Compounds useful in the treatment of KRAS mediated disorders

Abstract

Provided herein are compounds (e.g., compounds of Formula (I)) that target KRas and are thus useful in the treatment of cancer.

Description

[0001] COMPOUNDS USEFUL IN THE TREATMENT OF KRAS MEDIATED DISORDERS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Application Serial No. 63 / 515,724 filed July 26, 2023, which is incorporated herein by reference in its entirety.

[0004] BACKGROUND

[0005] 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 act as switches in the transduction of extracellular signals to intracellular response, thereby regulating processed such as, e.g., cell division. 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. Key roles for mutant KRas have been established in initiation, maintenance, progression, and metastasis of various cancers, and mutations are frequently correlated with poor prognosis and increased resistance to chemotherapy and biological therapies, including, e.g., therapies that target epidermal growth factor receptor. However, despite its key role and high prevalence in cancer, there is an absence of effective therapies that directly target this oncogene, leading to it being considered “undruggable.”

[0006] Thus, an ongoing need exists in the art for effective treatments for disease associated with overexpression, aggregation, and / or overactivation of KRas.

[0007] SUMMARY

[0008] Provided herein are hetero-bifunctional compounds that function to recruit a KRas protein or mutated version thereof, to an E3 ubiquitin ligase for targeted ubiquitination and subsequent proteasomal degradation. Such compounds include those having the chemical structure:

[0009] PTM— Li— VLM wherein:

[0010] PTM is a KRas targeting moiety, VLM is a Von-Hipple E3 ubiquitin ligase binding moiety, and Li is a chemical linking moiety covalently coupling the VLM to the PTM. Pharmaceutical compositions comprising these hetero-bifunctional compounds, methods for their preparation, and methods for treating KRas related conditions using the disclosed hetero-bifunctional compounds are also included.

[0011] Methods of treating conditions responsive to the modulation of Kras using the disclosed hetero-bifunctional compounds, pharmaceutically acceptable salts, and compositions thereof are also included.

[0012] In an embodiment, the hetero-bifunctional compounds provided herein are useful in the treatment of KRas-mediated disorders including cancer.

[0013] In an embodiment, the hetero-bifunctional compounds provided herein are useful in the treatment of cancer characterized by a KRas G12D mutation.

[0014] In an embodiment, provided herein are compounds having the chemical structure of (i):

[0015] PTM-Li-VLM; (i) or a pharmaceutically acceptable salt thereof, wherein:

[0016] (a) PTM is a small molecule Kirsten rat sarcoma (KRAS) targeting moiety such as e.g., one represented by the chemical structure: wherein:

[0017] R is H or OH;

[0018] R1is C1-6 alkyl or C=CH;

[0019] R2and R3aare each independently H or halo;

[0020] R3is 3-10 membered heterocyclyl; and

[0021] ■'wv is the point of attachment to the chemical linking moiety (Li);

[0022] (b) Li is a chemical linking moiety covalently coupling the VLM to the PTM, represented by the chemical structure: wherein: L is selected from -00-6 alkyl, 5-10 membered heterocyclyl, and -OCi-6 alkyl-(3-10 membered heterocyclyl)O-, wherein the -6 alkyl and heterocyclyl are optionally substituted with 0-6 alkyl or C3-6 cycloalkyl;

[0023] Q and Q1are each independently selected from CH and N;

[0024] X is absent, CH2, or O;

[0025] Ring A is absent, 3-5 membered heterocyclyl, or 6-10 membered heterocyclyl substituted with halo; and is the point of attachment to the PTM or the VHL; and

[0026] (c) VHL is a Von-Hipple E3 ubiquitin ligase binding moiety, represented by the chemical structure: wherein:

[0027] R4, R5, and R6are each independently selected from H, OH, and C1-6 alkyl;

[0028] R7is C1-6 alkyl; and is the point of attachment to the chemical linking moiety (Li).

[0029] In an embodiment, provided herein are compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein

[0030] Q and Q1are each independently selected from CH and N;

[0031] X is absent, CH2, or O; R is H or OH;

[0032] R1is C1-6 alkyl or C=CH;

[0033] R2and R3aare each independently H or halo;

[0034] R3is 3-10 membered heterocyclyl;

[0035] R4, R5, and R6are each independently selected from H, OH, and C1-6 alkyl;

[0036] R7is C1-6 alkyl;

[0037] Ring A is absent, 3-5 membered heterocyclyl, or 6-10 membered heterocyclyl substituted with halo; and

[0038] L is selected from -OC1-6 alkyl, 5-10 membered heterocyclyl, and -OCi-6 alkyl-(3-10 membered heterocyclyl)O-, wherein the C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl, provided that: when Ring A is absent, L is 5-10 membered heterocyclyl or -OCi-6 alkyl-(3-10 membered heterocyclyl)O-; when X is absent, Ring A is absent; when R2is H and L is -OC1-6 alkyl, then the C1-6 alkyl of L is substituted with C1-6 alkyl or C3-6 cycloalkyl; when X is CH2, R is OH, R2is halo, L is -OC1-6 alkyl, and Ring A is a 3-5 membered heterocyclyl, then R3is a 3-7 membered heterocyclyl; when X is O, then R2is halo and R4is chiral, wherein the absolute stereochemistry is in the S configuration.

[0039] In an embodiment, R3in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an 8-membered bridged heterocyclyl; and R5is OH.

[0040] Also provided herein are compounds of Formula (A): or a pharmaceutically acceptable salt thereof, wherein:

[0041] Q and Q1are each independently selected from CH and N;

[0042] R is H or OH;

[0043] R1is C1-3 alkyl or C=CH;

[0044] R2and R3aare each independently H or halo;

[0045] R3is

[0046] Y is NR3cor C1-3 alkylene;

[0047] R3cis H or C1-3 alkyl;

[0048] R4and R6are each independently selected from H, OH, and C1-3 alkyl;

[0049] R7is C1-3 alkyl;

[0050] X is C1-3 alkylene or O;

[0051] Ring A is selected from azetidinyl, pyrrolidinyl, piperazinyl, and piperidinyl, wherein azetidinyl, pyrrolidinyl, piperazinyl, and piperidinyl are each optionally substituted with halo; and

[0052] L is selected from -OC1-6 alkyl, 5-6-membered heterocyclyl, and -OC1-6 alkyl-(5— 6- membered heterocyclyl)O-, wherein C1-6 alkyl and 5-6-membered heterocyclyl are each optionally substituted with C1-3 alkyl or C3-6 cycloalkyl.

[0053] In another embodiment provided herein are compounds of Formula (Al): or a pharmaceutically acceptable salt thereof, wherein:

[0054] Q and Q1are each independently selected from CH and N; R is H or OH; R1is C1-3 alkyl or C=CH;

[0055] R2and R3aare each independently H or halo;

[0056] R3is

[0057] Y is NR3cor C1-3 alkylene;

[0058] R3cis H or C1-3 alkyl;

[0059] R4and R6are each independently selected from H, OH, and C1-3 alkyl;

[0060] R7is C1-3 alkyl;

[0061] Ring A is selected from azetidinyl, pyrrolidinyl, piperazinyl, and piperidinyl, wherein azetidinyl, pyrrolidinyl, piperazinyl, and piperidinyl are each optionally substituted with halo; and

[0062] L is selected from -OC1-6 alkyl, 5-6-membered heterocyclyl, and -OC1-6 alkyl-(5— 6- membered heterocyclyl)O-, wherein C1-6 alkyl and 5-6-membered heterocyclyl are each optionally substituted with C1-3 alkyl or C3-6 cycloalkyl.

[0063] In an embodiment, Q in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is N; and Q1is CH.

[0064] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is optionally substituted with halo, wherein the halo is F or Cl.

[0065] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is optionally substituted with halo, wherein the halo is F.

[0066] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is azetidinyl.

[0067] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is piperidinyl optionally substituted with halo.

[0068] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is piperidinyl substituted with halo.

[0069] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is piperidinyl optionally substituted with F.

[0070] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is piperidinyl optionally substituted with Cl.

[0071] In an embodiment, R6in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is methyl. In an embodiment, R7in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is methyl.

[0072] The compounds disclosed herein include:

[0073] or a pharmaceutically acceptable salt thereof.

[0074] Also provided herein are pharmaceutical compositions comprising the compounds described herein, and a pharmaceutically acceptable carrier.

[0075] Further, disclosed herein are methods of treating cancer, comprising administering to a subject an effective amount of any of the compounds disclosed herein, or an effective amount of any of the pharmaceutical compositions disclosed herein.

[0076] Also provided herein are methods of degrading a target protein in a cell comprising contacting the cell with an effective amount of any of the compounds disclosed herein or any of the pharmaceutical compositions disclosed herein.

[0077] DETAILED DESCRIPTION

[0078] Provided herein are hetero-bifunctional compounds that function to recruit a KRas protein or mutated version thereof, to an E3 ubiquitin ligase for targeted ubiquitination and subsequent proteasomal degradation.

[0079] Pharmaceutical compositions comprising these hetero-bifunctional compounds, methods for their preparation, and methods for treating KRas related conditions using the disclosed hetero-bifunctional compounds are also included.

[0080] Methods of treating conditions responsive to the modulation of Kras using the disclosed hetero-bifunctional compounds, pharmaceutically acceptable salts, and compositions thereof are also included.

[0081] In an embodiment, the hetero-bifunctional compounds provided herein are useful in the treatment of KRas-mediated disorders including cancer.

[0082] In an embodiment, the hetero-bifunctional compounds provided herein are useful in the treatment of cancer characterized by a KRas G12D mutation.

[0083] In an embodiment, provided herein are compounds (e.g., compounds of Formula (I)) that target KRas and are thus useful in the treatment of KRas-related diseases, such as cancer. In an embodiment, the cancer is characterized by a KRas G12D mutation.

[0084] Definitions

[0085] 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.

[0086] 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.

[0087] 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.

[0088] As used herein, the articles “a” and “an” refer to one or to more than one ( / .e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0089] 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.

[0090] 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 the symptoms of cancer.

[0091] As used herein, the term “prevent” or “prevention” 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.

[0092] 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.

[0093] As used herein, the term “subject” refers to a human or a non-human mammal. Nonhuman mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and marine mammals. Preferably the subject is human.

[0094] 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. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0095] As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate 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.

[0096] 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 nontoxic 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.

[0097] 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.

[0098] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the subject such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not injurious to the subject. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as 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. 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. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound disclosed herein. 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.

[0099] 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 ( / .e., C1-6 alkyl means an alkyl having one to six carbon atoms) and includes straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, pentyl, neopentyl, and hexyl. Other examples of C1-6 alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0100] 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.

[0101] As used herein, the term “cycloalkyl” means a non-aromatic carbocyclic system that is fully saturated having 1 , 2, or 3 rings wherein such rings may be fused. The term “fused” means that a second ring is present ( / .e., attached or formed) by having two adjacent atoms in common ( / .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. The term “cycloalkyl” includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1 .0]hexyl, spiro[3.3]heptanyl, and bicyclo[1.1.1]pentyl. In embodiments, cycloalkyl refers to C3-10 cycloalkyl. In another embodiment, cycloalkyl refers to C3-6 cycloalkyl.

[0102] As used herein, the term “heterocyclyl” means a non-aromatic carbocyclic system containing 1 , 2, 3, or 4 heteroatoms independently selected from N, O, and S and having 1 , 2, or 3 rings wherein such rings may be fused, wherein fused is defined above. The term “heterocyclyl” includes unsaturated compounds such as dihydropyridinyl, dihydropyridazinyl, dihydropyrimidinyl, and dihydropyrazinyl. Heterocyclyl also includes bicyclic structures that may be bridged or spirocyclic in nature with each individual ring within the bicycle varying from 3-8 atoms, and containing 0, 1 , or 2 N, O, or S atoms. The term “heterocyclyl” includes cyclic esters ( / .e., lactones) and cyclic amides ( / .e., lactams) and also specifically includes, but is not limited to, epoxidyl, oxetanyl, tetrahydro-furanyl, tetrahydropyranyl ( / .e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1 H-pyrrolyl, oxazolidinyl, thiazolidinyl , piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1 ,3-oxazinanyl, 1 ,3- thiazinanyl, 2-azabicyclo[2.1 .1]hexanyl, 5-azabicyclo[2.1.1]-hexanyl, 6-azabicyclo[3.1.1] heptanyl, 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2- azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, 3- oxa-9-azabicyclo[3.3.1]nonanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3- azabicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2- oxaspiro[3.3]heptanyl, 2-oxaspiro[3.5]nonanyl, 3-oxaspiro[5.3]nonanyl, and 8- oxabicyclo[3.2.1]octanyl. In embodiments, heterocyclyl refers to 3-10 membered heterocyclyl. In embodiments, heterocyclyl refers to 5-10 membered heterocyclyl. In embodiments, heterocyclyl refers to 6-10 membered heterocyclyl. In embodiments, heterocyclyl refers to 5-8 membered heterocyclyl. In embodiments, heterocyclyl refers to 6- 8 membered heterocyclyl. In embodiments, heterocyclyl refers to 3-7 membered heterocyclyl. In embodiments, heterocyclyl refers to 3-5 membered heterocyclyl. In embodiments, heterocyclyl refers to 4-membered heterocyclyl. In embodiments, heterocyclyl refers to 5-membered heterocyclyl. In embodiments, heterocyclyl refers to 6-membered heterocyclyl. In embodiments, heterocyclyl refers to 7-membered heterocyclyl. In embodiments, heterocyclyl refers to 8-membered heterocyclyl.

