Subunit-selective n-methyl-d-aspartate receptors modulators and uses related thereto

Abstract

Disclosed are subunit-selective N-methyl-D-aspartic acid receptor (NMDAR) modulators. In some cases, the compounds are positive allosteric modulators of the GluN2 subunit. In some cases, the compounds are positive allosteric modulators of the GluN2 subunit and are selective for GluN2C / D over GluN2A. In some cases, the compounds are positive allosteric modulators of the GluN2 subunit and are selective for GluN2C / D over both GluN2A and GluN2B. The present disclosure also relates to pharmaceutical formulations of the subunit-selective NMDAR modulators as well as methods for treating conditions, disorders, or diseases using the disclosed compounds and pharmaceutical formulations.

Description

[0001] SUBUNIT-SELECTIVE N-METHYL-D-ASPARTATE RECEPTORS MODULATORS

[0002] AND USES RELATED THERETO

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 676,665 filed July 29, 2024. The entirety of this application is hereby incorporated by reference for all purposes.

[0005] TECHNICAL FIELD

[0006] The present disclosure relates to subunit-selective N-methyl-D-aspartic acid receptor (NMDAR) modulators. It also relates to pharmaceutical formulations of the subunit-selective NMDA modulators as well as methods for treating conditions, disorders, or diseases using the subunit-selective NMDAR modulators.

[0007] BACKGROUND

[0008] N-methyl-D-aspartate receptors (NMDARs) belong to the family of ionotropic glutamate receptors that mediate excitatory neurotransmission in the mammalian central nervous system (CNS).

[0009] NMDAR dysfunction has been implicated in neurological disorders such as Parkinson’s disease, bipolar disorder, schizophrenia, and depression. See Zhou, et al., Neuropharmacology, 2013, 74:69-75; Hallett, et al., Pharmacol. Then, 2004, 102(2): 155-74; Glasgow, et al., J. Physiol., 2015, 593(1):83— 95; and Mota, et al., Neuropharmacology, 2014, 76: 16-26.

[0010] Stimulation of one or more of the subunits of NMDARs can be beneficial for the treatment of neurological disorders and neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease (Lin, et al., Curr Pharm Des., 2014, 20(32), 5169-79), as well as neuropsychiatric conditions, such as bipolar disorder, schizophrenia, and depression (Hanson, et al., Neuropsychopharmacology, 2024, 49(1), 51-66). In addition, enhancement of NMDAR function has utility in other conditions dependent on synaptic plasticity, such as motor retraining and rehabilitation after ischemic insult or traumatic brain injury, and conditions that involve impairment of movement, speech, vision, or other functions controlled by the brain. See, for example, Hansen, et al., Pharmacol Rev, 2021, 73:298-487; Traynelis, et al., Pharmacol Rev, 2010, 62:405–496; Hardingham & Bading, Nat Rev Neurosci, 2010, 11:682–696; Tang, et al., Nature, 401, 63–69 (1999); and Brigman, et al., J Neurosci, 2010, 30:4590–4600. Modulators that enhance NMDAR function can mitigate cognitive dysfunction in multiple other neuropsychiatric conditions (Peyrovian, et al., Prog Neuropsychopharmacol Biol Psychiatry, 2019, 92, 387–404). In addition, some conditions can lead to the production of antibodies against NMDAR subunits, which can produce NMDAR encephalitis and NMDAR hypofunction. See Radosevic, et al., J. Neurol Neuroimmunol Neuroinflamm, 2021, 9(1), e1122. NMDAR potentiation can relieve symptoms associated with NMDAR encephalitis and NMDAR hypofunction. Functional NMDARs are heterotetramers assembled from two glycine-binding GluN1 subunits with either two glutamate-binding GluN2 (A-D) subunits or a combination of one GluN2 and one GluN3. Each subunit is comprised of four semiautonomous domains: the amino terminal domain (ATD), the agonist binding domain (ABD), the transmembrane domain (TMD), and the carboxyl terminal domain (CTD). The GluN2 subunits are encoded by four different genes, which give rise to GluN2A, GluN2B, GluN2C, and GluN2D subunits. These four subunits show different spatiotemporal expression patterns in the brain and determine the distinct physiological processes associated with these receptors. Therefore, the development of subunit-selective modulators is of great therapeutic interest in treating diseases associated with dysfunction of NMDARs. See, for example, Hansen 2021, supra. While subunit selective compounds have been developed that inhibit GluN2A-containing NMDARs (prototype TCN-201) and GluN2B-containing NMDARs (prototype ifenprodil), compounds that target the GluN2C and / or GluN2D subunits, especially those that can potentiate the GluN2C and / or GluN2D subunits, are currently underdeveloped. There is an unmet need for GluN2 subunit-selective NMDAR modulators, especially for GluN2C / D subunit-selective NMDAR modulators. More importantly, there is an unmet need for GluN2 subunit-selective NMDAR potentiators, especially for GluN2C / D subunit-selective NMDAR potentiators. SUMMARY The present disclosure describes subunit-selective NMDAR modulators. Generally, the compounds are positive allosteric modulators of the GluN2 subunit. In some cases, the compounds are also GluN2-subtype selective. In some cases, the compounds are selective for GluN2C / D over GluN2A. In some cases, the compounds are selective for GluN2C / D over both GluN2A and GluN2B. In some cases, the compounds are selective for GluN2D over GluN2A, GluN2B, and GluN2C. Also disclosed are compositions containing a compound described herein, wherein the compound has one or more chiral centers and is in greater than 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess. In some embodiments, the compound in the compositions is in greater than 95% enantiomeric or diastereomeric excess. Also disclosed are pharmaceutical formulations of the disclosed compounds or compositions. In general, the pharmaceutical formulations contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical formulations are in a form chosen from tablets, capsules, caplets, pills, beads, granules, particles, powders, gels, creams, solutions, suspensions, emulsions, and nanoparticulate formulations. In some embodiments, the pharmaceutical formulations are oral formulations. In some embodiments, the pharmaceutical formulations are intravenous formulations. In some embodiments, the pharmaceutical formulations are intramuscular formulations. In some embodiments, the pharmaceutical formulations are in the form of solutions, such as aqueous solutions. In some embodiments, the pharmaceutical formulations are in the form of powders, such as lyophilized powders. In some embodiments, the pharmaceutical formulations are in the form of tablets, caplets, capsules, or pills. This disclosure also relates to (1) the compounds, compositions, and pharmaceutical formulations disclosed herein for treatment of a condition, disorder, or disease disclosed herein or use as a medicament, (2) the compounds, compositions, and pharmaceutical formulations disclosed herein for use in the treatment of a condition, disorder, or disease disclosed herein, or (3) the compounds, compositions, and pharmaceutical formulations disclosed herein for the manufacture of a medicament for treatment of a condition, disorder, or disease disclosed herein. This disclosure also provides methods of treating a condition, disorder, or disease in a subject in need thereof. The method includes administering an effective amount of a compound, composition, or pharmaceutical formulation disclosed herein to the subject. In some embodiments, the compound, composition, or pharmaceutical formulation is administered orally, intravenously, intranasally, or intramuscularly. In general, the condition, disorder, or disease relevant to this disclosure is related to NMDAR. In some embodiments, the condition, disorder, or disease may be caused by NMDAR hypofunction or loss of function. In some embodiments, the condition, disorder, or disease is a neurological disorder or condition. Exemplary neurological disorders or conditions include, but are not limited to, neurodegenerative disease or disorder, pain, epilepsy, essential tremor, movement disorder or impaired motor function, stroke, traumatic brain injury, transient ischemia, global ischemia, hypoxia, and spinal cord trauma. In some embodiments, the condition, disorder, or disease is a neuropsychiatric disorder or condition. Exemplary neuropsychiatric disorders or conditions include, but are not limited to, schizophrenia, depression, post-partum depression, post- traumatic stress disorder, bipolar disorder, fragile X syndrome, sleeping disorder, anxiety disorder, autism spectrum disorder, obsessive-compulsive disorder, addiction or use dependence, uncontrolled anger, cognitive deficit disorder, headache, migraine, eating disorder, and attention- deficit disorder. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS Figure 1 shows the normalized slope of evoked field EPSP recorded from brain slices of GluN2B-E413G mutant mice treated with vehicle (dot, n = 13), 3 µM (square, n = 4), 5 µM (diamond, n = 4), or 10 µM (triangle, n = 4) 1622-240. The top dashed line shows the maximal level LTP obtained in WT mice. The four triangles on the bottom of the figure depict the applications of theta burst stimulation at the indicated times to induce LTP. Figures 2A-2B show the effect of 1622-240 on the behaviors of mice monitored in an open field test (Figure 2A) and a light / dark box test (Figure 2B). Figure 2A is a summary of the behaviors of mice monitored in an open field for 10 min after 1 h of a 5 or 10 mg / kg IP administration of 1622-240. Figure 2B is a summary of the behaviors of mice in a light / dark chamber monitored for 10 min after 1 h of a 5 or 10 mg / kg IP administration of 1622-240. *, **, and *** indicate p ≤ 0.05, 0.01, and 0.001, respectively, by one way ANOVA (Tukey’s test). Figures 3A-3B show the effect of 1622-287 on the behaviors of mice monitored in an open field test (Figure 3A) and a light / dark box test (Figure 3B). Figure 3A is a summary of the behaviors of mice monitored in an open field for 10 min after 1 h of a 10 mg / kg IP administration of 1622-287. Figure 3B is a summary of the behaviors of mice in a light / dark chamber monitored for 10 min after 1 h of a 10 mg / kg IP administration of 1622-287. * and ** indicate p ≤ 0.05 and 0.01, respectively, by one way ANOVA (Tukey’s test). DETAILED DESCRIPTION The present disclosure describes subunit-selective NMDAR modulators. Generally, the compounds are positive allosteric modulators of the GluN2 subunit. In some cases, the compounds are also GluN2-subtype selective. In some cases, the compounds are selective for GluN2C / D over GluN2A. In some cases, the compounds are selective for GluN2C / D over both GluN2A and GluN2B. In some cases, the compounds are selective for GluN2D over GluN2A, GluN2B, and GluN2C. Also disclosed are pharmaceutical formulations containing a compound described herein and methods for treating conditions, disorders, or diseases using a compound described herein. In general, the condition, disorder, or disease relevant to this disclosure is related to NMDAR. In some embodiments, the condition, disorder, or disease may be caused by NMDAR hypofunction or loss of function, especially GluN2 hypofunction or loss of function. Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to the particular embodiments described herein, and as such, may vary in accordance with the scope of the present disclosure. 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 to which this disclosure belongs. All publications and patents cited in this specification are herein incorporated by reference as if each individual publication and patent were specifically and individually indicated to be incorporated by reference. They are incorporated by reference to disclose and describe the methods and / or materials in connection with which the publications and patents are cited. As will be apparent to those of ordinary skill in the art upon reading this disclosure, each of the particular embodiments described and illustrated herein has discrete components and / or features that may be readily separated from or combined with one or more components and / or features of any of the other embodiments described herein, without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited herein or in any other order that is logically possible. Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, medicinal chemistry, biochemistry, molecular biology, pharmacology, neurology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature, such as the publications and patents cited herein. I. DEFINITIONS As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. The terms “may,” “may be,” “can,” “can be,” and related terms are intended to convey that the subject matter involved is optional (that is, the subject matter is present in some examples and is not present in other examples), not a reference to a capability of the subject matter or to a probability, unless the context clearly indicates otherwise. The terms “optional” and “optionally” mean that the subsequently described event, circumstance, or material may or may not occur or be present, and that the description includes instances where the event, circumstance, or material occurs or is present as well as instances where it does not occur or is not present. Use of the term “about” is intended to describe values either above or below the stated value in a range of approx. ^ / ^ 10%; in other examples the values may range in value either above or below the stated value in a range of approx. ^ / ^ 5%; in other examples the values may range in value either above or below the stated value in a range of approx. ^ / ^ 2%; in other examples the values may range in value either above or below the stated value in a range of approx. ^ / ^ 1%. A carbon range (e.g., C1^C10) is intended to disclose individually every possible carbon value and / or sub-range encompassed within. For example, a carbon range of C1^C10discloses C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10, as well as sub-ranges encompassed therein, such as C2^C9, C3^C8, C1^C5, etc. As used herein, the term “subject” refers to an animal, including human and non-human animals. Human subjects may include pediatric patients and adult patients. Non-human animals may include domestic pets, livestock and farm animals, and zoo animals. In some cases, the non- human animals may be non-human primates. As used herein, the terms “prevent” and “preventing” include the prevention of the occurrence, onset, spread, and / or recurrence. It is not intended that the present disclosure is limited to complete prevention. For example, prevention is considered as achieved when the occurrence is delayed, the severity of the onset is reduced, or both. As used herein, the terms “treat” and “treating” include medical management of a condition, disorder, or disease of a subject as would be understood by a person of ordinary skill in the art (see, for example, Stedman’s Medical Dictionary). In general, treatment is not limited to cases where the subject is cured and the condition, disorder, or disease is eradicated. Rather, treatment also contemplates cases where a treatment regimen containing one of the compounds, compositions, or pharmaceutical formulations of the present disclosure provides an improved clinical outcome. The improved clinical outcome may include one or more of the following: abatement, lessening, and / or alleviation of one or more symptoms that result from or are associated with the condition, disorder, or disease to be treated; decreased occurrence of one or more symptoms; improved quality of life; diminishment of the extent of the condition, disorder, or disease; reaching or establishing a stabilized state (i.e., not worsening) of the condition, disorder, or disease; delay or slowing of the progression of the condition, disorder, or disease; amelioration or palliation of the state of the condition, disorder, or disease; partial or total remission; and improvement in survival (whether increase in the overall survival rate or prolonging of survival when compared to expected survival if the subject were not receiving the treatment). For example, the disclosure encompasses treatment that reduces one or more symptoms of and / or cognitive deficit associated with or caused by a brain injury. The terms “halogenated” and “halogenation” refer to replacement of one or more non- ionizable hydrogen atoms in a chemical compound / moiety with halogen such as fluorine. A halogenated chemical compound / group / moiety may be fully halogenated (i.e., all the non- ionizable hydrogen atoms in the chemical compound / moiety are replaced with halogen such as fluorine) or partially halogenated (i.e., one or more non-ionizable hydrogen atoms, but not all the non-ionizable hydrogen atoms, in the chemical compound / group / moiety are replaced with halogen such as fluorine). The terms “derivative” and “derivatives” refer to chemical compounds / groups / moieties with a structure similar to that of a parent compound / group / moiety but different from it in respect to one or more components, functional groups, atoms, etc. Optionally, the derivatives retain certain functional attributes of the parent compound / group / moiety. Optionally, the derivatives can be formed from the parent compound / group / moiety by chemical reaction(s). The differences between the derivatives and the parent compound / group / moiety can include, but are not limited to, replacement of one or more functional groups with one or more different functional groups or introducing or removing one or more substituents of hydrogen atoms. The term “alkyl” refers to univalent groups derived from alkanes (i.e., acyclic saturated hydrocarbons) by the removal of a hydrogen atom from any carbon atom. Alkyl groups can be linear or branched. Suitable alkyl groups can have one to 30 carbon atoms, i.e., C1^C30alkyl. If the alkyl is branched, it is understood that at least three carbon atoms are present. The term “alkenyl” refers to univalent groups derived from alkenes by removal of a hydrogen atom from any carbon atom. Alkenes are unsaturated hydrocarbons that contain at least one carbon-carbon double bond. Alkenyl groups can be linear or branched. Suitable alkenyl groups can have two to 30 carbon atoms, i.e., C2^C30 alkenyl. If the alkenyl is branched, it is understood that at least three carbon atoms are present. The term “alkynyl” refers to univalent groups derived from alkynes by removal of a hydrogen atom from any carbon atom. Alkynes are unsaturated hydrocarbons that contain at least one carbon-carbon triple bond. Alkynyl groups can be linear or branched. Suitable alkynyl groups can have two to 30 carbon atoms, i.e., C2^C30 alkynyl. If the alkynyl is branched, it is understood that at least four carbon atoms are present. The term “heteroalkyl” refers to alkyl groups where one or more carbon atoms are replaced with a heteroatom such as, O, N, S, or Si. Optionally, the nitrogen and / or sulphur heteroatom(s) may be oxidized, and the nitrogen heteroatom(s) may be quaternized. Heteroalkyl groups can be linear or branched. Suitable heteroalkyl groups can have one to 30 carbon atoms, i.e., C1^C30 heteroalkyl. If the heteroalkyl is branched, it is understood that at least one carbon atom and at least one heteroatom are present. The term “aryl” refers to univalent groups derived from arenes by removal of a hydrogen atom from a ring atom. Arenes are monocyclic or polycyclic aromatic hydrocarbons. In polycyclic arenes, the rings can be attached together in a pendant manner, a fused manner, or a combination thereof. Accordingly, in polycyclic aryl groups, the rings can be attached together in a pendant manner, a fused manner, or a combination thereof. Suitable aryl groups can have six to 30 carbon atoms, i.e., C6^C30 aryl. The number of “members” of an aryl group refers to the total number of carbon atoms in the ring(s) of the aryl group. The term “heteroaryl” refers to univalent groups derived from heteroarenes by removal of a hydrogen atom from a ring atom. Heteroarenes are heterocyclic compounds derived from arenes by replacement of one or more methine (^C^) and / or vinylene (^CH^CH^) groups by trivalent or divalent heteroatoms, respectively, in such a way as to maintain the continuous ^-electron system characteristic of aromatic systems and a number of out-of-plane ^-electrons corresponding to the Hückel rule (4n ^ 2). Heteroarenes can be monocyclic or polycyclic. In polycyclic heteroarenes, the rings can be attached together in a pendant manner, a fused manner, or a combination thereof. Accordingly, in polycyclic heteroaryl groups, the rings can be attached together in a pendant manner, a fused manner, or any combination thereof. Suitable heteroaryl groups can have one to 30 carbon atoms, i.e., C1^C30heteroaryl. The number of “members” of a heteroaryl group refers to the total number of carbon atom(s) and heteroatom(s) in the ring(s) of the heteroaryl group. “Carbocycle” or “carbocyclyl” refers to mono- and polycyclic ring systems containing only carbon atoms as ring atoms. The mono- and polycyclic ring systems may be aromatic, non- aromatic (saturated or unsaturated), or a mixture of aromatic and non-aromatic rings. Carbocyclyls are univalent, derived from carbocycles by removal of a hydrogen atom from a ring atom. Carbocycles include arenes; carbocyclyls include aryls. In polycyclic carbocycles or carbocyclyls, the rings can be attached together in a pendant manner (i.e., two rings are connected by a single bond), a spiro manner (i.e., two rings are connected through a defining single common atom), a fused manner (i.e., two rings share two adjacent atoms; in other words, two rings share one covalent bond), a bridged manner (i.e., two rings share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom), or a combination thereof. Suitable carbocycle or carbocyclyl groups can have three to 30 carbon atoms, i.e., C3^C30carbocycle or carbocyclyl. The number of “members” of a carbocycle or carbocyclyl group refers to the total number of carbon atoms in the ring(s) of the carbocycle or carbocyclyl group. “Heterocycle” or “heterocyclyl” refers to mono- and polycyclic ring systems containing at least one carbon atom and one or more heteroatoms independently selected from elements like nitrogen, oxygen, and sulfur, as ring atoms. Optionally, the nitrogen and / or sulphur heteroatom(s) may be oxidized, and the nitrogen heteroatom(s) may be quaternized. The mono- and polycyclic ring systems may be aromatic, non-aromatic, or a mixture of aromatic and non-aromatic rings. Heterocyclyls are univalent, derived from heterocycles by removal of a hydrogen atom from a ring atom. Heterocycles include heteroarenes; heterocyclyls include heteroaryls. In polycyclic heterocycle or heterocyclyl groups, the rings can be attached together in a pendant manner (i.e., two rings are connected by a single bond), a spiro manner (i.e., two rings are connected through a defining single common atom), a fused manner (i.e., two rings share two adjacent atoms; in other words, two rings share one covalent bond), a bridged manner (i.e., two rings share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom), or a combination thereof. Suitable heterocycle or heterocyclyl groups can have one to 30 carbon atoms, i.e., C1^C30 heterocycle or heterocyclyl. The number of “members” of a heterocycle or heterocyclyl group refers to the total number of carbon atom(s) and heteroatom(s) in the ring(s) of the heterocycle or heterocyclyl group. As used herein, the terms “halogen” and “halo” refer to fluorine, chlorine, bromine, and iodine. As used herein, “haloalkyl” refers to halogen-substituted alkyl groups. Optionally, the haloalkyl groups contain one halogen substituent. Optionally, the haloalkyl groups contain multiple halogen substituents, i.e., polyhaloalkyl. In some examples, the haloalkyl groups contain one or more fluorine substituents. As used herein, “haloalkenyl” refers to halogen-substituted alkenyl groups. Optionally, the haloalkenyl groups contain one halogen substituent. Optionally, the haloalkenyl groups contain multiple halogen substituents. In some examples, the haloalkenyl groups contain one or more fluorine substituents. As used herein, “haloalkynyl” refers to halogen-substituted alkynyl groups. Optionally, the haloalkynyl groups contain one halogen substituent. Optionally, the haloalkynyl groups contain multiple halogen substituents. In some examples, the haloalkynyl groups contain one or more fluorine substituents. As used herein, “halocarbocyclyl” refers to halogen-substituted carbocyclyl groups. Optionally, the halocarbocyclyl groups contain one halogen substituent. Optionally, the halocarbocyclyl groups contain multiple halogen substituents. In some examples, the halocarbocyclyl groups contain one or more fluorine substituents. As used herein, “haloheterocyclyl” refers to halogen-substituted heterocyclyl groups. Optionally, the haloheterocyclyl groups contain one halogen substituent. Optionally, the haloheterocyclyl groups contain multiple halogen substituents. In some examples, the haloheterocyclyl groups contain one or more fluorine substituents. As used herein, “haloaryl” refers to halogen-substituted aryl groups. Optionally, the haloaryl groups contain one halogen substituent. Optionally, the haloaryl groups contain multiple halogen substituents. In some examples, the haloaryl groups contain one or more fluorine substituents. As used herein, “haloheteroaryl” refers to halogen-substituted heteroaryl groups. Optionally, the haloheteroaryl groups contain one halogen substituent. Optionally, the haloheteroaryl groups contain multiple halogen substituents. In some examples, the haloheteroaryl groups contain one or more fluorine substituents. The term “substituted,” as used herein, means that the chemical group or moiety contains one or more substituents replacing the hydrogen atom(s) in the original chemical group or moiety. It is understood that any substitution is in accordance with a permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc., under room temperature. Unless otherwise specified, the substituents are R groups. The R groups, in each occurrence, can be independently selected from halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, halo(arylalkyl), alkylaryl, halo(alkylaryl), ^OH, ^SH, ^NH2, ^N3, ^OCN, ^NCO, ^ONO2, ^CN, ^NC, ^ONO, ^CONH2, ^NO, ^NO2, ^ONH2, ^SCN, ^SNCS, ^CF3, ^CH2CF3, ^CH2Cl, ^CHCl2, ^CH2NH2, ^NHCOH, ^CHO, ^COOH, ^SO3H, ^SO2CH3, ^PO3H2, ^OPO3H2, ^P(^O)(ORG1)(ORG2), ^OP(^O)(ORG1)(ORG2), ^BRG1(ORG2), ^B(ORG1)(ORG2), –Si(RG1)(RG2)(RG3), –C(RG1)(RG2)(RG3), –N[(RG1)(RG2)(RG3)]+, and ^GRG1, in which ^G– is ^O^, ^S^, ^NRG2^, ^C(^O)^, ^S(^O)^, ^SO2^, ^C(^O)O^, ^C(^O)NRG2^, ^OC(^O)^, ^NRG2C(^O)^, ^OC(^O)O^, ^OC(^O)NRG2^, ^NRG2C(^O)O^, ^NRG2C(^O)NRG3^, ^C(^S)^, ^C(^S)S^, ^SC(^S)^, ^SC(^S)S^, ^C(^NRG2)^, ^C(^NRG2)O^, ^C(^NRG2)NRG3^, ^OC(^NRG2)^, ^NRG2C(^NRG3)^, ^NRG2SO2^, ^C(^NRG2)NRG3^, ^OC(^NRG2)^, ^NRG2C(^NRG3)^, ^NRG2SO2^, ^NRG2SO2NRG3^, ^NRG2C(^S)^, ^SC(^S)NRG2^, ^NRG2C(^S)S^, ^NRG2C(^S)NRG3^, ^SC(^NRG2)^, ^C(^S)NRG2^, ^OC(^S)NRG2^, ^NRG2C(^S)O^, ^SC(^O)NRG2^, ^NRG2C(^O)S^, ^C(^O)S^, ^SC(^O)^, ^SC(^O)S^, ^C(^S)O^, ^OC(^S)^, ^OC(^S)O^, ^SO2NRG2^, ^BRG2^, or ^PRG2^, wherein each occurrence of RG1, RG2, and RG3is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, and haloheteroaryl. Optionally, two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle, halocarbocycle, heterocycle, or haloheterocycle. Alternatively, two R groups on the same atom can merge into one oxygen (=O) or sulfur (=S) atom. The term “optionally substituted,” as used herein, means that substitution is optional, and therefore it is possible for the designated atom / chemical group / compound to be unsubstituted. As used herein, “ester” refers to –C(=O)ORc1or –OC(=O)Rc2, wherein Rc1and Rc2are independently selected from alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be optionally and independently substituted by one or more R groups described above. Optionally, two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle. As used herein, “amino” refers to –NRd1Rd2, wherein Rd1and Rd2are independently selected from hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be optionally and independently substituted by one or more R groups described above. Optionally, two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle. When Rd1and Rd2are each hydrogen, the amino group is a primary amino group. As used herein, “acyl” refers –C(=O)Re, wherein Reis selected from alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted by one or more R groups described above. Optionally, two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle. As used herein, “amide” refers to –C(=O)NRf1Rf2, wherein Rf1and Rf2are independently selected from hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be optionally and independently substituted by one or more R groups described above. Optionally, two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle. When Rf1and Rf2are each hydrogen, the amide group is a carbamoyl group. As used herein, “carbonate ester” refers to –OC(=O)ORi, wherein Riis selected from alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted by one or more R groups described above. Optionally, two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle. As used herein, “carbamate” refers to –OC(=O)NRj1Rj2or –NRk[(C=O)ORl], wherein Rj1, Rj2, Rk, and Rlare independently selected from hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be optionally and independently substituted by one or more R groups described above. Optionally, two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle. As used herein, “sulfinyl” refers to –S(=O)Rm, wherein Rmis selected from alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted by one or more R groups described above. Optionally, two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle. As used herein, “sulfonyl” refers to –S(=O)2Rn, wherein Rnis selected from alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted by one or more R groups described above. Optionally, two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle. As used herein, “thioester” refers to –C(=O)SRo1or –SC(=O)Ro2, wherein Ro1and Ro2are independently selected from alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be optionally and independently substituted by one or more R groups described above. Optionally, two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle. As used herein, “sulfonamide” refers to –S(=O)2NRp1Rp2, wherein Rp1and Rp2are independently selected from hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be optionally and independently substituted by one or more R groups described above. Optionally, two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle. When Rp1and Rp2are each hydrogen, the amide group is a sulfamoyl group. As used herein, “thiol” refers to the univalent radical –SH. As used herein, “sulfonate” refers to –SO3-. As used herein, “silyl” refers to the univalent radical derived from silane by removal of a hydrogen atom, i.e., –SiH3. As used herein, “carbonate” refers to –O(C=O)OH. As used herein, the term “stereoisomer” refers to compounds made up of the same atoms having the same bond order but having different three-dimensional arrangements of atoms which are not interchangeable. As used herein, the term “enantiomer” refers to a pair of stereoisomers that are non-superimposable mirror images of one another. As used herein, the term “diastereomer” refers to two stereoisomers that are not mirror images but also not superimposable. The terms “racemate” and “racemic mixture” refer to a mixture of enantiomers. The term “chiral center” refers to a carbon atom to which four different groups are attached. Choice of the appropriate chiral column, eluent, and conditions necessary for effective separation of stereoisomers, such as a pair of enantiomers, is well known to one of ordinary skill in the art (e.g., Jacques et al., Enantiomers, Racemates, and Resolutions, John Wiley and Sons, Inc., 1981). As used herein, the term “pharmaceutically acceptable” refers to compounds, materials, compositions, or formulations which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and non-human animals without excessive toxicity, irritation, allergic response, or other problems or complications that commensurate with a reasonable benefit / risk ratio, in accordance with the guidelines of regulatory agencies of a certain country, such as the Food and Drug Administration (FDA) in the United States or its corresponding agencies in countries other than the United States (e.g., the European Medicines Agency (EMA) in Europe, the National Medical Products Administration (NMPA) in China). As used herein, the term “salt” refers to acid or base salts of the original compound. In some cases, the salt is formed in situ during preparation of the original compound, i.e., the designated synthetic chemistry procedures produce the salt instead of the original compound. In some cases, the salt is obtained via modification of the original compound. In some cases, the salt is obtained via ion exchange with an existing salt of the original compound. Examples of salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids and phosphonic acids. For original compounds containing a basic residue, the salts can be prepared by treating the compounds with an appropriate amount of a non-toxic inorganic or organic acid; alternatively, the salts can be formed in situ during preparation of the original compounds. Exemplary salts of the basic residue include salts with an inorganic acid selected from hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids or with an organic acid selected from acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic acids. For original compounds containing an acidic residue, the salts can be prepared by treating the compounds with an appropriate amount of a non-toxic base; alternatively, the salts can be formed in situ during preparation of the original compounds. Exemplary salts of the acidic residue include salts with a base selected from ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, aluminum hydroxide, ferric hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, and histidine. Optionally, the salts can be prepared by reacting the free acid or base form of the original compounds with a stoichiometric amount or more of an appropriate base or acid, respectively, in water or an aqueous solution, an organic solvent or an organic solution, or a mixture thereof. Lists of exemplary pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 20thEd., Lippincott Williams & Wilkins, Baltimore, MD, 2000 as well as Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH, Weinheim, 2002. As used herein, the term “excipient” refers to any components present in the pharmaceutical formulations disclosed herein, other than the active ingredient (i.e., a compound or composition of the present disclosure). As used herein, the term “effective amount” of a material refers to a nontoxic but sufficient amount of the material to provide the desired result. The exact amount required may vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition, disorder, or disease that is being treated, the active ingredient or therapy used, and the like. II. COMPOUNDS Disclosed are subunit-selective N-methyl-D-aspartic acid receptor (NMDAR) modulators. In some cases, the compounds are positive allosteric modulators of the GluN2 subunit. In some cases, the compounds are positive allosteric modulators of the GluN2 subunit and are selective for GluN2C / D over GluN2A. In some cases, the compounds are positive allosteric modulators of the GluN2 subunit and are selective for GluN2C / D over both GluN2A and GluN2B. In some cases, the compounds are positive allosteric modulators of the GluN2 subunit and are selective for GluN2D over GluN2A, GluN2B, and GluN2C. To the extent that chemical formulas described herein contain one or more unspecified chiral centers, the formulas are intended to encompass all stable stereoisomers, enantiomers, and diastereomers. Such compounds can exist as a single enantiomer, a racemic mixture, a mixture of diastereomers, or combinations thereof. It is also understood that the chemical formulas encompass all tautomeric forms if tautomerization occurs. Methods of making exemplary compounds are disclosed in subsequent sections and exemplified by the Examples. The synthetic methods disclosed herein are compatible with a wide variety of functional groups and starting materials. Thus, a wide variety of compounds can be obtained from the disclosed methods. Optionally, the alkyl groups described herein have 1–30 carbon atoms, i.e., C1–C30 alkyl. In some forms, the C1–C30alkyl can be a linear C1–C30alkyl or a branched C3–C30alkyl. Optionally, the alkyl groups have 1–20 carbon atoms, i.e., C1–C20alkyl. In some forms, the C1–C20alkyl can be a linear C1–C20 alkyl or a branched C3–C20 alkyl. Optionally, the alkyl groups have 1–10 carbon atoms, i.e., C1–C10 alkyl. In some forms, the C1–C10 alkyl can be a linear C1–C10 alkyl or a branched C3–C10alkyl. Optionally, the alkyl groups have 1–6 carbon atoms, i.e., C1–C6alkyl. In some forms, the C1–C6 alkyl can be a linear C1–C6 alkyl or a branched C3–C6 alkyl. Representative straight chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n- nonyl, and the like. Representative branched alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Optionally, the alkenyl groups described herein have 2–30 carbon atoms, i.e., C2–C30 alkenyl. In some forms, the C2–C30 alkenyl can be a linear C2–C30 alkenyl or a branched C3–C30 alkenyl. Optionally, the alkenyl groups have 2–20 carbon atoms, i.e., C2–C20alkenyl. In some forms, the C2–C20 alkenyl can be a linear C2–C20 alkenyl or a branched C3–C20 alkenyl. Optionally, the alkenyl groups have 2–10 carbon atoms, i.e., C2–C10 alkenyl. In some forms, the C2–C10 alkenyl can be a linear C2–C10alkenyl or a branched C3–C10alkenyl. Optionally, the alkenyl groups have 2–6 carbon atoms, i.e., C2–C6alkenyl. In some forms, the C2–C6alkenyl can be a linear C2– C6 alkenyl or a branched C3–C6 alkenyl. Representative alkenyl groups include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2- methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like. Optionally, the alkynyl groups described herein have 2–30 carbon atoms, i.e., C2–C30 alkynyl. In some forms, the C2–C30 alkynyl can be a linear C2–C30 alkynyl or a branched C4–C30 alkynyl. Optionally, the alkynyl groups have 2–20 carbon atoms, i.e., C2–C20alkynyl. In some forms, the C2–C20 alkynyl can be a linear C2–C20 alkynyl or a branched C4–C20 alkynyl. Optionally, the alkynyl groups have 2–10 carbon atoms, i.e., C2–C10 alkynyl. In some forms, the C2–C10 alkynyl can be a linear C2–C10alkynyl or a branched C4–C10alkynyl. Optionally, the alkynyl groups have 2–6 carbon atoms, i.e., C2–C6alkynyl. In some forms, the C2–C6alkynyl can be a linear C2–C6 alkynyl or a branched C4–C6 alkynyl. Representative alkynyl groups include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, and the like. Optionally, the heteroalkyl groups described herein have 1–30 carbon atoms, i.e., C1–C30heteroalkyl. In some forms, the C1–C30 heteroalkyl can be a linear C1–C30 heteroalkyl or a branched C1–C30heteroalkyl. Optionally, the heteroalkyl groups have 1–20 carbon atoms, i.e., C1–C20heteroalkyl. In some forms, the C1–C20heteroalkyl can be a linear C1–C20heteroalkyl or a branched C1–C20 heteroalkyl. Optionally, the heteroalkyl groups have 1–10 carbon atoms, i.e., C1–C10 heteroalkyl. In some forms, the C1–C10 heteroalkyl can be a linear C1–C10 heteroalkyl or a branched C1–C10heteroalkyl. Optionally, the heteroalkyl groups have 1–6 carbon atoms, i.e., C1– C6 heteroalkyl. In some forms, the C1–C6 heteroalkyl can be a linear C1–C6 heteroalkyl or a branched C1–C6 heteroalkyl. Optionally, the aryl groups described herein have 6–30 carbon atoms, i.e., C6–C30aryl. Optionally, the aryl groups have 6–20 carbon atoms, i.e., C6–C20aryl. Optionally, the aryl groups have 6–12 carbon atoms, i.e., C6–C12 aryl. Representative aryl groups include phenyl, naphthyl, and biphenyl. Optionally, the heteroaryl groups described herein have 1–30 carbon atoms, i.e., C1–C30heteroaryl. Optionally, the heteroaryl groups have 1–20 carbon atoms, i.e., C1–C20 heteroaryl. Optionally, the heteroaryl groups have 1–11 carbon atoms, i.e., C1–C11 heteroaryl. Optionally, the heteroaryl groups have 1–5 carbon atoms, i.e., C1–C5heteroaryl. Optionally, the heteroaryl groups are 5–20 membered heteroaryl groups. Optionally, the heteroaryl groups are 5–12 membered heteroaryl groups. Optionally, the heteroaryl groups are 5 or 6 membered heteroaryl groups. Representative heteroaryl groups include furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. Optionally, the carbocyclyl groups described herein have 3–30 carbon atoms, i.e., C3–C30carbocyclyl. Optionally, the carbocyclyl groups described herein have 3–20 carbon atoms, i.e., C3– C20 carbocyclyl. Optionally, the carbocyclyl groups described herein have 3–12 carbon atoms, i.e., C3–C12carbocyclyl. Representative saturated carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Representative unsaturated carbocyclyl groups include cyclopentenyl, cyclohexenyl, and the like. Optionally, the heterocyclyl groups described herein have 1–30 carbon atoms, i.e., C1–C30heterocyclyl. Optionally, the heterocyclyl groups described herein have 1–20 carbon atoms, i.e., C1–C20 heterocyclyl. Optionally, the heterocyclyl groups described herein have 1–11 carbon atoms, i.e., C1–C11heterocyclyl. Optionally, the heterocyclyl groups described herein have 1–6 carbon atoms, i.e., C1–C6heterocyclyl. Optionally, the heterocyclyl groups are 3–20 membered heterocyclyl groups. Optionally, the heterocyclyl groups are 3–12 membered heterocyclyl groups. Optionally, the heteroaryl groups are 4–7 membered heterocyclyl groups. The optionally substituted groups described in the chemical formulas described herein (e.g., Formula I and its sub-formulas), in each occurrence when not specified, may have one or more substituents in the form of the R groups described above. The R groups, in each occurrence, can be independently selected from halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, halo(arylalkyl), alkylaryl, halo(alkylaryl), ^OH, ^SH, ^NH2, ^N3, ^OCN, ^NCO, ^ONO2, ^CN, ^NC, ^ONO, ^CONH2, ^NO, ^NO2, ^ONH2, ^SCN, ^SNCS, ^CF3, ^CH2CF3, ^CH2Cl, ^CHCl2, ^CH2NH2, ^NHCOH, ^CHO, ^COOH, ^SO3H, ^SO2CH3, ^PO3H2, ^OPO3H2, ^P(^O)(ORG1)(ORG2), ^OP(^O)(ORG1)(ORG2), ^BRG1(ORG2), ^B(ORG1)(ORG2), –Si(RG1)(RG2)(RG3), –C(RG1)(RG2)(RG3), –N[(RG1)(RG2)(RG3)]+, and ^GRG1, in which ^G– is ^O^, ^S^, ^NRG2^, ^C(^O)^, ^S(^O)^, ^SO2^, ^C(^O)O^, ^C(^O)NRG2^, ^OC(^O)^, ^NRG2C(^O)^, ^OC(^O)O^, ^OC(^O)NRG2^, ^NRG2C(^O)O^, ^NRG2C(^O)NRG3^, ^C(^S)^, ^C(^S)S^, ^SC(^S)^, ^SC(^S)S^, ^C(^NRG2)^, ^C(^NRG2)O^, ^C(^NRG2)NRG3^, ^OC(^NRG2)^, ^NRG2C(^NRG3)^, ^NRG2SO2^, ^C(^NRG2)NRG3^, ^OC(^NRG2)^, ^NRG2C(^NRG3)^, ^NRG2SO2^, ^NRG2SO2NRG3^, ^NRG2C(^S)^, ^SC(^S)NRG2^, ^NRG2C(^S)S^, ^NRG2C(^S)NRG3^, ^SC(^NRG2)^, ^C(^S)NRG2^, ^OC(^S)NRG2^, ^NRG2C(^S)O^, ^SC(^O)NRG2^, ^NRG2C(^O)S^, ^C(^O)S^, ^SC(^O)^, ^SC(^O)S^, ^C(^S)O^, ^OC(^S)^, ^OC(^S)O^, ^SO2NRG2^, ^BRG2^, or ^PRG2^, wherein each occurrence of RG1, RG2, and RG3is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, and haloheteroaryl. Optionally, two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle, halocarbocycle, heterocycle, or haloheterocycle. Alternatively, two R groups on the same atom can merge into one oxygen (=O) or sulfur (=S) atom. In some examples, the R groups are independently selected from halogen, nitro, cyano, hydroxyl, formyl, carboxyl, thiol, =O (counting as two R groups), =S (counting as two R groups), sulfamoyl, alkyl (such as methyl, ethyl, isopropyl, tert-butyl), haloalkyl (such as trifluoromethyl), alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl (such as benzyl), halo(arylalkyl), alkylaryl, halo(alkylaryl), alkyloxy (such as methoxy, ethoxy), haloalkyloxy (such as trifluoromethoxy), carbocyclyloxy, halocarbocyclyloxy, heterocyclyloxy, haloheterocyclyloxy, aryloxy, haloaryloxy, heteroaryloxy, haloheteroaryloxy, alkylcarbonyl (such as acetyl), (haloalkyl)carbonyl, arylcarbonyl (such as benzoyl), (haloaryl)carbonyl, alkylcarbonyloxy (such as acetoxy), (haloalkyl)carbonyloxy, arylcarbonyloxy (such as benzoyloxy), (haloaryl)carbonyloxy, alkyloxycarbonyl (such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl), (haloalkyl)oxycarbonyl, aryloxycarbonyl, (haloaryl)oxycarbonyl, primary amino, alkylamino (such as methylamino, ethylamino, dimethylamino, diethylamino, N-methyl- N-ethylamino), haloalkylamino, alkylammonium (such as trimethylammonium), haloalkylammonium, alkylcarbonylamino (such as acetylamino), N-alkyl(alkylcarbonyl)amino, haloalkylcarbonylamino, N-alkyl(haloalkylcarbonyl)amino, arylcarbonylamino (such as benzoylamino), N-alkyl(arylcarbonyl)amino, haloarylcarbonylamino, N- alkyl(haloarylcarbonyl)amino, alkylsulfonylamino, N-alkyl(alkylsulfonyl)amino, haloalkylsulfonylamino, N-alkyl(haloalkylsulfonyl)amino, carbamoyl, N-alkylcarbamoyl (such as N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl), N-(haloalkyl)carbamoyl, alkylthio (such as methylthio, ethylthio), (haloalkyl)thio, alkylsulfinyl (such as methylsulfinyl, ethylsulfinyl), (haloalkyl)sulfinyl, alkylsulfonyl (such as mesyl, ethylsulfonyl), (haloalkyl)sulfonyl, N-alkylsulfamoyl (such as N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl), N-(haloalkyl)sulfamoyl, alkylsilyl (such as trimethylsilyl), and haloalkylsilyl. In some examples, the R groups are independently selected from halogen, nitro, cyano, hydroxyl, methyl, CHF2, CH2F, CF3, ethyl, isopropyl, cyclopropyl, ethynyl, methoxy, trifluoromethoxy, ethoxy, –O(CH2CF3), isopropyloxy, tetrahydropyranoxy, primary amino, formyl, carboxyl, carbamoyl, thiol, =O, =S, sulfamoyl, acetyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N- ethylamino, trimethylammonium, acetylamino, trifluoroacetylamino, N-methylacetylamino, N- methyltrifluoroacetylamino, (methylsulfonyl)amino, N-methyl(methylsulfonyl)amino, N- methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl- N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, trimethylsilyl (TMS), benzyl, and benzoyl. In some examples, the R groups are independently selected from halogen, cyano, hydroxyl, =O, =S, alkyl (such as methyl, ethyl, isopropyl, tert-butyl), haloalkyl (such as trifluoromethyl), alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl (such as benzyl), halo(arylalkyl), alkylaryl, halo(alkylaryl), alkyloxy (such as methoxy, ethoxy), haloalkyloxy (such as trifluoromethoxy), carbocyclyloxy, halocarbocyclyloxy, heterocyclyloxy, haloheterocyclyloxy, aryloxy, haloaryloxy, heteroaryloxy, haloheteroaryloxy, primary amino, alkylamino, and haloalkylamino. In some examples, the R groups are selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy. As used herein, “alkyloxy” refers to a hydroxyl group substituted by an alkyl group at the oxygen atom. Exemplary alkyloxy groups include, but are not limited to, methoxy, ethoxy, n- propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. As used herein, “haloalkyloxy” refers to a hydroxyl group substituted by a haloalkyl group at the oxygen atom. An example of haloalkyloxy is trifluoromethoxy. As used herein, “aryloxy” refers to a hydroxyl group substituted by an aryl group at the oxygen atom. As used herein, “alkylcarbonyl” refers to an alkyl group attached through a carbonyl bridge (–C(=O)–). As used herein, “arylcarbonyl” refers to an aryl group attached through a carbonyl bridge. As used herein, “alkylcarbonyloxy” refers to a hydroxyl group substituted by an alkylcarbonyl group at the oxygen atom of the hydroxyl group. As used herein, “arylcarbonyloxy” refers to a hydroxyl group substituted by an arylcarbonyl group at the oxygen atom of the hydroxyl group. As used herein, “alkyloxycarbonyl” refers to an alkyloxy group attached through a carbonyl bridge. As used herein, “aryloxycarbonyl” refers to an aryloxy group attached through a carbonyl bridge. As used herein, “alkylamino” refers to a primary amino group substituted by one or two alkyl groups. When the primary amino group is substituted by two alkyl groups, the two alkyl groups can be the same or different. An example of alkylamino is methylamino (i.e., –NH–CH3). As used herein, “alkylammonium” refers to a primary ammonium group substituted by one, two, or three alkyl groups. When the primary ammonium group is substituted by two or three alkyl groups, the two or three alkyl groups can be the same or different. An example of alkylammonium is trimethylammonium (i.e., –N(CH3)3+). As used herein, “alkylcarbonylamino” refers to a primary amino group substituted by one alkylcarbonyl group. As used herein, “arylcarbonylamino” refers to a primary amino group substituted by one arylcarbonyl group. As used herein, “N-alkylcarbamoyl” refers to a carbamoyl group (–C(=O)–NH2) substituted by one or two alkyl groups at the nitrogen atom. When the carbamoyl group is substituted by two alkyl groups, the two alkyl groups can be the same or different. As used herein, “alkylthio” refers to a thiol group substituted by an alkyl group at the sulfur atom. An example of alkylthio is methylthio (i.e., –S–CH3). As used herein, “alkylsulfinyl” refers to an alkyl group attached through a sulfinyl bridge (–S(=O)–). As used herein, “alkylsulfonyl” refers to an alkyl group attached through a sulfonyl bridge (–S(=O)2–). As used herein, “N-alkylsulfamoyl” refers to a sulfamoyl group (–S(=O)2–NH2) substituted by one or two alkyl groups at the nitrogen atom. When the sulfamoyl group is substituted by two alkyl groups, the two alkyl groups can be the same or different. A. General structure The compounds have a structure of Formula I or a pharmaceutically acceptable salt, hydrate, or hydrated salt of Formula I, wherein W is selected from O, S, and NR2; wherein Y is selected from O, S, and NR3; wherein Z is –C(R4R5)–; wherein Q is N or CR6; wherein T is N or CR7; wherein U1and U2are independently C or N; wherein V is selected from S, O, N, NR8, and CR9; wherein X is C or N; wherein G1, G2, G3, and G4are independently CH or N; wherein n is 0 or 1; wherein when n is 0, m is an integer selected from 0 to 6; wherein when n is 1, m is an integer selected from 0 to 8; wherein o is an integer selected from 1 to 5; wherein RAis selected from hydrogen, deuterium, methyl, CHF2, CH2F, CF3, CD3, CN, SF5, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (carbocyclyl)alkyl, optionally substituted (heterocyclyl)alkyl, optionally substituted (aryl)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted acyl, optionally substituted amide, and Si-substituted silyl; wherein RBand RC, in each occurrence, are independently selected from halogen, nitro, cyano, hydroxyl, formyl, carboxyl, sulfamoyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, halo(arylalkyl), alkylaryl, halo(alkylaryl), alkyloxy, haloalkyloxy, aryloxy, haloaryloxy, alkylcarbonyl, (haloalkyl)carbonyl, arylcarbonyl, (haloaryl)carbonyl, alkylcarbonyloxy, (haloalkyl)carbonyloxy, arylcarbonyloxy, (haloaryl)carbonyloxy, alkyloxycarbonyl, (haloalkyl)oxycarbonyl, aryloxycarbonyl, (haloaryl)oxycarbonyl, primary amino, alkylamino, haloalkylamino, alkylammonium, haloalkylammonium, alkylcarbonylamino, (haloalkyl)carbonylamino, arylcarbonylamino, (haloaryl)carbonylamino, carbamoyl, N-alkylcarbamoyl, N-(haloalkyl)carbamoyl, alkylthio, (haloalkyl)thio, alkylsulfinyl, (haloalkyl)sulfinyl, alkylsulfonyl, (haloalkyl)sulfonyl, N- alkylsulfamoyl, and N-(haloalkyl)sulfamoyl; wherein R2and R3are independently selected from hydrogen, hydroxyl, alkyl, haloalkyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, halo(arylalkyl), alkylaryl, halo(alkylaryl), alkyloxy, haloalkyloxy, aryloxy, and haloaryloxy; wherein R4and R5are independently selected from hydrogen, halogen, alkyl, and haloalkyl; wherein R6, R7, and R9are independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, formyl, carboxyl, sulfamoyl, alkyl, haloalkyl, hydroxylalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, hydroxylcarbocyclyl, heterocyclyl, haloheterocyclyl, hydroxylheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, halo(arylalkyl), alkylaryl, halo(alkylaryl), alkyloxy, haloalkyloxy, aryloxy, haloaryloxy, alkylcarbonyl, (haloalkyl)carbonyl, arylcarbonyl, (haloaryl)carbonyl, alkylcarbonyloxy, (haloalkyl)carbonyloxy, arylcarbonyloxy, (haloaryl)carbonyloxy, alkyloxycarbonyl, (haloalkyl)oxycarbonyl, aryloxycarbonyl, (haloaryl)oxycarbonyl, primary amino, alkylamino, haloalkylamino, alkylammonium, haloalkylammonium, alkylcarbonylamino, (haloalkyl)carbonylamino, arylcarbonylamino, (haloaryl)carbonylamino, carbamoyl, N- alkylcarbamoyl, N-(haloalkyl)carbamoyl, alkylthio, (haloalkyl)thio, alkylsulfinyl, (haloalkyl)sulfinyl, alkylsulfonyl, (haloalkyl)sulfonyl, N-alkylsulfamoyl, and N- (haloalkyl)sulfamoyl; and wherein R8is independently selected from hydrogen, alkyl, haloalkyl, hydroxylalkyl, carbocyclyl, halocarbocyclyl, hydroxylcarbocyclyl, heterocyclyl, haloheterocyclyl, hydroxylheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, halo(arylalkyl), alkylaryl, halo(alkylaryl), alkylcarbonyl, (haloalkyl)carbonyl, arylcarbonyl, (haloaryl)carbonyl, alkyloxycarbonyl, (haloalkyl)oxycarbonyl, aryloxycarbonyl, (haloaryl)oxycarbonyl, carbamoyl, N-alkylcarbamoyl, N-(haloalkyl)carbamoyl, alkylsulfinyl, (haloalkyl)sulfinyl, alkylsulfonyl, (haloalkyl)sulfonyl, N-alkylsulfamoyl, and N-(haloalkyl)sulfamoyl. It is understood that both Ring A and Ring B are aromatic. It is also understood that when RBis a substituent for any one of G1, G2, G3, and G4, the any one of G1, G2, G3, and G4is CH and the corresponding RBsubstituent replaces the hydrogen atom. In some embodiments, the compounds are in a non-salt form. In some embodiments, the compounds are in a salt form. 1. The W, Y, and Z moieties In some embodiments, W is O. In some embodiments, W is S. In some embodiments, W is NR2. In some embodiments, R2is selected from hydrogen, hydroxyl, alkyl, haloalkyl, carbocyclyl, and halocarbocyclyl. In some embodiments, R2is selected from hydrogen, hydroxyl, C1–C3alkyl, C1–C3 haloalkyl, C3–C6 carbocyclyl, and C3–C6 halocarbocyclyl. In some embodiments, R2is selected from hydrogen, hydroxyl, methyl, CHF2, CH2F, CF3, isopropyl, and cyclopropyl. In some embodiments, R2is hydrogen or hydroxyl. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is NR3. In some embodiments, R3is selected from hydrogen, hydroxyl, alkyl, haloalkyl, carbocyclyl, and halocarbocyclyl. In some embodiments, R3is selected from hydrogen, hydroxyl, C1–C3alkyl, C1–C3haloalkyl, C3–C6carbocyclyl, and C3–C6halocarbocyclyl. In some embodiments, R3is selected from hydrogen, hydroxyl, methyl, CHF2, CH2F, CF3, isopropyl, and cyclopropyl. In some embodiments, R3is hydrogen or hydroxyl. In some embodiments, W and Y are O. In some embodiments, W is O, and Y is NR3. In some embodiments, W is O, and Y is NH or N(OH). In some embodiments, Y is O, and W is NR3. In some embodiments, Y is O, and W is NH or N(OH). In some embodiments, W is NH or N(OH), and Y is NH or N(OH). In some embodiments, R4and R5are independently selected from hydrogen, halogen, cyano, C1–C3 alkyl, and C1–C3 haloalkyl. In some embodiments, R4and R5are independently selected from hydrogen, halogen, cyano, methyl, CHF2, CH2F, CF3, and isopropyl. In some embodiments, R4is H. In some embodiments, R4is H, and R5is selected from hydrogen, halogen, cyano, methyl, CHF2, CH2F, CF3, and isopropyl. In some embodiments, R5is H. In some embodiments, R5is H, and R4is selected from hydrogen, halogen, cyano, methyl, CHF2, CH2F, CF3, and isopropyl. In some embodiments, both R4and R5are hydrogen. In some embodiments, W and Y are O, and Z is –CH2–. In some embodiments, W is O, Y is NH or N(OH), and Z is –CH2–. In some embodiments, Y is O, W is NH or N(OH), and Z is – CH2–. In some embodiments, W is NH or N(OH), Y is NH or N(OH), and Z is –CH2–. 2. The bicyclic core In some embodiments, Q is N. In some embodiments, Q is CR6. In some embodiments, R6is selected from hydrogen, halogen, cyano, alkyl, and haloalkyl. In some embodiments, R6is selected from hydrogen, halogen, cyano, C1–C3alkyl, and C1–C3haloalkyl. In some embodiments, R6is selected from hydrogen, halogen, cyano, methyl, CHF2, CH2F, CF3, and isopropyl. In some embodiments, R6is H. In some embodiments, T is N. In some embodiments, T is CR7. In some embodiments, R7is selected from hydrogen, halogen, cyano, alkyl, and haloalkyl. In some embodiments, R7is selected from hydrogen, halogen, cyano, C1–C3 alkyl, and C1–C3 haloalkyl. In some embodiments, R7is selected from hydrogen, halogen, cyano, methyl, CHF2, CH2F, CF3, and isopropyl. In some embodiments, R7is H. In some embodiments, U1is C. In some embodiments, U1is N. In some embodiments, U2is C. In some embodiments, U2is N. In some embodiments, V is S. In some embodiments, V is O. In some embodiments, V is N. In some embodiments, V is NR8. In some embodiments, R8is selected from hydrogen, alkyl, haloalkyl, hydroxylalkyl, carbocyclyl, halocarbocyclyl, hydroxylcarbocyclyl, heterocyclyl, haloheterocyclyl, hydroxylheterocyclyl, aryl, haloaryl, heteroaryl, and haloheteroaryl. In some embodiments, R8is selected from hydrogen, C1–C3alkyl, C1–C3haloalkyl, C1–C3hydroxylalkyl, C3–C6 carbocyclyl, C3–C6 halocarbocyclyl, C3–C6 hydroxylcarbocyclyl, C1–C5 heterocyclyl, C1– C5 haloheterocyclyl, C1–C5 hydroxylheterocyclyl, C1–C5 heteroaryl, and C1–C5 haloheteroaryl. In some embodiments, R8is selected from hydrogen, methyl, CHF2, CH2F, CF3, ethyl, isopropyl,cyclopropyl, cyclobutyl, . In someembodiments, R8is hydrogen. In some embodiments, R8is methyl. In some embodiments, R8is CHF2, CH2F, or CF3. In some embodiments, R8is ethyl. In some embodiments, R8is isopropyl. In some embodiments, R8is cyclopropyl. In some embodiments, R8is cyclobutyl. In some embodiments, . In some embodiments, R8is . In some embodiments, R8is .In some embodiments, V i 9 s CR .In some embodiments, R9is selected from hydrogen, halogen, cyano, alkyl, haloalkyl, hydroxylalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, hydroxylcarbocyclyl, heterocyclyl, haloheterocyclyl, hydroxylheterocyclyl, aryl, haloaryl, heteroaryl, and haloheteroaryl. In some embodiments, R9is selected from hydrogen, halogen, cyano, C1–C3 alkyl, C1–C3 haloalkyl, C1–C3 hydroxylalkyl, C2–C3 alkenyl, C2–C3 haloalkenyl, C1– C3 alkynyl, C1–C3 haloalkynyl, C3–C6 carbocyclyl, C3–C6 halocarbocyclyl, C3–C6 hydroxylcarbocyclyl, C1–C5heterocyclyl, C1–C5haloheterocyclyl, C1–C5hydroxylheterocyclyl, C1–C5heteroaryl, and C1–C5haloheteroaryl. In some embodiments, R9is selected from hydrogen, halogen, cyano, methyl, CHF2, CH2F, CF3, ethyl, isopropyl, cyclopropyl, cyclobutyl, , .In some emb 9 odiments, R is hydrogen. In someembodiments, R9is halogen such as F or Cl. In some embodiments, R9is cyano. In some embodiments, R9is methyl. In some embodiments, R9is CHF2, CH2F, or CF3. In some embodiments, R9is ethyl. In some embodiments, R9is isopropyl. In some embodiments, R9is cyclopropyl. In some embodiments, R9is cyclobutyl. In some embodiments, R9is . In some embodiments, R9is . In some embodiments, R9is . In some embodiments, R9is In some embodiments, X is C. In some embodiments, X is N. In some embodiments, the moiety is selected from: In some embodiments, the moiety is selected from: . In some embodiments, the moiety is selected from: In some embodiments, R6and R7in the structures above are selected from hydrogen, halogen, cyano, alkyl, and haloalkyl. In some embodiments, R6and R7in the structures above are selected from hydrogen, halogen, cyano, C1–C3 alkyl, and C1–C3 haloalkyl. In some embodiments, R6and R7in the structures above are selected from hydrogen, halogen, cyano, methyl, CHF2, CH2F, CF3, and isopropyl. In some embodiments, R6and R7in the structures above are H. In some embodiments, R8in the structures above is selected from hydrogen, alkyl, haloalkyl, hydroxylalkyl, carbocyclyl, halocarbocyclyl, hydroxylcarbocyclyl, heterocyclyl, haloheterocyclyl, hydroxylheterocyclyl, aryl, haloaryl, heteroaryl, and haloheteroaryl. In some embodiments, R8in the structures above is selected from hydrogen, C1–C3 alkyl, C1–C3 haloalkyl, C1–C3 hydroxylalkyl, C3–C6 carbocyclyl, C3–C6 halocarbocyclyl, C3–C6 hydroxylcarbocyclyl, C1– C5heterocyclyl, C1–C5haloheterocyclyl, C1–C5hydroxylheterocyclyl, C1–C5heteroaryl, and C1– C5 haloheteroaryl. In some embodiments, R8in the structures above is selected from hydrogen, methyl, CHF2, CH2F, CF3, ethyl, isopropyl, cyclopropyl, cyclobutyl, , , , some embodiments, R8in the structures above is methyl. In some embodiments, R8in the structures above is CHF2, CH2F, or CF3. In some embodiments, R8in the structures above is ethyl. In some embodiments, R8in the structures above is isopropyl. In some embodiments, R8in the structures above is cyclopropyl. In some embodiments, R8in the structures above is cyclobutyl. In some embodiments, R8in the structures above is . In some embodiments, R8in the structures above is . In some embodiments, R8in the structures above is . In someembodiments, R8 in the structures above is .In some embodiments, R9in the structures above is selected from hydrogen, halogen, cyano, alkyl, haloalkyl, hydroxylalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, hydroxylcarbocyclyl, heterocyclyl, haloheterocyclyl, hydroxylheterocyclyl, aryl, haloaryl, heteroaryl, and haloheteroaryl. In some embodiments, R9in the structures above is selected from hydrogen, halogen, cyano, C1–C3 alkyl, C1–C3 haloalkyl, C1–C3 hydroxylalkyl, C2– C3alkenyl, C2–C3haloalkenyl, C1–C3alkynyl, C1–C3haloalkynyl, C3–C6carbocyclyl, C3–C6halocarbocyclyl, C3–C6 hydroxylcarbocyclyl, C1–C5 heterocyclyl, C1–C5 haloheterocyclyl, C1–C5 hydroxylheterocyclyl, C1–C5 heteroaryl, and C1–C5 haloheteroaryl. In some embodiments, R9in the structures above is selected from hydrogen, halogen, cyano, methyl, HF H F F h l,isopropyl, cyclopropyl, cyclobutyl, , some embodiments, R9in the structures above is hydrogen. In some embodiments, R9in the structures above is halogen such as F or Cl. In some embodiments, R9in the structures above is cyano. In some embodiments, R9in the structures above is methyl. In some embodiments, R9in the structures above is CHF2, CH2F, or CF3. In some embodiments, R9in the structures above is ethyl. In some embodiments, R9in the structures above is isopropyl. In some embodiments, R9in the structures above is cyclopropyl. In some embodiments, R9in the structures above is cyclobutyl. In some embodiments, R9in the structures above is . In some embodiments, R9in the structures above in the structures above is . In some embodiments, R9in the structures above in the structures above is . In some embodiments, R9in the structures above is moiety . In some embodiments, the moiety . In some em8 bodiments, R is selected from hydrogen, methyl, CHF2, CH2F, CF3, ethyl, isopropyl, cyclopropyl, cyclobutyl, .In some embodiments, R8is methyl. In some embodiments, R8is CHF2, CH2F, or CF3. In some embodiments, R8is ethyl. In some embodiments, R8is isopropyl. In some embodiments, R8is cyclopropyl. In some embodiments, R8is cyclobutyl. In some embodiments, R8is . In some embodiments, R8is . In some embodiments, R8is8 . In some embodiments, Rs some embodiments, R9is selected from hydrogen, halogen, cyano, methyl, CHF2, CH2F, CF3, ethyl,i some embodiments, R9is hydrogen. In some embodiments, R9is halogen such as F or Cl. In some embodiments, R9is cyano. In some embodiments, R9is methyl. In some embodiments, R9is CHF2, CH2F, or CF3. In some embodiments, R9is ethyl. In some embodiments, R9is isopropyl. In some embodiments, R9is cyclopropyl. In some embodiments, R9is cyclobutyl. In some embodiments, . In some embodiments, R9is . In some s s embodiments, the moiety some embodiments, the

