Antiviral compounds

Abstract

This disclosure relates compounds disclosed herein and pharmaceutical salts thereof, compositions and formulations containing such compounds, and methods of using and making such compounds.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 560,148, filed on March 1, 2024, and U.S. Provisional Application No. 63 / 560,405, filed on March 1, 2024, the entire contents of which is hereby incorporated by reference in its entirety. TECHNICAL FIELD

[0002] This disclosure relates antiviral compounds and pharmaceutical salts thereof, compositions and formulations containing such compounds, and methods of using and making such compounds. BACKGROUND

[0003] Human immunodeficiency virus-1 (HIV-1) infection is a major public health problem, with millions of people around the world dealing with the life-long consequences of HIV infection. While a number of successful treatments have been developed to suppress HIV replication, curing the disease remains a major challenge due to the establishment of viral reservoirs that evade clearance by the immune system. A key step in the HIV lifecycle is the production of the viral proteins contained in the gag-pol polyprotein. Inhibitors of such proteins are a mainstay of clinical antiretroviral therapy for the treatment of HIV or AIDS.

[0004] Certain small molecules bind to immature reverse transcriptase within the context of the gag-pol polyprotein and cause premature dimerization and protease activation. Active HIV protease is able to cleave a host inflammasome sensor in the cytoplasm and ultimately trigger an inflammatory form of cell death. These small molecule HIV protease activators (HPA) represent a selective mechanism by which HIV-infected cells can be cleared, and overall viral load reduced. SUMMARY

[0005] The present disclosure relates to compounds of Formula (I) or pharmaceutical salts thereof, wherein — is a single bond or a double bond; and R1, R2, R3, R4, R5, R6, R7, R14, M, W, Q, U, and V are defined herein.

[0006] In certain embodiments, the current disclosure relates to a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0007] In certain embodiments, the current disclosure relates to a method for treating or preventing an HIV infection in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0008] In certain embodiments, the current disclosure relates to a method for treating or preventing an HIV infection in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents.

[0009] Additional embodiments of the present disclosure are disclosed herein. DETAILED DESCRIPTION

[0010] The description below is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0011] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. A dash at the front or end of a chemical group is a matter of convenience to indicate the point of attachment to a parent moiety; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a chemical structure or a dashed line drawn through a line in a chemical structure indicates a point of attachment of a group. A dashed line within a chemical structure indicates an optional bond. A prefix such as “Cu-v” or (Cu-Cv) indicates that the following group has from u to v carbon atoms. For example, “Ci-ealkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

[0012] When trade names are used herein, it is intended to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product.

[0013] As used herein and in the appended claims, the singular forms “a” and “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays, and so forth.

[0014] The term “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity).

[0015] The term “alkyl” is a straight or branched saturated hydrocarbon. For example, an alkyl group can have 1 to 8 carbon atoms (i.e., (Ci-Cs)alkyl) or 1 to 6 carbon atoms (i.e., (Ci-Ce alkyl) or 1 to 4 carbon atoms (i.e., (Ci-C4)alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l-propyl (i-Bu, i-butyl, -CEECEhUEE^), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (- CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, and octyl (-(CH2)7CH3).

[0016] The term “alkenyl” is C2-Cis hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp2 double bond. Examples include, but are not limited to, ethylene or vinyl (—CH=CH2), allyl (—CH2CH=CH2), cyclopentenyl (—C5H7), and 5-hexenyl (—CH2 CH2CH2CH2CH=CH2).

[0017] The term “alkynyl” is C2-C18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. Examples include, but are not limited to, acetylenic (—C=CH) and propargyl (—CH2C=CH). [001.8] The term “aryl” as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., carbocycle). Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring. It is also to be understood that when reference is made to a certain atom-range membered aryl (e.g., 6-12 membered aryl), the atom range is for the total ring atoms of the aryl. For example, a 6membered aryl would include phenyl and a 10-membered aryl would include naphthyl and 1, 2, 3, 4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.

[0019] As used herein, an “at risk” individual is an individual who is at risk of developing a condition to be treated. An individual “at risk” may or may not have detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment of methods described herein. “At risk” denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a 4 higher probability of developing the disease or condition than an individual without these risk factor(s). For example, individuals at risk for AIDS are those having HIV.

[0020] As used herein, the term “Cn-m alkoxy” refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., / / -propoxy and isopropoxy), butoxy (e.g., / / -butoxy and ZerZ-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. [0021J The term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, and the term “achiral” refers to molecules which are superimposable on their mirror image partner.

[0022] The term “cycloalkyl” refers to a single saturated or partially unsaturated all carbon ring having 3 to 20 annular carbon atoms (i.e., C3-C20 cycloalkyl), for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms. The term “cycloalkyl” also includes multiple condensed, saturated and partially unsaturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, cycloalkyl includes multi cyclic carbocycles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 6 to 12 annular carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles with up to about 20 annular carbon atoms). The rings of a multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl and 1-cyclohex-3-enyl.

[0023] As used herein, the term “effective amount” refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The effective amount will vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0024] As used herein, “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and / or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition. For example, a method that “delays” development of AIDS is a method that reduces the probability of disease development in a given time frame and / or reduces extent of the disease in a given time frame, when compared to not using the method. Such comparisons may be based on clinical studies, using a statistically significant number of subjects. For example, the development of AIDS can be detected using known methods, such as confirming an individual's HIV+ status and assessing the individual's T-cell count or other indication of AIDS development, such as extreme fatigue, weight loss, persistent diarrhea, high fever, swollen lymph nodes in the neck, armpits or groin, or presence of an opportunistic condition that is known to be associated with AIDS (e.g., a condition that is generally not present in individuals with functioning immune systems but does occur in AIDS patients). Development may also refer to disease progression that may be initially undetectable and includes occurrence, recurrence and onset.

[0025] The term “halo” or “halogen” as used herein refers to fluoro, chloro, bromo and iodo.

[0026] The term “haloalkyl” as used herein includes an alkyl group substituted with one or more halogens (e.g. F, Cl, Br, or I). Representative examples of haloalkyl include trifluoromethyl, 2,2,2-trifluoroethyl, and 2,2,2-trifluoro-l-(trifluoromethyl)ethyl.

[0027] The term “heteroaryl” as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur, the term also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, the term includes single aromatic rings of from about 1 to 6 annular carbon atoms and about 1-4 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the rings. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Such rings include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. The term also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, can be condensed with one or more rings selected from heteroaryls (to form for example a naphthyridinyl such as 1,8-naphthyridinyl), heterocycloalkyls, (to form for example a 1, 2, 3, 4-tetrahydronaphthyridinyl such as 1, 2, 3, 4- tetrahydro-1,8-naphthyridinyl), cycloalkyls (to form for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system. Thus, a heteroaryl (a single aromatic ring or multiple condensed ring system) has about 1-20 annular carbon atoms and about 1-6 annular heteroatoms. Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycle portions of the condensed ring. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heteroaryl) can be at any position of the multiple condensed ring system including a heteroaryl, heterocycle, aryl or carbocycle portion of the multiple condensed ring system and at any suitable atom of the multiple condensed ring system including a carbon atom and heteroatom (e.g., a nitrogen). Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl and thianaphthenyl.

[0028] “Heterocycloalkyl” or “heterocyclyl” as used herein refers to a single saturated or partially unsaturated non-aromatic ring or a non-aromatic multiple ring system that has at least one heteroatom in the ring (at least one annular heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocycloalkyl group has from 5 to about 20 annular atoms, for example from 5 to 14 annular atoms, for example from 5 to 10 annular atoms. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) having from about 1 to 6 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The term also includes single saturated or partially unsaturated rings (e.g., 5, 6, 7, 8, 9, or 10-membered rings) having from about 4 to 9 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Heterocycloalkyl groups include, but are not limited to, azetidine, aziridine, imidazolidine, imino-oxoimidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, and the like. WO 2025 / 184609                                   PCT / US2025 / 017990

[0029] As used herein, the term “independently selected from” means that each occurrence of a variable or substituent is independently selected at each occurrence from the applicable list.

[0030] As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.

[0031] The term “n-membered” where n is an integer typically describes the number of ringforming atoms in a moiety where the number of ring-forming atoms is n. For example, pyridyl is an example of a 6-membered heteroaryl ring.

[0032] “Pharmaceutically acceptable” refers to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0033] “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-napththalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like, and salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, e.g., an alkali metal ion (e.g. a sodium or potassium), an alkaline earth ion (e.g. calcium or magnesium), or an aluminum ion; or coordinates with an organic base such as diethanolamine, triethanolamine, N-methylglucamine and the like. Also included in this definition are ammonium and substituted or quatemized ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in S. M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, Pa., (2005), at p. 732, Table 38-5, both of which are hereby incorporated by reference herein.

[0034] As used herein, “prevention” or “preventing” refers to a regimen that protects against the onset of the disease or disorder such that the clinical symptoms of the disease do not develop. Thus, “prevention” relates to administration of a therapy (e.g., administration of a therapeutic substance) to a subject before signs of the disease are detectable in the subject (e.g., administration of a therapeutic substance to an subject in the absence of detectable infectious agent (e.g., virus) in the subject). The subject may be an individual at risk of developing the disease or disorder, such as an individual who has one or more risk factors known to be associated with development or onset of the disease or disorder. Thus, the term “preventing HIV infection” refers to administering to a subject who does not have a detectable HIV infection an anti-HIV therapeutic substance. It is understood that the subject for anti-HIV preventative therapy may be an individual at risk of contracting the HIV virus.

[0035] “Subject” and “subjects” refers to humans, domestic animals (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys), and the like.

[0036] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results. For purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviation of a symptom and / or diminishment of the extent of a symptom and / or preventing a worsening of a symptom associated with a disease or condition. In one embodiment, “treatment” or “treating” includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.

[0037] Except as otherwise noted, the methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, 5th edition, New York: Oxford University Press, 2009; Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th edition, Wiley-Interscience, 2013.

[0038] In certain instances, the processes disclosed herein involve a step of forming a salt of a compound of the present disclosure.

[0039] Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, supercritical fluid chromatography (SFC), and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and / or alumina chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

[0040] During any of the processes for preparation of the subject compounds, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, New York 2006. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

[0041] Exemplary chemical entities useful in methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general preparation herein and the specific examples that follow. One of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. In some embodiments, each of the reactions depicted in the general schemes is run at a temperature from about -80 °C to the reflux temperature of the organic solvent used.

[0042] The compounds disclosed herein may display atropisomerism resulting from steric hindrance affecting the axial rotation rate around a single bond. The resultant conformational isomers may each be observed as distinct entities by characterization techniques such as NMR and HPLC. The compounds disclosed herein may exist as a mixture of atropisomers. However, the detection of atropisomers is dependent on factors such as temperature, solvent, conditions of purification, and timescale of spectroscopic technique. The interconversion rate at room temperature has a half-life of minutes to hours, hours to days, or days to years. The ratio of atropisomers at equilibrium may not be unity. Characterization data presented herein may not represent the equilibrium state depending on the conditions of isolation and characterization which may include but not limited to handling, solvents used, and temperature.

[0043] Compositions detailed herein may comprise a compound of the present disclosure in a racemic or non-racemic mixture of stereoisomers or may comprise a compound of the present disclosure as a substantially pure isomer. Stereoisomers include enantiomers and diastereomers. The compounds may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0044] It is understood by one skilled in the art that this disclosure also includes any compound disclosed herein that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (2H or D).

[0045] Disclosed are also compounds in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0046] Compounds of a given formula described herein encompasses the compound disclosed and all pharmaceutically acceptable salts, esters, stereoisomers, tautomers, prodrugs, solvates, and deuterated forms thereof, unless otherwise specified.

[0047] The compounds disclosed herein may contain chiral centers, which may be either of the (R) or (S) configuration, or which may comprise a mixture thereof. Accordingly, the present disclosure includes stereoisomers of the compounds described herein, where applicable, either individually or admixed in any proportions. Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present disclosure.

[0048] The compounds of the present disclosure may be compounds according to Formula (I) with one or more chiral centers, which may be either of the (R) or (S) configuration, or which may comprise a mixture thereof.

[0049] The present disclosure includes both racemic mixtures of a compound disclosed herein and isolated isomers or any variation thereof. Where more than one chiral center is present in a compound of the present disclosure, some, none, or all of the chiral centers may be enantiomerically enriched. Thus, mixtures of a compound disclosed herein may be racemic with respect to one or more chiral centers and / or enantiomerically enriched with respect to one or more chiral centers. Compounds

[0050] The present disclosure provides in some embodiments a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: — is a single bond or a double bond; R1 is selected from H, CN, halogen, Ci-3alkyl, Ci-3haloalkyl, -OR1A, -SR1A, -NHR1A, and -N(R1A)2; R2 is selected from H, CN, halogen, Ci-3alkyl, Ci-3haloalkyl, -OR2A, -SR2A, -NHR2A, and -N(R2A)2; R3 is selected from CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR3A, -CH2OR3A, -SR3A, -NHR3A, -N(R3A)2, C3-7cycloalkyl, and 3-7 membered heterocycloalkyl; R4 is selected from CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR4A, -CH2OR4A, -SR4A, -NHR4A, -N(R4A)2, C3-7cycloalkyl, and 3-7 membered heterocycloalkyl; or R1 and R3 together form a 6-10 membered aryl; R5 is selected from H, CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, -NHR5A, -N(R5A)2, -OR5A, C3-7cycloalkyl, 3-10 membered heterocycloalkyl, -(C=0)NHR5A, -(C=O)N(R5A)2, and -(C=O)OR5A; wherein the Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, and 3-10 membered heterocycloalkyl of R5 are each optionally substituted with 1 or 2 R8 groups; R6 and R7 are independently selected from H and Ci-ealkyl; or R6 and R7 together form a C3-7cycloalkyl or 3-7 membered heterocycloalkyl; each R8 is independently selected from halogen, CN, Ci-3alkyl, Ci-3haloalkyl, Ci-salkoxyl, C3-7cycloalkyl, and 3-7 membered heterocycloalkyl; M is selected from -CH2-, -CF2-, -CH2CH2-, and -CH2O-; W is selected from -O-, -S-, -C(RW)2-, -NRW-, and -C(=O)-; each Rwis independently selected from H, -ORW1, Ci-ealkyl, C3-7cycloalkyl, Ci-ehaloalkyl, and -(C=O)ORW1; Q, U, and V are independently selected from N, O, S, CRQ, C(RQ)2, NRV, N(RV)2+, S=O, SO2, C=CH2, C=CHF, and C=O; each Rq is independently selected from H, halogen, -ORQ2, CN, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, -NHRQ2, -N(RQ2)2, -(C=O)ORQ1, -(C=0)NHRQ2, -(C=O)N(RQ2)2, -NH(C=0)Rq1, -NH(C=0)0Rq1, -NH(C=0)NHRQ2, -NH(C=O)N(RQ2)2, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ are each optionally substituted with 1, 2, 3, or 4 R9 groups; each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RV1, -(C=O)ORV1, -(C=O)NHRV1, -(C=O)N(RV1)2, -S(O)RV1, and -S(O)2RV1; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rv are each optionally substituted with 1, 2, 3, or 4 R10 groups; each RQ2 is independently selected from H, CN, Ci-ealkyl, C1 -ehaloalky 1, Ci-ealkoxy, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RX1, -(C=O)ORX1, -(C=O)NHRX1, -(C=O)N(RX1)2, and -(SO2)RX1; wherein each C3- 7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ2 is optionally substituted with 1, 2, 3 or 4 R11 groups; or two RQ2 together form a 4-7 membered heterocycloalkyl; or two Rv together form a 4-7 membered heterocycloalkyl; or Rq and Rv together form a 4-11 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein the 4-11 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 R13 groups; each R9 and R10 are independently selected from halogen, -ORX2, CN, Ci-6alkyl, Ci-ehaloalkyl, Ci-ealkoxy, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, 510 membered heteroaryl, -(C=O)RX2, -(C=O)ORX2, -(C=0)NHRX2, -(C=O)N(RX2)2, and -(SO2)RX2; wherein each C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R9 and R10 are each optionally substituted with 1, 2, 3 or 4 R12 groups; each R11, R12 and R13 are independently selected from halogen, -ORX3, CN, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxyl, -NHRX3, -N(RX3)2, C3-7cycloalkyl, and 3-7 membered heterocycloalkyl; wherein each Ci-ealkyl of R11, R12 and R13 is optionally substituted with -ORX4; R14 is selected from H and Ci-ealkyl; and each R1a, R2A, R3A, R4A, R5A, Rq1, Rv1, Rw1, Rx1, RX2, RX3, andRX4 are independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, and 6-10 membered aryl. [0051J In some embodiments, the compound is a compound of Formula (la) or a pharmaceutically acceptable salt thereof, wherein: — is a single bond or a double bond; R1 is selected from H, CN, halogen, Ci-3alkyl, Ci-3haloalkyl, -OR1A, -SR1A, -NHR1A, and WO 2025 / 184609                                   PCT / US2025 / 017990 R2 is selected from H, CN, halogen, Ci-3alkyl, Ci-3haloalkyl, -OR2A, -SR2A, -NHR2A, and -N(R2A)2; R3 is selected from CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR3A, -CH2OR3A, -SR3A, -NHR3A, -N(R3A)2, C3-7cycloalkyl, and 3-7 membered heterocycloalkyl; R4 is selected from CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR4A, -CH2OR4A, -SR4A, -NHR4A, -N(R4A)2, C3-7cycloalkyl, and 3-7 membered heterocycloalkyl; R5 is selected from H, CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, -NHR5A, -N(R5A)2, -OR5A, C3-7cycloalkyl, 3-10 membered heterocycloalkyl, -(C=0)NHR5A, -(C=O)N(R5A)2, and -(C=O)OR5A; wherein the Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, and 3-10 membered heterocycloalkyl of R5 are each optionally substituted with 1 or 2 R8 groups; R6 and R7 are independently selected from H and Ci-ealkyl; or R6 and R7 together form a C3-7cycloalkyl or 3-7 membered heterocycloalkyl; each R8 is independently selected from halogen, CN, Ci-3alkyl, Ci-3haloalkyl, Ci-salkoxyl, C3-7cycloalkyl, and 3-7 membered heterocycloalkyl; M is selected from -CH2-, -CF2-, -CH2CH2-, and -CH2O-; W is selected from -O-, -S-, -C(RW)2-, and -NRW-; each Rwis independently selected from H, Ci-ealkyl, C3-7cycloalkyl, and Ci-ehaloalkyl; Q, U, and V are independently selected from N, O, S, CRQ, C(RQ)2, NRV, N(RV)2+, SO2, C=CH2, and C=O; each Rq is independently selected from H, halogen, -ORQ2, CN, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, -NHRQ2, -N(RQ2)2, -(C=O)ORQ1, -(C=0)NHRQ2, -(C=O)N(RQ2)2, -NH(C=0)Rq1, -NH(C=0)0Rq1, -NH(C=0)NHRQ2, -NH(C=O)N(RQ2)2, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ are each optionally substituted with 1, 2, 3, or 4 R9 groups; each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RV1, -(C=O)ORV1, -(C=O)NHRV1, -(C=O)N(RV1)2, -S(O)RV1, and -S(O)2RV1; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rv are each optionally substituted with 1, 2, 3, or 4 R10 groups; each RQ2 is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RX1, -(C=O)ORX1, -(C=O)NHRX1, -(C=O)N(RX1)2, and -(SO2)RX1; wherein the C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ2 is optionally substituted with 1, 2, 3 or 4 R11 groups; or two RQ2 together form a 4-7 membered heterocycloalkyl; or Rq and Rv together form a 4-7 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein the 4-7 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 R13 groups; each R9 and R10 are independently selected from halogen, -ORX2, CN, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RX2, -(C=O)ORX2, -(C=0)NHRX2, -(C=O)N(RX2)2, and -(SO2)RX2; wherein the C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R9 and R10 are each optionally substituted with 1, 2, 3 or 4 R12 groups; each R11, R12 and R13 are independently selected from halogen, -ORX3, CN, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxyl, -NHRX3, -N(RX3)2, C3-7cycloalkyl, and 3-7 membered heterocycloalkyl; and each R1a, R2A, R3A, R4A, R5A, Rq1, Rv1, Rx1, RX2 and RX3 are independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, and C3-7cycloalkyl.

[0052] In some embodiments, W is selected from -O-, -NRW-, -C(RW)2-, and -C(=O)-. In some embodiments, W is selected from -O- and -NRW-. In some embodiments, W is -NRW-. In some embodiments, Rw is selected from H and -ORW1.

[0053] In some embodiments, W is NH. In some embodiments, W is -CH(OH)-. In some embodiments, W is O. In some embodiments, W is C=O.

[0054] In some embodiments, R1 is selected from H, CN, halogen, Ci-3alkyl, Ci-3haloalkyl, -OR1A, and -SR1A. In some embodiments, R1 is selected from H, halogen, Ci-3alkyl, and Ci-shaloalkyl. In some embodiments, R1 is selected from H, Ci-3alkyl, and Ci-3haloalkyl. In some embodiments, R1 is H. In some embodiments, R1 is Ci-3alkyl. In some embodiments, R1 is Ci-shaloalkyl. In some embodiments, R1 is selected from H, methyl, and trifluoromethyl.

[0055] In some embodiments, R2 is selected from H, CN, halogen, Ci-3alkyl, Ci-3haloalkyl, -OR1A, and -SR1A. In some embodiments, R2 is selected from H, halogen, Ci-3alkyl, and Ci-shaloalkyl. In some embodiments, R2 is selected from H, Ci-3alkyl, and Ci-3haloalkyl. In some embodiments, R2 is H. In some embodiments, R2 is Ci-3alkyl. In some embodiments, R2 is Ci-shaloalkyl. In some embodiments, R2 is selected from H, methyl, and trifluoromethyl. In some embodiments, both R1 and R2 are H.

[0056] In some embodiments, R3 is selected from CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR3A, -CH2OR3A, -SR3A, -NHR3A, and -N(R3A)2. In some embodiments, R3 is selected from CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR3A, and -SR3A. In some embodiments, R3 is selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR3A, and -CH2OR3A. In some embodiments, R3 is halogen. In some embodiments, R3 is Ci-ealkyl. In some embodiments, R3 is Ci-ehaloalkyl. In some embodiments, R3 is -OR3A. In some embodiments, R3 is -CH2OR3A. In some embodiments, R3 is selected from methyl, ethyl, fluoro, chloro, difluoromethyl, methoxyl, and ethoxyl. In some embodiments, R3 is methyl.

[0057] In some embodiments, R4 is selected from CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR4A, -CH2OR4A, -SR4A, -NHR4A, and -N(R4A)2. In some embodiments, R4 is selected from CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR4A, and -SR4A. In some embodiments, R4 is selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR4A. In some embodiments, R4 is halogen. In some embodiments, R4 is Ci-ealkyl. In some embodiments, R4 is Ci-ehaloalkyl. In some embodiments, R4 is -OR4A. In some embodiments, R4 is selected from methyl, ethyl, fluoro, chloro, difluoromethyl, methoxyl, and ethoxyl. In some embodiments, R4 is methyl. In some embodiments, both R3 and R4 are selected from methyl, ethyl, fluoro, chloro, difluoromethyl, methoxyl, and ethoxyl. In some embodiments, both R3 and R4 are methyl.

[0058] In some embodiments, R5 is selected from H, CN, halogen, Ci-ealkyl, Ci-ehaloalky 1, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-10 membered heterocycloalkyl; wherein the Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, and 3-10 membered heterocycloalkyl of R5 are each optionally substituted with 1 or 2 R8 groups. In some embodiments, R5 is selected from H, CN, Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, 3-10 membered heterocycloalkyl; wherein the Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, and 3-10 membered heterocycloalkyl of R5 are each optionally substituted with 1 R8 group. In some embodiments, R5 is selected from H, CN, Ci-ehaloalkyl, 3-10 membered heterocycloalkyl. In some embodiments, R5 is H. In some embodiments, R5 is CN. In some embodiments, R5 is Ci-ehaloalkyl. In some embodiments, R5 is 3-10 membered heterocycloalkyl. In some embodiments, R5 is selected from H, CN, difluoroethyl, and oxetanyl. In some embodiments, R5 isCN.

[0059] In some embodiments, R6 and R7 are independently selected from H and Ci-ealkyl; or R6 and R7 together form a C3-7cycloalkyl. In some embodiments, R7 is Ci-ealkyl. In some embodiments, R6 is H and R7 is methyl. In some embodiments, R6 and R7 are H. In some embodiments, R6 and R7 together form a C3-7cycloalkyl. In some embodiments, R6 and R7 together form a cyclopropyl.

[0060] In some embodiments, both R1 and R2 are H, both R3 and R4 are methyl, both R5 is CN, and both R6 and R7 are H.

[0061] In some embodiments, both R1 and R2 are H, both R3 and R4 are methyl, R5 is CN, both R6 and R7 are H, and W is O.

[0062] In some embodiments, M is selected from -CH2- and -CF2-. In some embodiments, M is -CH2-. In some embodiments, M is -CF2-.

[0063] In some embodiments, both R1 and R2 are H, both R3 and R4 are methyl, R5 is CN, both R6 and R7 are H, W is O, and M is -CH2-.

[0064] In some embodiments, Q, U, and V are independently selected from N, O, S, CRQ, C(Rq)2, NRv, N(Rv)2+, S=O, C=CH2, C=CHF, and C=O. In some embodiments, Q, U, and V are independently selected from N, O, S, CRQ, C(RQ)2, NRV, N(RV)2+, C=CH2, and C=O. In some embodiments, at least one of Q, U, and V is N. In some embodiments, at least one of Q, U, and V is 0. In some embodiments, at least one of Q, U, and V is S. In some embodiments, at least one of Q, U, and V is CRQ. In some embodiments, at least one of Q, U, and V is C(RQ)2. In some embodiments, at least one of Q, U, and V is NRV. In some embodiments, at least one of Q, U, and V is N(RV)2+. In some embodiments, at least one of Q, U, and V is C=O. In some embodiments, at least one of Q, U, and V is C=CH2. In some embodiments, at least one of Q, U, and V is C=CHF. In some embodiments, at least one of Q, U, and V is S=O. In some embodiments, V is C=O, and U is NRV.

[0065] In some embodiments, each RQ is independently selected from H, halogen, -ORQ2, CN, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, -NHRQ2, -N(RQ2)2, -NH(C=O)RQ1, -NH(C=O)ORQ1, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ are each optionally substituted with 1 or 2 R9 groups.

[0066] In some embodiments, each RQ is independently selected from H, halogen, -ORQ2, CN, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, -NHRQ2, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ are each optionally substituted with 1 or 2 R9 groups. In some embodiments, each RQ is independently selected from H, halogen, -ORQ2, CN, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, -NHRQ2, and 5-10 membered heteroaryl; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, and 5-10 membered heteroaryl of RQ are each optionally substituted with 1 or 2 R9 groups. In some embodiments, each Rq is H. In some embodiments, each RQ is halogen. In some embodiments, each RQ is -ORQ2. In some embodiments, each RQ is CN. In some embodiments, each RQ is Ci-ealkyl optionally substituted with 1 or 2 R9 groups. In some embodiments, each RQ is Ci-ehaloalkyl optionally substituted with 1 or 2 R9 groups. In some embodiments, each RQ is C2-ealkenyl optionally substituted with 1 or 2 R9 groups. In some embodiments, each RQ is C3-7cycloalkyl optionally substituted with 1 or 2 R9 groups. In some embodiments, each RQ is 3-7 membered heterocycloalkyl optionally substituted with 1 or 2 R9 groups. In some embodiments, each RQ is -NHRQ2. In some embodiments, each RQ is 5-10 membered heteroaryl optionally substituted with 1 or 2 R9 groups. In some embodiments, RQ is selected from H, CN, OH, F, Cl, Br, I, NH2, NHRQ2, methyl, ethyl, ethylenyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, tetrahydropyranyl, oxazolyl, pyrazolyl, and pyrimidinyl.

[0067] In some embodiments, each RQ2 is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 510 membered heteroaryl, -(C=O)RX1, -(C=O)ORX1, -(C=O)NHRX1, -(C=O)N(RX1)2, and -(SO2)RX1; wherein each C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ2 is optionally substituted with 1 or 2 R11 groups; or two RQ2 together form a 4-7 membered heterocycloalkyl. In some embodiments, each RQ2 is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein each C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ2 is optionally substituted with 1 or 2 R11 groups; or two RQ2 together form a 4-7 membered heterocycloalkyl. In some embodiments, each RQ2 is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, 6-10 membered aryl, 5-10 membered heteroaryl; wherein each 6-10 membered aryl and 5-10 membered heteroaryl of RQ2 is optionally substituted with 1 or 2 R11 groups. In some embodiments, each RQ2 is independently selected from H, Ci-ealkyl, Ci-ealkoxy, 6-10 membered aryl, 5-10 membered heteroaryl; wherein each 6-10 membered aryl and 5-10 membered heteroaryl of RQ2 is optionally substituted with 1 or 2 R11 groups. In some embodiments, each RQ2 is H. In some embodiments, each RQ2 is Ci-ealkyl. In some embodiments, each RQ2 is Ci-ealkoxy.In some embodiments, each RQ2 is 6-10 membered aryl optionally substituted with 1 or 2 R11 groups. In some embodiments, each RQ2 is 5-10 membered heteroaryl optionally substituted with 1 or 2 R11 groups. In some embodiments, each RQ2 is 5-10 membered heteroaryl optionally substituted with 1 or 2 R11 groups. In some embodiments, RQ2 is selected from H, CN, methyl, and methoxyl.

[0068] In some embodiments, each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RV1, -(C=O)ORV1, -(C=O)NHRV1, and -(C=O)N(RV1)2; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rv are each optionally substituted with 1, 2, or 3 R10 groups. In some embodiments, each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RV1, -(C=O)ORV1, -(C=O)NHRV1, and -(C=O)N(RV1)2; wherein each Ci-6alkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rv are each optionally substituted with 1 or 2 R10 groups. In some embodiments, each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RV1, -(C=O)ORV1, -(C=O)NHRV1, and -(C=O)N(RV1)2; wherein each Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rv are each optionally substituted with 1 or 2 R10 groups. In some embodiments, each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and -(C=O)ORV1; wherein each Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, and 6-10 membered aryl of Rv are each optionally substituted with 1 or 2 R10 groups.

[0069] In some embodiments, each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 510 membered heteroaryl, and -(C=O)ORV1; wherein each Ci-ealkyl, Ci-ehaloalkyl, C3- 7cycloalkyl, 4-7 membered heterocycloalkyl, and 6-10 membered aryl of Rv are each optionally substituted with 1, 2, or 3 R10 groups. In some embodiments, each Rv is H. In some embodiments, each Rv is Ci-ealkyl optionally substituted with 1 or 2 R10 groups. In some embodiments, each Rv is Ci-ehaloalkyl optionally substituted with 1 or 2 R10 groups. In some embodiments, each Rv is C2-ealkenyl. In some embodiments, each Rv is C3-7cycloalkyl optionally substituted with 1 or 2 R10 groups. In some embodiments, each Rv is 4-7 membered heterocycloalkyl optionally substituted with 1 or 2 R10 groups. In some embodiments, each Rv is 6-10 membered aryl optionally substituted with 1 or 2 R10 groups. In some embodiments, each Rv is -(C=O)ORV1. In some embodiments, each Rv is independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, phenyl, and -(C=O)ORV1.

[0070] In some embodiments, RV1 is selected from H, Ci-ealkyl, Ci-ehaloalkyl, and C3-7cycloalkyl. In some embodiments, RV1 is Ci-ealkyl. In some embodiments, RV1 is methyl or tertbutyl.

[0071] In some embodiments, two Rv together form a 4-7 membered heterocycloalkyl. In some embodiments, RQ and Rv together form a 4-11 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein the 4-11 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted with 1 or 2 R13 groups.

[0072] In some embodiments, each R9 and R10 are independently selected from halogen, -ORX2, CN, Ci-ealkyl, C1 -ehaloalky 1, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RX2, -(C=O)ORX2, -(C=O)NHRX2, and -(C=O)N(RX2)2; wherein the C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R9 and R10 are each optionally substituted with 1 or 2 R12 groups. In some embodiments, each R9 and R10 are independently selected from halogen, -ORX2, CN, Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)NHRX2, and -(C=O)N(RX2)2; wherein the C3-7cycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R9 and R10 are each optionally substituted with 1 or 2 R12 groups. In some embodiments, each R9 and R10 are independently selected from halogen, -ORX2, CN, Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and -(C=O)NHRX2; wherein the C3-7cycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R9 and R10 are each optionally substituted with 1 or 2 R12 groups. In some embodiments, each R9 and R10 are independently selected from halogen, -ORX2, CN, Ci-ealkyl, C3-7cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and -(C=O)NHRX2; wherein the C3-7cycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R9 and R10 are each optionally substituted with 1 or 2 R12 groups. In some embodiments, each R9 and R10 are independently selected from fluoro, hydroxyl, methoxyl, CN, methyl, trifluoromethyl, cyclopropyl, morpholinyl, phenyl, pyrazole, and -(C=0)NHRX2. In some embodiments, each R9 and R10 are independently selected from fluoro, hydroxyl, methoxyl, CN, methyl, cyclopropyl, phenyl, pyrazole, and -(C=O)NHRX2.

[0073] In some embodiments, each R11, R12, and R13 are independently selected from halogen, -ORX3, CN, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxyl, C3-7cycloalkyl, and 3-7 membered heterocycloalkyl; wherein each Ci-ealkyl of R11, R12 and R13 is optionally substituted with -ORX4. In some embodiments, each R11 and R12 are independently selected from halogen, -ORX3, CN, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxyl, C3-7cycloalkyl, and 3-7 membered heterocycloalkyl.