[0103] A 6-membered heterocyclyl ring is a heterocyclyl group having six ring atoms wherein one or more (e.g., 1 , 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 6-membered ring heterocyclyls include piperidinyl, piperazinyl, dioxanyl thianyl, dithianyl, morpholinyl, thiomorpholinyl, and dihydropyridinyl.

[0104] A 7-membered heterocyclyl ring is a heterocyclyl group having seven ring atoms wherein one or more (e.g., 1 , 2, or 3) ring atoms are independently selected from N, O and S. Exemplary 7-membered ring heterocyclyls include azepinyl, oxepanyl, thiepanyl, oxathiepanyl, diazaspiro[3.3]heptanyl, and azaspiro[3.3]heptanyl.

[0105] As used herein, the term “bridged” refers to two rings that share at least three adjacent atoms with one another. Non-limiting examples of bridged moieties include bicyclo[1 .1 .1]pentyl, bicyclo[2.2.1]heptanyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octanyl, and (1S,5R)-3,8-diazabicyclo[3.2.1]octanyl. In an embodiment, 8-membered bridged heterocyclyl is (1R,5S)-3,8-diazabicyclo[3.2.1]octanyl. In an embodiment, 8-membered bridged heterocyclyl is (1S,5R)-3,8-diazabicyclo[3.2.1]octanyl.

[0106] It is to be understood that if a cycloalkyl or heterocyclyl moiety may be bonded or otherwise attached to a designated moiety through differing ring atoms ( / .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. 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).

[0107] As used herein, the term “optionally substituted” means that one or more hydrogens of the designated moiety may be replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group as valency permits. Optional substituents include, but are not limited to, one or more of the following groups selected from cyano (-CN), halo, imino -NR'S(0)2Riv, -NR'S(O)NRiiRiii,-SRi, -S(0)R, -S(0)2R, -S(0)NRiiRiv, -S(0)2NRiiRiv, alkyl, heteroalkyl, alkenyl, and alkynyl, wherein said alkyl, heteroalkyl, alkenyl, and alkynyl are each further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa, wherein each R', R", R'", and Rivis independently alkyl, heteroalkyl, alkenyl, and alkynyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qaor R" and R'" together with the N atom to which they are attached form heterocyclyl optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa, wherein each Qais independently selected from cyano, halo, imino, nitro, oxo, alkyl, heteroalkyl, alkenyl, alkynyl, -C(O)RV, - C(0)0Rv, -C(0)NRviRvii, -C(O)SRV, -C(NRv)NRviRvii, -C(S)RV, -C(S)ORV, -C(S)NRviRvii, - ORV, -0C(0)Rv, -0C(0)0Rv, -0C(0)NRviRvii, -0C(0)SRv, -0C(NRv)NRviRvii, -OC(S)RV, - 0C(S)0Rv, -0C(S)NRviRvii, -0S(0)Rv, -0S(0)2Rv, -0S(0)NRviRvii, -0S(0)2NRvRvii, - NRviRvii, -NRvC(0)Rviii, -NReC(0)0Rvi, -NRvC(0)NRviRvii, -NRvC(0)SRvi, - NRvC(NRviii)NRviRvii, -NRvC(S)Rviii, -NRvC(S)0Rvi, -NRvC(S)NRviRvii, -NRvS(0)Rviii, - NRvS(0)2Rviii, -NRvS(0)NRviRvii, -NRvS(0)2NRviRvii, -SRV, -S(O)RV, -S(O)2RV, -S(0)NRviRvii, and -S(0)2NRviRvii; wherein each Rv, Rvi, Rvii, and Rviiiis independently alkyl, alkenyl, or alkynyl; or (iii) Rviand Rviiitogether with the N atom to which they are attached form heterocyclyl.

[0108] Compounds

[0109] Provided herein are compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0110] Q and Q1are each independently selected from CH and N;

[0111] X is absent, CH2, or O;

[0112] R is H or OH;

[0113] R1is C1-6 alkyl or C=CH;

[0114] R2and R3aare each independently H or halo;

[0115] R3is 3-10 membered heterocyclyl;

[0116] R4, R5, and R6are each independently selected from H, OH, and C1-6 alkyl;

[0117] R7is C1-6 alkyl;

[0118] Ring A is absent, 3-5 membered heterocyclyl, or 6-10 membered heterocyclyl substituted with halo; and

[0119] L is selected from -OC1-6 alkyl, 5-10 membered heterocyclyl, and -OCi-6 alkyl-(3-10 membered heterocyclyl)O-, wherein the C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl, provided that: when Ring A is absent, L is 5-10 membered heterocyclyl or -OCi-6 alkyl-(3-10 membered heterocyclyl)O-; when X is absent, Ring A is absent; when R2is H and L is -OC1-6 alkyl, then the C1-6 alkyl of L is substituted with C1-6 alkyl or C3-6 cycloalkyl; when X is CH2, R is OH, R2is halo, L is -OC1-6 alkyl, and Ring A is a 3-5 membered heterocyclyl, then R3is a 3-7 membered heterocyclyl; when X is O, then R2is halo and R4is chiral, wherein the absolute stereochemistry is in the S configuration.

[0120] In an embodiment, R3in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an 8-membered bridged heterocyclyl; and R5is OH. In an embodiment, X in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is absent; Ring A is absent; and L is -OCi-3 alkyl-(5-6-membered heterocyclyl)O-, wherein 5-6-membered heterocyclyl is optionally substituted with C1-3 alkyl.

[0121] In an embodiment, X in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is absent; Ring A is absent; and L is -OCi-3 alkyl-(5-membered heterocyclyl )O-, wherein 5-membered heterocyclyl is optionally substituted with C1-3 alkyl.

[0122] In an embodiment, R2in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is H and L is -OC1-6 alkyl, wherein C1-6 alkyl is substituted with C1-3 alkyl or C3-6 cycloalkyl.

[0123] In an embodiment, R2in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is H and L is -OC1-6 alkyl, wherein C1-6 alkyl is substituted with C1-3 alkyl or C3-4 cycloalkyl

[0124] In an embodiment, R2in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R2is H and L is -OC1-6 alkyl, wherein C1-6 alkyl is substituted with CH3 or cyclopropyl.

[0125] In an embodiment, X in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is O; R2is H or halo; and R4is OH or C1-3 alkyl, wherein the absolute stereochemistry of R4is in the R configuration.

[0126] In another embodiment provided herein are compounds of Formula (A): or a pharmaceutically acceptable salt thereof, wherein:

[0127] Q and Q1are each independently selected from CH and N;

[0128] R is H or OH;

[0129] R1is C1-3 alkyl or C=CH;

[0130] R2and R3aare each independently H or halo;

[0131] R3is

[0132] Y is NR3cor C1-3 alkylene;

[0133] R3cis H or C1-3 alkyl;

[0134] R4and R6are each independently selected from H, OH, and C1-3 alkyl;

[0135] R7is C1-3 alkyl;

[0136] X is C1-3 alkylene or O;

[0137] Ring A is selected from azetidinyl, pyrrolidinyl, piperazinyl, and piperidinyl, wherein azetidinyl, pyrrolidinyl, piperazinyl, and piperidinyl are each optionally substituted with halo; and

[0138] L is selected from -OC1-6 alkyl, 5-6-membered heterocyclyl, and -OC1-6 alkyl-(5— 6- membered heterocyclyl)O-, wherein C1-6 alkyl and 5-6-membered heterocyclyl are each optionally substituted with C1-3 alkyl or C3-6 cycloalkyl.

[0139] In another embodiment provided herein are compounds of Formula (Al): or a pharmaceutically acceptable salt thereof, wherein:

[0140] Q and Q1are each independently selected from CH and N;

[0141] R is H or OH;

[0142] R1is C1-3 alkyl or C=CH;

[0143] R2and R3aare each independently H or halo;

[0144] R3is Y is NR3cor C1-3 alkylene;

[0145] R3cis H or C1-3 alkyl;

[0146] R4and R6are each independently selected from H, OH, and C1-3 alkyl;

[0147] R7is C1-3 alkyl;

[0148] Ring A is selected from azetidinyl, pyrrolidinyl, piperazinyl, and piperidinyl, wherein azetidinyl, pyrrolidinyl, piperazinyl, and piperidinyl are each optionally substituted with halo; and

[0149] L is selected from -OC1-6 alkyl, 5-6-membered heterocyclyl, and -OC1-6 alkyl-(5— 6- membered heterocyclyl)O-, wherein C1-6 alkyl and 5-6-membered heterocyclyl are each optionally substituted with C1-3 alkyl or C3-6 cycloalkyl.

[0150] In an embodiment, Q in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is N; and Q1is CH.

[0151] In an embodiment, Ring A of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is selected from azetidinyl, pyrrolidinyl, and piperidinyl, wherein azetidinyl, pyrrolidinyl, and piperidinyl are each optionally substituted with halo.

[0152] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is optionally substituted with halo, wherein the halo is F or Cl.

[0153] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is optionally substituted with halo, wherein the halo is F.

[0154] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is azetidinyl.

[0155] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is azetidinyl; R2is H or halo; and L is selected from -OC1-6 alkyl, 5-6-membered heterocyclyl, and -OC1-6 alkyl-(5-6-membered heterocyclyl )O-, wherein C1-6 alkyl is substituted with C1-3 alkyl or C3-6 cycloalkyl.

[0156] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is azetidinyl; R2is H or halo; and L is selected from -OC1-3 alkyl, 5-membered heterocyclyl, and -OCi-3 alkyl-(5-membered heterocyclyl )O-, wherein C1-3 alkyl is substituted with CH3 or cyclopropyl.

[0157] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is azetidinyl; L is -OC1-6 alkyl; and R is H.

[0158] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is azetidinyl; L is -OC1.3 alkyl; and R is H.

[0159] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is piperidinyl optionally substituted with halo. In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is piperidinyl optionally substituted with F.

[0160] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is piperidinyl optionally substituted with Cl.

[0161] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is piperidinyl substituted with halo.

[0162] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is piperidinyl substituted with F.

[0163] In an embodiment, Ring A in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is piperidinyl substituted with Cl.

[0164] In an embodiment, R3ain the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is halo.

[0165] In an embodiment, R3ain the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is Cl or F.

[0166] In an embodiment, R3ain the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is Cl.

[0167] In an embodiment, R3ain the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is F.

[0168] In an embodiment, R4and R6in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, are each independently selected from H and C1-3 alkyl;

[0169] In an embodiment, R6in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is methyl.

[0170] In an embodiment, R7in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is methyl.

[0171] In an embodiment, L in the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is selected from -OC1.3 alkyl, 5-membered heterocyclyl, and -OCi-3 alkyl-(5-membered heterocyclyl)O-, wherein C1-3 alkyl is optionally substituted with CH3 or cyclopropyl and 5-membered heterocyclyl is optionally substituted with C1-3 alkyl.

[0172] In embodiments, the compound of Formula (I) is a compound of Formula (IA): or a pharmaceutically acceptable salt thereof.

[0173] In embodiments of Formulae (I) and (IA),

[0174] Q and Q1are each independently selected from CH and N, provided that only one of Q and Q1is N;

[0175] X is absent, CH2, or O;

[0176] R is H or OH;

[0177] R1is C1-6 alkyl or C=CH;

[0178] R2is H or halo;

[0179] R3ais halo;

[0180] R3is a 5-8 membered heterocyclyl;

[0181] R4, R5, and R6are each independently selected from H, OH, and C1-6 alkyl;

[0182] R7is C1-6 alkyl;

[0183] Ring A is absent, 3-5 membered heterocyclyl, or 6-10 membered heterocyclyl substituted with halo; and

[0184] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl.

[0185] In embodiments of Formulae (I) and (IA),

[0186] Q and Q1are each independently selected from CH and N, provided that only one of Q and Q1is N;

[0187] X is absent, CH2, or O;

[0188] R is H or OH;

[0189] R1is C1-3 alkyl or C=CH;

[0190] R2is H or halo;

[0191] R3ais halo;

[0192] R3is a 6-8 membered heterocyclyl;

[0193] R4and R6are each independently H or C1-3 alkyl; R5is OH;

[0194] R7is C1-3 alkyl;

[0195] Ring A is absent, 3-5 membered heterocyclyl, or 6-8 membered heterocyclyl substituted with halo; and

[0196] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl.

[0197] In embodiments of Formulae (I) and (IA), R3ais F.

[0198] In embodiments, the compound of Formula (I) or (IA) is a compound of Formula (II): or a pharmaceutically acceptable salt thereof.

[0199] In embodiments of Formula (II),

[0200] X is CH2 or O; and

[0201] R is H or OH;

[0202] R1is C1-6 alkyl or C=CH;

[0203] R2is H or halo;

[0204] R3is a 5-8 membered heterocyclyl;

[0205] R4, R5, and R6are each independently selected from H, OH, and C1-6 alkyl;

[0206] R7is C1-6 alkyl;

[0207] Ring A is 3-5 membered heterocyclyl or 6-8 membered heterocyclyl substituted with halo; and

[0208] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl.

