1 H), Analogous 5.08 (dd, J = 5.2, 13.2 Hz, 1H), 4.67 - 4.44 (m, 5H), 4.39 - 4.26 (m, 3H), 4.16 - 4.14 (m, 1H), 4.01 - 3.90 (m, 1H), 3.62 - to Example 1.33.53 (m, 1 H), 3.38 - 3.34 (m, 4H), 3.13 - 3.11 (m, 5H), 2.97 - (Compound 46) 2.69 (m, 6H), 2.61 - 2.57 (m, 1H), 2.47 - 2.31 (m, 4H), 2.13 (d, J = 6.8 Hz, 2H), 2.07 - 1.88 (m, 4H), 1.85 - 1.64 (m, 9H), 1.59 - 1.46 (m, 3H), 1.11 - 0.95 (m, 2H), 0.77 (d, J = 7.2 Hz, 3H)1 H NMR (400 MHz, DMSO-d6) 6: 10.98 (s, 1 H), 9.73 - 8.89 (m, 1H), 8.14 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.54 (s, 1H), 6.46 (d, J = 2.0 Hz, 1H), 5.14 - 4.88 (m, 2H), 4.70 - 4.54 (m, 2H), 4.52 - 4.40 (m, 3H), 4.35 - 4.23 (m, 2H), 4.11 (dd, J = 3.2, 12.0 Hz, 1H), 3.93 - 3.82 (m, 1H), 3.67 Scheme 4 - 3.59 (m, 1 H), 3.51 - 3.43 (m, 2H), 3.38 (d, J = 8.8 Hz, 2H),3.11 (s, 6H), 2.98 - 2.76 (m, 4H), 2.74 - 2.65 (m, 3H), 2.58 (d, J = 16.4 Hz, 1H), 2.43 - 2.35 (m, 2H), 2.12 (d, J = 6.4 Hz, 2H), 2.05 - 1.94 (m, 3H), 1.92 - 1.85 (m, 2H), 1.82 - 1.72 (m, 3H), 1.65 (d, J = 10.4 Hz, 3H), 1.58 - 1.41 (m, 3H), 1.11 - 0.91 (m, 2H), 0.77 (d, J = 7.2 Hz, 3H)1 H NMR (400 MHz, DMSO-d6) 5: 10.98 (s, 1 H), 9.60 - 9.09 (m, 1H), 8.15 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.54 (s, 1H), 6.46 (s, 1H), 5.11 - 4.91 (m, 2H), 4.69 - 4.55 (m, 2H), 4.53 - 4.39 (m, 3H), 4.35 - 4.23 (m, 2H), 4.11 (dd, J = 3.2, 12.0 Hz, 1H), 3.94 - 3.83 (m, 1H), 3.68 - 3.59 (m, Scheme 41H), 3.53 - 3.38 (m, 4H), 3.11 (s, 6H), 3.02 - 2.74 (m, 4H), 2.73 - 2.65 (m, 3H), 2.58 (d, J = 16.8 Hz, 1H), 2.43 - 2.33 (m, 2H), 2.11 (d, J = 6.8 Hz, 2H), 2.05 - 1.94 (m, 3H), 1.92 - 1.84 (m, 2H), 1.83 - 1.71 (m, 3H), 1.71 - 1.60 (m, 3H), 1.58 - 1.43 (m, 3H), 1.10 - 0.96 (m, 2H), 0.77 (d, J = 7.2 Hz, 3H)1 H NMR (400 MHz, DMSO-d6) 6: 10.99 (s, 1 H), 9.57 - 8.88 (m, 1H), 8.18 (S, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1 H), 6.55 (d, J = 2.4 Hz, 1 H), 6.47 (d, J = 2.4 Hz, 1 H), 5.14 - 4.91 (m, 2H), 4.72 - 4.57 (m, 2H), 4.56 - 4.41 (m, 3H), Scheme 4 4.37 - 4.26 (m, 2H), 4.09 (dd, J = 3.6, 12.0 Hz, 1 H), 3.94 - 3.82 (m, 1H), 3.59 (dd, J = 10.2, 12.0 Hz, 1H), 3.50 - 3.40 (m, 2H), 3.12 (s, 4H), 2.98 - 2.88 (m, 1H), 2.86 - 2.78 (m, 2H), 2.76 - 2.65 (m, 3H), 2.59 (d, J = 16.4 Hz, 1H), 2.48 (s, 4H),2.43 - 2.39 (m, 1H), 2.13 (d, J = 7.2 Hz, 2H), 2.06 - 1.85 (m,ARVN-216-PCT / / ARVN0216WO25H), 1.83 - 1.72 (m, 3H), 1.71 - 1.61 (m, 3H), 1.58 - 1.43 (m, 3H), 1.11 - 0.95 (m, 2H), 0.77 (d, J = 7.0 Hz, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.99 (s, 1H), 9.59 - 9.02 (m, 1H), 8.15 (s, 1H), 7.48 (d, J - 8.0 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 5.08 (dd, J - 4.8, 13.2 Hz, 1H), 4.67 - 4.43 (m, 5H), 4.39 - 4.26 (m, 3H), Analogous4.16 - 4.14 (m, 1H), 4.01 - 3.89 (m, 1H), 3.58 - 3.56 (, 1H), 3.35 to Compound 46(s, 4H), 3.13 - 3.11 (m, 5 H), 2.98 - 2.69 (m, 6H), 2.63 - 2.56 (m, 1H), 2.47 - 2.32 (m, 4H), 2.12 (d, J = 6.8 Hz, 2H), 2.06 - 1.85 (m, 4H), 1.82 - 1.61 (m, 9H), 1.58 - 1.42 (m, 3H), 1.08 - 0.94 (m, 2H), 0.78 (d, J = 7.2 Hz, 3H)Example 1.51H NMR (400 MHz, DMSO-d6) 8: 10.98 (s, 1H), 10.29 - 9.63 (m, 1H). 8.14 (s, 1H), 7.75 (dd, J = 6.0, 9.2 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.38 - 7.29 (m, 2H), 7.14 (t, J = 8.0 Hz, 1H), 7.06 - Analogous 6.97 (m, 1H), 5.07 (dd, J = 5.2, 13.2 Hz, 1H), 4.68 ■ 4.43 (m, to Compound 46 5H), 4.41 - 4.27 (m, 3H), 4.23 - 4.14 (m, 1H), 4.02 - 3.92 (m,1H), 3.66 - 3.51 (m, 1H), 3.42 - 3.29 (m, 4H), 3.11 (s, 4H), 2.95 - 2.69 (m, 4H), 2.63 - 2.53 (m, 2H), 2.44 - 2.25 (m, 5H), 2.16 - 1.88 (m, 6H), 1.84 - 1.77 (m, 1H), 1.77 - 1.62 (m, 5H), 1.56 - 1.43 (m, 2H), 1.10 - 0.93 (m, 2H), 0.88 - 0.76 (m, 3H1H NMR (400 MHz, DMSO-d6) 8: 10.98 (s, 1H), 9.92(s, 1H), 8.14 (s, 1H), 7.75 (dd, J = 6.0, 9.2 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.37 - 7.32 (m, 1H), 7.32 - 7.29 (m, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.05 - 6.98 (m, 1H), 5.07 (dd, J = 5.2, 13.2 Hz, 1H), 4.67 - 4.55 (m, 2H), 4.53 - 4.45 (m, 3H), 4.40 - 4.26 (m, 3H), 4.23 - Analogous4.13 (m, 1H), 4.01 - 3.92 (m, 1H), 3.70 (d, J = 1.6 Hz, 1H), 3.64 to Compound 46 - 3.52 (m, 1H), 3.38 (s, 1H), 3.26 - 3.19 (m, 1H), 2.97 - 2.88 (m,2H), 2.86 - 2.78 (m, 2H), 2.76 - 2.67 (m, 1H), 2.64 - 2.55 (m, 2H), 2.45 - 2.36 (m, 5H), 2.35 - 2.23 (m, 3H), 2.12 - 1.94 (m, 5H), 1.93 - 1.78 (m, 2H), 1.74 (dd, J = 2.4, 6.8 Hz, 3H), 1.71 - 1.61 (m, 2H), 1.53 - 1.42 (m, 2H), 1.09 - 0.95 (m, 5H), 0.86 - 0.77 (m, 3H)1H NMR (400 MHz, DMSO-d6) 5:10.99 (s, 1H), 10.15 - 9.77 (m, 1H), 8.14 (s, 1H), 7.75 (dd, J - 6.0, 9.2 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.38 - 7.29 (m, 2H), 7.14 (t, J = 8.0 Hz, 1H), 7.07 - 6.97 Analogous (m, 1H), 5.08 (dd, J - 5.2, 13.2 Hz, 1H), 4.67 - 4.44 (m, 5H), to Compound 46 4.43 - 4.26 (m, 3H), 4.24 - 4.12 (m, 1H), 4.03 - 3.92 (m, 1H),3.68 - 3.51 (m, 1H), 3.38 - 3.30 (m, 4H), 3.13 (s, 4H), 2.98 - 2.73 (m, 4H), 2.63 - 2.55 (m, 2H), 2.46 - 2.25 (m, 5 H ), 2.22 - 1.91 (m, 6H), 1.87 - 1.79 (m, 1H), 1.77 - 1.63 (m, 5H), 1.56 -1.52 (m, 2H), 1.09 - 1.01 (m, 2H), 0.84 - 0.78 (m, 3H)ARVN-216-PCT / / ARVN0216WO21H NMR (400 MHz, DMSO-d6) 5: 10.97 (s, 1H), 9.31 - 9.20 (m, 1H), 6.97 (s, 1H), 6.54 (s, 1H), 6.46 (s, 1H), 5.08 - 4.96 (m. 2H), 4.68 - 4.63 (m, 1H), 4.59 (br d. J = 11.2 Hz. 1H), 4.54 - 4.41 (m, 3H), 4.40 - 4.34 (m, 1H), 4.31 (br s, 1H), 4.26 - 4.19 (m, 1H), 4.14 - General4.06 (m, 2H), 3.99 - 3.93 (m, 1H), 3.92 - 3.85 (m, Synthetic1H), 3.63 - 3.54 (m, 2H), 3.11 - 3.06 (m, 2H), 2.83 - Scheme 42.78 (m, 2H), 2.74 - 2.65 (m. 4H), 2.37 (br d. J = 2.8 Hz, 5H), 2.04 - 1.93 (m, 5H), 1.90 - 1.73 (m, 6H), 1.66 - 1.60 (m, 3H), 1.59 - 1.37 (m, 5H), 1.10 - 1.05 (m, 3H), 1.02 - 0.93 (m, 2H), 0.76 (br d, J - 6.8 Hz, 3H1H NMR (400 MHz, DMSO-d6) 5: 10.98 (s, 1H), 8.15 (s, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 7.6 Hz. 1H), 6.55 - 6.44 (m, 2H). 5.07 (dd, J = 5.2, 13.2 Hz, 1H), 5.03 - 4.91 (m, 1H), 4.69 - 4.62 (m, 1H), 4.61 - 4.52 (m, 1H), 4.51 - 4.42 (m, 3H), 4.34 - 4.27 (m, 2H), 4.16 - 4.08 (m, 1H), 3.92 - 3.85 (m, 1H), 3.60 - 3.54 (m, 2H), 3.28 - 3.24 (m, 2H), 3.10 - 3.04 (m. 1H), 2.96 - 2.88 (m, 4H). 2.87 - 2.80 (m, 3H), 2.70 - 2.66 (m, 3H), 2.62 - 2.55 (m, 2H), 2.45 - 2.34 (m, 4H), 2.06 - 1.94 (m, 4H), 1.92 - 1.84 (m, 2H), 1.81 - 1.72 (m, 2H), 1.71 - 1.63 (m, 2H), 1.61 - 1.53 (m, 1 H), 1.52 - 1.39 (m, 2H), 1.23 (d, J = 6.8 Hz, 4H), 1.03 - 0.97 (m, 4H). 0.43 (t, J = 6.8 Hz, 3H).Example 1.61H NMR (400 MHz, DMSO-d6) 510.95 (s, 1H), 10.02 - 9.82 (m, 1H), 7.75 (dd, J = 6.0, 9.2 Hz, 1H), General 7.37 - 7.32 (m, 1H), 7.3O (s, 1H), 7.17 (d, J = 8.0 Hz, Synthetic 1H), 7.06 - 6.97 (m. 1H). 6.93 (d, J = 8.43 Hz, 1H), Scheme 2 5.09 - 4.96 (m, 2H). 4.71 - 4.58 (m, 2H), 4.56 - 4.43(m, 2H), 4.36 (dd, J = 4.4, 9.2 Hz, 1H), 4.32 - 4.27 (m, 1H), 4.17 - 4.06 (m, 3H), 4.03 - 3.96 (m, 1H), 3.93 - 3.84 (m, 1H), 3.68 - 3.56 (m, 2H), 3.51 - 3.40ARVN-216-PCT / / ARVN0216WO2(m, 2H), 2.95 - 2.64 (m, 6H), 2.57 (d, J = 18.4 Hz, 2H), 2.44 - 2.32 (m, 3H), 2.15 (dd, J = 5.2, 10.4 Hz, 3H), 2.09 - 2.01 (m. 2H), 2.00 - 1.86 (m, 4H), 1.83 - 1.74 (m, 1H), 1.72 - 1.62 (m, 2H), 1.48 (d, J = 3.2 Hz, 2H), 1.11 (t, J = 4.8 Hz, 3H), 1.07 - 0.93 (m, 5H), 0.82 (td, J = 7.2, 10.6 Hz, 3H)1H NMR (400 MHz, DMSO-d6) 5: 11.00 (s, 1H), 9.95 - 9.93 (m, 1H), 7.77 - 7.73 (m, 1H), 7.51 (d, J = 7.6 Hz. 1H). 7.36 - 7.23 (m, 3H), 7.05 - 6.98 (m, 1H), General5.11 - 5.02 (m, 2H). 4.70 - 4.66 (m, 2H), 4.56 - 4.30 Synthetic(m, 5H), 4.14 - 4.10 (m, 1H), 3.93 - 3.88 (m, 1H), Scheme 23.69 - 3.41 (m, 6H), 2.94 - 2.57 (m, 6H), 2.45 - 2.21 (m, 6H), 2.10 - 1.80 (m, 8H), 1.79 - 1.47 (m, 4H), 1.11 - 0.99 (m, 2H), 0.90 - 0.79 (m, 9H).1H NMR (400 MHz, DMSO-d6) 5: 10.94 (s, 1H), 10.50 - 9.53 (m, 1H), 8.16 (s. 1H). 7.74 (dd, J = 6.0, 9.2 Hz, 1H), 7.39 - 7.27 (m, 2H), 7.17 (d, J = 8.2 Hz, 1H), 7.10 - 6.86 (m, 2H), 5.10 - 4.94 (m, 2H), 4.73 - 4.57 (m, 2H), 4.56 - 4.42 (m, 2H), 4.40 - 4.26 (m, General 2H), 4.18 - 4.04 (m, 3H), 4.02 - 3.86 (m, 2H), 3.66 - Synthetic 3.52 (m, 2H), 3.51 - 3.27 (m. 4H), 2.97 - 2.86 (m, Scheme 2 1H), 2.82 (s, 3H), 2.76 - 2.67 (m, 1H). 2.62 - 2.52 (m,2H), 2.46 - 2.32 (m, 3H), 2.31 - 2.21 (m, 1H), 2.20 - 2.09 (m, 3H), 2.08 - 1.84 (m, 6H), 1.82 - 1.74 (m, 1H), 1.73 - 1.58 (m, 2H), 1.47 (d, J = 4.4 Hz, 2H), 1.11 (t. J = 4.8 Hz, 3H), 1.03 (d, J = 4.8 Hz. 3H). 0.87 - 0.76 (m, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.97 (s, 1H), 9.92 (d, J = 6.0 Hz, 1H), 7.74 (dd, J = 6.2, 8.8 Hz, 1H), 7.48 - 7.41 (m, 1H), 7.38 - 7.28 (m, 2H), 7.14 - General 6.96 (m, 2H), 5.13 - 4.92 (m, 2H), 4.71 - 4.61 (m, Synthetic 1H), 4.61 - 4.41 (m, 4H), 4.39 - 4.25 (m, 2H), 4.16 - Scheme 2 4.05 (m, 1H), 3.94 - 3.84 (m. 1H), 3.69 - 3.47 (m,4H), 3.20 - 3.09 (m, 1H), 2.96 - 2.74 (m, 5H), 2.73 - 2.64 (m, 2H), 2.58 (d, J = 15.6 Hz, 2H), 2.47 - 2.29 (m, 4H), 2.28 - 2.19 (m, 1H), 2.09 - 1.73 (m, 6H), 1.60 - 1.43 (m, 3H), 1.34 - 1.13 (m, 3H), 0.92 (d, J =ARVN-216-PCT / / ARVN0216WO26.0 Hz, 3H), 0.86 - 0.75 (m, 3H), 0.62 - 0.48 (m, 2H), 0.35 (s, 2H)1H NMR (400 MHz, DMSO-d6) 8: 10.94 (s, 1H), 10.23 - 9.66 (m, 1H), 8.16 (s, 1H), 7.75 (dd, J = 6.0, 9.2 Hz, 1H), 7.39 - 7.28 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 7.07 - 6.97 (m, 1H), 6.86 (d, J = 8.4 Hz, 1H), 5.10 - 4.93 (m, 2H), 4.72 - 4.58 (m, 2H), 4.57 - 4.41 General (m, 2H), 4.40 - 4.23 (m, 2H). 4.18 - 4.01 (m, 3H), Synthetic 3.97 - 3.84 (m, 2H), 3.70 - 3.48 (m, 3H), 3.06 - 2.97 Scheme 2 (m, 2H), 2.95 - 2.79 (m, 3H), 2.76 - 2.63 (m, 1H),2.62 - 2.54 (m, 1H), 2.47 - 2.27 (m, 6H), 2.27 - 2.12 (m, 3H), 2.08 - 1.84 (m, 5H), 1.84 - 1.71 (m, 2H), 1.66 - 1.56 (m, 1H). 1.54 - 1.32 (m, 2H), 1.17 (d. J = 3.6 Hz. 3H), 1.11 - 0.95 (m, 2H), 0.92 (d, J = 5.2 Hz, 3H), 0.82 (td, J = 7.2, 12.0 Hz, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.94 (d, J = 2.0 Hz, 1H), 8.20 - 8.16 (m, 1H), 7.74 - 7.69 (m, 1H), 7.32 - 7.27 (m, 1H), 7.24 (s, 1H), 7.20 - 7.13 (m, 1H), 6.93 (d, J = 4.4 Hz, 1H), 6.89 - 6.77 (m. 1H), 5.07 - 4.98 (m, 2H), 4.69 - 4.57 (m, 2H), 4.55 - 4.39 (m, General3H), 4.37 - 4.22 (m, 3H), 4.18 - 4.04 (m, 4H). 4.01 - Synthetic3.86 (m, 3H), 3.65 - 3.55 (m, 4H), 2.93 - 2.88 (m, Scheme 21H), 2.80 (s, 3H), 2.74 - 2.63 (m, 2H), 2.57 (d, J = 16.4 Hz, 2H), 2.43 - 2.29 (m, 4H), 2.15 (s, 2H), 2.08 (s, 3H), 1.97 (s, 2H), 1.91 - 1.84 (m. 2H), 1.79 - 1.74 (m, 1H), 1.70 - 1.59 (m, 2H), 1.47 (d, J = 1.6 Hz, 2H), 1.10 (s, 3H), 1.03 (s, 3H), 0.79 - 0.70 (m, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.95 (s, 1H), 9.83 (br s, 1H), 8.16 (s, 1H), 7.71 (dd, J = 6.4, 8.8 Hz, General 1H), 7.36 - 7.26 (m, 1H), 7.26 - 7.22 (m, 1H), 7.17 (d, Synthetic J = 8.0 Hz. 1H). 6.93 (dd, J = 3.2, 8.4 Hz. 1H), 6.90 - Scheme 2 6.79 (m, 1H), 5.10 - 4.94 (m, 2H), 4.79 - 4.58 (m,2H), 4.54 - 4.40 (m, 2H), 4.37 - 4.30 (m, 1H). 4.29 - 4.23 (m, 1H), 4.17 - 4.04 (m, 3H), 4.02 - 3.95 (m, 1H), 3.90 (dt, J = 5.2, 11.6 Hz, 1H), 3.66 -3.54 (m,ARVN-216-PCT / / ARVN0216WO23H), 3.00 - 2.63 (m, 6H), 2.62 - 2.53 (m, 2H), 2.46 - 2.22 (m, 4H), 2.20 - 1.92 (m, 11H), 1.91 - 1.73 (m, 3H), 1.72 - 1.56 (m. 2H), 1.47 (br d, J = 5.2 Hz, 2H). 1.10 (br t, J = 4.0 Hz, 3H), 1.03 (br d, J = 4.8 Hz, 4H), 0.76 (td, J = 7.2, 14.8 Hz, 3H).1H NMR (400 MHz, DMSO-d6) 5: 11.95 (s, 1H), 9.98 - 9.84 (m, 1H), 7.76 - 7.72 (m, 1H), 7.36 - 7.31 (m, 2H), 7.06 - 6.99 (m, 1H), 6.88 - 6.84 (m, 1H), General 5.04 - 5.00 (m, 2H). 4.69 - 4.25 (m, 8H), 4.14 - 4.09 Synthetic (m, 1H), 3.94 - 3.87 (m, 1H). 3.69 - 3.56 (m, 1H), Scheme 2 3.48 - 3.38 (m, 2H), 3.25 - 3.22 (m, 2H), 2.91 - 2.66(m, 7H), 2.53 (s, 3H), 2.44 - 2.25 (m, 6H), 2.07 - 1.72 (m, 9H), 1.61 - 1.43 (m, 3H), 1.09 - 0.97 (m, 5H), 1.56 - 1.79 (m, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.94 (s, 1H), 10.35 - 9.56 (m, 1H), 8.15 (s. 1H). 7.74 (dd, J = 6.0, 9.2 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.16 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 5.03 (ddd, J = 2.8, 4.8, 13.2 Hz, 2H), 4.72 - 4.57 (m, General 2H), 4.55 - 4.45 (m, 2H), 4.40 - 4.24 (m, 2H), 4.18 - Synthetic 4.05 (m, 3H), 3.99 - 3.79 (m. 3H), 3.69 - 3.54 (m, Scheme 2 3H), 2.95 - 2.87 (m. 1H), 2.86 - 2.78 (m, 2H), 2.77 - 2.66 (m, 2H), 2.57 (br d, J = 18.0 Hz, 1H), 2.47 - 2.32 (m, 4H), 2.31 - 2.19 (m, 2H), 2.11 - 1.85 (m, 6H), 1.80 (d, J = 7.8 Hz, 4H), 1.61 - 1.38 (m, 3H), 1.16 (d, J = 4.0 Hz. 3H). 1.11 - 1.00 (m, 4H), 0.99 - 0.88 (m, 1H), 0.82 (td, J = 7.6, 11.6 Hz, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.94 (s, 1H), 8.17 (d, J = 4.4 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.33 - 7.27 (m, 1H), 7.24 (s, 1H), 7.17 (dd, J = 4.4, 8.2 Hz, 1H), 6.96 - 6.90 (m, 1H), 6.89 - 6.77 (m, 1H), 5.04 (d, General J = 12.8 Hz, 2H), 4.69 - 4.58 (m, 2H), 4.55 - 4.36 (m, Synthetic 3H), 4.35 - 4.18 (m. 3H), 4.17 - 4.04 (m, 4H), 4.03 - Scheme 2 3.86 (m, 3H), 3.69 - 3.56 (m, 4H), 2.94 - 2.88 (m,1H), 2.82 (s, 3H), 2.76 - 2.67 (m, 2H), 2.59 (s, 2H), 2.44 - 2.30 (m, 4H), 2.15 (d, J = 3.6 Hz, 2H), 2.07 (d, J = 4.4 Hz, 3H), 1.96 (s, 2H), 1.86 (d, J = 9.6 Hz, 2H),1.75 (dd. J = 2.6, 4.4 Hz, 1H), 1.65 (s. 2H). 1.47 (s,ARVN-216-PCT / / ARVN0216WO22H), 1.10 (d, J = 3.6 Hz, 3H), 1.03 (s, 3H), 0.76 (dt, J = 4.3, 7.0 Hz, 3H)1H NMR (400 MHz, DMSO-d6) 6: 10.95 (s, 1H), 9.83 (br s, 1H), 8.16 (s, 1H), 7.71 (dd, J = 6.4, 8.8 Hz, 1H), 7.36 - 7.26 (m, 1H), 7.26 - 7.22 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.93 (dd, J = 3.2, 8.4 Hz, 1H), 6.90 - 6.79 (m, 1H), 5.10 - 4.94 (m, 2H), 4.79 - 4.58 (m, General 2H), 4.54 - 4.40 (m. 2H), 4.37 - 4.30 (m, 1H), 4.29 - Synthetic 4.23 (m, 1H), 4.17 - 4.04 (m, 3H), 4.02 - 3.95 (m, Scheme 2 1H), 3.90 (dt, J = 5.2, 11.6 Hz, 1H), 3.66 - 3.54 (m,3H), 3.00 - 2.63 (m, 6H), 2.62 - 2.53 (m, 2H), 2.46 - 2.22 (m, 4H), 2.20 - 1.92 (m, 11H), 1.91 - 1.73 (m, 3H), 1.72 - 1.56 (m. 2H), 1.47 (br d. J = 5.2 Hz, 2H). 1.10 (br t, J = 4.0 Hz, 3H), 1.03 (br d, J = 4.8 Hz, 4H), 0.76 (td, J = 7.2, 14.8 Hz, 3H).1H NMR (400 MHz, DMSO-d6) 5: 10.95 (s, 1H), 8.14 (s, 1H), 7.74 (dd, JI = 6.0 Hz, J2 = 9.2 Hz, 1H), 7.45 - 7.25 (m, 3H), 7.12 - 6.92 (m, 2H), 5.10 - 4.96 (m. 2H), 4.71 - 4.42 (m, 4H). 4.44 (d, J = 16.8 Hz, 1H), 4.36 (dd, JI = 4.8 Hz, J2 = 9.2 Hz, 1H), 4.29 - General 4.23 (m, 1H), 4.15 - 4.07 (m, 1H), 3.93 - 3.86 (m, Synthetic 1H), 3.84 (s, 3H), 3.70 - 3.55 (m, 2H), 3.46 - 3.41 (m, Scheme 2 1H), 3.29 (d, J = 8.0 Hz, 3H), 2.95 - 2.79 (m, 5H),2.78 - 2.69 (m, 1H), 2.63 - 2.54 (m, 2H), 2.45 - 2.23(m, 4H), 2.34 - 2.23 (m, 2H), 2.09 - 1.86 (m. 6H), 1.84 - 1.70 (m, 2H), 1.59 (d, J = 10.4 Hz, 1H), 1.53 - 1.39 (m, 2H), 1.13 - 0.92 (m, 1H), 1.02 - 0.90 (m, 4H), 0.89 - 0.76(m, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.95 (s, 1H), 10.11 - 9.68 (m, 1H), 8.14 (s, 1H), 7.75 (dd, J = 6.0, General 9.0 Hz. 1H). 7.43 (d, J = 8.0 Hz, 1H), 7.39 - 7.26 (m, Synthetic 2H), 7.15 (t, J = 7.6 Hz, 1H), 7.09 - 6.90 (m, 1H), Scheme 2 5.10 - 4.92 (m, 1H), 4.79 - 4.62 (m, 3H), 4.59 (s, 1H),4.52 - 4.42 (m, 3H), 4.41 - 4.26 (m, 1H), 4.16 - 4.05 (m, 1H), 3.98 - 3.83 (m, 1H), 3.68 (d, J = 8.4 Hz, 2H),ARVN-216-PCT / / ARVN0216WO23.61 - 3.53 (m, 1H), 2.99 (dd, J = 12.0, 15.6 Hz, 2H), 2.93 - 2.87 (m, 1H), 2.87 - 2.78 (m, 2H), 2.77 - 2.66 (m, 3H), 2.65 - 2.55 (m, 3H). 2.45 - 2.19 (m, 6H), 2.14 - 1.96 (m, 4H), 1.95 - 1.76 (m, 3H), 1.73 - 1.58 (m, 2H), 1.48 (d, J = 4.4 Hz, 2H), 1.13 - 0.92 (m, 5H), 0.89 - 0.76 (m, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.99 (s, 1H), 8.14 (s, 1H), 7.77 - 7.73 (m, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.37 - 7.31 (m. 2H). 7.17 (t, J = 7.6 Hz, 1H), 7.06 - 6.98 (m, 1H), 5.10 - 4.97 (m, 2H), 4.70 - 4.47 General(m, 5H), 4.39 - 4.29 (m, 2H), 4.14 - 4.08 (m, 1H), Synthetic3.94 - 3.86 (m, 1H), 3.74 - 3.54 (m, 2H), 3.48 - 3.40 Scheme 2(m, 2H),.3.26 - 3.21 (m, 1H), 2.94 - 2.81 (m, 4H), 2.71 - 2.57 (m, 3H), 2.42 - 2.22 (m, 7H), 2.13 - 1.78 (m, 8H), 1.73 - 1.61 (m, 2H), 1.49 - 1.48 (m, 2H), 1.09 - 0.97 (m, 5H), 0.86 - 0.79 (m, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.99 (s, 1H), 10.29 - 9.55 (m, 1H), 8.14 (s, 1H), 7.80 - 7.70 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.39 - 7.28 (m, 2H), 7.23 (d, J = 8.4 Hz, 1H), 7.10 - 6.95 (m, 1H), 5.10 (dd, JI = 5.2 Hz, J2 = 13.2 Hz. 1H), 5.05 - 4.95 (m, General1H), 4.70 - 4.62 (m. 1H), 4.61 - 4.42 (m, 3H), 4.42 - Synthetic4.20 (m, 3H), 4.16 - 4.06 (m, 1H), 3.96 - 3.84 (m, Scheme 21H), 3.71 - 3.50 (m, 2H), 3.26 - 3.09 (m, 3H), 2.96 - 2.80 (m, 5H), 2.80 - 2.55 (m, 4H), 2.48 - 2.19 (m, 6H), 2.09 - 1.86 (m. 6H). 1.85 - 1.69 (m, 2H), 1.65 - 1.55 (m, 1H), 1.53 - 1.38 (m, 2H), 1.14 - 0.92 (m, 5H), 0.82 (td, J = 7.3, 11.4 Hz, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.98 (s, 1H), 8.17 (s, 1H), 7.78 - 7.69 (m, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.37 - 7.27 (m, 2H), 7.19 - 7.10 (m, 1H), 7.08 - General 6.95 (m, 1H), 5.07 (dd, JI = 5.2 Hz, J2 =13.2 Hz, 1H), Synthetic 5.04 - 4.95 (m, 1H). 4.72 - 4.58 (m, 2H), 4.57 - 4.43 Scheme 2 (m, 3H), 4.40 - 4.26 (m, 2H). 4.14 - 4.07 (m, 1H),3.95 - 3.85 (m, 1H), 3.71 - 3.50 (m, 3H), 3.48 - 3.34 (m, 2H), 3.22 - 3.15 (m, 1H), 2.96 - 2.84 (m, 2H), 2.81 - 2.71 (m, 3H), 2.70 - 2.55 (m, 3H), 2.48 - 2.16(m. 9H). 2.15 -2.07 (m. 1H), 2.06 - 1.85 (m, 3H). 1.82ARVN-216-PCT / / ARVN0216WO2- 1.70 (m, 1H), 1.68 - 1.47 (m, 3H), 1.36 (d, J = 8.8 Hz, 1H), 1.15 - 1.04 (m, 1H), 0.99 - 0.89 (m, 3H), 0.87 - 0.76 (m, 3H)1H NMR (400 MHz, DMSO-d6) 8: 10.97 (s, 1H), 8.17 (s. 1H), 7.79 - 7.69 (m, 1H), 7.46 (d, J = 8.0 Hz. 1H), 7.37 - 7.27 (m, 2H), 7.18 - 7.09 (m, 1H), 7.08 - 6.96 (m. 1H), 5.07 (dd,.11 = 5.2 Hz,.12 =13.2 Hz, 1H), 5.04 - 4.96 (m. 1H). 4.73 - 4.61 (m, 2H), 4.57 - 4.42 General (m. 3H), 4.39 - 4.27 (m, 2H), 4.16 - 4.07 (m, 1H), Synthetic 3.95 - 3.85 (m. 1H). 3.73 - 3.34 (m, 5H), 3.25 - 3.16 Scheme 2 (m, 1H), 2.96 - 2.83 (m. 3H), 2.74 - 2.65 (m, 2H),2.63 - 2.54 (m, 3H), 2.47 - 2.17 (m, 9H), 2.13 - 1.95 (m. 3H), 1.94 - 1.85 (m, 1H), 1.80 - 1.70 (m. 1H).1.66 - 1.50 (m, 3H), 1.34 (d, J = 8.4 Hz, 1H). 1.13 - 1.03 (m. 1H), 0.95 (d, J = 6.0 Hz, 3H), 0.87 - 0.76 (m, 3H).1H NMR (400 MHz, DMSO-d6) 5: 10.99 (s, 1H), 8.14 (s, 1H), 7.77 - 7.73 (m, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.06 - 6.98 (m, 1H), 5.10 - 5.00 (m, 2H), 4.70 - 4.47 General(m. 5H), 4.39 - 4.29 (m, 2H). 4.14 - 4.09 (m, 1H), Synthetic3.94 - 3.86 (m, 1H). 3.69 - 3.54 (m, 2H), 3.48 - 3.42 Scheme 2(m, 2H),.3.26 - 3.21 (m, 1H), 2.94 - 2.81 (m, 4H), 2.71 - 2.57 (m, 3H), 2.42 - 2.20 (m, 7H), 2.13 - 1.77 (m, 8H), 1.73 - 1.61 (m, 2H), 1.49 - 1.48 (m, 2H), 1.09 - 0.97 (m, 5H), 0.85 - 0.79 (m. 3H)1H NMR (400 MHz, DMSO-d6) 8: 10.99 (s, 1H), 8.16 (s, 1H), 7.78 - 7.70 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.16 (t. J = 7.6 Hz, 1H), 7.07 - 6.97 (m, 1H), 5.08 (dd, JI = 5.2 Hz, J2 =13.2 General Hz, 1H), 5.04 - 4.95 (m, 1H), 4.70 - 4.60 (m, 2H), Synthetic 4.56 - 4.44 (m, 2H), 4.42 - 4.27 (m, 3H), 4.15 - 4.06 Scheme 2 (m. 1H), 3.94 - 3.85 (m, 1H). 3.73 - 3.62 (m, 2H),3.60 - 3.53 (m, 1H), 3.50 - 3.33 (m, 3H), 3.26 - 3.20 (m, 1H), 2.96 - 2.87 (m, 2H), 2.85 - 2.74 (m, 3H), 2.71 - 2.64 (m, 1H), 2.62 - 2.55 (m, 1H), 2.45 - 2.33 (m, 3H), 2.32 - 2.17 (m, 5H), 2.07 - 1.95 (m, 3H),1.94 - 1.85 (m, 1H). 1.83 - 1.69 (m, 3H), 1.63 - 1.53ARVN-216-PCT / / ARVN0216WO2(m, 1H), 1.46 - 1.33 (m, 2H), 1.11 - 1.02 (m, 1H), 0.97 (d, J = 6.4 Hz, 3H), 0.86 - 0.76 (m, 3H)1H NMR (400 MHz, DMSO-d6) 8: 10.99 (s, 1H), 8.17 (s, 1H), 7.79 - 7.70 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.38 - 7.27 (m, 2H), 7.16 (t, J = 7.6 Hz, 1H), 7.08 - 6.97 (m, 1H), 5.08 (dd, J1 = 5.2 Hz, J2 =13.2 Hz, 1H), 5.05 - 4.96 (m, 1H), 4.72 - 4.59 (m, 2H), 4.58 - 4.50 (m, 2H). 4.48 - 4.42 (m, 1H), 4.39 - 4.28 General (m, 2H), 4.14 - 4.07 (m, 1H), 3.93 - 3.86 (m, 1H), Synthetic 3.72 - 3.62 (m, 2H), 3.60 - 3.53 (m, 1H), 3.49 - 3.35 Scheme 2 (m, 3H), 3.26 - 3.21 (m, 1H), 2.95 - 2.86 (m, 2H),2.81 - 2.67 (m, 3H), 2.63 - 2.55 (m, 2H), 2.47 - 2.39 (m. 3H), 2.36 - 2.31 (m, 2H). 