[0011] s s 3. Ring B In some embodiments, G1is CH. In some embodiments, G1is N. In some embodiments, G2is CH. In some embodiments, G2is N. In some embodiments, G3is CH. In some embodiments, G3is N. In some embodiments, G4is CH. In some embodiments, G4is N. In some embodiments, G1and G3are CH. In some embodiments, G1and G2are CH. In some embodiments, G2and G3are CH. In some embodiments, G2and G4are CH. In some embodiments, G1, G2, and G3are CH. In some embodiments, G1, G2, and G4are CH. In some embodiments, G2and G4are N. In some embodiments, G3and G4are N. In some embodiments, G1and G4are N. In some embodiments, G1and G3are N. In some embodiments, G1, G3, and G4are N. In some embodiments, G2, G3, and G4are N. In some embodiments, G1, G2, G3, and G4are CH. In some embodiments, G1, G2, and G3are CH, and G4is N. In some embodiments, G1, G2, and G4are CH, and G3is N. In some embodiments, G1and G3are CH, and G2and G4are N. In some embodiments, G1and G2are CH, and G3and G4are N. In some embodiments, G2and G3are CH, and G1and G4are N. In some embodiments, G2and G4are CH, and G1and G3are N. In some embodiments, G1, G3, and G4are N, and G2is CH. In some embodiments, G2, G3, and G4are N, and G1is CH. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, RB, in each occurrence, is independently selected from halogen, cyano, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, hydroxyl, alkyloxy, haloalkyloxy, primary amino, alkylamino, haloalkylamino, carbocyclyl, and halocarbocyclyl. In some embodiments, RB, in each occurrence, is independently selected from halogen, cyano, C1– C3 alkyl, C1–C3 haloalkyl, C2–C4 alkenyl, C2–C4 haloalkenyl, C2–C4 alkynyl, C2–C4 haloalkynyl, hydroxyl, C1–C3 alkyloxy, C1–C3 haloalkyloxy, primary amino, C1–C3 alkylamino, C1–C3 haloalkylamino, C3–C6carbocyclyl, and C3–C6halocarbocyclyl. In some embodiments, RB, in each occurrence, is independently selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy. In some embodiments, RB, in each occurrence, is independently halogen, such as F, Cl, and Br. In some embodiments, the carbon at the para position of Ring B is not substituted by RB. In some embodiments, the carbon at the para position of Ring B is substituted by RB. In some embodiments, the carbon at the para position of Ring B is substituted by halogen, cyano, C1–C3alkyl, C1–C3 haloalkyl, C2–C4 alkenyl, C2–C4 haloalkenyl, C2–C4 alkynyl, C2–C4 haloalkynyl, hydroxyl, C1–C3alkyloxy, C1–C3haloalkyloxy, primary amino, C1–C3alkylamino, C1–C3haloalkylamino, C3–C6carbocyclyl, and C3–C6halocarbocyclyl. In some embodiments, the carbon at the para position of Ring B is substituted by halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy. In some embodiments, the carbon at the para position of Ring B is substituted by halogen. In some embodiments, the carbon at the para position of Ring B is substituted by Cl or Br. In some embodiments, the carbon at the para position of Ring B is substituted by Cl. In some embodiments, the carbon at the para position of Ring B is substituted by Br. In some embodiments, the carbon at the para position of Ring B is substituted by F. In some embodiments, when G1is CH, its carbon is not substituted by RB. In some embodiments, when G1is CH, its carbon is substituted by RB. In some embodiments, when G1is CH, its carbon is substituted by halogen, cyano, C1–C3alkyl, C1–C3haloalkyl, C2–C4alkenyl, C2– C4 haloalkenyl, C2–C4 alkynyl, C2–C4 haloalkynyl, hydroxyl, C1–C3 alkyloxy, C1–C3 haloalkyloxy, primary amino, C1–C3 alkylamino, C1–C3 haloalkylamino, C3–C6 carbocyclyl, or C3–C6 halocarbocyclyl. In some embodiments, when G1is CH, its carbon is substituted by halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), or isopropyloxy. In some embodiments, when G1is CH, its carbon is substituted by halogen. In some embodiments, when G1is CH, its carbon is substituted by Cl or Br. In some embodiments, when G1is CH, its carbon is substituted by Cl. In some embodiments, when G1is CH, its carbon is substituted by Br. In some embodiments, when G1is CH, its carbon is substituted by F. In some embodiments, when G2is CH, its carbon is not substituted by RB. In some embodiments, when G2is CH, its carbon is substituted by RB. In some embodiments, when G2is CH, its carbon is substituted by halogen, cyano, C1–C3 alkyl, C1–C3 haloalkyl, C2–C4 alkenyl, C2– C4haloalkenyl, C2–C4alkynyl, C2–C4haloalkynyl, hydroxyl, C1–C3alkyloxy, C1–C3haloalkyloxy, primary amino, C1–C3alkylamino, C1–C3haloalkylamino, C3–C6carbocyclyl, or C3–C6halocarbocyclyl. In some embodiments, when G2is CH, its carbon is substituted by halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), or isopropyloxy. In some embodiments, when G2is CH, its carbon is substituted by halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, or ethynyl. In some embodiments, when G2is CH, its carbon is substituted by halogen. In some embodiments, when G2is CH, its carbon is substituted by Cl or Br. In some embodiments, when G2is CH, its carbon is substituted by Cl. In some embodiments, when G2is CH, its carbon is substituted by Br. In some embodiments, when G2is CH, its carbon is substituted by F. In some embodiments, when G2is CH, its carbon is substituted by cyano. In some embodiments, when G2is CH, its carbon is substituted by methyl, CHF2, CH2F, or CF3. In some embodiments, when G2is CH, its carbon is substituted by isopropyl or cyclopropyl. In some embodiments, when G2is CH, its carbon is substituted by ethynyl. In some embodiments, when G2is CH, its carbon is substituted by methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), or isopropyloxy. In some embodiments, when G3is CH, its carbon is not substituted by RB. In some embodiments, when G3is CH, its carbon is substituted by RB. In some embodiments, when G3is CH, its carbon is substituted by halogen, cyano, C1–C3alkyl, C1–C3haloalkyl, C2–C4alkenyl, C2– C4 haloalkenyl, C2–C4 alkynyl, C2–C4 haloalkynyl, hydroxyl, C1–C3 alkyloxy, C1–C3 haloalkyloxy, primary amino, C1–C3 alkylamino, C1–C3 haloalkylamino, C3–C6 carbocyclyl, or C3–C6 halocarbocyclyl. In some embodiments, when G3is CH, its carbon is substituted by halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), or isopropyloxy. In some embodiments, when G3is CH, its carbon is substituted by halogen. In some embodiments, when G3is CH, its carbon is substituted by Cl or Br. In some embodiments, when G3is CH, its carbon is substituted by Cl. In some embodiments, when G3is CH, its carbon is substituted by Br. In some embodiments, when G3is CH, its carbon is substituted by F. In some embodiments, when G4is CH, its carbon is not substituted by RB. In some embodiments, when G4is CH, its carbon is substituted by RB. In some embodiments, when G4is CH, its carbon is substituted by halogen, cyano, C1–C3 alkyl, C1–C3 haloalkyl, C2–C4 alkenyl, C2– C4haloalkenyl, C2–C4alkynyl, C2–C4haloalkynyl, hydroxyl, C1–C3alkyloxy, C1–C3haloalkyloxy, primary amino, C1–C3alkylamino, C1–C3haloalkylamino, C3–C6carbocyclyl, or C3–C6halocarbocyclyl. In some embodiments, when G4is CH, its carbon is substituted by halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), or isopropyloxy. In some embodiments, when G4is CH, its carbon is substituted by halogen. In some embodiments, when G4is CH, its carbon is substituted by Cl or Br. In some embodiments, when G4is CH, its carbon is substituted by Cl. In some embodiments, when G4is CH, its carbon is substituted by Br. In some embodiments, when G4is CH, its carbon is substituted by F. In some embodiments, the moiety i , wherein p is an integer selected from 0 to 3. In some embodiments, G1, G3, and G4are CH. In some embodiments, G1is N, G3is CH, and G4is CH. In some embodiments, G1is CH, G3is N, and G4is CH. In some embodiments, G1 is CH, G3is CH, and G4is N. In some embodiments, G1is N, G3is N, and G4is CH. In some embodiments, G1is CH, G3is N, and G4is N. In some embodiments, G1is N, G3is CH, and G4is N. In some embodiments, G1, G3, and G4are N. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, when G1is CH, its carbon is not substituted by RB. In some embodiments, when G1is CH, its carbon is substituted by RB. In some embodiments, when G1is CH, its carbon is substituted by halogen, cyano, C1–C3alkyl, C1–C3haloalkyl, C2–C4alkenyl, C2– C4 haloalkenyl, C2–C4 alkynyl, C2–C4 haloalkynyl, hydroxyl, C1–C3 alkyloxy, C1–C3 haloalkyloxy, primary amino, C1–C3alkylamino, C1–C3haloalkylamino, C3–C6carbocyclyl, or C3–C6halocarbocyclyl. In some embodiments, when G1is CH, its carbon is substituted by halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), or isopropyloxy. In some embodiments, when G1is CH, its carbon is substituted by halogen. In some embodiments, when G1is CH, its carbon is substituted by Cl or Br. In some embodiments, when G1is CH, its carbon is substituted by Cl. In some embodiments, when G1is CH, its carbon is substituted by Br. In some embodiments, when G1is CH, its carbon is substituted by F. In some embodiments, when G3is CH, its carbon is not substituted by RB. In some embodiments, when G3is CH, its carbon is substituted by RB. In some embodiments, when G3is CH, its carbon is substituted by halogen, cyano, C1–C3alkyl, C1–C3haloalkyl, C2–C4alkenyl, C2– C4haloalkenyl, C2–C4alkynyl, C2–C4haloalkynyl, hydroxyl, C1–C3alkyloxy, C1–C3haloalkyloxy, primary amino, C1–C3 alkylamino, C1–C3 haloalkylamino, C3–C6 carbocyclyl, or C3–C6 halocarbocyclyl. In some embodiments, when G3is CH, its carbon is substituted by halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), or isopropyloxy. In some embodiments, when G3is CH, its carbon is substituted by halogen. In some embodiments, when G3is CH, its carbon is substituted by Cl or Br. In some embodiments, when G3is CH, its carbon is substituted by Cl. In some embodiments, when G3is CH, its carbon is substituted by Br. In some embodiments, when G3is CH, its carbon is substituted by F. In some embodiments, when G4is CH, its carbon is not substituted by RB. In some embodiments, when G4is CH, its carbon is substituted by RB. In some embodiments, when G4is CH, its carbon is substituted by halogen, cyano, C1–C3 alkyl, C1–C3 haloalkyl, C2–C4 alkenyl, C2– C4 haloalkenyl, C2–C4 alkynyl, C2–C4 haloalkynyl, hydroxyl, C1–C3 alkyloxy, C1–C3 haloalkyloxy, primary amino, C1–C3 alkylamino, C1–C3 haloalkylamino, C3–C6 carbocyclyl, or C3–C6 halocarbocyclyl. In some embodiments, when G4is CH, its carbon is substituted by halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), or isopropyloxy. In some embodiments, when G4is CH, its carbon is substituted by halogen. In some embodiments, when G4is CH, its carbon is substituted by Cl or Br. In some embodiments, when G4is CH, its carbon is substituted by Cl. In some embodiments, when G4is CH, its carbon is substituted by Br. In some embodiments, when G4is CH, its carbon is substituted by F. In some embodiments, the RBsubstituent at the para position of Ring B is selected from halogen, cyano, C1–C3 alkyl, C1–C3 haloalkyl, C2–C4 alkenyl, C2–C4 haloalkenyl, C2–C4 alkynyl, C2–C4 haloalkynyl, hydroxyl, C1–C3 alkyloxy, C1–C3 haloalkyloxy, primary amino, C1–C3 alkylamino, C1–C3haloalkylamino, C3–C6carbocyclyl, and C3–C6halocarbocyclyl. In some embodiments, the RBsubstituent at the para position of Ring B is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy. In some embodiments, the RBsubstituent at the para position of Ring B is halogen. In some embodiments, the RBsubstituent at the para position of Ring B is Cl or Br. In some embodiments, the RBsubstituent at the para position of Ring B is Cl. In some embodiments, the RBsubstituent at the para position of Ring B is Br. In some embodiments, the RBsubstituent at the para position of Ring B is F. In some embodiments, the RBsubstituent at the G2position is selected from halogen, cyano, C1–C3alkyl, C1–C3haloalkyl, C2–C4alkenyl, C2–C4haloalkenyl, C2–C4alkynyl, C2–C4haloalkynyl, hydroxyl, C1–C3alkyloxy, C1–C3haloalkyloxy, primary amino, C1–C3alkylamino, C1–C3 haloalkylamino, C3–C6 carbocyclyl, and C3–C6 halocarbocyclyl. In some embodiments, the RBsubstituent at the G2position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy. In some embodiments, the RBsubstituent at the G2position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, and ethynyl. In some embodiments, the RBsubstituent at the G2position is halogen. In some embodiments, the RBsubstituent at the G2position is Cl or Br. In some embodiments, the RBsubstituent at the G2position is Cl. In some embodiments, the RBsubstituent at the G2position is Br. In some embodiments, the RBsubstituent at the G2position is F. In some embodiments, the RBsubstituent at the G2position is cyano. In some embodiments, the RBsubstituent at the G2position is methyl, CHF2, CH2F, or CF3. In some embodiments, the RBsubstituent at the G2position is isopropyl or cyclopropyl. In some embodiments, the RBsubstituent at the G2position is ethynyl. In some embodiments, the RBsubstituent at the G2position is methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), or isopropyloxy. In some embodiments, the RBsubstituent at the para position of Ring B is halogen, and the RBsubstituent at the G2position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy. In some embodiments, the RBsubstituent at the para position of Ring B is F, and the RBsubstituent at the G2position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy. In some embodiments, the RBsubstituent at the para position of Ring B is halogen, and the RBsubstituent at the G2position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, and ethynyl. In some embodiments, the RBsubstituent at the para position of Ring B is F, and the RBsubstituent at the G2position is Cl. In some embodiments, the RBsubstituent at the para position of Ring B is F, and the RBsubstituent at the G2position is Br. In some embodiments, the RBsubstituent at the para position of Ring B is F, and the RBsubstituent at the G2position is cyano. In some embodiments, the moiety is selected from , e embodiments, the moiety some embodiments, the . In some embodiments, the RBsubstituent at the para position of Ring B is selected from halogen, cyano, C1–C3alkyl, C1–C3haloalkyl, C2–C4alkenyl, C2–C4haloalkenyl, C2–C4alkynyl, C2–C4 haloalkynyl, hydroxyl, C1–C3 alkyloxy, C1–C3 haloalkyloxy, primary amino, C1–C3 alkylamino, C1–C3 haloalkylamino, C3–C6 carbocyclyl, and C3–C6 halocarbocyclyl. In some embodiments, the RBsubstituent at the para position of Ring B is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy. In some embodiments, the RBsubstituent at the para position of Ring B is halogen. In some embodiments, the RBsubstituent at the para position of Ring B is Cl or Br. In some embodiments, the RBsubstituent at the para position of Ring B is Cl. In some embodiments, the RBsubstituent at the para position of Ring B is Br. In some embodiments, the RBsubstituent at the para position of Ring B is F. In some embodiments, the RBsubstituent at the G2position is selected from halogen, cyano, C1–C3 alkyl, C1–C3 haloalkyl, C2–C4 alkenyl, C2–C4 haloalkenyl, C2–C4 alkynyl, C2–C4 haloalkynyl, hydroxyl, C1–C3 alkyloxy, C1–C3 haloalkyloxy, primary amino, C1–C3 alkylamino, C1–C3haloalkylamino, C3–C6carbocyclyl, and C3–C6halocarbocyclyl. In some embodiments, the RBsubstituent at the G2position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy. In some embodiments, the RBsubstituent at the G2position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, and ethynyl. In some embodiments, the RBsubstituent at the G2position is substituted by halogen. In some embodiments, the RBsubstituent at the G2position is Cl or Br. In some embodiments, the RBsubstituent at the G2position is Cl. In some embodiments, the RBsubstituent at the G2position is Br. In some embodiments, the RBsubstituent at the G2position is substituted by F. In some embodiments, the RBsubstituent at the G2position is cyano. In some embodiments, the RBsubstituent at the G2position is methyl, CHF2, CH2F, or CF3. In some embodiments, the RBsubstituent at the G2position is isopropyl or cyclopropyl. In some embodiments, the RBsubstituent at the G2position is ethynyl. In some embodiments, the RBsubstituent at the G2position is methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), or isopropyloxy. In some embodiments, the RBsubstituent at the para position of Ring B is halogen, and the RBsubstituent at the G2position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy. In some embodiments, the RBsubstituent at the para position of Ring B is F, and the RBsubstituent at the G2position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy. In some embodiments, the RBsubstituent at the para position of Ring B is halogen, and the RBsubstituent at the G2position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, and ethynyl. In some embodiments, the RBsubstituent at the para position of Ring B is F, and the RBsubstituent at the G2position is Cl. In some embodiments, the RBsubstituent at the para position of Ring B is F, and the RBsubstituent at the G2position is Br. In some embodiments, the RBsubstituent at the para position of Ring B is F, and the RBsubstituent at the G2position is cyano. , . In some embodiments, the moiety is, se moiety is selected from