[0209] In embodiments of Formula (II),

[0210] X is CH2 or O;

[0211] R is H or OH;

[0212] R1is C1-3 alkyl or C=CH; R2is H or halo;

[0213] R3is a 6-8 membered heterocyclyl;

[0214] R4and R6are each independently selected from H, and C1-3 alkyl;

[0215] R5is OH;

[0216] R7is C1-3 alkyl;

[0217] Ring A is 3-5 membered heterocyclyl or 6-8 membered heterocyclyl substituted with halo; and

[0218] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl.

[0219] In embodiments of Formula (l)-(ll), Ring A is a 4-5 membered heterocyclyl or 6 membered heterocyclyl substituted with halo.

[0220] In embodiments of Formula (A) and Formula (Al), Ring A is selected from: wherein:

[0221] RAis halo.

[0222] In embodiments of Formula (A) and Formula (Al), Ring A is: wherein RAis halo.

[0223] In embodiments of Formula (A) and Formula (Al), Ring A is:

[0224] In embodiments of Formula (A) and Formula (Al), Ring A is: wherein RAis halo.

[0225] In embodiments of Formula (A) and Formula (Al), RAis F. In embodiments of Formula (A) and Formula (Al), R6is C1-3 alkyl. In embodiments of Formula (A) and Formula (Al), R6is CH3. In embodiments of Formula (A) and Formula (Al), R7is C1-3 alkyl. In embodiments of Formula (A) and Formula (Al), R7is CH3.

[0226] In embodiments of Formula (l)-(ll), Ring A is selected from: wherein:

[0227] RAis halo.

[0228] In embodiments of Formula (l)-(ll), Ring A is: wherein RAis halo.

[0229] In embodiments, Ring A is:

[0230] In embodiments, Ring A is: wherein RAis halo.

[0231] In embodiments, RAis F.

[0232] In embodiments, the compound of Formula (I) or (IA) is a compound of Formula (III): (Ill) or a pharmaceutically acceptable salt thereof.

[0233] In embodiments of Formula (III),

[0234] R1is C1-6 alkyl or C=CH;

[0235] R2is H or halo;

[0236] R3is a 5-8 membered heterocyclyl;

[0237] R4, R5, and R6are each independently selected from H, OH, and C1-6 alkyl;

[0238] R7is C1-6 alkyl; and

[0239] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl.

[0240] In embodiments of Formula (III),

[0241] R1is C1-3 alkyl or C=CH;

[0242] R2is H or halo;

[0243] R3is a 6-8 membered heterocyclyl;

[0244] R4and R6are each independently selected from H, and C1-3 alkyl;

[0245] R5is OH;

[0246] R7is C1-3 alkyl; and

[0247] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl.

[0248] In embodiments of Formulae (l)-(lll), R5is OH.

[0249] In embodiments of Formulae (l)-(lll), R6is C1-3 alkyl. In embodiments of Formulae (I)- (III), R6is CH3.

[0250] In embodiments of Formulae (l)-(lll), R7is C1-3 alkyl. In embodiments of Formulae (I)- (III), R7is CH3.

[0251] In embodiments, the compound of Formulae (l)-(ll) is a compound of Formula (IVA): or a pharmaceutically acceptable salt thereof.

[0252] In embodiments of Formula (IVA),

[0253] X is CH2 or O;

[0254] R is H or OH;

[0255] R1is C1-6 alkyl or C=CH;

[0256] R2is H or halo;

[0257] R3is a 5-8 membered heterocyclyl;

[0258] R4is selected from H, OH, and C1-6 alkyl; and

[0259] L is selected from -00-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein -6 alkyl and heterocyclyl are optionally substituted with

[0260] C1-6 alkyl or C3-6 cycloalkyl.

[0261] In embodiments of Formula (IVA), X is CH2 or O;

[0262] R is H or OH;

[0263] R1is C1-3 alkyl or C=CH;

[0264] R2is H or halo;

[0265] R3is a 6-8 membered heterocyclyl;

[0266] R4is selected from H, and C1-3 alkyl; and

[0267] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl.

[0268] In embodiments, the compound of Formula (IVA) is a compound of Formula (IVA-I):

[0269]

[0270] (IVA-I) or a pharmaceutically acceptable salt thereof.

[0271] In embodiments of Formula (IVA-I),

[0272] X is CH2 or O;

[0273] R is H or OH;

[0274] R1is C1-6 alkyl or C=CH;

[0275] R2is H or halo;

[0276] R3is a 5-8 membered heterocyclyl;

[0277] R4is selected from H, OH, and C1-6 alkyl; and

[0278] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl.

[0279] In embodiments of Formula (IVA-I),

[0280] X is CH2 or O;

[0281] R is H or OH;

[0282] R1is C1-3 alkyl or C=CH;

[0283] R2is H or halo;

[0284] R3is a 6-8 membered heterocyclyl;

[0285] R4is selected from H, and C1-3 alkyl; and

[0286] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl. In embodiments, the compound of Formulae (l)-(ll) is a compound of Formula (IVB): or a pharmaceutically acceptable salt thereof.

[0287] In embodiments of Formula (IVB),

[0288] X is CH2 or O;

[0289] R is H or OH;

[0290] R1is C1-6 alkyl or C=CH;

[0291] R2is H or halo;

[0292] R3is a 5-8 membered heterocyclyl;

[0293] R4is selected from H, OH, and C1-6 alkyl; and

[0294] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl.

[0295] In embodiments of Formula (IVB),

[0296] X is CH2 or O;

[0297] R is H or OH;

[0298] R1is C1-3 alkyl or C=CH;

[0299] R2is H or halo;

[0300] R3is a 6-8 membered heterocyclyl;

[0301] R4is selected from H, and C1-3 alkyl; and

[0302] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl. In embodiments, the compound of Formula (IVB) is a compound of Formula (IVB-I):

[0303] (IVB-I) or a pharmaceutically acceptable salt thereof.

[0304] In embodiments of Formula (IVB-I),

[0305] X is CH2 or O;

[0306] R is H or OH;

[0307] R1is C1-6 alkyl or C=CH;

[0308] R2is H or halo;

[0309] R3is a 5-8 membered heterocyclyl;

[0310] R4is selected from H, OH, and C1-6 alkyl; and

[0311] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl.

[0312] In embodiments of Formula (IVB-I),

[0313] X is CH2 or O;

[0314] R is H or OH;

[0315] R1is C1-3 alkyl or C=CH;

[0316] R2is H or halo;

[0317] R3is a 6-8 membered heterocyclyl;

[0318] R4is selected from H, and C1-3 alkyl; and

[0319] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl.

[0320] In embodiments, the compound of Formulae (I), (IA), or (III) is a compound of Formula (V):

[0321] or a pharmaceutically acceptable salt thereof.

[0322] In embodiments of Formula (V),

[0323] R1is C1-6 alkyl or C=CH;

[0324] R2is H or halo;

[0325] R3is a 5-8 membered heterocyclyl;

[0326] R4is independently selected from H, OH, and C1-6 alkyl; and

[0327] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl.

[0328] In embodiments of Formula (V),

[0329] R1is C1-3 alkyl or C=CH;

[0330] R2is H or halo;

[0331] R3is a 6-8 membered heterocyclyl;

[0332] R4is independently selected from H, and C1-3 alkyl; and

[0333] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl.

[0334] In embodiments, the compound of Formulae (V) is a compound of Formula (V-l):

[0335] (V-l) or a pharmaceutically acceptable salt thereof.

[0336] In embodiments of Formula (V-l),

[0337] R1is C1-6 alkyl or C=CH;

[0338] R2is H or halo;

[0339] R3is a 5-8 membered heterocyclyl;

[0340] R4is independently selected from H, OH, and C1-6 alkyl; and

[0341] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl.

[0342] In embodiments of Formula (V-l),

[0343] R1is C1-3 alkyl or C=CH;

[0344] R2is H or halo;

[0345] R3is a 6-8 membered heterocyclyl;

[0346] R4is independently selected from H, and C1-3 alkyl; and

[0347] L is selected from -OC1-6 alkyl, 5-8 membered heterocyclyl, and -OCi-6 alkyl-(5-8 membered heterocyclyl)O-, wherein C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl.

[0348] Various Embodiments of Formulae (A) and (Al), or Pharmaceutically Acceptable Salts Thereof

[0349] In embodiments, R1is C1-6 alkyl. In embodiments, R1is C1-3 alkyl. In embodiments, R1is C=CH. In embodiments, R2is H. In embodiments, R2is halo. In embodiments, R1is C1-3 alkyl and R2is H. In embodiments, R1is C=CH and R2is halo. In embodiments, R2is F.

[0350] In embodiments, R4is C1-6 alkyl. In embodiments, R4is C1-3 alkyl.

[0351] In embodiments, R3is

[0352] In embodiments, R3is

[0353] In embodiments, R is H. In embodiments, R is OH.

[0354] In embodiments, L is selected from -OC1.6 alkyl, 5-membered heterocyclyl, and -OC1. e alkyl-(5-membered heterocyclyl )O-, wherein alkyl and heterocyclyl are optionally substituted with C1-3 alkyl or C3-4 cycloalkyl.

[0355] In embodiments, L is selected from -OC1.3 alkyl, 5-membered heterocyclyl, and -OC1. 3 alkyl-(5-membered heterocyclyl )O-, wherein alkyl and heterocyclyl are optionally substituted with CH3 or cyclopropyl.

[0356] In embodiments, 5-membered heterocyclyl contains one or two heteroatoms selected from N and S.

[0357] In embodiments, L has a structure selected from:

[0358] Various Embodiments of Formulae (l)-(V-l), or Pharmaceutically Acceptable Salts Thereof

[0359] In embodiments, Q is CH or N. In embodiments, Q1is CH or N. In embodiments, X is CH2 or O. In embodiments, X is absent. In embodiments, R is H. In embodiments, R is OH. In embodiments, R1is C1-6 alkyl or C=CH. In embodiments, R1is C1-6 alkyl. In embodiments, R1is C CH. In embodiments, R2is H or halo. In embodiments, R2is H. In embodiments, R2is halo. In embodiments, R2is F. In embodiments, R1is C1-3 alkyl and R2is H. In embodiments, R1is C=CH and R2is halo.

[0360] In embodiments, R3ais halo. In embodiments, R3ais F. In embodiments, R3is 6-8 membered heterocyclyl, wherein the heterocyclyl is an optionally fused heterocyclyl. In embodiments, R3is a 7-membered heterocyclyl. In embodiments, R3is an 8-membered fused heterocyclyl.

[0361] In embodiments, R3has the structure: wherein:

[0362] Y is NR3cor C1-3 alkylene;

[0363] R3aand R3bare independently selected from H and C1-6 alkyl; alternatively, R3ais connected to R3bvia C1-3 alkyl, thereby forming a fused ring system; and

[0364] R3cis H or C1-6 alkyl.

[0365] In embodiments, R3is: wherein:

[0366] R3aand R3bare each independently selected from H, OH, and C1-6 alkyl.

[0367] In embodiments, R3is:

[0368] In embodiments, R3is wherein:

[0369] R3aand R3bare independently selected from H and C1-6 alkyl; alternatively, R3ais connected to R3bvia C1-3 alkyl, thereby forming a fused ring system; and

[0370] R3cis H or C1-6 alkyl.

[0371] In embodiments, R3is wherein Y is NR3cor C1-3 alkylene.

[0372] In embodiments, R3is

[0373] In embodiments, R3is

[0374] In embodiments, R4is C1-6 alkyl. In embodiments, R4is C1-3 alkyl. In embodiments, R5is OH. In embodiments, R6is C1-3 alkyl. In embodiments, R6is CH3. In embodiments, R7is C1-3 alkyl. In embodiments, R7is CH3.

[0375] In embodiments, Ring A is 4-5-membered heterocyclyl or 6-membered heterocyclyl substituted with halo.

[0376] In embodiments, Ring

[0377] In embodiments, Ring

[0378] In embodiments, L is selected from -OC1-6 alkyl, 5-membered heterocyclyl, and -OC1- e alkyl-(5-membered heterocyclyl )0-, wherein alkyl and heterocyclyl are optionally substituted with C1-3 alkyl or C3-4 cycloalkyl.

[0379] In embodiments, L is selected from -OC1.3 alkyl, 5-membered heterocyclyl, and -OC1. 3 alkyl-(5-membered heterocyclyl )0-, wherein alkyl and heterocyclyl are optionally substituted with CH3 or C3 cycloalkyl.

[0380] In embodiments, L has a structure selected from:

[0381]

[0382] In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents are to be chosen in conformity with well-known principles of chemical structure connectivity and stability. In embodiments, the compound of Formula (I) is selected from a compound in Table

[0383] 1 , or a pharmaceutically acceptable salt thereof.

[0384] In embodiments, the compound of Formula (A) and Formula (Al), is selected from a compound in Table 1 , or a pharmaceutically acceptable salt thereof.

[0385] Table 1.

[0386]

[0387] In embodiments, the compound of Formula (I), or any subgeneric formula thereof, e.g., Formula (IA), (II), (III), (IVA), (IVA-I), (IVB) (IVB-I), (V), and (V-l), is selected from a compound in Table 1A, or a pharmaceutically acceptable salt thereof.

[0388] Table 1A.

[0389]

[0390] Also provided herein are pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable carrier. The compounds disclosed herein may exist as tautomers and optical isomers (e.g., enantiomers, diastereomers, diastereomeric mixtures, racemic mixtures, and the like).

[0391] Compounds provided herein can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971 ; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can used in various studies such as NMR spectroscopy, metabolism experiments, and / or assays.