[0074] In some embodiments, each R11, R12, and R13 are independently selected from halogen, -ORX3, CN, Ci-ealkyl, Ci-ehaloalkyl, and Ci-ealkoxyl wherein each Ci-ealkyl of R11, R12 and R13 is optionally substituted with -ORX4. In some embodiments, each R11 and R12 are independently selected from halogen, -ORX3, CN, Ci-ealkyl, Ci-ehaloalkyl, and Ci-ealkoxyl. In some embodiments, each R11, R12 and R13 are independently selected from halogen.

[0075] In some embodiments, each R11, R12, and R13 are independently selected from -ORX3 and Ci-ealkyl wherein each Ci-ealkyl of R11, R12 and R13 is optionally substituted with -ORX4.In some embodiments, each R11 and R12 are independently selected from -ORX3 and Ci-ealkyl. In some embodiments, each R11, R12 and R13 are independently selected from methoxyl and methyl. In some embodiments, each R11 and R12 are independently selected from methoxyl and methyl.

[0076] In some embodiments, R14is H. In some embodiments, R14 is Ci-ealkyl.

[0077] In some embodiments, each R1A, R2A, R3A, R4A, R5A, RQ1, RV1, RW1, RX1, RX2, RX3, and RX4 are independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, and C3-7cycloalkyl. In some embodiments, each R1A, R2A, R3A, R4A, R5A, RQ1, RX1, RX2 and RX3 are independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, and C3-7cycloalkyl. In some embodiments, each R1A, R2A, R3A, R4A, R5A, Rq1, Rv1, Rw1, Rx1, RX2, RX3, and RX4 are independently selected from H, Ci-ealkyl, and C3-7cycloalkyl. In some embodiments, each R1A, R2A, R3A, R4A, R5A, RQ1, RX1, RX2 and RX3 are independently selected from H, Ci-ealkyl, and C3-7cycloalkyl. In some embodiments, each R1A, R2A, R3A, R4A, R5A, Rq1, Rv1, Rw1, Rx1, RX2, RX3, and RX4 are independently selected from H and Ci-ealkyl. In some embodiments, each R1A, R2A, R3A, R4A, R5A, RQ1, RX1, RX2 and RX3 are independently selected from H and Ci-ealkyl. In some embodiments, RX2 is methyl. In some embodiments, RX3 is methyl. [0078J Some embodiments provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: — is a single bond or a double bond; R1 is selected from H, Ci-3alkyl, and Ci-shaloalkyl; R2 is selected from H, Ci-3alkyl, and Ci-shaloalkyl; R3 is selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR3A, -SR3A, -NHR3A, and -N(R3A)2; R4 is selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR4A, -SR4A, -NHR4A, and -N(R4A)2; R5 is selected from H, CN, Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, and 3-10 membered heterocycloalkyl; R6 and R7 are independently selected from H and Ci-ealkyl; or R6 and R7 together form a C3-7cycloalkyl or 3-7 membered heterocycloalkyl; M is selected from -CH2-, -CF2-, -CH2CH2-, and -CH2O-; W is selected from -0-, -S-, -C(RW)2-, -NRW-, and -C(=O)-; each Rwis independently selected from H, -ORW1, and Ci-ealkyl; Q, U, and V are independently selected from N, O, S, CRQ, C(RQ)2, NRV, N(RV)2+, S=0, S02, C=CH2, C=CHF, and C=0; each Rq is independently selected from H, halogen, -0RQ2, CN, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, -NHRQ2, -N(RQ2)2, 610 membered aryl, and 5-10 membered heteroaryl; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2. ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ are each optionally substituted with 1 or 2 R9 groups; each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2. ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RV1, -(C=O)ORV1, -(C=O)NHRV1, -(C=O)N(RV1)2, -S(O)RV1, and -S(O)2RV1; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rv are each optionally substituted with 1, 2, or 3 R10 groups; each RQ2 is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein the C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ2 is optionally substituted with 1 or 2 R11 groups; or two Rv together form a 4-7 membered heterocycloalkyl; or Rq and Rv together form a 4-11 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein the 4-11 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted with 1 or 2 R13 groups each R9 and R10 are independently selected from halogen, -ORX2, CN, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, 510 membered heteroaryl, -(C=O)RX2, -(C=O)ORX2, -(C=0)NHRX2, -(C=O)N(RX2)2, and -(SO2)RX2; wherein the C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R9 and R10 are each optionally substituted with 1 or 2 R12 groups; each R11, R12, and R13 are independently selected from halogen, -ORX3, CN, Ci-ealkyl, Ci-ehaloalkyl, and Ci-ealkoxyl; wherein each Ci-ealkyl of R11, R12 and R13 is optionally substituted with -ORX4; R14 H; and each R3A, R4A, Rv1, Rw1, RX2, RX3, andRX4 are independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, and C3-7cycloalkyl.

[0079] Some embodiments provide a compound of Formula (la), or a pharmaceutically acceptable salt thereof, wherein: = is a single bond or a double bond; R1 is selected from H, Ci-3alkyl, and Ci-3haloalkyl; R2 is selected from H, Ci-3alkyl, and Ci-3haloalkyl; R3 is selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR3A, -CH2OR3A, -SR3A, -NHR3A, and          -N(R3A)2; R4 is selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR4A, -CH2OR4A, -SR3A, -NHR3A, and          -N(R3A)2; R5 is selected from H, CN, Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, and 3-10 membered heterocycloalkyl; R6 and R7 are independently selected from H andCi-ealkyl; or R6 and R7 together form a C3-7cycloalkyl or 3-7 membered heterocycloalkyl; M is selected from -CH2-, -CF2-, -CH2CH2-, and -CH2O-; W is selected from -O-, -S-, -C(RW)2-, and -NRW-; each Rwis independently selected from H and Ci-ealkyl; WO 2025 / 184609                                   PCT / US2025 / 017990 Q, U, and V are independently selected from N, 0, S, CRQ, C(RQ)2, NRV, N(RV)2+, SO2, C=CH2, and C=0; each Rq is independently selected from H, halogen, -0RQ2, CN, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, -NHRQ2, -N(RQ2)2, 610 membered aryl, and 5-10 membered heteroaryl; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ are each optionally substituted with 1 or 2 R9 groups; each Rv is independently selected from H, Ci-6alkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RV1, -(C=O)ORV1, -(C=O)NHRV1, -(C=O)N(RV1)2, -S(O)RV1, and -S(O)2RV1; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rv are each optionally substituted with 1 or 2 R10 groups; each RQ2 is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein the C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ2 is optionally substituted with 1 or 2 R11 groups; each R9 and R10 are independently selected from halogen, -ORX2, CN, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, 510 membered heteroaryl, -(C=O)RX2, -(C=O)ORX2, -(C=0)NHRX2, -(C=O)N(RX2)2, and -(SO2)RX2; wherein the C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R9 and R10 are each optionally substituted with 1 or 2 R12 groups; each R11 and R12 are independently selected from halogen, -ORX3, CN, Ci-ealkyl, Ci-ehaloalkyl, and Ci-ealkoxyl; and each R3A, R4A, Rq1, Rv1, Rx1, RX2 and RX3 are independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, and C3-7cycloalkyl.

[0080] Some embodiments provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: — is a single bond or a double bond; R1 is selected from H and Ci-3haloalkyl; R2 is selected from H and Ci-3haloalkyl; R3 is selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, and -OR3A; R4 is selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, and -OR4A; R5 is selected from H, CN, Ci-ehaloalkyl, 3-10 membered heterocycloalkyl; WO 2025 / 184609                                   PCT / US2025 / 017990 R6 and R7 are independently selected from H and Ci-ealkyl; or R6 and R7 together form a C3-7cycloalkyl; M is selected from -CH2- and -CF2-; W is selected from -0-, -CH(OH)-, -NH-, and -C(=0)-; Q, U, and V are independently selected from N, 0, S, CRQ, C(RQ)2, NRV, N(RV)2+, C=CH2, and C=0; each Rq is independently selected from H, halogen, -0RQ2, CN, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, -NHRQ2, and 5-10 membered heteroaryl; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, and 5-10 membered heteroaryl of RQ are each optionally substituted with 1 or 2 R9 groups; each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and -(C=O)ORV1; wherein each Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, and 4-7 membered heterocycloalkyl of Rv are each optionally substituted with 1, 2, or 3 R10 groups; each RQ2 is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the 6-10 membered aryl, and 5-10 membered heteroaryl of RQ2 is optionally substituted with 1 or 2 R11 groups; or two Rv together form a 4-7 membered heterocycloalkyl; or Rq and Rv together form a 4-11 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein the 4-11 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 R13 groups; each R9 and R10 are independently selected from halogen, -ORX2, CN, Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and -(C=0)NHRX2; wherein the C3-7cycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R9 and R10 are each optionally substituted with 1 or 2 R12 groups; each R11, R12, and R13 are independently selected from halogen, -ORX3, CN, and Ci-ealkyl; wherein each Ci-ealkyl of R11, R12 and R13 is optionally substituted with -ORX4; R14 is H; and each R3A, R4A, Rv1, RX2 RX3, and RX4 are independently selected from H and Ci-ealkyl.

[0081] Some embodiments provide a compound of Formula (la), or a pharmaceutically acceptable salt thereof, wherein: = is a single bond or a double bond; R1 is selected from H and Ci-3haloalkyl; R2 is selected from H and Ci-3haloalkyl; R3 is selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, and -OR3A; R4 is selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, and -OR4A; R5 is selected from H, CN, Ci-ehaloalkyl, 3-10 membered heterocycloalkyl; R6 and R7 are H or R6 and R7 together form a C3-7cycloalkyl; M is selected from -CH2- and -CF2-; W is selected from -O- and -NH-; Q, U, and V are independently selected from N, O, S, CRQ, C(RQ)2, NRV, N(RV)2+, C=CH2, and C=0; each Rq is independently selected from H, halogen, -0RQ2, CN, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, -NHRQ2, and 5-10 membered heteroaryl; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, and 5-10 membered heteroaryl of RQ are each optionally substituted with 1 or 2 R9 groups; each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and -(C=O)ORV1; wherein each Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, and 4-7 membered heterocycloalkyl of Rv are each optionally substituted with 1 or 2 R10 groups; each RQ2 is independently selected from H, Ci-ealkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the 6-10 membered aryl, and 5-10 membered heteroaryl of RQ2 is optionally substituted with 1 or 2 R11 groups; each R9 and R10 are independently selected from halogen, -ORX2, CN, Ci-ealkyl, C3-7cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and -(C=0)NHRX2,; wherein the C3-7cycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R9 and R10 are each optionally substituted with 1 or 2 R12 groups; each R11 and R12 are independently selected from -ORX3, and Ci-ealkyl; and each R3A, R4A, Rv1, RX2 and RX3 are independently selected from H and Ci-ealkyl.

[0082] Some embodiments provide a compound of Formula (Ila), or a pharmaceutically acceptable salt thereof, CN                (Ila) wherein — is a single bond or a double bond; and R1, R2, R3, R4, R5, R6, R7, M, W, Q, U, and V are defined herein.

[0083] In some embodiments of Formula (Ila), both R1 and R2 are H. In some embodiments, both R3 and R4 are methyl. In some embodiments, R5 is CN. In some embodiments, both R6 and R7 are H.

[0084] In some embodiments, both R1 and R2 are H, both R3 and R4 are methyl, R5 is CN, both R6 and R7 are H, and W is O.

[0085] Some embodiments provide a compound of Formula selected from (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (Ili), and (Ilj), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, Rv, and RQ are defined herein.

[0086] Some embodiments provide a compound of Formula (lib), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, Rv, and RQ are defined herein.

[0087] In some embodiments of Formula (Hb), both R1 and R2 are H.

[0088] In some embodiments of Formula (Hb), each R3 and R4 is independently selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, and -OR3A. In some embodiments, each R3 and R4is independently selected from F, Cl, methyl, ethyl, methoxyl, and ethoxyl. In some embodiments, both R3 and R4 are methyl.

[0089] In some embodiments of Formula (lib), Rv is selected from H, Ci-ealkyl, Ci-ehaloalky 1, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl. In some embodiments of Formula (lib), Rv is selected from H, methyl, ethyl, -CHCHF2, -CH2F, -CHF2, and -CF3. In some embodiments of Formula (lib), Rv is selected from H, cyclopropyl, and -CHCHF2.

[0090] In some embodiments of Formula (lib), each RQ is independently selected from H, halogen, -ORQ2, Ci-ealkyl, Ci-ehaloalkyl, and C3-7cycloalkyl. In some embodiments, each RQ is independently selected from H, methyl, -OH, -CH2F, -CHF2, and -CF3.

[0091] Some embodiments provide a compound of Formula (lie), or a pharmaceutically acceptable salt thereof, CN            (lie) wherein R1, R2, R3, R4, and Rv are defined herein.

[0092] In some embodiments of Formula (lie), both R1 and R2 are H.

[0093] In some embodiments of Formula (lie), both R3 and R4are methyl.

[0094] In some embodiments of Formula (lie), each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, and C3-7cycloalkyl. In some embodiments, each Rv is independently selected from H, methyl, ethyl, -CH2F, -CHF2, and -CF3.

[0095] Some embodiments provide a compound of Formula (lid), or a pharmaceutically acceptable salt thereof, CN            (lid) wherein R1, R2, R3, R4, and RQ are defined herein.

[0096] In some embodiments of Formula (lid), both R1 and R2 are H.

[0097] In some embodiments of Formula (lid), both R3 and R4 are methyl. WO 2025 / 184609                                   PCT / US2025 / 017990

[0098] In some embodiments of Formula (lid), each RQ is independently selected from H, halogen, -ORQ2, Ci-ealkyl, Ci-ehaloalkyl, and C3-7cycloalkyl. In some embodiments, each RQ is independently selected from H, F, Cl, and methyl.

[0099] Some embodiments provide a compound of Formula (lie), or a pharmaceutically acceptable salt thereof, CN            (lie) wherein R1, R2, R3, R4, Rv, and RQ are defined herein.

[0100] In some embodiments of Formula (lie), both R1 and R2 are H.

[0101] In some embodiments of Formula (lie), both R3 and R4are methyl.

[0102] In some embodiments of Formula (lie), Rv is selected from H, Ci-ealkyl, Ci-ehaloalky 1, and -(C=O)ORV1. In some embodiments, Rv is selected from H, methyl, -C(O)OCH3, and -C(O)OC(CH3)3.

[0103] In some embodiments of Formula (lie), each RQ is independently selected from H, halogen, -ORQ2, Ci-ealkyl, Ci-ehaloalkyl, and C3-7cycloalkyl. In some embodiments, each RQ is independently selected from H, F, and methyl.

[0104] Some embodiments provide a compound of Formula (Ilf), or a pharmaceutically acceptable salt thereof, CN             (Ilf) wherein R1, R2, R3, R4, Rv, and RQ are defined herein.

[0105] In some embodiments of Formula (Ilf), both R1 and R2 are H.

[0106] In some embodiments of Formula (Ilf), both R3 and R4 are methyl.

[0107] In some embodiments of Formula (Ilf), each Rv is independently selected from Ci-ealkyl, and Ci-ehaloalkyl. In some embodiments, each Rv is methyl.

[0108] In some embodiments of Formula (Ilf), each RQ is independently selected from H, halogen, Ci-ealkyl, and Ci-ehaloalkyl. In some embodiments, each RQ is independently selected from H, and methyl.

[0109] Some embodiments provide a compound of Formula (Ilg), or a pharmaceutically acceptable salt thereof, CN            (IIg) wherein R1, R2, R3, R4, Rv, and RQ are defined herein. WO 2025 / 184609                                   PCT / US2025 / 017990

[0110] In some embodiments of Formula (Ilg), both R1 and R2 are H.

[0111] In some embodiments of Formula (Ilg), both R3 and R4 are methyl.

[0112] In some embodiments of Formula (Ilg), Rv is selected from H, Ci-ealkyl, and Ci-ehaloalkyl. In some embodiments, Rv is H.

[0113] In some embodiments of Formula (Ilg), each RQ is independently selected from H, halogen, Ci-ealkyl, and Ci-ehaloalkyl. In some embodiments, each RQ is independently selected from H, and methyl.

[0114] Some embodiments provide a compound of Formula (Ilh), or a pharmaceutically acceptable salt thereof, CN          (Uh) wherein R1, R2, R3, R4, and RQ are defined herein.

[0115] In some embodiments of Formula (Ilh), both R1 and R2 are H.

[0116] In some embodiments of Formula (Ilh), both R3 and R4 are methyl.

[0117] In some embodiments of Formula (Ilh), each RQ is independently selected from H, halogen, Ci-ealkyl, and Ci-ehaloalkyl. In some embodiments, each RQ is independently selected from H, and methyl.

[0118] Some embodiments provide a compound of Formula (Ili), or a pharmaceutically acceptable salt thereof, CN             (Ili) wherein R1, R2, R3, R4, and RQ are defined herein.

[0119] In some embodiments of Formula (Ili), both R1 and R2 are H.

[0120] In some embodiments of Formula (Ili), both R3 and R4 are methyl. [0121J In some embodiments of Formula (Ili), each RQ is independently selected from H, halogen, Ci-ealkyl, and Ci-ehaloalkyl. In some embodiments, each RQ is independently selected from H, and methyl.

[0122] Some embodiments provide a compound of Formula (Ilj), or a pharmaceutically acceptable salt thereof, CN              (Ilj).

[0123] In some embodiments of Formula (Ilj), both R1 and R2 are H.

[0124] In some embodiments of Formula (Ilj), both R3 and R4 are methyl.

[0125] In some embodiments of Formula (Ilj), each RQ is independently selected from H, halogen, Ci-ealkyl, and Ci-ehaloalkyl. In some embodiments, each RQ is independently selected from H, and methyl.

[0126] Some embodiments provide a compound of Formula (Illa), or a pharmaceutically acceptable salt thereof, U-— CN            (ma) wherein — is a single bond or a double bond; and R1, R2, R3, R4, R5, R6, R7, M, W, Q, U, and V are defined herein.

[0127] In some embodiments of Formula (Illa), both R1 and R2 are H.

[0128] In some embodiments of Formula (Illa), both R3 and R4 are methyl.

[0129] In some embodiments of Formula (Illa), W is O.

[0130] Some embodiments provide a compound of Formula selected from (Illb), (IIIc), (Illd), (Ilie), (Illf), (Illg), (IHh), (Illi), (Illj), (Illk), (III1), (Illm), and (Ilin), or a pharmaceutically acceptable salt thereof,

[0131] Some embodiments provide a compound of Formula (Illb), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, and RQ are defined herein. WO 2025 / 184609                                   PCT / US2025 / 017990

[0132] In some embodiments of Formula (Illb), both R1 and R2 are H.

[0133] In some embodiments of Formula (Illb), both R3 and R4 are methyl.

[0134] In some embodiments of Formula (Illb), W is O.

[0135] In some embodiments of Formula (Illb), RQ is selected from H, halogen, Ci-ealkyl, and Ci-ehaloalkyl. In some embodiments, RQ is selected from H, methyl, -CH2F, -CHF2, and -CF3.

[0136] Some embodiments provide a compound of Formula (IIIc), or a pharmaceutically acceptable salt thereof, CN         (me) wherein R1, R2, R3, R4, Rv, and RQ are defined herein.

[0137] In some embodiments of Formula (IIIc), both R1 and R2 are H.

[0138] In some embodiments of Formula (IIIc), both R3 and R4 are methyl.

[0139] In some embodiments of Formula (IIIc), W is O.

[0140] In some embodiments of Formula (IIIc), RQ is selected from H, halogen, Ci-ealkyl, Ci-ehaloalkyl, and -OCi-ealkyl, wherein Ci-ealkyl is optional substituted with one or two groups selected from OH, and -OCi-ealkyl. In some embodiments, RQ is selected from H, methyl, ethyl, -CH2F, -CHF2, -CF3, -0CH3, -OCH2CH3, -CH2OH, -CH(OH)CH3, and -CH2OCH3.

[0141] In some embodiments of Formula (IIIc), Rv is selected from H, Ci-ealkyl, and Ci-ehaloalkyl. In some embodiments, Rv is selected from H, methyl, ethyl, -CH2F, -CHF2, and -CF3. In some embodiments, Rv is -CHF2.

[0142] In some embodiments of Formula (IIIc), the compound is of formula (IIIcc): ON           (nice).

[0143] In some embodiments of Formula (IIIcc), both R1 and R2 are H.

[0144] In some embodiments of Formula (IIIcc), both R3 and R4 are methyl.

[0145] In some embodiments of Formula (IIIcc), RQ is selected from H, halogen, Ci-ealkyl, Ci-ehaloalkyl, and -OCi-ealkyl, wherein Ci-ealkyl is optional substituted with one or two groups selected from OH, and -OCi-ealkyl. In some embodiments, RQ is selected from H, methyl, ethyl, -CH2F, -CHF2, -CF3, -OCH3, -OCH2CH3, -CH2OH, -CH(OH)CH3, and -CH2OCH3.

[0146] In some embodiments of Formula (IIIcc), Rv is selected from H, Ci-ealkyl, and Ci-ehaloalkyl. In some embodiments, Rv is selected from H, methyl, ethyl, -CH2F, -CHF2, and -CF3. In some embodiments, Rv is -CHF2.

[0147] Some embodiments provide a compound of Formula (Illd), or a pharmaceutically acceptable salt thereof, CN            (Illd) wherein R1, R2, R3, R4, Rv, and RQ are defined herein.

[0148] In some embodiments of Formula (Hid), both R1 and R2 are H.

[0149] In some embodiments of Formula (Hid), both R3 and R4 are methyl.

[0150] In some embodiments of Formula (Hid), W is O.

[0151] In some embodiments of Formula (Hid), RQ is selected from H, Ci-ealkyl, and Ci-ehaloalkyl. In some embodiments, RQ is selected from H, methyl, and ethyl.

[0152] In some embodiments of Formula (Illd), Rv is selected from H, Ci-ealkyl, and Ci-ehaloalkyl.

[0153] Some embodiments provide a compound of Formula (Ilie), or a pharmaceutically acceptable salt thereof, Rv N—NZ CN           (ine) wherein R1, R2, R3, R4, Rv, and RQ are defined herein.

[0154] In some embodiments of Formula (Ilie), both R1 and R2 are H.

[0155] In some embodiments of Formula (Ilie), both R3 and R4 are methyl.

[0156] In some embodiments of Formula (Ilie), W is O.

[0157] In some embodiments of Formula (Ilie), RQ is selected from H, halogen, Ci-ealkyl, Ci-ehaloalkyl, and NH2. In some embodiments, RQ is selected from H, methyl, ethyl, Cl, Br, and NH2.

[0158] In some embodiments of Formula (Ilie), Rv is selected from H, Ci-ealkyl, and Ci-ehaloalkyl.

[0159] Some embodiments provide a compound of Formula (Illf), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, Rv, and RQ are defined herein.

[0160] In some embodiments of Formula (Illf), both R1 and R2 are H.

[0161] In some embodiments of Formula (Illf), both R3 and R4are methyl.

[0162] In some embodiments of Formula (Illf), W is O.

[0163] In some embodiments of Formula (Illf), RQ is selected from H, Ci-ealkyl, and Ci-ehaloalkyl. In some embodiments, RQ is selected from H, methyl, and ethyl.

[0164] In some embodiments of Formula (Illf), Rv is selected from H, Ci-ealkyl, and Ci-ehaloalkyl.

[0165] Some embodiments provide a compound of Formula (Illg), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, Rv, and RQ are defined herein.

[0166] In some embodiments of Formula (Illg), both R1 and R2 are H.

[0167] In some embodiments of Formula (Illg), both R3 and R4 are methyl.

[0168] In some embodiments of Formula (Illg), W is O.

[0169] In some embodiments of Formula (Illg), RQ is selected from H, Ci-ealkyl, and Ci-ehaloalkyl. In some embodiments, RQ is selected from H, methyl, and ethyl.

[0170] In some embodiments of Formula (Illg), Rv is selected from H, Ci-ealkyl, and Ci-ehaloalkyl.

[0171] Some embodiments provide a compound of Formula (Illh), or a pharmaceutically acceptable salt thereof, CN             (Illh) wherein R1, R2, R3, R4, Rv, and RQ are defined herein.

[0172] In some embodiments of Formula (Illh), both R1 and R2 are H.

[0173] In some embodiments of Formula (Illh), both R3 and R4 are methyl.

[0174] In some embodiments of Formula (Illh), W is O.

[0175] In some embodiments of Formula (Illh), RQ is selected from H, Ci-ealkyl, and Ci-ehaloalkyl. In some embodiments, RQ is selected from H, methyl, and ethyl.

[0176] In some embodiments of Formula (Illh), Rv is selected from H, Ci-ealkyl, and Ci-ehaloalkyl. WO 2025 / 184609                                   PCT / US2025 / 017990

[0177] Some embodiments provide a compound of Formula (Illi), or a pharmaceutically acceptable salt thereof, CN          (mi) wherein R1, R2, R3, R4, Rv, and RQ are defined herein.

[0178] In some embodiments of Formula (Illi), both R1 and R2 are H.

[0179] In some embodiments of Formula (Illi), both R3 and R4are methyl.

[0180] In some embodiments of Formula (Illi), W is O.

[0181] In some embodiments of Formula (Illi), each RQ is independently selected from H, Ci-ealkyl, and Ci-ehaloalkyl. In some embodiments, each RQ is independently selected from H, methyl, and ethyl.

[0182] In some embodiments of Formula (Illi), Rv is selected from H, Ci-ealkyl, and Ci-ehaloalkyl.

[0183] Some embodiments provide a compound of Formula (Illj), or a pharmaceutically acceptable salt thereof, (Illj) wherein R1, R2, R3, R4, and Rv are defined herein.

[0184] In some embodiments of Formula (Illj), both R1 and R2 are H.

[0185] In some embodiments of Formula (Illj), both R3 and R4are methyl.

[0186] In some embodiments of Formula (Illj), W is O.

[0187] In some embodiments of Formula (Illj), Rv is selected from H, Ci-ealkyl, and Ci- ehaloalkyl.

[0188] Some embodiments provide a compound of Formula (Illk), or a pharmaceutically acceptable salt thereof, CN             (Illk) wherein R1, R2, R3, R4, and Rv are defined herein.

[0189] In some embodiments of Formula (Illk), both R1 and R2 are H.

[0190] In some embodiments of Formula (Illk), both R3 and R4 are methyl.

[0191] In some embodiments of Formula (Illk), W is O. WO 2025 / 184609                                   PCT / US2025 / 017990

[0192] In some embodiments of Formula (Illk), Rv is selected from H, Ci-ealkyl, and Ci-ehaloalkyl.

[0193] Some embodiments provide a compound of Formula (III1), or a pharmaceutically acceptable salt thereof, cn            (nil) wherein R1, R2, R3, R4, and Rv are defined herein.

[0194] In some embodiments of Formula (III1), both R1 and R2 are H.

[0195] In some embodiments of Formula (III1), both R3 and R4are methyl.

[0196] In some embodiments of Formula (III1), W is O.

[0197] In some embodiments of Formula (III1), Rv is selected from H, Ci-ealkyl, and Ci- ehaloalkyl.

[0198] Some embodiments provide a compound of Formula (Illm), or a pharmaceutically acceptable salt thereof, CN            (Illm) wherein R1, R2, R3, R4, and RQ are defined herein.

[0199] In some embodiments of Formula (Illm), both R1 and R2 are H.

[0200] In some embodiments of Formula (Illm), both R3 and R4are methyl.

[0201] In some embodiments of Formula (Illm), W is O.

[0202] In some embodiments of Formula (Illm), RQis selected from H, Ci-ealkyl, and Ci- ehaloalkyl.

[0203] Some embodiments provide a compound of Formula (Ilin), or a pharmaceutically acceptable salt thereof, (Ilin). wherein R1, R2, R3, R4, RQ, and Rv are defined herein.

[0204] In some embodiments of Formula (Ilin), both R1 and R2 are H.

[0205] In some embodiments of Formula (Ilin), both R3 and R4 are methyl.

[0206] In some embodiments of Formula (Ilin), W is O.

[0207] In some embodiments of Formula (Ilin), Rv is selected from H, Ci-ealkyl, and Ci-ehaloalkyl. Pharmaceutical Compositions

[0208] Pharmaceutical compositions comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be prepared with conventional carriers (e.g., inactive ingredient or excipient material) which may be selected in accord with ordinary practice. Tablets may contain excipients including glidants, fillers, binders and the like. Aqueous compositions may be prepared in sterile form, and when intended for delivery by other than oral administration generally may be isotonic. All compositions may optionally contain excipients such as those set forth in the Rowe et al, Handbook of Pharmaceutical Excipients, 5th edition, American Pharmacists Association, 1986. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. In certain embodiments, the composition relates to a solid dosage form, including a solid oral dosage form. The pH of a composition may range from about 3 to about 11, but is ordinarily about 7 to 10.

[0209] While it is possible for the active ingredients to be administered alone, it may be preferable to present them as pharmaceutical compositions. The compositions, both for veterinary and for human use, comprise at least one compound disclosed herein, together with one or more acceptable carriers and optionally other therapeutic ingredients. In one embodiment, the pharmaceutical composition comprises a compound disclosed herein, or a tautomer or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier and one other therapeutic ingredient. The carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the composition and physiologically innocuous to the recipient thereof.

[0210] The compositions include those suitable for various administration routes, including oral administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active, ingredient (e.g., a compound disclosed herein disclosed herein or a pharmaceutical salt thereof) with one or more inactive ingredients (e.g., a carrier, pharmaceutical excipient, etc.). The compositions may be prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. Techniques and formulations generally are found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006. [0211J Compositions described herein that are suitable for oral administration may be presented as discrete units (a unit dosage form) including but not limited to capsules, cachets or tablets each containing a predetermined amount of the active ingredient.

[0212] Pharmaceutical compositions disclosed herein comprise one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0213] The amount of active ingredient that may be combined with the inactive ingredients to produce a dosage form may vary depending upon the intended treatment subject and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of carrier material (e.g., inactive ingredient or excipient material). In certain embodiments, the carrier material varies from about 5 to about 95% of the total compositions (weightweight). WO 2025 / 184609                                   PCT / US2025 / 017990

[0214] It should be understood that in addition to the ingredients particularly mentioned above the compositions of these embodiments may include other agents conventional in the art having regard to the type of composition in question, for example those suitable for oral administration may include flavoring agents.

[0215] In certain embodiments, a composition comprising an active ingredient disclosed herein (a compound disclosed herein or a pharmaceutically acceptable salt thereof) in one variation does not contain an agent that affects the rate at which the active ingredient is metabolized. Thus, it is understood that compositions comprising a compound disclosed herein in certain embodiments do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound disclosed herein or any other active ingredient administered separately, sequentially or simultaneously with a compound disclosed herein. It is also understood that any of the methods, kits, articles of manufacture and the like detailed herein in certain embodiments do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound disclosed herein or any other active ingredient administered separately, sequentially or simultaneously with a compound of any one disclosed herein. Methods of Use

[0216] Disclosed herein is a method of prematurely activating an HIV protease in an individual in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to the individual. Disclosed herein is a method of inhibiting an HIV reverse transcriptase in an individual in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to the individual. In certain embodiments, the individual in need thereof is a human who has been infected with HIV. In certain embodiments, the individual in need thereof is a human who has been infected with HIV but who has not developed AIDS. In certain embodiments, the individual in need thereof is an individual at risk for developing AIDS. In certain embodiments, the individual in need thereof is a human who has been infected with HIV and who has developed AIDS. In certain embodiments of the methods disclosed herein, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered to the individual separately, sequentially or simultaneously with another active ingredient for treating HIV, such as, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV Tat inhibitors, HIV Tat mimetics, gp41 inhibitors, CXCR4 inhibitors, gp!20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof. [0217J In certain embodiments, a method for treating or preventing an HIV viral infection in an individual (e.g., a human), comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to the individual is disclosed.

[0218] In certain embodiments, a method for inhibiting the replication of the HIV virus, treating AIDS or delaying the onset of AIDS in an individual (e.g., a human), comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to the individual is disclosed.

[0219] In certain embodiments, a method for preventing an HIV infection in an individual (e.g., a human), comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to the individual is disclosed. In certain embodiments, the individual is at risk of contracting the HIV virus, such as an individual who has one or more risk factors known to be associated with contracting the HIV virus.

[0220] In certain embodiments, a method for treating an HIV infection in an individual (eg., a human), comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to the individual is disclosed.

[0221] In certain embodiments, a method for treating an HIV infection in an individual (e.g., a human), comprising administering to the individual in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV Tat inhibitors, HIV Tat mimetics, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof is disclosed.

[0222] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof for use in medical therapy of an HIV viral infection (e.g. HIV-1 or the replication of the HIV virus (e.g. HIV-1) or AIDS or delaying the onset of AIDS in an individual (e.g., a human)) is disclosed. [0223J In certain embodiments, a compound of any disclosed herein, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating an HIV viral infection or the replication of the HIV virus or AIDS or delaying the onset of AIDS in an individual (e.g., a human) is disclosed. One embodiment relates to a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV infection or AIDS or for use in the therapeutic treatment or delaying the onset of AIDS is disclosed.

[0224] In certain embodiments, the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for an HIV virus infection in an individual (e.g., a human) is disclosed. In certain embodiments, a compound of any disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV virus infection is disclosed.

[0225] In certain embodiments, in the methods of use, the administration is to an individual (e.g., a human) in need of the treatment. In certain embodiments, in the methods of use, the administration is to an individual (e.g., a human) who is at risk of developing AIDS.

[0226] Disclosed herein is a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in therapy. In one embodiment, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is for use in a method of treating an HIV viral infection or the replication of the HIV virus or AIDS or delaying the onset of AIDS in an individual (e.g., a human).