2.28 - 2.20 (m, 3H), 2.05 - 1.95 (m, 3H), 1.93 - 1.85 (m, 1H), 1.81 - 1.68 (m, 3H), 1.53 - 1.45 (m, 1H), 1.44 - 1.33 (m, 2H), 1.07 - 1.01 (m, 1H), 0.97 (d, J = 6.4 Hz, 3H), 0.86 - 0.77 (m, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.97 (s, 1H), 10.05 - 9.84 (m. 1H), 7.75 (dd. J = 6.0, 9.0 Hz, 1H), 7.39 - 7.27 (m, 2H). 7.08 - 6.93 (m, 2H), 5.09 - 4.98 (m, 2H), 4.70 - 4.35 (m, 6H), 4.23 (dd, J = 4.2, 16.4 GeneralHz, 1H), 4.15 - 4.08 (m, 2H), 3.97 - 3.87 (m, 2H), Synthetic3.71 - 3.56 (m, 1H), 3.52 - 3.42 (m, 2H), 2.94 - 2.77 Scheme 2(m, 3H), 2.71 - 2.70 (m, 1H), 2.62 - 2.53 (m, 2H), 2.47 - 2.32 (m, 7H). 2.29 - 2.17 (m, 1H), 2.11 - 1.71 (m, 9H), 1.70 - 1.58 (m, 2H), 1.47 (d, J = 5.8 Hz, 2H), 1.12 - 0.93 (m, 5H), 0.82 (td, J = 7.4, 11.8 Hz, 3H) 1H NMR (400 MHz, DMSO-d6) 5: 10.98 (s, 1H), 9.98 - 9.88 (m, 1H), 7.75 (dd, J = 6.0, 9.2 Hz, 1H), General 7.49 - 7.41 (m, 1H), 7.39 - 7.27 (m, 2H), 7.12 (t, J = Synthetic 7.6 Hz. 1H). 7.07 - 6.92 (m, 1H), 5.14 - 4.95 (m, 2H), Scheme 2 4.72 - 4.58 (m, 2H). 4.57 - 4.42 (m, 3H), 4.41 - 4.34(m, 1H), 4.33 - 4.27 (m, 1H), 4.17 - 4.07 (m, 1H), 3.97 - 3.83 (m, 1H), 3.71 - 3.56 (m, 1H), 3.53 - 3.39 (m, 3H), 3.02 (d, J = 8.0 Hz, 1H), 2.86 (dd, J = 12.4,ARVN-216-PCT / / ARVN0216WO218.0 Hz, 4H), 2.71 - 2.59 (m, 3H), 2.58 - 2.53 (m, 1H), 2.47 - 2.33 (m, 3H), 2.31 - 2.17 (m, 3H), 2.11 - 1.86 (m, 7H), 1.83 - 1.59 (m. 4H), 1.56 - 1.31 (m, 3H), 1.11 - 0.92 (m, 2H), 0.82 (td, J = 7.6, 12.0 Hz, 3H), 0.76 - 0.67 (m, 3H)1H NMR (400 MHz, DMSO-d6) 8: 10.97 (s, 1H), 10.03 - 9.86 (m, 1H), 7.75 (dd, J = 6.0, 9.2 Hz, 1H), 7.39 - 7.29 (m, 2H), 7.07 - 6.97 (m, 1H), 6.90 (d, J = 7.2 Hz, 1H), 5.07 - 4.96 (m, 2H), 4.73 - 4.57 (m, 2H), 4.56 - 4.49 (m, 1H), 4.48 - 4.36 (m, 2H), 4.36 - 4.28 General (m, 1H), 4.24 (d, J = 16.8 Hz, 1H), 4.12 (dd, J = 4.4, Synthetic 12.4 Hz, 1H), 3.97 - 3.84 (m, 1H), 3.79 - 3.62 (m, Scheme 2 2H), 3.57 (t, J = 10.8 Hz, 1H), 3.51 - 3.36 (m, 3H),3.26 - 3.17 (m, 1H), 2.98 - 2.80 (m, 4H), 2.77 - 2.66 (m, 1H), 2.63 - 2.55 (m, 2H), 2.53 (s, 3H), 2.40 (s, 3H), 2.32 - 2.20 (m. 2H), 2.12 - 1.85 (m, 7H), 1.80 (d, J = 4.4 Hz, 1H), 1.66 (s, 2H), 1.48 (s, 2H), 1.12 - 1.00 (m, 2H), 0.98 (d, J = 6.0 Hz, 3H), 0.89 - 0.77 (m, 3H) H NMR (400 MHz, DMSO-d6) 5: 10.98 (s, 1H), 10.19 - 9.72 (m, 1H), 7.75 (dd, J = 6.0, 9.0 Hz, 1H), 7.42 - 7.27 (m, 2H), 7.09 - 6.94 (m, 2H), 5.10 - 4.97 (m. 2H), 4.71 - 4.61 (m, 2H). 4.54 (dd, J = 4.1, 13.3 Hz. 2H), 4.47 - 4.35 (m, 2H), 4.33 - 4.20 (m, 2H), General4.12 (dd, J = 4.6, 10.9 Hz, 2H), 3.98 - 3.87 (m, 2H), Synthetic3.70 - 3.56 (m, 1H), 3.51 - 3.42 (m, 2H), 2.96 - 2.88 Scheme 2(m, 1H), 2.86 - 2.77 (m, 2H), 2.75 - 2.66 (m, 1H), 2.59 (d, J = 16.2 Hz, 1H), 2.45 - 2.33 (m, 7H), 2.31 - 2.19 (m, 1H), 2.09 - 1.78 (m. 9H), 1.65 (d, J = 10.2 Hz, 2H), 1.48 (d, J = 4.9 Hz, 2H), 1.12 - 0.96 (m, 5H), 0.86 - 0.79 (m, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.99 (s, 1H), 8.16 (s, 1H), 7.74 (dd, J = 6.0, 9.2 Hz, 1H), 7.46 (d, J General = 8.0 Hz, 1H), 7.40 - 7.27 (m, 2H), 7.14 (t, J = 7.6 Hz, Synthetic 1H), 7.08 - 6.95 (m. 1H). 5.12 - 4.94 (m, 2H), 4.74 - Scheme 2 4.55 (m, 2H), 4.55 - 4.42 (m, 3H), 4.41 - 4.27 (m,2H), 4.16 - 4.07 (m, 1H), 3.96 - 3.84 (m, 1H), 3.79 - 3.70 (m, 1H), 3.69 - 3.54 (m, 2H), 3.21 (dd, J = 8.4, 18.0 Hz, 2H), 2.97 - 2.85 (m, 4H), 2.80 - 2.65 (m,ARVN-216-PCT / / ARVN0216WO22H), 2.64 - 2.53 (m, 4H), 2.47 - 2.31 (m, 4H), 2.30 - 2.18 (m, 1H), 2.11 - 1.88 (m, 4H), 1.86 (d, J = 5.2 Hz, 2H), 1.66 (d. J = 9.2 Hz, 2H), 1.55 - 1.41 (m, 2H), 1.22 - 1.03 (m, 2H), 0.96 (d, J = 6.0 Hz, 3H), 0.88 - 0.75 (m, 9H)1H NMR (400 MHz, DMSO-d6) 8: 10.79 (s, 1H), 7.80 - 7.70 (m, 1H), 7.53 (t, J = 2.4 Hz, 1H), 7.39 - 7.27 (m, 2H), 7.08 - 6.96 (m, 1H), 6.88 (d, J - 1.6 Hz, 1H), 5.08 - 4.94 (m, 1H), 4.71 - 4.57 (m, 2H), 4.56 - General 4.41 (m, 2H), 4.40 - 4.27 (m, 1H), 4.17 - 4.07 (m, Synthetic 2H), 4.05 - 3.97 (m. 1H), 3.94 - 3.85 (m, 1H). 3.79 - Scheme 2 3.73 (m, 1H), 3.73 - 3.62 (m, 2H), 3.61 - 3.50 (m,2H), 2.89 - 2.76 (m, 4H), 2.73 - 2.59 (m, 3H), 2.45 - 2.32 (m, 2H), 2.30 - 1.75 (m, 12H), 1.74 - 1.60 (m, 3H), 1.54 - 1.41 (m, 2H), 1.20 (d, J = 4.0 Hz, 3H), 1.12 - 0.95 (m, 2H). 0.88 - 0.75 (m, 3H)1H NMR (400 MHz, DMSO-d6) 8: 10.80 (s, 1H), 7.80 - 7.69 (m, 1H), 7.53 (t, J = 2.0 Hz, 1H), 7.40 - 7.25 (m, 2H), 7.09 - 6.94 (m, 1H), 6.88 (d, J = 1.2 Hz, 1H), 5.08 - 4.93 (m, 1H), 4.71 - 4.57 (m, 2H), 4.57 - General 4.41 (m, 2H), 4.40 - 4.27 (m, 1H), 4.17 - 4.07 (m, Synthetic 2H), 4.05 - 3.97 (m. 1H). 3.94 - 3.85 (m, 1H), 3.79 - Scheme 2 3.73 (m, 1H), 3.73 - 3.64 (m, 2H), 3.64 - 3.53 (m,2H), 2.89 - 2.76 (m, 4H), 2.73 - 2.57 (m, 3H). 2.48 - 2.34 (m, 2H), 2.33 - 1.76 (m, 12H), 1.74 - 1.59 (m, 3H), 1.55 - 1.40 (m, 2H), 1.20 (d, J = 4.0 Hz, 3H), 1.11 - 0.92 (m, 2H), 0.89 - 0.75 (m, 3H)1H NMR (400 MHz, DMSO-d6) 8: 10.95 (s, 1H), 10.12 - 9.72 (m. 1H), 8.16 (s. 1H). 7.75 (dd, J = 6.4, 8.8 Hz. 1H), 7.39 - 7.29 (m, 2H), 7.17 (d, J = 8.0 Hz, 1H), 7.07 - 6.95 (m, 1H), 6.86 (d, J = 8.4 Hz, 1H), General 5.08 - 4.95 (m, 2H), 4.72 - 4.58 (m, 2H), 4.58 - 4.43 Synthetic (m, 2H), 4.41 - 4.24 (m, 2H), 4.17 - 4.06 (m, 3H), Scheme 2 3.94 - 3.81 (m, 2H). 3.71 - 3.49 (m, 3H), 3.48 - 3.44(m, 1H), 2.95 - 2.78 (m, 5H). 2.73 - 2.57 (m, 3H), 2.43 - 2.31 (m, 3H), 2.30 - 2.20 (m, 1H), 2.18 - 2.11 (m, 1H), 2.05 (d, J = 5.6 Hz, 3H), 1.99 - 1.83 (m, 4H), 1.83 - 1.75 (m, 1H), 1.75 - 1.59 (m, 3H), 1.48 (d, J =ARVN-216-PCT / / ARVN0216WO24.0 Hz, 2H), 1.17 (d, J = 3.2 Hz, 3H), 1.12 - 0.94 (m, 2H), 0.89 - 0.76 (m, 3H)1H NMR (400 MHz, DMSO-d6) 6: 10.99 (s, 1H), 10.08 - 9.78 (m, 1H), 7.78 - 7.70 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.41 - 7.25 (m, 3H), 7.08 - 6.95 (m, 1H), 5.10 (dd, JI = 5.2 Hz, J2 = 13.2 Hz, 1H), 5.06 - 4.95 General (m, 1H), 4.71 - 4.58 (m, 2H), 4.56 - 4.50 (m, 1H), Synthetic 4.50 - 4.21 (m, 4H). 4.17 - 4.05 (m, 1H), 3.96 - 3.84 Scheme 2 (m, 1H), 3.70 - 3.53 (m, 2H), 3.50 - 3.41 (m, 2H),3.28 - 3.15 (m, 2H), 2.96 - 2.78 (m, 3H), 2.75 - 2.66 (m, 2H), 2.64 - 2.55 (m, 2H), 2.46 - 2.20 (m, 5H), 2.18 - 1.74 (m, 9H), 1.73 - 1.58 (m, 2H), 1.56 - 1.38 (m. 2H), 1.10 - 0.96 (m, 2H). 0.92 - 0.76 (m, 6H) 1H NMR (400 MHz, DIMETHYL SULFOXIDE -d6) 5: 10.98 (s, 1H), 8.14 (s, 1H), 7.76 - 7.73 (m, 1H), 7.52 - 7.43 (m, 1H), 7.39 - 7.27 (m, 2H), 7.20 - 7.09 (m, 1H), 7.08 - 6.94 (m, 1H), 5.16 - 4.93 (m, 2H), General 4.73 - 4.59 (m, 2H), 4.57 - 4.41 (m, 3H), 4.40 - 4.25 Synthetic (m. 2H), 4.12 (d, J = 11.2 Hz, 1H), 3.97 - 3.83 (m, Scheme 2 1H), 3.74 - 3.55 (m. 2H), 3.49 - 3.18 (m, 5H). 2.95 - 2.78 (m, 4H), 2.77 - 2.57 (m, 3H), 2.46 - 2.30 (m, 4H), 2.29 - 2.16 (m, 2H), 2.08 - 1.76 (m, 7H), 1.66 - 1.43 (m, 2H), 1.34 - 1.17 (m, 1H), 1.10 - 0.92 (m, 5H), 0.92 - 0.75 (m, 6H)1H NMR (400 MHz, DMSO-d6) 5: 10.99 (s, 1H), 9.94 (d, J = 11.2 Hz, 1H). 7.80 - 7.67 (m, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.38 - 7.26 (m, 2H), 7.19 - 7.10 (m, 1H), 7.07 - 6.95 (m, 1H), 5.12 - 4.96 (m, 2H), General4.72 - 4.62 (m, 2H), 4.58 - 4.52 (m, 1H), 4.52 - 4.44 Synthetic(m, 2H), 4.41 - 4.27 (m, 2H), 4.15 - 4.06 (m, 1H), Scheme 23.96 - 3.84 (m, 1H). 3.70 - 3.38 (m, 8H), 2.98 - 2.71 (m, 5H), 2.62 - 2.55 (m, 1H). 2.48 - 2.12 (m, 9H), 2.07 - 1.79 (m, 4H), 1.76 - 1.64 (m, 4H), 1.60 - 1.49 (m, 1H), 0.86 - 0.75 (m, 3H)ARVN-216-PCT / / ARVN0216WO21H NMR (400 MHz, DMSO-d6) 5: 1.00 (s, 1H), 10.04 - 9.80 (m, 1H), 8.15 (s, 1H), 7.79 - 7.70 (m, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.40 - 7.27 (m, 2H), 7.25 - 7.15 (m, 1H), 7.10 - 6.96 (m, 1H), 5.12 - 5.05 (m, 1H), 5.05 - 4.96 (m, 1H), 4.72 - 4.55 (m, 3H), General 4.54 - 4.46 (m, 2H), 4.38 - 4.27 (m, 2H), 4.16 - 4.07 Synthetic (m, 1H), 4.01 - 3.84 (m, 2H), 3.84 - 3.75 (m, 1H), Scheme 2 3.73 - 3.53 (m, 3H). 3.51 - 3.39 (m, 3H), 3.28 - 3.16(m, 2H), 3.01 - 2.82 (m, 4H). 2.77 - 2.66 (m, 1H), 2.64 - 2.55 (m, 2H), 2.46 - 2.32 (m, 3H), 2.30 - 2.19 (m, 1H), 2.11 - 2.02 (m, 2H), 2.01 - 1.89 (m, 3H), 1.85 - 1.74 (m, 1H), 1.60 - 1.46 (m, 4H), 0.95 - 0.77 (m. 6H)1H NMR (400 MHz, DMSO-d6) 8: 10.94 (s, 1H), 8.17 (s, 1H), 7.75 (dd, J = 5.8, 9.2 Hz, 1H), 7.37 - 7.32 (m, 1H), 7.31 - 7.29 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.06 - 6.97 (m, 1H), 6.86 (d, J = 8.4 Hz, 1H), 5.08 - 4.98 (m, 2H), 4.71 - 4.60 (m, 2H), 4.53 (td, J = General 13.2, 17.6 Hz, 2H), 4.43 (s, 1H), 4.31 - 4.25 (m, 1H), Synthetic 4.17 - 4.08 (m, 3H). 3.94 - 3.84 (m, 2H), 3.66 (dd, J = Scheme 2 9.6, 12.4 Hz, 1H), 3.56 (d, J = 11.2 Hz, 2H), 2.95 - 2.76 (m, 6H), 2.74 - 2.65 (m, 2H), 2.59 (s, 2H), 2.44 - 2.27 (m, 4H), 2.10 - 2.02 (m, 3H), 1.99 - 1.86 (m, 4H), 1.82 - 1.76 (m, 1H), 1.72 - 1.61 (m, 3H), 1.53 - 1.43 (m, 2H), 1.17 (d. J = 4.4 Hz, 3H), 1.10 - 0.93 (m, 2H), 0.85 - 0.78 (m. 3H)1H NMR (400 MHz, DMSO-d6) 8: 10.99 (s, 1H), 10.14 - 9.65 (m, 1H), 8.14 (s. 1H), 7.71 (dd, J = 6.0, 9.2 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 9.2 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.21 - 7.11 (m, 2H), General 7.05 - 6.91 (m, 1H), 5.13 - 4.94 (m, 2H), 4.72 - 4.63 Synthetic (m. 1H), 4.59 - 4.40 (m, 4H). 4.38 - 4.25 (m, 2H), Scheme 2 4.15 - 4.07 (m, 1H), 3.89 (d, J = 3.6 Hz, 1H), 3.74 - 3.52 (m, 3H), 3.29 - 3.11 (m, 4H), 2.96 - 2.77 (m, 4H), 2.67 (dd, J = 2.0, 3.6 Hz, 1H), 2.59 (d, J = 14.4 Hz, 2H), 2.41 (d, J = 6.4 Hz, 4H), 2.34 - 2.23 (m, 2H),2.12 - 1.84 (m, 7H). 1.80 - 1.72 (m, 1H), 1.66 (d. J =ARVN-216-PCT / / ARVN0216WO210.0 Hz, 2H), 1.53 - 1.39 (m, 2H), 1.12 - 1.00 (m, 2H), 0.97 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H).1H NMR (400 MHz, DMSO-d6) 8: 10.97 (s, 1H), 8.14 (s, 1H), 7.74 - 7.70 (m, 1H), 7.33 - 7.23 (m, 2H), 6.93 (s, 1H), 6.89 - 6.79 (m, 1H), 5.07 - 4.97 (m, 2H), 4.69 - 4.62 (m, 2H), 4.53 - 4.19 (m, 6H), 4.12 - General4.08 (m, 1H), 3.98 - 3.88 (m, 3H), 3.68 - 3.52 (m, Synthetic1H), 3.28 - 3.25 (m, 2H). 3.09 - 3.04 (m, 1H), 2.94 - Scheme 22.67 (m, 6H), 2.60 - 2.53 (m, 1H), 2.43 - 2.19 (m, 5H), 2.08 - 1.76 (m, 13H), 1.66 - 1.63 (m, 2H), 1.48 - 1.46 (m, 2H), 1.03 - 0.93 (m, 2H), 0.81 - 0.73 (m, 3H).1H NMR (400 MHz, DMSO-d6) 5: 10.99 (s, 1H), 10.13 - 9.83 (m. 1H), 7.75 (dd. J = 6.0, 9.2 Hz, 1H), 7.50 (d, J = 8.0Hz, 1H), 7.40 - 7.28 (m, 2H), 7.21 (t, J = 7.6 Hz, 1H), 7.09 - 6.95 (m, 1H), 5.15 - 4.94 (m, 2H), 4.76 - 4.63 (m, 2H), 4.58 - 4.43 (m, 3H), 4.41 - General 4.34 (m, 1H), 4.33 - 4.27 (m, 1H), 4.16 - 4.07 (m, Synthetic 1H), 3.98 - 3.83 (m. 1H). 3.72 - 3.53 (m, 2H), 3.51 - Scheme 2 3.39 (m, 3H), 3.26 (d. J = 8.8 Hz, 1H), 3.22 - 3.07 (m,6H), 2.99 - 2.86 (m, 2H), 2.81 - 2.69 (m, 1H). 2.59 (d, J = 16.0 Hz, 1H), 2.49 - 2.31 (m, 8H), 2.30 - 2.18 (m, 1H), 2.09 - 1.95 (m, 2H), 1.94 - 1.88 (m, 1H), 1.87 - 1.78 (m, 1H), 1.60 - 1.50 (m, 1H), 0.93 (d, J = 6.0 Hz, 3H), 0.88 - 0.73 (m. 3H)1H NMR (400 MHz, DMSO-d6) 8: 10.97 (s. 1H), 10.08 - 9.71 (m, 1H), 8.14 (s. 1H), 7.75 (dd, J = 6.0, 8.8 Hz, 1H), 7.43 - 7.26 (m, 3H), 7.17 - 6.94 (m, 2H), General 5.11 - 4.93 (m, 2H), 4.73 - 4.57 (m, 2H), 4.57 - 4.42 Synthetic (m, 3H), 4.41 - 4.28 (m, 2H), 4.27 - 4.19 (m, 1H), Scheme 2 4.16 - 4.04 (m, 1H). 3.97 - 3.88 (m, 1H), 3.86 (s, 3H),3.79 - 3.70 (m, 1H). 3.69 - 3.53 (m, 1H), 3.52 - 3.36 (m, 3H), 3.27 - 3.19 (m, 1H), 2.97 - 2.73 (m, 5H), 2.72 - 2.63 (m, 1H), 2.62 - 2.56 (m, 1H), 2.43 - 2.28 (m, 5H), 2.12 - 1.94 (m, 5H), 1.92 - 1.73 (m, 3H),ARVN-216-PCT / / ARVN0216WO21.72 - 1.58 (m, 2H), 1.55 - 1.41 (m, 2H), 1.11 - 0.96 (m, 2H), 0.96 - 0.88 (m, 3H), 0.87 - 0.76 (m, 3H)1H NMR (400 MHz, DMSO-d6) 8: 11.02 - 10.92 (m, 1H), 10.16 - 9.74 (m, 1H), 8.14 (s, 1H), 7.75 (dd, J = 6.0, 8.8 Hz, 1H), 7.42 - 7.26 (m, 3H), 7.08 - 6.96 (m, 2H), 5.13 - 4.92 (m, 2H), 4.72 - 4.60 (m, 2H), 4.59 (s, 2H), 4.48 - 4.40 (m, 2H), 4.39 - 4.30 (m, 1H), 4.30 - General 4.22 (m, 1H), 4.16 - 4.05 (m. 1H), 3.96 - 3.86 (m, Synthetic 1H), 3.86 - 3.78 (m, 3H), 3.72 - 3.61 (m, 1H). 3.60 (s, Scheme 2 1H), 3.52 - 3.36 (m, 3H), 3.16 - 3.01 (m, 4H), 2.97 - 2.74 (m, 4H), 2.73 - 2.65 (m, 1H), 2.58 (d, J = 16.0 Hz, 1H), 2.46 - 2.29 (m, 4H), 2.18 - 2.08 (m, 2H), 2.05 - 1.85 (m, 5H). 1.84 - 1.74 (m, 1H), 1.72 - 1.59 (m, 2H), 1.49 (s. 2H), 1.12 - 0.92 (m, 2H), 0.89 - 0.75 (m, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.99 (s, 1H), 7.71 (dd, J = 6.0, 9.2 Hz, 1H), 7.48 (d, J - 8.0 Hz, 1H), 7.31 (t, J = 9.2 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.20 - 7.12 (m, 2H). 7.06 - 6.92 (m, 1H), 5.13 - 4.96 (m, 2H), 4.71 - 4.63 (m, 1H). 4.60 - 4.43 (m, 4H), General4.31 (d, J = 17.2 Hz, 2H). 4.10 (d, J = 9.6 Hz, 1H), Synthetic3.95 - 3.83 (m, 1H), 3.75 - 3.50 (m, 3H), 3.25 (d, J = Scheme 29.2 Hz, 4H), 2.97 - 2.78 (m, 4H), 2.76 - 2.65 (m, 1H), 2.59 (d, J = 13.6 Hz, 2H), 2.44 - 2.34 (m, 4H), 2.32 - 2.22 (m, 2H), 2.13 - 1.93 (m. 7H), 1.81 - 1.72 (m, 1H), 1.66 (t, J = 10.6 Hz, 2H), 1.47 (d, J = 5.2 Hz, 2H), 1.09 - 0.95 (m, 5H), 0.88 (t, J = 7.2 Hz, 3H).1H NMR (400 MHz, DMSO-d6) 5: 10.97 (s, 1H), 9.84 (s, 1H), 8.13 (s, 1H), 7.74 - 7.70 (m, 1H), 7.33 - General 7.23 (m, 2H), 6.93 (s, 1H), 6.89 - 6.79 (m, 1H), 5.07 Synthetic - 4.97 (m, 2H), 4.73 - 4.59 (m. 2H). 4.55 - 4.21 (m, Scheme 2 6H), 4.12 - 4.08 (m, 1H). 3.98 - 3.88 (m, 3H), 3.68 - 3.52 (m, 1H), 3.28 - 3.25 (m, 2H), 3.09 - 3.04 (m, 1H), 2.94 - 2.67 (m, 6H), 2.60 - 2.53 (m, 1H), 2.43 - 2.19 (m, 5H), 2.08 - 1.76 (m, 13H), 1.66 - 1.63 (m,ARVN-216-PCT / / ARVN0216WO22H), 1.48 - 1.46 (m, 2H), 1.07 - 0.90 (m, 2H), 0.81 - 0.73 (m, 3H).1H NMR (400 MHz, DMSO-d6) 8: 11.00 (s, 1H), 10.41 - 9.75 (m, 1H), 7.74 (dd, J = 6.0, 8.8 Hz, 1H), 7.50 (d, J - 8.0 Hz, 1H), 7.40 - 7.28 (m, 2H), 7.21 (t, J = 8.0 Hz, 1H), 7.11 - 6.96 (m, 1H), 5.14 - 4.97 (m, 2H), 4.75 - 4.57 (m, 2H), 4.56 - 4.43 (m, 3H), 4.38 - General 4.25 (m, 2H), 4.16 - 4.06 (m. 1H), 3.90 (dd. J = 7.6, Synthetic 13.6 Hz, 1H), 3.76 - 3.63 (m, 2H), 3.61 - 3.47 (m, Scheme 2 3H), 3.28 - 3.16 (m, 5H), 3.02 - 2.85 (m, 4H), 2.79 - 2.65 (m, 1H), 2.59 (d, J = 18.4 Hz, 1H), 2.45 - 2.38 (m, 2H), 2.34 (d, J = 11.6 Hz, 1H), 2.29 - 2.18 (m, 1H), 2.12 - 2.02 (m. 2H), 2.00 - 1.87 (m, 5H). 1.85 - 1.76 (m, 1H), 1.64 - 1.45 (m, 3H), 0.96 (d, J = 6.0 Hz, 3H), 0.88 - 0.75 (m, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.99 (s, 1H), 10.04 - 9.84 (m, 1H), 7.75 (dd, J = 6.0, 9.2 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.40 - 7.29 (m, 2H), 7.24 - 7.15 (m, 1H), 7.11 - 6.96 (m. 1H). 5.14 - 4.94 (m, 2H), 4.76 - 4.58 (m. 2H), 4.57 - 4.42 (m, 3H), 4.39 - General4.25 (m, 2H), 4.18 - 4.05 (m, 1H), 4.01 - 3.85 (m, Synthetic2H), 3.83 - 3.64 (m, 3H), 3.61 - 3.44 (m, 5H), 3.26 - Scheme 23.16 (m, 2H), 3.01 - 2.85 (m, 2H), 2.77 - 2.66 (m, 1H), 2.65 - 2.59 (m, 1H), 2.47 - 2.39 (m, 2H), 2.38 - 2.21 (m, 4H), 2.09 - 1.95 (m. 4H), 1.94 - 1.85 (m, 1H), 1.84 - 1.72 (m, 1H), 1.56 - 1.39 (m, 3H), 1.20 (s, 3H), 0.90 (d, J = 6.0 Hz, 3H), 0.86 - 0.76 (m, 3H) 1H NMR (400 MHz, DMSO-d6) 5: 10.98 (s, 1H), 10.10 - 9.78 (m, 1H), 7.75 (dd, J = 6.0, 8.8 Hz, 1H), General 7.47 (d, J = 8.0 Hz, 1H), 7.39 - 7.27 (m, 2H), 7.12 (t, J Synthetic = 8.0 Hz, 1H). 7.07 - 6.95 (m, 1H), 5.11 - 4.95 (m.Scheme 2 2H), 4.73 - 4.57 (m. 2H), 4.56 - 4.43 (m, 3H), 4.40 - 4.24 (m, 2H), 4.17 - 4.06 (m, 1H), 3.99 - 3.83 (m, 1H), 3.74 - 3.52 (m, 1H), 3.51 - 3.39 (m, 2H), 3.26 (br s, 3H), 2.99 - 2.77 (m, 5H), 2.76 - 2.63 (m, 2H), 2.61 -ARVN-216-PCT / / ARVN0216WO22.54 (m, 1H), 2.44 - 2.32 (m, 4H), 2.31 - 2.15 (m, 2H), 2.09 - 1.84 (m, 6H), 1.82 - 1.68 (m, 2H), 1.63 - 1.54 (m, 1H), 1.52 - 1.36 (m. 2H), 1.13 - 1.01 (m, 1H), 1.01 - 0.89 (m, 4H), 0.82 (td, J = 7.2, 11.2 Hz, 3H)1H NMR (400 MHz, DMSO-d6) 8: 10.95 (s, 1H), 8.17 (s, 1H), 7.75 (dd, J = 6.0, 8.0 Hz, 1H), 7.43 - 7.25 (m, 2H), 7.19 (d, J = 8.0 Hz, 1H), 7.12 - 6.89 (m, 2H), 5.18 - 4.93 (m, 2H), 4.77 - 4.44 (m, 4H), 4.41 - General 4.22 (m, 3H), 4.12 (dd, J = 4.0, 16.4 Hz, 2H), 4.06 - Synthetic 3.85 (m, 2H), 3.74 - 3.39 (m. 6H), 3.26 - 3.17 (m, Scheme 2 1H), 2.99 - 2.78 (m, 5H), 2.75 - 2.66 (m, 1H). 2.58 (d, J = 16.0 Hz, 1H), 2.45 - 2.32 (m, 3H), 2.18 - 1.86 (m, 9H), 1.66 (d, J = 10.0 Hz, 2H), 1.48 (s, 2H), 1.19 (d, J = 2.8 Hz, 3H), 1.11 - 0.93 (m, 2H), 0.88 - 0.74 (m, 3H)1H NMR (400 MHz, DMSO-d6) 8: 10.95 (s, 1H), 10.25 - 9.76 (m, 1H), 8.15 (s. 1H), 7.75 (dd, J = 6.0, 9.2 Hz, 1H), 7.41 - 7.26 (m, 2H), 7.19 (d, J = 8.0 Hz, 1H), 7.11 - 6.85 (m, 2H), 5.14 - 4.96 (m, 2H), 4.76 - 4.38 (m, 5H), 4.37 - 4.24 (m, 3H), 4.12 (dd, J = 5.2, General16.4 Hz, 2H), 4.04 - 3.84 (m. 2H). 3.73 - 3.33 (m, Synthetic7H), 3.21 (d, J = 3.6 Hz, 1H), 2.97 - 2.85 (m, 3H), Scheme 22.79 - 2.68 (m, 1H), 2.58 (d, J = 16.4 Hz, 1H), 2.46 - 2.33 (m, 3H), 2.31 - 2.22 (m, 1H), 2.16 - 2.01 (m, 5H), 1.98 - 1.87 (m, 3H), 1.65 (s, 2H), 1.48 (d, J = 4.0 Hz, 2H), 1.27 - 1.15 (m, 3H), 1.12 - 0.94 (m, 2H), 0.83 (td, J = 7.2. 12.0Hz, 3H)1H NMR (400 MHz, DMSO-d6) 8: 10.95 (s, 1H), 10.03 - 9.62 (m, 1H), 8.15 (s. 1H), 7.78 - 7.65 (m, 1H), 7.35 - 7.26 (m, 1H), 7.26 - 7.22 (m, 1H), 7.18 (d, J - 8.4 Hz, 1H), 6.95 (d, J - 8.4 Hz, 1H), 6.91 - 6.76 General(m, 1H), 5.11 - 4.93 (m, 2H), 4.74 - 4.57 (m, 2H), Synthetic4.54 - 4.39 (m, 2H). 4.37 - 4.21 (m, 3H), 4.15 - 3.83 Scheme 2(m, 5H), 3.70 - 3.56 (m, 3H). 2.95 - 2.66 (m, 7H), 2.45 - 2.19 (m, 4H), 2.13 - 1.71 (m, 14H), 1.70 - 1.55 (m, 2H), 1.53 - 1.38 (m, 2H), 1.24 - 1.14 (m, 3H), 1.08 - 0.87 (m, 2H), 0.82 - 0.70 (m, 3H).ARVN-216-PCT / / ARVN0216WO21H NMR (400 MHz, DMSO-d6) 5: 10.95 (s, 1H), 9.85 (s, 1H), 8.14 (s, 1H), 7.74 - 7.70 (m, 1H), 7.33 - 7.27 (m, 1H), 7.25 - 7.24 (m. 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.95 (d. J = 7.6 Hz, 1H), 6.88 - 6.79 (m, 1H), General 5.06 - 4.96 (m, 2H), 4.70 - 4.60 (m, 2H), 4.52 - 4.41 Synthetic (m, 2H), 4.34 - 4.24 (m, 3H), 4.13 - 4.08 (m, 2H), Scheme 2 4.06 - 3.86 (m, 3H), 3.68 - 3.62 (m, 3H), 2.94 - 2.70(m. 7H), 2.45 - 2.23 (m, 4H). 2.08 - 1.73 (m, 14H).1.65 (d, J = 9.6 Hz, 2H), 1.48 (d. J = 1.2 Hz, 2H). 1.23 - 1.13 (m, 3H), 1.07 - 0.91 (m, 2H), 0.80 - 0.72 (m, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.81 (d, J = 2.8 Hz, 1H), 10.10 - 9.59 (m, 1H), 8.15 (s, 1H), 7.77 - 7.67 (m, 1H), 7.35 - 7.26 (m, 1H), 7.24 (t, J = 2.4 Hz, 1H), 6.90 - 6.78 (m. 1H), 6.59 (d, J = 12.8 Hz, 1H), 6.53 (s. 1H), 5.09 - 4.94 (m, 1H), 4.74 - 4.58 (m, 2H), 4.55 - 4.39 (m, 2H), 4.38 - 4.22 (m, 1H), 4.17 (d, J = General 10.4 Hz, 1H), 4.12 - 4.05 (m, 1H), 3.94 - 3.82 (m, Synthetic 2H), 3.77 - 3.70 (m, 1H), 3.68 - 3.51 (m, 1H), 3.50 - Scheme 2 3.35 (m, 3H), 3.27 - 3.17 (m. 1H), 3.08 - 2.95 (m,1H), 2.86 - 2.74 (m, 2H), 2.72 - 2.64 (m, 1H), 2.63 - 2.55 (m, 2H), 2.47 - 2.42 (m, 2H), 2.41 - 2.23 (m, 4H), 2.22 - 2.13 (m, 2H), 2.08 (d, J - 5.2 Hz, 3H), 2.03 - 1.95 (m, 4H), 1.91 - 1.72 (m, 3H), 1.67 - 1.54 (m. 2H), 1.52 - 1.37 (m, 2H). 1.05 - 0.88 (m, 5H), 0.84 - 0.70 (m, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.81 (d, J = 2.4 Hz, 1H), 10.16 - 9.52 (m, 1H), 8.16 (s, 1H), 7.72 (dd, JI = 6.0 Hz, J2 = 9.2 Hz, 1H), 7.36 - 7.20 (m, 2H), 6.92 - 6.76 (m, 1H), 6.65 - 6.49 (m, 2H), 5.08 - 4.94 General (m, 1H), 4.73 - 4.58 (m, 2H), 4.55 - 4.39 (m, 2H), Synthetic 4.37 - 4.23 (m, 1H). 4.21 - 4.06 (m, 2H), 3.95 - 3.82 Scheme 2 (m, 2H), 3.73 (dd, JI = 4.8 Hz, J2 = 11.6 Hz, 1H),3.69 - 3.52 (m, 1H), 3.50 - 3.36 (m, 3H), 3.25 - 3.18 (m, 1H), 3.07 - 2.95 (m, 1H), 2.85 - 2.57 (m, 6H), 2.41 - 2.23 (m, 4H), 2.21 - 2.14 (m, 2H), 2.08 (d, J =6.4 Hz. 3H). 2.03 - 1.73 (m, 8H), 1.61 (d, J = 9.6 Hz.ARVN-216-PCT / / ARVN0216WO22H), 1.52 - 1.37 (m, 2H), 0.97 (s, 5H), 0.81 - 0.71 (m, 3H)1H NMR (400 MHz, DMSO-d6) 8: 10.81 (d, J = 2.8 Hz, 1H), 9.98 - 9.67 (m, 1H), 8.14 (s, 1H), 7.77 - 7.66 (m, 1H), 7.35 - 7.20 (m, 2H), 6.93 - 6.76 (m, 1H), 6.66 - 6.49 (m, 2H), 5.11 - 4.94 (m, 1H), 4.80 - 4.57 (m, 2H), 4.55 - 4.40 (m, 2H), 4.38 - 4.22 (m, 1H), General 4.21 - 4.06 (m, 2H). 3.96 - 3.80 (m, 2H), 3.77 - 3.70 Synthetic (m, 1H), 3.69 - 3.50 (m, 1H), 3.50 - 3.35 (m, 3H), Scheme 2 3.26 - 3.18 (m, 1H), 3.07 - 2.96 (m, 1H), 2.86 - 2.76(m, 2H), 2.75 - 2.69 (m, 1H), 2.67 - 2.54 (m, 4H), 2.41 - 2.22 (m, 4H), 2.22 - 2.13 (m, 2H), 2.08 (d, J = 5.2 Hz. 3H), 2.04 - 1.97 (m, 4H), 1.92 - 1.73 (m, 3H), 1.69 - 1.54 (m, 2H), 1.52 - 1.39 (m, 2H), 1.09 - 0.88 (m, 5H), 0.82 - 0.70 (m, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.95 (s, 1H), 10.08 - 9.55 (m, 1H), 8.14 (s, 1H), 7.76 - 7.65 (m, 1H), 7.35 - 7.26 (m, 1H), 7.24 (t, J = 2.