[0012] 4. Nitrogen-containing heterocyclic moiety Azetidine (n is 0) When n is 0, the nitrogen-containing heterocyclic moiety in Formula I is an azetidine moiety. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, RC, in each occurrence, is independently selected from halogen, cyano, alkyl, and haloalkyl. In some embodiments, RC, in each occurrence, is independently selected from halogen, cyano, C1–C3 alkyl, and C1–C3 haloalkyl. In some embodiments, RC, in each occurrence, is independently selected from halogen, cyano, methyl, CHF2, CH2F, CF3, ethyl, isopropyl, and cyclopropyl. In some embodiments, the moiety some embodiments, one RCis halogen such as F, and the other RCis selected from halogen, cyano, alkyl, and haloalkyl. In some embodiments, one RCis halogen such as F, and the other RCis selected from halogen, cyano, C1–C3 alkyl, and C1–C3 haloalkyl. In some embodiments, one RCis halogen such as F, and the other RCis selected from halogen, cyano, methyl, CHF2, CH2F, CF3, ethyl, isopropyl, and cyclopropyl. In some embodiments, one RCis halogen such as F, and the other RCis alkyl or haloalkyl. In some embodiments, one RCis halogen, and the other RCis C1–C3 alkyl or C1–C3 haloalkyl. In some embodiments, one RCis F, and the other RCis selected from methyl, CHF2, CH2F, CF3, ethyl, isopropyl, and cyclopropyl. In some embodiments, the . Pyrrolidine (n is 1) When n is 1, the nitrogen-containing heterocyclic moiety in Formula I is an pyrrolidine moiety. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, RC, in each occurrence, is independently selected from halogen, cyano, alkyl, and haloalkyl. In some embodiments, RC, in each occurrence, is independently selected from halogen, cyano, C1–C3alkyl, and C1–C3haloalkyl. In some embodiments, RC, in each occurrence, is independently selected from halogen, cyano, methyl, CHF2, CH2F, CF3, ethyl, isopropyl, and cyclopropyl. In some embodiments, theC some embodiments, one R is halogen such as F, and the other RCis selected from halogen, cyano, alkyl, and haloalkyl. In some embodiments, one RCis halogen such as F, and the other RCis selected from halogen, cyano, C1–C3 alkyl, and C1–C3 haloalkyl. In some embodiments, one RCis halogen such as F, and the other RCis selected from halogen, cyano, methyl, CHF2, CH2F, CF3, ethyl, isopropyl, and cyclopropyl. In some embodiments, one RCis halogen such as F, and the other RCis alkyl or haloalkyl. In some embodiments, one RCis halogen, and the other RCis C1–C3 alkyl or C1–C3 haloalkyl. In some embodiments, one RCis F, and the other RCis selected from methyl, CHF2, CH2F, CF3, ethyl, isopropyl, and cyclopropyl. In some embodiments, one RCis F, and the other RCis methyl. In some embodiments, one RCis F, and the other RCis F. In some embodiments, the moiety is . In some embodiments, one RCis halogen such as F, and the other RCis selected from halogen, cyano, alkyl, and haloalkyl. In some embodiments, one RCis halogen such as F, and the other RCis selected from halogen, cyano, C1–C3 alkyl, and C1–C3 haloalkyl. In some embodiments, one RCis halogen such as F, and the other RCis selected from halogen, cyano, methyl, CHF2, CH2F, CF3, ethyl, isopropyl, and cyclopropyl. In some embodiments, one RCis halogen such as F, and the other RCis alkyl or haloalkyl. In some embodiments, one RCis halogen, and the other RCis C1–C3 alkyl or C1–C3 haloalkyl. In some embodiments, one RCis F, and the other RCis selected from methyl, CHF2, CH2F, CF3, ethyl, isopropyl, and cyclopropyl. In some embodiments, one RCis F, and the other RCis methyl. In some embodiments, one RCis F, and the other RCis F. 5. The RAgroup RAis selected from hydrogen, deuterium, methyl, CHF2, CH2F, CF3, CD3, CN, SF5, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (carbocyclyl)alkyl, optionally substituted (heterocyclyl)alkyl, optionally substituted (aryl)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted acyl, optionally substituted amide, and Si-substituted silyl. In some embodiments, RAis selected from methyl, CHF2, CH2F, CF3, CD3, CN, SF5, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (carbocyclyl)alkyl, optionally substituted (heterocyclyl)alkyl, optionally substituted (aryl)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted acyl, optionally substituted amide, and Si-substituted silyl. The optionally substituted groups, in each occurrence, may have one or more substituents in the form of the R groups described above. In some examples, the R groups are independently selected from halogen, nitro, cyano, hydroxyl, formyl, carboxyl, thiol, =O (counting as two R groups), =S (counting as two R groups), sulfamoyl, alkyl (such as methyl, ethyl, isopropyl, tert-butyl), haloalkyl (such as trifluoromethyl), alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl (such as benzyl), halo(arylalkyl), alkylaryl, halo(alkylaryl), alkyloxy (such as methoxy, ethoxy), haloalkyloxy (such as trifluoromethoxy), carbocyclyloxy, halocarbocyclyloxy, heterocyclyloxy, haloheterocyclyloxy, aryloxy, haloaryloxy, heteroaryloxy, haloheteroaryloxy, alkylcarbonyl (such as acetyl), (haloalkyl)carbonyl, arylcarbonyl (such as benzoyl), (haloaryl)carbonyl, alkylcarbonyloxy (such as acetoxy), (haloalkyl)carbonyloxy, arylcarbonyloxy (such as benzoyloxy), (haloaryl)carbonyloxy, alkyloxycarbonyl (such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl), (haloalkyl)oxycarbonyl, aryloxycarbonyl, (haloaryl)oxycarbonyl, primary amino, alkylamino (such as methylamino, ethylamino, dimethylamino, diethylamino, N-methyl- N-ethylamino), haloalkylamino, alkylammonium (such as trimethylammonium), haloalkylammonium, alkylcarbonylamino (such as acetylamino), N-alkyl(alkylcarbonyl)amino, haloalkylcarbonylamino, N-alkyl(haloalkylcarbonyl)amino, arylcarbonylamino (such as benzoylamino), N-alkyl(arylcarbonyl)amino, haloarylcarbonylamino, N- alkyl(haloarylcarbonyl)amino, alkylsulfonylamino, N-alkyl(alkylsulfonyl)amino, haloalkylsulfonylamino, N-alkyl(haloalkylsulfonyl)amino, carbamoyl, N-alkylcarbamoyl (such as N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl), N-(haloalkyl)carbamoyl, alkylthio (such as methylthio, ethylthio), (haloalkyl)thio, alkylsulfinyl (such as methylsulfinyl, ethylsulfinyl), (haloalkyl)sulfinyl, alkylsulfonyl (such as mesyl, ethylsulfonyl), (haloalkyl)sulfonyl, N-alkylsulfamoyl (such as N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl), N-(haloalkyl)sulfamoyl, alkylsilyl (such as trimethylsilyl), and haloalkylsilyl. In some examples, the R groups are independently selected from halogen, nitro, cyano, hydroxyl, methyl, CHF2, CH2F, CF3, ethyl, isopropyl, cyclopropyl, ethynyl, methoxy, trifluoromethoxy, ethoxy, –O(CH2CF3), isopropyloxy, tetrahydropyranoxy, primary amino, formyl, carboxyl, carbamoyl, thiol, =O, =S, sulfamoyl, acetyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N- ethylamino, trimethylammonium, acetylamino, trifluoroacetylamino, N-methylacetylamino, N- methyltrifluoroacetylamino, (methylsulfonyl)amino, N-methyl(methylsulfonyl)amino, N- methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl- N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, trimethylsilyl (TMS), benzyl, and benzoyl. In some examples, the R groups are independently selected from halogen, cyano, hydroxyl, =O, =S, alkyl (such as methyl, ethyl, isopropyl, tert-butyl), haloalkyl (such as trifluoromethyl), alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl (such as benzyl), halo(arylalkyl), alkylaryl, halo(alkylaryl), alkyloxy (such as methoxy, ethoxy), haloalkyloxy (such as trifluoromethoxy), carbocyclyloxy, halocarbocyclyloxy, heterocyclyloxy, haloheterocyclyloxy, aryloxy, haloaryloxy, heteroaryloxy, haloheteroaryloxy, primary amino, alkylamino, and haloalkylamino. In some examples, the R groups are selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy. In some examples, two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle, halocarbocycle, heterocycle, or haloheterocycle. In some embodiments, RAis selected from hydrogen, deuterium, methyl, CD3, CHF2, CH2F, CF3, CN, and SF5. In some embodiments, RAis selected from methyl, CD3, CHF2, CH2F, CF3, CN, and SF5. In some embodiments, RAis selected from methyl, CD3, CHF2, CH2F, and CF3. In some embodiments, RAis H. In some embodiments, RAis deuterium. In some embodiments, RAis methyl. In some embodiments, RAis CD3. In some embodiments, RAis CHF2. In some embodiments, RAis CH2F. In some embodiments, RAis CF3. In some embodiments, RAis CN. In some embodiments, RAis SF5. In some embodiments, RAis selected from optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments, RAis selected from optionally substituted alkyl, optionally substituted carbocyclyl, and optionally substituted aryl. In some embodiments, RAis selected from:

[0013] In some embodiments, . In some embodiments, In some embodiments, RAis selected from: In some embodiments, . In some embodiments, RAis selected from:

[0014] . In some embodiments, RAis optionally substituted heterocyclyl. In some embodiments, RAis selected from: In some embodiments, RAis optionally substituted heteroaryl. In some embodiments, RAis selected from:

[0015] In some embodiments, RAis selected from:

[0016] In some embodiments, RAis selected from optionally substituted (carbocyclyl)alkyl, optionally substituted (heterocyclyl)alkyl, optionally substituted (aryl)alkyl, and optionally substituted (heteroaryl)alkyl. In some embodiments, RAis selected from optionally substituted (carbocyclyl)propyl, optionally substituted (heterocyclyl)propyl, optionally substituted (aryl)propyl, and optionally substituted (heteroaryl)propyl. In some embodiments, RAis selected from optionally substituted (carbocyclyl)ethyl, optionally substituted (heterocyclyl)ethyl, optionally substituted (aryl)ethyl, and optionally substituted (heteroaryl)ethyl. In some embodiments, RAis selected from optionally substituted (carbocyclyl)methyl, optionally substituted (heterocyclyl)methyl, optionally substituted (aryl)methyl, and optionally substituted (heteroaryl)methyl. In some embodiments, RAis optionally substituted (carbocyclyl)propyl or optionally substituted (aryl)propyl. In some embodiments, RAis optionally substituted (carbocyclyl)ethyl or optionally substituted (aryl)ethyl. In some embodiments, RAis optionally substituted (carbocyclyl)methyl or optionally substituted (aryl)methyl. In some embodiments, RAis selected from: . . In some embodiments, RAis selected from:

[0017] . In some embodiments, RAis optionally substituted (heterocyclyl)propyl. In some embodiments, RAis optionally substituted (heterocyclyl)ethyl. In some embodiments, RAis optionally substituted (heterocyclyl)methyl. In some embodiments, RAis selected from:

[0018] In some embodiments, RAis optionally substituted (heteroaryl)propyl. In some embodiments, RAis optionally substituted (heteroaryl)ethyl. In some embodiments, RAis optionally substituted (heteroaryl)methyl. In some embodiments, RAis selected from:

[0019] In some embodiments, RAis selected from:

[0020] In some embodiments, RAis In some embodiments, RAis . In some embodiments, some embodimentsA , R is . In some embodiments, . In some embodiments, . In some embodiments, RAis selected from:

[0021] n some embodments, s seected rom:

[0022] In some embodiments, some embodiments, some embodiments, some embodiments, RAis . In some embodiments, s In some embodiments, RAis optionally substituted acyl. In some embodiments, RAis selected from:

[0023] . In some embodiments, wherein RAis selected from: In some embodiments, RAis optionally substituted amide. In some embodiments, RAis selected from:

[0024] In some embodiments, RAis optionally Si-substituted silyl. In some embodiments, RAis selected from: In some embodiments, RAis , wherein: RA1is selected from optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and RA2and RA3are (i) independently selected from hydrogen, halogen, cyano, alkyl, haloalkyl, hydroxyl, alkyloxy, haloalkyloxy, primary amino, alkylamino, and haloalkylamino, or (ii) join with the carbon atom to which they are attached to form a 3–6 membered carbocycle, 3–6 membered halocarbocycle, 3–6 membered heterocycle, or 3–6 membered haloheterocycle. In some embodiments, RA2and RA3are independently selected from hydrogen, halogen, cyano, C1–C3 alkyl, C1–C3 haloalkyl, hydroxyl, C1–C3 alkyloxy, C1–C3 haloalkyloxy, primary amino, C1–C3alkylamino, and C1–C3haloalkylamino. In some embodiments, RA2and RA3are independently selected from hydrogen, halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, hydroxyl, methoxy, trifluoromethoxy, –NH2, – NH(CH3), and –N(CH3)2. In some embodiments, RA2and RA3are hydrogen. In some embodiments, RA2is F and RA3is hydrogen. In some embodiments, RA2is methyl and RA3is hydrogen. In some embodiments, RA2and RA3are methyl. In some embodiments, RA2and RA3join with the carbon atom to which they are attached to form a 3–6 membered carbocycle or 3–6 membered halocarbocycle. In some embodiments, RAi In some embodiments, RA1is optionally substituted carbocyclyl or optionally substituted aryl. In some embodiments, RA1is selected from: In some embodiments, RA1is selected from: . In some embodiments, RA1is selected from: . In some embodiments, RA1is optionally substituted heterocyclyl. In some embodiments, RA1is selected from: In some embodiments, RA1is selected from: In some embodiments, RA1is optionally substituted heteroaryl. In some embodiments, RA1is selected from:

[0025] In some embodiments, RA1is selected from:

[0026] In some embodiments, RA1is . In some embodiments, RA1is . In some embodiments, some embodiments, RA1isA1 . In some embodiments, R . In some embodiments, RA1 A1 is . In some embodiments, R is . In some embodiments, RA1is optionally substituted nitrogen-containing 5-membered heteroaryl. In some embodiments, , wherei1 2 3 4 5 n W, W, W, W, and W are independently and individually C, CH, N, or NH, wherein at least one of W1, W2, W3, W4, and W5 is C or CH, wherein at least one of W1, W2, W3, W4, and W5is N or NH, wherein s is 0, 1, 2, 3, or 4, wherein Ry, in each occurrence, is independently and individually halogen, nitro, cyano, hydroxyl, formyl, carboxyl, sulfamoyl, alkyl such as methyl, haloalkyl such as CF3, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, alkylaryl, alkyloxy, haloalkyloxy, aryloxy, haloaryloxy, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkyloxycarbonyl, aryloxycarbonyl, primary amino, alkylamino, alkylammonium, alkylcarbonylamino, arylcarbonylamino, carbamoyl, N-alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or N- alkylsulfamoyl. It is understood by those skill in the art that when an Rygroup is present, it replaces the hydrogen atom at the ring atom that the Rygroup connects to. In some embodiments, W1is N. In some embodiments, W1is C. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, Ry, in each occurrence, is independently and individually halogen, cyano, alkyl such as methyl, or haloalkyl such as CF3. In some embodiments, Ry, in each occurrence, is independently and individually halogen, cyano, methyl, or CF3. In some embodiments, W1is N, and s is 1. In some embodiments, W1is N, s is 1, and Ryis selected from halogen, methyl, CF3, and cyano. In some embodiments, W1is N, and s is 0. In some embodiments, at least two of W1, W2, W3, W4, and W5are independently N or NH. For example, RA1is a diazole optionally substituted by Ry. In one implementation, RA1is an unsubstituted diazole. In one implementation, RA1is a diazole mono-substituted by halogen, methyl, CF3, or cyano. In some embodiments, at least three of W1, W2, W3, W4, and W5are independently N or NH. For example, RA1is a triazole optionally substituted by Ry. In one implementation, RA1is an unsubstituted triazole. In one implementation, RA1is a triazole mono- substituted by halogen, methyl, CF3, or cyano. In some embodiments, at least four of W1, W2, W3, W4, and W5are independently N or NH. For example, RA1is a tetrazole optionally substituted by Ry. In one implementation, RA1is an unsubstituted tetrazole. In one implementation, RA1is a tetrazole mono-substituted by halogen, methyl, CF3, or cyano. In some embodiments, RA1is selected from , , . In some embodiments, RA1is . In some embodiments, RA1 some embodiments,A1 some embodiments, R is embodiments, RA1is . In some embodiments, RA1is . In some embodiments, Ry, in each occurrence, is independently and individually halogen, cyano, alkyl such as methyl, or haloalkyl such as CF3. In some embodiments, Ry, in each occurrence, is independently and individually halogen, cyano, methyl, and CF3. , ,

[0027] . In some embodiments, . In some embodiments, RA1 . In some embodiments, RA1 . In some embodiments, some embodiments, some embodiments, RA1In some embodiments, RA1. In some eA1 mbodiments, R is . In some embodiments, Ry, if present, is halogen, cyano, alkyl such as methyl, or haloalkyl such as CF3. In some embodiments, Ry, if present, is halogen, cyano, methyl, or CF3. In some embodiments, RA1 . In some embodiments, . In some embodiments, RA1 In some embodiments, some embodiments, some embodimenA1 ts, R is . In some embodiments, . In some embodiments, RAis selected from: . In some embodiments, RAis . In some embodiments, RAis . In some embodiments, some embodiments, RAis . In some embodiments, RAis . In some embodiments, RAis . In some embodiments, RAis . In some embodiments, RAis , wherein RA1is as described above for r 6. Exemplary structures In some embodiments, the compounds have a structure of Formula I or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof: Formula I wherein W is O; wherein Y is O; wherein Z is –CH2–; wherein the moiety is selected from: e as those described above. In some embodiments, R6is hydrogen. In some embodiments, R7is hydrogen. In some embodiments, R8is selected from hydrogen, methyl, CHF2, CH2F, CF3, ethyl, isopropyl,cyclopropyl, cyclobutyl, . In someembodiments, R8is hydrogen. In some embodiments, R8is methyl. In some embodiments, R8is CHF2, CH2F, or CF3. In some embodiments, R8is ethyl. In some embodiments, R8is isopropyl. In some embodiments, R8is cyclopropyl. In some embodiments, R8is cyclobutyl. In some embodiments, R8is . In some embodiments, R8is . In some embodiments, R8is .In some embod 9 iments, R isselected from hydrogen, halogen, cyano, methyl, CHF2, CH2F, CF3, ethyl, isopropyl, cyclopropyl,cyclobutyl, . In some embo 9 diments, R ishydrogen. In some embodiments, R9is halogen such as F or Cl. In some embodiments, R9is cyano. In some embodiments, R9is methyl. In some embodiments, R9is CHF2, CH2F, or CF3. In some embodiments, R9is ethyl. In some embodiments, R9is isopropyl. In some embodiments, R9is cyclopropyl. In some embodiments, R9is cyclobutyl. In some embodiments, R9is . In s9i In some embodiments, the moiety is selected from: . I embodi , In some embodiments, the RBsubstituent at the para position of Ring B is halogen, and the RBsubstituent at the G2position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy. In some embodiments, the RBsubstituent at the para position of Ring B is F, and the RBsubstituent at the G2position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy. In some embodiments, the RBsubstituent at the para position of Ring B is halogen, and the RBsubstituent at the G2position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, and ethynyl. In some embodiments, the RBsubstituent at the para position of Ring B is F, and the RBsubstituent at the G2position is Cl. In some embodiments, the RBsubstituent at the para position of Ring B is F, and the RBsubstituent at the G2position is Br. In some embodiments, the RBsubstituent at the para position of Ring B is F, and the RBsubstituent at the G2position is cyano. In some embodiments, moiety some embodiments, the s moiety i embodiments, the moiety . In some embodiments, the In some embodiments, one RCis halogen, and the other RCis alkyl or haloalkyl. In some embodiments, one RCis F, and the other RCis selecte l, isopropyl, and cyclopropyl. In some embodiments, the In some embodiments, RAis selected from methyl, CD3, CHF2, CH2F, and CF3In some embodiments, RAis methyl. In some embodiments, RAis CD3. In some embodiments, RAis CHF2. In some embodiments, RAis CH2F. In some embodiments, RAis CF3. In some embodiments, RAis . In some embodiments, RA A . In some embodiments, R In some embo RAis In some embodiments, RAis selected from: In some embodiments, some embodiments, some embodiments, some embodimeA nts, R is . In some embodiments, In some embodiments, RAis selected from: . In some embodiments, some embodiments, some embodiments, some embodiments, RAis . In some embodiments, s In some embodiments, RAis selected from:

[0028] In some embodiments, RAis . In some embodiments, RAis embodiments,A some embodiments, R is . In some embodiments, . In some embodimentsA , R is . Exemplary compounds include, but are not limited to, the following structures and their salts, hydrates, or hydrated salts thereof:

[0029] , , a embodiments, the moiety . In some embodiments, the moiety i some embodiments, the moiety . In some embodiments, the moiety . In some embodiments, the moiety i . In some embodiments, the moiety i some embodiments, the moiety i some embodiments, the moiety i some embodiments, the moiety . Exemplary compounds include, but are not limited to, the following structures and their salts, hydrates, or hydrated salts thereof:

[0030] . III. COMPOSITIONS Disclosed are compositions containing a compound disclosed herein, wherein the compound has one or more chiral centers. In some embodiments, the compound in the composition is in greater than 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess. In some embodiments, the compound in the composition is in greater than 95% enantiomeric or diastereomeric excess. The disclosed compounds may be present in a mixture of a salt form and a non-salt form. In some embodiments, more than 50%, 60%, 70%, 80%, 90%, 95%, or 98% of the compound in the mixture may be in the non-salt form, calculated as the ratio of the weight of the non-salt form to the total weight of the mixture. In some embodiments, more than 90% of the compound in the mixture may be in the non-salt form. In some embodiments, more than 50%, 60%, 70%, 80%, 90%, 95%, or 98% of the compound in the mixture may be in the salt form, calculated as the ratio of the weight of the salt form to the total weight of the mixture. In some embodiments, more than 90% of the compound in the mixture may be in the salt form. IV. FORMULATIONS Disclosed are pharmaceutical formulations containing a compound or composition described herein. Generally, the pharmaceutical formulations also contain one or more pharmaceutically acceptable excipients. The pharmaceutical formulations can be in a form chosen from tablets, capsules, caplets, pills, powders, beads, granules, particles, creams, gels, solutions (such as aqueous solutions, e.g., buffer, saline, and buffered saline), emulsions, suspensions (including nano- and micro- suspensions), nanoparticulate formulations, etc. In some embodiments, the pharmaceutical formulations are formulated for oral administration. In some embodiments, the pharmaceutical formulations are formulated for intravenous administration. In some embodiments, the pharmaceutical formulations are formulated for intramuscular administration. In some embodiments, the pharmaceutical formulations are in the form of tablets, caplets, capsules, or pills. In some embodiment, the tablets, caplets, capsules, and pills have an enteric coating to prevent the gastric acids in the stomach from dissolving or degrading the active ingredients. Exemplary enteric coatings are known in the art and described in the sections below. As used herein, “emulsion” refers to a mixture of non-miscible components homogenously blended together. In some forms, the non-miscible components include a lipophilic component and an aqueous component. For example, an emulsion may be a preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil or an oleaginous substance is the dispersed liquid and water or an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or an aqueous solution is the dispersed phase and oil or an oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. As used herein, “biocompatible” refers to materials that are neither themselves toxic to the host (e.g., a non-human animal or human), nor degrade (if the material degrades) at a rate that produces monomeric or oligomeric subunits or other byproducts at toxic concentrations in the host. As used herein, “biodegradable” refers to degradation or breakdown of a polymeric material into smaller (e.g., non-polymeric) subunits or digestion of the material into smaller subunits. As used herein, “enteric polymers” refers to polymers that become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as they pass through the gastrointestinal tract. As used herein, “nanoparticulate formulations” generally refers to formulations containing nanoparticles, which are particles having a diameter from about 1 nm to about 1000 nm, from about 10 nm to about 1000 nm, from about 100 nm to about 1000 nm, or from about 250 nm to about 1000 nm. In some embodiments, “nanoparticulate formulations” can also refer to formulations containing microparticles, which are particles having a diameter from about 1 micron to about 100 microns, from about 1 to about 50 microns, from about 1 to about 30 microns, from about 1 micron to about 10 microns. In some embodiments, the nanoparticulate formulation may contain a mixture of nanoparticles, as defined above, and microparticles, as defined above. As used herein, “surfactant” refers to any agent which preferentially absorbs to an interface between two immiscible phases, such as the interface between water (or aqueous solution) and an organic solvent (or organic solution), between water (or aqueous solution) and air, or between organic solvent (or organic solution) and air. Surfactants generally possess a hydrophilic moiety and a lipophilic moiety. As used herein, “gel” is a semisolid system containing a dispersion of the active ingredient, i.e., a compound or composition according to the present disclosure, in a liquid vehicle that is rendered semisolid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle. The liquid vehicle may include a lipophilic component, an aqueous component or both. As used herein, “hydrogel” refers to a swollen, water-containing network of finely dispersed polymer chains that are water-insoluble, where the polymer molecules are in the external or dispersion phase and water (or an aqueous solution) forms the internal or dispersed phase. The polymer chains can be chemically cross-linked (chemical gels) or physically cross-linked (physical gels). Chemical gels possess polymer chains connected through covalent bonds, whereas physical gels have polymer chains linked by non-covalent interactions, such as van der Waals interactions, ionic interactions, hydrogen bonding interactions, and hydrophobic interactions. As used herein, “beads” refers to beads made with the active ingredient (i.e., a compound or composition according to the present disclosure) and one or more pharmaceutically acceptable excipients. The beads can be produced by applying the active ingredient to an inert support, e.g., inert sugar core coated with the active ingredient. Alternatively, the beads can be produced by creating a “core” comprising both the active ingredient and at least one of the one or more pharmaceutically acceptable excipients. As used herein, “granules” refers to a product made by processing particles of the active ingredient (i.e., a compound or composition according to the present disclosure) that may or may not include one or more pharmaceutical acceptable excipients. Typically, granules do not contain an inert support and are bigger in size compared to the particles used to produce them. Although beads, granules and particles may be formulated to provide immediate release, beads and granules are usually employed to provide delayed release. As used herein, “enzymatically degradable polymers” refers to polymers that are degraded by bacterial enzymes present in the intestines and / or lower gastrointestinal tract. A. Physical forms and unit dosages Depending upon the administration route, the compounds or compositions described herein may be formulated in a variety of ways. The pharmaceutical formulations can be prepared in various forms, such as tablets, capsules, caplets, pills, granules, powders, nanoparticle formulations, solutions (such as aqueous solutions, e.g., buffer, saline, and buffered saline), suspensions (including nano- and micro-suspensions), emulsions, creams, gels, and the like. In some embodiments, the pharmaceutical formulations are in a solid dosage form suitable for simple administration of precise dosages. For example, the solid dosage form may be selected from tablets, soft or hard gelatin or non-gelatin capsules, and caplets for oral administration. In some embodiments, the solid dosage form is hard gelatin capsules. Optionally, the solid dosage form is a lyophilized powder that can be readily dissolved and converted to a liquid dosage form for intravenous or intramuscular administration. In some embodiments, the lyophilized powder is manufactured by dissolving the active ingredient (i.e., a compound or composition disclosed herein) in an aqueous medium followed by lyophilization. In some embodiments, the aqueous medium is water, normal saline, PBS, or an acidic aqueous medium such as an acetate buffer. In some embodiments, the pharmaceutical formulations are in a liquid dosage form suitable for intravenous or intramuscular administration. Exemplary liquid dosage forms include, but are not limited to, solutions, suspensions, and emulsions. In some embodiments, the pharmaceutical formulations are in the form of a sterile aqueous solution. In some embodiments, the sterile aqueous solution is a sterile normal saline solution. In some embodiments, the sterile aqueous solution is a sterile PBS solution. In some embodiments, the sterile aqueous solution is an acidic, sterile aqueous solution such as a sterile acetate buffer. In some embodiments, the sterile aqueous solution is manufactured by dissolving a lyophilized powder containing the active ingredient (i.e., a compound or composition disclosed herein) in an aqueous medium. For example, the sterile aqueous solution can be prepared by dissolving the lyophilized powder containing the active ingredient in a dose-appropriate volume of sterile water, sterile normal saline, sterile PBS, or acidic, sterile aqueous medium such as a sterile acetate buffer. In some embodiments, the lyophilized powder containing the active ingredient is the same as those described in the paragraph above. In some embodiments, the pharmaceutical formulations are in a unit dosage form, and may be suitably packaged, for example, in a box, blister, vial, bottle, syringe, sachet, ampoule, or in any other suitable single-dose or multi-dose holder or container, optionally with one or more leaflets containing product information and / or instructions for use. B. Pharmaceutically acceptable excipients Exemplary pharmaceutically acceptable excipients include, but are not limited to, diluents, binders, lubricants, disintegrants, pH-modifying or buffering agents, salts (such as NaCl), preservatives, antioxidants, solubility enhancers, wetting or emulsifying agents, plasticizers, colorants (such as pigments and dyes), flavoring or sweetening agents, thickening agents, emollients, humectants, stabilizers, glidants, solvents or dispersion mediums, surfactants, pore formers, and coating or matrix materials. In some embodiments, the powders described herein, including the lyophilized powders, contain one or more of the following pharmaceutically acceptable excipients: pH-modifying or buffering agents, salts (such as NaCl), and preservatives. In some embodiments, the tablets, beads, granules, and particles described herein contain one or more of the following pharmaceutically acceptable excipients: coating or matrix materials, diluents, binders, lubricants, disintegrants, pigments, stabilizers, and surfactants. If desired, the tablets, beads, granules, and particles may also contain a minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH-buffering agents, and preservatives. Examples of the coating or matrix materials include, but are not limited to, cellulose polymers (such as methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, and carboxymethylcellulose sodium), vinyl polymers and copolymers (such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate, vinyl acetate-crotonic acid copolymer, and ethylene-vinyl acetate copolymer), acrylic acid polymers and copolymers (such as those formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, or ethyl methacrylate, as well as methacrylic resins that are commercially available under the tradename EUDRAGIT®), enzymatically degradable polymers (such as azo polymers, pectin, chitosan, amylose, and guar gum), zein, shellac, and polysaccharides. In some embodiments, the coating or matrix materials may contain one or more excipients such as plasticizers, colorants, glidants, stabilizers, pore formers, and surfactants. In some embodiments, the coating or matrix materials are pH-sensitive or pH-responsive polymers, such as the enteric polymers commercially available under the tradename EUDRAGIT®. For example, EUDRAGIT® L30D-55 and L100-55 are soluble at pH 5.5 and above; EUDRAGIT® L100 is soluble at pH 6.0 and above; EUDRAGIT® S is soluble at pH 7.0 and above. In some embodiments, the coating or matrix materials are water-insoluble polymers having different degrees of permeability and expandability, such as EUDRAGIT® NE, RL, and RS. Depending on the coating or matrix materials, the decomposition / degradation or structural change of the pharmaceutical formulations may occur at different locations of the gastrointestinal tract. In some embodiments, the coating or matrix materials are selected such that the pharmaceutical formulations can survive exposure to gastric acid and release the active ingredient in the intestines after oral administration. Diluents can increase the bulk of a solid dosage formulation so that a practical size is provided for compression of tablets or formation of beads, granules, or particles. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate, powdered sugar, and combinations thereof. Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet, bead, granule, or particle remains intact after the formation of the solid dosage formulation. Suitable binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (such as sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (such as acacia, tragacanth, and sodium alginate), cellulose (such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and ethylcellulose), veegum, and synthetic polymers (such as acrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid, polymethacrylic acid, and polyvinylpyrrolidone), and combinations thereof. Lubricants are used to facilitate tablet manufacture. Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil. Disintegrants are used to facilitate disintegration or “breakup” of a solid dosage formulation after administration. Suitable disintegrants include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, gums, and cross-linked polymers, such as cross-linked polyvinylpyrrolidone (e.g., POLYPLASDONE® XL). Plasticizers are normally present to produce or promote plasticity and flexibility and to reduce brittleness. Examples of plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil, and acetylated monoglycerides. Stabilizers are used to inhibit or retard decomposition reactions of the active ingredient in the pharmaceutical formulations or stabilize particles in a dispersion. For example, when the decomposition reactions involve an oxidation reaction of the active ingredient in the pharmaceutical formulations, the stabilizer can be an antioxidant or a reducing agent. Stabilizers also include nonionic emulsifiers such as sorbitan esters, polysorbates, and polyvinylpyrrolidone. Glidants are used to reduce sticking effects during film formation and drying. Exemplary glidants include, but are not limited to, talc, magnesium stearate, and glycerol monostearates. Preservatives can inhibit the deterioration and / or decomposition of a pharmaceutical formulation. Deterioration or decomposition can be brought about by one or more of microbial growth, fungal growth, and undesirable chemical or physical changes. Suitable preservatives include benzoate salts (e.g., sodium benzoate), ascorbic acid, methyl hydroxybenzoate, ethyl p- hydroxybenzoate, n-propyl p-hydroxybenzoate, n-butyl p-hydroxybenzoate, potassium sorbate, sorbic acid, propionate salts (e.g., sodium propionate), chlorobutanol, benzyl alcohol, and combinations thereof. Surfactants may be anionic, cationic, amphoteric, or nonionic surface-active agents. Exemplary anionic surfactants include, but are not limited to, those containing a carboxylate, sulfonate, or sulfate ion. Examples of anionic surfactants include sodium, potassium, and ammonium salts of long-chain (e.g., 13-21) alkyl sulfonates (such as sodium lauryl sulfate), alkylaryl sulfonates (such as sodium dodecylbenzene sulfonate), and dialkyl sulfosuccinates (such as sodium bis-(2-ethylthioxyl)-sulfosuccinate). Examples of cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene, and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, poloxamers (such as poloxamer 401), stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include, but are not limited to, sodium N-dodecyl-β-alanine, sodium N-lauryl-β-iminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine. Pharmaceutical formulations in the liquid dosage forms typically contain a solvent or dispersion medium such as water, aqueous solution (e.g., buffer, saline, buffered saline), ethanol, polyol (such as glycerol, propylene glycol, and polyethylene glycol), oil (such as vegetable oil, e.g., peanut oil, corn oil, sesame oil), and combinations thereof. In some embodiments, the pharmaceutical formulations in the liquid dosage forms are aqueous formulations. Suitable solvents or dispersion mediums for aqueous formulations include, but are not limited to, water, buffers (such as acidic buffers), salines (such as normal saline), buffered salines (such as PBS), and Ringer’s solution. In some embodiments, the pharmaceutical formulations contain β-cyclodextrin or derivatives thereof. For example, the pharmaceutical formulations contain sulfobutyl ether β- cyclodextrin. For example, the pharmaceutical formulations contain hydroxypropyl-β- cyclodextrin. Such pharmaceutical formulations can be in a solid or liquid dosage form. C. Pharmaceutical acceptable carriers In some embodiments, the pharmaceutical formulations are prepared using a pharmaceutically acceptable carrier, which encapsulates, embeds, entraps, dissolves, disperses, absorbs, and / or binds to a compound or composition disclosed herein. The pharmaceutical acceptable carrier is composed of materials that are considered safe and can be administered to a subject without causing undesirable biological side effects or unwanted interactions. Preferably, the pharmaceutically acceptable carrier does not interfere with the effectiveness of the compound or composition in performing its function. The pharmaceutically acceptable carrier can be formed of biodegradable materials, non-biodegradable materials, or combinations thereof. One or more of the pharmaceutical acceptable excipients described above may be present in the pharmaceutical acceptable carrier. In some embodiments, the pharmaceutical acceptable carrier is a controlled-release carrier, such as delayed-release carriers, sustained-release (extended-release) carriers, and pulsatile- release carriers. In some embodiments, the pharmaceutical acceptable carrier is pH-sensitive or pH- responsive. In some forms, the pharmaceutical acceptable carrier can decompose or degrade in a certain pH range. In some forms, the pharmaceutical acceptable carrier can experience a structural change when experiencing a change in the pH. Exemplary pharmaceutical acceptable carriers include, but are not limited to: nanoparticles, microparticles, and combinations thereof; liposomes; hydrogels; polymer matrices; and solvent systems. In some embodiments, the pharmaceutical acceptable carrier is nanoparticles, microparticles, or a combination thereof. In some embodiments, the compound or composition is embedded in the matrix formed by the materials of the nanoparticles, microparticles, or combination thereof. The nanoparticles, microparticles, or combination thereof can be biodegradable, and optionally are capable of biodegrading at a controlled rate for delivery of the compound or composition. The nanoparticles, microparticles, or combination thereof can be made of a variety of materials. Both inorganic and organic materials can be used. Both polymeric and non-polymeric materials can be used. For example, the nanoparticles, microparticles, or combination thereof are formed of one or more biocompatible polymers. In some forms, the biocompatible polymers are biodegradable. In some forms, the biocompatible polymers are non-biodegradable. In some forms, the nanoparticles, microparticles, or combination thereof are formed of a mixture of biodegradable and non-biodegradable polymers. The polymers used to form the nanoparticles, microparticles, or combination thereof may be tailored to optimize different characteristics of the nanoparticles, microparticles, or combination thereof, including: (i) interactions between the active ingredient and the polymer to provide stabilization of the active ingredient and retention of activity upon delivery; (ii) rate of polymer degradation and, thereby, rate of release; (iii) surface characteristics and targeting capabilities; and (iv) particle porosity. Exemplary polymers include, but are not limited to, polymers prepared from lactones (such as poly(caprolactone) (PCL)), polyhydroxy acids and copolymers thereof (such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and poly(lactic acid-co-glycolic acid) (PLGA)), polyalkyl cyanoacrylate, polyurethanes, polyamino acids (such as poly-L-lysine (PLL), poly(valeric acid), and poly-L-glutamic acid), hydroxypropyl methacrylate (HPMA), polyanhydrides, polyorthoesters, poly(ester amides), polyamides, poly(ester ethers), polycarbonates, ethylene vinyl acetate polymer (EVA), polyvinyl alcohols (PVA), polyvinyl ethers, polyvinyl esters (such as poly(vinyl acetate)), polyvinyl halides (such as poly(vinyl chloride) (PVC)), polyvinylpyrrolidone, polysiloxanes, polystyrene (PS), celluloses and derivatized celluloses (such as alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, hydroxypropylcellulose, and carboxymethylcellulose), polymers of acrylic acids (such as poly(methyl(meth)acrylate) (PMMA), poly(ethyl(meth)acrylate), poly(butyl(meth)acrylate), poly(isobutyl(meth)acrylate), poly(hexyl(meth)acrylate), poly(isodecyl(meth)acrylate), poly(lauryl(meth)acrylate), poly(phenyl(meth)acrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate)), polydioxanone, polyhydroxyalkanoates, polypropylene fumarate, polyoxymethylene, poloxamers, poly(butyric acid), polyphosphazenes, polysaccharides, polypeptides, and blends thereof. In some embodiments, the one or more biocompatible polymers forming the nanoparticles, microparticles, or combination thereof include an FDA-approved biodegradable polymer such as polyhydroxy acids (e.g., PLA, PGA, and PLGA), polyanhydrides, and polyhydroxyalkanoate (e.g., poly(3-butyrate) and poly(4-butyrate)). Materials other than polymers may be used to form the nanoparticles, microparticles, or combination thereof. Suitable materials include surfactants. The use of surfactants in the nanoparticles, microparticles, or combination thereof may improve surface properties by, for example, reducing particle-particle interactions, and render the surface of the particles less adhesive. Both naturally occurring surfactants and synthetic surfactants can be incorporated into the nanoparticles, microparticles, or combination thereof. Exemplary surfactants include, but are not limited to, phosphoglycerides such as phosphatidylcholines (e.g., L-^-phosphatidylcholine dipalmitoyl), diphosphatidyl glycerol, hexadecanol, fatty alcohols, polyoxyethylene-9-lauryl ether, fatty acids such as palmitic acid and oleic acid, sorbitan trioleate, glycocholate, surfactin, poloxomers, sorbitan fatty acid esters such as sorbitan trioleate, tyloxapol, and phospholipids. The nanoparticles, microparticles, or combination thereof may contain a plurality of layers. The layers can have similar or different release kinetic profiles for the active ingredient. For example, the nanoparticles, microparticles, or combination thereof can have a controlled-release core surrounded by one or more additional layers. The one or more additional layers can include an instant-release layer, preferably on the surface of the nanoparticles, microparticles, or combination thereof. The instant-release layer can provide a bolus of the active ingredient shortly after administration. The composition and structure of the nanoparticles, microparticles, or combination thereof can be selected such that the nanoparticles, microparticles, or combination thereof are pH-sensitive or pH-responsive. In some embodiments, the nanoparticles, microparticles, or combination thereof are formed of one or more pH-sensitive or pH-responsive polymers such as the enteric polymers commercially available under the tradename EUDRAGIT®, as described above. Depending on the particle materials, the decomposition / degradation or structural change of the nanoparticles, microparticles, or combination thereof may occur at different locations of the gastrointestinal tract. In some embodiments, the particle materials are selected such that the nanoparticles, microparticles, or combination thereof can survive exposure to gastric acid and release the active ingredient in the intestines after oral administration. D. Controlled release In some embodiments, the pharmaceutical formulations can be controlled-release formulations. Examples of controlled-release formulations include extended-release formulations, delayed-release formulations, and pulsatile-release formulations. 1. Extended release In some embodiments, the extended-release formulations are prepared as diffusion or osmotic systems, for example, as described in “Remington – The science and practice of pharmacy” (20th Ed., Lippincott Williams & Wilkins, 2000). A diffusion system is typically in the form of a matrix, generally prepared by combining the active ingredient with a slowly dissolving, pharmaceutically acceptable carrier, optionally in a tablet form. Suitable materials used in the preparation of the matrix include plastics, hydrophilic polymers, and fatty compounds. Suitable plastics include, but are not limited to, acrylic polymer, methyl acrylate-methyl methacrylate copolymer, polyvinyl chloride, and polyethylene. Suitable hydrophilic polymers include, but are not limited to, cellulosic polymers such as methyl ethyl cellulose, hydroxyalkylcelluloses (such as hydroxypropylcellulose and hydroxypropylmethylcellulose), sodium carboxymethylcellulose, CARBOPOL® 934, polyethylene oxides, and combinations thereof. Suitable fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate, wax-type substances such as hydrogenated castor oil and hydrogenated vegetable oil, and combinations thereof. In some embodiments, the plastic is a pharmaceutically acceptable acrylic polymer. In some embodiments, the pharmaceutically acceptable acrylic polymer is chosen from acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate copolymers, cyanoethyl methacrylate copolymers, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymers, poly(methyl methacrylate), poly(methacrylic acid), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. In some embodiments, the pharmaceutically acceptable acrylic polymer can be an ammonio methacrylate copolymer. Ammonio methacrylate copolymers are well known in the art and are described as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. In some embodiments, the pharmaceutically acceptable acrylic polymer is an acrylic resin lacquer such as those commercially available under the tradename EUDRAGIT®. In some embodiments, the pharmaceutically acceptable acrylic polymer contains a mixture of two acrylic resin lacquers, EUDRAGIT® RL (such as EUDRAGIT® RL30D) and EUDRAGIT® RS (such as EUDRAGIT® RS30D). EUDRAGIT® RL30D and EUDRAGIT® RS30D are copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral methacrylic esters being 1:20 in EUDRAGIT® RL30D and 1:40 in EUDRAGIT® RS30D. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these polymers. EUDRAGIT® RL / RS mixtures are insoluble in water and in digestive fluids. However, multi-particulate systems formed to include the same are swellable and permeable in aqueous solutions and digestive fluids. The EUDRAGIT® RL / RS mixtures may be prepared in any desired ratio in order to ultimately obtain a sustained-release formulation having a desirable release profile. Suitable sustained-release, multi-particulate systems may be obtained, for instance, from 90% EUDRAGIT® RL + 10% EUDRAGIT® RS, to 50% EUDRAGIT® RL + 50% EUDRAGIT® RS, and to 10% EUDRAGIT® RL + 90% EUDRAGIT® RS. In some embodiments, the pharmaceutically acceptable acrylic polymer can also be or include other acrylic resin lacquers, such as EUDRAGIT® S-100, EUDRAGIT® L-100, and mixtures thereof. Matrices with different release mechanisms or profiles can be combined in a final dosage form containing single or multiple units. Examples of multiple units include, but are not limited to, multilayer tablets and capsules containing beads, granules, and / or particles of the active ingredient. An immediate release portion can be added to the extended-release system by means of either applying an immediate release layer on top of the extended-release core using a coating or compression process or in a multiple unit system such as a capsule containing both extended- and immediate-release beads. Extended-release tablets containing one or more of the hydrophilic polymers can be prepared by techniques commonly known in the art such as direct compression, wet granulation, and dry granulation. Extended-release tablets containing one or more of the fatty compounds can be prepared using methods known in the art such as direct blend methods, congealing methods, and aqueous dispersion methods. In the congealing methods, the active ingredient is mixed with the fatty compound(s) and congealed. Alternatively, the extended-release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to a solid dosage form. In the latter case, the desired release profile can be achieved by combining low permeable and high permeable coating materials in suitable proportions. 2. Delayed release Delayed-release formulations can be prepared by coating a solid dosage form with a coating. In some embodiments, the coating is insoluble and impermeable in the acidic environment of the stomach and becomes soluble or permeable in the less acidic environment of the intestines and / or the lower GI tract. In some embodiments, the solid dosage form is a tablet for incorporation into a capsule, a tablet for use as an inner core in a “coated-core” dosage form, or a plurality of beads, granules, and / or particles containing the active ingredient, for incorporation into either a tablet or capsule. Suitable coating materials may be bioerodible polymers, gradually hydrolysable polymers, gradually water-dissolvable polymers, and enzymatically degradable polymers. In some embodiments, the coating material is or contains enteric polymers. Combinations of different coating materials may also be used. Multilayer coatings using different coating materials may also be applied. The coating may also contain one or more additives, such as plasticizers described above (optionally representing about 10 wt % to 50 wt % relative to the dry weight of the coating), colorants as described above, stabilizers as described above, glidants as described above, etc. 3. Pulsatile release Pulsatile-release formulations release a plurality of doses of the active ingredient at spaced- apart time intervals. Generally, upon administration, such as oral administration, of the pulsatile- release formulations, release of the initial dose is substantially immediate, e.g., the first release “pulse” occurs within about three hours, two hours, or one hour of administration. This initial pulse may be followed by a first time-interval (lag time) during which very little or no active ingredient is released from the formulations, after which a second dose may be released. Similarly, a second lag time (nearly release-free interval) between the second and third release pulses may be designed. The duration of the lag times will vary depending on the formulation design, especially on the length of the dosing interval, e.g., a twice daily dosing profile, a three-time daily dosing profile, etc. For pulsatile-release formulations providing a twice daily dosage profile, they deliver two release pulses of the active ingredient. In some embodiments, the one nearly release-free interval between the first and second release pulses may have a duration of between 3 hours and 14 hours. For pulsatile-release formulations providing a three daily dosage profile, they deliver three release pulses of the active ingredient. In some embodiments, the two nearly release-free interval between two adjacent pulses may have a duration of between 2 hours and 8 hours. In some embodiments, the pulsatile-release formulations contain a plurality of pharmaceutically acceptable carriers with different release kinetics. In some embodiments, the pulsatile-release formulations contain a pharmaceutically acceptable carrier with a plurality of layers loaded with the active ingredient. In some embodiments, the layers may have different release kinetics. In some embodiments, the layers may be separated by a delayed-release coating. For example, the pulsatile-release formulations may have a first layer loaded with the active ingredient on the surface for the first release pulse and a second layer, e.g., a core loaded with the active ingredient, for the second release pulse; the second layer may be surrounded by a delayed-release coating, which creates a lag time between the two release pulses. In some embodiments, the pulsatile-release profile is achieved with formulations that are closed and optionally sealed capsules housing at least two “dosage units” wherein each dosage unit within the capsules provides a different release profile. In some embodiments, at least one of the dosage units is a delayed-release dosage unit. Control of the delayed-release dosage unit(s) may be accomplished by a controlled-release polymer coating on the dosage unit(s) or by incorporation of the active ingredient in a controlled-release polymer matrix. In some embodiments, each dosage unit may comprise a compressed or molded tablet, wherein each tablet within the capsule provides a different release profile. E. Exemplary formulations for different routes of administration A subject suffering from a condition, disorder, or disease as described herein, can be treated by either targeted or systemic administration, via oral, inhalation, topical, trans- or sub-mucosal, subcutaneous, intramuscular, intravenous, or transdermal administration of a pharmaceutical formulation containing a compound or composition described herein. In some embodiments, the pharmaceutical formulation is suitable for oral administration. In some embodiments, the pharmaceutical formulation is suitable for subcutaneous, intravenous, or intramuscular administration. In some embodiments, the pharmaceutical formulation is suitable for inhalation or intranasal administration. In some embodiments, the pharmaceutical formulation is suitable for transdermal or topical administration. In some embodiments, the pharmaceutical formulation is an oral pharmaceutical formulation. In some embodiments, the active ingredient may be incorporated with one or more pharmaceutically acceptable excipients as described above and used in the form of tablets, pills, caplets, or capsules. For example, the corresponding oral pharmaceutical formulation may contain one or more of the following pharmaceutically acceptable excipients or those of a similar nature: a binder as described above, a disintegrant as described above, a lubricant as described above, a glidant as described above, a sweetening agent (such as sucrose and saccharin), and a flavoring agent (such as methyl salicylate and fruit flavorings). In some embodiments, when the oral pharmaceutical formulation is in the form of capsules, it may contain, in addition to the material(s) listed above, a liquid carrier (such as a fatty oil). In some embodiments, when the oral pharmaceutical formulation is in the form of capsules, each capsule may contain a plurality of beads, granules, and / or particles of the active ingredient. In some embodiments, the oral pharmaceutical formulation may contain one or more other materials which modify the physical form or one or more pharmaceutical properties of the dosage unit, for example, coatings of polysaccharides, shellac, or enteric polymers as described in previous sections. In some embodiments, the oral pharmaceutical formulation can be in the form of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active ingredient, one or more sweetening agents (such as sucrose and saccharine), one or more flavoring agents, one or more preservatives, and / or one or more dyes or colorings. In some embodiments, the pharmaceutical formulation is a subcutaneous, intramuscular, or intravenous pharmaceutical formulation. In some embodiments, the subcutaneous, intramuscular, or intravenous pharmaceutical formulation can be enclosed in an ampoule, syringe, or a single or multiple dose vial made of glass or plastic. In some embodiments, the subcutaneous, intramuscular, or intravenous pharmaceutical formulation contains a liquid pharmaceutically acceptable carrier for the active ingredient. Suitable liquid pharmaceutically acceptable carriers include, but are not limited to, water, buffer, saline, buffered saline (such as PBS), and combinations thereof. In some embodiments, the pharmaceutical formulation is a topical pharmaceutical formulation. Suitable forms of the topical pharmaceutical formulation include lotions, suspensions, ointments, creams, gels, tinctures, sprays, powders, pastes, slow-release transdermal patches, and suppositories for application to rectal, vaginal, nasal, or oral mucosa. In some embodiments, thickening agents, emollients (such as mineral oil, lanolin and its derivatives, and squalene), humectants (such as sorbitol), and / or stabilizers can be used to prepare the topical pharmaceutical formulations. Examples of thickening agents include petrolatum, beeswax, xanthan gum, and polyethylene. In some embodiments, the pharmaceutical formulation is an intranasal pharmaceutical formulation. In some embodiments, the intranasal pharmaceutical formulation is in the form of an aqueous suspension, which can be optionally placed in a pump spray bottle. Other than water, the aqueous suspension may contain one or more pharmaceutically acceptable excipients, such as suspending agents (e.g., microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl-methyl cellulose), humectants (e.g., glycerol, propylene glycol), acids, bases, and / or pH-buffering agents for adjusting the pH (e.g., citric acid, sodium citrate, phosphoric acid, sodium phosphate, and combinations thereof), surfactants (e.g., polysorbate 80), and preservatives (e.g., benzalkonium chloride, phenylethyl alcohol, potassium sorbate). In some embodiments, the pharmaceutical formulation is an inhalation pharmaceutical formulation. In some embodiments, the inhalation pharmaceutical formulation may be in the form of an aerosol suspension, a dry powder, or a liquid suspension. The inhalation pharmaceutical formulation may be prepared for delivery as a nasal spray or an inhaler, such as a metered dose inhaler (MDI). In some embodiments, MDIs can deliver aerosolized particles suspended in chlorofluorocarbon propellants such as CFC-11 and CFC-12, or non-chlorofluorocarbons or alternate propellants such as fluorocarbons (e.g., HFC-134A, HFC-227), with or without surfactants or suitable bridging agents. Dry-powder inhalers can also be used, either breath activated or delivered by pressure. In some embodiments, the active ingredient is prepared with a pharmaceutically acceptable carrier that will protect it against rapid degradation or elimination from the body of the subject after administration, such as the controlled-release formulations described in previous sections. V. METHODS OF USING Disclosed are methods of treating a condition, disorder, or disease in a subject in need thereof. The methods include administering an effective amount of a compound, composition, or pharmaceutical formulation disclosed herein to the subject. The compound, composition, or pharmaceutical formulation can be administered in a variety of manners, depending on whether local or systemic administration is desired. In some embodiments, the compound, composition, or pharmaceutical formulation is administered in a systemic manner, such as enteral administration (e.g., oral administration) and parenteral administration (e.g., injection, infusion, and implantation). In some embodiments, the compound, composition, or pharmaceutical formulation is directly administered to a specific bodily location of the subject, e.g., topical administration and intranasal administration. Exemplary administration routes include oral administration, intravenous administration such as intravenous injection or infusion, intramuscular administration such as intramuscular injection, intranasal administration, and topical administration. In some embodiments, the compound, composition, or pharmaceutical formulation is administered orally. In some embodiments, the compound, composition, or pharmaceutical formulation is administered intravenously. In some embodiments, the compound, composition, or pharmaceutical formulation is administered intranasally. In some embodiments, the compound, composition, or pharmaceutical formulation is administered intramuscularly. In some embodiments, the compound, composition, or pharmaceutical formulation is administered for a sufficient time period to alleviate one or more undesired symptoms and / or one or more clinical signs associated with the condition, disorder, or disease being treated. In some embodiments, the compound, composition, or pharmaceutical formulation is administered less than three times daily. In some embodiments, the compound, composition, or pharmaceutical formulation is administered once or twice daily. In some embodiments, the compound, composition, or pharmaceutical formulation is administered once daily. In some embodiments, the compound, composition, or pharmaceutical formulation is administered in a single oral dosage once a day. In some embodiments, the compound, composition, or pharmaceutical formulation is administered in a single intravenous dosage once a day. In some embodiments, the subject is a human. In some embodiments, the subject is an adult patient. In some embodiments, the subject is a pediatric patient. In some embodiments, the subject is a non-human animal, such as domestic pets, livestock and farm animals, and zoo animals. In some embodiments, the non-human animal may be a non-human primate. A. Indications As discussed above, NMDARs are heterotetramers containing GluN2. Stimulation of one or more of the subunits can be beneficial for the treatment of a wide range of neurological and neuropsychiatric disorders or conditions, conditions dependent on synaptic plasticity such learning, memory, cognition, motor function, and motor retraining and rehabilitation, as well as conditions that involve impairment of movement, speech, vision, or other normal functions controlled by the brain. In certain instances, the compounds disclosed herein, as demonstrated by the biological data in the Examples and ongoing studies by the applicant, can enhance maximal current, prolong deactivation, increase agonist potency, reduce single channel conductance, and / or decrease relative calcium permeability. In certain instances, the compounds can increase charge transfer for NMDAR-mediated EPSCs in both pyramidal cells and interneurons with more robust actions on interneurons. This can reflect enhanced potentiation of GluN2D, since GluN2D is expressed in interneurons. The preferential enhancement of NMDAR function on interneurons can increase inhibitory tone, which has been shown to have numerous effects including anticonvulsant actions, antidepressant actions, and anxiolytic actions. In certain instances, the compounds can decrease input resistance of interneurons but not pyramidal cells, reflective of interneuron expression of GluN2D. In certain instances, the compounds can depolarize and increase spike firing in interneurons. In certain instances, the compounds can produce anxiolytic effect. In certain instances, the compounds can reverse long-term potentiation caused by GluN2 hypofunction. In certain instances, the compounds can rectify deficits in NMDAR-dependent synaptic plasticity and mitigate behavioral deficits produced by non-selective NMDAR blockade. In view of the foregoing, the compounds and pharmaceutical formulations thereof can be used to treat or prevent neurological and neuropsychiatric disorders or conditions, which includes abnormalities of the nervous system as well as genetic alterations that impact brain function. These disorders can be characterized by primary location, dysfunction / abnormality, or cause. Central nervous system disorders impact the brain or spinal cord, while peripheral nervous system disorders affect the nerves. Causes may include, for example, genetic abnormalities, developmental abnormalities, injury, ischemia or trauma, infection, cancer, and diseases and disorders of the vasculature that supplies the nervous system, e.g., stroke. In some embodiments, the neurological and neuropsychiatric disorder or condition may be associated with NMDAR, including NMDAR hypofunction or loss of function. In some embodiments, the neurological and neuropsychiatric disorder or condition may be associated with NMDAR GluN2, including NMDAR GluN2 hypofunction or loss of function. In some embodiments, the neurological and neuropsychiatric disorder or condition may be associated with NMDAR GluN2B, including NMDAR GluN2B hypofunction or loss of function. In some embodiments, the neurological and neuropsychiatric disorder or condition may be associated with NMDAR GluN2C, including NMDAR GluN2C hypofunction or loss of function. In some embodiments, the neurological and neuropsychiatric disorder or condition may be associated with NMDAR GluN2D, including NMDAR GluN2D hypofunction or loss of function. Neurological disorders or conditions In some embodiments, the compounds and pharmaceutical formulations can be used to treat neurological disorders or conditions. They may include, without limitation, neurodegenerative disease or disorder, pain, epilepsy, essential tremor, movement disorder or impaired motor function, stroke, traumatic brain injury, transient ischemia, global ischemia, hypoxia, spinal cord trauma, and other neurologic events. Multiple forms of pain can be treated by the compounds and pharmaceutical formulations. In some embodiments, the pain is neuropathic pain, inflammatory pain, perioperative pain, or nociceptive pain. In some embodiments, the pain is acute pain. In some embodiments, the pain is chronic pain. In some embodiments, the pain is selected from peripheral diabetic neuropathy, postherpetic neuralgia, complex regional pain syndromes, peripheral neuropathies, chemotherapy- induced neuropathic pain, cancer neuropathic pain, neuropathic low back pain, HIV neuropathic pain, trigeminal neuralgia, and central post-stroke pain. In some embodiments, the pain is neuropathic pain. Neuropathic pain may result from peripheral or central nervous system pathologic events, including, but not limited to, trauma, ischemia, infections or endocrinologic disorders (e.g., diabetes mellitus, diabetic neuropathy, amyloidosis, amyloid polyneuropathy (primary and familial), neuropathies with monoclonal proteins, vasculitis neuropathy, HIV infection, herpes zoster shingles, and postherpetic neuralgia), neuropathy associated with Guillain-Barre syndrome, neuropathy associated with Fabry’s disease, entrapment due to anatomic abnormalities, trigeminal and other CNS neuralgias, malignancies, inflammatory conditions or autoimmune disorders (e.g., demyelinating inflammatory disorders, rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome), cryptogenic causes (e.g., idiopathic distal small-fiber neuropathy). Other causes of neuropathic pain that can be treated by the compounds and pharmaceutical formulations described herein include, but are not limited to, exposure to toxins or drugs (such as arsenic, thallium, alcohol, vincristine, cisplatin, and dideoxynucleosides), dietary or absorption abnormalities, immuno-globulinemias, hereditary abnormalities, and amputations (including mastectomy). Neuropathic pain can also result from compression of nerve fibers, such as radiculopathies and carpal tunnel syndrome. In some embodiments, the pain is perioperative pain, such as those associated with incision. In some embodiments, the pain is nociceptive pain, such as those caused by burn or tissue damage. Multiple forms of neurodegenerative diseases or disorders can be treated by the compounds and pharmaceutical formulations. The neurodegenerative diseases or disorders may include, without limitation, Alzheimer’s disease, dementia such as frontotemporal dementia and AIDS- induced dementia, chronic traumatic encephalopathy (CTE), Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, spinal muscular atrophy, bulbar muscular atrophy, spinocerebellar ataxia, familial spastic paraparesis, Machado Joseph disease, Friedreich’s ataxia, and Lewy body disease such as Lewy body dementia. Treatment by the compound or pharmaceutical formulation may reduce or reverse cognitive or memory impairment associated with these diseases or disorders. In some embodiments, the neurodegenerative disease or disorder is Alzheimer’s disease. In some embodiments, the neurodegenerative disease or disorder is Parkinson’s disease. In some embodiments, the neurodegenerative disease or disorder is Huntington’s disease. In some embodiments, the neurodegenerative disease or disorder is ALS. In some embodiments, the neurodegenerative disease or disorder is frontotemporal dementia. In some embodiments, the neurodegenerative disease or disorder is chronic traumatic encephalopathy (CTE). In some embodiments, the neurodegenerative disease or disorder is Lewy body dementia. In some embodiments, the neurodegenerative disease or disorder is spinal muscular atrophy or spinocerebellar ataxia. In some embodiments, the neurodegenerative disease or disorder is the result of a prion disease. In some embodiments, the neurodegenerative disease reflects or is caused by neuronal loss due to epileptic encephalopathy. Many forms of epilepsy or seizure disorder can be treated by the compounds and pharmaceutical formulations. In some embodiments, the epilepsy or seizure disorder may be selected from epilepsies that are inadequately controlled by existing medications (i.e., treatment- resistant epilepsy), infantile spasms, and epilepsies or seizure disorders caused by a rare disease or genetic condition (e.g., genetic mutation) that produces epilepsies, seizures, spasms, abnormally hypersynchronous brain activity, and / or other conditions associated with enhanced neuronal synchrony. In some embodiments, the subject may be a pediatric patient suffering from the epilepsy or seizure disorder. In some embodiments, the subject may be an adult patient suffering from the epilepsy or seizure disorder. In some embodiments, the compound or pharmaceutical formulation is used to reduce the severity and / or intensity of the epilepsy or seizure disorder. In some embodiments, the compound or pharmaceutical formulation is used to reduce the frequency of the epilepsy or seizure disorder. In some embodiments, the epilepsy is refractory epilepsy, such as Refractory Status Epilepticus. In some embodiments, the epilepsy is CDKL5 Deficiency Disorder. In some embodiments, the epilepsy is Established Status Epilepticus. In some embodiments, the epilepsy is Tuberous Sclerosis Complex. In some embodiments, the epilepsy is Lennox-Gastaut Syndrome. In some embodiments, the epilepsy is Dravet Syndrome. In some embodiments, the epilepsy is Developmental and Epileptic Encephalopathy. Many forms of movement disorder or impaired motor function can be treated by the compounds and pharmaceutical formulations. They may include ataxia, dyskinesia, and dystonia. Neuropsychiatric disorders or conditions In some embodiments, the compounds and pharmaceutical formulations can be used to treat neuropsychiatric disorders or conditions. They may include, without limitation, schizophrenia, depression, post-partum depression, post-traumatic stress disorder (PTSD), bipolar disorder, fragile X syndrome, sleeping disorder, anxiety disorder, autism spectrum disorder, obsessive-compulsive disorder, addiction or use dependence, uncontrolled anger, cognitive deficit disorder, headache, migraine, eating disorder, and attention-deficit disorder (such as ADHD). In some embodiments, the neuropsychiatric disorder or condition is schizophrenia, depression, addiction or use dependence, anxiety disorder, autism spectrum disorder, or bipolar disorder. In some embodiments, the neuropsychiatric disorder or condition is schizophrenia. In some embodiments, the neuropsychiatric disorder or condition is depression or post- partum depression. In some embodiments, the depression is major depressive disorder. In some embodiments, the depression is treatment-resistant depression. In some embodiments, the depression is bipolar depression. In some embodiments, the neuropsychiatric disorder or condition is addiction or use dependence. In some embodiments, the addiction or use dependence is alcohol addiction or use dependence, such as alcohol abuse. In some embodiments, the addiction or use dependence is substance addiction or use dependence, such as substance abuse. Treatment by the compound or pharmaceutical formulation may reduce or reverse cognitive or memory impairment associated with these disorders or conditions. In some embodiments, the neuropsychiatric disorder or condition is autism spectrum disorder. In some embodiments, the neuropsychiatric disorder or condition is anxiety disorder, such as generalized anxiety disorder, agoraphobia, and panic disorder. In some embodiments, the neuropsychiatric disorder or condition is bipolar disorder. In some embodiments, the bipolar disorder is cyclothymic disorder. In some embodiments, the bipolar disorder is treatment-resistant bipolar disorder. In some embodiments, the neuropsychiatric disorder or condition is sleeping disorder, such as those comorbid with other neuropsychiatric disorders or conditions. In some embodiments, the neuropsychiatric disorder or condition is attention deficit disorder. In some embodiments, the neuropsychiatric disorder or condition is cognitive deficit disorder. In some embodiments, the neuropsychiatric disorder or condition is uncontrolled anger. In some embodiments, the neuropsychiatric disorder or condition is headache or migraine. In some embodiments, the neuropsychiatric disorder or condition is eating disorder. Other indications The compounds and pharmaceutical formulations disclosed herein can be used to treat genetic mutations of NMDARs, especially those causing a loss of function in GluN2B, GluN2C, and / or GluN2D. Additionally, the compounds and pharmaceutical formulations disclosed herein can be used to promote or improve neuroplasticity. In some embodiments, the compounds and pharmaceutical formulations disclosed herein can be used to promote or improve synaptic plasticity. NMDARs play an important role in synaptic plasticity, learning, and memory. Deficits in synaptic plasticity are thought to contribute to cognitive dysfunction in a wide range of indications, including Alzheimer’s disease, autism, developmental delay, cognitive disability, schizophrenia, depression, and Parkinson’s disease. Therefore, the present disclosure further relates to methods of improving synaptic plasticity, learning, and memory by administering a compound or pharmaceutical formulation disclosed herein to a subject in need thereof. Further, the compounds and pharmaceutical formulations disclosed herein can be used to treat NMDAR encephalitis, an autoimmune condition in which the patient has antibodies against NMDARs. NMDAR encephalitis can produce a spectrum of complex neuropsychiatric features, including hallucinations and schizophrenia-like symptoms. EXAMPLES The examples below describe studies to synthesize and evaluate subunit-selective NMDAR modulators. The synthetic methods disclosed herein are compatible with a wide variety of functional groups and starting materials. Thus, a wide variety of compounds can be obtained from the disclosed methods. General information for synthetic chemistry: All chemicals were purchased from commercial vendors and used without further purification unless stated otherwise. All reactions were conducted using oven- or flame-dried glassware under an inert atmosphere of argon unless noted otherwise. Thin layer chromatography (TLC) was utilized to monitor reaction progress using silica gel 60 F254 aluminum-backed plates. TLC spots were visualized with UV light, KMnO4, PMA, or ninhydrin stains. Flash chromatography was performed using a Teledyne Isco CombiFlash Rf® system using RediSep® Rf silica gel disposable flash columns (60 Å pore size, 40–60 µm particle size). NMR spectra were acquired using a 400 MHz Varian INOVA® or a 600 MHz Bruker Avance III® NMR spectrometer. Chemical shifts are reported in δ ppm and referenced using residual solvent peaks (CHCl3, TMS, MeOH, DMSO, etc.). Rotamer signals are denoted with *. High resolution mass spectrometry (HRMS) was performed on a Thermo Exactive Plus Orbitrap® Mass Spectrometer using APCI or ESI ionization methods. General Procedure X (Sonogashira coupling): A solution of the iodide-containing precursor (1.0 eq), the alkyne-containing precursor (1.1 eq), and Et3N (4.0 eq) in 1,4-dioxane (0.16 M) or THF was deoxygenated with Ar for 30 min before adding PdCl2(PPh3)2(0.050 eq) and CuI (0.050 eq) and stirring at 60 °C for 16 h. The resulting solution was filtered through Celite, washed with EtOAc, and the filtrate was evaporated. Flash chromatography (RediSep Silver®, 12 g Flash Column) (60 – 95% EtOAc / hexanes) gave a semi-pure mixture, which was further purified by reverse phase chromatography (RediSepRf C18Aq, 30 g Column) (0 – 45% MeOH / H2O) or prep HPLC to give the title compound. For the Sonogashira coupling of aminoalkyne or hydroxylalkyne, the amino or hydroxyl group may be boc-protected. Accordingly, General Procedure X includes a boc deprotection step under these scenarios. See, for example, 1622-317, 1622-332, 1622-333, 1622-349, 1622-350, 1622-351, 1622-352, 1622-355, 1622-356, 1622-366, 1622-367, 1622-368, and 1622-AA. Further, following the Sonogashira coupling of hydroxylalkyne, the hydroxyl group may be oxidized (e.g., by Dess-Martin oxidation) after the coupling reaction to generate the ketone analog. See, for example, 1622-358, 1622-373, 1622-374, 1622-375, 1622-376, 1622-377, 1622- AAA, 1622-AAB). Additionally, for alkyne-containing precursors that were not commercially available, they were synthesized using the procedure below, with slight modifications as needed. Propargyl bromide (80% wt in PhCH3, 1.1 eq) was added to a solution of the heterocycle (1.0 eq) and K2CO3 (2.0 eq) in ACN (0.35 M) at 0 °C and stirred at room temperature for 16 h. The reaction was quenched with water and stirred for 30 min and then extracted with DCM (3×). The combined organic layers were washed with brine (1×), dried over Na2SO4, and concentrated. The resulting oil was used without further purification. Example 1. Chemical synthesis Preparation of 5-(3-chloro-4-fluorophenyl)-6-ethynyl-3-(2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-175) Prepared by General Procedure X. White solid, 42%.1H NMR (600 MHz, CDCl3) δ 8.09 (s, 1H), 7.57 (dd, J = 7.1, 2.2 Hz, 1H), 7.39 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.19 (t, J = 8.7 Hz, 1H), 4.60 (d, J = 15.4 Hz, 1H), 4.49 – 4.40 (m, 1H), 4.38 – 4.28 (m, 2H), 4.24 – 4.14 (m, 1H), 4.03 (ddd, J = 17.3, 11.3, 1.5 Hz, 1H), 3.38 (s, 1H), 1.65 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.75 (d, J = 3.2 Hz), 164.10, 158.98, 157.32, 156.50, 148.49, 140.90, 132.61, 130.35 (d, J = 7.7 Hz), 120.81, 120.30 (d, J = 18.1 Hz), 117.47, 115.88 (d, J = 21.1 Hz), 90.70, 89.34, 85.95, 75.54, 62.24 (d, J = 28.5 Hz), 60.73 (d, J = 27.9 Hz), 44.84, 22.97 (d, J = 25.6 Hz).19F NMR (565 MHz, CDCl3) δ -111.75 – -117.58 (m), -141.20 – -141.48 (m). HRMS: [APCI+] [M+H]+calc. for C20H15O2N3F2Cl³²S, 434.0536, observed 434.0534. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-((trimethylsilyl)ethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-239) Prepared by General Procedure X. White solid (21 mg, 33% yield).1H NMR (600 MHz, CDCl3) δ 7.81 (d, J = 6.8 Hz, 1H), 7.73 – 7.41 (m, 2H), 7.18 (t, J = 8.4 Hz, 1H), 4.65 (s, 1H), 4.53 – 4.28 (m, 3H), 4.26 – 4.16 (m, 1H), 4.06 (s, 1H), 1.72 – 1.64 (m, 4H), 0.22 (s, 9H).13C NMR (151 MHz, CDCl3) δ 165.72 (d, J = 3.1 Hz), 163.91, 159.71, 158.06, 156.40, 148.01, 139.06, 135.45, 131.53, 131.38, 131.33, 130.94, 130.92, 121.96, 120.82, 118.79, 115.51, 115.36, 107.97, 107.83, 97.83, 90.60, 89.23, 81.52, 77.81 – 76.06 (m), 62.24, 62.06, 60.70, 60.51, 44.80, 22.96, 22.79.19F NMR (565 MHz, CDCl3) δ -107.96, -140.11 – -142.72 (m). Preparation of 5-(3-bromo-4-fluorophenyl)-6-ethynyl-3-(2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-240) Prepared by General Procedure X. Beige solid, 38%.1H NMR (600 MHz, CDCl3) δ 8.09 (s, 1H), 7.74 – 7.70 (m, 1H), 7.46 – 7.42 (m, 1H), 7.17 (td, J = 8.4, 0.8 Hz, 1H), 4.61 (d, J = 15.4 Hz, 1H), 4.44 (dd, J = 18.8, 9.4 Hz, 1H), 4.34 (dd, J = 15.2, 5.9 Hz, 1H), 4.31 (ddd, J = 17.0, 9.6, 0.0 Hz, 1H), 4.19 (td, J = 19.9, 11.2 Hz, 1H), 4.03 (dd, J = 11.2, 6.1 Hz, 1H), 3.39 (s, 1H), 1.65 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.8 (d, JC-F = 3.1 Hz), 164.1, 159.1 (d, JC-F = 248.9 Hz), 156.5, 148.5, 140.8, 135.4, 131.2 (d, JC-F= 7.3 Hz), 130.7 (d, J = 3.9 Hz), 120.8, 117.5, 115.7 (d, J = 22.6 Hz), 108.3 (d, J = 21.2 Hz), 90.0 (d, J = 205.6 Hz), 86.0, 75.5, 62.3 (d, J = 28.6 Hz), 60.7 (d, J = 28.1 Hz), 44.8, 23.0 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -107.7, - 141.3. HRMS: [APCI+] [M+H]+calc. for C₂₀H₁₅O₂N₃ F₂⁷⁹Br³²S, 478.00309, observed, 478.00408. Preparation of 6-ethynyl-5-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-256) Prepared by General Procedure X. White solid, 40%.1H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.84 – 7.75 (m, 1H), 7.71 (ddd, J = 8.4, 4.7, 2.3 Hz, 1H), 7.24 (d, J = 9.3 Hz, 1H), 4.60 (d, J = 15.3 Hz, 1H), 4.45 (dd, J = 19.4, 9.6 Hz, 1H), 4.37 – 4.28 (m, 2H), 4.19 (dd, J = 20.1, 11.3 Hz, 1H), 4.07 – 3.98 (m, 1H), 3.39 (s, 1H), 1.64 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.61 (d, J = 3.2 Hz), 164.10, 156.43, 148.40, 140.53, 135.85 (d, J = 8.6 Hz), 129.39, 120.57, 117.56, 116.11 (d, J = 21.0 Hz), 90.55, 89.19, 85.95, 75.29, 62.19 (d, J = 28.6 Hz), 60.60 (d, J = 27.8 Hz), 53.44, 44.79, 31.61, 22.67, 14.14.19F NMR (565 MHz, CDCl3) δ -61.27 (d, J = 12.4 Hz), -114.85 – -114.98 (m), -141.23 – -141.58 (m). HRMS: [APCI+] [M+H]+calc. for C21H15O2N3F5³²S, 468.0800, observed 468.0800. Preparation of 5-(3,4-dichlorophenyl)-6-ethynyl-3-(2-(3-fluoro-3-methylazetidin-1- yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-271) Prepared by General Procedure X. White solid (21 mg, 32% yield).1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.2, 2.0 Hz, 1H), 4.64 (d, J = 15.4 Hz, 1H), 4.43 (dd, J = 17.4, 12.4 Hz, 2H), 4.36 – 4.14 (m, 2H), 4.10 – 3.98 (m, 1H), 2.39 (s, 3H), 1.72 – 1.57 (m, 3H).13C NMR (100 MHz, CDCl3) δ 165.4 (d, JC-F = 3.0 Hz), 159.4, 155.8, 146.7, 135.4, 133.9, 131.8, 131.7 (d, JC-F = 3.9 Hz), 131.6, 129.5 (d, JC-F = 5.0 Hz), 121.7, 90.7, 88.7, 61.9, 61.6, 60.5, 60.2, 44.6, 22.7, 22.5, 13.8.19F NMR (376 MHz, CDCl3) δ -134.34 – -145.98 (m). Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-286) Prepared by General Procedure X. White solid.48%.1H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.78 (dd, J = 6.6, 2.2 Hz, 1H), 7.45 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.18 (t, J = 8.5 Hz, 1H), 4.63 (d, J = 15.4 Hz, 1H), 4.56 – 4.42 (m, 1H), 4.43 – 4.29 (m, 2H), 4.22 (dd, J = 20.2, 11.3 Hz, 1H), 4.06 (ddd, J = 17.3, 11.3, 1.5 Hz, 1H), 1.68 (d, J = 21.4 Hz, 3H), 1.48 (s, 6H).13C NMR (151 MHz, CDCl3) δ 165.79 (d, J = 3.3 Hz), 163.85, 159.78, 158.13, 156.52, 148.17, 139.56, 135.39, 131.42 (d, J = 7.5 Hz), 131.02 (d, J = 3.9 Hz), 120.82, 118.36, 115.55 (d, J = 22.6 Hz), 107.98 (d, J = 21.1 Hz), 100.04, 90.70, 89.34, 76.30, 71.14, 62.24 (d, J = 28.5 Hz), 60.72 (d, J = 28.1 Hz), 44.86, 28.09, 23.00 (d, J = 25.6 Hz).19F NMR (565 MHz, CDCl3) δ -102.94 – -114.82 (m), -133.50 – -147.40 (m). HRMS: [APCI+] [M+H]+calc. for C24H23O3N3F2⁷⁹Br³²S, 550.0606, observed, 550.0617. Preparation of 5-(3-bromo-4-fluorophenyl)-6-(cyclopropylethynyl)-3-(2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-287) Prepared by General Procedure X. White solid, 59%.1H NMR (600 MHz, CDCl3) δ 8.05 (s, 1H), 7.73 (dd, J = 6.7, 2.2 Hz, 1H), 7.41 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.15 (t, J = 8.5 Hz, 1H), 4.60 (d, J = 15.3 Hz, 1H), 4.44 (dd, J = 19.4, 9.6 Hz, 1H), 4.39 – 4.27 (m, 2H), 4.19 (dd, J = 20.2, 11.2 Hz, 1H), 4.07 – 3.99 (m, 0H), 1.65 (d, J = 21.4 Hz, 3H), 1.45 – 1.36 (m, 1H), 0.99 – 0.84 (m, 1H), 0.79 – 0.73 (m, 2H).13C NMR (151 MHz, CDCl3) δ 165.90 (d, J = 3.1 Hz), 163.15, 159.64, 158.00, 156.50, 147.82, 138.25, 135.45, 131.37 (d, J = 7.2 Hz), 131.15 (d, J = 3.8 Hz), 120.79, 119.94, 115.46 (d, J = 22.5 Hz), 107.88 (d, J = 21.3 Hz), 103.21, 90.71, 89.35, 67.75, 62.27 (d, J = 28.6 Hz), 60.71 (d, J = 27.9 Hz), 44.87, 22.99 (d, J = 25.5 Hz), 9.24, 0.66.19F NMR (565 MHz, CDCl3) δ -104.43 – -113.77 (m), -134.25 – -147.92 (m). HRMS: [APCI+] [M+H]+calc. for C23H19O2N3F2⁷⁹Br³²S, 518.0344, observed, 518.0358. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(phenylethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-288) Prepared by General Procedure X. White solid, 42%.1H NMR (600 MHz, CDCl3) δ 8.09 (s, 1H), 7.87 (dd, J = 6.7, 2.2 Hz, 1H), 7.51 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.46 – 7.38 (m, 2H), 7.37 – 7.30 (m, 4H), 7.20 (t, J = 8.5 Hz, 1H), 4.62 (d, J = 15.3 Hz, 1H), 4.45 (dd, J = 19.4, 9.5 Hz, 1H), 4.41 – 4.27 (m, 2H), 4.20 (dd, J = 20.2, 11.3 Hz, 1H), 4.04 (ddd, J = 17.4, 11.3, 1.5 Hz, 1H), 1.66 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.83 (d, J = 3.1 Hz), 164.02, 159.82, 158.17, 156.51, 148.12, 139.17, 135.56, 131.64, 131.47 (d, J = 7.3 Hz), 131.04 (d, J = 3.9 Hz), 129.23, 128.62, 122.07, 120.93, 118.90, 115.55 (d, J = 22.6 Hz), 108.01 (d, J = 21.1 Hz), 97.94, 90.71, 89.34, 81.63, 62.26 (d, J = 28.5 Hz), 60.71 (d, J = 28.1 Hz), 44.91, 22.99 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -95.24 – -120.80 (m), -124.98 – -149.34 (m). HRMS: [APCI+] [M+H]+calc. for C26H18O2N3F279Br32S, 554.0613, observed, 554.0623. Preparation of 5-(3-bromophenyl)-6-ethynyl-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-289) Prepared by General Procedure X. White solid (31 mg, 42% yield).1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.2, 2.0 Hz, 1H), 4.64 (d, J = 15.4 Hz, 1H), 4.43 (dd, J = 17.4, 12.4 Hz, 2H), 4.36 – 4.14 (m, 2H), 4.10 – 3.98 (m, 1H), 2.39 (s, 3H), 1.72 – 1.57 (m, 3H).13C NMR (150 MHz, CDCl3) δ 165.71 (d, J = 2.9 Hz), 163.89, 156.31, 148.62, 141.55, 135.21, 133.09, 131.32, 129.05, 128.88, 121.49, 120.79, 117.31, 90.59, 89.23, 85.70, 75.48, 62.35, 62.16, 60.78, 60.60, 44.89, 23.01, 22.84.19F NMR (565 MHz, CDCl3) δ -141.29 (h, J = 19.2 Hz). Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)thieno[2,3-d]pyrimidin- 4(3H)-one (1622-297) Prepared by General Procedure X. Off-white solid, 26%.1H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.74 (dd, J = 6.6, 2.2 Hz, 1H), 7.45 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.18 (t, J = 8.5 Hz, 1H), 4.73 (t, J = 3.4 Hz, 1H), 4.62 (d, J = 15.4 Hz, 1H), 4.50 – 4.43 (m, 3H), 4.37 – 4.30 (m, 2H), 4.21 (dd, J = 20.2, 11.3 Hz, 1H), 4.06 (ddd, J = 17.3, 11.2, 1.5 Hz, 1H), 3.82 (ddd, J = 12.0, 9.3, 2.9 Hz, 1H), 3.53 – 3.49 (m, 1H), 1.83 (dddd, J = 16.3, 13.0, 6.7, 3.7 Hz, 1H), 1.74 (dddd, J = 13.4, 10.4, 3.9, 3.1 Hz, 1H), 1.69 (s, 3H), 1.64 – 1.61 (m, 2H), 1.58 – 1.53 (m, 2H).13C NMR (151 MHz, CDCl3) δ 165.68 (d, J = 3.2 Hz), 163.82, 159.70, 158.06, 156.38, 148.10, 139.60, 135.29, 131.08 (d, J = 7.5 Hz), 130.88 (d, J = 3.9 Hz), 96.97, 94.07, 90.57, 89.21, 77.57, 62.22, 62.04 (d, J = 3.0 Hz), 60.59 (d, J = 27.9 Hz), 44.70, 30.21, 25.30, 22.77, 18.96.19F NMR (565 MHz, CDCl3) δ -107.97, -141.33. HRMS: [APCI+] [M+H]+calc. for C26H₁5O4N3F2⁷⁹Br³²S, 592.0712, observed, 592.0712. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-hydroxyprop-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-298) Prepared by General Procedure X. White solid, 70%.1H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.75 (dd, J = 6.6, 2.2 Hz, 1H), 7.45 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.19 (t, J = 8.5 Hz, 1H), 4.62 (d, J = 15.4 Hz, 1H), 4.45 (s, 3H), 4.38 – 4.32 (m, 2H), 4.22 (dd, J = 20.2, 11.3 Hz, 1H), 4.06 (ddd, J = 17.4, 11.2, 1.5 Hz, 1H), 1.67 (d, J = 21.4 Hz, 9H).13C NMR (151 MHz, CDCl3) δ 165.66 (d, J = 2.9 Hz), 163.94, 159.74, 158.09, 148.17, 139.67, 135.29, 131.07 (d, J = 7.5 Hz), 130.73 (d, J = 3.9 Hz), 120.73, 117.86, 115.56 (d, J = 22.6 Hz), 108.05 (d, J = 21.2 Hz), 95.76, 90.57, 89.21, 77.54, 62.13 (d, J = 28.5 Hz), 60.60 (d, J = 28.1 Hz), 51.58, 44.74, 22.86 (d, J = 25.8 Hz).19F NMR (565 MHz, CDCl3) δ -107.77, -141.33. HRMS: [APCI+] [M+H]+calc. for C21H17O3N3F2⁷⁹Br³²S, 508.0137, observed, 508.0142. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-hydroxybut-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-310) Prepared by General Procedure X. White solid, 11%.1H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.77 (dd, J = 6.6, 2.2 Hz, 1H), 7.45 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.19 (t, J = 8.5 Hz, 1H), 4.72 – 4.68 (m, 1H), 4.62 (dd, J = 15.4, 2.5 Hz, 1H), 4.51 – 4.43 (m, 1H), 4.39 – 4.31 (m, 2H), 4.26 – 4.19 (m, 1H), 4.06 (dd, J = 17.4, 11.3 Hz, 1H), 1.68 (d, J = 21.4 Hz, 3H), 1.50 (d, J = 6.6 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.67 (d, J = 3.2 Hz), 163.89, 159.70, 158.05, 156.39, 148.11, 139.57, 135.29, 131.20 (d, J = 7.3 Hz), 130.70 (d, J = 3.9 Hz), 120.66, 117.90, 115.47 (d, J = 22.6 Hz), 107.90 (d, J = 21.3 Hz), 99.37, 90.57, 89.21, 76.04, 62.13 (d, J = 28.8 Hz), 60.59 (d, J = 27.9 Hz), 58.86, 44.75.19F NMR (376 MHz, CDCl3) δ -107.82, -141.37. HRMS: [APCI+] [M+H]+calc. for C22H19O3N3F2⁷⁹Br³²S, 522.0293, observed, 522.0300. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-methoxyprop-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-311) Prepared by General Procedure X. Off-white solid, 7%.1H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.76 (dd, J = 6.6, 2.1 Hz, 1H), 7.45 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.19 (t, J = 8.5 Hz, 1H), 4.63 (d, J = 15.4 Hz, 1H), 4.47 (dd, J = 19.3, 9.5 Hz, 1H), 4.39 – 4.30 (m, 2H), 4.28 (s, 2H), 4.22 (dd, J = 20.1, 11.2 Hz, 1H), 4.10 – 4.02 (m, 1H), 3.37 (s, 3H), 1.68 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.66 (d, J = 3.2 Hz), 163.89, 159.73, 158.08, 156.39, 148.16, 139.73, 135.26, 131.12 (d, J = 7.5 Hz), 130.82 (d, J = 3.9 Hz), 120.73, 117.97, 115.52 (d, J = 22.6 Hz), 108.04 (d, J = 21.1 Hz), 93.80, 90.57, 89.21, 78.23, 62.13 (d, J = 28.5 Hz), 60.60 (d, J = 28.0 Hz), 60.30, 57.87, 44.73, 22.86 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -107.83, -141.33. HRMS: [APCI+] [M+H]+calc. for C22H19O3N3F2⁷⁹Br³²S, 522.0293, observed, 522.0298. Preparation of 5-(3-bromo-4-fluorophenyl)-6-(cyclopentylethynyl)-3-(2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-312) Prepared by General Procedure X. Off-white solid, 95%.1H NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.79 (dd, J = 6.7, 2.2 Hz, 1H), 7.45 (ddd, J = 8.6, 4.7, 2.2 Hz, 1H), 7.17 (t, J = 8.5 Hz, 1H), 4.62 (d, J = 15.4 Hz, 1H), 4.46 (dd, J = 19.4, 9.6 Hz, 1H), 4.41 – 4.32 (m, 2H), 4.21 (dd, J = 20.2, 11.3 Hz, 1H), 4.05 (ddd, J = 17.4, 11.3, 1.6 Hz, 1H), 2.80 (p, J = 7.4 Hz, 1H), 1.98 – 1.88 (m, 2H), 1.76 – 1.62 (m, 7H), 1.58 (td, J = 7.3, 3.9 Hz, 2H).13C NMR (151 MHz, CDCl3) δ 165.79 (d, J = 2.9 Hz), 163.05, 159.49, 157.84, 156.40, 147.65, 137.89, 135.35, 131.30 (d, J = 7.2 Hz), 131.06 (d, J = 3.9 Hz), 120.67, 119.93, 115.25 (d, J = 22.3 Hz), 107.72 (d, J = 21.1 Hz), 104.23, 90.58, 89.22, 72.14, 62.13 (d, J = 28.4 Hz), 60.57 (d, J = 28.1 Hz), 44.74, 33.51, 30.99, 22.85 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -108.49, -141.38. HRMS: [APCI+] [M+H]+calc. for C25H23O2N3F2⁷⁹Br³²S, 546.0657, observed, 546.0662. Preparation of 5-(3-bromo-4-fluorophenyl)-6-(cyclobutylethynyl)-3-(2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-313) Prepared by General Procedure X. Off-white solid, 12%.1H NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.81 (dd, J = 6.7, 2.2 Hz, 1H), 7.46 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.18 (t, J = 8.5 Hz, 1H), 4.63 (d, J = 15.4 Hz, 1H), 4.50 – 4.43 (m, 1H), 4.38 – 4.32 (m, 2H), 4.21 (dd, J = 20.2, 11.3 Hz, 1H), 4.06 (ddd, J = 17.4, 11.3, 1.5 Hz, 1H), 3.19 (pd, J = 8.3, 1.1 Hz, 1H), 2.35 – 2.28 (m, 2H), 2.20 – 2.12 (m, 2H), 2.02 – 1.90 (m, 2H), 1.67 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.78 (d, J = 2.9 Hz), 163.17, 159.52, 157.87, 156.40, 147.68, 138.00, 135.38, 131.31 (d, J = 7.3 Hz), 131.02 (d, J = 4.1 Hz), 120.69, 119.75, 115.30 (d, J = 22.4 Hz), 107.75 (d, J = 21.4 Hz), 103.26, 90.58, 89.22, 73.33, 62.13 (d, J = 28.5 Hz), 60.57 (d, J = 28.1 Hz), 44.75, 29.65, 25.69, 22.86 (d, J = 25.5 Hz), 19.30.19F NMR (565 MHz, CDCl3) δ -108.43, -141.38. Preparation of 5-(3-bromo-4-fluorophenyl)-6-(cyclohexylethynyl)-3-(2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-314) Prepared by General Procedure X. Off-white solid, 77%.1H NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.79 (dd, J = 6.7, 2.2 Hz, 1H), 7.45 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.17 (t, J = 8.5 Hz, 1H), 4.62 (d, J = 15.4 Hz, 1H), 4.46 (ddd, J = 19.5, 9.7, 1.5 Hz, 1H), 4.39 – 4.31 (m, 2H), 4.21 (dd, J = 20.2, 11.3 Hz, 1H), 4.05 (ddd, J = 17.3, 11.2, 1.6 Hz, 1H), 1.82 – 1.75 (m, 2H), 1.67 (d, J = 21.4 Hz, 7H), 1.54 – 1.44 (m, 3H), 1.40 – 1.29 (m, 3H).13C NMR (151 MHz, CDCl3) δ 165.92, 163.30, 159.65, 158.00, 156.54, 147.81, 138.13, 135.51, 131.45 (d, J = 7.2 Hz), 131.15 (d, J = 4.3 Hz), 120.83, 119.88, 115.44 (d, J = 22.7 Hz), 107.96, 107.82, 103.37, 90.71, 89.34, 73.44, 62.27 (d, J = 28.4 Hz), 60.71 (d, J = 28.1 Hz), 44.88, 29.69, 25.99, 22.99 (d, J = 25.4 Hz), 19.43.19F NMR (565 MHz, CDCl3) δ -108.42 (d, J = 5.3 Hz), -137.31 – -146.43 (m). HRMS: [APCI+] [M+H]+calc. for C26H25O2N3F2⁷⁹Br³²S, 560.0813, observed, 560.0820. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-methylbut-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-315) General Procedure X. White solid, 61%.1H NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.80 (dd, J = 6.7, 2.2 Hz, 1H), 7.45 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.17 (t, J = 8.5 Hz, 1H), 4.63 (d, J = 15.4 Hz, 1H), 4.51 – 4.43 (m, 1H), 4.39 – 4.31 (m, 2H), 4.21 (dd, J = 20.2, 11.3 Hz, 1H), 4.06 (ddd, J = 17.4, 11.3, 1.5 Hz, 1H), 2.74 (p, J = 6.9 Hz, 1H), 1.67 (d, J = 21.4 Hz, 3H), 1.21 (d, J = 6.9 Hz, 6H).13C NMR (151 MHz, CDCl3) δ 165.78 (d, J = 3.2 Hz), 163.11, 159.50, 157.86, 156.40, 147.69, 138.05, 135.38, 131.33 (d, J = 7.6 Hz), 130.98 (d, J = 3.9 Hz), 120.66, 119.69, 115.26 (d, J = 22.6 Hz), 107.70 (d, J = 21.0 Hz), 105.04, 90.58, 89.22, 71.89, 62.13 (d, J = 28.5 Hz), 60.57 (d, J = 28.0 Hz), 44.74, 22.86 (d, J = 25.7 Hz), 21.54.19F NMR (565 MHz, CDCl3) δ -108.46, - 141.38. HRMS: [APCI+] [M+H]+calc. for C23H21O2N3F2⁷⁹Br³²S, 520.0500, observed, 520.0505. Preparation of 5-(3-bromo-4-fluorophenyl)-6-(3,3-dimethylbut-1-yn-1-yl)-3-(2-(3- fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-316) Prepared by General Procedure X. Off-white solid, 70%.1H NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.81 (dd, J = 6.7, 2.2 Hz, 1H), 7.45 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.17 (t, J = 8.5 Hz, 1H), 4.62 (d, J = 15.4 Hz, 1H), 4.50 – 4.44 (m, 1H), 4.39 – 4.31 (m, 2H), 4.21 (dd, J = 20.2, 11.3 Hz, 1H), 4.06 (ddd, J = 17.3, 11.2, 1.5 Hz, 1H), 1.67 (d, J = 21.4 Hz, 3H), 1.25 (s, 9H).13C NMR (151 MHz, CDCl3) δ 165.79 (d, J = 3.2 Hz), 163.10, 159.47, 157.82, 156.40, 147.66, 138.01, 135.38, 131.39 (d, J = 7.2 Hz), 130.98 (d, J = 3.9 Hz), 120.62, 119.73, 107.95 – 107.17 (m), 90.58, 89.22, 71.30, 62.13 (d, J = 28.5 Hz), 60.57 (d, J = 28.2 Hz), 44.75, 30.45, 28.47, 22.85 (d, J = 25.6 Hz).19F NMR (565 MHz, CDCl3) δ -108.50, -141.34. HRMS: [APCI+] [M+H]+calc. for C24H23O2N3F2⁷⁹Br³²S, 534.0657, observed, 324.0660. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-((3-hydroxyazetidin-3-yl)ethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-317) Prepared by General Procedure X. Off-white solid, 41%.1H NMR (600 MHz, CD3OD) δ 8.36 (s, 1H), 7.83 (dd, J = 6.7, 2.2 Hz, 1H), 7.57 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.30 (t, J = 8.6 Hz, 1H), 4.76 – 4.66 (m, 2H), 4.45 (dddd, J = 46.4, 17.6, 10.1, 1.6 Hz, 3H), 4.24 (d, J = 10.8 Hz, 2H), 4.19 – 4.02 (m, 5H), 1.66 (d, J = 21.5 Hz, 4H).13C NMR (151 MHz, CD3OD) δ 167.18 (d, J = 3.3 Hz), 164.35, 159.78, 158.14, 156.68, 149.90, 140.70, 135.10, 131.35 (d, J = 7.7 Hz), 130.98 (d, J = 4.1 Hz), 120.45, 115.92, 115.21 (d, J = 22.8 Hz), 107.21 (d, J = 21.3 Hz), 94.98, 90.69, 89.34, 77.69, 64.04, 61.67 (d, J = 28.7 Hz), 60.25 – 59.92 (m), 45.46, 21.32 (d, J = 25.5 Hz).19F NMR (565 MHz, CD3OD) δ -76.93, -109.90, -142.73. HRMS: [APCI+] [M+H]+calc. for C23H20O3N4F2⁷⁹Br³²S, 549.0402, observed, 549.0411. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-((2-hydroxybicyclo[2.2.1]heptan-1-yl)ethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-318) Prepared by General Procedure X. White solid, 53%.1H NMR (600 MHz, CDCl3) δ 8.09 (s, 1H), 7.77 (dd, J = 6.6, 2.2 Hz, 1H), 7.44 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.18 (t, J = 8.5 Hz, 1H), 4.62 (d, J = 15.4 Hz, 1H), 4.50 – 4.44 (m, 1H), 4.39 – 4.31 (m, 2H), 4.22 (dd, J = 20.2, 11.3 Hz, 1H), 4.09 – 4.02 (m, 1H), 2.41 (dd, J = 15.7, 4.3 Hz, 1H), 2.28 (t, J = 5.0 Hz, 1H), 2.14 – 2.09 (m, 1H), 1.99 (dddd, J = 13.2, 9.1, 4.5, 2.3 Hz, 2H), 1.67 (d, J = 21.4 Hz, 3H), 1.65 – 1.57 (m, 5H), 1.45 – 1.30 (m, 5H).13C NMR (151 MHz, CDCl3) δ 165.69 (d, J = 2.9 Hz), 163.68, 159.63, 157.98, 156.39, 147.97, 139.11, 135.25, 131.31 (d, J = 7.2 Hz), 130.89 (d, J = 3.9 Hz), 120.67, 118.50, 115.41 (d, J = 22.6 Hz), 107.87 (d, J = 21.2 Hz), 103.19, 90.57, 89.21, 75.21, 73.91 (d, J = 13.7 Hz), 62.12 (d, J = 28.4 Hz), 60.59 (d, J = 27.9 Hz), 49.64 (d, J = 10.0 Hz), 47.66 (d, J = 10.5 Hz), 44.75, 38.97, 36.90, 28.66, 22.77, 21.00.19F NMR (565 MHz, CDCl3) δ -107.95, -141.35. HRMS: [APCI+] [M+H]+calc. for C27H25O3N3F2⁷⁹Br³²S, 588.0763, observed, 588.0772. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-hydroxy-5-methylhex-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-319) Prepared by General Procedure X. White solid, 30%.1H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.75 (dd, J = 6.6, 2.2 Hz, 1H), 7.43 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.18 (t, J = 8.5 Hz, 1H), 4.64 – 4.56 (m, 2H), 4.49 – 4.44 (m, 1H), 4.38 – 4.32 (m, 2H), 4.22 (dd, J = 20.2, 11.2 Hz, 1H), 4.09 – 4.02 (m, 1H), 1.74 – 1.68 (m, 3H), 1.64 (d, J = 7.3 Hz, 2H), 1.60 – 1.55 (m, 2H), 0.93 (dd, J = 9.0, 6.6 Hz, 6H).13C NMR (151 MHz, CDCl3) δ 165.66 (d, J = 2.9 Hz), 163.80, 159.70, 158.05, 156.38, 148.09, 139.52, 135.23, 131.16 (d, J = 7.5 Hz), 130.86 (d, J = 3.9 Hz), 120.74, 118.10, 115.48 (d, J = 22.6 Hz), 107.96 (d, J = 21.1 Hz), 90.57, 89.21, 62.11 (d, J = 28.6 Hz), 61.59, 60.59 (d, J = 27.8 Hz), 46.41, 44.72, 24.78, 22.85 (d, J = 25.5 Hz), 22.47 (d, J = 3.0 Hz).19F NMR (565 MHz, CDCl3) δ -107.92, -141.32. HRMS: [APCI+] [M+H]+calc. for C25H25O3N3F2⁷⁹Br³²S, 564.0763, observed, 564.0771. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-((3-hydroxyoxetan-3-yl)ethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-320) Prepared by General Procedure X. White solid, 25%.1H NMR (600 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.83 (dd, J = 6.8, 2.2 Hz, 1H), 7.65 – 7.53 (m, 2H), 7.46 (t, J = 8.7 Hz, 1H), 6.69 (s, 1H), 4.69 (d, J = 1.7 Hz, 2H), 4.63 (d, J = 6.4 Hz, 2H), 4.56 – 4.53 (m, 2H), 4.44 – 4.30 (m, 2H), 4.05 – 3.94 (m, 2H), 1.60 (d, J = 22.1 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 166.26 (d, J = 2.9 Hz), 163.21, 158.86, 157.23, 155.80, 150.45, 139.50, 134.98, 132.11 – 131.61 (m), 131.58 – 130.83 (m), 128.76 (d, J = 11.7 Hz), 120.23, 116.02 – 115.48 (m), 106.82 (d, J = 21.4 Hz), 98.03, 91.68, 90.34, 83.50, 76.30, 65.93, 61.28 (d, J = 27.5 Hz), 60.00 (d, J = 27.2 Hz), 45.35, 22.35 (d, J = 24.9 Hz).19F NMR (565 MHz, DMSO-d6): δ -108.80, -139.11. HRMS: [APCI+] [M+H]+calc. for C23H19O4N3F2⁷⁹Br³²S, 550.0242, observed, 550.0250. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-hydroxypent-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-321) Prepared by General Procedure X. White solid, 33%.1H NMR (600 MHz, DMSO) δ 8.43 (s, 1H), 7.76 (dd, J = 6.8, 2.1 Hz, 1H), 7.49 (ddd, J = 8.5, 4.9, 2.2 Hz, 1H), 7.43 (t, J = 8.7 Hz, 1H), 4.68 (d, J = 1.9 Hz, 2H), 4.42 – 4.27 (m, 3H), 4.04 – 3.92 (m, 2H), 1.66 – 1.50 (m, 5H), 0.81 (t, J = 7.4 Hz, 3H).13C NMR (151 MHz, DMSO) δ 166.74 (d, J = 2.8 Hz), 163.22, 159.26, 157.63, 156.24, 150.72, 139.16, 135.35, 132.23 (d, J = 7.4 Hz), 131.68 (d, J = 3.9 Hz), 120.80, 116.95, 116.05 (d, J = 22.4 Hz), 107.29 (d, J = 21.2 Hz), 100.99, 92.15, 90.81, 75.48, 62.62, 61.74 (d, J = 27.6 Hz), 60.47 (d, J = 27.2 Hz), 45.79, 30.78, 22.82 (d, J = 25.2 Hz), 9.74.19F NMR (565 MHz, DMSO) δ -109.14, -139.08. HRMS: [APCI+] [M+H]+calc. for C23H21O3N3F2⁷⁹Br³²S, 536.0450, observed, 536.0459. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-hydroxy-4-methylpent-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622- 322) Prepared by General Procedure X. White solid, 49%.1H NMR (600 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.74 (dd, J = 6.8, 2.1 Hz, 1H), 7.47 (ddd, J = 8.5, 4.9, 2.1 Hz, 1H), 7.41 (t, J = 8.7 Hz, 1H), 5.50 (d, J = 5.4 Hz, 1H), 4.67 (d, J = 2.0 Hz, 2H), 4.41 – 4.30 (m, 2H), 4.20 (d, J = 5.5 Hz, 1H), 4.02 – 3.94 (m, 2H), 1.74 – 1.69 (m, 1H), 1.59 (d, J = 22.1 Hz, 3H), 0.80 (dd, J = 6.8, 3.3 Hz, 6H).13C NMR (151 MHz, DMSO-d6) δ 166.74 (d, J = 2.7 Hz), 163.16, 159.28, 157.65, 156.23, 150.71, 139.15, 135.30, 132.24 (d, J = 7.6 Hz), 131.84 (d, J = 3.8 Hz), 120.88, 116.08 (d, J = 22.3 Hz), 107.38 (d, J = 21.2 Hz), 99.96, 92.14, 90.80, 76.09, 66.83, 61.74 (d, J = 27.5 Hz), 60.46 (d, J = 27.2 Hz), 45.78, 34.53, 22.81 (d, J = 25.1 Hz), 18.15 (d, J = 117.8 Hz).19F NMR (565 MHz, DMSO-d6) δ -109.23, -139.08. HRMS: [APCI+] [M+H]+calc. for C24H23O3N3F2⁷⁹Br³²S, 550.0606, observed, 550.0613. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-hydroxy-3-methylpent-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622- 323) Prepared by General Procedure X. White solid, 22%.1H NMR (600 MHz, DMSO-d6): δ 8.43 (s, 1H), 7.77 (dd, J = 6.8, 2.2 Hz, 1H), 7.49 (ddd, J = 8.5, 4.9, 2.2 Hz, 1H), 7.43 (t, J = 8.7 Hz, 1H), 5.45 (s, 1H), 4.68 (d, J = 2.0 Hz, 2H), 4.42 – 4.29 (m, 2H), 4.04 – 3.94 (m, 2H), 1.63 – 1.50 (m, 5H), 1.33 (s, 3H), 0.81 (t, J = 7.4 Hz, 3H).13C NMR (151 MHz, DMSO-d6): δ 166.76 (d, J = 2.7 Hz), 163.17, 159.23, 157.60, 156.23, 150.67, 139.12, 135.32, 132.34 (d, J = 7.7 Hz), 131.65 (d, J = 3.8 Hz), 120.76, 117.04, 116.00 (d, J = 22.4 Hz), 107.23 (d, J = 21.4 Hz), 103.48, 92.14, 90.80, 74.22, 67.86, 61.75 (d, J = 27.6 Hz), 60.47 (d, J = 27.2 Hz), 45.80, 36.46, 29.29, 22.82 (d, J = 25.2 Hz), 9.26.19F NMR (565 MHz, DMSO-d6): δ -109.20, -139.08. HRMS: [APCI+] [M+H]+calc. for C24H23O3N3F2⁷⁹Br³²S, 550.0606, observed, 550.0612. Preparation of 5-(3-bromo-4-fluorophenyl)-6-(3-cyclopropyl-3-hydroxyprop-1-yn-1- yl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-324) Prepared by General Procedure X. White solid, 23%.1H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.74 (dd, J = 6.6, 2.2 Hz, 1H), 7.43 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.19 (t, J = 8.5 Hz, 1H), 4.62 (dd, J = 15.4, 3.2 Hz, 1H), 4.47 (dd, J = 19.4, 9.6 Hz, 1H), 4.38 – 4.31 (m, 3H), 4.22 (dd, J = 20.2, 11.3 Hz, 1H), 4.06 (dd, J = 17.4, 11.2 Hz, 1H), 1.95 (d, J = 6.3 Hz, 1H), 1.67 (d, J = 21.4 Hz, 3H), 1.29 – 1.23 (m, 1H), 0.63 – 0.51 (m, 2H), 0.40 – 0.33 (m, 2H).13C NMR (151 MHz, CDCl3) δ 165.64 (d, J = 3.1 Hz), 163.88, 159.72, 156.37, 148.13, 139.66, 135.21, 131.14 (d, J = 7.2 Hz), 130.83 (d, J = 4.1 Hz), 120.72, 117.91, 115.52 (d, J = 22.5 Hz), 108.03 (d, J = 21.1 Hz), 96.54, 90.57, 89.20, 66.27, 62.11 (d, J = 28.6 Hz), 60.59 (d, J = 27.7 Hz), 44.71, 22.86 (d, J = 25.5 Hz), 17.08, 3.34, 1.72, 0.01.19F NMR (565 MHz, CDCl3) δ -107.86, -141.33. HRMS: [APCI+] [M+H]+calc. for C24H21O3N3F2⁷⁹Br³²S, 548.0450, observed, 548.0453. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-((1-hydroxycyclopentyl)ethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-325) Prepared by General Procedure X. Off-white solid, 26%.1H NMR (600 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.79 (dd, J = 6.8, 2.2 Hz, 1H), 7.50 (ddd, J = 8.6, 4.9, 2.2 Hz, 1H), 7.43 (t, J = 8.7 Hz, 1H), 4.68 (d, J = 2.0 Hz, 2H), 4.43 – 4.28 (m, 2H), 1.86 – 1.63 (m, 5H), 1.63 – 1.53 (m, 4H).13C NMR (151 MHz, DMSO-d6) δ 166.76 (d, J = 2.9 Hz), 163.18, 159.20, 157.57, 156.24, 150.64, 138.93, 135.36, 132.35 (d, J = 7.5 Hz), 131.57 (d, J = 3.8 Hz), 120.70, 117.11, 115.97 (d, J = 22.4 Hz), 107.16 (d, J = 21.1 Hz), 103.76, 92.15, 90.81, 74.06, 73.43, 61.75 (d, J = 27.6 Hz), 60.47 (d, J = 27.2 Hz), 45.81, 42.13, 23.44, 22.82 (d, J = 25.1 Hz).19F NMR (565 MHz, DMSO-d6) δ - 109.11, -109.12, -139.08, -139.11. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-((1-hydroxycyclohexyl)ethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-326) Prepared by General Procedure X. White solid, 46%.1H NMR (600 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.77 (dd, J = 6.8, 2.2 Hz, 1H), 7.48 (ddd, J = 8.5, 4.9, 2.2 Hz, 1H), 7.43 (t, J = 8.7 Hz, 1H), 5.56 (s, 1H), 4.67 (d, J = 2.2 Hz, 2H), 4.43 – 4.29 (m, 2H), 4.04 – 3.95 (m, 2H), 1.76 (dd, J = 11.0, 5.7 Hz, 2H), 1.60 (d, J = 22.1 Hz, 3H), 1.54 (dt, J = 13.1, 4.4 Hz, 2H), 1.42 (td, J = 11.7, 3.7 Hz, 3H), 1.24 – 1.08 (m, 4H).13C NMR (151 MHz, DMSO-d6) δ 166.75 (d, J = 2.9 Hz), 163.05, 159.25, 157.62, 150.67, 139.18, 135.25, 132.32 (d, J = 7.5 Hz), 131.87 (d, J = 3.8 Hz), 120.87, 116.02 (d, J = 22.5 Hz), 107.31 (d, J = 21.1 Hz), 103.42, 92.14, 90.80, 67.91, 61.74 (d, J = 27.6 Hz), 60.46 (d, J = 27.2 Hz), 45.78, 25.20, 23.13, 22.81 (d, J = 25.1 Hz).19F NMR (565 MHz, DMSO-d6) δ -109.22, -139.12. HRMS: [APCI+] [M+H]+calc. for C26H25O3N3F2⁷⁹Br³²S, 576.0763, observed, 576.0759. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(oxetan-3-ylethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-327) Prepared by General Procedure X. Off-white solid, 32%.1H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.79 (dd, J = 6.6, 2.2 Hz, 1H), 7.46 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.19 (t, J = 8.5 Hz, 1H), 4.85 (dd, J = 8.5, 5.6 Hz, 2H), 4.72 (dd, J = 7.3, 5.6 Hz, 2H), 4.63 (d, J = 15.4 Hz, 1H), 4.51 – 4.43 (m, 1H), 4.40 – 4.31 (m, 2H), 4.22 (dd, J = 20.2, 11.3 Hz, 1H), 4.10 – 4.00 (m, 2H), 1.68 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.67 (d, J = 3.2 Hz), 163.65, 159.68, 158.03, 156.38, 139.13, 135.28, 131.17 (d, J = 7.2 Hz), 130.81 (d, J = 4.1 Hz), 118.39, 115.50 (d, J = 22.6 Hz), 107.95 (d, J = 21.1 Hz), 96.98, 90.57, 89.21, 62.12 (d, J = 28.7 Hz), 60.59 (d, J = 28.1 Hz), 44.73, 26.69, 22.86 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -107.84, -141.33. HRMS: [APCI+] [M+H]+calc. for C23H19O3N3F2⁷⁹Br³²S, 534.0293, observed, 534.0301. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-((tetrahydrofuran-3-yl)ethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-328) Prepared by General Procedure X. Off-white solid, 23%.1H NMR (600 MHz, CDCl3) δ 8.09 (s, 1H), 7.77 (dd, J = 6.6, 2.2 Hz, 1H), 7.44 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.18 (t, J = 8.5 Hz, 1H), 4.62 (dd, J = 15.4, 3.3 Hz, 1H), 4.46 (dd, J = 19.4, 9.6 Hz, 1H), 4.39 – 4.31 (m, 2H), 4.21 (dd, J = 20.2, 11.3 Hz, 1H), 4.09 – 4.00 (m, 2H), 3.93 – 3.83 (m, 2H), 3.66 (dd, J = 8.3, 6.8 Hz, 1H), 3.17 (dq, J = 8.5, 6.9 Hz, 1H), 2.25 (dddd, J = 12.2, 8.5, 7.4, 6.3 Hz, 1H), 2.02 – 1.95 (m, 1H), 1.67 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.71 (d, J = 3.2 Hz), 163.40, 159.59, 157.94, 156.38, 147.91, 138.74, 135.28, 131.25 (d, J = 7.2 Hz), 130.89 (d, J = 4.0 Hz), 120.65, 118.89, 115.39 (d, J = 22.5 Hz), 107.80 (d, J = 21.1 Hz), 99.39, 90.57, 89.21, 73.71, 72.82, 67.99, 62.11 (d, J = 28.5 Hz), 60.58 (d, J = 28.1 Hz), 44.73, 33.29, 31.06, 22.86 (d, J = 25.7 Hz).19F NMR (565 MHz, CDCl3) δ -108.04, -108.06, -141.33, -141.37. HRMS: [APCI+] [M+H]+calc. for C24H21O3N3F2⁷⁹Br³²S, 548.0450, observed, 548.0454. Preparation of 5-(3-bromo-4-fluorophenyl)-6-(3-cyclopentyl-3-hydroxyprop-1-yn-1- yl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-330) Prepared by General Procedure X. White solid, 28%.1H NMR (600 MHz, CDCl3) δ 8.09 (s, 1H), 7.73 (dd, J = 6.6, 2.2 Hz, 1H), 7.43 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.18 (t, J = 8.5 Hz, 1H), 4.62 (dd, J = 15.4, 2.4 Hz, 1H), 4.50 – 4.30 (m, 5H), 4.21 (dd, J = 20.2, 11.3 Hz, 1H), 4.09 – 4.01 (m, 1H), 2.20 (td, J = 8.2, 7.1 Hz, 1H), 1.97 (dd, J = 4.6, 1.5 Hz, 1H), 1.80 – 1.71 (m, 2H), 1.67 (d, J = 21.4 Hz, 4H), 1.60 – 1.53 (m, 4H), 1.39 – 1.29 (m, 2H).13C NMR (151 MHz, CDCl3) δ 165.65 (d, J = 3.2 Hz), 163.77, 159.70, 158.05, 156.38, 148.08, 139.43, 135.20, 131.17 (d, J = 7.3 Hz), 130.95 (d, J = 3.9 Hz), 120.76, 118.22, 115.48 (d, J = 22.6 Hz), 108.03 (d, J = 21.3 Hz), 98.45, 90.57, 89.21, 66.82, 62.10 (d, J = 28.6 Hz), 60.59 (d, J = 28.0 Hz), 46.03, 44.70, 28.81, 28.34, 25.68, 22.86 (d, J = 25.7 Hz).19F NMR (565 MHz, CDCl3) δ -107.96, -141.32, -141.36. HRMS: [APCI+] [M+H]+calc. for C26H25O3N3F2⁷⁹Br³²S, 576.0763, observed, 576.0768. Preparation of N-(3-(5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1- yl)-2-oxoethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)prop-2-yn-1-yl)-2,2,2- trifluoroacetamide (1622-331) Prepared by General Procedure X. Off-white solid, 36%.1H NMR (600 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.43 (s, 1H), 7.73 (dd, J = 6.8, 2.2 Hz, 1H), 7.49 (ddd, J = 8.5, 4.8, 2.2 Hz, 1H), 7.36 (t, J = 8.7 Hz, 1H), 4.67 (s, 1H), 4.44 – 4.27 (m, 2H), 4.23 (s, 2H), 4.04 – 3.92 (m, 2H), 1.59 (d, J = 22.0 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 166.27 (d, J = 2.8 Hz), 162.96, 158.85, 155.78, 150.44, 139.43, 135.00, 131.63 – 131.35 (m), 131.01 (d, J = 3.9 Hz), 128.77 (d, J = 12.1 Hz), 120.30, 115.69 (d, J = 13.8 Hz), 115.49, 106.90 (d, J = 21.5 Hz), 93.22, 91.69, 90.35, 74.39, 61.28 (d, J = 27.3 Hz), 60.01 (d, J = 27.1 Hz), 45.34, 29.56, 22.35 (d, J = 24.9 Hz).19F NMR (565 MHz, DMSO-d6) δ -74.31, -106.45 – -112.80 (m), -138.58 – -141.35 (m). HRMS: [APCI+] [M+H]+calc. for C23H17O3N4F5⁷⁹Br³²S, 603.0119, observed 603.0119. Preparation of 6-((1-aminocyclobutyl)ethynyl)-5-(3-bromo-4-fluorophenyl)-3-(2-(3- fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one trifluoroacetate (1622-332) Prepared by General Procedure X. Off-white solid, 50%.1H NMR (600 MHz, DMSO-d6) δ 8.64 (s, 2H), 8.47 (s, 1H), 7.86 (dd, J = 6.8, 2.2 Hz, 1H), 7.57 (ddd, J = 8.6, 4.8, 2.2 Hz, 1H), 7.47 (t, J = 8.7 Hz, 1H), 4.69 (d, J = 3.2 Hz, 2H), 4.45 – 4.29 (m, 2H), 4.09 – 3.90 (m, 2H), 2.46 (td, J = 9.3, 3.0 Hz, 2H), 2.39 – 2.31 (m, 2H), 2.01 – 1.93 (m, 2H), 1.60 (d, J = 22.1 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 166.24 (d, J = 2.9 Hz), 163.49, 158.96, 157.33, 155.80, 150.72, 140.47, 134.91, 131.88 (d, J = 7.7 Hz), 130.84 (d, J = 3.8 Hz), 120.24, 115.73 (d, J = 22.6 Hz), 114.68, 106.91 (d, J = 21.2 Hz), 96.07, 91.69, 90.36, 77.58, 61.29 (d, J = 27.6 Hz), 60.02 (d, J = 27.2 Hz), 48.62, 45.38, 33.83, 22.36 (d, J = 25.2 Hz), 14.33.19F NMR (565 MHz, DMSO-d6) δ 109.70, 79.15. HRMS: [APCI+] [M+H]+calc. for C24H22O2N4F2⁷⁹Br³²S, 547.0609, observed, 547.0610. Preparation of 6-((3-aminooxetan-3-yl)ethynyl)-5-(3-bromo-4-fluorophenyl)-3-(2-(3- fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one trifluoroacetate (1622-333) Prepared by General Procedure X. Off-white solid, 35%.1H NMR (600 MHz, DMSO-d6) δ 9.62 (brs, 3H), 9.12 (s, 1H), 8.49 (dd, J = 6.8, 2.2 Hz, 1H), 8.23 (ddd, J = 8.6, 4.8, 2.2 Hz, 1H), 8.10 (t, J = 8.7 Hz, 1H), 5.39 (d, J = 7.3 Hz, 2H), 5.37 – 5.31 (m, 4H), 5.09 – 4.92 (m, 2H), 4.70 – 4.58 (m, 2H), 2.24 (d, J = 22.1 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 167.41 (d, J = 2.8 Hz), 164.96, 160.20, 158.96 (d, J = 31.4 Hz), 158.57, 157.00, 152.03, 142.07, 136.19, 132.95 (d, J = 7.6 Hz), 131.82 (d, J = 3.7 Hz), 121.39, 117.00 (d, J = 22.4 Hz), 115.27, 108.17 (d, J = 21.1 Hz), 93.40, 92.87, 91.54, 80.79, 79.89, 62.47 (d, J = 27.6 Hz), 61.20 (d, J = 27.2 Hz), 56.10, 50.08, 46.57, 23.53 (d, J = 25.0 Hz).19F NMR (565 MHz, DMSO-d6) δ -106.92, -138.37, -174.57 – - 175.22 (m). HRMS: [APCI+] [M+H]+calc. for C23H20O3N4F2⁷⁹Br³²S, 549.0402, observed, 549.0408. Preparation of N-(3-(5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1- yl)-2-oxoethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)prop-2-yn-1-yl)acetamide (1622-334) Prepared by General Procedure X. White solid, 38%.1H NMR (600 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.33 (t, J = 5.5 Hz, 1H), 7.73 (dd, J = 6.8, 2.2 Hz, 1H), 7.49 (ddd, J = 8.5, 4.8, 2.2 Hz, 1H), 7.41 (t, J = 8.7 Hz, 1H), 4.67 (s, 1H), 4.46 – 4.27 (m, 2H), 4.05 (d, J = 5.5 Hz, 2H), 4.03 – 3.92 (m, 2H), 1.82 (s, 3H), 1.59 (d, J = 22.1 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 169.00, 166.28 (d, J = 2.7 Hz), 162.76, 158.80, 157.17, 155.78, 150.31, 135.01, 131.56 (d, J = 7.7 Hz), 131.07 (d, J = 4.0 Hz), 120.29, 116.27, 115.64 (d, J = 22.6 Hz), 106.94, 95.71, 91.68, 90.35, 73.29, 61.28 (d, J = 27.7 Hz), 60.01 (d, J = 27.2 Hz), 45.33, 28.68, 22.35 (d, J = 25.0 Hz), 22.34.19F NMR (565 MHz, DMSO-d6) δ -102.94 – -113.25 (m), -133.50 – -147.70 (m). Preparation of (R)-5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1- yl)-2-oxoethyl)-6-(3-hydroxybut-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-335) Prepared by General Procedure X. White solid, 23%.1H NMR (600 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.77 (dd, J = 6.8, 2.2 Hz, 1H), 7.50 (ddd, J = 8.5, 4.9, 2.2 Hz, 1H), 7.43 (t, J = 8.7 Hz, 1H), 5.52 (d, J = 4.9 Hz, 1H), 4.67 (d, J = 1.9 Hz, 2H), 4.57 – 4.50 (m, 1H), 4.43 – 4.29 (m, 2H), 4.04 – 3.93 (m, 2H), 1.59 (d, J = 22.1 Hz, 3H), 1.29 (d, J = 6.6 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 166.29 (d, J = 3.0 Hz), 162.81, 158.78, 157.15, 155.79, 150.26, 134.96, 131.77 (d, J = 7.7 Hz), 120.27, 116.37, 115.58 (d, J = 22.4 Hz), 106.76 (d, J = 21.1 Hz), 101.50, 91.69, 90.35, 74.21, 61.28 (d, J = 27.6 Hz), 60.01 (d, J = 27.1 Hz), 56.73, 45.34, 24.06, 22.35 (d, J = 25.0 Hz).19F NMR (565 MHz, DMSO-d6) δ 107.95, -141.33, -141.36. HRMS: [APCI+] [M+H]+calc. for C22H19O3N3F2⁷⁹Br³²S, 522.0293, observed, 522.0299. Preparation of (S)-5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)- 2-oxoethyl)-6-(3-hydroxybut-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-336) Prepared by General Procedure X. White solid, 34%.1H NMR (600 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.77 (dd, J = 6.8, 2.1 Hz, 1H), 7.65 – 7.52 (m, 1H), 7.51 – 7.48 (m, 1H), 7.43 (t, J = 8.7 Hz, 1H), 5.53 (s, 1H), 4.67 (d, J = 1.9 Hz, 2H), 4.53 (q, J = 6.6 Hz, 1H), 4.41 – 4.30 (m, 2H), 4.02 – 3.95 (m, 2H), 1.59 (d, J = 22.0 Hz, 3H), 1.29 (d, J = 6.6 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 166.21 (d, J = 2.7 Hz), 162.73, 158.71, 157.07, 155.71, 150.18, 138.60, 134.88, 131.69 (d, J = 7j.7 Hz), 130.99 (d, J = 3.7 Hz), 120.19, 116.29, 115.49 (d, J = 22.5 Hz), 106.68 (d, J = 21.1 Hz), 101.42, 91.60, 90.26, 74.13, 61.20 (d, J = 27.6 Hz), 59.93 (d, J = 27.2 Hz), 56.65, 45.26, 23.98, 22.27 (d, J = 25.1 Hz).19F NMR (565 MHz, DMSO-d6) δ -109.62 (d, J = 7.2 Hz), - 139.64 (d, J = 20.9 Hz). HRMS: [APCI+] [M+H]+calc. for C22H19O3N3F2⁷⁹Br³²S, 522.0293, observed, 522.0299. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)thieno[2,3-d]pyrimidin-4(3H)- one (1622-337) Prepared by General Procedure X. White solid, 33%.1H NMR (600 MHz, DMSO) δ 8.34 (s, 1H), 7.62 (dd, J = 6.8, 2.2 Hz, 1H), 7.44 (t, J = 8.7 Hz, 1H), 7.33 (ddd, J = 8.5, 4.8, 2.2 Hz, 1H), 4.65 (d, J = 1.8 Hz, 2H), 4.46 – 4.22 (m, 2H), 4.15 – 3.87 (m, 2H), 1.59 (d, J = 22.0 Hz, 3H).13C NMR (151 MHz, DMSO) δ 167.15, 166.28 (d, J = 2.8 Hz), 158.73, 157.11, 154.82, 149.27, 139.99, 134.94, 133.78 (d, J = 3.8 Hz), 131.73 (d, J = 7.6 Hz), 121.30, 115.87 (d, J = 22.4 Hz), 107.03 (d, J = 21.3 Hz), 91.67, 90.33, 81.26, 61.23 (d, J = 27.4 Hz), 59.98 (d, J = 27.3 Hz), 45.24, 22.42.19F NMR (565 MHz, DMSO) δ 975.53 (dd, J = 14.2, 6.3 Hz), 955.07 – 931.58 (m, J = 21.3 Hz). Preparation of 6-(3-amino-3-methylbut-1-yn-1-yl)-5-(3-bromo-4-fluorophenyl)-3-(2- (3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-349) General Procedure X. Beige powder, 69%.1H NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.76 (dd, J = 6.6, 2.2 Hz, 1H), 7.43 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.16 (t, J = 8.5 Hz, 1H), 4.60 (d, J = 15.4 Hz, 1H), 4.44 (dd, J = 19.4, 9.6 Hz, 1H), 4.38 – 4.28 (m, 2H), 4.18 (dd, J = 20.2, 11.2 Hz, 1H), 4.03 (ddd, J = 17.6, 11.2, 1.4 Hz, 1H), 1.65 (d, J = 21.4 Hz, 3H), 1.46 (s, 6H).13C NMR (151 MHz, CDCl3) δ 165.77 (d, J = 3.1 Hz), 163.70, 159.62, 157.97, 156.37, 148.06, 139.27, 135.26, 131.35 (d, J = 7.4 Hz), 130.74 (d, J = 3.9 Hz), 120.59, 118.16, 115.39 (d, J = 22.5 Hz), 107.68 (d, J = 21.4 Hz), 90.58, 89.22, 62.12 (d, J = 28.5 Hz), 60.58 (d, J = 28.1 Hz), 46.79, 44.77, 30.25, 22.84 (d, J = 25.7 Hz), 13.60.19F NMR (565 MHz, CDCl3) δ -107.95, -141.35. HRMS: [APCI+] [M+H]+calc. for C₂₃H₂₂O₂N₄F2⁷⁹Br³²S 535.06094 found: 535.06115. Preparation of 6-(3-aminobut-1-yn-1-yl)-5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro- 3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-350) General Procedure X. Yellow powder, 72%.1H NMR (600 MHz, CDCl3) δ 8.07 (s, 1H), 7.76 (dd, J = 6.6, 2.2 Hz, 1H), 7.42 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.16 (t, J = 8.5 Hz, 1H), 4.59 (d, J = 15.4 Hz, 1H), 4.48 – 4.40 (m, 1H), 4.37 – 4.28 (m, 2H), 4.19 (dd, J = 20.2, 11.3 Hz, 1H), 4.07 – 3.99 (m, 1H), 3.87 (q, J = 6.8 Hz, 1H), 1.93 (s, 2H), 1.65 (d, J = 21.4 Hz, 3H), 1.37 (d, J = 6.8 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.72 (d, J = 3.1 Hz), 163.56, 159.61, 157.96, 156.38, 147.97, 138.86, 135.30, 131.29 (d, J = 7.2 Hz), 130.83 (d, J = 4.0 Hz), 120.65, 118.59, 115.41 (d, J = 22.3 Hz), 107.77 (d, J = 21.2 Hz), 90.57, 89.21, 62.11 (d, J = 28.4 Hz), 60.58 (d, J = 27.8 Hz), 44.75, 39.64, 23.74, 22.85 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -108.02, -141.32. HRMS: [APCI+] [M+H]+calc. for C₂₂H₂₀O₂N₄F2⁷⁹Br³²S 521.04529, observed 521.04545. Preparation of 6-((1-amino-3,3-difluorocyclobutyl)ethynyl)-5-(3-bromo-4- fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin- 4(3H)-one (1622-351) General Procedure X was followed to afford the title compound as powder, 57% yield.1H NMR (600 MHz, DMSO-d6) δ 8.62 (s, 2H), 8.47 (s, 1H), 7.78 (dd, J = 6.7, 2.2 Hz, 1H), 7.54 (ddd, J = 8.5, 4.8, 2.2 Hz, 1H), 7.45 (t, J = 8.7 Hz, 1H), 4.69 (d, J = 2.4 Hz, 2H), 4.43 – 4.29 (m, 2H), 4.05 – 3.93 (m, 2H), 3.26 (td, J = 15.6, 11.6 Hz, 2H), 3.10 – 3.01 (m, 2H), 1.60 (d, J = 22.1 Hz, 3H13C NMR (151 MHz, DMSO-d6) δ 166.70 (d, J = 3.0 Hz), 164.13, 159.47, 157.84, 156.26, 151.27, 141.36, 135.37, 132.16 (d, J = 7.6 Hz), 131.17 (d, J = 3.7 Hz), 120.70, 116.23 (d, J = 22.5 Hz), 107.42 (d, J = 21.4 Hz), 92.15, 90.81, 77.79, 61.76 (d, J = 27.6 Hz), 60.49 (d, J = 27.1 Hz), 48.27 (t, J = 24.3 Hz), 45.83, 22.82 (d, J = 24.9 Hz).19F NMR (565 MHz, DMSO-d6) δ -83.95 (d, J = 197.9 Hz), -95.23 (d, J = 198.9 Hz), -108.54, -139.08. HRMS: [APCI+] [M+H]+calc. for C₂₄H₂₀O₂N₄ F₄⁷⁹Br³²S583.0421, observed 583.04198. Preparation of 6-((3-aminotetrahydrofuran-3-yl)ethynyl)-5-(3-bromo-4- fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin- 4(3H)-one (1622-352) General Procedure X was followed to afford the title compound as white powder, 64%.1H NMR (600 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.79 (dd, J = 6.8, 2.2 Hz, 1H), 7.52 (ddd, J = 8.6, 4.9, 2.2 Hz, 1H), 7.43 (t, J = 8.7 Hz, 1H), 4.68 (d, J = 1.7 Hz, 2H), 4.45 – 4.27 (m, 2H), 4.04 – 3.93 (m, 2H), 3.89 – 3.83 (m, 1H), 3.78 (td, J = 8.1, 5.0 Hz, 1H), 3.66 (d, J = 8.2 Hz, 1H), 3.57 (d, J = 8.2 Hz, 1H), 2.11 – 1.91 (m, 2H), 1.60 (d, J = 22.1 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 166.77 (d, J = 2.8 Hz), 163.20, 159.21, 157.58, 156.25, 150.66, 138.99, 135.42, 132.34 (d, J = 7.6 Hz), 131.48 (d, J = 3.7 Hz), 120.63, 116.00 (d, J = 22.7 Hz), 107.15 (d, J = 21.3 Hz), 92.14, 90.80, 79.80, 73.87, 67.48, 61.76 (d, J = 27.5 Hz), 60.47 (d, J = 27.2 Hz), 55.30, 45.81, 42.36, 22.82 (d, J = 24.9 Hz).19F NMR (565 MHz, DMSO-d6) δ -109.01, -139.08. HRMS: [APCI+] [M+H]+calc. for C₂₄H₂₂O₃N₄ F₂⁷⁹Br³²S 563.05586, observed563.05569. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-hydroxy-3,4,4-trimethylpent-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-353) Prepared by General Procedure X. Off-white solid, 36%.1H NMR (600 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.73 (dd, J = 6.8, 2.1 Hz, 1H), 7.46 (ddd, J = 8.5, 4.9, 2.1 Hz, 1H), 7.41 (t, J = 8.7 Hz, 1H), 4.66 (d, J = 2.1 Hz, 2H), 4.47 – 4.26 (m, 2H), 4.06 – 3.92 (m, 2H), 3.35 (brs, 1H), 1.59 (d, J = 22.0 Hz, 3H), 1.31 (s, 3H), 0.85 (s, 9H).13C NMR (151 MHz, DMSO-d6) δ 166.75 (d, J = 2.6 Hz), 163.05, 159.26, 157.63, 156.22, 150.63, 138.98, 135.25, 132.31 (d, J = 7.7 Hz), 131.93 (d, J = 3.8 Hz), 120.89, 117.37, 116.05 (d, J = 22.6 Hz), 107.36 (d, J = 21.4 Hz), 103.58, 92.13, 90.79, 73.07, 61.75 (d, J = 27.4 Hz), 60.46 (d, J = 27.3 Hz), 45.76, 38.36, 25.40, 25.11, 22.89.19F NMR (565 MHz, DMSO-d6) δ -109.34 (d, J = 7.2 Hz), -136.79 – -141.57 (m). HRMS: [APCI+] [M+H]+calc. for C26H27O3N3F2⁷⁹Br³²S, 578.0919, observed, 578.0927. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-((1-hydroxycyclopropyl)ethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-354) Prepared by General Procedure X. White solid, 29%.1H NMR (800 MHz, CDCl3) δ 8.07 (s, 1H), 7.73 (dd, J = 6.6, 2.2 Hz, 1H), 7.42 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.16 (t, J = 8.5 Hz, 1H), 4.60 (d, J = 15.4 Hz, 1H), 4.48 – 4.41 (m, 1H), 4.36 – 4.29 (m, 2H), 4.19 (dd, J = 20.1, 11.3 Hz, 1H), 4.03 (ddd, J = 17.3, 11.2, 1.5 Hz, 1H), 1.65 (d, J = 21.4 Hz, 3H), 1.20 – 1.14 (m, 2H), 1.07 – 0.99 (m, 2H). 13C NMR (201 MHz, CDCl3) δ 165.69, 163.75, 159.44, 158.21, 156.37, 148.00, 139.19, 135.27, 131.23 (d, J = 6.7 Hz), 130.77 (d, J = 3.7 Hz), 120.64, 118.32, 115.44 (d, J = 22.2 Hz), 107.82 (d, J = 21.5 Hz), 99.57, 90.40, 89.38, 74.31, 62.13 (d, J = 28.2 Hz), 60.59 (d, J = 28.1 Hz), 45.95, 44.75, 22.86 (d, J = 25.9 Hz), 18.15.19F NMR (753 MHz, CDCl3) δ -104.43 – -110.26 (m), -141.35 (d, J = 20.0 Hz). HRMS: [APCI+] [M+H]+calc. for C23H19O3N3F2⁷⁹Br³²S, 534.0293, observed 534.0297. Preparation of 6-(3-aminoprop-1-yn-1-yl)-5-(3-bromo-4-fluorophenyl)-3-(2-(3- fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-355) General Procedure X was followed to afford the title compound as yellow powder, 32%.1H NMR (600 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.76 (dd, J = 6.8, 2.1 Hz, 1H), 7.51 (ddd, J = 8.5, 4.9, 2.2 Hz, 1H), 7.42 (t, J = 8.7 Hz, 1H), 4.67 (d, J = 1.6 Hz, 2H), 4.43 – 4.28 (m, 2H), 4.07 – 3.93 (m, 2H), 3.47 (s, 2H), 1.59 (d, J = 22.1 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 166.77 (d, J = 3.0 Hz), 163.00, 156.25, 150.61, 138.49, 135.49, 132.09 (d, J = 7.6 Hz), 131.67 (d, J = 3.8 Hz), 120.76, 117.48, 116.11 (d, J = 22.4 Hz), 107.28 (d, J = 21.2 Hz), 100.99, 92.15, 90.81, 73.80, 61.74 (d, J = 27.6 Hz), 60.47 (d, J = 27.2 Hz), 45.80, 31.93, 22.82 (d, J = 25.0 Hz).19F NMR (565 MHz, DMSO-d6) δ -109.18, -139.12. HRMS: [APCI+] [M+H]+calc. for C₂₁H₁₇O₂N₄ F₂⁷⁹Br³²S 506.02182,observed 506.02196. Preparation of 6-((1-aminocyclopropyl)ethynyl)-5-(3-bromo-4-fluorophenyl)-3-(2-(3- fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-356) General Procedure X was followed to afford the title compound as white powder, 28%.1H NMR (600 MHz, DMSO-d6) δ 8.57 (s, 2H), 8.46 (s, 1H), 7.79 (dd, J = 6.7, 2.2 Hz, 1H), 7.52 (ddd, J = 8.5, 4.9, 2.2 Hz, 1H), 7.45 (t, J = 8.7 Hz, 1H), 4.68 (d, J = 3.0 Hz, 2H), 4.43 – 4.29 (m, 2H), 4.04 – 3.93 (m, 2H), 1.60 (d, J = 22.1 Hz, 3H), 1.37 – 1.31 (m, 2H), 1.31 – 1.24 (m, 2H).13C NMR (151 MHz, DMSO-d6) δ 166.70 (d, J = 2.8 Hz), 163.85, 159.40, 157.76, 156.24, 151.15, 140.83, 135.44, 132.20 (d, J = 7.7 Hz), 131.23 (d, J = 3.8 Hz), 120.66, 116.20 (d, J = 22.5 Hz), 115.35, 107.35 (d, J = 21.4 Hz), 95.63, 92.15, 90.82, 74.51, 61.74 (d, J = 27.6 Hz), 60.48 (d, J = 27.1 Hz), 45.83, 24.76, 22.82 (d, J = 25.0 Hz), 15.17.19F NMR (565 MHz, DMSO-d6) δ -108.64, -139.08. HRMS: [APCI+] [M+H]+calc. for C₂₃H₂₀O₂N₄F2⁷⁹Br³²S 533.04529, observed 533.04559. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-oxobut-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-358) Prepared by General Procedure X. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-methoxy-3-methylbut-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-360) Prepared by General Procedure X. Off-white solid, 16%.1H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.78 (dd, J = 6.6, 2.2 Hz, 1H), 7.45 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.18 (t, J = 8.5 Hz, 1H), 4.63 (d, J = 15.4 Hz, 1H), 4.50 – 4.44 (m, 1H), 4.40 – 4.31 (m, 2H), 4.22 (dd, J = 20.2, 11.3 Hz, 1H), 4.08 – 4.03 (m, 1H), 3.29 (s, 3H), 1.68 (d, J = 21.4 Hz, 3H), 1.48 (s, 6H).13C NMR (151 MHz, CDCl3) δ 165.66 (d, J = 3.0 Hz), 163.71, 159.65, 158.00, 156.39, 148.04, 139.43, 135.26, 130.88 (d, J = 3.9 Hz), 120.68, 118.22, 115.41 (d, J = 22.6 Hz), 107.77, 99.87, 90.57, 89.21, 76.21, 71.09, 62.11 (d, J = 28.4 Hz), 60.59 (d, J = 28.0 Hz), 51.92, 44.72, 27.94, 22.86 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -107.94, -141.33. HRMS: [APCI+] [M+H]+calc. for C24H23O3N3F2⁷⁹Br³²S, 550.0606, observed, 550.0609. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-isopropoxy-3-methylbut-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622- 361) Prepared by General Procedure X. Preparation of 4-(5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)- 2-oxoethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)-2-methylbut-3-yn-2-yl acetate (1622-362) Prepared by General Procedure X, followed by esterification using (Ac)2O. White solid, 21%.1H NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.76 (dd, J = 6.6, 2.2 Hz, 1H), 7.42 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.16 (t, J = 8.5 Hz, 1H), 4.60 (d, J = 15.4 Hz, 1H), 4.49 – 4.40 (m, 1H), 4.38 – 4.27 (m, 2H), 4.20 (dd, J = 20.2, 11.3 Hz, 1H), 4.03 (ddd, J = 17.4, 11.3, 1.5 Hz, 1H), 3.26 (s, 3H), 1.65 (d, J = 21.5 Hz, 3H), 1.45 (s, 6H).13C NMR (151 MHz, CDCl3) δ 165.66 (d, J = 3.0 Hz), 163.71, 159.65, 158.00, 148.04, 135.26, 131.28 (d, J = 7.2 Hz), 130.88 (d, J = 3.9 Hz), 120.68, 118.22, 115.41 (d, J = 22.6 Hz), 107.84 (d, J = 21.0 Hz), 99.87, 90.57, 76.21, 71.09, 62.11 (d, J = 28.3 Hz), 60.59 (d, J = 27.9 Hz), 51.92, 44.72, 27.94, 22.86 (d, J = 25.4 Hz).19F NMR (565 MHz, CDCl3) δ -107.94, -136.56 – -151.21 (m). Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-fluoro-3-methylbut-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-364) Prepared by General Procedure X, followed by a DAST reaction to install the fluorine atom. Off-white solid, 20%.1H NMR (600 MHz, CDCl3) δ 8.11 (s, 1H), 7.78 (dd, J = 6.6, 2.2 Hz, 1H), 7.46 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.19 (t, J = 8.5 Hz, 1H), 4.63 (d, J = 15.4 Hz, 1H), 4.47 (dd, J = 19.6, 9.7 Hz, 1H), 4.40 – 4.31 (m, 2H), 4.22 (dd, J = 20.1, 11.3 Hz, 1H), 4.06 (ddd, J = 17.3, 11.2, 1.5 Hz, 1H), 1.67 (dd, J = 20.8, 7.5 Hz, 9H).13C NMR (151 MHz, CDCl3) δ 165.62 (d, J = 3.0 Hz), 164.26, 159.75, 158.10, 156.38, 148.26, 140.49 (d, J = 2.5 Hz), 135.26, 131.26 (d, J = 7.5 Hz), 130.54 (d, J = 4.1 Hz), 120.61, 117.16 (d, J = 3.9 Hz), 115.45 (d, J = 22.6 Hz), 107.86 (d, J = 21.1 Hz), 97.48 (d, J = 29.9 Hz), 90.57, 89.20, 87.97, 86.87, 62.12 (d, J = 28.5 Hz), 60.59 (d, J = 27.9 Hz), 44.74, 28.82 (d, J = 26.5 Hz), 22.87 (d, J = 25.6 Hz).19F NMR (565 MHz, CDCl3) δ - 107.67, -107.68, -127.17, -141.33, -141.36 (m). HRMS: [APCI+] [M+H]+calc. for C23H20O2N3F3⁷⁹Br³²S, 538.0406, observed, 538.0415. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-((1-fluorocyclopropyl)ethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-365) Prepared by General Procedure X, followed by a DAST reaction to install the fluorine atom. Off-white solid, 22%.1H NMR (600 MHz, CDCl3) δ 8.09 (s, 1H), 7.72 (dd, J = 6.6, 2.2 Hz, 1H), 7.43 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.17 (t, J = 8.5 Hz, 1H), 4.60 (d, J = 15.4 Hz, 1H), 4.45 (dd, J = 19.4, 9.6 Hz, 1H), 4.39 – 4.28 (m, 2H), 4.20 (dd, J = 20.2, 11.3 Hz, 1H), 4.04 (dd, J = 17.3, 11.3 Hz, 1H), 1.65 (d, J = 21.4 Hz, 3H), 1.44 – 1.36 (m, 2H), 1.11 – 1.05 (m, 2H).13C NMR (151 MHz, CDCl3) δ 165.62 (d, J = 3.3 Hz), 164.30, 158.12, 148.26, 140.41, 135.25, 131.17, 130.54 (d, J = 3.9 Hz), 120.63, 115.52 (d, J = 22.6 Hz), 107.92 (d, J = 21.5 Hz), 94.12 (d, J = 30.8 Hz), 90.57, 89.20, 78.56 (d, J = 10.0 Hz), 68.76, 67.37, 62.13 (d, J = 28.4 Hz), 60.59 (d, J = 27.9 Hz), 44.74, 22.86 (d, J = 25.4 Hz), 15.39 (d, J = 13.8 Hz).19F NMR (565 MHz, CDCl3) δ -107.63 (d, J = 6.1 Hz), -138.06 – -143.37 (m), -179.34. HRMS: [APCI+] [M+H]+calc. for C23H18O2N3F3⁷⁹Br³²S, 536.0250, observed 536.0263. Preparation of 6-((1-aminocyclopropyl)ethynyl)-5-(3-bromo-4-fluorophenyl)-3-(2-(3- fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one trifluoroacetate (1622-AA) Prepared by General Procedure X. Off-white solid, 32%.1H NMR (600 MHz, CDCl3) δ 8.12 (s, 1H), 7.66 (dd, J = 6.6, 2.2 Hz, 1H), 7.39 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.14 (t, J = 8.5 Hz, 1H), 4.58 (d, J = 15.5 Hz, 1H), 4.44 (dd, J = 19.4, 9.7 Hz, 1H), 4.31 (dd, J = 17.1, 9.6 Hz, 1H), 4.17 (dd, J = 20.1, 11.3 Hz, 1H), 4.02 (dd, J = 17.4, 11.3 Hz, 1H), 1.65 (d, J = 21.4 Hz, 3H), 1.41 – 1.34 (m, 2H), 1.18 – 1.12 (m, 2H).13C NMR (151 MHz, CDCl3) δ 165.99 (d, J = 3.1 Hz), 163.99, 159.84, 158.19, 156.42, 148.65, 140.28, 135.27, 131.33 (d, J = 7.5 Hz), 130.63 (d, J = 3.9 Hz), 120.64, 117.41, 115.70 (d, J = 22.6 Hz), 107.92 (d, J = 21.2 Hz), 90.70, 89.34, 74.46, 62.24 (d, J = 28.5 Hz), 60.73 (d, J = 28.1 Hz), 44.96, 41.00, 25.33, 22.94 (d, J = 25.5 Hz), 16.28.19F NMR (565 MHz, CDCl3) δ -107.50, -142.41 – -142.68 (m), -172.75 – -173.37 (m). Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(pyrrolidin-3-ylethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-366) General Procedure X was followed to afford the title compound as white powder, 10%.1H NMR (600 MHz, CDCl3) δ 8.06 (s, 1H), 7.76 (dd, J = 6.6, 2.2 Hz, 1H), 7.42 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.16 (t, J = 8.5 Hz, 1H), 4.60 (dd, J = 15.4, 1.9 Hz, 1H), 4.48 – 4.40 (m, 1H), 4.37 – 4.28 (m, 2H), 4.19 (dd, J = 20.2, 11.3 Hz, 1H), 4.07 – 3.99 (m, 1H), 3.14 (dd, J = 11.0, 7.2 Hz, 1H), 3.04 (ddd, J = 11.3, 8.2, 6.0 Hz, 1H), 3.00 – 2.85 (m, 3H), 2.09 (dddd, J = 12.6, 8.7, 7.9, 6.0 Hz, 1H), 1.80 (ddt, J = 12.4, 8.2, 6.1 Hz, 1H), 1.65 (d, J = 21.4 Hz, 3H).19F NMR (565 MHz, CDCl3) δ -108.13, -141.37.13C NMR (151 MHz, CDCl3) δ 165.73 (d, J = 3.0 Hz), 163.25, 159.55, 157.90, 156.38, 147.80, 138.37, 135.28, 131.29 (d, J = 7.3 Hz), 130.99 (d, J = 3.9 Hz), 120.66, 119.32, 115.36 (d, J = 22.4 Hz), 107.76 (d, J = 21.1 Hz), 101.96, 73.03, 62.12 (d, J = 28.7 Hz), 60.58 (d, J = 27.9 Hz), 54.11, 46.99, 44.74, 33.80, 31.40, 22.86 (d, J = 25.7 Hz). HRMS: [APCI+] [M+H]+calc. for C₂₄H₂₂O₂N₄F2⁷⁹Br³²S 547.06094, observed 547.06086. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(pyrrolidin-2-ylethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-367) General Procedure X was followed to afford the title compound as white powder, 22%.1H NMR (600 MHz, CDCl3) δ 8.09 (d, J = 3.1 Hz, 1H), 7.74 – 7.67 (m, 1H), 7.43 (t, J = 7.1 Hz, 1H), 7.17 (t, J = 8.5 Hz, 1H), 4.65 – 4.49 (m, 2H), 4.49 – 4.26 (m, 3H), 4.19 (dd, J = 20.2, 11.3 Hz, 1H), 4.03 (ddd, J = 17.0, 11.3, 5.4 Hz, 1H), 3.34 (qt, J = 11.7, 6.4 Hz, 2H), 2.33 (d, J = 7.3 Hz, 1H), 2.12 – 2.02 (m, 3H), 1.65 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.78, 164.49, 158.16, 156.32 (d, J = 2.6 Hz), 148.60, 141.30, 135.03, 131.30 (d, J = 7.5 Hz), 130.55, 120.54, 116.21, 115.68 (d, J = 23.3 Hz), 107.89 (d, J = 21.2 Hz), 90.49 (d, J = 23.3 Hz), 79.86, 62.12 (d, J = 28.9 Hz), 60.59 (d, J = 28.4 Hz), 49.78, 44.79 (d, J = 12.1 Hz), 32.39, 22.93, 22.75 (d, J = 3.5 Hz).19F NMR (565 MHz, CDCl3) δ -107.29, -141.29. HRMS: [APCI+] [M+H]+calc. for C₂₄H₂₂O₂N₄F2⁷⁹Br³²S 547.06094, observed547.06168. Preparation of 6-(azetidin-3-ylethynyl)-5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-368) General Procedure X was followed to afford the title compound as white powder, 24%.1H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.71 (dd, J = 6.6, 2.2 Hz, 1H), 7.42 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.18 (t, J = 8.5 Hz, 1H), 4.60 (d, J = 15.4 Hz, 1H), 4.49 – 4.40 (m, 1H), 4.38 – 4.28 (m, 2H), 4.25 – 4.15 (m, 3H), 4.10 (t, J = 9.2 Hz, 2H), 4.06 – 3.92 (m, 2H), 1.65 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.67 (d, J = 3.2 Hz), 164.10, 159.81, 158.16, 156.35, 148.41, 140.33, 135.13, 131.11 (d, J = 7.3 Hz), 130.59 (d, J = 3.9 Hz), 120.67, 117.01, 115.71 (d, J = 22.6 Hz), 107.97 (d, J = 21.2 Hz), 93.40, 90.58, 89.22, 62.11 (d, J = 28.6 Hz), 60.60 (d, J = 28.0 Hz), 51.20, 44.78, 23.52, 22.85 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -107.33, -141.30. HRMS: [APCI+] [M+H]+calc. for C₂₃H₂₀O₂N₄F2⁷⁹Br³²S 533.04529, observed 533.04622. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-oxopent-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-373) General Procedure X was followed to afford the title compound as beige powder, 61%.1H NMR (800 MHz, CDCl3) δ 8.12 (s, 1H), 7.76 (dd, J = 6.5, 2.2 Hz, 1H), 7.45 (ddd, J = 8.4, 4.6, 2.2 Hz, 1H), 7.21 (t, J = 8.4 Hz, 1H), 4.60 (d, J = 15.5 Hz, 1H), 4.48 – 4.42 (m, 1H), 4.37 (d, J = 15.5 Hz, 1H), 4.32 (ddd, J = 16.9, 9.6, 1.6 Hz, 1H), 4.20 (dd, J = 20.2, 11.3 Hz, 1H), 4.07 – 4.01 (m, 1H), 2.55 (q, J = 7.4 Hz, 2H), 1.66 (d, J = 21.4 Hz, 3H), 1.09 (t, J = 7.4 Hz, 3H).13C NMR (201 MHz, CDCl3) δ 187.42, 166.02, 165.41 (d, J = 3.0 Hz), 159.93, 158.68, 156.31, 149.08, 144.44, 135.20, 131.13 (d, J = 7.4 Hz), 130.18 (d, J = 4.1 Hz), 120.81, 115.76 (d, J = 22.8 Hz), 115.03, 108.23, 94.74, 90.38, 89.36, 82.52, 62.17, 60.62 (d, J = 28.1 Hz), 44.75, 38.68, 22.93, 7.95.19F NMR (753 MHz, CDCl3) δ -106.56, -141.32. HRMS: [APCI+] [M+H]+calc. for C₂₃H₁₉O₃N₃F2⁷⁹Br³²S 534.02931, observed 534.03081. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(4-methyl-3-oxopent-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-374) General Procedure X was followed to afford the title compound as beige powder, 52%.1H NMR (800 MHz, CDCl3) δ 8.12 (s, 1H), 7.75 (dd, J = 6.5, 2.2 Hz, 1H), 7.45 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.21 (t, J = 8.4 Hz, 1H), 4.60 (d, J = 15.5 Hz, 1H), 4.48 – 4.42 (m, 1H), 4.37 (d, J = 15.5 Hz, 1H), 4.31 (ddd, J = 16.9, 9.6, 1.6 Hz, 1H), 4.20 (dd, J = 20.1, 11.3 Hz, 1H), 4.07 – 4.01 (m, 1H), 2.60 (hept, J = 7.0 Hz, 1H), 1.66 (d, J = 21.4 Hz, 3H), 1.10 (d, J = 7.0 Hz, 6H).13C NMR (201 MHz, CDCl3) δ 191.00, 165.98, 165.40 (d, J = 3.5 Hz), 159.92, 158.68, 156.31, 149.05, 144.27, 135.15, 131.10 (d, J = 7.4 Hz), 130.34 (d, J = 3.8 Hz), 120.86, 115.78 (d, J = 22.4 Hz), 115.27, 108.37 (d, J = 21.5 Hz), 94.14, 89.35, 83.13, 62.09 (d, J = 28.7 Hz), 60.62 (d, J = 28.1 Hz), 44.73, 42.98, 22.86 (d, J = 25.3 Hz), 17.71.19F NMR (753 MHz, CDCl3) δ -106.64, -141.32. HRMS: [APCI+] [M+H]+calc. for C₂₃H₁₉O₃N₃F2⁷⁹Br³²S 534.02931, observed 534.03039. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(5-methyl-3-oxohex-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-375) General Procedure X was followed to afford the title compound as white powder, 31%.1H NMR (600 MHz, CDCl3) δ 8.12 (s, 1H), 7.75 (dd, J = 6.5, 2.2 Hz, 1H), 7.44 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.21 (t, J = 8.4 Hz, 1H), 4.60 (d, J = 15.4 Hz, 1H), 4.45 (dd, J = 19.4, 9.6 Hz, 1H), 4.37 (d, J = 15.5 Hz, 1H), 4.31 (ddd, J = 16.9, 9.6, 1.6 Hz, 1H), 4.20 (dd, J = 20.2, 11.3 Hz, 1H), 4.08 – 4.00 (m, 1H), 2.39 (d, J = 7.1 Hz, 2H), 1.66 (d, J = 21.4 Hz, 4H), 0.91 (d, J = 6.7 Hz, 6H).13C NMR (151 MHz, CDCl3) δ 186.82, 166.02, 160.14, 158.48, 156.31, 149.09, 144.54, 135.14, 131.12 (d, J = 7.4 Hz), 130.30 (d, J = 4.0 Hz), 120.87, 115.83, 115.14, 108.30 (d, J = 21.5 Hz), 95.15, 90.56, 89.19, 82.36, 62.09 (d, J = 28.7 Hz), 60.63 (d, J = 28.1 Hz), 54.26, 44.74, 25.29, 22.87 (d, J = 25.7 Hz), 22.38.19F NMR (565 MHz, CDCl3) δ -106.64, -141.29. HRMS: [APCI+] [M+H]+calc. for C₂₅H₂₃O₃N₃F2⁷⁹Br³²S 562.06061, observed 562.06198. Preparation of 5-(3-bromo-4-fluorophenyl)-6-(3-cyclopropyl-3-oxoprop-1-yn-1-yl)-3- (2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-376) General Procedure X was followed to afford the title compound as white powder, 28%.1H NMR (800 MHz, CDCl3) δ 8.12 (s, 1H), 7.74 (dd, J = 6.5, 2.2 Hz, 1H), 7.44 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.22 (t, J = 8.4 Hz, 1H), 4.60 (d, J = 15.5 Hz, 1H), 4.48 – 4.42 (m, 1H), 4.37 (d, J = 15.5 Hz, 1H), 4.31 (ddd, J = 16.9, 9.6, 1.6 Hz, 1H), 4.23 – 4.17 (m, 1H), 4.04 (ddd, J = 17.4, 11.2, 1.6 Hz, 1H), 1.99 (tt, J = 8.0, 4.6 Hz, 1H), 1.66 (d, J = 21.4 Hz, 3H), 1.11 – 1.00 (m, 4H).13C NMR (201 MHz, CDCl3) δ 187.17, 165.95, 165.40 (d, J = 3.0 Hz), 159.93, 158.69, 156.30, 149.05, 144.24, 135.08, 131.03 (d, J = 7.6 Hz), 130.35 (d, J = 3.9 Hz), 120.86, 115.84 (d, J = 22.8 Hz), 115.16, 108.43 (d, J = 21.5 Hz), 93.43, 90.38, 82.04, 62.09 (d, J = 28.7 Hz), 60.62 (d, J = 28.0 Hz), 44.73, 24.62, 22.86 (d, J = 25.8 Hz), 11.27.19F NMR (753 MHz, CDCl3) δ -106.57, -141.32. HRMS: [APCI+] [M+H]+calc. for C₂₄H₁₉O₃N₃F2⁷⁹Br³²S 546.02931, observed 546.03069. Preparation of 5-(3-bromo-4-fluorophenyl)-6-(3-cyclopentyl-3-oxoprop-1-yn-1-yl)-3- (2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-377) General Procedure X was followed to afford the title compound as yellow powder, 63%.1H NMR (600 MHz, CDCl3) δ 8.10 (d, J = 0.8 Hz, 1H), 7.71 (ddd, J = 6.5, 2.2, 0.8 Hz, 1H), 7.41 (dddd, J = 7.7, 4.7, 2.2, 0.8 Hz, 1H), 7.19 (td, J = 8.4, 0.8 Hz, 1H), 4.57 (d, J = 15.4 Hz, 1H), 4.43 (dd, J = 19.4, 9.6 Hz, 1H), 4.34 (d, J = 15.5 Hz, 1H), 4.32 – 4.25 (m, 1H), 4.18 (dd, J = 20.2, 11.3 Hz, 1H), 4.01 (dd, J = 17.4, 11.3 Hz, 1H), 2.84 (p, J = 8.0 Hz, 1H), 1.81 – 1.70 (m, 3H), 1.63 (d, J = 21.4 Hz, 3H), 1.57 – 1.49 (m, 5H).13C NMR (151 MHz, CDCl3) δ 189.95, 165.94, 165.40 (d, J = 3.2 Hz), 160.11, 158.46, 156.31, 149.03, 144.19, 135.13, 131.11 (d, J = 7.4 Hz), 130.42 (d, J = 4.1 Hz), 120.89, 115.76 (d, J = 22.7 Hz), 115.37, 108.38 (d, J = 21.4 Hz), 94.50, 90.56, 89.19, 82.75, 62.08 (d, J = 28.5 Hz), 60.62 (d, J = 28.1 Hz), 53.64, 44.72, 28.93, 25.87, 22.87 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -106.74, -141.32. HRMS: [APCI+] [M+H]+calc. for C₂₆H₂₃O₃N₃F2⁷⁹Br³²S 574.06061, observed 574.06165. Preparation of 3-(3-chloro-4-fluorophenyl)-2-(cyclopropylethynyl)-5-(2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)pyrazolo[1,5-a]pyrazin-4(5H)-one (1622-387) 1622-387 was prepared according to General Procedure X. White solid, 34%.1H NMR (600 MHz, CDCl3) δ 7.78 (dd, J = 7.1, 2.2 Hz, 1H), 7.58 (ddd, J = 8.6, 4.6, 2.3 Hz, 1H), 7.41 (d, J = 6.0 Hz, 1H), 7.19 (t, J = 8.8 Hz, 1H), 6.74 (d, J = 6.0 Hz, 1H), 4.58 (d, J = 15.5 Hz, 1H), 4.44 (ddd, J = 19.5, 9.7, 1.7 Hz, 1H), 4.35 – 4.25 (m, 2H), 4.19 (dd, J = 20.3, 11.3 Hz, 1H), 4.03 (ddd, J = 17.5, 11.3, 1.6 Hz, 1H), 1.66 (d, J = 21.4 Hz, 3H), 1.45 (tt, J = 8.3, 5.1 Hz, 1H), 0.97 – 0.80 (m, 4H).13C NMR (151 MHz, CDCl3) δ 166.18 (d,4JC-F = 3.1 Hz), 157.67 (d,1JC-F = 249.9 Hz), 154.69, 136.29, 132.43, 130.57 (d,3JC-F= 7.3 Hz), 128.29, 127.00 (d,4JC-F= 3.9 Hz), 123.19, 120.33, 120.12 (d,2JC-F= 18.0 Hz), 115.86 (d,2JC-F= 21.1 Hz), 110.67, 99.31, 89.95 (d,1JC-F= 205.1 Hz), 66.50, 62.12 (d,2JC-F = 28.6 Hz), 60.51 (d,2JC-F = 27.9 Hz), 46.46, 22.91 (d,2JC-F = 25.5 Hz), 8.86, 0.22.19F NMR (565 MHz, CDCl3) δ -116.71 – -116.77 (m), -141.08 – -141.51 (m). HRMS: [APCI+] [M+H]+calc. for C23H20N4O2F235Cl, 457.1237, observed 457.1235. Preparation of 5-(3-chloro-4-fluorophenyl)-6-(cyclopropylethynyl)-3-(2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (1622-388) 1622-388 was prepared according to General Procedure X. White solid (29 mg, 30% yield).1H NMR (600 MHz, CDCl3) δ 8.24 (s, 1H), 7.75 (dd, J = 6.6, 2.1 Hz, 1H), 7.43 (ddd, J = 8.6, 4.7, 2.2 Hz, 1H), 7.16 (t, J = 8.5 Hz, 1H), 4.60 (d, J = 14.6 Hz, 1H), 4.47 – 4.27 (m, 2H), 4.23 – 4.14 (m, 1H), 4.03 (dd, J = 17.4, 11.1 Hz, 1H), 1.69 – 1.59 (m, 3H), 1.41 (tt, J = 8.3, 5.0 Hz, 1H), 0.94 – 0.84 (m, 2H), 0.80 – 0.73 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 165.78 (d, J = 2.9 Hz), 159.49, 157.84, 156.20, 138.14, 135.33, 131.31, 131.28, 131.04 (d, J = 3.9 Hz), 119.86, 115.39, 115.25, 107.78, 107.64, 103.18, 90.62, 89.26, 77.86 – 76.32 (m), 67.57, 62.25, 62.06, 60.70, 60.52, 45.00, 22.95, 22.78, 9.13, 0.54.19F NMR (565 MHz, CDCl3) δ -108.35 (q, J = 6.6 Hz), -141.25 (dq, J = 39.0, 19.6 Hz). Preparation of 5-(3-chloro-4-fluorophenyl)-7-cyclopropyl-6-ethynyl-3-(2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (1622-398) 1622-398 was prepared according to General Procedure X. White solid (28 mg, 31% yield).1H NMR (600 MHz, CDCl3) δ 7.99 (s, 1H), 7.85 (dd, J = 7.2, 2.2 Hz, 1H), 7.68 (ddd, J = 8.6, 4.6, 2.2 Hz, 1H), 7.15 (t, J = 8.8 Hz, 1H), 6.98 (s, 1H), 4.69 (d, J = 15.3 Hz, 1H), 4.61 – 4.35 (m, 3H), 4.31 – 4.01 (m, 2H), 3.71 – 3.30 (m, 1H), 1.84 – 1.55 (m, 4H), 1.29 – 0.94 (m, 4H), 0.02 (s, 1H).13C NMR (151 MHz, CDCl3) δ 166.72 (d, J = 3.0 Hz), 157.90 (d, J = 2.8 Hz), 156.27, 149.36, 145.97, 130.77 (d, J = 4.0 Hz), 128.24 (d, J = 7.0 Hz), 121.62, 120.44 (d, J = 17.7 Hz), 118.65, 116.17 (d, J = 21.0 Hz), 105.06, 90.67, 89.31, 62.24 (d, J = 28.4 Hz), 60.51 (d, J = 27.8 Hz), 44.87, 27.15, 22.85 (d, J = 25.5 Hz), 6.45 (d, J = 3.2 Hz).19F NMR (565 MHz, CDCl3) δ -119.13 (dd, J = 12.9, 7.8 Hz), -136.27 – -147.23 (m). Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(pyrimidin-5-ylethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-400) Prepared according to General Procedure X.1H NMR (600 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.90 (s, 2H), 8.49 (s, 1H), 7.91 (dd, J = 6.8, 2.2 Hz, 1H), 7.65 (ddd, J = 8.6, 4.8, 2.2 Hz, 1H), 7.50 (t, J = 8.7 Hz, 1H), 4.71 (s, 2H), 4.45 – 4.31 (m, 2H), 4.06 – 3.95 (m, 2H), 1.61 (d, J = 22.1 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 166.70 (d, JC-F = 2.8 Hz), 164.39, 159.50, 159.01, 157.86, 157.70, 156.29, 151.22, 141.11, 135.60, 132.23 (d, JC-F= 7.7 Hz), 131.25 (d, JC-F= 3.8 Hz), 120.78, 118.46, 116.30 (d, JC-F = 22.4 Hz), 115.37, 107.41 (d, JC-F = 21.2 Hz), 92.16, 90.78 (d, JC-F = 12.2 Hz), 88.25, 61.76 (d, JC-F = 27.6 Hz), 60.49 (d, JC-F = 27.1 Hz) , 45.86, 22.83 (d, JC-F = 25.0 Hz).19F NMR (565 MHz, DMSO-d6) δ -108.33, -138.96. HRMS: [APCI+] [M+H]+calc. for C24H16F2N5O279Br32S, 556.02489, observed 556.02494. Preparation of 6-(3-(1H-pyrazol-1-yl)prop-1-yn-1-yl)-5-(3-bromo-4-fluorophenyl)-3- (2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-401) Prepared according to General Procedure X.1H NMR (600 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.74 (dd, J = 6.8, 2.2 Hz, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.50 – 7.46 (m, 2H), 7.37 (t, J = 8.7 Hz, 1H), 6.29 (t, J = 2.1 Hz, 1H), 5.28 (s, 2H), 4.67 (s, 2H), 4.43 – 4.29 (m, 2H), 4.06 – 3.96 (m, 2H), 1.60 (d, J = 22.1 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 166.71 (d, JC-F = 2.9 Hz), 163.53, 159.32, 157.69, 156.24, 150.95, 139.99 (d, JC-F= 28.6 Hz), 135.42, 131.96 (d, JC-F= 7.7 Hz), 131.48 (d, JC-F= 3.7 Hz), 130.23, 120.77, 116.21, 116.02 (d, JC-F= 11.6 Hz), 107.42 (d, JC-F= 21.4 Hz), 106.36, 92.96, 91.47 (d, JC-F = 201.8 Hz), 76.84, 61.73 (d, JC-F = 27.5 Hz), 60.47 (d, JC-F = 27.2 Hz), 45.79, 41.83, 22.81 (d, JC-F = 25.0 Hz).19F NMR (565 MHz, DMSO-d6) δ -108.89, - 139.23. HRMS: [APCI+] [M+H]+calc. for C24H18F2N5O279Br32S, 558.04054, observed 558.04069. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-402) Prepared according to General Procedure X.1H NMR (600 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.76 (dd, J = 6.8, 2.2 Hz, 1H), 7.50 – 7.46 (m, 1H), 7.42 (t, J = 8.7 Hz, 1H), 4.67 (s, 2H), 4.42 – 4.30 (m, 2H), 4.04 – 3.96 (m, 2H), 3.50 (s, 2H), 2.41 (s, 8H), 2.27 (s, 3H), 1.60 (d, J = 22.1 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 166.73 (d, JC-F = 2.8 Hz), 163.06, 159.31, 157.68, 156.22, 150.76, 139.35, 135.28, 132.21 (d, JC-F = 7.7 Hz), 131.83 (d, JC-F = 3.8 Hz), 120.84, 116.97, 116.16 (d, JC-F= 22.4 Hz), 107.43 (d, JC-F= 21.2 Hz), 94.80, 91.47 (d, JC-F= 201.8 Hz), 77.25, 61.74 (d, JC-F= 27.5 Hz), 60.46 (d, JC-F= 27.2 Hz), 54.58, 50.98, 47.09, 45.78, 22.82 (d, JC-F= 25.1 Hz).19F NMR (565 MHz, DMSO-d6) δ -109.11, -138.97. HRMS: [APCI+] [M+H]+calc. for C26H26F2N5O279Br32S, 590.1018, observed 590.10351. Preparation of 5-(3-bromo-4-fluoro-phenyl)-6-(3-cyclohexylprop-1-ynyl)-3-[2-(3- fluoro-3-methyl-azetidin-1-yl)-2-oxo-ethyl]thieno[2,3-d]pyrimidin-4-one (1622-404) Prepared according to General Procedure X.1H NMR (600 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.73 (dd, J = 6.8, 2.1 Hz, 1H), 7.54 – 7.31 (m, 2H), 4.66 (s, 2H), 4.42 – 4.28 (m, 2H), 4.10 – 3.88 (m, 2H), 2.31 (d, J = 6.4 Hz, 2H), 1.65 – 1.53 (m, 7H), 1.43 – 1.35 (m, 1H), 1.25 – 1.11 (m, 3H), 1.06 – 0.98 (m, 1H), 0.90 – 0.82 (m, 2H).13C NMR (151 MHz, DMSO-d6) δ 166.75 (d, JC-F= 2.9 Hz), 162.59, 159.22, 157.59, 156.18, 150.51, 138.62, 135.26, 132.24 (d, JC-F = 7.7 Hz), 132.12 (d, JC-F= 3.8 Hz), 120.88, 118.08, 116.02 (d, JC-F= 22.4 Hz), 107.32 (d, JC-F= 21.3 Hz), 98.98, 92.13, 90.80, 73.90, 61.73 (d, JC-F= 27.6 Hz), 60.45 (d, JC-F= 27.2 Hz), 45.75, 36.92, 32.30, 27.00, 26.03 (d, JC-F = 12.2 Hz), 22.81 (d, JC-F = 24.9 Hz).19F NMR (565 MHz, DMSO-d6) δ -109.78, -138.97. HRMS: [APCI+] [M+H]+calc. for C27H26F2N3O279Br32S, 574.09699, observed 574.09773. Preparation of 5-(3-bromo-4-fluoro-phenyl)-3-[2-(3-fluoro-3-methyl-azetidin-1-yl)-2- oxo-ethyl]-6-(2-pyrazin-2-ylethynyl)thieno[2,3-d]pyrimidin-4-one (1622-405) General Procedure X.1H NMR (600 MHz, DMSO-d6) δ 8.72 (d, J = 1.6 Hz, 1H), 8.70 – 8.66 (m, 1H), 8.64 (d, J = 2.5 Hz, 1H), 8.49 (s, 1H), 7.90 (dd, J = 6.8, 2.2 Hz, 1H), 7.63 (ddd, J = 8.5, 4.8, 2.2 Hz, 1H), 7.50 (t, J = 8.7 Hz, 1H), 4.71 (s, 2H), 4.44 – 4.31 (m, 2H), 4.06 – 3.97 (m, 2H), 1.61 (d, J = 22.1 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 166.68 (d, JC-F = 2.8 Hz), 164.60, 159.55, 157.91, 156.27, 151.34, 147.93, 145.59, 144.55, 141.84, 138.68, 135.58, 132.19 (d, JC-F = 7.8 Hz), 131.29 (d, JC-F= 3.8 Hz), 120.87, 116.29 (d, JC-F= 22.6 Hz), 114.99, 107.50 (d, JC-F= 21.4 Hz), 93.62, 91.49 (d, JC-F= 201.8 Hz), 84.86, 61.75 (d, JC-F= 27.5 Hz), 60.50 (d, JC-F= 27.2 Hz), 45.85, 22.82 (d, JC-F = 25.0 Hz).19F NMR (376 MHz, DMSO-d6) δ -108.32, -139.12. HRMS: [APCI+] [M+H]+calc. for C24H16F2N5O279Br32S, 556.02355, observed 556.02459. Preparation of 5-(3-bromo-4-fluorophenyl)-6-(3-cyclopentylprop-1-yn-1-yl)-3-(2-(3- fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-406) General Procedure X.1H NMR (600 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.74 (dd, J = 6.8, 2.1 Hz, 1H), 7.46 (ddd, J = 8.5, 5.0, 2.1 Hz, 1H), 7.42 (t, J = 8.7 Hz, 1H), 4.66 (s, 2H), 4.41 – 4.29 (m, 2H), 4.03 – 3.95 (m, 2H), 2.42 (d, J = 6.5 Hz, 2H), 2.00 – 1.93 (m, 1H), 1.66 – 1.56 (m, 5H), 1.53 – 1.43 (m, 4H), 1.15 – 1.07 (m, 2H).13C NMR (151 MHz, DMSO-d6) δ 166.76 (d, JC-F= 2.9 Hz), 162.64, 159.21, 157.58, 156.20, 150.53, 138.54, 135.26, 132.24 (d, JC-F = 7.5 Hz), 132.01 (d, JC-F = 3.8 Hz), 120.84, 117.99, 116.01 (d, JC-F = 22.7 Hz), 107.29 (d, JC-F = 21.1 Hz), 99.58, 91.47 (d, JC-F= 201.8 Hz), 73.09, 61.73 (d, JC-F= 27.5 Hz), 60.46 (d, JC-F= 27.4 Hz), 45.77, 38.60, 31.81, 25.18, 24.95, 22.81 (d, JC-F = 25.0 Hz).19F NMR (376 MHz, DMSO-d6) δ -109.40, -139.18. HRMS: [APCI+] [M+H]+calc. for C26H24F2N3O279Br32S, 560.08134, observed 560.08082. Preparation of 5-(3-bromo-4-fluoro-phenyl)-6-[3-(dimethylamino)prop-1-ynyl]-3-[2- (3-fluoro-3-methyl-azetidin-1-yl)-2-oxo-ethyl]thieno[2,3-d]pyrimidin-4-one (1622-407) General Procedure X.1H NMR (600 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.78 (dd, J = 6.8, 2.1 Hz, 1H), 7.49 (ddd, J = 8.5, 4.9, 2.2 Hz, 1H), 7.43 (t, J = 8.7 Hz, 1H), 4.67 (s, 2H), 4.42 – 4.28 (m, 2H), 4.04 – 3.96 (m, 2H), 3.45 (s, 2H), 2.10 (s, 6H), 1.60 (d, J = 22.1 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 166.74 (d, JC-F = 2.9 Hz), 163.01, 159.27, 157.64, 156.22, 150.72, 139.08, 135.37, 132.28 (d, JC-F = 7.7 Hz), 131.89 (d, JC-F = 3.8 Hz), 120.85, 117.12, 116.11 (d, JC-F = 22.5 Hz), 107.37 (d, JC-F= 21.1 Hz), 94.81, 92.14, 90.81, 77.36, 61.73 (d, JC-F= 27.4 Hz), 60.46 (d, JC-F= 27.2 Hz), 48.21, 45.78, 43.95, 22.82 (d, JC-F= 24.9 Hz).19F NMR (565 MHz, DMSO-d6) δ - 109.14, -138.97. HRMS: [APCI+] [M+H]+calc. for C₂₃H₂₂O₂N₄F₂79Br32S, 535.06094, observed 535.06074. Preparation of 5-(3-bromo-4-fluorophenyl)-6-(3-(diethylamino)prop-1-yn-1-yl)-3-(2- (3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-409) Prepared according to General Procedure X.1H NMR (600 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.74 (dd, J = 6.8, 2.1 Hz, 1H), 7.46 (ddd, J = 8.5, 5.0, 2.1 Hz, 1H), 7.42 (t, J = 8.7 Hz, 1H), 4.66 (s, 2H), 4.41 – 4.29 (m, 2H), 4.02 – 3.95 (m, 2H), 3.57 (s, 2H), 2.31 (q, J = 7.2 Hz, 4H), 1.60 (d, J = 22.0 Hz, 3H), 0.91 (t, J = 7.2 Hz, 6H).13C NMR (151 MHz, DMSO-d6) δ 166.26 (d, JC-F= 2.8 Hz), 162.42, 158.79, 157.16, 155.72, 150.22, 138.74, 134.79, 131.75 (d, JC-F = 7.6 Hz), 131.57 (d, JC-F= 3.7 Hz), 120.44, 116.79, 115.62 (d, JC-F= 22.6 Hz), 106.91 (d, JC-F= 21.1 Hz), 94.40, 91.66, 90.33, 76.47, 61.26 (d, JC-F= 27.5 Hz), 59.98 (d, JC-F= 27.2 Hz), 46.63, 45.29, 41.01, 22.34 (d, JC-F = 25.0 Hz), 12.56.19F NMR (565 MHz, DMSO-d6) δ -109.33, -138.98. HRMS: [APCI+] [M+H]+calc. for C₂₅H₂₆O₂N₄F₂79Br32S, 563.09224, observed 563.09323. Preparation of 5-(3-bromo-4-fluoro-phenyl)-3-[2-(3-fluoro-3-methyl-azetidin-1-yl)-2- oxo-ethyl]-6-(4-hydroxybut-1-ynyl)thieno[2,3-d]pyrimidin-4-one (1622-410) Prepared according to General Procedure X.1H NMR (600 MHz, CDCl3) δ 8.41 (s, 1H), 7.76 (dd, J = 6.8, 2.2 Hz, 1H), 7.51 (ddd, J = 8.5, 4.8, 2.2 Hz, 1H), 7.42 (t, J = 8.8 Hz, 1H), 4.90 (t, J = 5.6 Hz, 1H), 4.67 (s, 2H), 4.42 – 4.29 (m, 3H), 4.03 – 3.96 (m, 2H), 3.50 (q, J = 5.6 Hz, 2H), 2.53 (t, J = 6.8 Hz, 2H), 1.59 (d, J = 22.1 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 166.30 (d, JC-F = 2.9 Hz), 162.32, 158.69, 157.06, 155.76, 150.07 (d, JC-F = 9.3 Hz), 137.95, 134.99, 131.71, 131.20 (d, JC-F= 3.8 Hz), 120.20, 117.29, 106.71 (d, JC-F= 21.1 Hz), 97.70, 91.67, 90.33, 72.95, 61.26 (d, JC-F= 27.6 Hz), 59.99 (d, JC-F= 27.3 Hz), 59.25, 45.32, 23.55, 22.34 (d, JC-F= 25.0 Hz).19F NMR (565 MHz, CDCl3) δ -104.47, -134.22. HRMS: [APCI+] [M+H]+calc. for C₂₂H₁₉O₃N₃F₂79Br32S, 522.02931, observed 522.0296. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622- 411) Prepared according to General Procedure X.1H NMR (600 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.80 (dd, J = 6.8, 2.2 Hz, 1H), 7.51 (ddd, J = 8.6, 4.9, 2.2 Hz, 1H), 7.43 (t, J = 8.7 Hz, 1H), 5.02 (t, J = 5.9 Hz, 1H), 4.68 (s, 2H), 4.43 – 4.30 (m, 3H), 4.03 – 3.97 (m, 2H), 3.27 (d, J = 5.9 Hz, 2H), 1.60 (d, J = 22.0 Hz, 3H), 1.12 (s, 6H).13C NMR (151 MHz, DMSO-d6) δ 166.79 (d, JC-F= 2.9 Hz), 162.81, 159.10, 157.47, 156.23, 150.51, 138.57, 135.42, 132.46 (d, JC-F= 7.6 Hz), 131.56 (d, JC-F = 3.8 Hz), 120.58, 117.70, 115.87 (d, JC-F = 22.5 Hz), 107.00 (d, JC-F = 21.1 Hz), 105.88, 92.15, 90.81, 72.96, 69.65, 61.76 (d, JC-F= 27.6 Hz), 60.47 (d, JC-F= 27.1 Hz), 45.81, 34.82, 25.29, 22.83 (d, JC-F= 25.0 Hz).19F NMR (565 MHz, DMSO-d6) δ -109.25, -139.23. HRMS: [APCI+] [M+H]+calc. for C₂₄H₂₃O₃N₃F₂79Br32S, 550.06061, observed 550.06201.