[0392] Methods of Treatment

[0393] This application pertains to methods of treating or ameliorating a disease state or condition that is modulated through or causally related to the target protein, i.e., KRas.

[0394] Provided herein are methods of treating a disease or disorder comprising administering to a subject a compound disclosed herein, or a pharmaceutical composition disclosed herein.

[0395] In embodiments, the disease or disorder is cancer.

[0396] In embodiments the cancer is characterized by a KRas mutation.

[0397] In embodiments the cancer is characterized by a KRas G12D mutation.

[0398] In embodiments, the cancer is bladder cancer, bowel cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovary cancer, pancreatic cancer, prostate cancer, stomach cancer, uterine cancer, ovarian cancer, testicular cancer, thyroid cancer, pineal cell tumor, carcinoma, cytoma, ependymoma, ganglioglioma, ganglioneuroma, glioblastoma, glioma, leukemia, lymphoma, medulloblastoma, melanoma, meningioma, myeloma, nephroblastoma, neuroblastoma, neurofibroma, oligodendroglioma peripheral neuroepithelioma, sarcoma, or schwannoma. In embodiments, the carcinoma is teratocarcinoma. In embodiments, the cytoma is astrocytoma.

[0399] In embodiments, the carcinoma is squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma. In embodiments, the leukemia is precursor B-lymphoblastic leukemia, T-cell acute lymphoblastic Leukemia, adult T-cell leukemia, Philadelphia chromosome positive acute lymphoblastic leukemia, Philadelphia chromosome positive chronic myeloid leukemia, or acute lymphoblastic leukemia.

[0400] In embodiment, the lymphoma is Burkitt lymphoma, non-Hodgkin’s lymphoma, precursor T-lymphoblastic lymphoma, peripheral T-cell lymphoma, precursor lymphoblastic lymphoma, diffuse large B-cell lymphoma, or B-cell lymphoma.

[0401] In embodiment, the lymphoma is Hodgkin’s lymphoma (HL).

[0402] In embodiments, the nephroblastoma is Wilms’ tumor. In embodiments, the sarcoma is selected from carcinosarcoma, Ewing’s sarcoma, hemangiosarcoma, Kaposi’s sarcoma, liposarcoma, myosarcoma, synovial sarcoma, and meningeal sarcoma.

[0403] In aspects, provided herein is a method for regulating KRas protein activity in a subject comprising administering to the subject an amount of any of the compounds disclosed herein, or a pharmaceutical composition comprising any of the compounds disclosed herein.

[0404] Provided herein are methods of degrading a target protein in a cell comprising contacting the cell with a compound disclosed herein, or a pharmaceutical composition disclosed herein.

[0405] Administration / Dosages / Formulations

[0406] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0407] Injectable preparations (for example, sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0408] To prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0409] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax that are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0410] Solid compositions of a similar type also can be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0411] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

[0412] Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this disclosure.

[0413] The ointments, pastes, creams, and gels may contain, in addition to an active compound of this disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0414] Powders and sprays can contain, in addition to the compounds of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

[0415] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0416] Compounds of the present disclosure may be administered intratympanically, wherein a long, narrow, bore needle is passed through the ear canal and through the eardrum to administer medications into the middle ear space where they are absorbed by the inner ear.

[0417] 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.

[0418] 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 age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5 mg / kg per body weight. An indicated daily dosage in the larger mammal, e.g., humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered, e.g., in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca. 1 to 50 mg active ingredient. In embodiments, a therapeutic amount or dose of the compounds of the present disclosure may range from about 0.1 mg / Kg to about 500 mg / Kg, alternatively from about 1 to about 50 mg / Kg. In general, treatment regimens according to the present disclosure comprise administration to a subject in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this disclosure per day in single or multiple doses. Therapeutic amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.

[0419] Upon improvement of a subject’s condition, a maintenance dose of a compound, composition or combination of this disclosure may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained; when the symptoms have been alleviated to the desired level, treatment should cease. The subject may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

[0420] 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.

[0421] 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.

[0422] Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; polyacrylates; waxes; polyethylenepolyoxypropylene-block polymers; wool fat; 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 a propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solutions. Further, non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The protein kinase inhibitors or pharmaceutical salts thereof may be formulated into pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions, which comprise an amount of the protein inhibitor effective to treat or prevent a protein kinase-mediated condition and a pharmaceutically acceptable carrier, are other embodiments of the present disclosure.

[0423] Kits

[0424] 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.

[0425] The disclosure provides a kit comprising a compound capable of degrading KRas selected from a compound disclosed herein.

[0426] Also provided herein are kits comprising a compound disclosed herein for the treatment of any of the indications disclosed herein.

[0427] Equivalents and scope

[0428] While various disclosure embodiments have been particularly shown and described in the present disclosure, it will be understood by those skilled in the art that various changes in form and details may be made without departing from the spirit and scope of the embodiments disclosed herein and set forth in the appended claims.

[0429] 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 were 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.

[0430] 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.

[0431] The contents of all references (including literature references, issued patents, published patent applications, and co-pending applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.

[0432] 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.

[0433] EXAMPLES

[0434] 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.

[0435] 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.

[0436] Abbreviations

[0437] AcOH or HOAc Acetic acid CBz Benzyl chloroformate

[0438] Boc tert-butoxycarbonyl

[0439] CDCI3 Chloroform-d

[0440] CS2CO3 Cesium carbonate

[0441] DIEA Diisopropylethylamine

[0442] Dmax Maximal degradation (%)

[0443] DMF A / ,A / -Dimethylformamide

[0444] DMSO Dimethyl sulfoxide

[0445] DMSO-de Deuterated dimethyl sulfoxide (C2D6SO)

[0446] DTT Dithiothreitol

[0447] ESI Electrospray ionization

[0448] EtOH Ethanol eq Equivalent(s) g Gram(s) h Hour(s) Hz Hertz HCI Hydrochloric acid HPLC High performance liquid chromatography DC50 Half maximal degradation concentration K2CO3Potassium carbonate K3PO4Potassium phosphate min Minute(s) m / z Mass / charge MS Mass spectrometry MHz Megahertz

[0449] MeOH Methanol

[0450] MOM Methoxymethyl pL Microliter(s) pm Micrometer(s) mg Milligram(s) mm Millimeter(s) mL Milliliter(s) mmol Millimole(s) NH4CI Ammonium chloride nM Nanomolar

[0451] NMR Nuclear magnetic resonance

[0452] Pd(dppf)CI2[1 ,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane

[0453] PMB para-m ethoxy benzyl psi Pound(s) per square inch TEA Triethylamine

[0454] TFA Trifluoroacetic acid

[0455] Tf Trifluoromethanesulfonate

[0456] TIPS Triisopropylsilyl ether

[0457] TBDPS tert-butyldiphenylsilyl

[0458] THF Tetrahydrofuran

[0459] TLC Thin-layer chromatography

[0460] Synthetic Procedures

[0461] Example 1. Exemplary Synthesis of (2S,4R)-1-[(2R)-2-[3-[3-[[1-[(1S)-2-[4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3- d]pyrimidin-2-yl]oxy-1-methyl-ethyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl- butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2- carboxamide (Compound 1) Step 1: Preparation of 2,6-dibenzyloxy-4-iodo-pyridine

[0462] To a mixture of 2,6-difluoro-4-iodo-pyridine (25.0 g, 104 mmol, 1.0 eq) in acetonitrile (250 mL) were added benzyl alcohol (33.66 g, 311 mmol, 3.0 eq) and cesium carbonate (135 g, 415 mmol, 4.0 eq) under nitrogen atmosphere, and the reaction mixture was stirred at 90 °C for 15 h. The mixture was filtered, washed with EtOAc (500 mL), and then concentrated under reduced pressure. The residue was purified by flash column chromatography on SiC>2 (0% to 5% ethyl acetate in petroleum ether) to afford 2,6- dibenzyloxy-4-iodo-pyridine (38.36 g, 87%) as a white solid. LC / MS (ESI) m / z: 417.8 [M+H]+.

[0463] Step 2: Preparation of tert-butyl 3-[(2,6-dibenzyloxy-4-pyridyl)methylene]azetidine-1- carboxylate

[0464] To a mixture of 2,6-dibenzyloxy-4-iodo-pyridine (8.75 g, 21 mmol, 1.0 eq) in DMF (100 mL) were added tert-butyl 3-methyleneazetidine-1-carboxylate (8.87 g, 52 mmol, 2.5 eq) and triethylamine (14.6 mL, 105 mmol, 5.0 eq) and Pd(dppf)Cl2 (1.54 g, 2.1 mmol, 0.1 eq) under nitrogen atmosphere, and the reaction mixture was stirred at 100 °C for 15 h. The mixture was partitioned between water (100 mL) and EtOAc (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic extract was washed with water (3 x 200 mL), brine (3 x 200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on SiO2 (0-6% ethyl acetate in petroleum ether) to afford tert-butyl 3-[(2,6-dibenzyloxy-4-pyridyl)methylene]azetidine-1 -carboxylate (5.34 g, 42%) as a brown solid. LC / MS (ESI) m / z: 459.0 [M+H]+.

[0465] Step 3: Preparation of tert-butyl 3-[(2,6-dioxo-4-piperidyl)methyl]azetidine-1-carboxylate

[0466] To tert-butyl 3-[(2,6-dibenzyloxy-4-pyridyl)methylene]azetidine-1-carboxylate (5.34 g, 8.85 mmol, 1.0 eq) in EtOAc (200 mL) was added 10% palladium on carbon (550 mg) under argon atmosphere, and the suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was stirred under hydrogen (30 psi) at 50 °C for 15 h. The mixture was filtered, washed with EtOAc, and the filtrate was concentrated under reduced pressure to afford tert-butyl 3-[(2,6-dioxo-4-piperidyl)methyl]azetidine-1- carboxylate (2.67 g, crude) as a white solid. LC / MS (ESI) m / z: 305.1 [M+Na]+. Step 4: Preparation of tert-butyl 3-[[1-[(1 S)-2-benzyloxy-1-methyl-ethyl]-2,6-dioxo-4- piperidyl]methyl]azetidine-1 -carboxylate

[0467] To a mixture of tert-butyl 3-[(2,6-dioxo-4-piperidyl)methyl]azetidine-1-carboxylate (2.4 g, 8.5 mmol, 1.0 eq), (2F?)-1-benzyloxypropan-2-ol (1.84 g, 11 mmol, 1.3 eq), and triphenylphosphine (3.35 g, 13 mmol, 1.5 eq) in THF (50 mL) was added diisopropyl azodicarboxylate (2.47 mL, 13 mmol, 1.5 eq) in one portion at 0 °C under nitrogen, and the reaction mixture was stirred at 70 °C for 15 h. The mixture was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (0-15% THF in petroleum ether) to afford tert-butyl 3-[[1-[(1 S)-2-benzyloxy-1-methyl-ethyl]-2,6-dioxo- 4-piperidyl]methyl]azetidine-1-carboxylate (3.71 g, 65%) as a colorless oil. LC / MS (ESI) m / z: 453.2 [M+Na]+.

[0468] Step 5: Preparation of tert-butyl 3-[[1-[(1 S)-2-benzyloxy-1-methyl-ethyl]-4- piperidyl]methyl]azetidine-1 -carboxylate

[0469] To a mixture of tert-butyl 3-[[1-[(1S)-2-benzyloxy-1-methyl-ethyl]-2,6-dioxo-4- piperidyl]methyl]azetidine-1-carboxylate (3.71 g, 6.72 mmol, 1.0 eq) in THF (50 mL) was added borane dimethylsulfide (10 M, 6.72 mL, 10 eq) dropwise at 0 °C, and the reaction mixture was stirred at 70 °C for 1 h. The reaction mixture was cooled to room temperature and quenched with water (20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL), anmd the combined organic extract was washed with brine (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting colorless oil (2.71 g) colorless oil was dissolved in DMF (30 mL). Potassium peroxymonosulfate (8.28 g, 13 mmol, 2.0 eq) was then added, and the reaction mixture was stirred at 25 °C for 3 h. The mixture was filtered and washed with EtOAc (30 mL). The filtrate solution was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extract was washed with water (3 x 30 mL) and brine (3 x 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-4% then up to 6% methanol in dichloromethane) to afford tert-butyl 3-[[1- [(1S)-2-benzyloxy-1-methyl-ethyl]-4-piperidyl]methyl]azetidine-1-carboxylate (1.45 g, crude) as a colorless oil. LC / MS (ESI) m / z: 403.3 [M+H]+. Step 6: Preparation of 4-(azetidin-3-ylmethyl)-1-[(1S)-2-benzyloxy-1-methyl-ethyl]piperidine

[0470] To tert-butyl 3-[[1-[(1 S)-2-benzyloxy-1-methyl-ethyl]-4-piperidyl]methyl]azetidine-1- carboxylate (1.45 g, 3.6 mmol, 1.0 eq) in dichloromethane (20 mL) was added TFA (10 mL), and the reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with water (20 mL) and saturated aqueous sodium carbonate solution to adjust the pH to 10. The mixture was extracted with 10:1 dichloromethane / methanol (3 x 50 mL), and the combined organic extract was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-(azetidin- 3-ylmethyl)- 1 -[( 1 S)-2-benzyloxy-1-methyl-ethyl]piperidine (1 .09 g, crude) as a yellow oil. LC / MS (ESI) m / z: 303.4 [M+H]+.