[0227] Also disclosed herein is a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing HIV in an individual in need thereof. In certain embodiments, the individual in need thereof is a human who has been infected with HIV. In certain embodiments, the individual in need thereof is a human who has been infected with HIV but who has not developed AIDS. In certain embodiments, the individual in need thereof is an individual at risk for developing AIDS. In certain embodiments, the individual in need thereof is a human who has been infected with HIV and who has developed AIDS.

[0228] Also disclosed herein is a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic treatment or delaying the onset of AIDS.

[0229] Also disclosed herein is a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV infection. WO 2025 / 184609                                   PCT / US2025 / 017990

[0230] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof can be used as a research tool (e.g. to study the premature activation of HIV protease in a subject or in vitro). Routes of Administration

[0231] One or more compounds disclosed herein (also referred to herein as the active ingredients) can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with, for example, the condition of the recipient. In certain embodiments, the compounds disclosed are orally bioavailable and can be dosed orally. HIV Combination Therapy

[0232] In certain embodiments, a method for treating an HIV infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In one embodiment, a method for treating an HIV infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents.

[0233] In one embodiment, pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient are provided.

[0234] In certain embodiments, the present disclosure provides a method for treating an HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents which are suitable for treating an HIV infection.

[0235] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, or four additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or they can be selected from different classes of therapeutic agents. Administration of HIV Combination Therapy

[0236] In certain embodiments, a compound disclosed herein is administered with one, two, three, or four additional therapeutic agents. Co-administration of a compound disclosed herein with one, two, three, or four additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one, two, three, or four additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and the one, two, three, or four additional therapeutic agents are both present in the body of the patient. When administered sequentially, the combination may be administered in two or more administrations.

[0237] Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one, two, three, or four additional therapeutic agents. For example, the compound disclosed herein may be administered within seconds, minutes, or hours of the administration of the one, two, three, or four additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one, two, three, or four additional therapeutic agents. Alternatively, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes. In other embodiments, a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one, two, three, or four additional therapeutic agents. In yet other embodiments, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound disclosed herein.

[0238] In certain embodiments, a kit comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, or four) additional therapeutic agents is provided.

[0239] In a specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV capsid inhibitor or an HIV capsid polymerization inhibitor. HIV Combination Therapy

[0240] In the above embodiments, the additional therapeutic agent or agents may be an anti-HIV agent. In some instances, the additional therapeutic agent can be HIV non-nucleoside or nonnucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, HIV Tat or Rev inhibitors, inhibitors of Tat-TAR-P-TEFb, HIV Tat mimetics, dipeptidyl peptidase IX (DPP9) inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc fingercleases, homing nucleases, synthetic nucleases, TALENs), cell therapies (such as chimeric antigen receptor T-cell, CAR-T, and engineered T-cell receptors, TCR-T, autologous T-cell therapies, engineered B cells, NK cells), HIV latency reversing agents, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and “antibody-like” therapeutic proteins, HIV pl7 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, Fatty acid synthase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, HIV-1 Nef modulators, TNF alpha ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, IFN antagonists, retrocyclin modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, Cytochrome P450 3 inhibitors, CXCR4 modulators, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, HPK1 (MAP4K1) inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-Glycoprotein modulators, RNA polymerase modulators, TAT protein inhibitors, Prolyl endopeptidase inhibitors, Phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, anti-HIV peptides, and combinations thereof.

[0241] In some embodiments, the additional therapeutic agent or agents are selected from combination drugs for HIV, other drugs for treating HIV, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, HIV latency reversing agents, capsid inhibitors, immunebased therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and “antibody-like” therapeutic proteins, and combinations thereof.

[0242] In some embodiments, the additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, HIV latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and “antibodylike” therapeutic proteins, and combinations thereof.

[0243] In some embodiments, the additional therapeutic agent or agents are chosen from HIV nonnucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, Nef inhibitors, HIV latency reversing agents, HIV bNAbs, agonists of TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, T cell and NK cell recruiting bispecific antibodies, chimeric T cell receptors targeting HIV antigens, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.

[0244] In some embodiments, the additional therapeutic agent or agents are chosen from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and combinations thereof. HIV Combination Drugs

[0245] Examples of combination drugs include, but are not limited to, ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat); efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine ;tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; tenofovir analog; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); BIKTARVY® (bictegravir + emtricitabine + tenofovir alafenamide), DOV ATO® (dolutegravir and lamivudine), TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; PREZCOBIX® (darunavir and cobicistat); dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dolutegravir + lamivudine, HA-722 (dolutegravir + lamivudine + tenofovir disoproxil fumarate), lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, ACC-008 (ACC-007 + lamivudine + tenofovir disoproxil fumarate), VM-1500 + emtricitabine+tenofovir disoproxil, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, lopinavir + ritonavir + abacavir + lamivudine, lamivudine, cabotegravir + rilpivirine, 3-BNC117 + albuvirtide, (elsulfavirine, VM-1500), depulfavirine (VM-1500A), lenacapavir + islatravir (oral, injectable), and dual-target HIV-1 reverse transcriptase / nucleocapsid protein 7 inhibitors. Other HIV Drugs

[0246] Examples of other drugs for treating HIV include, but are not limited to, aspemigrin C, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, VSSP, Hlviral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, bevirimat, ABBV-382, obefazimod (ABX-464), AG-1105, APH-0812, APH0202, bryostatin-1, bryostatin-23, bryostatin analogs, SUW-133, BIT-225, BRU-732, BRII-778, Codivir, CYT-107, CS-TATI-1, fluoro-beta-D-arabinose nucleic acid (FANA)-modified antisense oligonucleotides, FX-101, griffithsin, HGTV-43, HPH-116, HRS-5685, HivCide-I, hydroxychloroquine, IMB-10035, IMO-3100, IND-02, JL-18008, LADAVRU, LLDT-8, MK-1376, MK-2048, MK-4250, ulonivirine (MK-8507), MK-8558, islatravir (MK-8591), NOV-205, OB-002H, ODE-Bn-TFV, PA-1050040 (PA-040), PC-707, PGN-007, QF-036, S-648414, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, DIACC-1010, Fasnall, Immuglo, 2-CLIPS peptide, HRF-4467, thrombospondin analogs, TBL-1004HI, VG-1177, xl-081, AVI-CO-004, rfhSP-D, [18F]-MC-225, URMC-099-C, RES-529, Verdinexor, IMC-M113 V, IML-106, antiviral fc conjugate (AVC), WP-1096, WP-1097, Gammora, ISR-CO48, ISR-48, ISR-49, MK-8527, cannabinoids, ENOB-HV-32, T-1144, VIR-576, nipamovir, Covimro, WP-1122, ZFP-362, MK-8510, and ABBV-1882. HIV Ribonuclease H Inhibitors

[0247] Examples of HIV ribonuclease H inhibitors include, but are not limited to, NSC-727447. HIV Nef Inhibitors

[0248] Examples of HIV Nef inhibitors include, but are not limited to, FP-1. HIV Reverse Transcriptase Inhibitors

[0249] Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include, but are not limited to, dapivirine, delavirdine, delavirdine mesylate, doravirine, difluoro-biphenyl-diarylpyrimidines (DAPY), efavirenz, etravirine, GS-5894, lentinan, nevirapine, rilpivirine, ACC-007, ACC-018, AIC-292, F-18, KM-023, PC-1005, Ml-TFV, M2-TFV, VM-1500A-LAI, PF-3450074, elsulfavirine (sustained release oral), doravirine + islatravir (fixed dose combination / oral tablet formulation), elsulfavirine (long acting injectable nanosuspension), and elsulfavirine (VM-1500).

[0250] Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include, but are not limited to, adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir octadecyl oxy ethyl ester (AGX-1009), tenofovir amibufenamide fumarate (HS-10234), tenofovir disoproxil hemifumarate, VIDEX® and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafovir etalafenamide (GS-9131), GS-9148, GSK-4023991, MK-8504, islatravir, MK-8583, VM-2500, CL-197, and KP-1461.

[0251] Additional examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include, but are not limited to, those described in patent publications US2007049754, US2016250215, US2016237062, US2016251347, US2002119443, US2013065856, US2013090473, US2014221356, and WO04096286. HIV Integrase Inhibitors

[0252] Examples of HIV integrase inhibitors include, but are not limited to, elvitegravir, elvitegravir (extended-release microcapsules), curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, PEGylated raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, cabotegravir (long acting injectable), diketo quinolin-4-1 derivatives, GS-1720, GS-6212, integrase-LEDGF inhibitor, ledgins, M-522, M-532, MK-0536, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, S-365598, stilbenedisulfonic acid, T169, STP-0404, VM-3500, XVIR-110, and ACC-017.

[0253] Examples of HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) include, but are not limited to, CX-05045, CX-05168, and CX-14442.

[0254] Additional examples of HIV capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication Nos. US2014221356 and US2016016973. HIV Viral Infectivity Factor Inhibitors

[0255] Examples of HIV viral infectivity factor inhibitors include, but are not limited to, 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives, and Irino-L. HIV Entry Inhibitors

[0256] Examples of HIV entry (fusion) inhibitors include, but are not limited to, AAR-501, LBT-5001, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gpl20 inhibitors, gpl60 inhibitors, and CXCR4 inhibitors.

[0257] Examples of CCR5 inhibitors include, but are not limited to, aplaviroc, vicriviroc, maraviroc, maraviroc (long acting injectable nanoemulsion), cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, thioraviroc and vMIP (Haimipu).

[0258] Examples of gp41 inhibitors include, but are not limited to, albuvirtide, enfuvirtide, griffithsin (gp41 / gpl20 / gpl60 inhibitor), BMS-986197, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT-31, C13hmAb, lipovirtide, PIE-12 trimer and sifuvirtide.

[0259] Examples of CD4 attachment inhibitors include, but are not limited to, ibalizumab and CADA analogs.

[0260] Examples of gpl20 inhibitors include, but are not limited to, anti-HIV microbicide, Radha-108 (receptol) 3B3-PE38, BMS818251, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831, VVX-004, and BMS-663068.

[0261] Examples of gpl60 inhibitors include, but are not limited to, fangchinoline.

[0262] Examples of CXCR4 inhibitors include, but are not limited to, plerixafor, ALT-1188, N15 peptide, balixafortide and vMIP (Haimipu). HIV Maturation Inhibitors

[0263] Examples of HIV maturation inhibitors include, but are not limited to, BMS-955176, fipravirimat mesylate (GSK-3 640254), VH-3739937 (GSK-3739937), HRF-10071 and GSK-2838232. HIV Latency Reversing Agents

[0264] Examples of latency reversing agents include, but are not limited to, toll-like receptor (TLR) agonists (including TLR7 agonists, e.g., GS-9620, TLR8 agonists, and TLR9 agonists), histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors (such as ZL-0580, apabetalone), ionomycin, IAP antagonists (inhibitor of apoptosis proteins, such as APG-1387, LBW-242), HIV Tat inhibitors, HIV Tat mimetics, SMAC mimetics (including TL32711, LCL161, GDC-0917, HGS1029, xevinapant (AT-406, Debio-1143)), PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), NIZ-985, IL-15 modulating antibodies (including IL-15, IL-15 fusion proteins, and IL-15 receptor agonists), JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, APH-0812, ixazomib, and GSK-343. Examples of PKC activators include, but are not limited to, indolactam, prostratin, ingenol B, and DAG-lactones.

[0265] Additional examples of TLR7 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2010143301.

[0266] Additional examples of TLR8 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2017071944. Histone Deacetylase (HDAC) Inhibitors

[0267] In some embodiments, the agents as described herein are combined with an inhibitor of a histone deacetylase, e.g., histone deacetylase 1, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HD AC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include without limitation, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CT-101, CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), resminostat, ricolinostat, romidepsin, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat. DPP9 Inhibitors

[0268] Examples of DPP9 inhibitors include, but are not limited to, talobostat. HIV Tat Inhibitors

[0269] Examples of Tat inhibitors include, but are not limited to, CS-TATI-1. Capsid Inhibitors

[0270] Examples of capsid inhibitors include, but are not limited to, capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodi carbonamide, HIV p24 capsid protein inhibitors, lenacapavir (GS-6207), GS-4182, GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series, PF-3450074, VH-4004280, VH-4011499, and compounds described in (GSK WO2019 / 087016).

[0271] Additional examples of capsid inhibitors include, but not limited to, those described in U.S. Patent Application Publication Nos. US2018051005 and US2016108030. Cytochrome P450 3A inhibitors

[0272] Examples of Cytochrome P450 3A inhibitors include, but are not limited to, those described in U.S. Patent No. 7,939,553. RNA polymerase modulators

[0273] Examples of RNA polymerase modulators include, but are not limited to, those described in U.S. Patent Nos. 10,065,958 and 8,008,264. Immune Checkpoint Modulators

[0274] In various embodiments, the agents as described herein, are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and / or with one or more stimulators, activators or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blockade or inhibition of inhibitory immune checkpoints can positively regulate T-cell or NK cell activation and prevent immune escape of infected cells. Activation or stimulation of stimulatory immune check points can augment the effect of immune checkpoint inhibitors in infective therapeutics. In various embodiments, the immune checkpoint proteins or receptors regulate T cell responses (e.g., reviewed in Xu et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, the immune checkpoint proteins or receptors regulate NK cell responses (e.g., reviewed in Davis et al., Semin Immunol. (2017) 31:64-75 and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0275] Examples of immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2, B7H7); inducible T cell co-stimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILRI), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD 155); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activating 3 (LAG3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD 150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); ULI6 binding protein 1 (ULBP1); ULI6 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript IE (RAET1E; ULBP4); retinoic acid early transcript IG (RAET1G; ULBP5); retinoic acid early transcript IL (RAET1L; ULBP6); lymphocyte activating 3 (CD223); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor KI (KLRKl, NKG2D, CD314); killer cell lectin like receptor C2 (KLRC2, CD 159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two 63 Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor DI (KLRD1); SLAM family member 7 (SLAMF7); and Hematopoietic Progenitor Kinase 1 (HPK1, MAP4K1).

[0276] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors. Illustrative T-cell inhibitory immune checkpoint proteins or receptors include without limitation CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD 152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activating 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In various embodiments, the agents, as described herein, are combined with one or more agonist or activators of one or more T-cell stimulatory immune checkpoint proteins or receptors. Illustrative T-cell stimulatory immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, 0X40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu et al., J Exp Clin Cancer Res. (2018) 37:110.

[0277] In various embodiments, the agents as described herein, are combined with one or more blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or receptors. Illustrative NK-cell inhibitory immune checkpoint proteins or receptors include without limitation killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); and killer cell lectin like receptor DI (KLRD1, CD94). In various embodiments, the agents as described herein, are combined with one or more agonist or activators of one or more NK-cell stimulatory immune checkpoint proteins or receptors. Illustrative NK-cell stimulatory immune checkpoint proteins or receptors include without limitation CD 16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., Davis et al., Semin Immunol. (2017) 31:64-75; Fang et al., Semin Immunol. (2017) 31:37-54; and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0278] In some embodiments, the one or more immune checkpoint inhibitors comprises a proteinaceous (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, the one or more immune checkpoint inhibitors comprises a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550 and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002.

[0279] Examples of inhibitors of CTLA4 that can be co-administered include without limitation ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, as well as multi-specific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0280] Examples of inhibitors of PD-L1 (CD274) or PD-1 (PDCD1) that can be co-administered include without limitation pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301,envafolimab (ASC-22, KN-035), PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS- 001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, budigalimab (ABBV-181), PD1-PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostarlimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, as well as multi-specific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-l / LAG-3), FS-118 (LAG-3 / PD-L1) MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-l / TIM-3), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), M7824 (PD-L1 / TGFP-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1). [0281J In various embodiments, the agents as described herein are combined with anti-TIGIT antibodies, such as BMS-986207, RG-6058, and AGEN-1307. TNF Receptor Superfamily (TNFRSF) Member Agonists or Activators

[0282] In various embodiments, the agents as described herein are combined with an agonist of one or more TNF receptor superfamily (TNFRSF) members, e.g., an agonist of one or more of TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID: 355), TNFRSF7 (CD27, NCBI Gene ID: 939), TNFRSF8 (CD30, NCBI Gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI Gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILRI, NCBI Gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI Gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI Gene ID: 8794), TNFRSF 10D (CD264, TRAILR4, NCBI Gene ID: 8793), TNFRSF 11A (CD265, RANK, NCBI Gene ID: 8792), TNFRSF 1 IB (NCBI Gene ID: 4982), TNFRSF12A (CD266, NCBI Gene ID: 51330), TNFRSF13B (CD267, NCBI Gene ID: 23495), TNFRSF13C (CD268, NCBI Gene ID: 115650), TNFRSF16 (NGFR, CD271, NCBI Gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI Gene ID: 608), TNFRSF18 (GITR, CD357, NCBI Gene ID: 8784), TNFRSF19 (NCBI Gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI Gene ID: 27242), and TNFRSF25 (DR3, NCBI Gene ID: 8718).

[0283] Examples of anti-TNFRSF4 (OX40) antibodies that can be co-administered include without limitation, MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF-04518600, RG- 7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0284] Examples of anti-TNFRSF5 (CD40) antibodies that can be co-administered include without limitation RG7876, SEA-CD40, APX-005M and ABBV-428.

[0285] In some embodiments, the anti-TNFRSF7 (CD27) antibody variilumab (CDX-1127) is coadministered.

[0286] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that can be co-administered include without limitation urelumab, utomilumab (PF-05082566), AGEN2373 and ADG-106.

[0287] Examples of anti-TNFRSF18 (GITR) antibodies that can be co-administered include without limitation, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, an antibody, or fragment thereof, co-targeting TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, e.g., in WO2017096179 and WO2018089628. Bi-and Tri-Specific Natural Killer (NK)-Cell Engagers

[0288] In various embodiments, the agents as described herein, are combined with a bi-specific NK-cell engager (BiKE) or a tri-specific NK-cell engager (TriKE) (e.g., not having an Fc) or bispecific antibody (e.g., having an Fc) against an NK cell activating receptor, e.g., CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H and NKG2F), natural cytotoxicity receptors (NKp30, NKp44 and NKp46), killer cell C-type lectin-like receptor (NKp65, NKp80), Fc receptor FcyR (which mediates antibody-dependent cell cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6 and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1 and CD137 (41BB). As appropriate, the anti-CD16 binding bi-specific molecules may or may not have an Fc. Illustrative bi-specific NK-cell engagers that can be co-administered target CD16 and one or more HIV-associated antigens as described herein. BiKEs and TriKEs are described, e.g., in Felices et al., Methods Mol Biol. (2016) 1441:333-346; Fang et al., Semin Immunol. (2017) 31:37-54. Examples of trispecific NK cell engagers (TRiKE) include, but are not limited to, OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3 TriKe. Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

[0289] In various embodiments, the agents as described herein are combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO 1 inhibitors 67 WO 2025 / 184609                                   PCT / US2025 / 017990 include without limitation, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccine, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, shlDO-ST, EOS-200271, KHK-2455, and LY-3381916. Toll-Like Receptor (TLR) Agonists

[0290] In various embodiments, the agents as described herein are combined with an agonist of a toll-like receptor (TLR), e.g., an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793). Example TLR7 agonists that can be co-administered include without limitation AL-034, DSP-0509, GS-9620 (vesatolimod), LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, SHR-2150, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and the compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). TLR7 / TLR8 agonists include without limitation NKTR-262, telratolimod and BDB-001. TLR8 agonists include without limitation E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and the compounds disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). TLR9 agonists include without limitation AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, litenimod, MGN- 1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod and PUL-042. Examples of TLR3 agonist include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, andND-1.1. TLR4 agonists include, but are not limited to, G-100 and GSK-1795091. CDK inhibitors or antagonists

[0291] In some embodiments, the agents described herein are combined with an inhibitor or antagonist of CDK. In some embodiments, the CDK inhibitor or antagonist is selected from the group consisting of VS2-370. STING agonists, RIG-I and NOD2 modulators

[0292] In some embodiments, the agents described herein are combined with a stimulator of interferon genes (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, STING agonist (latent HIV), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic-GAMP (cGAMP) and cyclic-di-AMP. In some embodiments, the agents described herein are combined with a RIG-I modulator such as RGT-100, orNOD2 modulator, such as SB-9200, and IR-103. LAG-3 and TIM-3 inhibitors

[0293] In certain embodiments, the agents as described herein are combined with an anti-TIM-3 antibody, such as TSR-022, LY-3321367, MBG-453, INCAGN-2390.

[0294] In certain embodiments, the antibodies or antigen-binding fragments described herein are combined with an anti LAG-3 (Lymphocyte-activation) antibody, such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385. Interleukin agonists

[0295] In certain embodiments, the agents described herein are combined with an interleukin agonist, such as IL-2, IL-7, IL-15, IL-10, IL-12 agonists; examples of IL-2 agonists such as proleukin (aldesleukin, IL-2); BC-IL (Cel-Sci), pegylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707), bempegaldesleukin, AIC-284, ALKS-4230, CUI-101, Neo-2 / 15; examples of IL-15 agonists, such as nogapendekin alfa (ALT-803), NKTR-255, and hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 Synthorin (pegylated 11-15), 69 P-22339, and a IL-15 -PD-1 fusion protein N-809; examples of IL-7 include without limitation CYT-107.

[0296] Examples of additional immune-based therapies that can be combined with an agent of this disclosure include, but are not limited to, interferon alfa, interferon alfa-2b, interferon alfa-n3, pegylated interferon alfa, interferon gamma; FLT3 agonists such as CDX-301, GS-3583, gepon, normferon, peginterferon alfa-2a, and peginterferon alfa-2b. Phosphatidylinositol 3-kinase (PI3K) Inhibitors

[0297] Examples of PI3K inhibitors include, but are not limited to, idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474. alpha-4 / beta-7 Antagonists

[0298] Examples of Integrin alpha-4 / beta-7 antagonists include, but are not limited to, PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab. HPK1 Inhibitors

[0299] Examples of HPK1 inhibitors include, but are not limited to, ZYF-0272, and ZYF-0057. HIV Targeting Antibodies

[0300] Examples of HIV antibodies, bi specific antibodies, and “antibody-like” therapeutic proteins include, but are not limited to, DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bNAbs (broadly neutralizing HIV-1 antibodies), TMB-360, TMB-370, and those targeting HIV gpl20 or gp41, antibody-Recruiting Molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, gpl20 bispecific monoclonal antibody, CCR5 bispecific antibodies, anti-Nef single domain antibodies, anti-Rev antibody, camelid derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gpl40 targeted antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAbs (PGT-121), PGT121.414ES, Immuglo, MB-66, clone 3 human monoclonal antibody targeting KLIC (HIV infection), GS-9721, teropavimab (GS-5423), teropavimab (GS-2872), BG-HIV, VRC-HIVMAB091-00-AB. Anti- CD4 antibodies such as ibalizumab, TMB-365, and MGD-020. [0301J Various bNAbs may be used. Examples include, but are not limited to, those described in U.S. Patent No. 8673307, 9,493,549, 9,783,594, 10,239,935, US2018371086, US2020223907, WO2014 / 063059, WO2012 / 158948, WO2015 / 117008, and PCT / US2015 / 41272, and WO2017 / 096221, including antibodies 12A12, 12A21, NIH45-46, bANC131, 8ANC134, IB2530, INC9, 8ANC195. 8ANC196, 10-259, 10-303, 10-410, 10- 847, 10-996, 10-1074, 10-1121, 101130, 10-1146, 10-1341, 10-1369, and 10-1074GM. Additional examples include those described in Klein et al., Nature, 492(7427): 118-22 (2012), Horwitz et al., Proc Natl Acad Sci USA, 110(41): 16538-43 (2013), Scheid et al., Science, 333 : 1633-1637(2011), Scheid et al., Nature, 458:636-640 (2009), Eroshkin et al, Nucleic Acids Res., 42 (Database issue):Dl 133-9 (2014), Mascola et al., Immunol Rev., 254(1):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (all of which bind the MPER of gp41); PG9, PG16, CHO 1-04 (all of which bind VIV2-glycan), 2G12 (which binds to outer domain glycan); bl2, HJ16, CH103-106, VRC01-03, VRC-PG04, 04b, VRC-CH30-34, 3BNC62, 3BNC89, 3BNC91, 3BNC95, 3BNC104, 3BNC176, and 8ANC131 (all of which bind to the CD4 binding site). [0302J Additional broadly neutralizing antibodies that can be used as a second therapeutic agent in a combination therapy are described, e.g., in U.S. Patent Nos. 8,673,307; 9,493,549; 9,783,594; and WO 2012 / 154312; WO2012 / 158948; WO 2013 / 086533; WO 2013 / 142324; WO2014 / 063059; WO 2014 / 089152, WO 2015 / 048462; WO 2015 / 103549; WO 2015 / 117008; WO2016 / 014484; WO 2016 / 154003; WO 2016 / 196975; WO 2016 / 149710; WO2017 / 096221; WO 2017 / 133639; WO 2017 / 133640, which are hereby incorporated herein by reference in their entireties for all purposes. Additional examples include, but are not limited to, those described in Sajadi et al., Cell. (2018) 173(7): 1783-1795; Sajadi et al., J Infect Dis. (2016) 213(1): 156-64; Klein et al., Nature, 492(7427): 118-22 (2012), Horwitz et al., Proc Natl Acad Sci U S A, 110(41): 16538-43 (2013), Scheid et al., Science, 333: 1633-1637 (2011), Scheid et al., Nature, 458:636-640 (2009), Eroshkin et al., Nucleic Acids Res., 42 (Database issue):Dl 133-9 (2014), Mascola et al., Immunol Rev., 254(1):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2, 10-1074, and LN01 (all of which bind the MPER of gp41).

[0303] Examples of additional antibodies include, but are not limited to, bavituximab, UB-421, BF520.1, BilA-SG, CHOI, CH59, C2F5, C4E10, C2F5+C2G12+C4E10, CAP256V2LS, 3BNC117, 3BNC117-LS, 3BNC60, DH270.1, DH270.6, D1D2, 10-1074-LS, C13hmAb, GS-9722 (elipovimab), DH411-2, BG18, GS-9721, GS-9723, PGT145, PGT121, PGT-121.60, PGT-121.66, PGT122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-151, PGT-130, PGT-133, PGT-134, PGT-135, PGT-128, PGT-136, PGT-137, PGT-138, PGT-139, MDX010 (ipilimumab), DH511, DH511-2, N6, GSK-3810109 (N6LS), N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45-46, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGDM1400, PGDM-1400LS, PGDM12, PGDM21, PCDN-33A, 2Dm2m, 4Dm2m, 6Dm2m, PGDM1400, MDX010 (ipilimumab), VRC01, VRC-01-LS, VRC01-23LS, A32, 7B2, 10E8, VRC-07-523, VRC07-523LS, VRC24, VRC41.01, 10E8VLS, 3810109, 10E8v4, IMC-HIV, iMabm36, eCD4-Ig, IOMA, CAP256-VRC26.25, DRVIA7,VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, VRC07, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, VRC29.03, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01, PGT-151, CAP248-2B, 35022, ACS202, VRC34 and VRC34.01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, andLNOl.

[0304] Examples of HIV bispecific and trispecific antibodies include without limitation GS-8588, MGD014, B12BiTe, BilA-SG, TMB-bispecific, SAR-441236, VRC-01 / PGDM-1400 / 10E8v4, 10E8.4 / iMab, 10E8v4 / PGT121-VRC01.

[0305] Examples of in vivo delivered bNAbs include without limitation AAV8-VRC07; mRNA encoding anti-HIV antibody VRC01; and engineered B-cells encoding 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301). Pharmacokinetic Enhancers

[0306] Examples of pharmacokinetic enhancers include, but are not limited to, cobicistat and ritonavir. Additional Therapeutic Agents

[0307] Examples of additional therapeutic agents include, but are not limited to, the compounds disclosed in WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco), US 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO 2013 / 091096 (Boehringer Ingelheim). HIV Vaccines

[0308] Examples of HIV vaccines include, but are not limited to, peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, HIV MAG DNA vaccine, CD4-derived peptide vaccines, vaccine combinations, adenoviral vector vaccines (an adenoviral vector such as Ad5, Ad26 or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus i.e. rhAd), adeno-associated virus vector vaccines, Chimpanzee adenoviral vaccines (e.g., ChAdOXl, ChAd68, ChAd3, ChAd63, ChAd83, ChAdl55, ChAdl57, Pan5, Pan6, Pan7, Pan9), Coxsackieviruses based vaccines, enteric virus based vaccines, Gorilla adenovirus vaccines, lentiviral vector based vaccine, arenavirus vaccines (such as LCMV, Pichinde), bi-segmented or tri-segmented arenavirus based vaccine, trimer-based HIV-1 vaccine, measles virus based vaccine, flavivirus vector based vaccines, tobacco mosaic virus vector based vaccine, Varicella-zoster virus based vaccine, Human parainfluenza virus 3 (PIV3) based vaccines, poxvirus based vaccine (modified vaccinia virus Ankara (MVA), orthopoxvirus-derived NYVAC, and avipoxvirus-derived ALVAC (canarypox virus) strains); fowlpox virus based vaccine, rhabdovirus-based vaccines, such as VSV and marabavirus; recombinant human CMV (rhCMV) based vaccine, alphavirus-based vaccines, such as semliki forest virus, Venezuelan equine encephalitis virus and sindbis virus; (see Lauer, Clinical and Vaccine Immunology, 2017, DOI: 10.1128 / CVI00298-16); LNP formulated mRNA based therapeutic vaccines; LNP-formulated self-replicating RNA / self-amplifying RNA vaccines.

[0309] Examples of vaccines include: AAVLP-HIV vaccine, AdC6-HIVgpl40, AE-298p, anti-CD40.Env-gpl40 vaccine, Ad4-EnvC150, BG5O5 SOSIP.664 gpl40 adjuvanted vaccine, BG505 SOSIP.GTl.l gpl40 adjuvanted vaccine, ChAdOxl.tHIVconsvl vaccine, CMV-MVA triplex vaccine, ChAdOxl.HTI, C62-M4, Chimigen HIV vaccine, ConM SOSIP.v7 gpl40, ALVAC HIV (vCP1521), AIDSVAX BZE (gpl20), monomeric gpl20 HIV-1 subtype C vaccine, MPER-656 liposome subunit vaccine, Remune, ITV-1, Centre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, poly-ICLC adjuvanted vaccines, Tatlmmune, GTU-multiHIV (FIT-06), ChAdV63.HIVconsv, gpl40[delta]V2.TVl+MF-59, rVSVINHIV-1 gag vaccine, SeV-EnvF, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIV AX, HIVAX-2, N123-VRC-34.01 inducing epitope-based HIV vaccine, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAVl-PG9DP, GOVX-B11, GOVX-B21, GOVX-73 C55, GS-1983, GS-6708 , TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, ENOB-HV-11, ENOB-HV-12, exoVACC, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, AD VAX, MYM-V201, MVA-CMDR, MagaVax, DNA-Ad5 gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, DNA and Sev vectors vaccine expressing SCaVn, rcAD26.MOSl.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV + MVA mosaic vaccine + gpl40, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, VIR-1111, IHV-001, UVAX-1107, repRNA vaccine (LION nanoparticle, HIV-1), 763SIP8 / MPLA-5 vaccine, BG505 SOSIP.664 gpl40 adjuvanted vaccine, and virus-like particle vaccines such as pseudovirion vaccine, CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptides vaccine, dendritic-cell vaccines (such as DermaVir), gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key / MHC class II epitope hybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, rgpl60 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, UBI HIV gpl20, Vacc-4x + romidepsin, variant gpl20 polypeptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNAHTI and MVAHTI, MVA.tHIVconsv3, MVA.tHIVconsv4, VRC-HIVDNAO16-00-VP + VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gpl45 C.6980; eOD-GT8 60mer based vaccine, PD-201401, env (A, B, C, A / E) / gag (C) DNA Vaccine, gpl20 (A,B,C,A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE adjuvanted), HIV p24gag prime-boost plasmid DNA vaccine, HIV-1 iglb 12 neutralizing VRC-01 antibody-stimulating anti-CD4 vaccine, arenavirus vector-based vaccines (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, mRNA based vaccines, VPI-211, HIV ANTI-CD40.ENV GP140, HIV ANTI-CD40.HIV5PEP, multimeric HIV gpl20 vaccine TBL-1203HI, CH505 TF chTrimer, CD40.HIVRI.Env vaccine, VRC-HIVRGP096-00-VP, Drep-HIV-PT-1, BG505 MD39.3 mRNA, BG505 MD39.3 gpl51 CD4KO mRNA, BG505 MD39.3 gpl51 mRNA, mRNA-1644, mRNA-1547, and mRNA-1574, and anti-HIV vaccines described in WO2021011544 and WO2022155258. Birth Control (Contraceptive) Combination Therapy

[0310] In certain embodiments, the agents described herein are combined with a birth control or contraceptive regimen. Therapeutic agents used for birth control (contraceptive) that can be combined with an agent of this disclosure include without limitation cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl Estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norelgestromin, norethindrone, noretynodrel, norgestimate, ormeloxifene, segestersone acetate, ulipristal acetate, and any combinations thereof. [0311J In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, or four additional therapeutic agents selected from ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF +FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); BIKTARVY ® (bictegravir + emtricitabine + tenofovir alafenamide), adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir alafenamide and elvitegravir; tenofovir alafenamide + elvitegravir (rectal formulation, HIV infection); tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; EDURANT® (dolutegravir + rilpivirine); raltegravir; PEGylated raltegravir; raltegravir and lamivudine; lamivudine+lopinavir+ritonavir+abacavir; maraviroc; tenofovir + emtricitabine + maraviroc, enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfmavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0312] In some embodiments, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase. In an additional embodiment, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0313] In another embodiment, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with a first additional therapeutic agent chosen from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir and a second additional therapeutic agent chosen from emtricitabine and lamivudine.