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.95 (d. J = 8.4 Hz, 1H), 6.90 General- 6.77 (m, 1H), 5.11 - 4.93 (m, 2H), 4.78 - 4.56 (m, Synthetic2H), 4.54 - 4.39 (m, 2H), 4.36 - 4.21 (m, 3H). 4.15 - Scheme 23.83 (m, 5H), 3.69 - 3.57 (m, 3H), 2.95 - 2.65 (m, 7H), 2.45 - 2.18 (m, 4H), 2.13 - 1.71 (m, 14H), 1.69 - 1.55 (m, 2H), 1.52 - 1.39 (m, 2H), 1.24 - 1.14 (m, 3H), 1.10 - 0.86 (m. 2H), 0.82 - 0.69 (m, 3H).1H NMR (400 MHz, DMSO-d6) 8: 10.95 (s, 1H), 9.84 (s. 1H), 8.14 (s, 1H), 7.76 - 7.65 (m, 1H), 7.35 - 7.26 (m, 1H), 7.24 (t, J = 2.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.95 (d, J - 8.4 Hz, 1H), 6.90 - 6.77 (m, 1H), General5.11 - 4.93 (m, 2H), 4.78 - 4.56 (m, 2H), 4.54 - 4.39 Synthetic(m. 2H), 4.36 - 4.21 (m, 3H). 4.15 - 3.83 (m, 5H), Scheme 23.69 - 3.57 (m, 3H). 2.95 - 2.65 (m, 7H), 2.45 - 2.18 (m, 4H), 2.13 - 1.71 (m, 14H), 1.69 - 1.55 (m, 2H), 1.52 - 1.39 (m, 2H), 1.24 - 1.14 (m, 3H), 1.10 - 0.86 (m, 2H), 0.82 - 0.69 (m, 3H).ARVN-216-PCT / / ARVN0216WO21H NMR (400 MHz, DMSO-d6) 5: 10.81 (d, J = 2.4 Hz, 1H), 10.16 - 9.52 (m, 1H), 8.16 (s, 1H), 7.72 (dd, JI = 6.0 Hz, J2 = 9.2 Hz, 1H), 7.37 - 7.20 (m. 2H), 6.91 - 6.78 (m, 1H), 6.65 - 6.50 (m, 2H), 5.11 - 4.94 (m, 1H), 4.78 - 4.57 (m, 2H), 4.55 - 4.39 (m, 2H), General 4.36 - 4.23 (m, 1H), 4.21 - 4.06 (m, 2H), 3.95 - 3.82 Synthetic (m, 2H), 3.73 (dd, JI = 4.8 Hz, J2 = 11.6 Hz, 1H), Scheme 2 3.69 - 3.51 (m, 1H). 3.50 - 3.36 (m, 3H), 3.22 (d. J =11.6 Hz, 1H), 3.02 (t, J = 8.8 Hz. 1H), 2.85 - 2.55 (m, 6H), 2.46 - 2.24 (m, 4H), 2.21 - 2.14 (m, 2H), 2.08 (d, J - 6.4 Hz, 3H), 2.04 - 1.83 (m, 7H), 1.82 - 1.70 (m, 1H), 1.66 - 1.54 (m, 2H), 1.50 - 1.37 (m, 2H), 1.05 - 0.87 (m, 5H), 0.83 - 0.69 (m. 3H)1H NMR (400 MHz, DMSO-d6) 8: 10.98 (s, 1H), 10.26 - 9.53 (m, 1H), 8.15 (s. 1H). 7.73 (dd, J = 6.0, 9.2 Hz, 1H), 7.38 - 7.20 (m, 2H), 7.03 - 6.83 (m, 2H), 5.11 - 4.91 (m, 2H), 4.82 - 4.65 (m, 2H), 4.64 - 4.46 General (m, 2H), 4.46 - 4.34 (m, 2H), 4.34 - 4.17 (m, 2H), Synthetic 4.11 (br dd, J = 2.8, 8.8 Hz, 2H), 4.00 - 3.84 (m, 2H), Scheme 2 3.67 (br dd, J = 10.0, 12.0 Hz, 1H), 2.96 - 2.88 (m.1H), 2.87 - 2.66 (m, 4H), 2.63 - 2.53 (m, 2H), 2.46 - 2.21 (m, 8H), 2.14 - 1.74 (m, 9H), 1.71 - 1.55 (m, 2H), 1.54 - 1.34 (m, 2H), 1.14 - 0.89 (m, 5H), 0.87 - 0.74 (m, 3H)1H NMR (400 MHz, DMSO-d6) 5: 10.97 (s, 1H), 9.95 - 9.78 (m, 1H). 7.73 (dd, J = 9.2, 6.0 Hz. 1H).7.35 - 7.29 (m, 1H), 7.28 - 7.26 (m. 1H), 7.01 - 6.84 (m, 2H), 5.10 - 4.97 (m, 2H), 4.80 - 4.62 (m, 2H), General4.61 - 4.51 (m, 1H), 4.41 - 4.28 (m, 3H), 4.26 - 4.19 Synthetic(m, 1H), 4.16 - 4.07 (m, 2H), 3.99 - 3.84 (m, 2H), Scheme 23.72 - 3.33 (m, 7H), 2.96 - 2.71 (m, 3H), 2.64 - 2.51 (m. 2H), 2.45 - 2.28 (m, 7H). 2.13 - 1.82 (m, 8H), 1.71 - 1.41 (m, 4H), 1.12 - 1.00 (m, 4H), 0.88 - 0.76 (m, 3H).ARVN-216-PCT / / ARVN0216WO21H NMR (400 MHz, DMSO-d6) 5: 10.80 (d, J = 2.0 Hz, 1H), 9.99 - 9.78 (m, 1H), 7.73 (dd, J = 9.2, 6.0 Hz. 1H), 7.36 - 7.22 (m, 2H). 6.99 - 6.86 (m, 1H), 6.63 - 6.50 (m, 2H), 5.09 - 4.94 (m, 1H), 4.81 - 4.61 (m, 2H), 4.61 - 4.27 (m, 3H), 4.21 - 4.07 (m, 2H), General3.94 - 3.80 (m, 2H), 3.77 - 3.63 (m, 1H), 3.59 - 3.37 Synthetic(m, 3H), 3.26 - 3.19 (m, 1H), 3.08 - 2.97 (m, 1H), Scheme 22.86 - 2.70 (m, 3H). 2.66 - 2.56 (m, 2H), 2.42 - 2.27 (m, 4H), 2.23 - 2.13 (m, 2H). 2.07 - 1.76 (m, 9H), 1.67 - 1.54 (m, 2H), 1.53 - 1.38 (m, 2H), 1.27 - 1.21 (m, 1H), 1.03 - 0.92 (m, 4H), 0.88 - 0.83 (m, 2H), 0.83 - 0.77 (m, 2H).1H NMR (400 MHz, DMSO-d6) 5: 10.85 - 10.76 (m, 1H), 9.93 - 9.84 (m, 1H), 7.73 (dd, J = 9.2, 6.0 Hz, 1H), 7.35- 7.25 (m, 2H), 6.95 - 6.85 (m, 1H). 6.80 - 6.70 (m, 1H), 6.60 - 6.50 (m, 1H), 5.10 - 4.95 (m, 1H), 4.79 - 4.63 (m, 2H), 4.61 - 4.29 (m, 3H), 4.20 - General 4.07 (m, 2H), 3.95 - 3.83 (m, 2H), 3.77 - 3.64 (m, Synthetic 1H), 3.59 - 3.36 (m, 3H), 3.30 - 3.19 (m, 2H), 3.15 - Scheme 2 2.97 (m, 1H), 2.88 - 2.70 (m. 3H), 2.65 - 2.55 (m,2H), 2.34 - 2.24 (m, 3H), 2.22 - 2.13 (m, 2H), 2.06 - 1.95 (m, 5H), 1.95 - 1.78 (m, 4H), 1.66 - 1.55 (m, 2H), 1.51 - 1.38 (m, 2H), 1.30 - 1.20 (m, 1H), 1.09 - 0.94 (m, 5H), 0.88 - 0.82 (m, 2H), 0.82 - 0.76 (m, 2H).1H NMR (400 MHz, DMSO-d6) 8: 10.96 (s, 1H), 10.17 - 9.58 (m, 1H), 7.73 (dd, J = 6.0, 9.2 Hz, 1H), 7.37 - 7.24 (m, 2H), 6.99 - 6.84 (m, 2H), 5.12 - 4.95 (m, 2H), 4.80 - 4.63 (m, 2H), 4.62 - 4.45 (m, 2H), 4.44 - 4.34 (m, 2H), 4.34 - 4.16 (m, 3H), 4.11 (d, J = General12.0 Hz, 1H), 4.04 - 3.83 (m, 3H), 3.73 - 3.56 (m, Synthetic1H), 3.56 - 3.45 (m. 2H), 3.07 (t, J = 10.4 Hz. 1H).Scheme 22.95 - 2.85 (m, 1H), 2.82 - 2.64 (m, 5H), 2.58 (d, J = 16.8 Hz, 1H), 2.46 - 2.28 (m, 4H), 2.18 (d, J = 3.2 Hz, 1H), 2.12 - 2.03 (m, 3H), 2.02 - 1.90 (m, 4H), 1.89 - 1.77 (m, 2H), 1.64 (d, J = 9.6 Hz, 2H), 1.54 - 1.38 (m, 2H), 1.11 - 0.89 (m. 2H). 0.89 - 0.76 (m, 3H)ARVN-216-PCT / / ARVN0216WO2(400 MHz, DMSO-d6) 5: 11.20 - 10.81 (m, 1H), 8.24 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 6.56 - 6.54 (m. 1H), 6.49 - 6.42 (m, 1H), 5.12 (dd, J = 5.2, 13.2 Hz, 1H), 5.06 - 4.96 (m, 1H), 4.71 - 4.61 General (m, 2H), 4.57 - 4.42 (m, 3H), 4.37 - 4.27 (m, 2H), 4.11 Synthetic - 4.07 (m, 1H), 3.92 - 3.83 (m, 1H), 3.61 - 3.55 (m, Scheme 4 1H), 3.49 - 3.34 (m, 3H), 3.11 - 3.07 (m, 1H), 3.05 - 2.99 (m, 3H), 2.94 - 2.86 (m. 1H), 2.82 - 2.69 (m, 3H), 2.62 - 2.56 (m, 1H), 2.47 - 2.42 (m, 1H), 2.21 - 1.98 (m, 4H), 1.88 - 1.62 (m, 9H), 1.58 - 1.48 (m, 2H), 0.74 (d, J - 7.2 Hz, 3H)GeneralSyntheticScheme 4GeneralSyntheticScheme 4GeneralSyntheticScheme 2GeneralSyntheticScheme 2GeneralSyntheticScheme 2GeneralSyntheticScheme 2(400 MHz, DMSO-d6) 5: 10.94 (s, 1H), 10.05 - 9.83 (m, 1H), 7.74 (dd, J = 6.0, 9.2 Hz, 1H), 7.51 (d, J = 9.2 General Hz. 1H), 7.38 - 7.27 (m, 2H), 7.05 - 6.94 (m, 3H), 5.10 Synthetic - 4.97 (m, 2H), 4.71 - 4.60 (m, 2H), 4.57 - 4.47 (m.Scheme 2 2H), 4.39 - 4.25 (m, 2H), 4.23 - 4.15 (m, 1H), 4.14 - 4.03 (m, 1H), 3.91 - 3.78 (m, 1H), 3.67 - 3.50 (m, 1H),3.49 - 3.37 (m, 2H), 3.36 - 3.33 (m, 2H), 3.25 (s, 3H),ARVN-216-PCT / / ARVN0216WO22.98 - 2.78 (m, 2H), 2.64 - 2.54 (m, 4H), 2.49 - 2.48 (m, 2H), 2.39 - 2.28 (m, 2H), 2.27 - 2.14 (m, 1H), 2.07 - 1.92 (m, 2H), 1.91 - 1.77 (m, 2H), 1.63 - 1.46 (m.1H), 0.79 (q, J = 7.5 Hz, 3H)(400 MHz, DMSO-d6) 8: 10.98 (s. 1H), 10.11 - 9.69 (m, 1H), 8.16 (s, 1H), 7.74 (dd, J = 6.0, 9.2 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.47 - 7.39 (m, 1H), 7.37 - 7.24 (m, 3H), 7.08 - 6.90 (m, 1H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 5.05 - 4.92 (m. 1H). 4.71 - 4.59 (m, 2H), General 4.58 - 4.48 (m, 2H), 4.42 - 4.22 (m, 3H), 4.10 (ddd, J = Synthetic 4.0, 7.6, 12.0 Hz, 1H), 3.94 - 3.82 (m, 1H), 3.72 - 3.56 Scheme 2 (m, 1H), 3.52 - 3.41 (m, 2H), 2.96 (d, J - 8.8 Hz, 2H),2.94 - 2.83 (m, 1H), 2.78 (t, J = 11.2 Hz, 1H), 2.61 (s, 2H), 2.48 - 2.42 (m, 1H), 2.41 - 2.30 (m, 2H), 2.24 (d, J = 1.6 Hz. 1H), 2.18 - 2.04 (m, 2H), 2.03 - 1.92 (m, 2H), 1.91 - 1.70 (m, 4H), 1.68 - 1.45 (m, 3H), 0.86 - 0.71 (m, 3HGeneralSyntheticScheme 4GeneralSyntheticScheme 4(400 MHz. DMSO-d6) 8: 10.98 (s. 1H), 9.38 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.23 - 7.11 (m, 1H), 6.25 (s, 2H), 5.07 (dd, J = 4.8, 13.2 Hz, 1H), 5.02 - 4.91 (m, 1H), 4.71 - 4.57 (m, 2H), 4.54 - 4.49 (m, 1H), 4.49 - 4.40 (m, 2H), 4.36 - 4.26 (m, 2H), 4.19 - 4.13 (m, 1H), 4.13 - 4.00 (m, 2H). 3.94 - 3.81 (m, 1H), 3.76 - 3.67 (m, 1H), 3.66 - 3.52 (m, 1H), 3.52 - 3.41 (m, 1H), 3.41 - 3.35 (m, 1H), 3.29 -3.20 (m, 1H), 3.10 - 3.00 (m, 1H), 2.98 - 2.85 (m, 2H), 2.81 (d, J = 9.2 Hz, 2H), 2.75 - 2.65 (m, 1H), 2.65 - 2.54 (m, 2H), 2.47 - 2.38 (m, 3H), 2.37 - 2.23 (m. 2H), 2.14 - 2.03 (m, 2H), 2.03 - 1.92 (m, 4H), 1.92 - 1.82 (m, 2H), 1.81 - 1.74 (m, 1H),1.72 - 1.55 (m, 3H), 1.48 (dd, J = 3.2, 4.4 Hz, 2H),ARVN-216-PCT / / ARVN0216WO21.12 - 1.00 (m, 2H), 0.98 (d, J = 6.4 Hz, 3H), 0.83 (d, J = 5.6 Hz, 3H)(400 MHz, DMSO-d6) 5: 11.01 - 10.93 (m, 1H), 9.24 (d, J = 4.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.23 - 7.18 (m, 1H), 6.54 (d, J = 2.4 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 5.04 - 4.97 (m, 1H), 4.68 - 4.61 (m, 2H), 4.54 - 4.48 (m, 2H), 4.44 General - 4.38 (m, 1H), 4.30 (dd, J = 4.8, 9.2 Hz, 1H), 4.24 (d, Synthetic J = 17.2 Hz, 1H), 4.08 (dd. J = 4.0, 12.0 Hz, 1H). 3.90 Scheme 4 - 3.81 (m, 1H), 3.56 (d, J = 10.0 Hz, 1H), 3.48 - 3.40 (m, 2H), 3.05 (s. 5H), 2.95 - 2.78 (m, 3H), 2.71 (s, 2H), 2.61 (s, 4H), 2.44 (d, J - 8.4 Hz, 1H), 2.02 - 1.95 (m, 2H), 1.91 - 1.78 (m, 3H), 1.77 - 1.70 (m, 2H), 1.64 (dd, J = 5.2, 9.0 Hz, 1H), 1.59 - 1.51 (m, 2H), 0.74 (d, J = 7.2 Hz. 3H)(400 MHz. DMSO-d6) 5: 10.99 (br s, 1H), 9.25 (br s, 1H), 8.21 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.11 (br t, J = 7.6 Hz, 1H), 6.54 (s, 1H), 6.45 (br s, 1H), 5.16 - 4.95 (m, 2H), 4.75 - 4.60 (m, 2H), 4.56 - 4.41 (m, 3H), 4.36 - 4.26 (m, 2H), 4.08 (br dd, J = 3.6, 12.0 Hz, 1H), 3.94 General- 3.81 (m, 1H), 3.70 (br d, J = 1.2 Hz, 1H), 3.56 (br d, J Synthetic= 10.4 Hz, 1H), 3.45 (br d, J = 4.8 Hz. 1H), 3.24 (br d, Scheme 4J = 9.6 Hz, 2H), 3.07 (br d, J = 1.6 Hz, 1H), 2.98 - 2.85 (m, 2H), 2.77 - 2.65 (m, 4H), 2.63 - 2.53 (m, 3H), 2.44 - 2.31 (m, 2H), 2.09 - 1.94 (m, 2H), 1.94 - 1.81 (m, 2H), 1.77 - 1.48 (m. 5H). 0.92 (br d. J = 6.0 Hz, 3H). 0.73 (br d, J = 6.8 Hz, 3H)(400 MHz. DMSO-d6) 5: 11.05 - 10.94 (m, 1H), 9.30 - 9.12 (m, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.43 - 7.36 (m, 1H), 6.61 - 6.51 (m, 1H), 6.48 - 6.39 (m, 1H), 5.10 (dd, General J = 5.2, 13.2 Hz, 1H), 5.03 - 4.95 (m, 1H), 4.68 - 4.59 Synthetic (m, 2H), 4.57 - 4.47 (m, 3H), 4.39 - 4.26 (m, 2H), 4.08 Scheme 4 (dd, J = 3.6, 12.0 Hz, 1H), 3.91 - 3.81 (m. 1H), 3.63 - 3.53 (m, 1H), 3.48 - 3.40 (m, 2H), 3.13 - 3.07 (m, 1H), 3.02 - 2.94 (m, 2H), 2.92 - 2.82 (m, 2H), 2.78 (d, J = 12.0 Hz, 1H), 2.73 - 2.66 (m, 2H), 2.63 - 2.56 (m, 1H), 2.44 (s, 1H), 2.21 - 2.12 (m, 1H), 2.08 - 1.95 (m, 3H),ARVN-216-PCT / / ARVN0216WO21.91 - 1.60 (m, 10H), 1.53 (dd, J = 3.6, 8.4 Hz, 2H), 0.74 (d, J = 7.2 Hz, 3H)(400 MHz, DMS0-d6) 5: 10.98 (s, 1H), 9.43 - 9.07 (m, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 4.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.56 - 6.54 (m. 1H), 6.47 - 6.45 (m, 1H), 5.09 (dd, J = 4.8, 13.2 Hz. 1H), 5.05 - General 4.96 (m, 1H), 4.70 - 4.60 (m, 2H), 4.53 - 4.49 (m, 2H), Synthetic 4.43 - 4.23 (m, 3H), 4.14 - 4.05 (m, 1H), 3.91 - 3.82 Scheme 4 (m, 1H), 3.63 - 3.55 (m, 1H), 3.46 - 3.42 (m, 1H), 3.15 - 3.08 (m, 1H), 3.02 - 2.88 (m, 3H), 2.81 - 2.57 (m, 6H), 2.41 - 2.32 (m. 1H), 2.20 - 1.93 (m, 5H), 1.90 - 1.72 (m, 6H), 1.68 - 1.49 (m, 5H), 0.75 (d, J = 6.8 Hz, 3H)(400 MHz, DMS0-d6) 8: 11.00 (s, 1H), 10.27 - 9.63 (m, 1H), 8.16 (s, 1H), 7.74 (dd, J = 6.0, 9.2 Hz, 1H), 7.54 - 7.47 (m, 1H), 7.46 - 7.38 (m, 1H), 7.37 - 7.26 (m. 2H), 7.08 - 6.94 (m, 1H). 5.10 (dd, J = 5.2, 13.3 Hz, 1H), 5.05 - 4.93 (m, 1H), 4.73 - 4.59 (m, 2H), 4.57 General- 4.44 (m, 3H), 4.41 - 4.26 (m, 2H), 4.18 - 4.07 (m, Synthetic1H), 3.94 - 3.82 (m, 1H), 3.73 - 3.56 (m, 1H), 3.52 - Scheme 23.40 (m, 2H), 2.97 (d, J = 11.2 Hz, 2H), 2.94 - 2.84 (m, 2H), 2.83 - 2.67 (m. 1H). 2.59 (d, J = 16.8 Hz, 1H), 2.47 (d, J = 4.4 Hz, 1H), 2.44 - 2.30 (m, 2H), 2.27 - 2.12 (m, 2H), 2.11 - 1.95 (m, 3H), 1.92 - 1.80 (m, 2H), 1.72 (s, 4H), 1.61 - 1.46 (m, 1H), 0.89 - 0.70 (m, 3H) (400 MHz, DMS0-d6) 8: 11.07 (s, 1H), 9.55 - 8.91 (m, 1H), 8.15 (s, 1H), 7.93 (s, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.23 (dd, J = 1.9, 9.2 Hz, 1H), 7.07 (d, J = 1.6 Hz, General 1H), 6.54 (d. J = 2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz. 1H). Synthetic 5.75 (dd, J = 4.9, 11.6 Hz, 1H), 5.06 - 4.92 (m, 1H), Scheme 4 4.70 - 4.41 (m, 4H), 4.35 - 4.24 (m, 1H), 4.09 (dd, J =3.8, 12.0 Hz, 1H), 3.93 - 3.83 (m, 1H), 3.62 - 3.52 (m, 3H), 3.10 (dd, J = 1.6, 4.8 Hz, 2H), 2.91 - 2.63 (m,11H), 2.46 - 2.37 (m, 3H), 2.31 - 2.19 (m. 2H), 2.07 -ARVN-216-PCT / / ARVN0216WO21.38 (m, 15H), 1.10 - 0.90 (m, 5H), 0.76 (d, J = 7.2 Hz, 3H)(400 MHz, DMSO-d6) 5: 11.09 (d, J = 9.6 Hz, 1H), 9.48 - 9.01 (m, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.26 - 7.19 (m, 1H), 7.09 (d. J = 8.4 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 6.50 - 6.44 (m, 2H), 5.76 (dd, J = 5.2 Hz, 11.6 Hz, 1H), 5.05 - 4.94 (m, 1H), 4.69 - 4.57 (m, 2H), 4.55 - 4.42 (m, 2H), 4.36 - 4.27 (m, 1H), 4.12 - 4.01 (m, General 2H), 3.92 - 3.83 (m, 1H), 3.62 - 3.55 (m, 1H), 3.46 (dd, Synthetic J = 4.0 Hz. 8.8 Hz, 1H), 3.37 (d, J = 9.2 Hz, 2H). 3.12 Scheme 4 - 3.06 (m, 2H), 2.88 - 2.79 (m, 3H), 2.71 (s. 6H), 2.57 - 2.53 (m, 1H), 2.45 - 2.44 (m, 1H), 2.45 (s, 1H), 2.38 (d, J = 13.2 Hz, 1H), 2.28 - 2.19 (m, 2H), 2.13 - 2.06 (m, 2H), 2.04 - 1.96 (m, 2H), 1.92 - 1.84 (m, 2H), 1.81 - 1.73 (m, 3H), 1.70 - 1.62 (m, 3H), 1.58 - 1.44 (m, 3H), 1.10 - 1.02 (m. 1H), 0.98 (t, J = 6.0 Hz, 3H), 0.77 (d, J = 7.2 Hz, 3H)(400 MHz, DMSO-d6) 8: 10.98 (s. 1H), 9.97 (d, J = 11.6 Hz, 1H), 7.79 - 7.66 (m, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.37 - 7.27 (m, 2H), 7.20 - 7.10 (m, 1H), 7.09 - 6.97 (m, 1H), 5.12 - 4.97 (m, 2H), 4.91 - 4.60 (m, 2H), General 4.56 - 4.45 (m, 2H). 4.43 - 4.24 (m, 3H), 4.15 - 4.06 Synthetic (m, 1H), 3.95 - 3.85 (m, 1H). 3.73 - 3.40 (m, 5H), 3.21 Scheme 2 - 3.02 (m, 5H), 2.94 - 2.85 (m, 1H), 2.79 - 2.53 (m,3H), 2.45 - 2.29 (m, 3H), 2.26 - 2.11 (m, 2H), 2.10 - 1.94 (m, 4H), 1.90 - 1.82 (m, 2H), 1.80 - 1.73 (m, 3H), 1.70 - 1.57 (m, 3H), 1.52 - 1.30 (m, 1H), 1.19 (s, 3H), 0.85 - 0.75 (m, 3H).(400 MHz. DMSO-d6) 8: 10.98 (s. 1H). 10.08 - 9.80 (m, 1H), 8.14 (s, 1H), 7.74 (dd, J = 9.2 Hz, 1H), 7.46 General (d, J = 8.0 Hz, 1H), 7.37 - 7.32 (m, 1H), 7.32 - 7.30 Synthetic (m, 1H), 7.10 (t, J = 7.6 Hz, 1H), 7.07 - 6.98 (m, 1H), Scheme 2 5.11 - 4.95 (m, 2H), 4.72 - 4.58 (m, 2H), 4.57 - 4.45(m. 3H), 4.40 - 4.28 (m, 2H). 4.15 - 4.07 (m, 1H), 3.95- 3.85 (m, 1H), 3.73 - 3.62 (m, 1H), 3.61 - 3.54 (m.ARVN-216-PCT / / ARVN0216WO21H), 3.51 - 3.42 (m, 3H), 3.13 - 3.06 (m, 2H), 3.00 - 2.79 (m, 8H), 2.63 - 2.55 (m, 1H), 2.47 - 2.33 (m, 4H), 2.30 - 2.14 (m, 2H). 2.10 - 1.87 (m, 5H), 1.86 - 1.78 (m, 1H), 1.70 (t, J= 11.6 Hz, 2H), 1.56 - 1.47 (m, 1H). 1.40 (dd, J = 3.2 Hz, 1H), 1.02 (d, J = 5.6 Hz, 6H), 0.82 (td, J = 11.2 Hz, 3H)(400 MHz, DMSO-d6) 6: 10.98 (s, 1H), 10.44 - 9.46 (m, 1H), 8.14 (s, 1.5 H), 7.74 (dd, J = 6.0, 9.2 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.38 - 7.27 (m. 2H), 7.12 (t. J = 8.0 Hz. 1H), 7.09 - 6.92 (m, 1H), 5.13 - 4.95 (m, 2H), 4.73 - 4.58 (m, 2H), 4.56 - 4.42 (m, 3H). 4.41 - General4.26 (m, 2H), 4.19 - 4.07 (m, 1H), 3.90 (dt, J - 5.6, 8.8 SyntheticHz, 1H), 3.69 - 3.53 (m, 3H), 3.50 - 3.45 (m, 2H), 2.97 Scheme 2- 2.84 (m, 3H), 2.82 - 2.66 (m, 3H), 2.59 (d, J = 12.4 Hz. 3H), 2.49 - 2.32 (m, 5H). 2.31 - 2.17 (m, 1H), 2.09 - 1.87 (m, 5H), 1.86 - 1.78 (m, 1H), 1.77 - 1.65 (m, 2H), 1.59 - 1.45 (m, 1H), 1.44 - 1.31 (m, 1H), 1.02 (d, J = 5.6 Hz, 8H), 0.89 - 0.72 (m, 3H)(400 MHz, DMSO-d6) 5: 10.96 (s, 1H), 10.46 - 9.35 (m, 1H), 8.15 (s, 1H), 7.74 (dd, J = 6.0, 9.2 Hz, 1H), 7.38 - 7.28 (m, 2H). 7.08 - 6.96 (m, 1H), 6.89 (d. J = 7.2 Hz. 1H), 5.07 - 4.94 (m, 2H), 4.72 - 4.58 (m, 2H), 4.56 - 4.49 (m, 1H), 4.48 - 4.41 (m, 1H), 4.41 - 4.28 (m, 2H), 4.24 (d, J - 17.2 Hz, 1H), 4.16 - 4.07 (m, 1H), General3.95 - 3.85 (m, 1H), 3.75 - 3.65 (m, 2H), 3.59 (d, J = Synthetic12.0 Hz, 1H), 3.48 - 3.45 (m. 1H). 3.24 - 3.19 (m, 1H), Scheme 22.97 - 2.87 (m, 2H). 2.87 - 2.78 (m, 2H), 2.76 - 2.66 (m, 1H), 2.59 (d, J = 14.0 Hz, 2H), 2.54 - 2.52 (m, 3H), 2.47 - 2.32 (m, 5H), 2.31 - 2.20 (m, 2H), 2.14 - 2.00 (m, 3H), 2.00 - 1.84 (m, 4H), 1.84 - 1.75 (m, 1H), 1.72 - 1.58 (m, 2H), 1.47 (d, J = 4.4 Hz, 2H), 1.09 - 0.93 (m. 5H), 0.82 (td, J = 7.2. 12.2 Hz. 3H)(400 MHz. DMSO-d6) 5: 10.97 (s. 1H). 9.93 (d, J = General 10.4 Hz, 1H), 7.74 (dd, J = 6.0, 8.8 Hz, 1H), 7.45 (dd, Synthetic J = 1.2, 8.0 Hz, 1H), 7.37 - 7.26 (m, 2H), 7.15 (t, J = Scheme 2 7.6 Hz, 1H), 7.08 - 6.96 (m, 1H), 5.11 - 4.97 (m, 2H),4.75 - 4.58 (m, 2H), 4.56 - 4.41 (m, 3H), 4.38 - 4.26 (m, 2H), 4.16 - 4.07 (m, 1H), 3.97 - 3.83 (m, 1H), 3.70ARVN-216-PCT / / ARVN0216WO2- 3.38 (m, 6H), 3.05 - 2.85 (m, 4H), 2.76 - 2.55 (m, 3H), 2.47 - 2.22 (m, 5H), 2.14 - 1.67 (m, 9H), 1.62 - 1.37 (m, 4H), 0.91 - 0.70 (m. 9H).(400 MHz, DMSO-d6) 5: 10.98 (s, 1H), 9.94 (s, 1H), 7.74 (dd, J = 6.0, 9.2 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.39 - 7.27 (m, 2H). 7.12 (t, J = 8.0 Hz, 1H), 7.08 - 6.96 (m, 1H), 5.15 - 4.95 (m, 2H), 4.71 - 4.64 (m, 1H), General4.63 - 4.42 (m, 4H), 4.39 - 4.24 (m, 2H), 4.17 - 4.04 Synthetic(m, 1H), 3.96 - 3.83 (m, 1H), 3.70 - 3.36 (m, 5H), 3.17 Scheme 2- 3.10 (m, 1H), 3.07 - 3.00 (m, 1H), 2.95 - 2.84 (m, 2H), 2.77 - 2.57 (m. 5H). 2.48 - 2.30 (m, 3H), 2.29 - 1.95 (m, 5H), 1.94 - 1.68 (m, 5H), 1.66 - 1.46 (m, 2H), 1.42 - 1.30 (m, 2H), 0.94 (s, 6H), 0.87 - 0.77(m, 3H) (400 MHz, DMSO-d6) 5: 10.94 (s. 1H), 9.99 (d, J = 12.8 Hz, 1H), 7.74 (dd, J = 6.0, 9.2 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.14 (t, J = 8.0 Hz, 1H), 7.08 - 6.97 (m, 1H), 5.11 - 4.96 (m, 2H), 4.80 - General4.60 (m, 2H), 4.57 - 4.50 (m. 1H), 4.50 - 4.38 (m, 2H), Synthetic4.37 - 4.26 (m, 2H), 4.14 - 4.05 (m, 1H), 3.95 - 3.84 Scheme 2(m, 1H), 3.75 - 3.70 (m, 1H), 3.68 - 3.39 (m, 8H), 2.99 - 2.80 (m, 4H), 2.68 - 2.55 (m, 2H), 2.49 - 2.19 (m, 5H), 2.18 - 1.74 (m, 9H), 1.66 - 1.52 (m, 3H), 1.26 - 1.07 (m, 3H), 0.87 - 0.76 (m. 3H).(400 MHz. DMSO-d6) 5: 11.01 (s, 1H). 9.28 (s, 1H), 7.87 - 7.64 (m, 1H). 7.60 - 7.23 (m, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 5.12 (dd, J = 4.0, 12.0 Hz, 1H), 5.07 - 4.97 (m, 1H), 4.83 - 4.72 (m, 1H), General 4.68 (d, J = 9.6 Hz, 1H), 4.53 (d, J = 12.8 Hz, 1H), Synthetic 4.48 - 4.23 (m, 4H), 4.15 - 4.06 (m, 1H), 3.95 - 3.84 Scheme 4 (m. 1H), 3.82 - 3.54 (m, 6H). 3.47 (d, J = 6.8 Hz. 2H),3.29 - 3.18 (m, 2H), 3.16 - 2.97 (m, 4H), 2.94 - 2.83 (m, 2H), 2.74 - 2.58 (m, 4H), 2.26 - 1.82 (m, 10H), 1.79 - 1.33 (m, 7H), 1.30 - 0.81 (m, 4H), 0.80 - 0.70 (m, 3H).ARVN-216-PCT / / ARVN0216WO2(400 MHz, DMSO-d6) 5: 10.99 (s, 1H), 9.28 (s, 1H), 7.30 - 6.82 (m, 1H), 6.56 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H). 5.11 - 4.96 (m, 2H), 4.86 - 4.73 (m, 1H), 4.72 - 4.62 (m, 1H), 4.52 (d, J = 13.2 Hz, 1H), General 4.48 - 4.22 (m, 4H), 4.16 - 4.05 (m, 1H), 3.96 - 3.85 Synthetic (m, 1H), 3.83 - 3.73 (m, 1H), 3.69 - 3.54 (m, 4H), 3.45 153Scheme 4 (s, 4H), 3.30 - 3.19 (m, 2H), 3.15 - 2.99 (m, 4H), 2.96 - 2.83 (m, 2H), 2.72 (s. 2H), 2.64 - 2.54 (m, 4H). 2.47 - 2.33 (m, 2H), 2.23 - 2.07 (m, 3H), 2.05 - 1.82 (m, 6H), 1.74 (d, J = 6.8 Hz, 2H), 1.68 - 1.40 (m, 4H), 1.26 - 0.88 (m, 4H), 0.79 - 0.70 (m, 3H).(400 MHz, DMSO-d6) 8: 10.97 (s, 1H), 9.91 (br d, J = 10.4 Hz, 1H), 8.13 (s, 1H), 7.74 (dd, J = 6.0, 9.2 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.38 - 7.28 (m, 2H), 7.15 (t, J = 8.0 Hz, 1H), 7.08 - 6.96 (m, 1H), 5.14 - 4.96 (m, General 2H), 4.71 - 4.59 (m, 2H), 4.57 - 4.42 (m, 3H), 4.38 - Synthetic 4.25 (m, 2H), 4.17 - 4.06 (m, 1H), 3.96 - 3.84 (m, 1H), 154Scheme 2 3.69 - 3.54 (m, 2H), 3.52 - 3.40 (m, 3H), 2.98 - 2.86(m, 3H), 2.71 (br d, J = 3.2 Hz, 3H), 2.63 - 2.52 (m, 2H), 2.48 - 2.36 (m. 3H), 2.35 - 1.85 (m, 8H), 1.84 - 1.70 (m, 3H), 1.61 - 1.46 (m, 3H), 1.44 - 1.30 (m, 2H), 0.82 (td, J = 7.2, 12.0 Hz, 3H).(400 MHz, DMSO-d6) 8: 10.95 (s, 1H), 10.22 - 9.62 (m, 1H), 8.14 (s, 1H), 7.74 (dd, J - 6.0, 9.0 Hz, 1H), 7.43 - 7.27 (m, 3H), 7.08 - 6.91 (m, 2H), 5.09 - 4.96 (m. 2H), 4.73 - 4.60 (m, 2H). 4.60 - 4.48 (m, 2H), 4.47 - 4.39 (m, 2H), 4.36 (td, J = 4.8, 9.8 Hz, 1H), 4.29 - 4.24 (m, 1H), 4.14 - 4.08 (m, 1H), 3.92 - 3.85 (m, 1H). General3.70 - 3.62 (m, 1H), 3.58 (d, J = 11.2 Hz, 1H), 3.50 - 155 Synthetic3.46 (m, 4H), 2.96 - 2.84 (m, 2H), 2.83 - 2.77 (m, 2H), Scheme 22.74 (s, 2H), 2.70 - 2.66 (m, 1H), 2.61 - 2.56 (m, 3H), 2.46 - 2.31 (m, 4H). 2.27 - 2.23 (m, 2H), 2.06 - 2.00 (m, 1H), 1.98 - 1.92 (m, 2H), 1.87 (d, J = 1.2 Hz, 3H), 1.81 - 1.74 (m, 1H), 1.65 - 1.56 (m, 2H), 1.51 - 1.36 (m, 2H), 1.04 - 0.92 (m, 2H), 0.82 (td, J = 7.2, 12.5 Hz, 3H)