[0031] Preparation of 5-(3-bromo-4-fluorophenyl)-6-(3-ethyl-3-hydroxypent-1-yn-1-yl)-3- (2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-412) General Procedure X.1H NMR (600 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.76 (dd, J = 6.8, 2.2 Hz, 1H), 7.48 (ddd, J = 8.5, 4.9, 2.2 Hz, 1H), 7.43 (t, J = 8.7 Hz, 1H), 5.28 (s, 1H), 4.68 (d, J = 2.1 Hz, 2H), 4.44 – 4.30 (m, 2H), 4.03 – 3.96 (m, 2H), 1.60 (d, J = 22.1 Hz, 3H), 1.57 – 1.50 (m, 4H), 0.83 (t, J = 7.4 Hz, 6H).13C NMR (151 MHz, DMSO-d6) δ 166.75 (d, JC-F = 2.8 Hz), 163.13, 159.25, 157.62, 156.23, 150.68, 139.15, 135.27, 132.33 (d, JC-F= 7.7 Hz), 131.76 (d, JC-F= 3.8 Hz), 120.82, 117.14, 116.02 (d, JC-F= 22.4 Hz), 107.29 (d, JC-F= 21.4 Hz), 102.55, 92.15, 90.81, 75.18, 71.33, 61.75 (d, JC-F = 27.4 Hz), 60.47 (d, JC-F = 27.1 Hz), 45.79, 34.18 (d, JC-F = 9.2 Hz), 22.82 (d, JC-F= 25.1 Hz), 8.91.19F NMR (565 MHz, DMSO-d6) δ -109.28, -138.97. HRMS: [APCI+] [M+H]+calc. for C₂₅H₂₅O₃N₃BrF₂79Br32S, 564.07626, observed 564.07764. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(pyrimidin-2-ylethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-413) Prepared according to General Procedure X.1H NMR (600 MHz, DMSO-d6) δ 8.83 (d, J = 4.9 Hz, 2H), 8.50 (s, 1H), 7.88 (dd, J = 6.8, 2.2 Hz, 1H), 7.61 (ddd, J = 8.5, 4.8, 2.2 Hz, 1H), 7.52 (t, J = 4.9 Hz, 1H), 7.49 (t, J = 8.7 Hz, 1H), 4.71 (d, J = 1.3 Hz, 2H), 4.44 – 4.32 (m, 2H), 4.04 – 3.98 (m, 2H), 1.61 (d, J = 22.1 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 166.66 (d, JC-F = 2.9 Hz), 164.64, 159.55, 158.36, 157.92, 156.27, 151.83, 151.43, 142.33, 135.59, 132.12 (d, JC-F = 7.6 Hz), 131.35 (d, JC-F = 3.8 Hz), 121.53, 121.01, 116.27 (d, JC-F = 22.4 Hz), 114.85, 107.59 (d, JC-F = 21.4 Hz), 95.63, 92.16, 90.83, 78.69, 61.84, 61.65, 60.59, 60.41, 45.85, 22.91, 22.74.19F NMR (565 MHz, DMSO-d6) δ -108.46, -138.95. HRMS: [APCI+] [M+H]+calc. for C₂₄H₁₇O₂N₅F₂79Br32S, 556.02489, observed 556.02626. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-hydroxy-4,4-dimethylpent-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-414) General Procedure X was followed to prepare the title compound to afford the title compound as white powder, 67%.1H NMR (600 MHz, CDCl3) δ 8.07 (s, 1H), 7.70 (dd, J = 6.6, 2.2 Hz, 1H), 7.40 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.15 (t, J = 8.5 Hz, 1H), 4.59 (dd, J = 15.4, 2.8 Hz, 1H), 4.48 – 4.40 (m, 1H), 4.37 – 4.27 (m, 2H), 4.23 – 4.18 (m, 1H), 4.16 (d, J = 6.4 Hz, 1H), 4.07 – 3.99 (m, 1H), 1.87 (d, J = 6.3 Hz, 1H), 1.65 (d, J = 21.4 Hz, 3H), 0.92 (s, 9H).13C NMR (151 MHz, CDCl3) δ 165.65 (d, J = 2.9 Hz), 163.74, 159.72, 158.07, 156.38, 148.09, 139.43, 135.20, 131.15 (d, J = 7.2 Hz), 131.01 (d, J = 4.1 Hz), 120.80, 118.28, 115.54 (d, J = 22.3 Hz), 108.10 (d, J = 21.3 Hz), 97.75, 90.57, 89.21, 77.50, 71.92, 62.10 (d, J = 28.4 Hz), 60.59 (d, J = 28.1 Hz), 44.69, 36.17, 25.24, 22.86 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -107.94, - 141.35. HRMS: [APCI+] [M+H]+calc. for C₂₅H₂₅O₃N₃F₂⁷⁹Br³²S 564.07626, observed 564.07546. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(4-hydroxy-5-methylhex-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-415) General Procedure X was followed to afford the title compound as white powder, 60%.1H NMR (600 MHz, CDCl3) δ 8.06 (s, 1H), 7.73 (dd, J = 6.6, 2.2 Hz, 1H), 7.41 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.16 (t, J = 8.5 Hz, 1H), 4.60 (d, J = 15.4 Hz, 1H), 4.48 – 4.40 (m, 1H), 4.36 – 4.28 (m, 2H), 4.19 (dd, J = 20.2, 11.3 Hz, 1H), 4.03 (ddd, J = 17.3, 11.2, 1.5 Hz, 1H), 3.49 (p, J = 5.6 Hz, 1H), 2.64 – 2.52 (m, 2H), 1.70 – 1.61 (m, 5H), 0.91 (dd, J = 21.2, 6.8 Hz, 6H).13C NMR (151 MHz, CDCl3) δ 165.70 (d, J = 2.9 Hz), 163.26, 159.62, 157.98, 156.37, 147.91, 138.69, 135.24, 131.14, 120.76, 119.18, 115.41, 107.93, 96.22, 90.58, 89.22, 74.80, 62.11 (d, J = 28.5 Hz), 60.58 (d, J = 28.1 Hz), 44.70, 32.85, 26.10, 22.86 (d, J = 25.6 Hz), 18.83, 17.40.19F NMR (565 MHz, CDCl3) HRMS: [APCI+] [M+H]+calc. for C₂₅H₂₅O₃N₃F₂⁷⁹Br³²S 564.07626, observed 564.0756. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(4-hydroxy-5,5-dimethylhex-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622- 416) General Procedure X was followed to afford the title compound as white powder, 81%.1H NMR (600 MHz, CDCl3) δ 8.06 (s, 1H), 7.76 (dd, J = 6.7, 2.2 Hz, 1H), 7.43 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.17 (t, J = 8.5 Hz, 1H), 4.60 (dd, J = 15.4, 4.3 Hz, 1H), 4.44 (dd, J = 19.4, 9.6 Hz, 1H), 4.37 – 4.28 (m, 2H), 4.19 (dd, J = 20.2, 11.3 Hz, 1H), 4.07 – 3.99 (m, 1H), 3.45 (dt, J = 9.7, 3.5 Hz, 1H), 2.62 (dd, J = 17.1, 2.9 Hz, 1H), 2.44 (dd, J = 17.0, 9.6 Hz, 1H), 1.86 (d, J = 4.2 Hz, 1H), 1.65 (d, J = 21.4 Hz, 3H), 0.91 (s, 9H).13C NMR (151 MHz, CDCl3) δ 165.72 (d, J = 3.2 Hz), 163.28, 159.61, 157.97, 156.38, 147.88, 138.54, 135.26, 131.19 (d, J = 7.5 Hz), 131.05 (d, J = 3.9 Hz), 120.70, 119.18, 115.50 (d, J = 22.6 Hz), 107.93 (d, J = 21.1 Hz), 97.56, 90.58, 89.22, 77.64, 74.28, 62.12 (d, J = 28.6 Hz), 60.58 (d, J = 28.1 Hz), 44.73, 34.85, 25.58, 23.96, 22.86 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -107.98, -141.33. HRMS: [APCI+] [M+H]+calc. for C₂₆H₂₇O₃N₃F2⁷⁹Br³²S 578.09191, observed 578.09104. Preparation of 5-(3-bromo-4-fluorophenyl)-6-(4-cyclopropyl-4-hydroxybut-1-yn-1- yl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-417) General Procedure X was followed to afford the title compound as white powder, 49%.1H NMR (600 MHz, CDCl3) δ 8.06 (s, 1H), 7.75 (dd, J = 6.6, 2.2 Hz, 1H), 7.42 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.15 (t, J = 8.5 Hz, 1H), 4.59 (dd, J = 15.5, 1.6 Hz, 1H), 4.48 – 4.40 (m, 1H), 4.38 – 4.28 (m, 2H), 4.19 (dd, J = 20.2, 11.3 Hz, 1H), 4.07 – 3.99 (m, 1H), 3.06 (d, J = 6.9 Hz, 1H), 2.77 – 2.64 (m, 2H), 1.80 (d, J = 3.3 Hz, 1H), 1.65 (d, J = 21.4 Hz, 3H), 0.93 (qt, J = 8.2, 4.9 Hz, 1H), 0.57 – 0.47 (m, 2H), 0.38 – 0.31 (m, 1H), 0.23 – 0.17 (m, 1H).13C NMR (151 MHz, CDCl3) δ 165.71 (d, J = 3.2 Hz), 163.28, 159.59, 157.94, 156.38, 147.88, 138.56, 135.26, 131.23 (d, J = 7.4 Hz), 120.73, 119.25, 115.45 (d, J = 22.5 Hz), 107.93 (d, J = 21.1 Hz), 96.13, 90.58, 89.22, 74.61, 62.11 (d, J = 28.5 Hz), 60.58 (d, J = 28.0 Hz), 44.71, 28.48, 22.86 (d, J = 25.6 Hz), 16.99, 2.95, 2.72.19F NMR (565 MHz, CDCl3) δ -108.07, -141.36. HRMS: [APCI+] [M+H]+calc. for C₂₅H₂₃O₃N₃F2⁷⁹Br³²S 562.06061, observed 562.06028. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-hydroxyhex-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-418) General Procedure X was followed to afford the title compound as white powder, 68%.1H NMR (600 MHz, CDCl3) δ 8.07 (s, 1H), 7.73 (dd, J = 6.6, 2.2 Hz, 1H), 7.41 (ddd, J = 8.4, 4.7, 2.2 Hz, 1H), 7.16 (t, J = 8.5 Hz, 1H), 4.60 (dd, J = 15.4, 2.8 Hz, 1H), 4.53 (td, J = 6.6, 5.8 Hz, 1H), 4.44 (dd, J = 19.4, 9.6 Hz, 1H), 4.37 – 4.28 (m, 2H), 4.19 (dd, J = 20.2, 11.3 Hz, 1H), 4.07 – 3.99 (m, 1H), 1.87 (dd, J = 5.8, 1.1 Hz, 1H), 1.75 – 1.60 (m, 5H), 1.38 (h, J = 7.5 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.66 (d, J = 3.2 Hz), 163.82, 159.71, 158.06, 156.38, 148.10, 139.55, 135.25, 131.19 (d, J = 7.3 Hz), 120.72, 118.08, 115.47 (d, J = 22.3 Hz), 107.96 (d, J = 21.1 Hz), 98.77, 90.57, 89.21, 62.79, 62.11 (d, J = 28.5 Hz), 60.59 (d, J = 28.0 Hz), 44.72, 39.50, 22.86 (d, J = 25.6 Hz), 18.33, 13.74.19F NMR (565 MHz, CDCl3) δ -107.91, -141.32. HRMS: [APCI+] [M+H]+calc. for C₂₄H₂₃O₃N₃F2⁷⁹Br³²S 550.06061, observed 550.05997. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(4-hydroxyhex-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-419) General Procedure X was followed to afford the title compound as white powder, 38%.1H NMR (600 MHz, CDCl3) δ 8.06 (s, 1H), 7.73 (dd, J = 6.6, 2.2 Hz, 1H), 7.42 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.16 (t, J = 8.5 Hz, 1H), 4.59 (dd, J = 15.5, 1.2 Hz, 1H), 4.48 – 4.40 (m, 1H), 4.36 – 4.28 (m, 2H), 4.19 (dd, J = 20.2, 11.3 Hz, 1H), 4.03 (ddd, J = 17.4, 11.2, 1.7 Hz, 1H), 3.72 – 3.65 (m, 1H), 2.66 – 2.46 (m, 2H), 1.70 (d, J = 5.4 Hz, 1H), 1.65 (d, J = 21.4 Hz, 3H), 1.56 – 1.42 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.71 (d, J = 3.2 Hz), 163.28, 159.63, 157.98, 156.37, 147.92, 138.70, 135.26, 131.14 (d, J = 7.4 Hz), 120.74, 119.13, 115.48 (d, J = 22.6 Hz), 107.99 (d, J = 21.1 Hz), 95.86, 90.58, 89.22, 74.68, 71.29, 62.11 (d, J = 28.7 Hz), 60.58 (d, J = 28.0 Hz), 44.71, 29.28, 28.22, 22.86 (d, J = 25.5 Hz), 9.90.19F NMR (565 MHz, CDCl3) δ - 107.99, -141.32. HRMS: [APCI+] [M+H]+calc. for C₂₄H₂₃O₃N₃F2⁷⁹Br³²S 550.06061, observed 550.06006. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622- 420) General Procedure X was followed to afford the title compound as white solid, 40%.1H NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.83 (dd, J = 6.7, 2.2 Hz, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.47 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.17 (t, J = 8.5 Hz, 1H), 4.61 (d, J = 15.3 Hz, 1H), 4.45 (dd, J = 19.3, 9.9 Hz, 1H), 4.38 – 4.30 (m, 2H), 4.20 (dd, J = 20.2, 11.3 Hz, 1H), 4.04 (ddd, J = 17.3, 11.2, 1.5 Hz, 1H), 3.90 (s, 3H), 1.66 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.9 (d, J = 3.0 Hz), 163.7, 159.8, 158.1, 156.5, 147.9, 142.2, 138.3, 135.5, 133.2, 131.4 (d, J = 7.3 Hz), 131.1 (d, J = 3.9 Hz), 120.9, 119.3, 115.6 (d, J = 22.6 Hz), 108.0 (d, J = 21.4 Hz), 102.4, 90.7, 89.7, 89.4, 82.2, 62.3 (d, J = 28.5 Hz), 60.7 (d, J = 28.1 Hz), 44.9, 39.4, 23.0 (d, J = 25.7 Hz).19F NMR (565 MHz, CDCl3) δ -102.04 – -112.58 (m), -137.61 – -149.57 (m). HRMS: [APCI+] [M+H]+calc. for C24H₁9O2N5F2⁷⁹Br³²S, 558.0405, observed, 558.0410. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-((1-methyl-1H-pyrazol-3-yl)ethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622- 421) General Procedure X was followed to afford the title compound as white solid, 43%.1H NMR (600 MHz, CDCl3) δ 8.07 (s, 1H), 7.81 (dd, J = 6.7, 2.2 Hz, 1H), 7.50 (ddd, J = 8.6, 4.7, 2.2 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.16 (t, J = 8.5 Hz, 1H), 6.37 (d, J = 2.3 Hz, 1H), 4.59 (d, J = 15.4 Hz, 1H), 4.42 (dd, J = 19.5, 9.7 Hz, 1H), 4.37 – 4.27 (m, 2H), 4.17 (dd, J = 20.2, 11.3 Hz, 1H), 4.02 (dd, J = 17.3, 10.5 Hz, 1H), 3.89 (s, 3H), 1.63 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.8 (d, J = 3.2 Hz), 164.1, 159.8, 158.1, 156.5, 148.2, 139.3, 135.5, 133.6, 131.3 (d, J = 7.5 Hz), 130.9 (d, J = 3.9 Hz), 130.8, 120.8, 118.5, 115.5 (d, J = 22.4 Hz), 110.7, 108.0, 90.7 (d, J = 11.9 Hz), 89.3, 81.4, 62.2 (d, J = 28.3 Hz), 60.6 (d, J = 28.1 Hz), 44.9, 39.5, 22.9 (d, J = 25.4 Hz).19F NMR (565 MHz, CDCl3) δ -108.01 – -108.08 (m), -140.94 – -141.53 (m). HRMS: [APCI+] [M+H]+calc. for C24H₁9O2N5F2⁷⁹Br³²S, 558.0405, observed, 558.0411. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(4-hydroxypent-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-422) General Procedure X was followed to afford the title compound as white solid, 40%.1H NMR (600 MHz, CDCl3) δ 8.07 (s, 1H), 7.74 (dd, J = 6.6, 2.2 Hz, 1H), 7.42 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.16 (t, J = 8.5 Hz, 1H), 4.60 (d, J = 15.4 Hz, 1H), 4.44 (dd, J = 19.3, 9.7 Hz, 1H), 4.37 – 4.26 (m, 2H), 4.19 (dd, J = 20.2, 11.3 Hz, 1H), 4.03 (dd, J = 17.5, 12.4 Hz, 1H), 3.97 (p, J = 5.7 Hz, 1H), 2.61 – 2.50 (m, 2H), 1.69 (d, J = 5.0 Hz, 1H), 1.65 (d, J = 21.4 Hz, 3H), 1.57 (s, 1H), 1.22 (d, J = 6.2 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.8 (d, J = 2.9 Hz), 163.5, 159.8, 158.1, 156.5, 148.1, 138.9, 135.4, 131.3 (d, J = 7.3 Hz), 131.2 (d, J = 3.9 Hz), 120.9, 119.2, 115.6 (d, J = 22.6 Hz), 108.1 (d, J = 21.4 Hz), 95.9, 90.7, 89.3, 74.9, 66.5, 62.3 (d, J = 28.6 Hz), 60.71(d, J = 28.0 Hz), 44.9, 30.4, 23.0 (d, J = 25.6 Hz), 22.7.19F NMR (565 MHz, CDCl3) δ -107.88 – -107.93 (m), -141.17 – -141.52 (m). HRMS: [APCI+] [M+H]+calc. for C23H21O3N3F2⁷⁹Br³²S, 536.0450, observed, 536.0452. Preparation of N-(3-(5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1- yl)-2-oxoethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)prop-2-yn-1- yl)methanesulfonamide (1622-429) General Procedure X was followed to afford the title compound as white solid, 28%.1H NMR (800 MHz, CDCl3) δ 8.09 (s, 1H), 7.67 (dd, J = 6.5, 2.2 Hz, 1H), 7.66 – 7.64 (m, 0.5H), 7.58 – 7.51 (m, 0.3H), 7.48 – 7.43 (m, 0.7H), 7.38 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.17 (t, J = 8.4 Hz, 1H), 4.96 (t, J = 5.9 Hz, 1H), 4.59 (d, J = 15.5 Hz, 1H), 4.44 (dd, J = 19.5, 9.6 Hz, 1H), 4.37 (d, J = 15.6 Hz, 1H), 4.30 (dd, J = 16.9, 9.6 Hz, 1H), 4.19 (dd, J = 20.2, 11.3 Hz, 1H), 4.03 (dd, J = 17.4, 11.3 Hz, 1H), 2.88 (s, 3H), 1.65 (d, J = 21.4 Hz, 3H).13C NMR (201 MHz, CDCl3) δ 165.8 (d, J = 3.1 Hz), 164.1, 159.7, 158.5, 156.5, 148.7, 140.2, 135.2, 132.2 (d, J = 9.7 Hz), 132.1 (d, J = 2.9 Hz), 131.2 (d, J = 7.3 Hz), 130.9 (d, J = 3.8 Hz), 128.7 (d, J = 11.9 Hz), 120.9, 117.3, 115.9 (d, J = 22.4 Hz), 108.3 (d, J = 21.4 Hz), 92.7, 90.6, 89.5, 76.9, 62.2 (d, J = 28.4 Hz), 60.8 (d, J = 28.0 Hz), 44.9, 41.3, 33.7, 23.0 (d, J = 25.4 Hz).19F NMR (753 MHz, CDCl3) δ -107.17 – -107.24 (m), -141.02 – -141.49 (m, J = 20.8, 20.3 Hz). HRMS: [APCI+] [M+H]+calc. for C22H20O4N4F2⁷⁹Br³²S2, 585.0072, observed, 558.0085.