[0471] Step 7: Preparation of methyl 3-methyl-2-[3-(1 ,1 ,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)- isoxazol-5-yl]butanoate

[0472] To a mixture of methyl 2-(3-hydroxyisoxazol-5-yl)-3-methyl-butanoate (20.0 g, 100 mmol, 1 eq) and potassium carbonate (6.94 g, 50.2 mmol, 0.5 eq) in acetonitrile (100 mL) at 0 °C was added 1 ,1 ,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (60.7 g, 201 mmol, 2 eq) dropwise under nitrogen, and the reaction mixture was stirred at 20 °C for 12 h. The mixture was diluted with EtOAc (100 mL) and washed with saturated ammonium chloride solution (100 mL). The aqueous phase was extracted with EtOAc (3 x 120 mL), and the combined organic extract was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-1% THF in petroleum ether) to afford methyl 3-methyl-2-[3- (1 ,1 ,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)isoxazol-5-yl]butanoate (37.4 g, 71%) as a colorless oil. LC / MS (ESI) m / z: 481.8 [M+H]+.

[0473] Step 8: Preparation of methyl 2-[3-[3-[[1-[(1S)-2-benzyloxy-1-methyl-ethyl]-4- piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl-butanoate

[0474] To 4-(azetidin-3-ylmethyl)-1-[(1S)-2-benzyloxy-1-methyl-ethyl]piperidine (1.06 g, 3.5 mmol, 1.0 eq) in DMA (10 mL) were added 4A molecular sieves (5 g) and triethylamine (1.46 mL, 10 mmol, 3.0 eq), and the resulting mixture was heated to 130 °C. A solution of methyl 3-methyl-2-[3-(1 ,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)isoxazol-5-yl]butanoate (3.37 g, 7 mmol, 2.0 eq) in DMA (15 mL) was then added over 3 h. The reaction mixture was stirred at 130 °C for 15 h. The mixture was filtered, washed with EtOAc (20 mL), and concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: Welch Xtimate C18250*50mm*10um; mobile phase: [15-55% CH3CN in water (TFA)]). The pure fractions were collected, and solid sodium carbonate was added to adjust the pH to 8-9. The resulting mixture was concentrated, and the residue was extracted with EtOAc (3 x 100 mL). The combined organic extract was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford methyl 2-[3-[3-[[1-[(1 S)-2-benzyloxy-1-methyl-ethyl]-4- piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl-butanoate (880 mg, 49%) as a brown oil. LC / MS (ESI) m / z: 484.5 [M+H]+

[0475] Step 9: Preparation of methyl 2-[3-[3-[[1-[(1S)-2-hydroxy-1-methyl-ethyl]-4- piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl-butanoate

[0476] To a solution of methyl 2-[3-[3-[[1-[(1S)-2-benzyloxy-1-methyl-ethyl]-4- piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl-butanoate (780 mg, 1.5 mmol, 1.0 eq) in dichloromethane (16 mL) was added boron tribromide (2 M, 2.3 mL, 3.0 eq) under nitrogen at -78 °C, and the reaction mixture was stirred under nitrogen at -78 °C for 1 h. The reaction was quenched with triethylamine (3 mL), then concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: Xtimate C18 150*40mm*10um; mobile phase: [0-38% CH3CN in water (TFA)]) to afford methyl 2-[3-[3-[[1-[(1S)-2-hydroxy-1-methyl- ethyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl-butanoate (220 mg, 28%, TFA salt) as a brown oil. LC / MS (ESI) m / z: 394.2 [M+H]+.

[0477] Step 10: Preparation of 2-[3-[3-[[1-[(1 S)-2-hydroxy-1-methyl-ethyl]-4- piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl-butanoic acid

[0478] To methyl 2-[3-[3-[[1-[(1S)-2-hydroxy-1-methyl-ethyl]-4-piperidyl]methyl]azetidin-1- yl]isoxazol-5-yl]-3-methyl-butanoate (230 mg, 453 pmol, 1.0 eq, TFA) in THF (6 mL) was added a solution of lithium hydroxide hydrate (81 mg, 1.9 mmol, 4 eq) in water (3 mL), and the reaction mixture was stirred at 25 °C for 15 h. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with water (5 mL) and 2 M aqueous hydrochloric acid to adjust the pH to 7. The mixture was lyophilized to afford 2-[3-[3-[[1-[(1S)- 2-hydroxy-1-methyl-ethyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl-butanoic acid (171.9 mg, crude) as a yellow solid. LC / MS (ESI) m / z: 380.2 [M+H]+.

[0479] Step 11 : Preparation of (2S,4R)-1-tert-butoxycarbonyl-4-[tert-butyl(diphenyl)silyl]oxy- pyrrolidine-2-carboxylic acid

[0480] PTBDPS Boc- cr "OH

[0481] To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (5.0 g, 21 mmol, 1.0 eq) in acetonitrile (50 mL) were added 1 ,8-diazabicyclo[5.4.0]undec-7- ene (11.52 g, 76 mmol, 3.5 eq) and tert-butyl(chloro)diphenylsilane (11.89 g, 43 mmol, 2.0 eq), and the reaction mixture was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure, acidified with 0.2 M hydrochloric acid solution to pH = 3, then extracted with ethyl acetate (80 mL x 3). The combined organic extracts were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on SiC>2 (0 - 50% ethyl acetate in petroleum ether) to afford (2S,4R)-1-tert-butoxycarbonyl-4-[tert-butyl(diphenyl)silyl]oxy-pyrrolidine-2- carboxylic acid (8.3 g, 80%) as a white gum. LC / MS (ESI) m / z: 470.2 [M+H]+.

[0482] Step 12: Preparation of tert-butyl (2S,4R)-2-[[(1S)-1-(4-bromophenyl)ethyl]carbamoyl]-4- [tert-butyl(diphenyl)silyl]oxy-pyrrolidine-1-carboxylate To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-[tert-butyl(diphenyl)silyl]oxy- pyrrolidine-2-carboxylic acid (8.29 g, 17 mmol, 1 .0 eq) in anhydrous DMF (43 mL) were added HATU (7.20 g, 19 mmol, 1.10 eq) and triethylamine (5.4 mL, 39 mmol, 2.25 eq) followed by (1S)-1-(4-bromophenyl)ethanamine (3.62 g, 17 mmol, 1.02 eq), and the reaction mixture was stirred at 20 °C for 2 h. The mixture was diluted with ethyl acetate (250 mL), washed with water (120 mL x 2) and brine (120 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on SiC>2 (7-11% methyl tert-butyl ether in petroleum ether) to afford tert- butyl (2S,4R)-2-[[(1S)-1-(4-bromophenyl)ethyl]carbamoyl]-4-[tert-butyl(diphenyl)silyl]oxy- pyrrolidine-1 -carboxylate (8.06 g, 72%) as a colorless gum. LC / MS (ESI) m / z: 652.9 [M+H]+;1H NMR (400 MHz, CDCI3) 5 7.62 (d, J = 6.8 Hz, 4H), 7.47-7.33 (m, 8H), 7.17 (d, J = 8.4 Hz, 2H), 5.14-4.83 (m, 1 H), 4.54-4.20 (m, 2H), 3.83-3.35 (m, 1 H), 3.31-3.09 (m, 1 H), 2.46-2.21 (m, 1H), 2.16-1.81 (m, 1H), 1.53-1.31 (m, 12H), 1.04 (s, 9H).

[0483] Step 13: Preparation of tert-butyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[[(1S)-1-[4-(4- methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1 -carboxylate

[0484] To tert-butyl (2S,4R)-2-[[(1S)-1-(4-bromophenyl)ethyl]carbamoyl]-4-[tert- butyl(diphenyl)silyl]oxy-pyrrolidine-1 -carboxylate (2.20 g, 3 mmol, 1.0 eq) in N,N- dimethylacetamide (17 mL) were added 4-methylthiazole (636 mg, 6 mmol, 1.9 eq), Pd(OAc)2 (75 mg, 334 umol, 0.1 eq), and potassium acetate (1.09 g, 11 mmol, 3.29 eq) in a sealed tube, and the reaction mixture was purged with nitrogen and stirred at 120 °C for 7.5 h. The reaction was cooled to room temperature and diluted with ethyl acetate (100 mL). The mixture was washed with water (45 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on SiC>2 (8-18% ethyl acetate in petroleum ether) to afford tert-butyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[[(1S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl] pyrrolidine-1 -carboxylate (2.00 g, 88%) as a yellow gum. LC / MS (ESI) m / z 671.2 [M+H]+;1H NMR (400 MHz, CDCI3) 5 8.86-8.61 (m, 1H), 7.69-7.54 (m, 4H), 7.51-7.28 (m, 10H), 5.22-4.88 (m, 1 H), 4.55-4.24 (m, 2H), 3.80-3.37 (m, 1H), 3.30-3.13 (m, 1 H), 2.58-2.38 (m, 3H), 2.38-2.22 (m, 1 H), 2.16-1.85 (m, 2H), 1.52-1.29 (m, 12H), 1.04 (s, 9H). Step 14: Preparation of (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-N-[(1S)-1-[4-(4-methylthiazol-

[0485] 5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0486] To a solution of tert-butyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[[(1S)-1-[4-(4- methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate (2.00 g, 3 mmol, 1.0 eq) in anhydrous dichloromethane (9.0 mL) was added trifluoroacetic acid (1.8 mL) at 0 °C dropwise, And the reaction mixture was stirred at 20 °C for 3 h. The reaction was quenched by 1 M aqueous sodium carbonate solution (30 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic extracts were washed with brine (25 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-N-[(1S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]pyrrolidine-2-carboxamide (1.64 g, crude) as a yellow gum. LC / MS (ESI) m / z: 570.5 [M+H]+.

[0487] Step 15: Preparation of (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-[2-[3-[3-[[1-[(1 S)-2-hydroxy- 1-methyl-ethyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl-butanoyl]-A / -[(1S)-1-[4- (4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0488] To a mixture of 2-[3-[3-[[1-[(1S)-2-hydroxy-1-methyl-ethyl]-4-piperidyl]methyl]azetidin- 1-yl]isoxazol-5-yl]-3-methyl-butanoic acid (171.9 mg, 0.5 mmol, 1.0 eq) and (2S,4R)-4-[tert- butyl(diphenyl)silyl]oxy-A / -[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2- carboxamide hydrochloride (274.6 mg, 0.5 mmol, 1.0 eq) in DMF (3 mL) were added DIEA (395 pL, 2 mmol, 5.0 eq) and HATU (189 mg, 0.5 mmol, 1.1 eq), and the reaction mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extract was washed with water (3 x 20 mL), then brine (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on SiC>2 (0-6% methanol in dichloromethane) to afford (2S,4f?)-4-[tert-butyl(diphenyl)silyl]oxy-1-[2-[3-[3-[[1- [(1S)-2-hydroxy-1-methyl-ethyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl- butanoyl]-A / -[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (212 mg, 46%) as a yellow oil. LC / MS (ESI) m / z: 466.5 [M / 2+H]+.

[0489] Step 16: Preparation of tert-butyl N-(2-chloro-3-fluoro-4-pyridyl)carbamate F Boc

[0490] To a solution of 2-chloro-3-fluoro-pyridine-4-carboxylic acid (40.0 g, 228 mmol, 1.0 eq) in toluene (200 mL) and tert-butanol (262 mL) was added 4A molecular sieves (68 g) and triethylamine (95 mL, 0.7 mol, 3.0 eq), and the reaction mixture was stirred at 110 °C under nitrogen for 30 min, then cooled to 20 °C and diphenyl phosphoryl azide (74 mL, 0.3 mol, 1.5 eq) was added. The reaction mixture was stirred at 110 °C under nitrogen for 16 h. The reaction mixture was filtered. The filtrate was poured into water (300 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-8% ethyl acetate in petroleum ether) to afford tert-butyl N-(2-chloro-3-fluoro-4-pyridyl)carbamate (108.8 g, 93%) as a yellow oil. MS (ESI) m / z: 247.1 [M+H]+.

[0491] Step 17: Preparation of 2-chloro-3-fluoro-pyridin-4-amine

[0492] To a solution of tert-butyl N-(2-chloro-3-fluoro-4-pyridyl)carbamate (108.8 g, 422 mmol, 1.0 eq) in acetonitrile (120 mL) was added 4 M hydrochloric acid in dioxane (250 mL), and the reaction mixture was stirred at 25 °C for 16 h. The mixture was concentrated, and the resulting residue was dissolved in water (100 mL), the treated with saturated aqueous sodium bicarbonate to adjust the pH to 8-9. The resulting mixture was extracted with ethyl acetate (200 mL x 2), and the combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 2-chloro-3-fluoro- pyridin-4-amine (58.6 g, 85%) as a white solid. LC / MS (ESI) m / z: 147.1 [M+H]+.

[0493] Step 18: Preparation of 2-chloro-3-fluoro-5-iodo-pyridin-4-amine

[0494] To a solution of 2-chloro-3-fluoro-pyridin-4-amine (58.6 g, 376 mmol, 1.0 eq) in acetonitrile (800 mL) were added N-iodosuccinimide (108 g, 480 mmol, 1.2 eq) and p- toluenesulfonic acid (3.4 g, 20 mmol, 0.05 eq), and the reaction mixture was stirred at 70 °C for 16 h under nitrogen. The reaction was quenched by saturated sodium thiosulfate solution (800 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic extract was washed with saturated sodium bicarbonate solution (500 mL x 3) and brine (500 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 2-chloro-3-fluoro-5- iodo-pyridin-4-amine (110 g, 99%) as a yellow solid. LC / MS (ESI) m / z: 272.9 [M+H]+.