[0314] In some embodiments, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with a first additional therapeutic agent (a contraceptive) selected from the group consisting of cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl Estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone , misoprostol, nomegestrol acetate, norelgestromin, norethindrone, noretynodrel, norgestimate, ormeloxifene , segestersone acetate, ulipristal acetate, and any combinations thereof. Gene Therapy and Cell Therapy

[0315] In certain embodiments, the agents described herein are combined with a gene or cell therapy regimen. Gene therapy and cell therapy include without limitation the genetic modification to silence a gene; genetic approaches to directly kill the infected cells; the infusion of immune cells designed to replace most of the patient’s own immune system to enhance the immune response to infected cells, or activate the patient’s own immune system to kill infected cells, or find and kill the infected cells; genetic approaches to modify cellular activity to further alter endogenous immune responsiveness against the infection. Examples of cell therapy include without limitation LB-1903, ENOB-HV-01, ENOB-HV-21, ENOB-HV-31, GOVX-B01, HSPCs overexpressing ALDH1 (LV-800, HIV infection), AGT103-T, and SupTl cell based therapy. Examples of dendritic cell therapy include without limitation AGS-004. CCR5 gene editing agents include without limitation SB-728T, SB-728-HSPC. CCR5 gene inhibitors include without limitation Cal-1, and lentivirus vector CCR5 shRNA / TRIM5alpha / TAR decoy-transduced autologous CD34-positive hematopoietic WO 2025 / 184609                                   PCT / US2025 / 017990 progenitor cells (HIV infection / HIV-related lymphoma). In some embodiments, C34-CCR5 / C34-CXCR4 expressing CD4-positive T-cells are co-administered with one or more multi-specific antigen binding molecules. In some embodiments, the agents described herein are co-administered with AGT-103-transduced autologous T-cell therapy or AAV-eCD4-Ig gene therapy. Gene Editors

[0316] In certain embodiments, the agents described herein are combined with a gene editor, e.g., an HIV targeted gene editor. In various embodiments, the genome editing system can be selected from the group consisting of: a CRISPR / Cas9 complex, a zinc finger nuclease complex, a TALEN complex, a homing endonucleases complex, and a meganuclease complex. An illustrative HIV targeting CRISPR / Cas9 system includes without limitation EBT-101, XVIR-TAT. CAR-T Cell Therapy

[0317] In some embodiments, the agents described herein can be co-administered with a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen binding domain. The HIV antigen include an HIV envelope protein or a portion thereof, gpl20 or a portion thereof, a CD4 binding site on gp!20, the CD4-induced binding site on gpl20, N glycan on gpl20, the V2 of gpl20, the membrane proximal region on gp41. The immune effector cell is a T-cell or an NK cell. In some embodiments, the T-cell is a CD4+ T-cell, a CD8+ T-cell, or a combination thereof. Cells can be autologous or allogeneic. Examples of HIV CAR-T include A-1801, A-1902, convertible CAR-T, VC-CAR-T, CMV-N6-CART, anti-HIV duoCAR-T, anti-Env duoCAR T, anti-CD4 CART-cell therapy, CD4 CAR+C34-CXCR4+CCR5 ZFN T-cells, dual anti-CD4 CART-T cell therapy (CD4 CAR+C34-CXCR4 T-cells), anti-CD4 MicAbody antibody + anti-MicAbody CAR T-cell therapy (iNKG2D CAR, HIV infection), GP-120 CAR-T therapy, autologous hematopoietic stem cells genetically engineered to express a CD4 CAR and the C46 peptide. TCR T-cell Therapy

[0318] In certain embodiments, the agents described herein are combined with a population of TCR-T-cells. TCR-T-cells are engineered to target HIV derived peptides present on the surface of virus-infected cells.

[0319] In certain embodiments, the agents described herein are combined with IMC-M113 V, a TCR bispecific having a TCR binding domain that targets a peptide derived from the Gag protein WO 2025 / 184609                                   PCT / US2025 / 017990 presented by HLA*A02 on the surface of HIV infected cells and a second antigen binding domain that targets CD3. B-cell Therapy

[0320] In certain embodiments, the agents described herein are combined with a population of B cells genetically modified to express broadly neutralizing antibodies, such as 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301, Moffett et al., Sci. Immunol. 4, eaax0644 (2019) 17 May 2019.

[0321] A compound as disclosed herein (e.g., any compound of formula I, II, III, IV, or V) may be combined with one, two, three, or four additional therapeutic agents in any dosage amount of the compound of formula I, II, III, IV, or V (e.g., from 1 mg to 500 mg of compound).

[0322] In one embodiment, kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are provided.

[0323] In one embodiment, the additional therapeutic agent or agents of the kit is an anti-HIV agent, selected from HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), cell therapies (such as chimeric antigen receptor T-cell, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapies), compounds that target the HIV capsid, latency reversing agents, HIVbNAbs, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broadly neutralizing HIV antibodies, bispecific antibodies and “antibody-like” therapeutic proteins, HIV pl7 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infectivity factor inhibitors, TAT protein inhibitors, HIV Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxy cytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[0324] In some embodiments, the additional therapeutic agent or agents of the kit are selected from combination drugs for HIV, other drugs for treating HIV, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and “antibody-like” therapeutic proteins, and combinations thereof.

[0325] In a specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide inhibitor of reverse transcriptase. In a specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide inhibitor of reverse transcriptase. In an additional embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. In a specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV capsid inhibitor. In a specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an HIV nucleoside inhibitor of reverse transcriptase and an HIV capsid inhibitor. In a specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an HIV capsid inhibitor. In a specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and one, two, three or four HIV bNAbs. In a specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, one, two, three or four HIV bNAbs and an HIV capsid inhibitor. In a specific embodiment, the kit includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, one, two, three or four HIV bNAbs, an HIV capsid inhibitor, and an HIV nucleoside inhibitor of reverse transcriptase. HIV Long Acting Therapy

[0326] Examples of drugs that are being developed as long acting regimens include, but are not limited to, lenacapavir, cabotegravir, rilpivirine, any integrase LA, VM-1500 LAI, GS-1614, maraviroc (LAI), tenofovir implant, islatravir, islatravir implant, islatravir prodrug, doravirine, LYN-172, raltegravir, XVIR-120, GSK-3739937 (long-acting), and long acting dolutegravir, CABENUVA® (cabotegravir LA + rilpivirine LA), VOCABRIA® (cabotegravir LA), APRETUDE® (cabotegravir LAI), REKAMBYS®(rilpivirine LA). Kits and Articles of Manufacture

[0327] In one embodiment, kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are provided.

[0328] The present disclosure relates to a kit comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof. The kit may further comprise instructions for use, e.g., for use in inhibiting an HIV reverse transcriptase, such as for use in treating an HIV infection or AIDS or as a research tool. The instructions for use are generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable.

[0329] The present disclosure also relates to a pharmaceutical kit comprising one or more containers comprising a compound of any disclosed herein, or a pharmaceutically acceptable salt thereof. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice reflects approval by the agency for the manufacture, use or sale for human administration. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelflife permit. The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0330] Also disclosed are articles of manufacture comprising a unit dosage of a compound of any disclosed herein, or a pharmaceutically acceptable salt thereof, in suitable packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and / or sealed. EXAMPLES

[0321] Representative syntheses of compounds of the present disclosure are described in schemes below, and the particular examples that follow. The following examples are merely illustrative, and not intended to limit this disclosure in any way. It is to be understood that individual steps described herein may be combined. It is also to be understood that separate batches of a compound may be combined and carried forth in the next synthetic step. Scheme 1 N

[0322] Scheme 1 shows a general synthesis of the compounds of the embodiments. The methodology is compatible with a wide variety of functionalities.

[0323] In Scheme 1, a suitably substituted heteroaryl chloride (or the corresponding bromo- or fluoro-compound) is combined with a nucleophile (e.g. aryl amine, aryl alcohol, alkyl amine etc.) in a suitable solvent system (e.g. NMP, DMF, DMAc, DMSO, acetonitrile, EtOH, THF etc.) in the presence of a base (e.g. CS2CO3, K2CO3, triethylamine, DIPEA, NaH etc.) at ambient or elevated temperature (e.g., ranging from about 20-120 °C). Scheme 2 N

[0324] Scheme 2 shows a general synthesis of the compounds of the embodiments. The methodology is compatible with a wide variety of functionalities.

[0325] In Scheme 2, a suitably substituted heteroaryl chloride (or the corresponding bromo compound) is combined with a fluoride ion source (e.g. KF, CsF, TBAF etc.) and a nucleophilic tertiary amine (e.g. DABCO, quinuclidine etc.) in a suitable solvent system (e.g. DMF, DMSO, NMP, DMAc, / BuOH etc.) at ambient or elevated temperature (e.g., ranging from about 20-100 °C). The resulting heteroaryl fluoride is combined with a suitable alkyl amine nucleophile (e.g. 3-aminobicyclo[l.l.l]pentane-l-carbonitrile; hydrochloride) and base (e.g. K2CO3, CS2CO3, NaH etc.) at ambient or elevated temperature (e.g., ranging from about 20-120 °C). Scheme 3 N

[0326] Scheme 3 shows a general synthesis of the compounds of the embodiments. The methodology is compatible with a wide variety of functionalities.

[0327] In Scheme 3, a suitably substituted heteroaryl thioether is combined with an oxidant (e.g. mCBPA, ammonium molybdate / hydrogen peroxide etc.) in a suitable solvent system (e.g. NMP, DCM, EtOH etc.) at cryogenic or ambient temperature (e.g., ranging from about 0-20 °C). The resulting heteroaryl sulfone is combined with a suitable alkyl amine nucleophile (e.g. 3-aminobicyclo[l.l.l]pentane-l-carbonitrile; hydrochloride) and base (e.g. K2CO3, CS2CO3, triethylamine, DIPEA, NaH etc.) at ambient or elevated temperature (e.g., ranging from about 20-120 °C).

[0328] Scheme 4 shows a general synthesis of the compounds of the embodiments. The methodology is compatible with a wide variety of functionalities.

[0329] In Scheme 4, a suitably substituted heteroaryl chloride (or the corresponding bromo- or fluoro-compound) is combined with a nucleophile (e.g. aryl amine, aryl alcohol, alkyl amine etc.) in a suitable solvent system (e.g. NMP, DMF, DMAc, DMSO, acetonitrile, EtOH, THF etc.) in the presence of a base (e.g. CS2CO3, K2CO3, triethylamine, DIPEA, NaH etc.) at ambient or elevated temperature (e.g., ranging from about 20-120 °C).

[0330] The resulting nitro-substituted heteroaryl compound is combined with a reductant (e.g. zinc, iron etc.) and acid (e.g. acetic acid, formic acid, hydrochloric acid, ammonium chloride etc.) in a suitable solvent (e.g. DCM, EtOH, THF, water, DMSO, dioxane etc.) at cryogenic or elevated temperature (e.g., ranging from about 0-60 °C).

[0331] The resulting PMB-amine is combined with an acid (e.g. trifluoroacetic acid, hydrochloric acid etc.) at ambient temperature (e.g., ranging from about 15-25 °C). The resulting diamine reacts with a range of different annulation reagents to provide substituted bicycloheteroaryl compounds. Scheme 5

[0332] Scheme 5 shows a general synthesis of the compounds of the embodiments. The methodology is compatible with a wide variety of functionalities.

[0333] In Scheme 5, a suitably substituted heteroaryl chloride (or the corresponding bromo- or fluoro-compound) is combined with a nucleophile (e.g. aryl amine, aryl alcohol, alkyl amine etc.) in a suitable solvent system (e.g. NMP, DMF, DMAc, DMSO, acetonitrile, EtOH, THF etc.) in the presence of a base (e.g. CS2CO3, K2CO3, triethylamine, DIPEA, NaH etc.) at ambient or elevated temperature (e.g., ranging from about 20-120 °C).

[0334] The resulting heteroaryl compound is combined with an electrophilic halogen source (N-bromosuccinimide, bromine etc) in a suitable solvent system (NMP, DMF, DMAc, DMSO, acetonitrile, EtOH, THF etc) at ambient temperature.

[0335] The resulting bromo heteroaryl compound (or the corresponding chloro- or iodocompound) is combined with an organotin reactant (e.g. tributyl(l-ethoxy vinyl)stannane) in a suitable solvent system (e.g. DMF, DMAc, NMP, DMSO, THF, toluene etc.) in the presence of a palladium catalyst (e.g. tetrakis(triphenylphosphine)palladium(0), Pd2(dba)3, Pd(dppf)C12 etc.) at elevated temperature (e.g., ranging from about 90-150 °C), which can be performed in microwave reactor or with conventional heating. The reaction product is combined with an acid (e.g. hydrochloric acid, phosphoric acid, acetic acid, trifluoroacetic acid etc.) at ambient temperature (e.g., ranging from about 15-25 °C).

[0336] The resulting heteroaryl keto-ester reacts with a range of different annulation reagents WO 2025 / 184609                                   PCT / US2025 / 017990 (e.g. alkyl amines, aryl amines, heteroaryl amines etc.) to provide substituted bicycloheteroaryl compounds. Scheme 6 N

[0337] Scheme 6 shows a general synthesis of the compounds of the embodiments. The methodology is compatible with a wide variety of functionalities.

[0338] In Scheme 6, a suitably substituted heteroaryl chloride (or the corresponding bromo compound) is combined with a amine nucleophile (e.g. alkyl amine etc.) in a suitable solvent system (e.g. dioxane, THF, toluene, NMP, DMAc etc.) in the presence of a palladium catalyst (e.g. rac BINAP Pd G3, XPhos Pd G3, SPhos Pd G4, BrettPhos Pd G4, tBuXPhos Pd G3, RuPhos Pd G4 etc. and using either catalytic or stoichiometric quantities) and base (e.g. CS2CO3, K2CO3, K3PO4 etc.) at elevated temperature (e.g., ranging from about 40-120 °C), which can be performed in microwave reactor or with conventional heating.

[0339] In certain instances, the above processes further involve the step of forming a salt of a compound of the present disclosure. Embodiments are directed to the other processes described herein; and to the product prepared by any of the processes described herein.

[0340] Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, 5th edition, New York: Oxford University Press. 2009; Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th edition, Wiley-Interscience, 2013. List of Abbreviations and Acronyms Abbreviation—Meaning Ac—Acetyl B2pin2—4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi(l,3,2-dioxaborolane) BAST—Bis(2-methoxy ethyl)aminosulfur Trifluoride BINAP Pd G3—[2'-(amino-KA)[l, 1 '-biphenyl]-2-yl-KC][[2'-(diphenylphosphino)[l, 1 binaphthalen]-2-yl]diphenylphosphine-KP](methanesulfonato-K(9)- palladium bs—Broad singlet ° C.—Degree Celsius d—Doublet DCM—Dichloromethane dd—Doublet of doublet DIPEA—N,N-Diisopropylethylamine DMF—N,N-Dimethylformamide DMSO—Dimethylsulfoxide dppf— 1,1 '-Bi s(diphenylphosphino)ferrocene dtbpf— 1,1 '-Bi s(di-tert-butylphosphino)ferrocene EC50—Half maximal effective concentration Equi v / eq—Equi val ents Et—Ethyl EtOH—Ethanol g—Grams HPLC—High-performance liquid chromatography hrs / h—Hours Hz—Hertz J—Coupling constant LCMS—Liquid chromatography-mass spectrometry LiHMDS—Lithium bis(trimethylsilyl)amide M—Molar m—Multiplet m / z—mass-to-charge ratio M+—Mass peak Me—Methyl mg—Milligram MHz—Megahertz min—Minute mL—Milliliter mM—Millimolar mm—Millimeter mmol—Millimole mol—Mole MS—mass spectrometry MW—Micro wave nM—Nanomolar NMP—N-Methyl-2-pyrrolidone NMR—Nuclear magnetic resonance P(oTol)3—Tri(o-tolyl)phosphine P(t-Bu)3—Tri-tert-butylphosphine Pd2(dba)3—Tris(dibenzylideneacetone)palladium(0) q—Quartet quant—Quantitative Rf—Retention factor RT / rt / r.t.—Room temperature s—Singlet sat.—Saturated SPhos—Dicyclohexyl(2',6'-dimethoxy-[l,l'-biphenyl]-2-yl)phosphine t—Triplet TFA—Trifluoroacetic acid TMS—Trimethyl silyl Tr / tr—Retention time UV—Ultraviolet wt.—Weight Xantphos—(9,9-Dimethyl-9H-xanthene-4,5 - diy 1 )b i s(diphenylphosphine) 5—Chemical shift pL—Microliter pM—Micromolar pmol—Micromole The following examples are merely illustrative, and do not limit this disclosure in any way. Example 1 o Br

[0341] 4-bromo-2-chlorophenyl acetate (Intermediate la): To a solution of 4-bromo-2-chlorophenol (78.0 g, 376.0 mmol) in DCM (1600 mL) was added EtsN (76.1 g, 752.0 mmol). The mixture was cooled to 0 °C, then acetyl chloride (44.3 g, 564.0 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h. IN HC1 (550 mL) was added and the mixture was extracted with DCM (500 mL). The organic layer was washed with brine (800 mL x 2) and dried over Na2SO4 and concentrated to give a crude product which was used to next step directly. XHNMR (400 MHz, CDC13) 3 7.60 (d, J= 2.0 Hz, 1H), 7.41-7.39 (m, 1H), 7.03 (d, 7= 8.8 Hz, 1H), 2.40 (s, 3H). O OH Br

[0342] l-(5-bromo-3-chloro-2-hydroxyphenyl)ethan-l-one(Intermediate lb): A mixture of compound Intermediate la (104.0 g, crude) and AICI3 (83.4 g, 625 mmol) was stirred at 140 °C for 2 h. The mixture was cooled to 60 -70 °C and then poured into ice water (500 mL). The mixture was extracted with EtOAc (300 mL x 3). The combined organic layer was washed with brine (300 mL x 3) and dried over Na2SO4 and concentrated to give crude material which was purified by silica gel flash column chromatography (Petroleum ether / EtOAc = 5: 1) to afford Intermediate lb. MS (m / z) 246.8, 248.8 [M-H]'. 'HNMR (400 MHz, CDCI3) 3 12.74 (s, 1H), 7.78 (d, J= 2.0 Hz, 1H), 7.70 (d, J= 2.4 Hz, 1H), 2.67 (s, 3H). OH Br

[0343] 4-bromo-2-chloro-6-ethylphenol(Intermediate 1c): Sodium hydroxide (16.1 g, 402.5 mmol) and hydrazine monohydrate (24.1g, 481.4 mmol) were added to a solution of Intermediate lb (40.0 g, 160.3 mmol) dissolved in triethylene glycol (200 mL). The reaction mixture was heated to 160 °C overnight. The mixture was cooled to room temperature was adjusted to pH 5 with 1 N HC1 then extracted with EtOAc (200 ml x 2). The organic layer was washed with saturated NaHCOs, brine, dried over Na2SO4 and concentrated in vacuo to yield a crude residue which was subjected to silica gel flash chromatography to afford the title compound. MS (m / z) 233.0, 234.0 [M-H]'. 'HNMR (400 MHz, CDC13) 3 7.31 (d, J= 2.0 Hz, 1H), 7.49 (d, J= 2.0 Hz, 1H), 5.55 (s, 1H), 2.69 (q, J= 7.2 Hz, 2H), 1.23 (t, J= 5.2 Hz, 3H). OH

[0344] 3-chloro-5-ethyl-4-hydroxybenzaldehyde (Intermediate Id): To a mixture of compound Intermediate 1c (22.0 g, 93.4 mmol) in THF (325 mL) was added dropwise n-BuLi (2.5M in n-hexane, 82 mL, 205.5 mmol) at -78 °C under N2 atmosphere. Then the mixture was stirred at -70 °C for 2 h.DMF (28.0 g, 382.9 mmol) was then added dropwise at -78 °C. The mixture was then stirred at room temperature overnight. The mixture was quenched with 2 N HC1 and adjusted to pH 3-4. The mixture was extracted with EtOAc (300 mL x 3) and the organic phase was washed with brine (300 mL x 3), dried over Na2SO4 and concentrated in vacuo. The crude product was subjected to silica gel flash column chromatography (Petroleum ether / EtOAc = 15: 1 to 10: 1) to afford the title compound. MS (m / z) 183.0 [M-H]'. 1H NMR (400 MHz, CDCI3) d 9.82 (s, 1H), 7.75 (d, J= 2.0 Hz, 1H), 7.62 (s, 1H), 6.13 (s, 1H), 2.78 (q, J = 7.6 Hz, 2H), 1.27 (t, J= 7.6 Hz, 3H). OH N

[0345] (E)-3-(3-chloro-5-ethyl-4-hydroxyphenyl)acrylonitrile (Intermediate le): To a mixture of diethyl (cyanomethyl)phosphonate (13.7 g, 77.5 mmol) in THF (220 mL) was added NaH (6.0 g, 149.0 mmol) at 0 °C. The mixture was stirred at room temperature for 0.5 h then was cooled to 0 °C and a mixture of Intermediate Id (11.0 g, 59.6 mmol) in THF (110 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 5 h. The mixture was quenched with water (300 mL) and adjusted to pH 2 with IN HC1. The solution was extracted with EtOAc (400 mL x 3) and the isolated organic phase was washed with brine (400 mL x 3), dried over Na2SO4 and concentrated en vacuo. The crude material was subjected to silica gel flash column chromatography (Petroleum ether / EtOAc = 5: 1) to afford crude product, which was triturated with heptane to give the title compound. MS (m / z) 206.0 [M-H]'. 1H NMR (400 MHz, DMSO-d6) 3 ppm 9.79 (brs, 1H), 7.58 (d, J= 2.0 Hz, 1H), 7.50 (d, J= 16.8 Hz, 1H), 7.40 (d, J= 2.0 Hz, 1H), 6.33 (d, J= 16.4Hz, 1H), 2.64 (q, J= 7.2 Hz, 2H), 1.14 (t, J= 7.6 Hz, 3H). Preparation of Compound 1 (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethyl-3-(trifluoromethyl)phenoxy)-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-6- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile: Step 2 N

[0346] Step 1, preparation of Intermediate Iftert-butyl (E)-6-chloro-4-(2-chloro-4-(2-cyanovinyl)-6-ethylphenoxy)-3-methyl-2H-pyrazolo[3,4-d]pyrimidine-2-carboxylate (Intermediate If). (E)-3-(3-chloro-5-ethyl-4-hydroxyphenyl)acrylonitrile (1.23 mmol, 256 mg), 4,6-dichloro-3-methyl-lH-pyrazolo[3,4-d]pyrimidine (1.23 mmol, 250 mg), and potassium carbonate (3.69 mmol, 511 mg) were suspended in DMF (5.0 mL). The mixture was stirred at room temperature for one hour. To the mixture was then added BOC2O (1.85 mmol, 403 mg), triethylamine (6.16 mmol, 0.86 mL), and DMAP (0.123 mmol, 15.0 mg). The mixture was stirred at room temperature for 1.5 hours at which point water (40 mL) was added to the mixture. The mixture was vigorously stirred and then subsequently filtered to yield a solid. This solid was purified via silica gel chromatography (0-100% EtOAc in hexanes) to afford the title compound (180 mg, 31% yield). MS (m / z) 473.46 [M+H]+. 'HNMR (400 MHz, DMSO-t / 6) 8 7.89 (s, 1H), 7.73 (s, 1H), 7.69 (d, J = 16.8 Hz, 1H), 6.64 (d, J = 16.7, 1H), 2.67 (s, 3H), 2.57 (m, 2H), 1.63 (s, 9H), 1.22- 1.11 (m, 3H).

[0347] Step 2, preparation of (E)-3-((4-(2-chloro-4-(2-cyanovinyl)-6-ethylphenoxy)-3-methyl-lH-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile: Intermediate If (0.105 mmol, 50.0 mg), 3-aminobicyclo[l.l.l]pentane-l-carbonitrile;hydrochloride (0.211 mmol, 30.5 mg), and potassium carbonate (0.527 mmol, 72.8 mg) were suspended in NMP (0.3 mL). The mixture was heated to 50 °C and stirred at this temperature overnight. The mixture was then filtered using 1 mL DCM to wash the filtered solids. To the combined filtrate was added 1 mL of TFA and the mixture was stirred at room temperature for two hours. The mixture was concentrated in vacuo and purified via preparative HPLC (0-100% MeCN in water, 0.1% TFA) then lyophilized to afford the title compound. MS (m / z) 446.25 [M+H]+. 'H NMR (400 MHz, Chloroform^) 5 7.56 (d, J= 2.0 Hz, 1H), 7.44 -7.39 (m, 2H), 5.99 (d, J= 16.7 Hz, 1H), 2.75 (s, 3H), 2.70 - 2.57 (m, 2H), 2.23 (br s, 6H), 1.32 -1.19 (m, 3H). Example 2 O OH Br

[0348] 5-bromo-3-chloro-2-hydroxybenzaldehyde (Intermediate 2a): 4-bromo-2-chlorophenol (50.0 g, 241.0 mmol) was dissolved in TFA (500 mL) at 0 °C, then hexamethylenetetramine (67.6 g, 482.0 mmol) was added at room temperature. The mixture was heated to 90°C and stirred for 12 h. The mixture was cooled to room temperature and poured into a mixture of water (500 mL) and 50% aqueous H2SO4 (250 mL). The mixture was filtered and the filter cake was dried under vacuum at 45 °C for 16 h to give the title compound which was used for next step directly. MS (m / z) 232.8, 234.8 [M-H]_1H NMR (300 MHz, DMSO-^) 3 11.21 (s, 1H), 10.11 (s, 1H), 7.98 (d, 7= 2.4 Hz, 1H), 7.83 (d, 7=2.7 Hz, 1H). ^0 0^ Br

[0349] 5-bromo-3-chloro-2-(methoxymethoxy)benzaldehyde (Intermediate 2b): To a mixture of Intermediate 2a (45.0 g, 191.1 mmol) in DCM (1350 mL) was added MOMBr (59.7 g, 477.8 mmol) and DIEA (98.8 g, 764.4 mmol) at room temperature under N2 atmosphere. Then the mixture was stirred at room temperature for 6 h. The mixture was poured into saturated aqueous NH4CI (900 mL). After separation, the aqueous layer was extracted with DCM (400 mL x 3). The combined organic layers were washed with brine (900 mL), dried over Na2SO4 and concentrated to give a crude product, which was purified by silica gel flash column chromatography (Petroleum ether / EtOAc = 30: 1) to give the title compound. 1H NMR (400 MHz, DMSO-tL) 3 10.13 (s, 1H), 8.15 (d, J= 2.4 Hz, 1H), 7.82 (d, J= 2.4 Hz, 1H), 5.21 (s, 2H), 3.53 (s, 3H). ^0 Br

[0350] 5-bromo-l-chloro-3-(difluoromethyl)-2-(methoxymethoxy)benzene (Intermediate 2c): To a mixture of Intermediate 2b (32.0 g, 114.5 mmo) in DCM (450 mL) was added BAST (63.0 g, 284.8 mmol) and EtOH (1.5 g, 32.6 mmol) at room temperature under N2 atmosphere. The mixture was stirred at room temperature overnight. The mixture was poured into saturated aqueous NaHCOs (500 mL). After separation and the aqueous layer was extracted with DCM (300 mL x 2). The combined organic phases were washed with brine (300 mL x 3) and dried over Na2SO4 and concentrated to give a crude product, which was purified by silica gel flash column chromatography (Petroleum ether / EtOAc = 30: 1) to give the title compound. 'HNMR (300 MHz, DMSO-tL) 3 8.00 (t, J= 1.2 Hz, 1H), 7.72 (d, J= 2.4 Hz, 1H), 7.10 (t, J= 54.3 Hz, 1H), 5.13 (s, 2H), 3.53 (s, 3H).

[0351] 3-chloro-5-(difluoromethyl)-4-(methoxymethoxy)benzaldehyde (Intermediate 2d): To a mixture of compound Intermediate 2c (21.0 g, 69.6 mmol) in THF (275 mL) was added dropwise w-BuLi (2.5M in w-hexane, 61 mL, 153.1 mmol) at -78 °C under N2 atmosphere. Then the mixture was stirred at -78 °C for 2 h. To the mixture was added dropwise DMF (20.9 g, 285.4 mmol) at -78 °C. Then the mixture was stirred at -78 °C for 2 h. The mixture was quenched with 2 N HC1 and adjusted pH to 3-4. The solution was extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (200 mL x 3), dried over Na2SO4 and concentrated to give a crude product (21.0 g, crude) which was used for next step without further purification.

[0352] 3-chloro-5-(difluoromethyl)-4-hydroxybenzaldehyde(Intermediate 2e): To a mixture of Intermediate 2d (52.0 g, 207.5 mmol) in MeOH (520 mL) was added HC1 (312 mL) at room temperature and the mixture was stirred at room temperature for 2 h. The mixture was poured into ice water (800 mL) and was extracted with MTBE (400 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over Na2SO4 and concentrated to give a crude product, which was purified by silica gel flash column chromatography (Petroleum ether / EtOAc = 10: 1) to give the title compound. MS (m / z) 205.0 [M-H]'. 'H NMR (300 MHz, DMSO-tL) 3 9.87 (s, 1H), 8.07 (t, J= 0.9 Hz, 1H), 7.97 (t, J= 0.6 Hz, 1H), 7.19 (t, J= 54.6 Hz, 1H).

[0353] (E)-3-(3-chloro-5-(difluoromethyl)-4-hydroxyphenyl)acrylonitrile (Intermediate 2f): To a mixture of diethyl (cyanomethyl)phosphonate (22.3 g, 125.8 mmol, 2.0 eq) in THF (250 mL) was added NaH (10.1 g, 251.6 mmol) in portions at 0 °C. Then the mixture was stirred at room temperature for 0.5 h. The mixture was cooled to 0 °C and a mixture of Intermediate 2e (13.0 g, 62.9 mmol, 1.0 eq) in THF (110 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 5 h. The mixture was quenched with water (300 mL) and adjusted pH to 2 with IN HC1. The solution was extracted with EtOAc (400 mL x 3). The combined organic phases were washed with brine (400 mL x 3), dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (Petroleum ether / EtOAc = 5: 1) to give crude product, which was triturated with heptane (50 mL) and then further purified by SFC separation Dto give the title compound as a light yellow solid. MS (m z) 228.0 [M-Hj-^H NMR (300 MHz, DMSO-t / e): 3 ppm 11.09 (brs, 1H), 7.95 (s, 1H), 7.74 (s, 1H), 7.67 (d, J= 14.4 Hz, 1H), 7.14 (t, J= 54.9 Hz, 1H), 6.49 (d, J= 16.5 Hz, 1H).