[0032] Preparation of N-(3-(5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1- yl)-2-oxoethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)prop-2-yn-1-yl)-N- methylmethanesulfonamide (1622-430) General Procedure X was followed to afford the title compound as white solid, 37%.1H NMR (800 MHz, CDCl3) δ 8.08 (s, 1H), 7.68 (dd, J = 6.6, 2.2 Hz, 1H), 7.39 (ddd, J = 8.6, 4.6, 2.2 Hz, 1H), 7.18 (t, J = 8.4 Hz, 1H), 4.58 (d, J = 15.5 Hz, 1H), 4.43 (dd, J = 19.5, 9.7 Hz, 1H), 4.36 (d, J = 15.6 Hz, 1H), 4.29 (ddd, J = 17.0, 9.7, 1.6 Hz, 1H), 4.25 (s, 2H), 4.19 (dd, J = 20.2, 11.3 Hz, 1H), 4.02 (ddd, J = 17.5, 11.4, 1.7 Hz, 1H), 2.85 (s, 3H), 2.68 (s, 3H), 1.65 (d, J = 21.4 Hz, 3H).13C NMR (201 MHz, CDCl3) δ 165.6 (d, J = 3.0 Hz), 164.1, 159.7, 158.5, 156.5, 148.6, 140.3, 135.1, 131.2 (d, J = 7.3 Hz), 131.1 (d, J = 4.2 Hz), 121.0, 117.3, 115.9 (d, J = 22.7 Hz), 108.3 (d, J = 21.0 Hz), 90.8, 90.5, 89.5, 78.4, 62.2 (d, J = 28.7 Hz), 60.7 (d, J = 28.0 Hz), 44.8, 40.6, 36.3, 34.7, 23.0 (d, J = 25.8 Hz).19F NMR (753 MHz, CDCl3) δ -106.83 – -107.17 (m), -141.21 – - 141.38 (m). HRMS: [APCI+] [M+H]+calc. for C23H22O4N4F2⁷⁹Br³²S2, 599.0228, observed, 599.0228. Preparation of 5-(3-bromo-4-fluorophenyl)-6-(3-(1,1-dioxidoisothiazolidin-2-yl)prop- 1-yn-1-yl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)- one (1622-431) General Procedure X was followed to afford the title compound as white solid, 27%.1H NMR (800 MHz, CDCl3) δ 8.07 (s, 1H), 7.71 (dd, J = 6.5, 2.2 Hz, 1H), 7.43 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.18 (t, J = 8.4 Hz, 1H), 4.58 (d, J = 15.5 Hz, 1H), 4.43 (dd, J = 19.5, 9.7 Hz, 1H), 4.36 (d, J = 15.5 Hz, 1H), 4.30 (dd, J = 16.9, 9.6 Hz, 1H), 4.18 (dd, J = 20.2, 11.3 Hz, 1H), 4.06 – 3.99 (m, 3H), 3.23 (t, J = 6.8 Hz, 2H), 3.08 – 3.04 (m, 2H), 2.36 – 2.27 (m, 2H), 1.64 (d, J = 21.4 Hz, 3H).13C NMR (201 MHz, CDCl3) δ 165.7 (d, J = 3.0 Hz), 164.0, 159.6, 158.4, 156.5, 148.4, 140.0, 135.2, 131.4 (d, J = 7.4 Hz), 131.1 (d, J = 4.1 Hz), 120.8, 117.7, 115.8 (d, J = 22.8 Hz), 108.1 (d, J = 21.4 Hz), 91.3, 90.5, 89.5, 77.5, 62.2 (d, J = 28.7 Hz), 60.7 (d, J = 28.1 Hz), 46.5, 46.2, 44.8, 35.7, 23.0 (d, J = 25.3 Hz), 18.9.19F NMR (753 M Hz, CDCl3) δ -105.18 – -111.75 (m), -139.10 – -144.63 (m). HRMS: [APCI+] [M+H]+calc. for C24H22O4N4F2⁷⁹Br³²S2, 611.0228, observed, 611.0228. Preparation of 6-(3-(1H-1,2,4-triazol-1-yl)prop-1-yn-1-yl)-5-(3-bromo-4- fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin- 4(3H)-one (1622-432) General Procedure X was followed to afford the title compound as white solid, 20%.1H NMR (800 MHz, CDCl3) δ 8.15 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.70 (dd, J = 6.6, 2.2 Hz, 1H), 7.39 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.16 (t, J = 8.4 Hz, 1H), 5.16 (s, 2H), 4.60 (d, J = 15.5 Hz, 1H), 4.44 (dd, J = 19.5, 9.8 Hz, 1H), 4.35 (d, J = 15.5 Hz, 1H), 4.31 (dd, J = 16.6, 9.3 Hz, 1H), 4.19 (dd, J = 19.9, 11.0 Hz, 1H), 4.03 (dd, J = 17.3, 11.3 Hz, 1H), 1.65 (d, J = 21.4 Hz, 3H).13C NMR (201 MHz, CDCl3) δ 165.7 (d, J = 3.3 Hz), 164.5, 159.8, 158.6, 156.5, 152.6, 148.7, 142.9, 141.2, 135.3, 131.0 (d, J = 7.3 Hz), 130.7 (d, J = 3.8 Hz), 120.9, 116.6, 115.9 (d, J = 22.8 Hz), 108.4 (d, J = 21.4 Hz), 90.5, 89.5, 88.5, 79.3, 62.2 (d, J = 28.3 Hz), 60.7 (d, J = 28.1 Hz), 44.9, 40.4, 23.0 (d, J = 25.4 Hz).19F NMR (753 MHz, CDCl3) δ -107.02 – -107.07 (m), -138.06 – - 143.89 (m). HRMS: [APCI+] [M+H]+calc. for C23H18O2N6F2⁷⁹Br³²S, 559.0358, observed, 559.0358.