[0495] Step 19: Preparation of ethyl 4-amino-6-chloro-5-fluoro-pyridine-3-carboxylate

[0496] To a solution of 2-chloro-3-fluoro-5-iodo-pyridin-4-amine (108.8 g, 395 mmol, 1.0 eq) in ethanol (1000 mL) were added triethylamine (200 mL) and bis(triphenylphosphine)palladium(ll) dichloride (14.0 g, 20 mmol, 0.05 eq), and the reaction mixture was degassed under vacuum and purged with carbon monoxide several times, then stirred at 80 °C under carbon monoxide (15 psi) for 48 h. The mixture was concentrated under reduced pressure, then filtered. The filter cake was washed with MTBE (300 mL x 2) and dried to afford ethyl 4-amino-6-chloro-5-fluoro-pyridine-3-carboxylate (63.5 g, 60%) as a gray solid. LC / MS (ESI) m / z: 219.0 [M+H]+.

[0497] Step 20: Preparation of 4-amino-6-chloro-5-fluoro-pyridine-3-carboxylic acid

[0498] To ethyl 4-amino-6-chloro-5-fluoro-pyridine-3-carboxylate (20.0 g, 91 mmol, 1.0 eq) in THF (180 mL) was added a solution of sodium hydroxide (14.6 g, 366 mmol, 4 eq) in water (90 mL), and the reaction mixture was stirred at 20 °C for 16 h. The mixture was concentrated under reduced pressure, then 2 N aqueous hydrochloric acid was added to adjust the pH to 2. The resulting suspension was filtered, and the filter cake was dissolved in EtOAc / THF (300 mL, v / v = 2 / 1). The resulting mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-amino-6-chloro-5-fluoro- pyridine-3-carboxylic acid (17.1 g, crude) as a gray solid. LC / MS (ESI) m / z: 190.9 [M+H]+.

[0499] Step 21 : Preparation of 7-chloro-8-fluoro-2-thioxo-1H-pyrido[4,3-d]pyrimidin-4-one

[0500] A mixture of 4-amino-6-chloro-5-fluoro-pyridine-3-carboxylic acid (17.1 g, 90 mmol, 1 eq) in phosphorus oxychloride (167 mL) was stirred at 90 °C for 2 h, then concentrated under reduced pressure. To the resulting residue was added THF (150 mL) followed by a solution of ammonium thiocyanate (13.7 mL, 179 mmol, 2 eq) in THF (150 mL), and the reaction mixture was stirred at 35 °C under nitrogen for 24 h. The reaction was quenched with water (400 mL) and extracted with EtOAc (200 mL x 3). The combined organic extract was washed with brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc / petroleum ether (50 mL, v / v = 1 / 1) to afford 7-chloro-8-fluoro-2-thioxo-1 H-pyrido[4,3-d]pyrimidin-4-one (12.14 g, 58%) as a yellow solid. LC / MS (ESI) m / z: 231.8 [M+H]+.

[0501] Step 22: Preparation of 7-chloro-8-fluoro-2-methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one

[0502] To 7-chloro-8-fluoro-2-thioxo-1H-pyrido[4,3-d]pyrimidin-4-one (12.14 g, 52.4 mmol, 1 eq) in DMF (120 mL) was added sodium methoxide (2.83 g, 52 mmol, 1 eq), and the mixture was stirred at 20 °C under nitrogen for 10 minutes, lodomethane (3.26 mL, 52.4 mmol, 1 eq) was then added slowly, and the reaction mixture was stirred at 20 °C under nitrogen for 2 h. The mixture was poured into ice water (200 mL) and filtered. The filter cake was washed with ice water (80 mL x 3) and dried under vacuum to afford 7-chloro-8-fluoro-2- methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one (11.3 g, 88%) as a yellow solid. LC / MS (ESI) m / z: 245.8 [M+H]+.

[0503] Step 23: Preparation of 4,7-dichloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidine

[0504] To 7-chloro-8-fluoro-2-methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one (5.00 g, 20 mmol, 1 eq) in toluene (50 mL) were added DIEA (7.09 mL, 40.7 mmol, 2 eq) and phosphorus oxychloride (7.57 mL, 81.4 mmol, 4 eq), and the reaction mixture was stirred at 90 °C under nitrogen for 2 h, then concentrated under reduced pressure to afford 4,7- dichloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidine (5.35 g, crude) as a brown solid. LC / MS (ESI) m / z 263.8 [M+H]+.

[0505] Step 24: Preparation of tert-butyl 3-(7-chloro-8-fluoro-2-methylsulfanyl-pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0506] To 4,7-dichloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidine (5.35 g, 20.3 mmol, 1 eq) in dichloromethane (50 mL) were added DIEA (17.6 mL, 101 mmol, 5 eq) and a solution of tert-butyl (1S,5R)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.30 g, 20.3 mmol, 1 eq) in dichloromethane (50 mL) at -40 °C, and the reaction mixture was stirred at -40 °C under nitrogen for 0.5 h. The mixture was poured into water (60 mL), then extracted with dichloromethane (60 mL x 2). The combined organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on SiC>2 (0-25% ethyl acetate in petroleum ether) to afford tert-butyl 3-(7-chloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (7.14 g, 80%) as a yellow solid. LC / MS (ESI) m / z: 440.0 [M+H]+.

[0507] Step 25: Preparation of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0508] To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.14 g, 9.41 mmol, 1 eq) and 2-[8-ethyl-3- (methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (3.76 g, 11.0 mmol, 1.17 eq) in dioxane (70 mL) were added tripotassium phosphate (2 M, 14.1 mL, 3 eq) and cataCXium A Pd G3 (685 mg, 0.9 mmol, 0.1 eq), and the reaction mixture was degassed under vacuum and purged with nitrogen several times, then stirred at 85 °C under nitrogen for 16 h. The reaction was quenched with water (70 mL) and extracted with EtOAc (70 mL x 3). The combined organic extract was washed with brine (70 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on SiC>2 (0-18% tetrahydrofuran in petroleum ether) to afford tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-methylsulfanyl- pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.69 g, 97%) as a yellow solid. LC / MS (ESI) m / z: 620.4 [M+H]+.

[0509] Step 26: Preparation of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- methylsulfonyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0510] To tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-methylsulfanyl- pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.95 g, 16 mmol, 1 eq) in DMF (200 mL) was added 4A molecular sieves (15.0 g), and the mixture was stirred at 28 °C for 16 h. Oxone (29.6 g, 48 mmol, 3 eq) was then added, and the reaction mixture was stirred at 25 °C for 24 h. The reaction was quenched with saturated aqueous sodium thiosulfate (100 mL) and saturated aqueous sodium bicarbonate (100 mL), and the resulting mixture was extracted with EtOAc (180 mL x 3). The combined organic extract was washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc / petroleum ether (200 mL, V / V = 3 / 17) to afford tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- methylsulfonyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.03 g, 77%) as a yellow solid. LC / MS (ESI) m / z 652.2 [M+H]+.

[0511] Step 27: Preparation of tert-butyl 3-[2-[(2S)-2-[4-[[1-[5-[1-[(2S,4R)-4-[tert- butyl(diphenyl)silyl]oxy-2-[[(1 S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine- 1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]azetidin-3-yl]methyl]-1-piperidyl]propoxy]-7-[8- ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-c(]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0512] To a mixture of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- methylsulfonyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (162 mg, 0.2 mmol, 1.2 eq) and (2S,4f?)-4-[tert-butyl(diphenyl)silyl]oxy-1-[2-[3-[3-[[1-[(1 S)-2- hydroxy-1-methyl-ethyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl-butanoyl]-A / - [(1 S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (212 mg, 0.2 mmol, 1 .0 eq) in dioxane (6 mL) was added 4A molecular sieves (400 mg), and the mixture was cooled to 0 °C. Sodium tert-butoxide (2.0 M, 621 pL, 6.0 eq) was then added, and the reaction mixture was stirred at 0 °C for 0.5 h. The reaction was quenched with saturated aqueous ammonium chloride (2 mL), then filtered. The filter cake was washed with EtOAc (20 mL), and the filtrate was washed with water (3 x 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on SiC>2 (0-10% methanol in dichloromethane) to afford tert-butyl 3-[2-[(2S)- 2-[4-[[1-[5-[1-[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[[(1 S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]azetidin-3- yl]methyl]-1-piperidyl]propoxy]-7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro- pyrido[4,3-c(]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (155 mg, 47%) as a yellow solid. LC / MS (ESI) m / z: 752.2 [M / 2+H]+.

[0513] Step 28: Preparation of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [(2S)-2-[4-[[1-[5-[1-[(2S,4R)-4-hydroxy-2-[[(1 S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]azetidin-3- yl]methyl]-1-piperidyl]propoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0514] To tert-butyl 3-[2-[(2S)-2-[4-[[1-[5-[1-[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[[(1S)- 1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl- propyl]isoxazol-3-yl]azetidin-3-yl]methyl]-1-piperidyl]propoxy]-7-[8-ethyl-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (155 mg, 97 pmol, 1.0 eq) in THF (3 mL) was added TBAF (1.0 M, 194 pL, 2.0 eq), and the reaction mixture was stirred at 25 °C for 2 h. The mixture was diluted with EtOAc (100 mL) and washed with water (6 x 20 mL), followed by brine (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[(2S)-2- [4-[[1-[5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]azetidin-3- yl]methyl]-1-piperidyl]propoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (122 mg, crude) as a yellow solid. LC / MS (ESI) m / z: 1264.6 [M+H]+.

[0515] Step 29: Preparation of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [(2S)-2-[4-[[1-[5-[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]azetidin-3- yl]methyl]-1-piperidyl]propoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate and tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[(2S)-2- [4-[[1-[5-[(1R)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]azetidin-3- yl]methyl]-1-piperidyl]propoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0516]

[0517] The epimers of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [(2S)-2-[4-[[1-[5-[1-[(2S,4R)-4-hydroxy-2-[[(1 S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]azetidin-3- yl]methyl]-1-piperidyl]propoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (122 mg) were separated by SFC (column: DAICEL CHIRALPAK IA (250mm*30mm,10 urn); mobile phase: [40% heptane in[(4: 1 ethanol:acetonitrile) 0.1% ammonia]) to afford tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[(2S)- 2-[4-[[1-[5-[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]azetidin-3- yl]methyl]-1-piperidyl]propoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (51 mg, 42%) as a yellow solid, and tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)- 1-naphthyl]-8-fluoro-2-[(2S)-2-[4-[[1-[5-[(1R)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4- methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3- yl]azetidin-3-yl]methyl]-1-piperidyl]propoxy]pyrido[4,3-c(]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (41 mg, 34%) as a yellow solid.

[0518] Step 30: Preparation of (2S,4R)-1-[(2R)-2-[3-[3-[[1-[(1S)-2-[4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-7-(8-ethyl-3-hydroxy-1 -naphthyl )-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxy-1 -methyl- ethyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1- [4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 1 )

[0519] To a solution of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [(2S)-2-[4-[[1-[5-[(1R)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methylpropyl]isoxazol-3-yl]azetidin-3- yl]methyl]-1 -piperidyl]propoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1 ]octane-8- carboxylate (40 mg, 32 pmol, 1.0 eq) in dichloromethane (1.5 mL) was added TFA (0.5 mL), and the reaction mixture was stirred at 20 °C under nitrogen for 0.5 h. The reaction was concentrated under reduced pressure, and saturated aqueous sodium carbonate solution was then added to adjust the pH to 9. The resulting mixture was extracted with dichloromethane / methanol (3 x 20 mL, v / v = 10 / 1), and the combined organic extract was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Xtimate C18 150*40mm*10um; mobile phase: [0-38% CH3CN in water (formic acid)]) to afford (2S,4R)-1-[(2R)-2-[3-[3-[[1-[(1S)-2-[4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1 -naphthyl )-8-fluoro-pyrido[4, 3- d]pyrimidin-2-yl]oxy-1-methyl-ethyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl- butanoyl]-4-hydroxy-A / -[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2- carboxamide (26.4 mg, 74%, formic acid salt) as a yellow solid.

[0520] Example 2. Synthesis of (2S,4R)-1-[(2R)-2-[3-[3-[[1-[[1-[[4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-7-(8-ethyl-3-hydroxy-1 -naphthyl )-8-fluoro-pyrido[4, 3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl- butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2- carboxamide (Compound 4)

[0521] Step 1: Preparation of [1-(tetrahydropyran-2-yloxymethyl)cyclopropyl]methanol

[0522] To a solution of [1-(hydroxymethyl)cyclopropyl]methanol (16.0 g, 156 mmol, 1.0 eq) in toluene (312 mL) were added 3,4-dihydro-2H-pyran (47.0 mL, 517 mmol, 3.3 eq) and sodium hydrogen sulfate monohydrate (21.63 g, 157 mmol, 1.0 eq), and the reaction mixture was stirred at 30 °C for 1 h. Solid sodium carbonate (140 g) was added to the mixture, and the resulting suspension was stirred for 30 min at 25 °C and filtered. The filter cake was washed with toluene (100 mL x 4), and the combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on SiC>2 (0- 12% ethyl acetate in petroleum ether) to afford [1-(tetrahydropyran-2- yloxymethyl)cyclopropyl]methanol (23.3 g, 79%) as colorless liquid.1H NMR (400 MHz, CDCI3) 54.61 - 4.60 (m, 1 H), 3.91 - 3.85 (m, 1 H), 3.76 - 3.74 (m, 1H), 3.63 - 3.60 (m, 1H), 3.54 - 3.48 (m, 2H), 3.40 - 3.37 (m, 1H), 2.63 - 2.44 (m, 1H), 1.85 - 1.71 (m, 2H), 1.61 - 1.52 (m, 4H), 0.55 - 0.49 (m, 4H).