[0354] The following compounds were prepared using the two-step procedure described for the synthesis of Compound 1 (E)-3-((4-(2-chloro-4-(2-cyanovinyl)-6-ethylphenoxy)-3-methyl-lH-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile, with the following modifications:

[0355] tert-but(E)(E)-6-chloro-4-(2-chloro-4-(2-cyanovinyl)-6-(difluoromethyl)phenoxy)-3-methyl-2H-pyrazolo[3,4-d]pyrimidine-2-carboxylate (Intermediate 2g): (E)-3-(3-chloro-5-(difluoromethyl)-4-hydroxyphenyl)acrylonitrile was used in place of (E)-3-(4-hydroxy-3,5-dimethyl-2-(trifluoromethyl)phenyl)acrylonitrile to afford the title compound . 1H NMR (400 MHz, DMSO-d6) 5 8.27 (s, 1H), 8.05 (s, 1H), 7.78 (d, J = 16.7 Hz, 1H), 7.21 (t, J = 53.6 Hz, 93 1H), 6.75 (d, J = 16.8 Hz, 1H), 2.66 (s, 3H), 1.63 (s, 9H). n-nh

[0356] (E)-3-((4-(2-chloro-4-(2-cyanovinyl)-6-(difluoromethyl)phenoxy)-3-methyl-lH-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile Compound 2: Intermediate 2g was used in place of Intermediate If and the product was purified by preparative HPLC (0-100% MeCN in water, 0.1% TFA) to afford the title compound. MS (m / z) 468.29, 470.18 [M+H]+. 'HNMR (400 MHz, Acetonitrile-d3) 5 7.97 (s, 1H), 7.87 (s, 1H), 7.56 (d, J = 16.7 Hz, 1H), 6.89 (t, J = 54.1 Hz, 1H), 6.26 (d, J = 16.7 Hz, 1H), 2.58 (s, 3H), 2.15 (s, 6H). 19F NMR (376 MHz, CD3CN) 5 -77.32, -116.22. Example 3 OH

[0357] 3-chloro-5-ethoxy-4-hydroxybenzaldehyde (Intermediate 3a): To a solution of 3-ethoxy-4-hydroxybenzaldehyde (20.0 g, 120.4 mmol) in CCh (200 mL) was added DMSO (1.9 g, 24.1 mmol). To the mixture was added NCS (80.4 g, 602.0 mmol) at 0 °C and the mixture was allowed to slowly warm to room temperature and stir overnight. A saturatedaqueous solution of Na2S20s (100 mL) was added to the mixture and the mixture was extracted with DCM (200 mL x 3). The combined organic phases were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was subjected to silica gel flash column chromatography (Petroleum ether / EtOAc = 10 to 1) and then triturated with MTBE (30 mL) to give Intermediate 3a. MS (m / z) 199.0 [M-H]’. 'H NMR (300 MHz, DMSO4) d 10.47 (s, 1H), 9.77 (s, 1H), 7.58 (s, 1H), 7.38 (s, 1H), 4.17 (q, J= 7.0 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H). OH N

[0358] (E)-3-(3-chloro-5-ethoxy-4-hydroxyphenyl)acrylonitrile (Intermediate 3b): To a solution of diethyl (cyanomethyl)phosphonate (7.6 g, 42.8 mmol) in THF (40 mL) was added NaH (3.3 g, 82.2 mmol) at 0 °C under N2 atmosphere. The mixture was stirred at room temperature for 0.5 h at which point Intermediate 3a(6.6 g, 32.9 mmol) in THF (30 mL) was added dropwise at 0 °C. The mixture was stirred at room temperature overnight. The mixture was quenched with water (50 mL), adjusted pH to 2 with IN HC1 (40 mL). The solution was extracted with EtOAc (50 mL x 3). The organic phase was washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was subjected to silica gel flash column chromatography (Petroleum ether / EtOAc = 10 to 1) and triturated with MTBE (20 mL) to yield the title compound. MS (m / z) 222.0 [M-H]-^ NMR (300 MHz, DMSO4) d 9.92 (s, 1H), 7.48 (d, J = 16.6 Hz, 1H), 7.29 (dd, J= 9.3, 1.9 Hz, 2H), 6.37 (d, J= 16.6 Hz, 1H), 4.12 (q, J= 7.0 Hz, 2H), 1.36 (t, J= 7.0 Hz, 3H). Boc N-N

[0359] tert-butyl (E)-6-chloro-4-(2-chloro-4-(2-cyanovinyl)-6-ethoxyphenoxy)-3-methyl-2H-pyrazolo[3,4-d]pyrimidine-2-carboxylate (Intermediate 3c): (E)-3-(3-chioro-5-ethoxy-4-hydroxyphenyl)acrylonitrile was used in place of (E)-3-(4-hydroxy-3,5-dimethyl-2- (trifluoromethyl)phenyl)acrylonitrile to afford the title compound (145 mg, 24% yield). MS (m / z) 492.18 [M+H]+. n-nh

[0360] (E)-3-((4-(2-chloro-4-(2-cyanovinyl)-6-ethoxyphenoxy)-3-methyl-lH-pyrazolo[3,4- d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile Compound 3: Intermediate 3a was used in place of Intermediate If and the product was purified by preparative HPLC (0- 100% MeCN in water, 0.1% TFA) to afford the title compound. MS (m / z) 462.25, 464.24 [M+H]+. 'HNMR (400 MHz, Acetonitrile-d3) 5 7.48 (d, J = 16.7 Hz, 1H), 7.38 (s, 1H), 7.26 (s, 1H), 6.23-6.15 (m, 1H), 4.21-4.03 (m, 2H), 2.58 (s, 3H), 2.16 (s, 6H), 1.19 (t, J = 7.0 Hz, 3H). Example 4

[0361] (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethyl-3-(trifluoromethyl)phenoxy)-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 4:

[0362] Step 1, Intermediate 4a(E)-3-(4-((6-chloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3,5-dimethyl-2-(trifluoromethyl)phenyl)acrylonitrile (c): (E)-3-(4-hydroxy-3,5-dimethyl-2-(trifluoromethyl)phenyl)acrylonitrile (1.63 mmol, 392 mg), 4,6-dichloro-2-methyl-pyrazolo[3,4-d] pyrimidine (1.48 mmol, 300 mg), and potassium carbonate (2.22 mmol, 306 mg) were suspended in DMF (6.0 mL). The mixture was stirred at room temperature for 2 h at which point water (20 mL) was added to the mixture. The mixture was vigorously stirred and then subsequently filtered to yield a damp solid. This solid was further dried under vacuum to afford the title compound. MS (m / z) 408.13 [M+H]+.

[0363] Step 2, preparation of (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethyl-3-(trifluoromethyl)phenoxy)-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile Compound 4. Intermediate 4a (0.123 mmol, 50.0 mg), potassium fluoride (0.61 mmol, 36 mg), and l,4-diazabicyclo[2.2.2]octane (0.061, mmol, 6.9 mg) were suspended in DMF (0.5 mL). The mixture was stirred at 60 °C for two hours and then cooled to room temperature. To the mixture was added 3-aminobicyclo[l.l.l]pentane-l-carbonitrile;hydrochloride (0.31 mmol, 44 mg) and potassium carbonate (0.61 mmol, 85 mg). The mixture stirred at 50 °C overnight, at which point the mixture was then cooled to room temperature and passed through a filter. The filtrate was purified by preparative HPLC (0-100% MeCN in water) then lyophilized to afford the title compound (4.2 mg, 7.1% yield). MS (m / z) 480.19 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 8.57 (s, 1H), 7.90 (m, 2H), 7.65 (s, 1H), 6.30 (d, J = 16.3 Hz, 1H), 4.04 (s, 3H), 2.21 (m, 3H), 96 2.15 (s, 3H), 2.00 (br s, 6H). 19F NMR (376 MHz, DMS0-d6) 5 -51.99. Example 5 OH

[0364] 3-chloro-5-fluoro-4-hydroxybenzaldehyde (Intermediate 5a): To a mixture of 2-chloro-6-fluorophenol (20.0 g, 136.5 mmol) in TFA (40 mL) was added dropwise a solution of hexamethylenetetramine (38.3 g, 273.0 mmol) in TFA (100 mL) at 60 °C. Then the mixture was stirred at 70 °C for 12 h. The mixture was cooled to room temperature and poured into water (300 mL). The precipitated solid was collected by filtration, washed with water (100 mL) and dried to give a residue which was triturated with 10:1 Petroleum ether: EtOAc (150 mL) and filtered to give the title compound. MS (m / z) 173.0 [M-H]'. 'H NMR (300 MHz, DMSO-^) 3 ppm 11.79 (br s, 1H), 9.80 (d, J= 1.8 Hz, 1H), 7.83 (s, 1H), 7.69 (dd, J= 1.8 Hz, 10.4 Hz, 1H). OH N

[0365] (E)-3-(3-chloro-5-fluoro-4-hydroxyphenyl)acrylonitrile (Intermediate 5b): To a mixture of diethyl (cyanomethyl)phosphonate (26.4 g, 148.9 mmol) in THF (200 mL) was added NaH (11.5 g, 286.4 mmol) at 0 °C. Then the mixture was stirred at room temperature for 30 min. The mixture was cooled to 0 °C and a mixture of Intermediate 5a (20.0 g, 114.6 mmol) in THF (100 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 5 h. The mixture was quenched with water (250 mL) and the pH was acidified to 2 with IN HC1. The solution was extracted with EtOAc (300 mL x 3). The organic phase was washed with brine (250 mL x 3), dried over Na2SO4 and concentrated in vacuo. The resulting residue was subjected to silica gel flash column chromatography (Petroleum ether: EtOAc = 5: 1~3: 1) and recrystallized with EtOAc (80 mL) to afford the title compound. MS (m / z) 196.0 [M-HJ / H NMR (400 MHz, DMSO-tL) 3 ppm 11.19 (br s, 1H), 7.61-7.55 (m, 2H), 7.50 (d,J= 16.6 Hz, 1H), 6.42 (d, J = 16.6 Hz, 1H).

[0366] The following compounds were prepared using the two-step procedure described for the synthesis of (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethyl-3-(trifluoromethyl)phenoxy)-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l. 1. l]pentane-l-carbonitrile, with the following modifications: N

[0367] (E)-3-(3-chloro-4-((6-chloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-5-fluorophenyl)acrylonitrile (Intermediate 5c): (E)-3-(3 -chioro-5-fluoro-4- hydroxyphenyl)acrylonitrile (1.63 mmol, 321 mg) was used in place of (E)-3-(4-hydroxy-3,5-dimethyl-2-(trifluoromethyl)phenyl)acrylonitrile to afford the title compound. MS (m / z) 365.91 [M+H]+. N

[0368] (E)-3-((4-(2-chloro-4-(2-cyanovinyl)-6-fluorophenoxy)-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 5: Intermediate 5c (0.137 mmol, 50.0 mg) was used in place of Intermediate 4a Intermediate 4aand the product was purified by preparative HPLC (0-100% MeCN in water, 0.1% TFA) to afford the title compound. MS (m / z): 436.25, 438.16 [M+H]+. 'HNMR (400 MHz, Acetonitrile-d3) 5 8.32 (s, 1H), 7.69 (s, 1H), 7.59 (d, J = 10.3 Hz, 1H), 7.52 (d, J = 16.7 Hz, 1H), 6.24 (d, J = 16.7 Hz, 1H), 4.10 (d, J = 0.6 Hz, 3H), 2.26 (s, 6H). Example 6 OH

[0369] 3-chloro-4-hydroxy-5-methylbenzaldehyde (Intermediate 6a): To a solution of 4-bromo-2-chloro-6-methylphenol(37.0 g, 167.1 mmol) in THF (462 mL) was added dropwise n-BuLi (2.5 M in / / -hexane, 150 mL) at -70 °C under N2 atmosphere. The mixture was stirred at -70 °C for 2 h. To the mixture was added dropwise DMF (50.1 g, 684.9 mmol). The mixture was stirred at room temperature for 12 h. 2N HC1 (300 mL) was added and the mixture was stirred at 0 °C for 15 min. Saturated aqueous NaHCOs was added to adjust the pH to 8 and the mixture was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over Na2SO4 , filtered, and concentrated in vacuo to give a residue, which was subjected to silica gel flash column chromatogrpahy (Petroleum ether / EtOAc = 10: 1) to afford the title compound. MS (m / z) 169.0 [M-Hl'.'HNMR (400 MHz, DMSO^) 3 10.36 (s, 1H), 9.77 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 2.27 (s, 3H). OH N

[0370] (E)-3-(3-chloro-4-hydroxy-5-methylphenyl)acrylonitrile (Intermediate 6b): To a solution of diethyl (cyanomethyl)phosphonate (13.5 g, 76.2 mmol) in THF (100 mL) was added NaH (5.9 g, 146.5 mmol) at 0 °C. The mixture was stirred at room temperature for 15 min. Then to the mixture was added dropwise a solution of Intermediate 6a (10.0 g, 58.6 mmol) in THF (200 mL). The mixture was stirred at room temperature for 12 h. Water (200 mL) was added into the crude mixture and IN HC1 was added to adjust the pH to 2. The aqueous layer was extracted with EtOAc (250 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a crude product, which was purified by silica gel (eluted with Petroleum ether / EtOAc = 1: 1) to afford the title compound. MS (m / z) 192.0 [M-H]'. N

[0371] (E)-3-(3-chloro-4-((6-chloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-5-methylphenyl)acrylonitrile (Intermediate 6c) : (E)-3-(3-chloro-4-hydroxy-5-methyl-phenyl)prop-2-enenitrile (1.48 mmol, 315 mg) was used in place of (E)-3-(4-hydroxy-3,5-dimethyl-2-(trifluoromethyl)phenyl)acrylonitrile to afford the title compound. MS (m / z) 360.15, 362.10 [M+H]+. \-N N

[0372] (E)-3-((4-(2-chloro-4-(2-cyanovinyl)-6-methylphenoxy)-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 6: Intermediate 6c was used in place of Intermediate 4a Intermediate 4a and the product was purified by preparative HPLC (0-100% MeCN in water, 0.1% TFA) to afford the title compound. MS (m / z) 432.21 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 8.55 (s, 1H), 7.88 (s, 2H), 7.71 (s, 1H), 7.66 (d, J = 16.7 Hz, 1H), 6.59 (d, J = 16.7 Hz, 1H), 4.04 (s, 3H), 2.16 (s, 3H), 2.15 (br s, 6H). Example 7

[0373] (E)-3-(3-chloro-4-((6-chloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-5-ethylphenyl)acrylonitrile (Intermediate 7a): (E)-3-(3-chloro-4-hydroxy-5-ethyl-phenyl)prop-2-enenitrile (1.48 mmol, 315 mg) was used in place of (E)-3-(4-hydroxy-3,5-dimethyl-2-(trifluoromethyl)phenyl)acrylonitrile to afford the title compound. MS (m / z) 374.10, 376.09 [M+H]+. N-n N

[0374] (E)-3-((4-(2-chloro-4-(2-cyanovinyl)-6-ethylphenoxy)-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 7: Intermediate 7a (0.13 mmol, 50 mg) was used in place of Intermediate 4a and the product was purified by preparative HPLC (0-100% MeCN in water, 0.1% TFA) to afford the title compound . MS (m / z) 446.25, 448.18 [M+H]+. 'HNMR (400 MHz, Acetonitrile-d3) 5 8.36 (s, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.54 (d, J = 16.7 Hz, 1H), 6.22 (d, J = 16.7 Hz, 1H), 4.10 (d, J = 0.6 Hz, 3H), 2.61 (q, J = 7.6 Hz, 2H), 2.17 (s, 6H), 1.20 (t, J = 7.6 Hz, 3H). Example 8 OH XX

[0375] 4-hydroxy-2,3,5-trimethylbenzaldehyde (Intermediate 8a): To a mixture of 2,3,6-trimethylphenol (50.0 g, 367.1 mmol) in AcOH (150 mL) was added a solution of hexamethylenetetramine (25.7 g, 183.6 mmol) in AcOH (50 mL) dropwise at 120 °C. Then the mixture was stirred at 120 °C for 3 h. The mixture was then cooled to 100 °C and 20% H2SO4 (200 mL) was added. Then the mixture was stirred for 0.5 h. The mixture was poured into ice water (200 mL) and filtered to afford the title compound. MS (m / z) 165.2 [M+H]+. OH N

[0376] (E)-3-(4-hydroxy-2,3,5-trimethylphenyl)acrylonitrile (Intermediate 8b): To a mixture of diethyl (cyanomethyl)phosphonate (129.5 g, 730.8 mmol) in THF (300 mL) was added NaH (24.4 g, 609.0 mmol) at 0 °C. Then the mixture was stirred at room temperature for 30 min. The mixture was cooled to 0 °C and a solution of Intermediate 8a (40.0 g, 243.6 mmol) in THF (500 mL) was added dropwise at 0 °C. The mixture was stirred at room temperature for 5 h. The mixture was then quenched with water (400 mL), adjusted to pH 2 with IN HC1 (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic phases were washed with brine (250 mL x 3), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was subjected to silica gel flash column chromatography (Petroleum ether: EtOAc = 5:1) and recrystallized with THF / n-hexane (10: 1) to afford the title compound. MS (m z) 186.0 [M-H]-. 'HNMR (400 MHz, DMSO-tL) 3 8.73 (s, 1H), 7.80 (d, J= 16.4 Hz, 1H), 7.32 (s, 1H), 6.06 (d, J= 16.4 Hz, 1H), 2.22 (s, 3H), 2.15 (s, 3H), 2.11 (s, 3H). \ n-n

[0377] (E)-3-(4-((6-chloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-2,3,5- trimethylphenyl)acrylonitrile (Intermediate 8c): (E)-3-(4-hydroxy-2,3,5- trimethylphenyl)acrylonitrile (1.48 mmol, 304 mg) was used in place of (E)-3-(4-hydroxy-3,5-dimethyl-2-(trifluoromethyl)phenyl)acrylonitrile to afford the title compound. MS (m / z) 354.13 [M+H]+

[0378] (E)-3-((4-(4-(2-cyanovinyl)-2,3,6-trim ethylphenoxy )-2-methyl-2H-pyrazolo[3,4- d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 8: Intermediate 8c (0.17 mmol, 57.2 mg) was used in place of Intermediate 4a, and more 3- aminobicyclo[l.l.l]pentane-l-carbonitrile;hydrochloride (0.424 mmol, 61.3 mg) was used. Furthermore, after heating overnight, water (1 mL) was added to the mixture which was extracted with ethyl acetate (3x1 mL). The organic layers were combined and concentrated in vacuo. The resulting residue was purified by preparative HPLC (0-100% MeCN in water, 0.1% TFA) to afford the title compound. MS (m / z) 426.20 [M+H]+. 1H NMR (400 MHz, Acetonitrile-d3) 5 8.29 (s, 1H), 7.89 (d, J = 16.5 Hz, 1H), 7.44 (s, 1H), 5.99 (d, J = 16.5 Hz, 1H), 4.07 (s, 3H), 2.34 (s, 3H), 2.11 (s, 3H), 2.08 (br s, 6H), 2.07 (s, 3H). Example 9

[0379] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-(4-methoxybenzyl)-8-methyl- 7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 9:

[0380] (E)-3-[4-[2-chloro-7-[(4-methoxyphenyl)methyl]-8-methyl-purin-6-yl]oxy-3,5-dimethyl-phenyl]prop-2-enenitrile (48.0 mg, 0.104 mmol), 3-aminobicyclo[l.l.l]pentane-l-carbonitrile (13.5 mg, 0.125 mmol), Bis(triphenylphosphine)palladium chloride (7.3 mg, 0.0104 mmol), rac-BINAP (6.5 mg, 0.0104 mmol), and cesium carbonate (102 mg, 0.313 mmol) were combined in a microwave vial and dioxane (0.75 mL) was added. The mixture was degassed with N2 and then the vial sealed and heated to 110 °C for 8 h. The mixture was then cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-20% MeOH / DCM) to afford the title compound. MS (m / z) 532.1 [M+H]+. Example 10

[0381] (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-lH-pyrazolo[3,4-d]pyrimidin-6- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 10:

[0382] Step 1: Preparation of (E)-3-(3,5-dimethyl-4-((6-(methylthio)-lH-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)phenyl)acrylonitrile (Intermediate 10a): To a solution of 4-chloro-6-methylsulfanyl-lH-pyrazolo[3,4-d]pyrimidine (348 mg, 1.73 mmol) in DMF (10 mL) was added potassium carbonate (470 mg, 3.40 mmol ) and (E)-3-(4-hydroxy-3,5-dimethyl-phenyl)prop-2-enenitrile (300 mg, 1.73 mmol). The mixture was stirred at room temperature overnight and then heated at 50 °C for 3 hours. To the mixture was added water and the resulting precipitate was filtered off and dissolved in EtOAc and DCM. The organic solution was dried over MgSO4, filtered, then concentrated in vacuo onto silica gel and subjected to silica gel flash column chromatography (0-100% hexane / EtOAc) to afford the title compound. MS (rn / z) 338.15 [M+H]+.

[0383] Step 2: preparation of tert-butyl (E)-4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-6-(methylthio)-lH-pyrazolo[3,4-d]pyrimidine-l-carboxylate (Intermediate 10b): To a solution of (E)-3-(3,5-dimethyl-4-((6-(methylthio)-lH-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)phenyl)acrylonitrile (50 mg, 0.15 mmol) in acetonitrile (2 mL) was added tri ethylamine (0.104 mL, 0.74 mmol), di-tert-butyl dicarbonate (64.7 mg, 0.296 mmol) and 4-dimethylaminopyridine (2.0 mg, 0.015 mmol). The mixture was stirred at room temperature overnight. Then the mixture was concentrated in vacuo and the resulting residue was subjected to silica gel flash column chromatography (0-100% hexane / EtOAc) to yield the title compound. MS (m / z) 437.83 [M+H]+.

[0384] Step 3: Preparation of tert-butyl (E)-6-((3-cyanobicyclo[l.l.l]pentan-l-yl)amino)-4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-lH-pyrazolo[3,4-d]pyrimidine-l-carboxylate (Intermediate 10c): to a solution of tert-butyl (E)-4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-6-(methylthio)-lH-pyrazolo[3,4-d]pyrimidine-l-carboxylate (30 mg, 0.068 mmol) in NMP (2 mL) was added 3-chloroperoxybenzoic acid (31.6 mg, 0.137 mmol). The mixture was stirred at room temperature overnight. To this mixture was added potassium carbonate (66 mg, 0.48 mmol) and 3-aminobicyclo[l.l.l]pentane-l-carbonitrile;hydrochloride (30 mg, 0.206 mmol). The mixture was stirred at room temperature for 4 hours. Water was added to the mixture which was subsequently extracted three times with EtOAc. The organic phase was combined, dried over MgSO4, filtered, concentrated in vacuo, and subjected to silica gel flash column chromatography (0-100% hexane / EtOAc) to afford the title compound. MS (m / z) 497.67 [M+H]+.

[0385] Step 4: Preparation of (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-lH-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 10: tert-butyl (E)-6-((3-cyanobicyclo[l.l.l]pentan-l-yl)amino)-4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-lH-pyrazolo[3,4-d]pyrimidine-l-carboxylate was suspended in a 1:1 DCM / TFA solution (1 mL) and stirred at room temperature for 2 hours. The mixture was then concentrated in vacuo and subjected to reverse phase HPLC (5-100% acetonitrile / water, containing 0.1% TFA). The fraction was dissolved in DCM, neutralized by saturated aqueousNaHCO3, the organic phase was separated, dried over MgSO4, filtered, concentrated in vacuo and subjected to silica gel flash column chromatography (0-100% hexane / EtOAc then 010% DCM / MeOH) yield the title compound.MS (m / z) 398.22 [M+H]+. 'H NMR (400 MHz, MeOD) 5 7.97 (s, 1H), 7.54 (d, J = 16.7 Hz, 1H), 7.48 (s, 2H), 6.24 (d, J = 16.6 Hz, 1H), 2.17 (s, 12H). Example 11 THF, -40 °C K2CO3, DMF; then K2CO3 Zn, AcOH DCM, 0 °C tort

[0386] Step 1, preparation of 2,6-dichloro-N-(2,4-dimethoxybenzyl)-5-nitropyrimidin-4-amine (Intermediate Ila).

[0387] To a solution of 2,4,6-trichloro-5-nitro-pyrimidine (5.00 g, 21.9 mmol) in THF (100 mL) at -40 °C was added (2,4-dimethoxyphenyl)methanamine (3.29 mL, 21.9 mmol) followed by DIPEA (4.58 mL, 26.3 mmol), over the course of 15 min. The mixture was stirred at -40 °C for 30 min, then saturated NH4CI aqueous solution was added and the aqueous phase extracted twice with EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-100% EtOAc / hexanes) to afford the title compound. MS (m / z): 358.9 [M+H]+. ^0 N

[0388] Step 2, preparation of (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile (Intermediate 11b).

[0389] A mixture of 2,6-dichloro-N-(2,4-dimethoxybenzyl)-5-nitropyrimidin-4-amine (1490 mg, 8.60 mmol), (E)-3-(4-hydroxy-3,5-dimethyl-phenyl)prop-2-enenitrile (1490 mg, 8.60 mmol), and potassium carbonate (5945 mg, 43.0 mmol) in DMF (45 mL) was stirred at room temperature overnight. 3-aminobicyclo[l.l.l]pentane-l-carbonitrile (1396 mg, 12.9 mmol) was then added, followed by potassium carbonate (1189 mg, 8.61 mmol), and the mixture stirred at room temperature overnight. The mixture was then diluted with EtOAc and washed twice with brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-100% EtOAc / hexanes) to afford the title compound. MS (m / z) 568.1 [M+H]+.

[0390] Step 3, preparation (E)(E)-3-((5-amino-4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile (Intermediate 11c).

[0391] To a solution of (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidin-2-yl)amino)bicyclo[l. 1. l]pentane-l-carbonitrile (1.38 g, 2.44 mmol) in DCM (25 mL) at 0 °C was added zinc dust (2.39 g, 36.5 mmol), followed by acetic acid (1.05 mL, 18.3 mmol) (steadily dropwise). The mixture was stirred for 1 h, then 106 filtered through celite to remove zinc, and the filtrate concentrated in vacuo. The resulting residue was diluted with EtOAc, then basified with saturated aqueous NaHCOs, layers separated, and the aqueous phase extracted with additional EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was used without further purification. MS (mlz) 538.2 [M+H]+.

[0392] Step 4, preparation of (E)-3-((4,5-diamino-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)pyrimidin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile (Intermediate lid).

[0393] (E)-3-((4,5-diamino-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)pyrimidin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-8-methyl-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile with the following modifications: (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile was used in place of (E)-3-(4-((2-chloro-7-(2,4-dimethoxybenzyl)-8-methyl-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile. MS (m / z): 388.1 [M+H]+.

[0394] (E)-3-((7-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-lH-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile (Intermediate lie) was prepared as follows: A microwave vial was charged with (E)-3-((4,5-diamino-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)pyrimi din-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile (50.0 mg, 0.129 mmol), which was then suspended in H2O (0.2 mL) and acetic acid (0.2 mL). The mixture was cooled to 0 °C and NaNCh (16.0 mg, 0.232 mmol) was added as a solution in 0.2 mL H2O. After 30 min, H2O was added and the aqueous phase extracted with EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was used without further purification. MS (mlz) 398.9 [M+H]+.

[0395] (E)-3-((7-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-l-(difluoromethyl)-lH-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 11 was prepared using the procedure described for the synthesis of Compound 20 with the following modifications: lododifluoromethane (10.0 % in THF) was used in place of l,l-difluoro-2-iodo-ethane, and the reaction was stirred at room temperature (eluted as isomer 1). MS (mlz) 448.8 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 8.79 - 8.39 (m, 2H), 7.64 (d, J = 16.7 Hz, 1H), 7.58 (s, 2H), 6.46 (d, J = 16.7 Hz, 1H), 2.20 - 1.72 (m, 12H). Example 12 I o

[0396] 2,6-dichloro-7-(4-methoxybenzyl)-7H-purine (Intermediate 12a) was prepared as follows: To mixture of 2,6-dichloro-9H-purine (1.00 g, 5.29 mmol), (4-methoxyphenyl)methanol (877 mg, 6.35 mmol), and triphenylphosphine (1804 mg, 6.88 mmol) in THF (30 mL) was added diisopropyl azodicarboxylate (1.35 mL, 6.88 mmol), and the mixture stirred at room temperature overnight. The mixture was then concentrated in vacuo and purified by silica gel chromatography (0-100% EtOAc / hexanes) to afford the title compound. MS (m / z): 309.0 [M+H]+. I o

[0397] (E)-3-(4-((2-chloro-7-(4-methoxybenzyl)-7H-purin-6-yl)oxy)-3,5- dimethylphenyl)acrylonitrile (Intermediate 12b) was prepared using the procedure described WO 2025 / 184609                                   PCT / US2025 / 017990 for the synthesis of (E)-3-(4-((2-chloro-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 176a) with the following modifications: 2,6-dichloro-7-(4-methoxybenzyl)-7H-purine was used in place of 2,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]-5-nitro-pyrimidin-4-amine. MS (m / z): 446.0 [M+H]+.

[0398] (E)-3-(4-((2-chloro-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 12c) was prepared as follows: A mixture of (E)-3-[4-[2-chloro-7-[(4-methoxyphenyl)methyl]purin-6-yl]oxy-3,5-dimethyl-phenyl]prop-2-enenitrile (500 mg, 1.12 mmol) in TFA (10 mL) was heated to 60 °C for 5 h. The mixture was then concentrated in vacuo, rediluted with EtOAc, and quenched with saturated NaHCOs aqueous solution, the layers separated, and the aqueous phase extracted with additional EtOAc. Combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash column chromatography (0-20% MeOH / DCM) to afford the title compound. MS (m / z): 326.0 [M+H]+.

[0399] (E)-3-(4-((2-chloro-7-(difluoromethyl)-7H-purin-6-yl)oxy)-3,5- dimethylphenyl)acrylonitrile (Intermediate 12d) was prepared as follows: To a solution of (E)-3-[4-[(2-chloro-7H-purin-6-yl)oxy]-3,5-dimethyl-phenyl]prop-2-enenitrile (50.0 mg, 0.153 mmol) in 2-MeTHF (8.00 mL) was added LiHMDS (1.00 mol / L, 0.169 mL, 0.169 mmol), and the reaction mixture stirred at room temperature for 30 min. lododifluoromethane (10.0 % in THF, 0.369 mL, 0.184 mmol) was then added, and the mixture stirred at room temperature overnight. The mixture was then quenched with saturated ammonium chloride aqueous solution and extracted with EtOAc. Combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash column chromatography (0-100% EtOAc / hexanes) to afford the title compound. MS (m / z): 376.0 [M+H]+. F / =^ \^N 1 Ta O N NH : N

[0400] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-(difluoromethyl)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 12 was prepared using the procedure described for the synthesis of Compound 4 with the following modifications: (E)-3-(4-((2-chloro-7-(difluoromethyl)-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile was used in place of (E)-3-(4-((6-chloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3,5-dimethyl-2-(trifluoromethyl)phenyl)acrylonitrile (Intermediate 4a). MS (m / z): 448.0 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 8.75 (s, 1H), 8.22 - 7.84 (m, 2H), 7.63 (d, J = 16.7 Hz, 1H), 7.56 (s, 2H), 6.45 (d, J = 16.7 Hz, 1H), 2.28 - 1.81 (m, 12H). Example 13 I o r=N / 1 \  Yj

[0401] 2,6-dichloro-7-(2,4-dimethoxybenzyl)-8-methyl-7H-purine (Intermediate 13a) was prepared using the procedure described for the synthesis of 2,6-dichloro-7-(4-methoxybenzyl)-7H-purine with the following modifications: 2,6-dichloro-8-methyl-9H-purine and (2,4-dimethoxyphenyl)methanol were used in place of 2,6-dichloro-9H-purine and (4-methoxyphenyl)methanol, respectively. MS (m / z): 352.9 [M+H]+.