[0162] The compounds of Formula Q-I may also generally be prepared as follows:ARVN-216-PCT / / ARVN0216WO2 General Synthetic Scheme 1HCI / Dioxane POCI3, DIEA NaHINT-1 INT-3 X = F, ClINT-7 INT-8NaBH(OAc)3, DIEA, Ti(i-PrO)4INT-9wherein moiety A is defined herein and the linker is moieties -B-C as defined herein.ARVN-216-PCT / / AR VN0216WO2 General Synthetic Scheme 2wherein moiety A is defined herein and the linker is moieties -B-C as defined herein.ARVN-216-PCT / / ARVN0216WO2Synthetic Procedures of exemplary compounds of Formula Q-IAbbreviations:cataCXium A Pd G3 mesylate[(di(l-adamantyl)-n-butylphosphine)-2-(2'-amino-l,l'- biphenyl)] palladium(II)CS2CO3 cesium carbonateDCM dichloromethaneDess-Martin periodinane 1,1,1 -tris(acetyloxy)- 1, 1 -dihydro- 1,2-benziodoxol-3-( lH)-one DIEA N, N-DiisopropylethylamineDMA N, N-DimethylacetamideEtOAc ethyl acetateEtOH ethyl alcoholKI potassium iodideLiHMDS lithium bis(trimethylsilyl)amideMTBE methyl r -butyl etherNaBH(OAc)3 sodium triacetoxyborohydrideNa CCh sodium carbonateNaOAc sodium acetateNa2SC>4 sodium sulfateNH4CI ammonium chloriderac-BINAP-Pd-G3 [2'-(amino-KA [l,l'-biphenyl]-2-yl-KC][[2'- (diphenylphosphino)[ 1, 1 '-binaphthalen]-2-yl]diphenylphosphine- KP] (methanesulfonato-KO )- palladiumRuPhos Pd G4 [dicyclohexyl(2’,6'-diisopropoxy-2-biphenylyl)phosphine- KP](methanesulfonatato-K<?)[2'-(methylamino-KAr)-2-biphenylyl- KC2] palladiumSPhos Pd G3 (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino- 1, 1 '-biphenyl)] palladium(II) methanesulfonateTBAF tetrabutylammonium fluorideTFA trifluoroacetic acidTHF tetrahydrofuranSFC Supercritical fluid chromatographyARVN-216-PCT / / ARVN0216WO2Example Q-l.l:Exemplary synthesis of Compound Q-2: 3-[4-chloro-5-[7-[[l-[[l-[[(85)-13-(8-ethyl-7-fluoro-3-hydroxy-l-naphthyl)-14-fluoro-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02, 8.015,19]nonadeca-l(19),ll,13,15,17-pentaen-17-yl]oxymethyl]cyclopropyl]methyl]-4-fluoro-4-piperidyl]methyl]-2,7-diazaspiro[3.5]nonan-2-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dioneStep 1:

[0163] To a mixture of (85’)-13-chloro-14-fluoro-17-methylsulfonyl-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13.15,17-pentaene (2.5 g, 6 mmol) and [l-(hydroxymethyl)cyclopropyl]methanol (1.31 g, 13 mmol) in N, N-dimethylacetamide (40 mL) is added cesium carbonate (6.29 g, 19 mmol), and the mixture is stirred at 25 °C for 1 h. The reaction mixture is diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase is washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (petroleum etherethyl acetate = 10 / 1 to 0 / 1) to afford [l-[[(85)-13-chloro-14-fluoro-6, 10-dioxa-2, 12, 16,18-tetrazatetracy clo [9.7.1.02,8.015,19] nonadeca- 1(19), 11.13, 15, 17 -pentaen- 17 -yl]oxymethyl]cyclopropyl]methanol (1.8 g, 68%) as a yellow solid. MS (ESI) m / z 411.1 [M+H]+; NMR (400 MHz, CDCh) 3 5.26 - 5.16 (m, 1H), 4.67 (dd, J = 13.6, 4.4 Hz, 1H), 4.52 - 4.41 (m. 3H), 4.19 (dd. J = 3.6, 12.8 Hz, 1H), 4.11 - 3.94 (m. 2H), 3.78 - 3.66 (m, 1H), 3.48 - 3.44 (m, 2H), 3.44 - 3.23 (m, 2H), 2.28 - 2.16 (m, 1H), 2.06 - 1.97 (m, 1H), 1.77 - 1.66 (m, 1H), 0.72 - 0.66 (m, 2H), 0.65 - 0.60 (m, 2H).Step 2:ARVN-216-PCT / / ARVN0216WO2