[0523] Step 2: Preparation of 1-(tetrahydropyran-2-yloxymethyl)cyclopropanecarbaldehyde

[0524] To a solution of [1-(tetrahydropyran-2-yloxymethyl)cyclopropyl]methanol (3.0 g, 16 mmol, 1.0 eq) in dichloromethane (60 mL) were added tetrapropylammonium perruthenate (1 .13 g, 3 mmol, 0.2 eq) and NMO (3.77 g, 32 mmol, 2.0 eq), and the reaction mixture was stirred at 25 °C for 16 h. The mixture was diluted with dichloromethane (80 mL) and washed with water (20 mL x 3). and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on SiC>2 (0-10% ethyl acetate in petroleum ether) to afford 1- (tetrahydropyran-2-yloxymethyl)cyclopropanecarbaldehyde (1.75 g, 58%) as colorless liquid.1H NMR (400 MHz, CDCI3) 5 9.08 (s, 1H), 4.67 - 4.65 (m, 1H), 3.87 - 3.83 (m, 2H), 3.77 - 3.74 (m, 1H), 3.53 - 3.49 (m, 1H), 1.84 - 1.77 (m, 1H), 1.75 - 1.69 (m, 1 H), 1.59 - 1.51 (m, 4H), 1.25 - 1.24 (m, 2H), 1.14 - 1.12 (m, 2H).

[0525] Step 3: Preparation of methyl 3-methyl-2-[3-[3-(4-piperidylmethyl)azetidin-1-yl]isoxazol-5- yl]butanoate

[0526] To a solution of tert-butyl 4-[[1-[5-(1-methoxycarbonyl-2-methyl-propyl)isoxazol-3- yl]azetidin-3-yl]methyl]piperidine-1-carboxylate (800 mg, 1.8 mmol, 1.0 eq) in dichloromethane (5 mL) was added trifluoroacetic acid (4.1 mL), and reaction the mixture was stirred at 25 °C for 30 min. Nitrogen was then bubbled through the reaction mixture to remove TFA, and the mixture was diluted with saturated sodium bicarbonate solution (20 mL). The resulting mixture was extracted with dichloromethane / methanol (20 mL x 3, v / v = 10 / 1), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford methyl 3-methyl-2-[3-[3-(4- piperidylmethyl)azetidin-1-yl]isoxazol-5-yl]butanoate (1 .2 g, crude) as light yellow oil. LC / MS (ESI) m / z: 336.2 [M+H]+.

[0527] Step 4: Preparation of methyl 3-methyl-2-[3-[3-[[1-[[1-(tetrahydropyran-2- yloxymethyl)cyclopropyl]methyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]butanoate To a solution of methyl 3-methyl-2-[3-[3-(4-piperidylmethyl)azetidin-1-yl]isoxazol-5- yl]butanoate (1.2 g, 4 mmol, 1.0 eq) and 1-(tetrahydropyran-2- yloxymethyl)cyclopropanecarbaldehyde (1.98 g, 11 mmol, 3.0 eq) in dichloromethane (15 mL) and isopropanol (15 mL) were added acetic acid (0.82 mL) and 2-picoline borane complex (1.53 g, 14 mmol, 4.0 eq), and the reaction mixture was stirred at 50 °C for 16 h. The mixture was basified with triethylamine until pH 8 and concentrated under reduced pressure. The residue was purified by flash column chromatography on SiC>2 (0-50% ethyl acetate in petroleum ether) to afford methyl 3-methyl-2-[3-[3-[[1-[[1-(tetrahydropyran-2- yloxymethyl)cyclopropyl]methyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]butanoate (1.58 g, 87%) as light yellow oil. LC / MS (ESI) m / z: 504.4 [M+H]+.

[0528] Step 5: Preparation of 3-methyl-2-[3-[3-[[1-[[1-(tetrahydropyran-2- yloxymethyl)cyclopropyl]methyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]butanoic acid

[0529] To a solution of methyl 3-methyl-2-[3-[3-[[1-[[1-(tetrahydropyran-2- yloxymethyl)cyclopropyl]methyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]butanoate (1.58 g, 3 mmol, 1.0 eq) in THF (20 mL) and water (5 mL) was added lithium hydroxide hydrate (405 mg, 11 mmol, 3.5 eq), and the reaction mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure, then treated with 2 M aqueous hydrochloric acid solution to adjust the pH to 7. The resulting solution was lyophilized to afford 3-methyl-2-[3-[3-[[1-[[1-(tetrahydropyran-2-yloxymethyl)cyclopropyl]methyl]-4- piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]butanoic acid (1.7 g, crude) as a white foam. LC / MS (ESI) m / z 490.5 [M+H]+.

[0530] Step 6: Preparation of (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-[3-methyl-2-[3-[3-[[1-[[1- (tetrahydropyran-2-yloxymethyl)cyclopropyl]methyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol- 5-yl]butanoyl]-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide To a solution of 3-methyl-2-[3-[3-[[1-[[1-(tetrahydropyran-2- yloxymethyl)cyclopropyl]methyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]butanoic acid (1.7 g, 3 mmol, 1.0 eq) and (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-N-[(1S)-1-[4-(4- methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (2.74 g, 4.5 mmol, 1 .3 eq) in DMF (35 mL) were added DIEA (3.0 mL, 17 mmol, 5.0 eq) and HATU (1.45 g, 3.8 mmol, 1.1 eq), and the resulting mixture was stirred at 25 °C for 4 h. (2S,4R)-4-[tert- Butyl(diphenyl)silyl]oxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2- carboxamide hydrochloride (1.05 g, 1.7 mmol, 0.5 eq), DIEA (3.0 mL, 17 mmol, 5.0 eq), and HATU (396 mg, 1 mmol, 0.3 eq) were then added, and the reaction mixture was stirred at 25 °C for 1 h. The mixture was diluted with ethyl acetate (80 mL) and washed with water (10 mL x 5). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on SiC>2 (0-7% methanol in dichloromethane) to afford (2S,4R)-4-[tert- butyl(diphenyl)silyl]oxy-1-[3-methyl-2-[3-[3-[[1-[[1-(tetrahydropyran-2- yloxymethyl)cyclopropyl]methyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]butanoyl]-N- [(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (1.18 g, 32%) as a yellow solid. LC / MS (ESI) m / z: 1041.7 [M+H]+.

[0531] Step 7: Preparation of (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-[2-[3-[3-[[1-[[1- (hydroxymethyl)cyclopropyl]methyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl- butanoyl]-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0532] To (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-[3-methyl-2-[3-[3-[[1-[[1-(tetrahydropyran- 2-yloxymethyl)cyclopropyl]methyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]butanoyl]-N- [(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (1.18 g, 1 mmol, 1.0 eq) in methanol (15 mL) was added pyridinium p-toluenesulfonate (1.14 g, 4 mmol, 4.0 eq), and the reaction mixture was stirred at 60 °C for 16 h. The reaction was suspended in dichloromethane (60 mL) and filtered. The filtrate was washed with water (20 mL), saturated aqueous sodium bicarbonate (20 mL) and brine (20 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-[2-[3-[3-[[1-[[1-(hydroxymethyl)cyclopropyl]methyl]- 4-piperidyl]methyl]azetidin-1 -yl]isoxazol-5-yl]-3-methyl-butanoyl]-N-[(1 S)-1 -[4-(4- methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (1.06 g, crude) as a light yellow solid. LC / MS (ESI) m / z: 957.5 [M+H]+.

[0533] Step 8: Preparation of tert-butyl 3-[2-[[1-[[4-[[1-[5-[1-[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-

[0534] 2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl- propyl]isoxazol-3-yl]azetidin-3-yl]methyl]-1-piperidyl]methyl]cyclopropyl]methoxy]-7-[8-ethyl-

[0535] 3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0536] To a solution of (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-1-[2-[3-[3-[[1-[[1- (hydroxymethyl)cyclopropyl]methyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl- butanoyl]-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (1.21 g, 1 mmol, 1.0 eq) and tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- methylsulfonyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (989 mg, 1.5 mmol, 1.2 eq) in 1 ,4-dioxane (32 mL) was added 4A molecular sieves (1.2 g, 1.3 mmol, 1.0 eq), and the resulting mixture was stirred at 20 °C for 1 h. Sodium tert-butoxide (364 mg, 3.8 mmol, 3.0 eq) was then added at 0 °C, and the reaction mixture was stirred at 20 °C for 30 min. The reaction was quenched with saturated aqueous ammonium chloride (30 mL) and filtered through celite pad. The filtrate was extracted with ethyl acetate (50 mL x 3), and the combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on SiC>2 (0-7% methanol in dichloromethane) to afford tert-butyl 3-[2-[[1-[[4-[[1-[5-[1-[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[[(1S)-1-[4- (4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl- propyl]isoxazol-3-yl]azetidin-3-yl]methyl]-1-piperidyl]methyl]cyclopropyl]methoxy]-7-[8-ethyl- 3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.12 g, 57%) as a light yellow foam. LC / MS (ESI) m / z: 765.3 [M / 2+H]+. Step 9: Preparation of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1- [[4-[[1-[5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]azetidin-3- yl]methyl]-1-piperidyl]methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0537] To a solution of tert-butyl 3-[2-[[1-[[4-[[1-[5-[1-[(2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-

[0538] 2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl- propyl]isoxazol-3-yl]azetidin-3-yl]methyl]-1-piperidyl]methyl]cyclopropyl]methoxy]-7-[8-ethyl-

[0539] 3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.12 g, 0.7 mmol, 1.0 eq) in DMF (16 mL) was added cesium fluoride (1.11 g, 7 mmol, 10 eq), and the reaction mixture was stirred at 25 °C for 16 h. The mixture was diluted with ethyl acetate (50 mL) and washed with water (10 mL x 6). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on SiC>2 (0-9% methanol in dichloromethane) to afford tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[1-[[4-[[1-[5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]azetidin-3- yl]methyl]-1-piperidyl]methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.01 g, 85%) as a light yellow solid. LC / MS (ESI) m / z: 1291.0 [M+H]+.

[0540] Step 10: Preparation of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [[1-[[4-[[1-[5-[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]azetidin-3- yl]methyl]-1-piperidyl]methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[1-[[4-[[1-[5-[(1 R)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]azetidin-3- yl]methyl]-1-piperidyl]methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0541] The epimers of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1- [[4-[[1-[5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]azetidin-3- yl]methyl]-1-piperidyl]methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.01 g) were separated by SFC (column: DAICEL CHIRALPAK IA(250mm*30mm, 10 urn); mobile phase: [40% heptane in[(4: 1 ethanol:acetonitrile), 0.1% ammonia]) to afford tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[1-[[4-[[1-[5-[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]azetidin-3- yl]methyl]-1-piperidyl]methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (419 mg, 41%) as a light yellow solid and tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-[[4-[[1-[5-[(1R)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2- methyl-propyl]isoxazol-3-yl]azetidin-3-yl]methyl]-1- piperidyl]methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (445 mg, 44%) as a light yellow solid. LC / MS (ESI) m / z: 1290.8 [M+H]+.

[0542] Step 11 : Preparation of (2S,4R)-1-[(2R)-2-[3-[3-[[1-[[1-[[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-(8-ethyl-3-hydroxy-1 -naphthyl )-8-fluoro-pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]-3-methyl- butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2- carboxamide

[0543] To a solution of tert-butyl 3-[7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1- [[4-[[1-[5-[(1 R)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]azetidin-3- yl]methyl]-1-piperidyl]methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (425 mg, 0.3 mmol, 1.0 eq) in dichloromethane (5 mL) was added TFA (1 mL), and the reaction mixture was stirred at 20 °C for 30 min. Nitrogen was bubbled through the mixture to remove most of the TFA, and the resulting residue was diluted with saturated aqueous sodium bicarbonate (15 mL), then extracted with dichloromethane / methanol (15 mL x 3, v / v = 10 / 1). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Xtimate C18 150*40mm*10um; mobile phase: [0-38% CH3CN in water (formic acid)]) to afford (2S,4R)-1-[(2R)-2-[3-[3-[[1-[[1-[[4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxy-1 -naphthyl )-8-fluoro-pyrido[4, 3- d]pyrimidin-2-yl]oxymethyl]cyclopropyl]methyl]-4-piperidyl]methyl]azetidin-1-yl]isoxazol-5-yl]- 3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2- carboxamide (149 mg, 37%, formic acid salt) as a white solid.

[0544] The following compounds may be prepared by procedures analogous to the above examples: Compound 2 Compound 3 Compound 5 Compound 6 Compound 7 Compound 8 Compound 9 Compound 10

[0545] Characterization data for the compounds of the disclosure is presented below in Table 2.