[0402] (E)-3-(4-((2-chloro-7-(2,4-dimethoxybenzyl)-8-methyl-7H-purin-6-yl)oxy)-3,5- dimethylphenyl)acrylonitrile (Intermediate 13b) was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidin-4- yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 176a) with the following modifications: 2,6-dichloro-7-(2,4-dimethoxybenzyl)-8-methyl-7H-purine was used in place of 2,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]-5-nitro-pyrimidin-4-amine. MS (m / z): 489.9 [M+H]+. N

[0403] (E)-3-(4-((2-chloro-8-methyl-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 13c) was prepared as follows: A mixture of (E)-3-(4-((2-chloro-7-(2,4-dimethoxybenzyl)-8-methyl-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (1.78 g, 3.63 mmol) in TFA (35 mL) was stirred at room temperature for 6 h. The mixture was then concentrated in vacuo, rediluted with EtOAc, and quenched with saturated NaHCOs aqueous solution, the layers separated, and the aqueous phase extracted with additional EtOAc. Combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was used without further purification. MS (m / z): 339.9 [M+H]+. N

[0404] (E)-3-(4-((2-chloro-7-(difluoromethyl)-8-methyl-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 13d) was prepared as follows: To a mixture of (E)-3-(4-((2-chloro-8-methyl-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (750 mg, 2.21 mmol) and lithium carbonate (0.489 g, 6.62 mmol) in DMF (11 mL) was added ethyl 2-bromo-2,2-difluoro-acetate (0.425 mL, 3.31 mmol), and the mixture was heated to 70 °C overnight. The mixture was then diluted with EtOAc and washed twice with brine. Organics were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash column chromatography (0-100% EtOAc / hexanes) to afford the title compound. MS (m / z): 389.9 [M+H]+. AN

[0405] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-(difluoromethyl)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 13 was prepared as follows: (E)-3-(4-((2-chloro-7-(difluoromethyl)-8-methyl-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (104 mg, 0.267 mmol), 3-aminobicyclo[l.l.l]pentane-l-carbonitrile (72.1 mg, 0.667 mmol), rac BINAP Pd G3 (265 mg, 0.267 mmol), and cesium carbonate (261 mg, 0.800 mmol) were combined in a microwave vial and 1,4-dioxane (2.5 mL) was added. The mixture was degassed with N2 and then the vial sealed and heated to 60 °C for 12 h. The mixture was then cooled to room temperature and concentrated in vacuo. The resulting residue was purified by preparative HPLC (0-100% MeCN / water) to afford the title compound. MS (m / z) 461.9 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 8 8.23 - 7.87 (m, 2H), 7.63 (d, J = 16.7 Hz, 1H), 7.56 (s, 2H), 6.44 (d, J = 16.7 Hz, 1H), 2.70 (s, 3H), 2.22 - 1.83 (m, 12H). 19F NMR (376 MHz, DMSO-d6) 6 -92.09 (d, J = 57.1 Hz). Example 14

[0406] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-7H-purin-2- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 14 was prepared as follows: To a mixture of 3-[[4,5-diamino-6-[4-[(E)-2-cyanovinyl]-2,6-dimethyl-phenoxy]pyrimidin-2-yl]amino]bicyclo[l.l.l]pentane-l-carbonitrile (721 mg, 1.86 mmol) in DCM (9 mL) and MeOH (9 mL) was added acetaldehyde (246 mg, 5.58 mmol), followed by Ferric chloride (453 mg, 2.79 mmol) and acetic acid (0.0107 mL, 0.186 mmol). The mixture was stirred at room temperature overnight, then partitioned between water / EtOAc, the layers separated, and the aqueous phase extracted with additional EtOAc. The combined organics were dried over MgS04, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash column chromatography (0-20% MeOH / DCM) to afford the title compound. MS (m / z) 411.9 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 12.50 (s, 1H), 7.70 (s, 1H), 7.62 (d, J = 16.6 Hz, 1H), 7.54 (s, 2H), 6.43 (d, J = 16.7 Hz, 1H), 2.42 (s, 3H), 2.09 - 2.00 (m, 12H). Example 15

[0407] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-9-(difluoromethyl)-8-methyl-9H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 15 was prepared as follows: (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile (9.67 mg, 0.0235 mmol), lithium carbonate (0.00521 g, 0.0705 mmol), and iododifluoromethane (10.0 % in THF, 0.0706 mL, 0.0353 mmol) were combined and heated to 60 °C overnight. Additional iododifluoromethane (10.0 % in THF, 0.0235 mL, 0.0118 mmol) was added and the mixture heated to 80 °C for 2 h, then to 100 °C overnight. The mixture was then diluted with DMF / H2O and purified by preparative HPLC (0100% MeCN / water) to afford the title compound. MS (m / z) 461.9 [M+H]+. 'H NMR (400 MHz, Acetonitrile-d3) 5 7.70 - 7.40 (m, 2H), 7.39 (s, 2H), 6.25 (s, 1H), 6.06 (d, J = 16.7 Hz, 1H), 2.64 (d, J = 1.6 Hz, 3H), 2.13 - 2.04 (m, 12H). 19F NMR (376 MHz, Acetonitrile-d3) 5 -99.46 (d, J = 58.3 Hz). Example 17

[0408] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-(difluoromethyl)-8-ethyl-7H- WO 2025 / 184609                                   PCT / US2025 / 017990 purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 17 was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-7-(difluoromethyl)-8-methyl-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile with the following modifications: (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-ethyl-7H-purin-2- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile was used in place of (E)-3-(4-((2-chloro-8-methyl-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile, and the reaction was heated to 60 °C. MS (mlz) 475.9 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 8.25 - 7.89 (m, 2H), 7.63 (d, J = 16.7 Hz, 1H), 7.55 (s, 2H), 6.44 (d, J = 16.7 Hz, 1H), 3.05 (q, J = 7.4 Hz, 2H), 2.24 - 1.85 (m, 12H), 1.33 (t, J = 7.4 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) 5 -92.04, -92.19. Example 18

[0409] (E)-3-((7-((lH-pyrazol-5-yl)methyl)-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 18 was prepared as follows: A mixture of (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile (20.0 mg, 0.0486 mmol), 5-(chloromethyl)-lH-pyrazole hydrochloride (0.015 g, 0.097 mmol), lithium carbonate (0.0108 g, 0.146 mmol), and potassium iodide (0.00403 g, 0.0243 mmol) in DMF (0.5 mL) was heated to 100 °C overnight. The mixture was then diluted with DMF / H2O and purified by preparative HPLC (0-100% MeCN / water) to afford the title compound (eluted as isomer 1). MS (mlz) 491.9 [M+H]+. XH NMR (400 MHz, DMSO-d6) 5 12.76 (s, 1H), 7.73 - 7.56 (m, 3H), 7.51 (s, 2H), 6.41 (d, J = 16.7 Hz, 1H), 6.11 (t, J = 2.1 Hz, 1H), 5.51 (s, 2H), 2.57 (s, 3H), 2.12-1.90 (m, 12H). Example 19

[0410] (E)-3-((9-((lH-pyrazol-5-yl)methyl)-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-9H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile was prepared using the procedure described for the synthesis of Compound 18 (eluted as isomer 2). MS (mlz) 491.9 [M+H]+. 'H NMR (400 MHz, Acetonitrile-d3) 5 7.56 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 16.7 Hz, 1H), 7.38 (s, 2H), 6.32 (s, 1H), 6.24 (d, J = 2.3 Hz, 1H), 6.06 (d, J = 16.7 Hz, 1H), 5.30 (s, 2H), 2.63 (s, 3H), 2.17 (s, 6H), 2.11 (s, 6H). Example 20

[0411] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-(2,2-difluoroethyl)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 20 was prepared as follows: A mixture of (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile (6.00 mg, 0.0146 mmol), potassium carbonate (0.00605 g, 0.0437 mmol), and l,l-difluoro-2-iodo-ethane (0.00193 mL, 0.0219 mmol) in DMF (0.2 mL) was heated to 60 °C overnight. The mixture was then diluted with DMF / H2O and purified by preparative HPLC (0-100% MeCN / water) to afford the title compound (eluted as isomer 1). MS (mlz) 475.9 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 7.71 (s, 1H), 7.63 (d, J = 16.6 Hz, 1H), 7.55 (s, 2H), 6.66 - 6.32 (m, 2H), 4.91 - 4.80 (m, 2H), 3.39 (s, 3H), 2.16 - 1.95 (m, 12H). 19F NMR (376 MHz, DMSO-d6) 5 -123.26 (dt, J = 54.3, 15.7 Hz). Example 21

[0412] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-9-(2,2-difluoroethyl)-8-methyl-9H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 21 was prepared using the procedure described for the synthesis of Compound 20 (eluted as isomer 2). MS (mlz) 475.9 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 7.95 (s, 1H), 7.61 (d, J = 16.7 Hz, 1H), 7.52 (s, 2H), 6.59 - 6.24 (m, 2H), 4.55 (t, J = 15.6 Hz, 2H), 3.31 - 3.26 (m, 3H), 2.38 - 1.62 (m, 12H). 19F NMR (376 MHz, DMSO-d6) 5 -122.30 (dt, J = 54.7, 15.9 Hz). Example 22 F

[0413] (E)-3-((7-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-2-(difluoromethyl)-2H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile -Compound 22 was prepared using the procedure described for the synthesis of Compound 12 (eluted as isomer 2). MS (mlz) 448.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 8.64 (d, J = 79.3 Hz, 1H), 8.36 (t, J = 57.4 Hz, 1H), 7.72 - 7.41 (m, 3H), 6.52 - 6.37 (m, 1H), 2.54 (s, 3H), 2.19-2.08 (m, 6H), 1.97 (s, 3H). Example 23 N

[0414] (E)-3-(4-((5-chlorothiazolo[5,4-d]pyrimidin-7-yl)amino)-3,5- dimethylphenyl)acrylonitrile (Intermediate 23a) was prepared as follows: To a solution 5,7-dichlorothiazolo[5,4-d]pyrimidine (200 mg, 0.971 mmol) and (E)-3-(4-amino-3,5-dimethyl-phenyl)prop-2-enenitrile hydrochloride (203 mg, 0.971 mmol) in THF (4 mL) at 0 °C was added LiHMDS (1 mol / L, 2.43 mL, 2.43 mmol). The ice bath was removed and the mixture allowed to warm to rt overnight. Saturated NH4CI aqueous solution was then added and the aqueous phase extracted with EtOAc. The combined organics were dried over MgSO4, filtered through celite, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (020% MeOH / DCM). MS (m!z) 342.0 [M+H]+. N

[0415] (E)-3-((7-((4-(2-cyanovinyl)-2,6-dimethylphenyl)amino)thiazolo[5,4-d]pyrimidin-5-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 23 was prepared using the procedure described for the synthesis of (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-(4-methoxybenzyl)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile with the following modifications: (E)-3-(4-((5-chlorothiazolo[5,4-d]pyrimidin-7-yl)amino)-3,5-dimethylphenyl)acrylonitrile was used in place of (E)-3-[4-[2-chloro-7-[(4- methoxyphenyl)methyl]-8-methyl-purin-6-yl]oxy-3,5-dimethyl-phenyl]prop-2-enenitrile, and the reaction was heated to 120 °C. MS (m / z) 414.1 M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 9.51 (br s, 1H), 8.84 (s, 1H), 7.77 (s, 1H), 7.61 (d, J = 16.7 Hz, 1H), 7.48 (s, 2H), 6.43 (d, J = 16.7 Hz, 1H), 2.28 - 1.85 (m, 12H). Example 24 N

[0416] (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-6-((2,4-dimethoxybenzyl)amino)-5-(methylamino)pyrimidin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile (Intermediate 24a)was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-7-(difluoromethyl)-8-methyl-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile with the following modifications: (E)-3-((5-amino-4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-2-yl)amino)bicyclo[ 1.1.1 ]pentane-1 -carbonitrile and iodomethane (1 equiv) were used in place of (E)-3-(4-((2-chloro-8-methyl-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile and ethyl 2-bromo-2,2-difluoro-acetate, respectively, and the mixture was heated at 50 °C. MS (mlz) 552.1 [M+H]+.

[0417] (E)-3-((4-amino-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-5- (methylamino)pyrimidin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile (Intermediate 24b) was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-8-methyl-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile with the following modifications: (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-6-((2,4- dimethoxybenzyl)amino)-5-(methylamino)pyrimi din-2-yl)amino)bicyclo[l. 1.1 ]pentane-l-carbonitrile was used in place of (E)-3-(4-((2-chloro-7-(2,4-dimethoxybenzyl)-8-methyl-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile. MS (mlz) 402.1 [M+H]+. N

[0418] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile Compound 24) was prepared as follows: Dioxane (0.4 mL) was added to 3-[[4-amino-6-[4-[(E)-2-cyanovinyl]-2,6-dimethyl-phenoxy]-5-(methylamino)pyrimidin-2-yl]amino]bicyclo[l.l.l]pentane-l-carbonitrile (15.0 mg, 0.0374 mmol) and carbonyldiimidazole (0.00909 g, 0.0560 mmol), and the mixture was heated to 115 °C overnight. The mixture was diluted with DMF / H2O and purified by preparative HPLC (0-100% MeCN / water) to afford the title compound. MS (m / z) 428.0 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 11.57 (s, 1H), 7.67 (s, 1H), 7.61 (d, J = 16.7 Hz, 1H), 7.53 (s, 2H), 6.42 (d, J = 16.7 Hz, 1H), 3.43 (s, 3H), 2.11 (s, 6H), 1.99 (s, 6H). Example 25 F N

[0419] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(difluoromethyl)-7-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 25 was prepared as follows: A mixture of 3-[[4-amino-6-[4-[(E)-2-cyanovinyl]-2,6-dimethyl-phenoxy]-5-(methylamino)pyrimidin-2-yl]amino]bicyclo[l.l.l]pentane-l-carbonitrile (15.0 mg, 0.0374 mmol), 1-ethoxy-2,2-difluoro-ethanol (0.00741 mL, 0.0673 mmol), and acetic acid (0.00256 mL, 0.0448 mmol) in DMF (0.4 mL) was heated to 100 °C overnight. The mixture was then basified with NaHCOs saturated aqueous solution and purified by preparative HPLC (0-100% MeCN / water) to afford the title compound. MS (m / z) 461.9 [M+H]+. 'H NMR (400 MHz, DMS0-d6) 5 7.91 (s, 1H), 7.64 (d, J = 16.7 Hz, 1H), 7.57 (s, 2H), 7.55 - 7.27 (m, 1H), 6.45 (d, J = 16.7 Hz, 1H), 4.12 (s, 3H), 2.11 (d, J = 22.9 Hz, 12H). Example 26 N

[0420] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(difluoromethyl)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 26 was prepared using the procedure described for the synthesis of Compound 25 with the following modifications: (E)-3-((4,5-diamino-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)pyrimidin-2- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile was used in place of 3-[[4-amino-6-[4-[(E)-2-cyanovinyl]-2,6-dimethyl-phenoxy]-5-(methylamino)pyrimidin-2- yl]amino]bicyclo[l.l.l]pentane-l-carbonitrile. MS (mlz) 447.9 [M+H]+. XH NMR (400 MHz, DMSO-d6) 5 13.67 (s, 1H), 8.07 (s, 1H), 7.63 (d, J = 16.6 Hz, 1H), 7.55 (s, 2H), 7.17 (t, J = 53.0 Hz, 1H), 6.44 (d, J = 16.7 Hz, 1H), 2.27 - 1.78 (m, 12H). 19F NMR (376 MHz, DMSO-d6) 5 -115.79 (d, J = 52.9 Hz). Example 27

[0421] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-oxo-8,9-dihydro-7H-purin-2- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 27 was prepared using the WO 2025 / 184609                                   PCT / US2025 / 017990 procedure described for the synthesis of Compound 25 with the following modifications: (E)-3-((4,5-diamino-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)pyrimidin-2- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile was used in place of 3-[[4-amino-6-[4-[(E)-2-cyanovinyl]-2,6-dimethyl-phenoxy]-5-(methylamino)pyrimidin-2- yl]amino]bicyclo[l.l.l]pentane-l-carbonitrile, and the mixture was heated to 100 °C. MS (mlz) 414.0 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 11.34 (s, 1H), 10.85 (s, 1H), 7.69 - 7.57 (m, 2H), 7.52 (s, 2H), 6.41 (d, J = 16.7 Hz, 1H), 2.08 (s, 6H), 2.00 (s, 6H). Example 28 N

[0422] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7,9-bis(difluoromethyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 28 was prepared using the procedure described for the synthesis of Compound 21 with the following modifications: (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile and difluoro(iodo)methane (10.0 % in THF) were used in place of (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile and l,l-difluoro-2-iodo-ethane, respectively. MS (mlz) 513.9 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 8.51 (s, 1H), 7.89 - 7.37 (m, 5H), 6.43 (d, J = 16.7 Hz, 1H), 2.19 - 1.76 (m, 12H). 19F NMR (376 MHz, DMSO-d6) 5 -97.72 (d, J = 57.2 Hz), -103.72 (d, J = 57.3 Hz). Example 29

[0423] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-(isothiazol-5-ylmethyl)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 29 was prepared as follows: To a mixture of (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile (27.0 mg, 0.0656 mmol), isothiazol-5-ylmethanol (0.0203 mL, 0.236 mmol), and triphenylphosphine (0.0671 g, 0.256 mmol) in THF (0.7 mL) was added diisopropyl azodi carb oxy late (0.0504 mL, 0.256 mmol), and the mixture was stirred at rt overnight. The mixture was then diluted with DMF / H2O and purified by preparative HPLC (0-100% MeCN / water) to afford the title compound (eluted as isomer 1). MS (mlz) 508.9 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 8.50 (d, J = 1.7 Hz, 1H), 7.85 (s, 1H), 7.60 (d, J = 16.7 Hz, 1H), 7.50 (s, 2H), 7.25 (d, J = 1.7 Hz, 1H), 6.41 (d, J = 16.7 Hz, 1H), 5.96 (s, 2H), 2.61 (s, 3H), 2.04 (s, 6H), 1.90 (s, 6H). Example 30

[0424] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-9-(isothiazol-5-ylmethyl)-8-methyl-9H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 30 was prepared using the procedure described for the synthesis of Compound 29 (eluted as isomer 2). MS (m / z) 508.9 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 8.49 (d, J = 1.7 Hz, 1H), 7.95 (s, 1H), 7.61 (d, J = 16.7 Hz, 1H), 7.52 (s, 2H), 7.35 (s, 1H), 6.42 (d, J = 16.7 Hz, 1H), 5.64 (s, 2H), 2.50 (s, 3H), 2.31 - 1.71 (m, 12H). Example 31

[0425] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-7-((l-methyl-lH-pyrazol-3-yl)methyl)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile-Compound 31 was prepared using the procedure described for the synthesis of Compound 29 with the following modifications: (l-methylpyrazol-3-yl)m ethanol was used in place of isothiazol-5-ylmethanol (title compound eluted as isomer 1). MS (mlz) 505.9 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 7.94 (s, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 16.7 Hz, 1H), 7.52 (s, 2H), 6.42 (d, J = 16.7 Hz, 1H), 6.16 (d, J = 2.2 Hz, 1H), 5.54 (s, 2H), 3.75 (s, 3H), 2.66 (s, 3H), 2.22- 1.84 (m, 12H). Example 32

[0426] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-9-((l-methyl-lH-pyrazol-3-yl)methyl)-9H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 32 was prepared using the procedure described for the synthesis of Compound 31 (title compound eluted as isomer 2). MS (m / z) 506.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 7.95 (s, 1H), 7.66 - 7.57 (m, 2H), 7.52 (s, 2H), 6.42 (d, J = 16.7 Hz, 1H), 6.13 (d, J = 2.2 Hz, 1H), 5.21 (s, 2H), 3.77 (s, 3H), 2.54 (s, 3H), 2.31 - 1.78 (m, 12H). Example 33 H N

[0427] (E)-3-((7-((lH-pyrazol-4-yl)methyl)-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8- methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 33 was prepared using the procedure described for the synthesis of Compound 29 with the following modifications: lH-pyrazol-4-ylmethanol was used in place of isothiazol-5-ylmethanol (title compound eluted as isomer 1). MS (m / z) 491.9 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 8.09 (s, 1H), 7.67 - 7.58 (m, 3H), 7.54 (s, 2H), 6.43 (d, J = 16.8 Hz, 1H), 5.50 (s, 2H), 2.71 (s, 3H), 2.30- 1.87 (m, 12H). Example 34

[0428] (E)-3-((9-((lH-pyrazol-4-yl)methyl)-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-9H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 34 was prepared using the procedure described for the synthesis of Compound 33 (title compound eluted as isomer 1). MS (mlz) 492.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 7.99 (s, 1H), 7.61 (d, J = 17.2 Hz, 3H), 7.52 (s, 2H), 6.42 (d, J = 16.7 Hz, 1H), 5.16 (s, 2H), 2.55 (s, 3H), 2.31 - 1.78 (m, 12H). Example 35

[0429] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-7-((l-methyl-lH- pyrazol-5-yl)methyl)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 35 was prepared using the procedure described for the synthesis of Compound 29 with the following modifications: (2-methylpyrazol-3-yl)methanol was used in place of isothiazol-5-ylmethanol (title compound eluted as isomer 1). MS (m / z) 505.9 [M+H]+. 'H NMR (400 MHz, DMS0-d6) 5 7.69 (s, 1H), 7.59 (d, J = 16.6 Hz, 1H), 7.48 (s, 2H), 7.30 (d, J = 2.0 Hz, 1H), 6.40 (d, J = 16.7 Hz, 1H), 5.70 - 5.62 (m, 3H), 3.80 (s, 3H), 2.53 (s, 3H), 2.03 (s, 6H), 1.87 (s, 6H). Example 36

[0430] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-9-((l-methyl-lH-pyrazol-5-yl)methyl)-9H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 36 was prepared using the procedure described for the synthesis of Compound 35 (title compound eluted as isomer 2). MS (m / z) 505.9 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 7.94 (s, 1H), 7.62 (d, J = 16.7 Hz, 1H), 7.53 (s, 2H), 7.33 (d, J = 1.9 Hz, 1H), 6.42 (d, J = 16.7 Hz, 1H), 6.02 (s, 1H), 5.37 (s, 2H), 3.89 (s, 3H), 2.48 (s, 3H), 2.34 - 1.77 (m, 12H). Example 37

[0431] (E)-3-((7-((l,3,4-thiadiazol-2-yl)methyl)-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 37 was prepared using the procedure described for the synthesis of Compound 29 with the following modifications: l,3,4-thiadiazol-2-ylmethanol was used in place of isothiazol-5-ylmethanol (title compound eluted as isomer 1). MS (m / z) 509.9 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 9.61 (s, 1H), 7.77 (s, 1H), 7.60 (d, J = 16.7 Hz, 1H), 7.49 (s, 2H), 6.41 (d, J = 16.7 Hz, 1H), 6.10 (s, 2H), 2.61 (s, 3H), 2.04 (s, 6H), 1.89 (s, 6H). Example 38

[0432] (E)-3-((9-((l,3,4-thiadiazol-2-yl)methyl)-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-9H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 38 was prepared using the procedure described for the synthesis of Compound 37 (title compound eluted as isomer 2). MS (mlz) 509.8 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 9.59 (s, 1H), 7.96 (s, 1H), 7.61 (d, J = 16.7 Hz, 1H), 7.52 (s, 2H), 6.42 (d, J = 16.7 Hz, 1H), 5.81 (s, 2H), 2.55 (s, 3H), 2.45 - 1.64 (m, 12H). Example 39

[0433] (E)-3-((7-((l-cyanocyclopropyl)methyl)-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 39 was prepared using the procedure described for the synthesis of Compound 18 with the following modifications: l-(bromomethyl)cyclopropanecarbonitrile was used in place of 5-(chloromethyl)-IH-pyrazole hydrochloride (title compound eluted as isomer 1). MS (mlz) 490.9 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 7.75 (s, 1H), 7.63 (d, J = 16.7 Hz, 1H), 7.55 (s, 2H), 6.44 (d, J = 16.7 Hz, 1H), 4.56 (s, 2H), 2.65 (s, 3H), 2.17 - 1.96 (m, 12H), 1.46 - 1.39 (m, 2H), 1.36 (td, J = 7.0, 6.1, 3.2 Hz, 2H).

[0434] (E)-3-((9-((l-cyanocyclopropyl)methyl)-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-9H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 40 was prepared using the procedure described for the synthesis of Compound 39 (eluted as isomer 2). MS (m / z) 491.0 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 7.75 (s, 1H), 7.63 (d, J = 16.7 Hz, 1H), 7.55 (s, 2H), 6.44 (d, J = 16.7 Hz, 1H), 4.56 (s, 2H), 2.65 (s, 3H), 2.17 - 1.96 (m, 12H), 1.46 - 1.39 (m, 2H), 1.36 (td, J = 7.0, 6.1, 3.2 Hz, 2H). Example 41 F

[0435] 2,6-dichloro-8-(l,l-difluoroethyl)-7-methyl-7H-purine (Intermediate 41a)

[0436] To a heterogeneous, rigorously stirred, mixture of 2,6-dichloro-7-methyl-7H-purine (500 mg, 2.46 mmol, 1 equiv) and sodium 1,1-difluoroethyl sulfinate (1.12 g, 7.39 mmol, 3 equiv) in DMSO (8 mL) and water (2 mL) was added tert-butyl hydroperoxide (1.76 mL, 70 wt% in water, 12.3 mmol, 5 equiv) dropwise over 15 minutes. The reaction was stirred at room temperature for 2 hours before diluting with EtOAc / water. The resulting mixture was extracted twice with EtOAc, the combined organics were dried over MgSO4, filtered and concentrated in vacuo. The title compound was purified by silica gel chromatography (0-50% EtOAc / hexanes). MS (m / z) 266.90 / 268.91 [M+H]+.

[0437] (E)-3-(4-((2-chloro-8-(l,l-difluoroethyl)-7-methyl-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 41b) was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 176a) with the following modifications: 2,6-dichloro-8-(l,l-difluoroethyl)-7-methyl-7H-purine was used in place of 2,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]-5-nitro-pyrimidin-4-amine. MS (m / z): 404.0 [M+H]+.

[0438] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(l,l-difluoroethyl)-7-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 41 was prepared using the procedure described for the synthesis of (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-(4-methoxybenzyl)-8-methyl-7H-purin-2- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile with the following modifications: (E)-3-(4-((2-chloro-8-(l,l-difluoroethyl)-7-methyl-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile was used in place of (E)-3-[4-[2-chloro-7-[(4-methoxyphenyl)methyl]-8-methyl-purin-6-yl]oxy-3,5-dimethyl-phenyl]prop-2-enenitrile, and the mixture was heated to 120 °C for 1 h. MS (mlz) 476.1 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 7.86 (s, 1H), 7.63 (d, J = 16.7 Hz, 1H), 7.55 (s, 2H), 6.44 (d, J = 16.7 Hz, 1H), 4.15 (s, 3H), 2.27 - 1.93 (m, 15H). Example 42

[0439] 2,6-dichloro-9-(4-methoxybenzyl)-9H-purine (Intermediate 42a) was prepared using the procedure described for the synthesis of 2,6-dichloro-7-(4-methoxybenzyl)-7H-purine (eluted as isomer 1). MS (m / z): 309.0 [M+H]+. N

[0440] (E)-3-(4-((2-chloro-9-(4-methoxybenzyl)-9H-purin-6-yl)oxy)-3,5- dimethylphenyl)acrylonitrile (Intermediate 42b) was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 176a) with the following modifications: 2,6-dichloro-9-(4-methoxybenzyl)-9H-purine was used in place of 2,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]-5-nitro-pyrimidin-4-amine. MS (m / z): 446.0 [M+H]+.

[0441] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-9-(4-methoxybenzyl)-9H-purin-2- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 42 was prepared using the procedure described for the synthesis of (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-(4-methoxybenzyl)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile with the following modifications: (E)-3-(4-((2-chloro-9-(4-methoxybenzyl)-9H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile was used in place of (E)-3-[4-[2-chloro-7-[(4-methoxyphenyl)methyl]-8-methyl-purin-6-yl]oxy-3,5-dimethyl-phenyl]prop-2-enenitrile, and the mixture was heated to 120 °C for 3 h. MS (m / z) 518.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 8.18 (s, 1H), 7.96 (s, 1H), 7.61 (d, J = 16.7 Hz, 1H), 7.57-7.45 (m, 2H), 7.31 (d, J = 8.3 Hz, 2H), 6.96 - 6.85 (m, 2H), 6.42 (d, J = 16.7 Hz, 1H), 5.22 (s, 2H), 3.72 (s, 3H), 2.40 -1.67 (m, 12H). Example 43 I o

[0442] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-(4-methoxybenzyl)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 43 was prepared using the procedure described for the synthesis of (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-(4-methoxybenzyl)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile with the following modifications: (E)-3-(4-((2-chloro-7-(4-methoxybenzyl)-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile was used in place of (E)-3-[4-[2-chloro-7-[(4-methoxyphenyl)methyl]-8-methyl-purin-6-yl]oxy-3,5-dimethyl-phenyl]prop-2-enenitrile, and the mixture was heated to 120 °C for 3 h. MS (m / z) 518.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 8.51 (s, 1H), 7.69 (s, 1H), 7.60 (d, J = 16.6 Hz, 1H), 7.49 (s, 2H), 7.20 - 7.11 (m, 2H), 6.95 - 6.85 (m, 2H), 6.40 (d, J = 16.7 Hz, 1H), 5.49 (s, 2H), 3.71 (s, 3H), 2.04 (s, 6H), 1.84 (s, 6H). Example 44 N

[0443] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7H-purin-2- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 44 was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile with the following modifications: (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-(4-methoxybenzyl)-7H-purin-2-yl)amino)bicyclo[l. 1. l]pentane-l-carbonitrile was used in place of (E)-3-[4-[2-chloro-7-[(4-methoxyphenyl)methyl]purin-6-yl]oxy-3,5-dimethyl-phenyl]prop-2-enenitrile, and the reaction was heated to 40 °C. The title compound was purified by preparative HPLC (0-100% MeCN / water). MS (mlz) 398.1 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 12.72 (s, 1H), 8.01 (s, 1H), 7.71 (s, 1H), 7.62 (d, J = 16.7 Hz, 1H), 7.54 (s, 2H), 6.42 (d, J = 16.7 Hz, 1H), 2.18 - 1.96 (m, 12H). Example 45

[0444] (E)-3-((9-((l-cyanocyclopropyl)methyl)-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-9H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 45 was prepared using the procedure described for the synthesis of Compound 19with the following modifications: (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7H-purin-2- yl)amino)bicyclo[ 1.1.1 ]pentane-1 -carbonitrile and 1 -(bromomethyl)cyclopropanecarbonitrile were used in place of (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile and 5-(chloromethyl)-lH-pyrazole hydrochloride, WO 2025 / 184609                                   PCT / US2025 / 017990 respectively. MS (mlz) 477.0 [M+H]+. 'HNMR (400 MHz, Acetonitrile-d3) 5 7.93 (s, 1H), 7.48 (d, J = 16.7 Hz, 1H), 7.39 (s, 2H), 6.19 (s, 1H), 6.06 (d, J = 16.7 Hz, 1H), 4.19 (s, 2H), 2.13 -2.08 (m, 12H), 1.39 - 1.28 (m, 4H). Example 46 \ o—\ ^NH

[0445] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-((2-methoxyethyl)amino)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 46 was prepared as follows: To a mixture of (E)-3-((4,5-diamino-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)pyrimidin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile (20.0 mg, 0.0516 mmol) in pyridine (0.25 mL) was added l-isothiocyanato-2-methoxy-ethane (0.00779 mL, 0.0671 mmol), followed by N,N'-Diisopropylcarbodiimide (0.0104 mL, 0.0671 mmol). The vial was capped and heated to 60 °C overnight. The reaction mixture was then diluted with DMF / H2O and purified by preparative HPLC (0-100% MeCN / water with 0.1% TFA) to afford the title compound. MS (mlz) 471.1 [M+H]+. ‘HNMR (400 MHz, DMSO-d6) 5 11.18 (s, 1H), 7.61 (d, J = 16.6 Hz, 1H), 7.51 (s, 2H), 7.27 (d, J = 43.6 Hz, 1H), 7.04 (d, J = 28.9 Hz, 1H), 6.40 (d, J = 16.7 Hz, 1H), 3.48 (d, J = 3.9 Hz, 4H), 3.28 (s, 3H), 2.08 (s, 6H), 2.02 (s, 6H). Example 47 ^NH

[0446] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(ethylamino)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 47 was prepared using the procedure described for the synthesis of Compound 46 with the following modifications: 132 isothiocyanatoethane was used in place of l-isothiocyanato-2-methoxy-ethane. MS (m / z) 441.1 [M+H]+. 'H NMR (400 MHz, Acetonitrile-d3) 5 7.48 (d, J = 16.6 Hz, 1H), 7.40 (s, 2H), 6.07 (d, J = 16.7 Hz, 1H), 3.50 - 3.39 (m, 2H), 2.13 (s, 6H), 2.06 (s, 6H), 1.29 (t, J = 7.2 Hz, 3H). Example 48

[0447] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-((l-methyl-lH-pyrazol-3-yl)amino)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 48 was prepared using the procedure described for the synthesis of Compound 46 with the following modifications: 3-isothiocyanato-l-methyl-pyrazole was used in place of l-isothiocyanato-2-methoxy-ethane. MS (miz) 493.1 [M+H]+. *HNMR (400 MHz, DMSO-d6) 5 11.50 - 10.90 (m, 1H), 10.47 - 9.59 (m, 1H), 7.68 - 7.57 (m, 2H), 7.54 (s, 2H), 7.43 (d, J = 20.5 Hz, 1H), 6.43 (d, J = 16.7 Hz, 1H), 6.30 - 5.97 (m, 1H), 3.86 - 3.74 (m, 3H), 2.20 - 1.94 (m, 12H). Example 49 N

[0448] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-cyclopropyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 49 was prepared as follows: To a mixture of 3-[[4,5-diamino-6-[4-[(E)-2-cyanovinyl]-2,6-dimethyl-phenoxy]pyrimidin-2-yl]amino]bicyclo[l.l.l]pentane-l-carbonitrile (11.0 mg, 0.0284 mmol) in DCM (0.5 mL) and MeOH (0.5 mL) was added cyclopropanecarbaldehyde (0.00212 mL, 0.0284 mmol), followed by acetic acid (0.000162 mL, 0.00284 mmol). The mixture was stirred at 40 °C overnight. The mixture was then basified using saturated NaHCOs aqueous solution, diluted with DMF / H2O, and purified by preparative HPLC (0-100% MeCN / water) to afford the title compound. MS (mlz) 438.2 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 12.59 (br s, 1H), 7.67 (s, 1H), 7.61 (d, J = 16.7 Hz, 1H), 7.53 (s, 2H), 6.42 (d, J = 16.7 Hz, 1H), 2.18 - 1.93 (m, 13H), 1.09 - 0.98 (m, 4H). Example 50

[0449] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-cyclobutyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 50 was prepared using the procedure described for the synthesis of Compound 49 with the following modifications: cyclobutanecarbaldehyde was used in place of cyclopropanecarbaldehyde. MS (mlz) 452.1 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 12.74 (s, 1H), 7.81 (s, 1H), 7.62 (d, J = 16.7 Hz, 1H), 7.54 (s, 2H), 6.43 (d, J = 16.7 Hz, 1H), 3.67 (p, J = 8.7 Hz, 1H), 2.46 - 2.38 (m, 2H), 2.38 -2.27 (m, 2H), 2.18- 1.95 (m, 13H), 1.94- 1.84 (m, 1H). Example 51 N

[0450] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-cyclohexyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 51 was prepared using the procedure described for the synthesis of Compound 49 with the following modifications: cyclohexanecarbaldehyde was used in place of cyclopropanecarbaldehyde. MS (mlz) 480.1 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 12.46 (s, 1H), 7.68 (s, 1H), 7.62 (d, J = 16.7 Hz, 1H), 7.53 (s, 2H), 6.42 (d, J = 16.6 Hz, 1H), 2.83 - 2.70 (m, 1H), 2.05 (d, J = 13.2 Hz, 13H), 1.85- 1.74 (m, 2H), 1.74 - 1.48 (m, 4H), 1.44-1.21 (m, 3H). Example 52

[0451] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(tetrahydro-2H-pyran-4-yl)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 52 was prepared as follows: To a mixture of3-[[4,5-diamino-6-[4-[(E)-2-cyanovinyl]-2,6-dimethyl-phenoxy]pyrimidin-2-yl]amino]bicyclo[l.l.l]pentane-l-carbonitrile (30.0 mg, 0.0774 mmol) in DCM (0.4 mL) and MeOH (0.4 mL) was added tetrahydropyran-4-carbaldehyde (0.012 mL, 0.116 mmol) and acetic acid (0.000886 mL, 0.0155 mmol). The mixture was stirred at 40 °C for 1 h, then iron(III) chloride (0.0188 g, 0.116 mmol) was added. The mixture was stirred at 40 °C overnight, then basified using saturated NaHCOs aqueous solution, diluted with DMF / H2O, and purified by preparative HPLC (0-100% MeCN / water) to afford the title compound. MS (mlz) 482.1 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 12.57 (s, 1H), 7.70 (s, 1H), 7.62 (d, J = 16.6 Hz, 1H), 7.53 (s, 2H), 6.42 (d, J = 16.7 Hz, 1H), 3.94 (d, J = 11.5 Hz, 2H), 3.50 - 3.40 (m, 2H), 3.09-2.96 (m, 1H), 2.18 - 1.98 (m, 12H), 1.94 (d, J =12.6 Hz, 2H), 1.81 (q, J = 11.1, 10.6 Hz, 2H). Example 53

[0452] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-cyclopentyl-7H-purin-2- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 53 was prepared using the procedure described for the synthesis of Compound 52 with the following modifications: cyclopentanecarbaldehyde was used in place of tetrahydropyran-4-carbaldehyde. MS (mlz) 482.1 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 12.57 (s, 1H), 7.70 (s, 1H), 7.62 (d, J = 16.6 Hz, 1H), 7.53 (s, 2H), 6.42 (d, J = 16.7 Hz, 1H), 3.94 (d, J = 11.5 Hz, 2H), 3.50 - 3.40 (m, 2H), 3.09-2.96 (m, 1H), 2.18 - 1.98 (m, 12H), 1.94 (d, J =12.6 Hz, 2H), 1.81 (q, J = 11.1, 10.6 Hz, 2H). Example 54 N

[0453] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(4,4-difluorocyclohexyl)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 54 was prepared using the procedure described for the synthesis of Compound 52 with the following modifications: 4,4-difluorocyclohexanecarbaldehyde was used in place of tetrahydropyran-4-carbaldehyde. MS (mlz) 516.1 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 12.61 (s, 1H), 7.70 (s, 1H), 7.62 (d, J = 16.6 Hz, 1H), 7.53 (s, 2H), 6.42 (d, J = 16.6 Hz, 1H), 3.04 - 2.91 (m, 1H), 2.20- 1.74 (m, 20H). Example 55 N

[0454] (E)-3-(4-((5-chloro-2-methylthiazolo[5,4-d]pyrimidin-7-yl)amino)-3,5- dimethylphenyl)acrylonitrile (Intermediate 55a) was prepared as follows: A mixture of 5,7- dichloro-2-methyl-thiazolo[5,4-d]pyrimidine (50.0 mg, 0.227 mmol), (E)-3-(4-amino-3,5- WO 2025 / 184609                                   PCT / US2025 / 017990 dimethyl-phenyl)prop-2-enenitrile hydrochloride (47.4 mg, 0.227 mmol), and DIPEA (0.198 mL, 1.14 mmol) in dioxane (1 mL) was stirred at 120 °C for 72 h. The mixture was then cooled to rt, concentrated in vacuo, and the resulting residue purified by silica gel chromatography (0100% EtOAc / hexanes). MS (m / z) 356.0 [M+H]+.