[0164] A mixture of [l-[[(8S)-13-chloro-14-fluoro-6, 10-dioxa-2, 12, 16,18-tetrazatetracy clo [9.7.1.02,8.015,19] nonadeca- 1(19), 11.13, 15, 17 -pentaen- 17 -yl]oxymethyl]cyclopropyl]methanol (900 mg, 2.2 mmol), 2-[8-ethyl-7-fhioro-3-(methoxymethoxy)-l-naphthyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.03 g, 2.9 mmol), potassium phosphate (1.40 g, 6.6 mmol) and cataCXium A Pd G3 (159 mg, 0.2 mmol) in dioxane (20 mL) and water (3 mL) is degassed and purged with nitrogen several times, the mixture is stirred at 90 °C for 12 h under nitrogen atmosphere. The reaction mixture is diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase is washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20 / 1 to 0:1) to afford [l-[[(8S)-13-[8-ethyl-7-fhroro-3-(methoxymethoxy)-l-naphthyl]-14-fluoro-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7. L02,8.015,19]nonadeca-l(19).ll,13,15,17-pentaen-17-yl]oxymethyl]cyclopropyl]methanol (1.05 g, 79%) as a yellow solid. MS (ESI) m / z 609.3 [M+H]+.Step 3:MOMO

[0165] To a solution of [l-[[(85)-13-[8-ethyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-14-fluoro-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-ARVN-216-PCT / / ARVN0216WO21(19), 11,13, 15, 17-pentaen-l7-yl]oxymethyl]cyclopropyl]methanol (1.0 g, 1.6 mmol) in dichloromethane (20 mL) is added l,l-bis(acetyloxy)-3-oxo-3H-lk5,2-benziodaoxol-l-yl acetate (1.05 g. 2.5 mmol) at 0 °C, and the mixture is stirred at 25 °C for 1 h. The reaction mixture is diluted with saturated sodium sulfite solution (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phase is washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford l-[[(8S)-13-[8-ethyl-7-fhioro-3-(methoxymethoxy)-l-naphthyl]-14-fluoro-6,10-dioxa-2,12,16,18-tetrazatetracy clo [9.7.1.02,8.015,19] nonadeca- 1(19), 11, 13, 15, 17 -pentaen- 17 -yl]oxymethyl]cyclopropanecarbaldehyde (990 mg, crude) as a yellow solid, which is used in the next step directly. MS (ESI) m / z'. 607.3 [M+H]+.Step 4:

[0166] To a solution of 3-(4-chloro-5-fluoro-l-oxo-isoindolin-2-yl)piperidine-2, 6-dione (3.13 g, 11 mmol) in dimethyl sulfoxide (35 mL) are added A iisopropylethylamine (9.19 mL, 53 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (3.05 g. 12 mmol). The mixture is stirred at 130 °C for 12 h, then cooled to 25 °C and poured into water (100 mL). The mixture is extracted with ethyl acetate (50 mL x 3) and tetrahydrofuran (50 mL x 3). The combined organic phase is washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC (40%-70% acetonitrile in water (formic acid) over 23 min) to afford tert-butyl 2-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-2,7-diazaspiro[3.5]nonane-7 -carboxylate (3.27 g, 62%) as a gray solid. MS (ESI) m / 503.1 [M+H]+.Step 5:ARVN-216-PCT / / ARVN0216WO2DCM / TFA 25°C, 1h

[0167] To a solution of tert-butyl 2-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (1.91 g, 3.8 mmol) in dichloromethane (20 mL) is added trifluoroacetic acid (6 mL). The mixture is stirred at 25 °C for 1 h, then concentrated under reduced pressure. The residue is triturated with methyl tert-butyl ether (20 mL) at 25 °C to afford 3-[4-chloro-5-(2, 7 -diazaspiro[3.5]nonan-2-yl)-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (1.04 g, 53%, trifluoroacetate salt) as a gray solid. MS (ESI) m / z 403.1 [M+H]+.Step 6:DIEA, NaBH(OAc)3, DCM / DMSO, 25°C