[0546] Table 2.

[0547] Additional compounds are presented below in Table 2A.

[0548] Table 2A.

[0549]

[0550] Example 3: Biological Assays

[0551] Reagents

[0552] AsPC-1 (CRL-1682) cells were purchased from ATCC and are homozygous for the G12D mutation in KRas. AsPC-1 cells were cultured in GIBCO RPMI-1640 (ThermoFisher Scientific, catalog# 61870-036, with Glutamax, no HEPES, no Na Pyruvate) supplemented with 10% FBS (ThermoFisher Scientific, catalog# 2060357) and 1X Penicillin-Streptomycin (ThermoFisher Scientific, catalog# 15140122, 10000 U / ml, 100X). For degradation assays, 384 well plates were used. Alamar blue was purchased from ThermoFisher Scientific (A50101) and used according to manufacturer instructions. The Nano-Gio® HiBiT Lytic Detection System and Nano-Gio® HiBiT Blotting System were purchased from Promega (#N3050 and #N2410) and used according to manufacturer instructions.

[0553] To create the AsPC-1 HiBiT-KRasG12D cell line, CRISPR-Cas9 was used to insert the HiBiT tag onto the N-terminus of one or more of the endogenous KRas alleles. See Schwinn, M.K. et al. (2018) CRISPR-mediated tagging of endogenous proteins with a luminescent peptide, ACS Chem. Biol. 13(2), 467-474. After knock-in of the tag, individual clones were isolated by single cell dilution and screened for HiBiT insertion by PCR. A clone was identified that contained the desired HiBiT-KRasG12D sequence at one allele while the remaining two KRasG12D alleles were untagged. This clone was used in further studies. HiBiT degradation assays (G12D)

[0554] AsPC-1 HiBiT-KRasG12D cells were plated at 9000 or 15,000 cells / well in a 384 well plate (Corning #3770). Compounds of the present disclosure and positive controls were diluted in the appropriate cell media and applied to the plated cells resulting in a final concentration titration of 10 pM to 508 pM in 0.5% DMSO. Gambogic acid was used as a positive control for cytotoxicity and titrated from 10 pM to 78 nM. All assays were performed in triplicate. Cells were treated with compounds for 24 hr at 37 °C in an incubator containing 5% CO2. Following treatment, alamar blue was used to determine if any compounds led to a loss in cell viability after 24 hr. The 10X alamar blue reagent was added to a final concentration of 1X as recommended by the manufacturer and cells were returned to the incubator for 4 hr. Plates were then allowed to equilibrate to RT and fluorescence was measured using a Perkin-Elmer EnVision. After completion of the fluorescence read, the liquid from each well was removed and the cells were washed with PBS. The Nano-Gio® HiBiT detection reagent was prepared according to the manufacturer’s instructions and added to each well after the PBS wash was removed. Following incubation at room temperature for 45 min, the luminescence was read using the ultra-sensitive luminescence aperture on the Envision instrument.

[0555] Data analysis

[0556] Fluorescence values from the alamar blue treatment were normalized to the DMSO- only control for each compound titration. HiBiT luminescence was normalized to the DMSO- only control and the fractional HiBiT signal was plotted versus the log of the PROTAC concentration and fit to a 4-parameter dose-response model to obtain the concentration of the compound that leads to half maximal degradation (DC50) as well as the maximum degradation observed (Dmax, conventionally expressed as a percentage of control).

[0557] Degradation data is presented below in Table 3. Table 3. Degradation of KRas-GD12 in AsPC-1 cells at 24h with compounds of the disclosure

[0558] DC5O'- A, B, C, or D. According to the code, A represents a DC5o value <100.0 nM; B represents a DC5o value >100.0 nM and <250.0 nM; C represents a DC5o value >250.0 nM and <1000.0 nM; D represents an DCso value >1000 nM.

[0559] DmaxA, B, C, or D. According to the code, A represents a Dmax value >70%; B represents a Dmax value >50% and <70%; C represents a Dmax value >25% and <50%; D represents a Dmax value <25%.

[0560] *nd = not determined

[0561] The disclosed subject matter is not to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[0562] All references (e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.

Claims

CLAIMS1. A compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof, wherein:Q and Q1are each independently selected from CH and N;X is absent, CH2, or O;R is H or OH;R1is C1-6 alkyl or C=CH;R2and R3aare each independently H or halo;R3is 3-10-membered heterocyclyl;R4, R5, and R6are each independently selected from H, OH, and C1-6 alkyl;R7is C1-6 alkyl;Ring A is absent, 3-5-membered heterocyclyl, or 6-10-membered heterocyclyl substituted with halo; andL is selected from -OC1-6 alkyl, 5-10-membered heterocyclyl, and -OC1-6 alkyl-(3— 10 membered heterocyclyl)O-, wherein the C1-6 alkyl and heterocyclyl are optionally substituted with C1-6 alkyl or C3-6 cycloalkyl, provided that: when Ring A is absent, L is 5-10 membered heterocyclyl or -OCi-6 alkyl-(3-10 membered heterocyclyl)O-; when X is absent, Ring A is absent; when R2is H and L is -OC1-6 alkyl, then the C1-6 alkyl of L is substituted with C1-6 alkyl or C3-6 cycloalkyl; when X is CH2, R is OH, R2is halo, L is -OC1-6 alkyl, and Ring A is a 3-5-membered heterocyclyl, then R3is a 3-7-membered heterocyclyl; when X is O, then R2is halo and R4is chiral, wherein the absolute stereochemistry is in the S configuration.

2. The compound of claim 1 , wherein R3is an 8-membered bridged heterocyclyl; and R5is OH.

3. A compound of Formula (A):or a pharmaceutically acceptable salt thereof, wherein:Q and Q1are each independently selected from CH and N;R is H or OH;R1is C1-3 alkyl or C=CH;R2and R3aare each independently H or halo;R3isY is NR3cor C1-3 alkylene;R3cis H or C1-3 alkyl;R4and R6are each independently selected from H, OH, and C1-3 alkyl;R7is C1-3 alkyl;X is C1-3 alkylene or O;Ring A is selected from azetidinyl, pyrrolidinyl, piperazinyl, and piperidinyl, wherein azetidinyl, pyrrolidinyl, piperazinyl, and piperidinyl are each optionally substituted with halo; andL is selected from -OC1-6 alkyl, 5-6-membered heterocyclyl, and -OC1.6 alkyl-(5— 6- membered heterocyclyl)O-, wherein C1-6 alkyl and 5-6-membered heterocyclyl are each optionally substituted with C1-3 alkyl or C3-6 cycloalkyl.

4. The compound of any one of claims 1-3, wherein the compound is a compound of Formula (Al):or a pharmaceutically acceptable salt thereof, wherein:Q and Q1are each independently selected from CH and N;R is H or OH;R1is C1-3 alkyl or C=CH;R2and R3aare each independently H or halo;R3is0N JW I VY is NR3cor C1-3 alkylene;R3cis H or C1-3 alkyl;R4and R6are each independently selected from H, OH, and C1-3 alkyl;R7is C1-3 alkyl;Ring A is selected from azetidinyl, pyrrolidinyl, piperazinyl, and piperidinyl, wherein azetidinyl, pyrrolidinyl, piperazinyl, and piperidinyl are each optionally substituted with halo; andL is selected from -OC1-6 alkyl, 5-6-membered heterocyclyl, and -OC1-6 alkyl-(5— 6- membered heterocyclyl)O-, wherein C1-6 alkyl and 5-6-membered heterocyclyl are each optionally substituted with C1-3 alkyl or C3-6 cycloalkyl.

5. The compound of claim 3 or 4, wherein 5-6-membered heterocyclyl contains one or two ring heteroatoms selected from N and O.

6. The compound of any one of claims 1-5, wherein Q is N; and Q1is CH.

7. The compound of any one of claims 1-6, wherein Ring A is optionally substituted with halo, wherein the halo is F or Cl.

8. The compound of any one of claims 1-7, wherein Ring A is optionally substituted with halo, wherein the halo is F.

9. The compound of any one of claims 1-8, wherein Ring A is azetidinyl.

10. The compound of any one of claims 1-9, wherein Ring A is azetidinyl; R2is H or halo; and L is selected from -OC1-6 alkyl, 5-6-membered heterocyclyl, and -OCi-6 alkyl-(5-6- membered heterocyclyl)O-, wherein C1-6 alkyl is substituted with C1-3 alkyl or C3-6 cycloalkyl.1 1. The compound of any one of claims 1-10, wherein Ring A is azetidinyl; R2is H or halo; and L is selected from -OC1.3 alkyl, 5-6-membered heterocyclyl, and -OCi-3 alkyl-(5- membered heterocyclyl)O-, wherein C1-3 alkyl is substituted with CH3 or cyclopropyl.

12. The compound of any one of claims 1-1 1 , wherein Ring A is azetidinyl; L is -OC1-6 alkyl; and R is H.

13. The compound of any one of claims 1-12, wherein Ring A is azetidinyl; L is -OC1.3 alkyl; and R is H.

14. The compound of any one of claims 1-8, wherein Ring A is piperidinyl optionally substituted with halo.

15. The compound of any one of claims 1-8 and 14, wherein Ring A is piperidinyl optionally substituted with F.

16. The compound of any one of claims 1-8, 14, and 15, wherein Ring A is piperidinyl optionally substituted with Cl.

17. The compound of any one of claims 1-8 and 14-16, wherein Ring A is piperidinyl substituted with halo.

18. The compound of any one of claims 1-8, 14, 15, and 17, wherein Ring A is piperidinyl substituted with F.

19. The compound of any one of claims 1-8, 14, 16, and 17, wherein Ring A is piperidinyl substituted with Cl.

20. In an embodiment, R3ain the compound of Formula (A) and Formula (Al), or a pharmaceutically acceptable salt thereof, is halo.

21. The compound of any one of claims 1-20, wherein R3ais Cl or F.

22. The compound of any one of claims 1-21 , wherein R3ais Cl.

23. The compound of any one of claims 1-21 , wherein R3ais F.

24. The compound of any one of claims 1-23, wherein R4and R6are each independently selected from H and C1-3 alkyl;25. The compound of any one of claims 1-24, wherein R6is methyl.

26. The compound of any one of claims 1-25, wherein R7is methyl.

27. The compound of any one of claims 1-26, wherein L is selected from -OC1.3 alkyl, 5- membered heterocyclyl, and -OCi-3 alkyl-(5-membered heterocyclyl)O-, wherein C1-3 alkyl is optionally substituted with CH3 or cyclopropyl and 5-membered heterocyclyl is optionally substituted with C1-3 alkyl.

28. The compound of any one of claims 1-6, wherein Ring A is selected from:wherein:RAis halo.

29. The compound of any one of claims 1-7, wherein Ring A is:wherein RAis halo.

30. The compound of any one of claims 1-8, wherein Ring A is:31 . The compound of any one of claims 1-8, wherein Ring A is:wherein RAis halo.

32. The compound of any one of claims 7, 8, and 10, wherein RAis F.

33. The compound of any one of claims 1-11 , wherein R6is C1-3 alkyl.

34. The compound of any one of claims 1-12, wherein R6is CH3.

35. The compound of any one of claims 1-13, wherein R7is C1-3 alkyl.

36. The compound of any one of claims 1-14, wherein R7is CH3.

37. The compound of any one of claims 1-17, wherein R1is C1-3 alkyl.

38. The compound of any one of claims 1-17, wherein R1is C=CH.

39. The compound of any one of claims 1-19, wherein R2is H.

40. The compound of any one of claims 1-19, wherein R2is halo.

41. The compound of any one of claims 1-18 and 21 , wherein R1is C1-3 alkyl and R2is H.

42. The compound of any one of claims 1-17, 19, and 21 , wherein R1is C=CH and R2is halo.

43. The compound of claim 1-21 and 23, wherein R2is F.

44. The compound of any one of claims 1-24, wherein R4is C1-3 alkyl.

45. The compound of any one of claims 1-25, wherein R3is46. The compound of any one of claims 1-26, wherein R3is47. The compound of any one of claims 1-27, wherein R is H.

48. The compound of any one of claims 1-27, wherein R is OH.

49. The compound of any one of claims 1-9 and 14-48, wherein L is selected from -OC1.6 alkyl, 5-membered heterocyclyl, and -OC1.6 alkyl-(5-membered heterocyclyl)O-, wherein alkyl and heterocyclyl are optionally substituted with C1-3 alkyl or C3-4 cycloalkyl.

50. The compound of any one of claims 1-9 and 14-49, wherein L is selected from -OC1.3 alkyl, 5-membered heterocyclyl, and -OC1-3 alkyl-(5-membered heterocyclyl )O-, wherein alkyl and heterocyclyl are optionally substituted with CH3 or cyclopropyl.51 . The compound of claim 49 or 50, wherein 5-membered heterocyclyl contains one or two heteroatoms selected from N and S.

52. The compound of any one of claims 1-51 , wherein L has a structure selected from:

53. The compound of any one of claims 1-52, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof.

55. A pharmaceutical composition comprising a compound of any one of claims 1-54 and a pharmaceutically acceptable carrier.

56. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound according to any one of claims 1-54, or the pharmaceutical composition of claim 55.

57. The method of claim 56, wherein the cancer is characterized by a KRas mutation.

58. The method of claim 56 or 57, wherein the cancer is characterized by a KRas G12D mutation.

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