[0455] (E)-3-((7-((4-(2-cyanovinyl)-2,6-dimethylphenyl)amino)-2-methylthiazolo[5,4-d]pyrimidin-5-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 55 was prepared using the procedure described for the synthesis of (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-(4-methoxybenzyl)-8-methyl-7H-purin-2- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile with the following modifications: (E)-3-(4-((5-chloro-2-methylthiazolo[5,4-d]pyrimidin-7-yl)amino)-3,5-dimethylphenyl)acrylonitrile was used in place of (E)-3-[4-[2-chloro-7-[(4-methoxyphenyl)methyl]-8-methyl-purin-6-yl]oxy-3,5-dimethyl-phenyl]prop-2-enenitrile, and the mixture was heated to 120 °C for 3 h. MS (m / z) 428.0 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 9.34 (s, 1H), 7.66 (s, 1H), 7.60 (d, J = 16.7 Hz, 1H), 7.47 (s, 2H), 6.42 (d, J = 16.6 Hz, 1H), 2.70 (s, 3H), 2.25 - 1.89 (m, 12H). Example 56

[0456] 5,7-dibromothiazolo[5,4-d]pyrimidine (Intermediate 56a) was prepared as follows: To a mixture of 5,7-dichlorothiazolo[5,4-d]pyrimidine (400 mg, 1.94 mmol) in MeCN (10 mL) was added bromotrimethylsilane (0.769 mL, 5.82 mmol), and the mixture heated to 60 °C for 3 h. Additional bromotrimethylsilane (0.128 g, 0.97 mmol) and the mixture heated to 60 °C for another 3 h. The mixture was then cooled to rt and saturated NaHCOs aqueous solution was added. The aqueous phase was extracted with EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was used without further purification. MS (m / z) 293.8 [M+H]+.

[0457] (E)-3-(4-((5-bromothiazolo[5,4-d]pyrimidin-7-yl)oxy)-3,5- dimethylphenyl)acrylonitrile (Intermediate 56b) was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 176a) with the following modifications: 5,7-dibromothiazolo[5,4-d]pyrimidine was used in place of 2,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]-5-nitro-pyrimidin-4-amine. MS (m / z): 386.9 [M+H]+.

[0458] (E)-3-((7-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)thiazolo[5,4-d]pyrimidin-5-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 56 was prepared as follows: (E)-3-(4-((5-bromothiazolo[5,4-d]pyrimidin-7-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (40.0 mg, 0.103 mmol), 3-aminobicyclo[l.l.l]pentane-l-carbonitrile (0.0168 g, 0.155 mmol), XPhos Pd G3 (0.00874 g, 0.0103 mmol), and cesium carbonate (0.0673 g, 0.207 mmol) were combined in a microwave vial and dioxane (1 mL) was added. The mixture was degassed with N2 and then the vial sealed and heated to 60 °C for 6 h. The mixture was then cooled to room temperature and concentrated in vacuo. The resulting residue was purified by preparative HPLC (0-100% MeCN / water) to afford the title compound. MS (m / z) 415.0 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 9.04 (s, 1H), 8.42 (s, 1H), 7.64 (d, J = 16.7 Hz, 1H), 7.56 (d, J = 14.0 Hz, 2H), 6.46 (d, J = 16.7 Hz, 1H), 2.22 - 1.80 (m, 12H). Example 57

[0459] (E)-3-((9-(2-cyanoethyl)-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-methyl-9H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 57 was prepared using the procedure described for the synthesis of Compound 19 with the following modifications: 3-bromopropanenitrile was used in place of 5-(chloromethyl)-lH-pyrazole hydrochloride. MS (mlz) 465.0 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 7.93 (s, 1H), 7.61 (d, J = 16.7 Hz, 1H), 7.52 (s, 2H), 6.42 (d, J = 16.7 Hz, 1H), 4.44 - 4.24 (m, 2H), 3.07 (t, J = 6.5 Hz, 2H), 2.55 (s, 3H), 2.41 - 1.73 (m, 12H). Example 58 /

[0460] (E)-3-(4-((2-chloro-7-(4-methoxybenzyl)-8-methyl-7H-purin-6-yl)oxy)-3,5-difluorophenyl)acrylonitrile (Intermediate 58a) was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 176a) with the following modifications: 2,6-dichloro-7-(2,4-dimethoxybenzyl)-8-methyl-7H-purine and (E)-3-(3,5-difluoro-4-hydroxy-phenyl)prop-2-enenitrile were used in place of 2,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]-5-nitro-pyrimidin-4-amine and (E)-3-(4-hydroxy-3,5-dimethyl- phenyl)prop-2-enenitrile, respectively, and the mixture was heated to 60 °C. MS (m / z): 468.0 [M+H]+.

[0461] (E)-3-((6-(4-(2-cyanovinyl)-2,6-difluorophenoxy)-7-(4-methoxybenzyl)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile (Intermediate 58b) was prepared using the procedure described for the synthesis of (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-(4-methoxybenzyl)-8-methyl-7H-purin-2- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile with the following modifications: (E)-3-(4-((2-chloro-7-(4-methoxybenzyl)-8-methyl-7H-purin-6-yl)oxy)-3,5-difluorophenyl)acrylonitrile was used in place of ((E)-3-[4-[2-chloro-7-[(4-methoxyphenyl)methyl]-8-methyl-purin-6-yl]oxy-3,5-dimethyl-phenyl]prop-2-enenitrile, and the reaction was heated to 125 °C overnight. MS (mlz) 540.1 [M+H]+. N

[0462] (E)-3-((6-(4-(2-cyanovinyl)-2,6-difluorophenoxy)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 58 was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile with the following modifications: (E)-3-((6-(4-(2-cyanovinyl)-2,6-difluorophenoxy)-7-(4-methoxybenzyl)-8-methyl-7H-purin-2- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile was used in place of (E)-3-[4-[2-chloro-7-[(4-methoxyphenyl)methyl]purin-6-yl]oxy-3,5-dimethyl-phenyl]prop-2-enenitrile, and the reaction was heated to 40 °C. MS (m / z) 420.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8 12.66 (br s, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.73 - 7.63 (m, 2H), 6.66 (d, J = 16.6 Hz, 1H), 2.40 (s, 3H), 2.15 (s, 6H). Example 59

[0463] (E)-3-(3,5-dichloro-4-((2-chloro-7-(4-methoxybenzyl)-8-methyl-7H-purin-6-yl)oxy)phenyl)acrylonitrile (Intermediate 59a) was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 176a) with the following modifications: 2,6-dichloro-7-(2,4-dimethoxybenzyl)-8-methyl-7H-purine and (E)-3-(3,5-dichloro-4-hydroxy-phenyl)prop-2-enenitrile were used in place of 2,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]-5-nitro-pyrimidin-4-amine and (E)-3-(4-hydroxy-3,5-dimethyl-phenyl)prop-2-enenitrile, respectively, and the mixture was heated to 90 °C. MS (m / z): 499.9 [M+H]+. I Cl Vycl

[0464] (E)-3-((6-(2,6-dichloro-4-(2-cyanovinyl)phenoxy)-7-(4-methoxybenzyl)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile (Intermediate 59b) was prepared using the procedure described for the synthesis of (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-(4-methoxybenzyl)-8-methyl-7H-purin-2- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile with the following modifications: (E)-3-(3,5-dichloro-4-((2-chloro-7-(4-methoxybenzyl)-8-methyl-7H-purin-6-yl)oxy)phenyl)acrylonitrile was used in place of ((E)-3-[4-[2-chloro-7-[(4-methoxyphenyl)methyl]-8-methyl-purin-6-yl]oxy-3,5-dimethyl-phenyl]prop-2-enenitrile, and the reaction was heated to 125 °C overnight. MS (m / z) 572.0 [M+H]+. N

[0465] (E)-3-((6-(2,6-dichloro-4-(2-cyanovinyl)phenoxy)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 59 was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile with the following modifications: (E)-3-((6-(2,6-dichloro-4-(2-cyanovinyl)phenoxy)-7-(4-methoxybenzyl)-8-methyl-7H-purin-2- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile was used in place of (E)-3-[4-[2-chloro-7-[(4-methoxyphenyl)methyl]purin-6-yl]oxy-3,5-dimethyl-phenyl]prop-2-enenitrile, and the reaction was heated to 40 °C. MS (m / z) 451.9 [M+H]+. 'H NMR (400 MHz, Methanol-d4) 5 7.90 (s, 2H), 7.57 (d, J = 16.6 Hz, 1H), 6.43 (d, J = 16.7 Hz, 1H), 2.54 (s, 3H), 2.21 (s, 6H). Example 60 I

[0466] 2-(2,6-dichloro-7-(4-methoxybenzyl)-7H-purin-8-yl)propan-2-ol (Intermediate 60a) was prepared using the procedure described for the synthesis of 2,6-dichloro-7-(4-methoxybenzyl)-7H-purine with the following modifications: 2-(2,6-dichloro-7H-purin-8-yl)propan-2-ol was used in place of 2,6-dichloro-9H-purine. MS (m / z): 367.0 [M+H]+.

[0467] (E)-3-(4-((2-chloro-8-(2-hydroxypropan-2-yl)-7-(4-methoxybenzyl)-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 60b)was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 176a) with the following modifications: 2-(2,6-dichloro-7-(4-methoxybenzyl)-7H-purin-8-yl)propan-2-ol was used in place of 2,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]-5-nitro-pyrimidin-4-amine. MS (m / z): 504.1 [M+H]+.

[0468] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(2-hydroxypropan-2-yl)-7-(4- methoxybenzyl)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile (Intermediate 60c) was prepared using the procedure described for the synthesis of (E)-3-((6-(4-(2- cyanovinyl)-2,6-dimethylphenoxy)-7-(4-methoxybenzyl)-8-methyl-7H-purin-2- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile with the following modifications: (E)-3-(4-((2-chloro-8-(2-hydroxypropan-2-yl)-7-(4-methoxybenzyl)-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile was used in place of ((E)-3-[4-[2-chloro-7-[(4-methoxyphenyl)methyl]-8-methyl-purin-6-yl]oxy-3,5-dimethyl-phenyl]prop-2-enenitrile, and the reaction was heated to 120 °C for 4 h. MS (mlz) 5162 [M+H]+.

[0469] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(2-hydroxypropan-2-yl)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 60 was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-7H-purin-6-yl)oxy)-3,5-dimethylphenyl)acrylonitrile with the following modifications: (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(2-hydroxypropan-2-yl)-7-(4-methoxybenzyl)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile was used in place of (E)-3-[4-[2-chloro-7-[(4-methoxyphenyl)methyl]purin-6-yl]oxy-3,5-dimethyl-phenyl]prop-2-enenitrile, and the reaction was heated to 40 °C. MS (mlz) 456.1 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 12.58 (s, 1H), 7.75 (s, 1H), 7.62 (d, J = 16.6 Hz, 1H), 7.54 (s, 2H), 6.42 (d, J = 16.7 Hz, 1H), 5.49 (s, 1H), 2.17 - 1.89 (m, 12H), 1.55 (s, 6H). Example 63

[0470] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(lH-pyrazol-3-yl)-7H-purin-2- yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 63 was prepared using the procedure described for the synthesis of Compound 52 with the following modifications: 1H-pyrazole-3-carbaldehyde was used in place of tetrahydropyran-4-carbaldehyde, and the mixture was stirred at rt. MS (mlz) 464.1 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 13.54 - 12.85 (m, 2H), 7.91 (s, 1H), 7.85 (s, 1H), 7.64 (d, J = 16.7 Hz, 1H), 7.56 (s, 2H), 6.89 (s, 1H), 6.44 (d, J = 16.7 Hz, 1H), 2.20 - 1.95 (m, 12H). Example 64

[0471] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(l-methyl-lH-pyrazol-4-yl)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 64 was prepared using the procedure described for the synthesis of Compound 52 with the following modifications: 1-methylpyrazole-4-carbaldehyde was used in place of tetrahydropyran-4-carbaldehyde, and the mixture was stirred at rt after the addition of iron(III) chloride. MS (mlz) 478.1 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 12.97 (s, 1H), 8.33 (s, 1H), 8.06 (s, 1H), 7.76 (s, 1H), 7.61 (s, 1H), 7.55 (s, 2H), 6.46 (s, 1H), 3.93 (s, 3H), 2.20 - 1.95 (m, 12H). Example 65

[0472] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(l-methyl-lH-pyrazol-3-yl)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 65 was prepared using the procedure described for the synthesis of Compound 52 with the following modifications: 1-methylpyrazole-3-carbaldehyde was used in place of tetrahydropyran-4-carbaldehyde, and the mixture was stirred at rt. MS (mlz) 478.1 [M+H]+. 'H NMR (400 MHz, DMS0-d6) 5 13.13 (s, 1H), 7.87 (s, 2H), 7.64 (d, J = 16.7 Hz, 1H), 7.56 (s, 2H), 6.87 (s, 1H), 6.44 (d, J = 16.7 Hz, 1H), 3.97 (s, 3H), 2.15 - 1.82 (m, 12H). Example 66 HN'% -N N

[0473] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(lH-pyrazol-4-yl)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 66 was prepared using the procedure described for the synthesis of Compound 52 with the following modifications: 1H-pyrazole-4-carbaldehyde was used in place of tetrahydropyran-4-carbaldehyde, and the mixture was stirred at rt. MS (mlz) 464.1 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 13.26 (s, 1H), 12.94 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 7.77 (s, 1H), 7.64 (d, J = 16.6 Hz, 1H), 7.55 (s, 2H), 6.44 (d, J =16.7 Hz, 1H), 2.18 - 1.95 (m, 12H). Example 67

[0474] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-((3,5-dimethylisoxazol-4-yl)amino)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 67 was prepared using the procedure described for the synthesis of Compound 46 with the following modifications: 3,5-dimethyl-4-isoxazolyl isothiocyanate was used in place of 1-isothiocyanato-2-methoxy-ethane. MS (mlz) 507.9 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 9.42 (s, 1H), 7.81 (s, 1H), 7.63 (d, J = 16.7 Hz, 1H), 7.55 (s, 2H), 6.43 (d, J = 16.7 Hz, 1H), 2.34 (s, 3H), 2.15 (s, 3H), 2.10 (s, 6H), 2.05 (s, 6H). Example 68

[0475] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(pyridin-2-ylamino)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 68 was prepared using the procedure described for the synthesis of Compound 47 with the following modifications: 2-isothiocyanatopyridine was used in place of l-isothiocyanato-2-methoxy-ethane. MS (m / z) 490.1 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 8.35 (d, J = 5.2 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.75 (s, 1H), 7.64 (d, J = 16.7 Hz, 1H), 7.56 (s, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.07 (dd, J = 7.1, 5.3 Hz, 1H), 6.43 (d, J = 16.8 Hz, 1H), 2.18 - 1.99 (m, 12H).

[0476] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(pyridin-3-ylamino)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 69 was prepared using the procedure described for the synthesis of Compound 46 with the following modifications: 3-pyridyl isothiocyanate was used in place of l-isothiocyanato-2-methoxy-ethane. MS (m / z) 489.9 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 10.34 (s, 1H), 9.24 (s, 1H), 8.52 (d, J = 8.9 Hz, 1H), 8.39 (d, J = 4.7 Hz, 1H), 7.77 (dd, J = 8.4, 4.8 Hz, 1H), 7.70 - 7.59 (m, 2H), 7.55 (s, 2H), 6.43 (d, J = 16.7 Hz, 1H), 2.11 (s, 6H), 2.06 (s, 6H). Example 70

[0477] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(phenylamino)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 70 was prepared using the procedure described for the synthesis of Compound 46 with the following modifications: isothiocyanatobenzene was used in place of l-isothiocyanato-2-methoxy-ethane. MS (mlz) 489.1 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 9.82 (s, 1H), 7.80 - 7.59 (m, 4H), 7.55 (s, 2H), 7.36 (t, J = 7.9 Hz, 2H), 7.04 (t, J = 7.2 Hz, 1H), 6.43 (d, J = 16.7 Hz, 1H), 2.21 - 1.93 (m, 12H). Example 71

[0478] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(isoxazol-4-yl)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 71

[0479] (E)-3-((4,5-diamino-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)pyrimidin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile (40.0 mg, 0.103 mmol) and isoxazole-4-carbaldehyde (15.0 mg, 0.155 mmol) were combined in a vial. MeOH (0.560 mL) and DCM (0.560 mL) were added to the vial, and the mixture was stirred for 1 h at 40 °C. The mixture was then concentrated to dryness in vacuo and DMF was added (1.120 mL). KI (34.3 mg, 0.206 mmol) and L (26.2 mg, 0.103 mmol) were added to the solution and stirred overnight at 40°C, then purified by HPLC (15-95% MeCN / H2O) and dried overnight on the lyo to provide the title compound. ES / MS m / z: 465.1 [M+l], XH NMR (400 MHz, DMSO-d6) 5 13.30 (s, 1H), 9.55 (s, 1H), 9.23 (s, 1H), 7.93 (s, 1H), 7.64 (d, J = 16.6 Hz, 1H), 7.54 (d, J = 13.2 Hz, 2H), 6.44 (d, J = 16.7 Hz, 1H), 2.23 - 1.91 (m, 12H). Example 72

[0480] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(pyrimidin-5-yl)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 72 was prepared using the procedure described for the synthesis of Compound 71, but replacing isoxazole-4-carbaldehyde with pyrimidine-5-carbaldehyde, and stirred overnight at 80°C instead of 40°C. ES / MS m / z: 476.1 [M+l], 'HNMR (400 MHz, DMSO-d6) 5 13.61 (s, 1H), 9.45 (s, 2H), 9.28 (s, 1H), 8.03 (s, 1H), 7.64 (d, J = 16.6 Hz, 1H), 7.57 (s, 2H), 6.45 (d, J = 16.7 Hz, 1H), 2.29 - 1.81 (m, 12H). Example 73 N

[0481] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8-(isoxazol-5-yl)-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 72 was prepared using the procedure described for the synthesis of Compound 71 with the following modifications: isoxazole-5-carbaldehyde was used in place of isoxazole-4-carbaldehyde. MS (m / z) 464.9 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 13.79 (s, 1H), 8.81 (s, 1H), 8.09 (s, 1H), 7.64 (d, J = 16.7 Hz, 1H), 7.57 (s, 2H), 7.17 (s, 1H), 6.45 (d, J = 16.7 Hz, 1H), 2.22 - 1.85 (m, 12H). Example 74 XX

[0482] 4,6-dichloro-2-phenyl-2H-pyrazolo[3,4-d]pyrimidine was prepared as follows: Step 1, preparation of ethyl 3-amino-l-phenyl-lH-pyrazole-4-carboxylate (Intermediate 74a)

[0483] Anisaldehyde (25.0 g, 183 mmol, 1.00 equiv) and phenylhydrazine (19.8 g, 183 mmol, 1 equiv) were refluxed in toluene (300 mL) employing a Dean-Stark trap to remove water. The mixture was stirred at 120 °C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in xylene (80 mL), to the above mixture was added ethyl (2E)-2-cyano-3-ethoxyprop-2-enoate (31.1 g, 183 mmol, 1.00 equiv), the mixture was stirred at 140 °C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford the intermediate (12.5 g). The intermediate was dissolved on in EtOH (25 mL), to the above mixture was added cone. HC1 (5.4 mL). The mixture was stirred at 80 °C for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was diluted with NaHCOs (sat., aq.) (500 mL) and extracted with EA (2 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:5) to afford the title compound. MS (mlz) 232.15 [M+H]+.

[0484] Step 2, preparation of ethyl l-phenyl-3-ureido-lH-pyrazole-4-carboxylate (Intermediate 74b)

[0485] A mixture of ethyl 3-amino-l-phenyl-lH-pyrazole-4-carboxylate (9.00 g, 38.9 mmol, 1.00 equiv) and potassium cyanate (6.31 g, 77.8 mmol, 2.00 equiv) in AcOH (40 mL) was stirred at 25 °C for 4 h. The mixture was diluted with NaHCOs (sat., aq.) (250 mL) and extracted with EA (2 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:5) to afford the title compound. MS (mlz) 275.15 [M+H]+.

[0486] Step 3, preparation of 2-phenyl-2,7-dihydro-4H-pyrazolo [3,4-d]pyrimidine-4,6(511)-dione (Intermediate 74c)

[0487] A mixture of ethyl l-phenyl-3-ureido-lH-pyrazole-4-carboxylate (5.90 g, 21.5 mmol, 1.00 equiv) and sodium ethoxide (2.93 g, 43.0 mmol, 2.00 equiv) in EtOH (60 mL) was stirred at 80 °C for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (100 mL) and the mixture was acidified to pH 5 with HC1 (2 M). The resulting mixture was extracted with EA (5 x 300 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound. MS (m / z) 229.10 [M+H]+.

[0488] Step 4. 4,6-dichloro-2-phenyl-2H-pyrazolo [3,4-d] pyrimidine (Intermediate 74d)

[0489] A mixture of 2-phenyl-2,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione (3 g, 13.2 mmol, 1.00 equiv) in POCL (20 mL) was stirred at 100 °C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EA (30 mL) and quenched by the addition of ice water (300 mL). The resulting mixture was extracted with EA (2 x 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCMZEA (10:1) to afford the title compound. MS (mlz) 265.00, 267.00 [M+H]+. 1H NMR (400 MHz, Chloroform-d) 5 8.64 (s, 1H), 7.98 - 7.90 (m, 2H), 7.64 - 7.49 (m, 3H).

[0490] (E)-3-(4-((6-chloro-2-phenyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 74e) was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 176a) with the following modifications: 4,6-dichloro-2-phenyl-2H-pyrazolo[3,4-d]pyrimidine was used in place of 2,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]-5-nitro-pyrimidin-4-amine. MS (m / z): 402.0 [M+H]+. N

[0491] (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-2-phenyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 74 was prepared using the procedure described for the synthesis of Compound 4 with the following modifications: (E)-3-(4-((6-chloro-2-phenyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acrylonitrile was used in place of Intermediate 4a. MS (m / z) 474.1 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 9.39 (s, 1H), 8.31 - 7.78 (m, 3H), 7.71 - 7.48 (m, 5H), 7.45 (t, J = 7.4 Hz, 1H), 6.45 (d, J = 16.7 Hz, 1H), 2.26 - 1.80 (m, 12H). Example 75

[0492] (E)-3-(4-((5-chlorothiazolo[4,5-d]pyrimidin-7-yl)oxy)-3,5- dimethylphenyl)acrylonitrile - Intermediate 75a was prepared using the procedure described for the synthesis of (E)-3-(4-((2-chloro-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 176a) with the following WO 2025 / 184609                                   PCT / US2025 / 017990 modifications: 5,7-dichlorothiazolo[4,5-d]pyrimidine was used in place of 2,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]-5-nitro-pyrimidin-4-amine. MS (m / z) 343.0 [M+H]+.

[0493] (E)-3-((7-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)thiazolo[4,5-d]pyrimidin-5-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 75: Intermediate 75a (35.0 mg, 0.102 mmol) and 3-aminobicyclo[l.l.l]pentane-l-carbonitrile (55.2 mg, 0.510 mmol) were added to a vial and dissolved in NMP (0.20 mL). The vial was evacuated and backfilled once with argon gas, then the solution was heated to 140 °C for hour via microwave irradiation. The solution was cooled to room temperature then subjected to preparative HPLC (0-100% MeCN / water) to afford the title compound. MS (m / z) 415.15 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 9.71 (s, 1H), 8.33 (br s, 1H) 7.64 (d, J = 16.7 Hz, 1H), 7.56 (s, 2H), 6.46 (d, J= 16.7 Hz, 1H), 2.08 (s, 6H) 2.03 (br s, 6H). Example 76 NHBoc

[0494] tert-butyl (3-carbamoyl-2,2-difluorobicyclo[l.l.l]pentan-l-yl)carbamate (Intermediate 76a): 3-((tert-butoxycarbonyl)amino)-2,2-difluorobicyclo[l. 1.l]pentane-l-carboxylic acid (100 mg, 0.380 mmol) was suspended in THF (3.8 mL) and cooled to 0 °C. To the mixture was added triethylamine (34 pL, 0.46 mmol) and ethyl chloroformate (40 pL, 0.42 mmol). After one hour of stirring at 0 °C, 30% aqueous NH4OH (2.2 mL, 19 mmol) was added to the mixture which was stirred at room temperature for 2 hours. To the mixture was added water (30 mL) and the solution was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford the title compound. 1H NMR (400 MHz, DMSO-de) 8 8.01 (br s, 1H), 7.47 (s, 1H), 7.31 (s, 1H), 2.31 (s, 2H), 1.94 (t, J= 10.5 Hz, 2H), 1.39 (s, 9H). 19F NMR (377 MHz, DMSO-t / 6) 6 -121.76 (t, J= 10.5 Hz). NHBoc

[0495] tert-butyl (3-cyano-2,2-difluorobicyclo[l.l.l]pentan-l-yl)carbamate (Intermediate 76b) : Intermediate 76a (99.7 mg, 0.380 mmol) was suspended in di chloromethane (2 mL) and triethylamine (0.32 mL, 2.3 mmol). To mixture was cooled to 0 °C and tri chloroacetyl chloride (0.13 mL. 1.2 mmol) was added to the mixture. After 1.5 hours stirring at 0 °C, the mixture was diluted with di chloromethane (10 mL) and extracted with EtOAc (3x5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was subjected to silica gel flash column chromatography (0-100% EtOAc / hexanes) to afford a crude solid. This solid was used as is in the next transformation. 1H NMR (400 MHz, Chloroform-tZ) 3.38 (dq, J= 28.3, 7.2 Hz, 2H), 2.34 (s, 2H), 1.45 (s, 9H). 19F NMR (377 MHz, Chloroform-tZ) 5 -120.55 (s). NH, HC1 N

[0496] 3-amino-2,2-difluorobicyclo[l.l.l]pentane-l-carbonitrile hydrochloride: Intermediate 76b (92.8 mg, 0.38 mmol) was suspended in a solution of 4.0 M HC1 in 1,4-dioxane (2 mL, 8 mmol) and the mixture was stirred at room temperature for an hour. Trifluoroacetic acid (3 mL) was added. After 30 minutes, additional 4.0 M HC1 in 1,4-dioxane (1 mL, 4 mmol) was added. The mixture was allowed to stir at room temperature overnight and was then concentrated in vacuo. The resulting solid was resuspended in trifluoroacetic acid (1 mL) and diethyl ether (5 mL) and hexanes (5 mL) was added to the mixture which was allowed to briefly stir at room temperature. The mixture was filtered to afford the HC1 salt. 1H NMR (400 MHz, DMSO-6 / 6) 5 8.87 (br s, 3H), 2.32 (s, 2H), 2.15 - 2.04 (m, 2H). 19F NMR (376 MHz, DMSO-de) 8 -747.40 (s, 3F) -122.73 (t, J= 10.4 Hz, 2F).

[0497] (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-2,2-difluorobicyclo[l.l.l]pentane-l-carbonitrile - Compound 76

[0498] Int-Compound 121A (30.0 mg, 0.883 mmol), 3-amino-2,2-difluoro-bicyclo[l.l.l]pentane-l-carbonitrile;hydrochloride (31.9 mg, 0.177 mmol), cesium carbonate (86.3 mg, 0.265 mmol), and rac BINAP Pd G3 precatalyst (8.8 mg, 0.0088 mmol) were combined in a vial. To the vial was added 1,4-dioxane (0.25 mL) and argon gas was bubbled through the mixture for 5 minutes. The vial was then sealed and heated to 120 °C for 3 hours. The mixture was then cooled to room temperature at which point 3-amino-2,2-difluoro-bicyclo[l.l.l]pentane-l-carbonitrile;hydrochloride (10.0 mg, 0.0555 mmol) and rac BINAP Pd G3 precatalyst (3.0 mg, 0.0030 mmol) was added to the mixture. Argon gas was bubbled through the mixture for 5 minutes and the reaction was sealed and heated at 120 °C for 2 additional hours. The mixture was cooled to room temperature and filtered over celite then subjected to preparative HPLC (0-100% MeCN / water) to afford the title compound (5.6 mg, 14.2% yield). MS (mlz) 448.13 [M+H], 'HNMR (400 MHz, DMSO-d6) 5 8.52 (s, 1H), 8.27 (s, 1H), 7.62 (d, J = 16.7 Hz, 1H), 7.52 (s, 2H), 6.44 (d, J = 16.7 Hz, 1H), 4.04 (s, 3H), 2.21 (br s, 4H) 2.07 (s, 6H). 19F NMR (377 MHz, DMSO) 5 -118.90. Example 77 n-nh N

[0499] (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-3-methyl-lH-pyrazolo[3,4- d]pyrimidin-6-yl)amino)-2,2-difluorobicyclo[l.l.l]pentane-l-carbonitrile- Compound 77: Prepared in a similar manner to Compound 76, except using Int-Compound 119A (30.0 mg, 0.883 mmol) instead of Int-Compound 120. MS (mlz) 448.16 [M+H], 'HNMR (400 MHz, DMSO-d6) 5 12.91 (s, 1H), 8.43 (s, 1H), 7.63 (d, J = 16.8 Hz, 1H), 7.52 (s, 2H), 6.44 (d, J = 16.6 Hz, 1H), 2.52 (s, 3H), 2.08 (s, 6H). 2.10 (br s, 4H). 19F NMR (377 MHz, DMSO) 5 -118.79. Example 78 N

[0500] (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-5,6-dihydrofuro[2,3-d]pyrimidin-2-yl)amino)-2,2-difluorobicyclo[l.l.l]pentane-l-carbonitrile - Compound 78: Intermediate 118a (50 mg, 0.153 mmol), 3-amino-2,2-difluoro-bicyclo[l.l.l]pentane-l-carboxamide;hydrochloride (45.4 mg, 0.229 mmol), and potassium carbonate (105 mg, 0.763 mmol) were added to a vial and suspended in NMP (0.3 mL). The vial was sealed and heated to 140 °C for 2.5 hours. The mixture was cooled to room temperature and water (20 mL), brine (5 mL), and EtOAc (10 mL) were added to the solution which was subsequently mixed. The organic layer was isolated and the aqueous layer was further extracted with EtOAc (2 x 5mL). The combined organic layers were dried over sodium sulfate, filtered, then concentrated in vacuo. The resulting residue was dissolved in DCM (1.0 mL) then triethylamine (0.13 ml. 0.92 mmol) and tri chloroacetyl chloride (0.052 uL, 0.459 mmol) were added in sequence. The solution was stirred at room temperature for 1 hour, at which time saturated aqueous sodium bicarbonate (2 mL) was added. The mixture was extracted with EtOAc (3x1 mL) and the combined organic layers were dried over sodium sulfate, filtered, then concentrated in vacuo. The resulting residue was subjected to preparative HPLC (0-100% MeCN / water) to afford the title compound. MS (mlz') 436.08 [M+H]+. 'HNMR (400 MHz, Acetonitrile-d3) 5 7.46 (d, J = 16.7 Hz, 1H), 7.34 (s, 2H), 6.38 (s, 1H), 6.04 (d, J = 16.7 Hz, 1H), 4.68 - 4.61 (m, 2H), 3.12 (t, J = 8.6 Hz, 2H), 2.13 (s, 6H), 2.10 (br s, 4H). 19F NMR (376 MHz, CD3CN) 5 -120.91 (br s). Example 79 F k2co3, nmp

[0501] Step 1: (E)-3-(4-((7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 79a): (E)-3-(4-hydroxy-3,5-dimethyl-phenyl)prop-2-enenitrile (132 mg, 0.761 mmol), 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (150 mg, 0.634 mmol), and potassium carbonate (175 mg, 1.27 mmol) were suspended in DMF (2.4 mL) and the solution was stirred at room temperature for 2.5 hours. To the solution was added water (5 mL) and the resulting solids were filtered off and lyophilized to afford the crude title compound which was used as is in the subsequent transformation.