[0168] To a solution of 3-[4-chloro-5-(2,7-diazaspiro[3.5]nonan-2-yl)-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (520 mg, 1 mmol, trifluoroacetate) and A iisopropylethylamine (390 mg, 3 mmol) in dichloromethane (5 mL) and dimethyl sulfoxide (5 mL) are added tert-butyl 4-fluoro-4-formyl-piperidine-l -carboxylate (302 mg, 1.3 mmol) and sodium triacetoxyborohydride (533 mg, 2.5 mmol). The mixture is stirred for 0.5 h, and acetic acid (120 mg, 2 mmol) is added. The reaction mixture is stirred at 25 °C for 11.5 h, then diluted with water (50 mL) and extracted with chloromethane (50 mL x 3). The combined organic phase is washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 4-[[2-[4-chloro-2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin- 5 -yl] -2,7-diazaspiro [3.5] nonan-7-...

Claims

ARVN-216-PCT / / ARVN0216WO2CLAIMS1. A compound having the chemical structure of Formula I:PTM-L-ULM (I)comprising (i) a Kirsten Rat Sarcoma (KRAS) protein targeting moiety (PTM); (ii) a linker (L) comprising a chemical structure -O-CH2-(geminal halocyclopropyl)methyl- (optionally substituted heterocycloalkylene); and (iii) a Cereblon E3 ubiquitin ligase targeting moiety (ULM), in free or salt form.

2. The compound according to claim 1, wherein the PTM comprises a chemical structure 6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-l(19),ll,13,15,17- pentaen-17-yl.

3. The compound according to any of claims 1-2, wherein the compound is a compound of Formula 1(A)’:1(A)’in free or salt form, wherein:Ri and R2 are independently halo (e.g., fluoro);R3 is H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);Rzis H or Ci-4alkyl (e.g., methyl);Moiety A is a 4-12 membered heterocycloalkylene (e.g.. piperidinylene, piperazinylene, 2-azabicyclo[2.

2. l]heptanylene or 3,9-diazaspiro[5,5]undecanylene, hexahydropyrrolo [3,4-c] pyrrolylene);ARVN-216-PCT / / ARVN0216WO2Each of moiety B and moiety C is independently a bond, C(O), S(O)2, O, Ci-4alkylene (e.g., methylene, ethylene or propylene for example prop-2-ylene), C3- ecycloalkylene (e.g., cyclopropylene) or a 4-12 membered heterocycloalkylene (e.g., piperazinylene, piperidinylene, diazepanylene or 2,7- diazaspir 0 [3.5 ] nonanylene);wherein each of moieties A, B and C is independently optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or -OCi-4alkyl (e.g., methoxy);Moiety D is an aryl or a 6-12 membered heterocycloalkyl, each optionally substituted with one or more hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl), Ci-4haloalkyl (e.g., difluoromethyl), -OCi-4alkyl (e.g., methoxyl or ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl); andULM is selected from:ARVN-216-PCT / / ARVN0216WO2ULM-11 ULM-12 OULM-13 ULM-13-X ULM-15andwherein:R4a is H or Ci-4alkyl (e.g., methyl);R4bis H or halo (e.g., fluoro):Rs is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;R9 is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy (e.g., methoxy);Riox is Ci-4alkyl (e.g., methyl);Qi, Q10 and Qu are independently C(O) or C(Ra)(Rb);Raand Rb are independently H or Ci-4alkyl (e.g., methyl);R11 is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl) or Ci-4alkoxy; Ri3Xis Ci- alkyl (e.g.. methyl);Q12 is O;R14 is H or Ci-4alkyl (e.g., methyl);ARVN-216-PCT / / ARVN0216WO2Ri4b is H or Ci-4alkyl (e.g., methyl);R15 is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;Ri6 and Ris are independently H or Ci-4alkyl (e.g., methyl); or-A-B-C together with the ULM forms any of the following structure:Formula J Formula K wherein R17 is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy.

4. The compound according to any of claims 1-2, wherein the compound is a compound of Formula 1(A):KA)in free or salt form, wherein:Ri and R2 are independently halo (e.g. fluoro);R3 is H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);ARVN-216-PCT / / ARVN0216WO2Moiety A is a 4-12 membered heterocycloalkylene (e.g., piperidinylene, piperazinylene, 3,9-diazaspiro[5,5]undecanylene, or hexahydropyrrolo[3,4-c]pyrrolylene);Each of moiety B and moiety C is independently a bond. Ci-4alkylene (e.g., methylene), or a 4-12 membered heterocycloalkylene (e.g., piperazinylene, piperidinylene, or 2,7-diazaspir 0 [3.5] nonanylene);wherein each of moieties A, B and C is independently optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or -OCi-4alkyl (e.g., methoxy);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), Ci-4haloalkyl (e.g., difluoromethyl), -OCi-4alkyl (e.g., methoxyl or ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl); and ULM is selected from:wherein:Rs is H, halo (e.g., chloro or fluoro), Ci alkyl (e.g., methyl), OH, or Ci-4alkoxy;R9 is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy;Qi and Q10 are independently C(O) or C(Ra)(Rb);Raand Rb are H;Q12 is O;R14 is H or Ci-4alkyl (e.g., methyl);R15 is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy; or-A-B-C together with the ULM forms any of the following structure:ARVN-216-PCT / / ARVN0216WO2Formula J Formula K wherein Rn is H, halo (e.g., fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy.

5. The compound according to claim 3 or 4, wherein the compound is a compound of Formula 1(A)’ -1(a) or 1(A)’ -1(b):ARVN-216-PCT / / ARVN0216WO2Formula T(A)’-1 (a), orULMFormula 1(A)’ -1(b).in free or salt form.

6. The compound according to any of claims 3-5, wherein the compound is a compound of Formula I(A)’-l(a)’ or I(A)’-l(b)’:C - ULMARVN-216-PCT / / ARVN0216WO2, C - ULM Bor Formula I(A)’-l(b)’in free or salt form.

7. The compound according to any of claims 3-6, wherein the compound is a compound of Formula 1(A)- 1(a) or Formula 1(A)- 1(b):Formula 1(A)- 1(a)orARVN-216-PCT / / ARVN0216WO2Formula 1(A)- 1(b)in free or salt form.

8. The compound according to any of claims 3-7, wherein moiety A is selected from:

9. The compound according to any of claims 3-8, wherein moiety B is a bond, C(O), S(O)2, O, C3-6cycloalkylene (e.g., cyclopropylene) or Ci-4alkylene (e.g., methylene).

10. The compound according to any of claims 3-9, wherein moiety C is a bond or a 4-12 membered heterocycloalkylene (e.g., piperazinylene, piperidinylene, diazepanylene or 2,7-diazaspiro[3.5]nonanylene), each optionally substituted with one or more hydroxy, halo, Ci-4alkyl (e.g., methyl) or -OCi-4alkyl (e.g., methoxy).

11. The compound according to any of claims 3-9, wherein moiety C is selected from a bond and:ARVN-216-PCT / / AR VN0216WO212. The compound according to any of claims 3-11, wherein -A-B-C- is:ARVN-216-PCT / / ARVN0216WO213. The compound according to any one of claims 3-12, wherein D has the chemical structure of Formula D- 1:wherein:each of R4, Rs and Re is independently H, hydroxy, halo (e.g. fluoro or chloro), Ci-4alkyl (e.g., methyl or ethyl) Ci-4haloalkyl (e.g., difluoromethyl), -OCi-4alkyl (e.g., methoxyl orARVN-216-PCT / / ARVN0216WO2ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl); and Rsais Ci-4alkyl (e.g., ethyl).

14. The compound according to any of claims 3-13, wherein the ULM is selected from:ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / ARVN0216WO2ARVN-216-PCT / / AR VN0216WO215. The compound according to any of claims 3-13, wherein A-B-C together with the ULM- forms any of the following structure:ARVN-216-PCT / / ARVN0216WO2Formula J or Formula Kwherein R17 is H or halo (e.g., fluoro).

16. The compound according to claim 15, wherein -A-B-C together with the UML forms the following:Formula K17. The compound according to any of claims 1-16, wherein the compound is selected from Compounds 1-26 of Table 1 or Compounds 27-155 of Table 1-A, in free or salt form.

18. A pharmaceutical composition comprising the compound according to any one of claims 1-17, in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable earner.

19. 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 1-17, in free or pharmaceutically acceptable salt form, or the pharmaceutical composition according to claim 18.ARVN-216-PCT / / ARVN0216WO220. 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 1-17, in free or pharmaceutically acceptable salt form, or the pharmaceutical composition according to claim 18.

21. The method according to claim 19 or 20, wherein the KRAS-mediated disease or disorder is cancer.

22. The method according to claim 21, 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.

23. The method according to claim 21, wherein cancer is pancreatic cancer, colorectal cancer or lung cancer.

24. The method according to claim 21, wherein the cancer is pancreatic ductal adenocarcinoma, non-small cell lung cancer, non-squamous non-small cell lung cancer or non-squamous colorectal cancer.

25. 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 1-17, in free or salt form, or the pharmaceutical composition of claim 18, wherein the compound effectuates the degradation of the KRAS target protein.

26. A compound of Formula Q-I(A):ARVN-216-PCT / / ARVN0216WO2in free or salt form, wherein:R3 is H, Ci-4alkyl (e.g., methyl) or halo (e.g. fluoro or chloro);Moiety A is a 4-12 membered heterocycloalkylene (e.g., piperidinylene or piperazinylene);Each of moiety B and moiety C is independently a bond, Ci-4alkylene (e.g., methylene), or a 4-12 membered heterocycloalkylene (e.g., piperazinylene, piperidinylene or 2,7-diazaspiro[3.5]nonanylene);wherein each of moieties A, B and C is independently optionally substituted with one or more halo, hydroxy, Ci-4alkyl (e.g., methyl) or OCi-4alkyl (e.g., methoxy); 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) Ci-4haloalkyl (e.g., difluoromethyl), -OCi-4alkyl (e.g., methoxyl or ethoxy), -OCi-4haloalkyl (e.g., difluoromethoxy), or C2-4alkynyl (e.g., ethynyl); andULM is:ULM-1wherein:Rs is H, halo (e.g., chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy; R9 is H, halo (e.g.. chloro or fluoro), Ci-4alkyl (e.g., methyl), OH, or Ci-4alkoxy; Q₁ is C(Rₐ)(Rb) or C=O; andRₐ and Rbare H.ARVN-216-PCT / / ARVN0216WO227. The compound according to claim 26, wherein the compound is selected from Compounds Q-l TO Q-4 of Table Q-l or Compounds Q-6 to Q-ll of Table Q-l-A, in free or salt form.

28. A pharmaceutical composition comprising the compound according to any one of claims 26-27, 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 26-27, in free or pharmaceutically acceptable salt form, or the pharmaceutical composition according to claim 28.

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