[0502] Step 2: (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)amino)bicydo[l.l.l]pentane-l-carbonitrile - Compound 79: mCBPA (64.7 mg, 0.281 mmol) was added to a solution of Intermediate 79a (50.0 mg, 0.134 mmol) in NMP (0.30 mL) and the mixture was stirred at room temperature for two hours. To the mixture was added potassium carbonate (92.6 mg, 0.670 mmol) and 3-aminobicyclo[l.l.l]pentane-l-carbonitrile; hydrochloride (48.4 mg, 0.335 mmol). The mixture was stirred at 40 °C for 30 minutes, then additional NMP (0.15 mL) was added and the solution was stirred at 50 °C for 1.5 hours. Additional potassium carbonate (100 mg, 0.362 mmol) was added and the solution was stirred at 50 °C overnight. The mixture was then cooled to room temperature and water (2 mL) was added. The mixture was extracted with EtOAc (3x1 mL) and the combined organic layers were concentrated in vacuo and subjected to preparative HPLC (0-100% MeCN / water) and lyophilized to afford the title compound. MS (m / z) 434.23 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 8.47 (s, 1H), 7.62 (d, J = 16.7 Hz, 1H), 7.55 (s, 2H), 6.43 (d, J = 16.7 Hz, 1H), 2.94 (br s, 2H), 2.63 (m, 2H), 2.07 (s, 6H), 1.96 (br s, 6H). 19F NMR (377 MHz, DMSO) 5-93.93. Example 80

[0503] €-3-((7-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 80: (E)-3-((4,5-diamino-6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)pyrimidin-2-yl)amino)bicyclo[l. 1. l]pentane-l-carbonitrile (20.0 mg, 0.0516 mmol) was suspended in water (0.1 mL) and acetic acid (0.2 mL) then cooled to 0 °C. To the solution was added an 0.9 M aqueous solution of sodium nitrite (0.1 mL, 0.09 mmol). After 15 minutes, the solution was extracted with ethyl acetate (1 mL). The organic layer was washed with saturated sodium bicarbonate (3x1 mL). The combined aqueous layers were further extracted with ethyl acetate (2x1 mL). The organic layers were combined and concentrated in vacuo. The crude residue was subjected to preparative HPLC (15-95% MeCN / H2O) and lyophilized to provide the title compound. MS (m / z) 399.14 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 15.79 (br s, 1H), 8.34 (br s, 1H), 7.64 (d, J = 16.7 Hz, 1H), 7.57 (s, 2H), 6.46 (d, J = 16.7 Hz, 1H), 2.11 (s, 6H), 2.10 (br s, 6H). Example 81

[0504] (E)-3-((7-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-l-methyl-lH-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 81: Compound 80(40.0 mg, 0.100 mmol) and potassium carbonate (27.8 mg, 0.201 mmol) were charged to a vial and suspended in DMF (1.0 mL). To the solution was added iodomethane (7.5 uL, 0.120 mmol) and the mixture was stirred at room temperature. After one hour, water (1 ml) was added the mixture and the solution was extracted with ethyl acetate (3x1 mL). The organic layers were combined and concentrated in vacuo. The crude residue was subjected to subjected to preparative HPLC (15-95% MeCN / H2O) and lyophilized to provide the title compound. MS (m / z) 413.14 [M+H]+. XH NMR (400 MHz, DMSO-d6) 5 8.19 (s, 1H), 7.64 (d, J = 16.7 Hz, 1H), 158 7.56 (s, 2H), 6.46 (d, J = 16.7 Hz, 1H), 4.43 (s, 3H), 2.13 (s, 6H), 2.10 (br s, 6H). Example 82

[0505] (E)-3-((7-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-2-methyl-2H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 82: Compound 80 (40.0 mg, 0.100 mmol) and potassium carbonate (27.8 mg, 0.201 mmol) were charged to a vial and suspended in DMF (1.0 mL). To the solution was added iodomethane (7.5 uL, 0.120 mmol) and the mixture was stirred at room temperature. After one hour, water (1 ml) was added the mixture and the solution was extracted with ethyl acetate (3x1 mL). The organic layers were combined and concentrated in vacuo. The crude residue was subjected to subjected to preparative HPLC (15-95% MeCN / H2O) and lyophilized to provide the title compound. MS (m / z) 413.17 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 5 8.29 (s, 1H), 7.70 - 7.51 (m, 3H), 6.45 (d, J = 16.7 Hz, 1H), 4.41 (s, 3H), 2.10 (s, 6H), 1.97 (br ss, 6H). Example 83 F N-N N

[0506] (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-2-(2,2-difluoroethyl)-3-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 83: A vial was charged with the trifluoroacetic acid salt of Compound 119 (30.0 mg, 0.0571 mmol) and cesium carbonate (93.0 mg, 0.285 mmol). To the vial was added NMP (0.5 mL) and two drops of l,l-difluoro-2-iodo-ethane. The mixture was stirred at room temperature for 3 hours, at which point the mixture was filtered over celite and subjected to preparative HPLC (15-95% MeCN / H20) and lyophilized to afford the title compound. MS (m / z) 476.26 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 8.44 (br s, 1H), 7.57 (m, 3H), 6.60 - 6.20 (m, 2H), 4.56 (s, 2H), 2.54 (s, 3H), 2.10 (s, 6H), 1.96 (br s, 6H). 19F NMR (377 MHz, DMSO-d6) 5 -122.50 (dt, J = 54.4, 15.0 Hz). Example 84 N

[0507] (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-3-methyl-2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 84: A vial was charged with the trifluoroacetic acid salt of Compound 119 (30.0 mg, 0.0571 mmol) and cesium carbonate (93.0 mg, 0.285 mmol). To the vial was added NMP (0.5 mL) and two drops of 2,2,2-trifluoroethyl trifluoromethanesulfonate. The mixture was stirred at room temperature for 3 hours, at which point another portion of 2,2,2-trifluoroethyl trifluoromethanesulfonate was added. After an additional 1.5 hours, the mixture was filtered over celite and subjected to preparative HPLC (15-95% MeCN / H2O) and lyophilized to afford the title compound. MS (mlz) 494.28 [M+H]+. H NMR (400 MHz, DMSO-d6) 5 8.44 (br s, 1H), 7.54 (m, 3H), 6.44 (d, J = 16.7 Hz, 1H), 5.04 (d, J = 54.4 Hz, 2H), 2.54 (s, 3H), 2.11 (s, 6H), 1.96 (br s, 6H). 19F NMR (377 MHz, DMSO) 5 -69.88. Example 85

[0508] (E)-3-(3-chloro-4-((6-chloro-3-methyl-lH-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-5- methylphenyl)acrylonitrile (Intermediate 85a): (E)-3-(3-chloro-4-hydroxy-5-methylphenyl)acrylonitrile (250 mg, 0.739 mmol), 4,6-dichloro-3-methyl-lH-pyrazolo[3,4-d]pyrimidine (150 mg, 0.739 mmol), and potassium carbonate (306 mg, 2.22 mmol) were suspended in NMP (1.5 mL) and the solution was stirred at room temperature for 1 hour. To the solution was added water (5 mL) and the mixture was extracted with ethyl acetate (3x1 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo onto silica gel and subjected to silica gel flash column chromatography (0-100% EtOAc / hexanes) to afford the title product. 'H NMR (400 MHz, Acetonitrile-d3) 5 11.57 (br s, 1H), 7.65 (d, J = 2.1 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 16.7 Hz, 1H), 6.17 (d, J = 16.7 Hz, 1H), 2.70 (s, 3H), 2.25 (d, J = 0.8 Hz, 3H). MS (m / z) 360.10 [M+H]+.

[0509] (E)-3-((4-(2-chloro-4-(2-cyanovinyl)-6-methylphenoxy)-3-methyl-lH-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile-Compound 85: A vial was charged with Intermediate 85a (58.0 mg, 0.161 mmol), 3-aminobicyclo[l.l.l]pentane-l-carbonitrile;hydrochloride (163 mg, 1.13 mmol), and potassium carbonate (223 mg, 1.61 mmol) followed by NMP (0.3 mmol). The solution was heated at 140 °C for 1.5 hours, then at 150 °C for two hours. The mixture was cooled to room temperature at which point water (1.0 mL) was added. The solution was extracted with EtOAc (3x1 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was subjected to preparative HPLC (0-100% MeCN / H2O, 0.1% trifluoroacetic acid modifier). The fractions with the product were pooled and diluted with EtOAc (20 mL) and washed with saturated aqueous sodium bicarbonate (10 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was subjected to flash column chromatography (020% MeOH / DCM) to afford the title compound. MS (m / z) 432.10 [M+H]+. 1H NMR (400 MHz, Acetonitrile-d3) 5 10.69 (br s, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.54 (s, 1H), 7.51 (d, J = 16.7 Hz, 1H), 6.30 (br s, 1H), 6.17 (d, J = 16.7 Hz, 1H), 2.58 (s, 3H), 2.23 (s, 3H), 2.18 (br s, 6H). Example 86 \ N—N

[0510] Preparation of €-3-(4-((6-chloro-2,3-dimethyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 86a) : To a solution of 4,6-dichloro-3-methyl-lH-pyrazolo[3,4-d]pyrimidine (170 mg, 0.84 mmol) in DMF was added potassium carbonate (579 mg, 4.19 mmol) and iodomethane (155 mg, 1.1 mmol). The mixture was stirred at room temperature for 1 hour. Then to the mixture was added €-3 -(4-hydroxy-3,5-dimethyl -phenyl)prop-2-enenitrile (144 mg, 0.84 mmol). The mixture was stirred at room temperature overnight. Water was added to the mixture and the solution was extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was subjected to silica gel flash column chromatography, (0-100% hexane / EtOAc) to afford the titled product. MS (m / z) 354.08. 'HNMR (400 MHz, Acetonitrile-d3) 5 7.48 (d, J = 16.7 Hz, 1H), 7.39 (s, 2H), 6.09 (d, J = 16.7 Hz, 1H), 4.07 (s, 3H), 2.81 (s, 3H), 2.17 (s, 6H). \ n-n N

[0511] Preparation of (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-2,3-dimethyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 86: the title compound was prepared using the procedure described for the synthesis of Compound 4with the modification that Intermediate 86a was used in place of Intermediate 4a. MS (m / z) 426.21. 'HNMR (400 MHz, Methanol-d4) 5 7.59 - 7.47 (m, 3H), 6.25 (d, J = 16.7 Hz, 1H), 3.99 (s, 3H), 2.79 (s, 3H), 2.25-2.11 (m, 12H). Example 87 \ n-n

[0512] (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-3-iodo-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 87 was prepared using the two step procedure described for the synthesis of Compound 86with the modification that 4,6-dichloro-3-iodo-lH-pyrazolo[3,4-d]pyrimidine was used in place of 4,6-dichloro-3-methyl-lH-pyrazolo[3,4-d]pyrimidine. MS (m / z) 538.20. 'HNMR (400 MHz, Methanol-d4) 5 7.54 (d, J = 16.7 Hz, 1H), 7.48 (s, 2H), 6.24 (d, J = 16.7 Hz, 1H), 4.13 (s, 3H), 2.25-2.16 (m, 12H). Example 88 PdCl2(dppf) k2co3 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane dioxane / H2O

[0513] Preparation of (E)-3-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-2-methyl-3-vinyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile- Compound 88: A mixture of 3-[[4-[4-[(E)-2-cyanovinyl]-2,6-dimethyl-phenoxy]-3-iodo-2-methyl-pyrazolo[3,4-d]pyrimidin-6-yl]amino]bicyclo[l.l.l]pentane-l-carbonitrile (20 mg, 0.037 mmol), 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (11.5 mg, 0.0744 mmol), potassium carbonate (25.7 mg, 0.186 mmol), PdC12(dppf) (4 mg, 0.0056 mmol) in 9:1 dioxane / water (2 mL) was stirred at 90 °C overnight. To mixture was added saturated aqueous NaHCOs and the solution was extracted with EtOAc. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was subjected to reverse phase HPLC (5-100% acetonitrile / water, modified with 0.1% TFA) and lyophilized. The resulting solid was subjected to silica gel flash column chromatography (0-100% hexane / EtOAc) to afford the title compound. MS (m / z) 438.27 [M+H]+. 'H NMR (400 MHz, Methanol-d4) 5 7.60 - 7.46 (m, 3H), 7.10 (dd, J= 17.4, 11.8 Hz, 1H), 6.52 (d, J =17.4 Hz, 1H), 6.25 (d, J =16.7 Hz, 1H), 5.94 (d, J = 11.8 Hz, 1H), 4.10 (s, 3H), 2.22-2.15 (m, 12H). Example 89

[0514] (E)-3-(4-((2-chloro-7-methyl-4,5-dihydro-7H-purin-6-yl)oxy)-3,5- dimethylphenyl)acrylonitrile (Intermediate 89a)was prepared using the procedure prescribed to synthesize (E)-3-(4-((2-chloro-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acrylonitrile (Intermediate 176a) with the modification that 2,6-dichloro-7-methyl-4,5-dihydro-7H-purine was used in place of 2,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]-5-nitro-pyrimidin-4-amine.

[0515] (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-methyl-4,5-dihydro-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 89 was prepared using the procedure described for the synthesis of (E)-3-((6-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-7-(4-methoxybenzyl)-8-methyl-7H-purin-2-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile with the modification that Intermediate 89a was used in place of E)-3-[4-[2-chloro-7-[(4-methoxyphenyl)methyl]-8-methyl-purin-6-yl]oxy-3,5-dimethyl-phenyl]prop-2-enenitrile. . MS (m / z) 412.19 [M+H]+. XH NMR (400 MHz, Methanol-d4) 5 8.78 (s, 1H), 7.61 - 7.48 (m, 3H), 6.26 (d, J = 16.6 Hz, 1H), 4.22 (s, 3H), 2.22-2.16 (m, 12H). Example 90 N

[0516] (E)-3-((3-bromo-4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-lH-pyrazolo[3,4-d]pyrimidin-6-yl)amino)bicyclo[l.l.l]pentane-l-carbonitrile - Compound 90 was synthesized using the procedure described for the synthesis of Compound 10, with the modification that 3-bromo-4-chloro-6-methylsulfanyl-lH-pyrazolo[3,4-d]pyrimidine was used in place of 4-chloro-6-methylsulfanyl-lH-pyrazolo[3,4-d]pyrimidine. MS (m / z) 476.20, 478.15 [M+H]+. 'H NMR (400 MHz, Methanol-^) 8 7.54 (d, J= 16.7 Hz, 1H), 7.48 (s, 2H), 6.24 (d, J = 16.7 Hz, 1H), 2.42 (d, J= 56.4 Hz, 2H), 2.19 (s, 6H), 2.06 (d, J= 21.6 Hz, 4H). Example 91 N

[0517] tert-butyl (E)-6-chloro-4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-3-formyl-lH-pyrazolo[3,4-d]pyrimidine-l-carboxylate (Intermediate 91a) was synthesized using the procedure described for the synthesis of Intermediate If, with the modifications that 4,6-dichloro-lH-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde was used in place of (E)-3-(3-chloro-5-ethyl-4-hydroxyphenyl)acrylonitrile, the first step reaction was heated at 50 °C, and product was isolated using silica gel flash column chromatography before B...

Claims

A compound of Formula (I)or a pharmaceutically acceptable salt thereof, wherein:— is a single bond or a double bond;R1 is selected from H, CN, halogen, Ci-3alkyl, Ci-3haloalkyl, -OR1A, -SR1A, -NHR1A, and -N(R1A)2;R2 is selected from H, CN, halogen, Ci-3alkyl, Ci-3haloalkyl, -OR2A, -SR2A, -NHR2A, and -N(R2A)2;R3 is selected from CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR3A, -CH2OR3A, -SR3A, -NHR3A, -N(R3A)2, C3-7cycloalkyl, and 3-7 membered heterocycloalkyl;R4 is selected from CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR4A, -CH2OR4A, -SR4A, -NHR4A, -N(R4A)2, C3-7cycloalkyl, and 3-7 membered heterocycloalkyl;or R1 and R3 together form a 6-10 membered aryl;R5 is selected from H, CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, -NHR5A, -N(R5A)2, -OR5A, C3-7cycloalkyl, 3-10 membered heterocycloalkyl, -(C=0)NHR5A, -(C=O)N(R5A)2, and -(C=O)OR5A; wherein the Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, and 3-10 membered heterocycloalkyl of R5 are each optionally substituted with 1 or 2 R8 groups;R6 and R7 are independently selected from H and Ci-ealkyl; or R6 and R7 together form a C3-7cycloalkyl or 3-7 membered heterocycloalkyl;each R8 is independently selected from halogen, CN, Ci-3alkyl, Ci-3haloalkyl, Ci-salkoxyl, C3-7cycloalkyl, and 3-7 membered heterocycloalkyl;M is selected from -CH2-, -CF2-, -CH2CH2-, and -CH2O-;W is selected from -O-, -S-, -C(RW)2-, -NRW-, and -C(=O)-;each Rwis independently selected from H, -ORW1, Ci-ealkyl, C3-7cycloalkyl, Ci-ehaloalkyl, and -(C=O)ORW1;Q, U, and V are independently selected from N, 0, S, CRQ, C(RQ)2, NRV, N(RV)2+, S=0, S02, C=CH2, C=CHF, and C=0;each Rq is independently selected from H, halogen, -0RQ2, CN, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, -NHRQ2, -N(RQ2)2, -(C=0)0Rq1, -(C=0)NHRQ2, -(C=O)N(RQ2)2, -NH(C=0)Rq1, -NH(C=0)0Rq1, -NH(C=0)NHRQ2, -NH(C=O)N(RQ2)2, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ are each optionally substituted with 1, 2, 3, or 4 R9 groups;each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RV1, -(C=O)ORV1, -(C=O)NHRV1, -(C=O)N(RV1)2, -S(O)RV1, and -S(O)2RV1; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rv are each optionally substituted with 1, 2, 3, or 4 R10 groups;each RQ2 is independently selected from H, CN, Ci-ealkyl, C1 -ehaloalky 1, Ci-ealkoxy, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RX1, -(C=O)ORX1, -(C=O)NHRX1, -(C=O)N(RX1)2, and -(SO2)RX1; wherein each C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ2 is optionally substituted with 1, 2, 3 or 4 R11 groups;or two RQ2 together form a 4-7 membered heterocycloalkyl;or two Rv together form a 4-7 membered heterocycloalkyl;or Rq and Rv together form a 4-11 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein the 4-11 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 R13 groups;each R9 and R10 are independently selected from halogen, -ORX2, CN, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, 510 membered heteroaryl, -(C=O)RX2, -(C=O)ORX2, -(C=0)NHRX2, -(C=O)N(RX2)2, and -(SO2)RX2; wherein each C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R9 and R10 are each optionally substituted with 1, 2, 3 or 4 R12 groups;WO 2025 / 184609                                   PCT / US2025 / 017990each R11, R12 and R13 are independently selected from halogen, -0RX3, CN, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxyl, -NHRX3, -N(RX3)2, Cs-vcycloalkyl, and 3-7 membered heterocycloalkyl; wherein each Ci-ealkyl of R11, R12 and R13 is optionally substituted with -ORX4;R14 is selected from H and Ci-ealkyl; andeach R1a, R2A, R3A, R4A, R5A, Rq1, Rv1, Rw1, Rx1, RX2, RX3, andRX4 are independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, and 6-10 membered aryl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (la):CN            (la)wherein:— is a single bond or a double bond;R1 is selected from H, CN, halogen, Ci-3alkyl, Ci-3haloalkyl, -OR1A, -SR1A, -NHR1A, and -N(R1A)2;R2 is selected from H, CN, halogen, Ci-3alkyl, Ci-3haloalkyl, -OR2A, -SR2A, -NHR2A, and -N(R2A)2;R3 is selected from CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR3A, -CH2OR3A, -SR3A, -NHR3A, -N(R3A)2, C3-7cycloalkyl, and 3-7 membered heterocycloalkyl;R4 is selected from CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR4A, -CH2OR4A, -SR4A, -NHR4A, -N(R4A)2, C3-7cycloalkyl, and 3-7 membered heterocycloalkyl;R5 is selected from H, CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, -NHR5A, -N(R5A)2, -OR5A, C3-7cycloalkyl, 3-10 membered heterocycloalkyl, -(C=0)NHR5A, -(C=O)N(R5A)2, and -(C=O)OR5A; wherein the Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-6alkynyl, C3-7cycloalkyl, and 3-10 membered heterocycloalkyl of R5 are each optionally substituted with 1 or 2 R8 groups;WO 2025 / 184609                                   PCT / US2025 / 017990R6 and R7 are independently selected from H and Ci-ealkyl; or R6 and R7 together form a C3-7cycloalkyl or 3-7 membered heterocycloalkyl;each R8 is independently selected from halogen, CN, Ci-3alkyl, Ci-3haloalkyl, Ci-salkoxyl, C3-7cycloalkyl, and 3-7 membered heterocycloalkyl;M is selected from -CH2-, -CF2-, -CH2CH2-, and -CH2O-;W is selected from -0-, -S-, -C(RW)2-, and -NRW-;each Rwis independently selected from H, Ci-ealkyl, C3-7cycloalkyl, and Ci-ehaloalkyl;Q, U, and V are independently selected from N, 0, S, CRQ, C(RQ)2, NRV, N(RV)2+, SO2, C=CH2, and C=0;each Rq is independently selected from H, halogen, -0RQ2, CN, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, -NHRQ2, -N(RQ2)2, -(C=O)ORQ1, -(C=0)NHRQ2, -(C=O)N(RQ2)2, -NH(C=0)Rq1, -NH(C=0)0Rq1, -NH(C=0)NHRQ2, -NH(C=O)N(RQ2)2, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ are each optionally substituted with 1, 2, 3, or 4 R9 groups;each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RV1, -(C=O)ORV1, -(C=O)NHRV1, -(C=O)N(RV1)2, -S(O)RV1, and -S(O)2RV1; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rv are each optionally substituted with 1, 2, 3, or 4 R10 groups;each RQ2 is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RX1, -(C=O)ORX1, -(C=O)NHRX1, -(C=O)N(RX1)2, and -(SO2)RX1; wherein each C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ2 is optionally substituted with 1, 2, 3 or 4 R11 groups;or two RQ2 together form a 4-7 membered heterocycloalkyl;or Rq and Rv together form a 4-7 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein the 4-7 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 R13 groups;each R9 and R10 are independently selected from halogen, -ORX2, CN, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl, -(C=O)RX2, -(C=O)ORX2, -(C=0)NHRX2, -(C=O)N(RX2)2, and -(SO2)RX2; wherein each C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R9 and R10 are each optionally substituted with 1, 2, 3 or 4 R12 groups;each R11, R12 and R13 are independently selected from halogen, -ORX3, CN, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxyl, -NHRX3, -N(RX3)2, Cs-vcycloalkyl, and 3-7 membered heterocycloalkyl; andeach R1a, R2A, R3A, R4A, R5A, Rq1, Rv1, Rx1, RX2 and RX3 are independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, and C3-7cycloalkyl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein W is selected from -O-, -NRW-, -C(RW)2-, and -C(=O)-.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein W is selected from -O- and -NRW-.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein W is O.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H, CN, halogen, Ci-3alkyl, Ci-3haloalkyl, -OR1A, and -SR1A.

7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H, Ci-3alkyl, and Ci-3haloalkyl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H, CN, halogen, Ci-3alkyl, Ci-3haloalkyl, -OR1A, and -SR1A.

9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H, Ci-3alkyl, and Ci-3haloalkyl.

10. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are H.WO 2025 / 184609                                   PCT / US2025 / 01799011. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR3A, -CH2OR3A, -SR3A, -NHR3A, and -N(R3A)2.

12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, and -OR3A.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, -OR4A, -SR4A, -NHR4A, and -N(R4A)2.

14. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, and -OR4A.

15. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are each independently selected from methyl, ethyl, fluoro, chloro, difluoromethyl, methoxyl, and ethoxyl.

16. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are methyl.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from H, CN, halogen, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-10 membered heterocycloalkyl; wherein the Ci-ealkyl, Ci-ehaloalky 1, C2. ealkenyl, C2-ealkynyl, C3-7cycloalkyl, and 3-10 membered heterocycloalkyl of R5 are each optionally substituted with 1 or 2 R8 groups.

18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from H, CN, Ci-ehaloalkyl, 3-10 membered heterocycloalkyl.

19. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R5 is CN.WO 2025 / 184609                                   PCT / US2025 / 01799020. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R6 and R7 are independently selected from H and Ci-ealkyl; or R6 and R7 together form a C3-7cycloalkyl.

21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R6 and R7 are H.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein M is selected from -CH2- and -CF2-.

23. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein M is -CH2-.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein Q, U, and V are independently selected from N, O, S, CRQ, C(RQ)2, NRV, N(RV)2+, S=O, C=CH2, C=CHF, and C=O.

25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein Q, U, and V are independently selected from N, O, S, CRQ, C(RQ)2, NRV, N(RV)2+, C=CH2, and C=0.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein each RQ is independently selected from H, halogen, -0RQ2, CN, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, -NHRQ2, -N(RQ2)2, -NH(C=0)Rq1, -NH(C=0)0Rq1, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of RQ are each optionally substituted with 1 or 2 R9 groups.

27. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein each RQ is independently selected from H, halogen, -ORQ2, CN, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, -NHRQ2, and 5-10 membered heteroaryl; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C3-7cycloalkyl, 3-7membered heterocycloalkyl, and 5-10 membered heteroaryl of RQ are each optionally substituted with 1 or 2 R9 groups.

28. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein RQ is selected from H, CN, hydroxyl, fluoro, chloro, bromo, iodo, NH2, NHRQ2, methyl, ethyl, ethylenyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, di fluoroethyl, trifluoroethyl, tetrahydropyranyl, oxazolyl, pyrazolyl, and pyrimidinyl.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein each RQ2 is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, 6-10 membered aryl, 5-10 membered heteroaryl; wherein each 6-10 membered aryl and 5-10 membered heteroaryl of RQ2 is optionally substituted with 1 or 2 R11 groups.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RV1, -(C=O)ORV1, -(C=O)NHRV1, and -(C=O)N(RV1)2; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rv are each optionally substituted with 1, 2, or 3 R10 groups.

31. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and -(C=O)ORV1; wherein each Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, and 6-10 membered aryl of Rv are each optionally substituted with 1, 2, or 3 R10 groups.

32. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein each Rv is independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, phenyl, and -(C=O)ORV1.

34. The compound of any one of claims 1-25, wherein two Rv together form a 4-7 membered heterocycloalkyl.

35. The compound of any one of claims 1-25, wherein RQ and Rv together form a 4-11 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein the 4-11 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted with 1 or 2 R13 groups.

36. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein each R9 and R10 are independently selected from halogen, -ORX2, CN, Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C=O)RX2, -(C=O)ORX2, -(C=0)NHRX2, and -(C=O)N(RX2)2; wherein the C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R9 and R10 are each optionally substituted with 1 or 2 R12 groups.

37. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein each R9 and R10 are independently selected from halogen, -ORX2, CN, Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and -(C=O)NHRX2; wherein the C3-7cycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R9 and R10 are each optionally substituted with 1 or 2 R12 groups.

38. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein each R9 and R10 are independently selected from fluoro, hydroxyl, methoxyl, CN, methyl, trifluoromethyl, cyclopropyl, morpholinyl, phenyl, pyrazole, and -(C=O)NHRX2.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein each R11, R12 and R13 are independently selected from halogen, -ORX3, CN, Ci-ealkyl, Ci-ehaloalkyl, and Ci-ealkoxyl wherein each Ci-ealkyl of R11, R12 and R13 is optionally substituted with -ORX4.

40. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein each R11, R12 and R13 are independently selected from methoxyl and methyl.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, wherein R14 is H.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein each R1A, R2A, R3A, R4A, R5A, RQ1, RV1, RW1, RX1, RX2, RX3, and RX4 are independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, and C3-7cycloalkyl.

43. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:— is a single bond or a double bond;R1 is selected from H and Ci-3haloalkyl;R2 is selected from H and Ci-3haloalkyl;R3 is selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, and -OR3A;R4 is selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, and -OR4A;R5 is selected from H, CN, Ci-ehaloalkyl, 3-10 membered heterocycloalkyl;R6 and R7 are independently selected from H and Ci-ealkyl; or R6 and R7 together form a C3-7cycloalkyl;M is selected from -CH2- and -CF2-;W is selected from -O-, -CH(OH)-, -NH-, and -C(=O)-;Q, U, and V are independently selected from N, O, S, CRQ, C(RQ)2, NRV, N(RV)2+, C=CH2, and C=O;each Rq is independently selected from H, halogen, -ORQ2, CN, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, -NHRQ2, and 5-10 membered heteroaryl; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, and 5-10 membered heteroaryl of RQ are each optionally substituted with 1 or 2 R9 groups;each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and -(C=O)ORV1; wherein each Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, and 4-7 membered heterocycloalkyl of Rv are each optionally substituted with 1, 2, or 3 R10 groups;each RQ2 is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the 6-10 membered aryl, and 5-10 membered heteroaryl of RQ2 is optionally substituted with 1 or 2 R11 groups;or two Rv together form a 4-7 membered heterocycloalkyl;or Rq and Rv together form a 4-11 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein the 4-11 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 R13 groups;each R9 and R10 are independently selected from halogen, -ORX2, CN, Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and -(C=0)NHRX2; wherein the C3-7cycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R9 and R10 are each optionally substituted with 1 or 2 R12 groups;each R11, R12, and R13 are independently selected from halogen, -ORX3, CN, and Ci-ealkyl; wherein each Ci-ealkyl of R11, R12 and R13 is optionally substituted with -ORX4;R14 is H; andeach R3A, R4A, Rv1, RX2 RX3, and RX4 are independently selected from H and Ci-ealkyl.

44. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein:— is a single bond or a double bond;R1 is selected from H and Ci-3haloalkyl;R2 is selected from H and Ci-3haloalkyl;R3 is selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, and -OR3A;R4 is selected from halogen, Ci-ealkyl, Ci-ehaloalkyl, and -OR4A;R5 is selected from H, CN, Ci-ehaloalkyl, 3-10 membered heterocycloalkyl;R6 and R7 are H or R6 and R7 together form a C3-7cycloalkyl;M is selected from -CH2- and -CF2-;W is selected from -O- and -NH-;Q, U, and V are independently selected from N, O, S, CRQ, C(RQ)2, NRV, N(RV)2+, C=CH2, and C=O;each Rq is independently selected from H, halogen, -ORQ2, CN, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, -NHRQ2, and 5-10 membered heteroaryl; wherein each Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, and 5-10 membered heteroaryl of RQ are each optionally substituted with 1 or 2 R9 groups;each Rv is independently selected from H, Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and -(C=O)ORV1; wherein each Ci-ealkyl, Ci-ehaloalkyl, C3-7cycloalkyl, and 4-7 membered heterocycloalkyl of Rv are each optionally substituted with 1 or 2 R10 groups;each RQ2 is independently selected from H, Ci-ealkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the 6-10 membered aryl, and 5-10 membered heteroaryl of RQ2 is optionally substituted with 1 or 2 R11 groups;each R9 and R10 are independently selected from halogen, -ORX2, CN, Ci-ealkyl, C3-7cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and -(C=O)NHRX2; wherein the C3-7cycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R9 and R10 are each optionally substituted with 1 or 2 R12 groups;each R11 and R12 are independently selected from -ORX3, and Ci-6alkyl; andeach R3A, R4A, Rv1, RX2 and RX3 are independently selected from H and Ci-ealkyl.

45. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula selected from (lib), (lie), (lid), (lie), (Ilf), (Ilg),(Ilh), (Ili), and (Ilj):

46. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula selected from (Illb), (IIIc), (IIIcc), (Illd), (nie), (Illf), (Illg), (nih), (Illi), (Illj), (ink), (III1), (nim), and (Ilin)47. A compound selected from examples 1-155, or a pharmaceutically acceptable salt thereof.

48. A compound selected from examples 176-316, or a pharmaceutically acceptable salt thereof.

49. A pharmaceutical composition comprising a compound of any one of claims 1-48, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.WO 2025 / 184609                                   PCT / US2025 / 01799050. The pharmaceutical composition of claim 49, further comprising at least one additional therapeutic agent.

51. The pharmaceutical composition of claim 49 or 50, wherein the at least one or more additional therapeutic agent is selected from the group consisting of HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and combinations thereof.

52. A method of activating an HIV protease in a subject in need thereof, comprising administering a compound of any of claims 1-48, a pharmaceutically acceptable salt thereof, to the subject.

53. A method for treating or preventing an HIV infection in a subject comprising administering to the subject a compound of any of claims 1-48, or a pharmaceutically acceptable salt thereof.

54. A method for treating or preventing an HIV infection in a subject comprising administering to the subject in need thereof a compound of any of claims 1-48, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating or preventing HIV, and combinations thereof.

55. A compound of any of claims 1-48, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

56. A compound of any of claims 1-48, or a pharmaceutically acceptable salt thereof, for use in treating or preventing an HIV virus infection in a subject.

57. The use of a compound of any of claims 1-48, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing an HIV virus infection in a subj ect.

58. The use of a compound of any of claims 1-48, or a pharmaceutically acceptable salt thereof, for treating or preventing an HIV virus infection in a subject.

59. The use of a compound of any of claims 1-48, or a pharmaceutically acceptable salt thereof, for activating HIV protease in a subject.

60. The use of a compound of any of claims 1-48, or a pharmaceutically acceptable salt thereof, for activating HIV protease in vitro.