[0033] Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-(2-oxopyrrolidin-1-yl)prop-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-433) General Procedure X was followed to afford the title compound as white solid, 34%.1H NMR (800 MHz, CDCl3) δ 8.07 (s, 1H), 7.71 (dd, J = 6.6, 2.2 Hz, 1H), 7.40 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.17 (t, J = 8.4 Hz, 1H), 4.59 (d, J = 15.5 Hz, 1H), 4.44 (dd, J = 19.6, 9.9 Hz, 1H), 4.35 (d, J = 15.5 Hz, 1H), 4.31 (dd, J = 16.9, 9.6 Hz, 1H), 4.27 (s, 2H), 4.19 (dd, J = 20.2, 11.3 Hz, 1H), 4.03 (dd, J = 17.4, 11.3 Hz, 1H), 3.36 – 3.31 (m, 2H), 2.39 (t, J = 8.1 Hz, 2H), 2.10 – 1.97 (m, 2H), 1.65 (d, J = 21.4 Hz, 3H).13C NMR (201 MHz, CDCl3) δ 174.7, 165.8 (d, J = 3.0 Hz), 163.9, 159.6, 158.4, 156.5, 148.3, 139.8, 135.3, 131.3 (d, J = 7.3 Hz), 131.1 (d, J = 3.9 Hz), 120.9, 118.1, 115.7 (d, J = 22.4 Hz), 108.1 (d, J = 21.4 Hz), 92.2, 90.5, 89.5, 76.1, 62.2 (d, J = 28.3 Hz), 60.7 (d, J = 28.1 Hz), 46.6, 44.8, 33.0, 30.7, 23.0 (d, J = 25.8 Hz), 17.8.19F NMR (753 MHz, CDCl3) δ -105.40 – -109.51 (m), -139.33 – -144.11 (m, J = 20.3 Hz). HRMS: [APCI+] [M+H]+calc. for C25H22O3N4F2⁷⁹Br³²S, 575.0559, observed, 575.0559. Preparation of 3-(3-(5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1- yl)-2-oxoethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)prop-2-yn-1-yl)oxazolidin-2- one (1622-434) General Procedure X was followed to afford the title compound as white solid, 35%.1H NMR (800 MHz, CDCl3) δ 8.08 (s, 1H), 7.70 (dd, J = 6.6, 2.2 Hz, 1H), 7.68 – 7.62 (m, 1H), 7.56 – 7.51 (m, 1H), 7.48 – 7.43 (m, 1H), 7.41 (ddd, J = 8.4, 4.6, 2.2 Hz, 1H), 7.17 (t, J = 8.4 Hz, 1H), 4.58 (d, J = 15.5 Hz, 1H), 4.43 (dd, J = 19.6, 9.5 Hz, 1H), 4.37 (d, J = 15.6 Hz, 1H), 4.34 – 4.32 (m, 2H), 4.29 (dd, J = 16.9, 9.7 Hz, 1H), 4.25 (s, 2H), 4.18 (dd, J = 20.4, 10.8 Hz, 1H), 4.02 (ddd, J = 17.4, 11.2, 1.6 Hz, 1H), 3.55 – 3.47 (m, 2H), 1.64 (d, J = 21.5 Hz, 3H).13C NMR (201 MHz, CDCl3) δ 165.7 (d, J = 3.2 Hz), 164.0, 159.6, 158.4, 157.9, 156.5, 148.5, 140.1, 135.2, 132.9, 132.4, 132.2 (d, J = 10.2 Hz), 132.1 (d, J = 2.8 Hz), 131.3 (d, J = 7.4 Hz), 131.1 (d, J = 3.8 Hz), 128.6 (d, J = 12.1 Hz), 120.8, 117.5, 115.8 (d, J = 22.6 Hz), 108.0 (d, J = 21.2 Hz), 91.0, 90.5, 89.5, 62.2, 62.1, 62.1, 60.7 (d, J = 28.0 Hz), 44.9, 44.1, 35.1, 22.9 (d, J = 25.4 Hz).19F NMR (753 MHz, CDCl3) δ -105.70 – -111.75 (m), -138.80 – -143.36 (m). HRMS: [APCI+] [M+H]+calc. for C25H22O3N4F2⁷⁹Br³²S, 577.0351, observed, 577.0358. Preparation of 6-((1-(2H-1,2,3-triazol-2-yl)cyclopropyl)ethynyl)-5-(3-bromo-4- fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin- 4(3H)-one (1622-435) General Procedure X was followed to afford the title compound as white solid, 23%.1H NMR (800 MHz, CDCl3) δ 8.07 (s, 1H), 7.69 (dd, J = 6.6, 2.2 Hz, 1H), 7.62 (s, 2H), 7.39 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.12 (t, J = 8.4 Hz, 1H), 4.59 (d, J = 15.4 Hz, 1H), 4.44 (dd, J = 19.5, 9.9 Hz, 1H), 4.37 – 4.28 (m, 2H), 4.19 (dd, J = 20.1, 11.3 Hz, 1H), 4.03 (dd, J = 17.3, 11.3 Hz, 1H), 1.91 – 1.85 (m, 2H), 1.65 (d, J = 21.4 Hz, 3H), 1.62 – 1.59 (m, 2H).13C NMR (201 MHz, CDCl3) δ 165.8 (d, J = 3.0 Hz), 164.1, 159.6, 158.4, 156.5, 148.3, 140.2, 135.4, 134.9, 131.3 (d, J = 7.4 Hz), 130.7 (d, J = 3.8 Hz), 120.7, 117.8, 115.6 (d, J = 22.3 Hz), 108.0 (d, J = 21.1 Hz), 96.0, 90.5, 89.5, 74.3, 62.3 (d, J = 28.4 Hz), 60.7 (d, J = 28.1 Hz), 44.9, 37.0, 23.0 (d, J = 25.8 Hz), 18.7.19F NMR (753 MHz, CDCl3) δ -103.68 – -111.53 (m), -141.28 – -141.43 (m). HRMS: [APCI+] [M+H]+calc. for C25H20O2N6F2⁷⁹Br³²S, 585.0514, observed, 585.0514. Preparation of 5-(3-bromo-4-fluoro-phenyl)-3-[2-(3-fluoro-3-methyl-azetidin-1-yl)-2- oxo-ethyl]-6-[2-(3-fluorooxetan-3-yl)ethynyl]thieno[2,3-d]pyrimidin-4-one (1622-436) Prepared by General Procedure X, followed by a DAST reaction to install the fluorine atom.1H NMR (800 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.78 (dd, J = 6.8, 2.2 Hz, 1H), 7.49 (ddd, J = 8.6, 4.8, 2.2 Hz, 1H), 7.40 (t, J = 8.7 Hz, 1H), 4.78 – 4.72 (m, 4H), 4.62 (s, 2H), 4.35 – 4.24 (m, 2H), 3.96 – 3.88 (m, 2H), 1.5313 = 22.0 Hz, 3H). C NMR (201 MHz, DMSO-d6) δ 166.67 (d, JC-F = 3.1 Hz), 164.46, 159.28, 158.06, 156.27, 151.34, 141.82 (d, JC-F = 2.7 Hz), 135.46, 132.19 (d, JC-F= 7.7 Hz), 131.14 (d, JC-F= 3.9 Hz), 120.69, 116.22 (d, JC-F= 22.4 Hz), 114.29 (d, JC-F= 4.0 Hz), 107.39 (d, JC-F = 21.0 Hz), 91.99, 90.98, 90.71 (d, JC-F = 34.8 Hz), 87.58, 86.58, 82.06, 81.13 (d, JC-F = 27.0 Hz), 61.75 (d, JC-F = 27.5 Hz), 60.49 (d, JC-F = 27.2 Hz), 45.83, 22.82 (d, JC-F = 25.0 Hz).19F NMR (753 MHz, DMSO-d6) δ -108.28, -138.99, -141.42. HRMS: [APCI+] [M+H]+calc. for C₂₃H₁₈O₃N₃F379Br32S 552.01989, observed 552.02124. Preparation of 3-(5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)- 2-oxoethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)-N-ethylpropiolamide (1622-437) Prepared according to General Procedure X.1H NMR (600 MHz, DMSO-d6) δ 8.80 (t, J = 5.6 Hz, 1H), 8.48 (s, 1H), 7.81 (dd, J = 6.7, 2.2 Hz, 1H), 7.54 (ddd, J = 8.5, 4.8, 2.2 Hz, 1H), 7.47 (t, J = 8.7 Hz, 1H), 4.70 (s, 2H), 4.42 – 4.31 (m, 2H), 4.03 – 3.96 (m, 2H), 3.14 – 3.09 (m, 2H), 1.60 (d, J = 22.0 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 166.66 (d, JC-F = 2.8 Hz), 164.59, 159.57, 157.93, 156.24, 151.49 (d, JC-F = 13.3 Hz), 142.41, 135.48, 131.99 (d, JC-F = 7.7 Hz), 131.17 (d, JC-F = 3.8 Hz), 120.88, 116.32 (d, JC-F = 22.6 Hz), 114.17, 107.59 (d, JC-F= 21.4 Hz), 92.16, 91.02 (d, JC-F= 60.1 Hz), 75.30, 61.74 (d, JC-F= 27.6 Hz), 60.49 (d, JC-F= 27.2 Hz), 45.83, 34.39, 22.82 (d, JC-F = 25.0 Hz), 14.68.19F NMR (565 MHz, DMSO-d6) δ -108.36, -139.22. HRMS: [APCI+] [M+H]+calc. for C₂₃H₂₀O₃N₄F279Br32S 549.03752, observed 549.03922. Preparation of 5-(3-bromo-4-fluoro-phenyl)-3-[2-(3-fluoro-3-methyl-azetidin-1-yl)-2- oxo-ethyl]-6-(3-pyrrol-1-ylprop-1-ynyl)thieno[2,3-d]pyrimidin-4-one (1622-438) Prepared according to General Procedure X.1H NMR (600 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.76 (dd, J = 6.8, 2.2 Hz, 1H), 7.48 (ddd, = 8.5, 4.9, 2.2 Hz, 1H), 7.40 (t, J = 8.7 Hz, 1H), 6.73 (t, J = 2.1 Hz, 2H), 6.03 (t, J = 2.1 Hz, 2H), 5.06 (s, 2H), 4.68 (d, J = 1.6 Hz, 2H), 4.42 – 4.29 (m, 2H), 4.03 – 3.96 (m, 2H), 1.60 (d, J = 22.1 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 166.72 (d, J = 2.8 Hz), 163.44, 159.34, 157.71, 156.23, 150.92, 139.98, 135.38, 132.00 (d, J = 7.7 Hz), 131.60 (d, J = 3.9 Hz), 120.97, 120.81, 116.25, 116.14 (d, J = 10.8 Hz), 108.81, 107.44 (d, J = 21.2 Hz), 93.95, 92.15, 90.81, 76.55, 61.74 (d, J = 27.6 Hz), 60.47 (d, J = 27.3 Hz), 45.80, 38.92, 22.82 (d, J = 25.0 Hz).19F NMR (565 MHz, DMSO-d6) δ -109.35, -139.22. HRMS: [APCI+] [M+H]+calc. for C₂₅H₂₀O₂N₄F279Br32S 557.04529, observed 557.04442. Preparation of 5-(3-bromo-4-fluoro-phenyl)-3-[2-(3-fluoro-3-methyl-azetidin-1-yl)-2- oxo-ethyl]-6-[3-(4-methylpyrazol-1-yl)prop-1-ynyl]thieno[2,3-d]pyrimidin-4-one (1622-439) Prepared according to General Procedure X.1H NMR (600 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.74 (dd, J = 6.8, 2.1 Hz, 1H), 7.48 (ddd, J = 8.5, 4.9, 2.2 Hz, 1H), 7.41 – 7.37 (m, 2H), 7.27 (d, J = 0.7 Hz, 1H), 5.19 (s, 2H), 4.68 (d, J = 1.6 Hz, 2H), 4.42 – 4.29 (m, 2H), 4.03 – 3.96 (m, 2H), 2.01 (s, 3H), 1.60 (d, J = 22.1 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 166.71 (d, JC-F= 3.1 Hz), 163.48, 159.33, 157.69, 156.23, 150.94, 140.20, 140.08, 135.40, 132.01 (d, JC-F= 7.6 Hz), 131.55 (d, JC-F = 3.8 Hz), 128.61, 120.80, 116.22, 116.10, 116.05 (d, JC-F = 5.0 Hz), 107.42 (d, JC- F = 21.2 Hz), 93.06, 92.15, 90.81, 76.81, 61.74 (d, JC-F = 27.6 Hz), 60.47 (d, JC-F = 27.2 Hz), 45.79, 41.79, 22.82 (d, JC-F = 25.0 Hz), 9.11.19F NMR (565 MHz, DMSO-d6) δ -108.98, -139.22. HRMS: [APCI+] [M+H]+calc. for C₂₅H₂₁O₂N₅F279Br32S 572.05619, observed 572.05746. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-(3-hydroxyoxetan-3-yl)prop-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-440) Prepared according to General Procedure X.1H NMR (800 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.74 (dd, J = 6.8, 2.1 Hz, 1H), 7.51 (ddd, J = 8.5, 4.8, 2.2 Hz, 1H), 7.41 (t, J = 8.7 Hz, 1H), 5.97 (s, 1H), 4.68 (s, 2H), 4.40 – 4.29 (m, 6H), 4.02 – 3.96 (m, 2H), 2.84 (s, 2H), 1.60 (d, J = 22.0 Hz, 3H).13C NMR (201 MHz, DMSO-d6) δ 166.77 (d, JC-F= 2.8 Hz), 162.90, 158.99, 157.77, 156.24, 150.62, 138.78, 135.42, 132.11 (d, JC-F = 7.5 Hz), 131.75 (d, JC-F = 3.7 Hz), 120.72, 117.55, 116.03 (d, JC-F = 22.5 Hz), 107.27 (d, JC-F = 20.9 Hz), 96.61, 91.98, 90.97, 82.46, 73.65, 72.61, 61.75 (d, JC-F= 27.7 Hz), 60.47 (d, JC-F= 27.3 Hz), 45.79, 29.60, 22.82 (d, JC-F= 24.8 Hz).19F NMR (753 MHz, DMSO-d6) δ -109.48, -139.00. HRMS: [APCI+] [M+H]+calc. for C₂₄H₂₁O₄N₃F279Br32S 564.03987, observed 564.04148. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-oxo-3-(pyrrolidin-1-yl)prop-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-441) Prepared according to General Procedure X.1H NMR (800 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.85 (dd, J = 6.7, 2.2 Hz, 1H), 7.54 (ddd, J = 8.6, 4.8, 2.2 Hz, 1H), 7.48 (t, J = 8.7 Hz, 1H), 4.69 (s, 2H), 4.42 – 4.30 (m, 2H), 4.03 – 3.96 (m, 2H), 3.31 – 3.27 (m, 4H), 1.84 – 1.80 (m, 4H), 1.60 (d, J = 22.0 Hz, 3H).13C NMR (201 MHz, DMSO-d6) δ 166.61 (d, JC-F = 3.2 Hz), 164.94, 159.41, 158.18, 156.23, 151.57, 150.77, 143.14, 135.19, 132.23 (d, JC-F = 7.6 Hz), 131.49 (d, JC-F = 3.7 Hz), 121.00, 116.37 (d, JC-F= 22.7 Hz), 114.11, 107.63 (d, JC-F= 21.4 Hz), 91.98, 90.98, 90.14, 79.98, 61.74 (d, JC-F = 27.5 Hz), 60.48 (d, JC-F = 27.3 Hz), 47.84, 45.82, 45.60, 25.29, 24.49, 22.81 (d, JC-F = 24.8 Hz).19F NMR (753 MHz, DMSO-d6) δ -108.33, -139.11. HRMS: [APCI+] [M+H]+calc. for C₂₅H₂₂O₃N₄F279Br32S 575.05586, observed 575.05743. Preparation of 5-(3-bromo-4-fluorophenyl)-6-(4,4-dimethyl-3-oxopent-1-yn-1-yl)-3- (2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-442) General Procedure X was followed to afford the title compound as white powder, 16%.1H NMR (600 MHz, CDCl3) δ 8.12 (s, 1H), 7.72 (dd, J = 6.5, 2.2 Hz, 1H), 7.43 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.20 (t, J = 8.4 Hz, 1H), 4.59 (d, J = 15.4 Hz, 1H), 4.48 – 4.40 (m, 1H), 4.37 (d, J = 15.5 Hz, 1H), 4.30 (ddd, J = 16.9, 9.6, 1.6 Hz, 1H), 4.20 (dd, J = 20.2, 11.3 Hz, 1H), 4.03 (ddd, J = 17.4, 11.3, 1.4 Hz, 1H), 1.65 (d, J = 21.4 Hz, 3H), 1.09 (s, 9H).13C NMR (151 MHz, CDCl3) δ 193.33, 166.05, 165.54 (d, J = 3.0 Hz), 160.26, 158.60, 156.45, 149.16, 144.16, 135.25, 131.19 (d, J = 7.6 Hz), 130.65 (d, J = 3.9 Hz), 121.06, 115.97 (d, J = 22.7 Hz), 115.67, 108.61 (d, J = 21.2 Hz), 93.60, 90.69, 89.33, 83.69, 62.21 (d, J = 28.6 Hz), 60.76 (d, J = 27.9 Hz), 44.87 (d, J = 6.7 Hz), 25.91, 23.00 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -106.74, -141.32. HRMS: [APCI+] [M+H]+calc. for C₂₅H₂₃O₃N₃F2⁷⁹Br³²S 562.06061, observed 562.06113. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-oxohex-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-443) General Procedure X was followed to afford the title compound as yellow powder, 39%.1H NMR (600 MHz, CDCl3) δ 8.12 (s, 1H), 7.76 (dd, J = 6.5, 2.2 Hz, 1H), 7.45 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.21 (t, J = 8.4 Hz, 1H), 4.60 (d, J = 15.4 Hz, 1H), 4.49 – 4.41 (m, 1H), 4.37 (d, J = 15.5 Hz, 1H), 4.31 (ddd, J = 16.9, 9.6, 1.6 Hz, 1H), 4.20 (dd, J = 20.2, 11.3 Hz, 1H), 4.04 (ddd, J = 17.3, 11.3, 1.5 Hz, 1H), 2.52 – 2.46 (m, 2H), 1.66 (d, J = 21.4 Hz, 3H), 1.60 (q, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 187.04, 166.03, 165.41 (d, J = 3.2 Hz), 160.14, 158.49, 156.31, 149.09, 144.49, 135.17, 131.14 (d, J = 7.4 Hz), 130.24 (d, J = 4.0 Hz), 120.84, 115.76 (d, J = 22.7 Hz), 115.09, 108.29 (d, J = 21.4 Hz), 94.93, 90.56, 82.46, 62.10 (d, J = 28.5 Hz), 60.63 (d, J = 28.1 Hz), 47.21, 44.75, 22.87 (d, J = 25.5 Hz), 17.59, 13.53.19F NMR (565 MHz, CDCl3) δ -106.60, -141.32. HRMS: [APCI+] [M+H]+calc. for C₂₄H₂₁O₃N₃F2⁷⁹Br³²S 548.04496, observed 548.04608. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-((3-hydroxytetrahydrofuran-3-yl)ethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-444) General Procedure X was followed to afford the title compound as white powder, 62%.1H NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.75 (dd, J = 6.6, 2.2 Hz, 1H), 7.42 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.17 (t, J = 8.5 Hz, 1H), 4.60 (dd, J = 15.4, 2.4 Hz, 1H), 4.45 (dd, J = 19.4, 9.7 Hz, 1H), 4.40 – 4.28 (m, 2H), 4.20 (dd, J = 20.2, 11.3 Hz, 1H), 4.05 (td, J = 8.4, 7.0 Hz, 2H), 4.02 – 3.95 (m, 1H), 3.90 (dd, J = 9.4, 1.1 Hz, 1H), 3.83 (d, J = 9.4 Hz, 1H), 2.35 – 2.21 (m, 3H), 1.65 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.75 (d, J = 2.9 Hz), 164.22, 159.87, 158.22, 156.50, 148.39, 140.18, 135.34, 131.39 (d, J = 7.5 Hz), 130.72 (d, J = 3.9 Hz), 120.74, 117.46, 115.66 (d, J = 22.6 Hz), 108.00 (d, J = 21.4 Hz), 97.14, 90.70, 89.33, 79.97, 73.79, 67.82, 62.25 (d, J = 28.4 Hz), 60.74 (d, J = 28.0 Hz), 44.90, 42.60, 22.99 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -107.49, -141.34. HRMS: [APCI+] [M+H]+calc. for C₂₄H₂₁O₄N₃F2⁷⁹Br³²S 564.03987, observed 564.04009. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)thieno[2,3-d]pyrimidin- 4(3H)-one (1622-445) General Procedure X was followed to afford the title compound as white powder, 17%.1H NMR (600 MHz, CDCl3) δ 8.09 (d, J = 2.4 Hz, 1H), 7.72 (dd, J = 6.6, 2.2 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.17 (t, J = 8.5 Hz, 1H), 4.60 (dd, J = 15.4, 5.3 Hz, 1H), 4.45 (dd, J = 19.4, 9.6 Hz, 1H), 4.39 – 4.28 (m, 2H), 4.19 (dd, J = 20.2, 11.3 Hz, 1H), 4.07 – 4.00 (m, 1H), 3.66 (d, J = 3.8 Hz, 1H), 3.33 – 3.27 (m, 2H), 2.90 (s, 3H), 2.46 (ddd, J = 12.8, 5.1, 3.8 Hz, 1H), 2.28 (dt, J = 12.7, 8.5 Hz, 1H), 1.65 (d, J = 21.5 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 171.09, 165.84 (d, J = 3.2 Hz), 164.34, 159.81, 158.16, 156.50, 148.48, 140.46, 135.25, 131.49 (d, J = 7.5 Hz), 130.88 (d, J = 3.9 Hz), 120.67, 117.35, 115.68 (d, J = 22.6 Hz), 107.91 (d, J = 21.1 Hz), 95.55, 90.69, 89.33, 70.84, 62.25 (d, J = 28.5 Hz), 60.72 (d, J = 28.0 Hz), 45.10 (d, J = 60.7 Hz), 35.35, 30.76, 22.99 (d, J = 25.6 Hz).19F NMR (565 MHz, CDCl3) δ -107.67, -141.36. HRMS: [APCI+] [M+H]+calc. for C₂₅H₂₂O₄N₄F2⁷⁹Br³²S 591.05077, observed 591.05104. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-hydroxy-3-(pyridin-4-yl)prop-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-446) N General Procedure X was followed to afford the title compound as yellow powder, 16%. 1H NMR (600 MHz, CDCl3) δ 8.89 – 8.85 (m, 3H), 8.14 (s, 1H), 7.78 – 7.74 (m, 3H), 7.73 (s, 1H), 7.59 (dd, J = 6.5, 2.2 Hz, 1H), 7.24 (t, J = 8.3 Hz, 1H), 4.63 (d, J = 15.6 Hz, 1H), 4.50 – 4.18 (m, 5H), 4.06 (dd, J = 17.4, 11.3 Hz, 1H), 1.68 (d, J = 21.4 Hz, 4H).13C NMR (151 MHz, CDCl3) δ 188.35, 165.44 (d, J = 3.2 Hz), 164.77, 160.20, 158.54, 156.30, 150.97, 149.13, 143.71, 140.99, 136.63, 135.44, 133.98, 131.15 (d, J = 7.5 Hz), 130.18 (d, J = 4.1 Hz), 122.79, 122.45, 121.34, 116.07 (d, J = 22.6 Hz), 108.81 (d, J = 21.2 Hz), 90.56, 89.20, 62.08 (d, J = 28.7 Hz), 60.64 (d, J = 28.1 Hz), 44.63, 22.86 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -106.58, -141.29. HRMS: [APCI+] [M+H]+ calc. for C₂₆H₂₀O₃N₄⁷⁹BrF₂³²S, 585.04021, observed, 585.04006. Preparation of 1-(3-(5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1- yl)-2-oxoethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)prop-2-yn-1-yl)pyrrolidine- 2,5-dione (1622-447) General Procedure X was followed to afford the title compound as pale-yellow powder, 5.5%.1H NMR (600 MHz, CDCl3) δ 8.11 (s, 1H), 7.72 – 7.65 (m, 1H), 7.44 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.23 – 7.16 (m, 1H), 4.67 – 4.58 (m, 1H), 4.51 – 4.42 (m, 3H), 4.40 – 4.31 (m, 2H), 4.21 (dd, J = 20.2, 11.3 Hz, 1H), 4.06 (dd, J = 16.7, 11.8 Hz, 1H), 2.78 (s, 4H), 2.72 (d, J = 26.6 Hz, 0H), 1.67 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 175.54, 165.65 (d, J = 3.2 Hz), 163.82, 159.71, 158.06, 156.33, 148.22, 140.16, 135.26, 131.18 (d, J = 7.4 Hz), 130.60 (d, J = 3.8 Hz), 120.61, 117.49, 115.57 (d, J = 22.3 Hz), 107.92 (d, J = 21.1 Hz), 90.66, 89.21, 74.96, 62.14 (d, J = 28.4 Hz), 60.60 (d, J = 27.9 Hz), 44.74, 28.62, 28.26, 22.86 (d, J = 25.5 Hz). 19F NMR (565 MHz, CDCl3) δ -107.82, -141.37. HRMS: [APCI+] [M+H]+ calc. for C₂₅H₂₀O₄N₄⁷⁹BrF₂³²S, 589.03512, observed, 589.03503. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-((1-hydroxycyclobutyl)ethynyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-448) General Procedure X was followed to afford the title compound as white powder, 51.9%.1H NMR (600 MHz, DMSO) δ 8.44 (s, 1H), 7.83 (dd, J = 6.8, 2.1 Hz, 1H), 7.53 (ddd, J = 8.5, 4.9, 2.2 Hz, 1H), 7.45 (t, J = 8.7 Hz, 1H), 5.97 (s, 1H), 4.68 (d, J = 2.0 Hz, 2H), 4.44 – 4.30 (m, 2H), 4.05 – 3.94 (m, 2H), 2.25 (ddt, J = 11.9, 8.4, 3.5 Hz, 2H), 2.16 (qd, J = 9.3, 2.7 Hz, 2H), 1.67 – 1.57 (m, 4H).13C NMR (151 MHz, DMSO) δ 166.76 (d, J = 2.8 Hz), 163.28, 159.23, 157.60, 156.25, 150.70, 139.21, 135.35, 132.35 (d, J = 7.6 Hz), 131.65 (d, J = 3.8 Hz), 120.72, 116.97, 116.09, 107.13, 103.17, 92.15, 90.81, 74.24, 67.13, 61.75 (d, J = 27.7 Hz), 60.47 (d, J = 27.2 Hz), 45.82, 22.82 (d, J = 25.1 Hz), 13.11.19F NMR (565 MHz, DMSO) δ -109.05, -139.07. HRMS: [APCI+] [M+H]+calc. for C₂₄H₂₁O₃N₃⁷⁹BrF₂³²S, 548.04496, observed, 548.04353. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-hydroxy-3-phenylprop-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622- 449) General Procedure X was followed to afford the title compound as yellow powder, 18%.1H NMR (600 MHz, CDCl3) δ 8.13 (s, 1H), 8.03 – 7.98 (m, 2H), 7.70 (d, J = 15.3 Hz, 1H), 7.64 – 7.58 (m, 2H), 7.56 – 7.49 (m, 2H), 7.40 (d, J = 15.3 Hz, 1H), 7.23 (t, J = 8.4 Hz, 1H), 4.64 (d, J = 15.5 Hz, 1H), 4.50 – 4.17 (m, 5H), 4.06 (dd, J = 17.3, 11.3 Hz, 1H), 1.68 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 189.06, 165.54 (d, J = 3.0 Hz), 164.33, 160.09, 158.43, 156.35, 148.80, 139.74, 137.61, 135.45, 134.75 (d, J = 19.9 Hz), 133.19, 131.18 (d, J = 7.5 Hz), 130.43 (d, J = 4.2 Hz), 128.63 (d, J = 43.1 Hz), 123.84, 122.75, 115.99 (d, J = 22.6 Hz), 108.72 (d, J = 21.5 Hz), 90.57, 89.21, 62.09 (d, J = 28.6 Hz), 60.62 (d, J = 28.1 Hz), 44.61, 22.86 (d, J = 25.6 Hz).19F NMR (565 MHz, CDCl3) δ -107.07, -141.31. HRMS: [APCI+] [M+H]+calc. for C₂₇H₂₁O₃N₃⁷⁹BrF₂³²S, 584.04496, observed, 584.0453. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-hydroxy-3-(p-tolyl)prop-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622- 450) General Procedure X was followed to afford the title compound as yellow powder, 7%.1H NMR (600 MHz, CDCl3) δ 8.12 (s, 1H), 7.93 – 7.87 (m, 2H), 7.69 (d, J = 15.3 Hz, 1H), 7.40 (d, J = 15.3 Hz, 1H), 7.34 – 7.32 (m, 2H), 7.23 (t, J = 8.4 Hz, 1H), 4.63 (d, J = 15.5 Hz, 1H), 4.34 (tdd, J = 71.1, 19.8, 10.5 Hz, 5H), 4.06 (dd, J = 17.2, 11.4 Hz, 1H), 2.46 (s, 3H), 1.67 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 188.52, 165.56 (d, J = 3.2 Hz), 164.23, 160.06, 158.41, 156.35, 148.74, 144.16, 139.50, 135.45, 135.06, 134.82, 134.38, 131.18 (d, J = 7.4 Hz), 130.48 (d, J = 3.9 Hz), 129.47, 128.63, 123.95, 122.74, 115.97 (d, J = 22.7 Hz), 108.71 (d, J = 21.4 Hz), 90.58, 89.22, 62.09 (d, J = 28.6 Hz), 60.62 (d, J = 28.1 Hz), 44.61, 22.85 (d, J = 25.6 Hz), 21.75.19F NMR (565 MHz, CDCl3) δ -107.16, -141.32. HRMS: [APCI+] [M+H]+calc. for C₂₈H₂₃O₃N₃⁷⁹BrF₂³²S, 598.06061, observed, 598.0606. Preparation of 5-(3-bromo-4-fluorophenyl)-6-(3-cyclohexyl-3-hydroxyprop-1-yn-1- yl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-451) General Procedure X was followed to afford the title compound as white powder, 26%.1H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.73 (dd, J = 6.6, 2.2 Hz, 1H), 7.42 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.19 (t, J = 8.5 Hz, 1H), 4.62 (dd, J = 15.4, 3.1 Hz, 1H), 4.50 – 4.18 (m, 5H), 4.06 (ddd, J = 17.4, 11.2, 1.5 Hz, 1H), 1.90 – 1.53 (m, 11H), 1.30 – 0.91 (m, 4H).13C NMR (151 MHz, CDCl3) δ 165.65 (d, J = 3.2 Hz), 163.74, 159.71, 158.06, 156.38, 148.09, 139.54, 135.23, 131.16 (d, J = 7.4 Hz), 131.03 (d, J = 4.0 Hz), 120.80, 118.29, 115.51 (d, J = 22.6 Hz), 108.08 (d, J = 21.2 Hz), 97.93, 90.58, 89.22, 67.73, 62.10 (d, J = 28.5 Hz), 60.59 (d, J = 28.0 Hz), 44.70, 44.02, 28.51, 27.99, 26.24, 25.79 (d, J = 4.8 Hz), 22.87 (d, J = 25.7 Hz).19F NMR (565 MHz, CDCl3) δ -107.98, -141.34. HRMS: [APCI+] [M+H]+calc. for C₂₇H₂₇O₃N₃⁷⁹BrF₂³²S, 590.09191, observed, 590.09154. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-hydroxy-3-(thiophen-3-yl)prop-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-452) General Procedure X was followed to afford the title compound as yellow powder, 13%.1H NMR (600 MHz, CDCl3) δ 8.17 (dd, J = 2.9, 1.3 Hz, 1H), 8.12 (s, 1H), 7.69 (d, J = 15.2 Hz, 1H), 7.64 (dd, J = 5.1, 1.3 Hz, 1H), 7.59 (dd, J = 6.5, 2.2 Hz, 1H), 7.39 (dd, J = 5.1, 2.9 Hz, 1H), 7.27 – 7.21 (m, 2H), 4.63 (d, J = 15.5 Hz, 1H), 4.50 – 4.17 (m, 5H), 4.06 (dd, J = 17.2, 11.2 Hz, 1H), 1.67 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 182.57, 165.54 (d, J = 3.2 Hz), 164.27, 160.08, 158.43, 156.34, 148.80, 142.62, 139.68, 135.46, 134.53, 134.14, 132.48, 131.18 (d, J = 7.5 Hz), 130.41 (d, J = 4.2 Hz), 127.34, 126.78, 124.61, 122.74, 115.99 (d, J = 22.7 Hz), 108.72 (d, J = 21.2 Hz), 90.58, 89.22, 62.09 (d, J = 28.5 Hz), 60.62 (d, J = 28.1 Hz), 44.62, 22.85 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -107.07, -141.31. HRMS: [APCI+] [M+H]+calc. for C₂₁H₁₅ON₉⁷⁹BrF₂³²S₂, 590.0013, observed, 590.00149. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-(4-hydroxy-1H-pyrazol-1-yl)prop-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)- one (1622-454) General Procedure X was followed to afford the title compound as white solid, 35%.1H NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.69 (dd, J = 6.6, 2.2 Hz, 1H), 7.37 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.28 (s, 2H), 7.13 (t, J = 8.5 Hz, 1H), 4.72 (s, 2H), 4.60 (d, J = 15.4 Hz, 1H), 4.44 (dd, J = 19.4, 9.6 Hz, 1H), 4.37 – 4.27 (m, 2H), 4.19 (dd, J = 20.2, 11.3 Hz, 1H), 4.03 (dd, J = 17.2, 11.1 Hz, 1H), 1.65 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.7 (d, J = 3.0 Hz), 164.3, 159.9, 158.2, 156.5, 148.5, 144.4, 140.5, 135.3, 131.2 (d, J = 7.5 Hz), 130.9 (d, J = 3.9 Hz), 120.9, 117.5, 115.8 (d, J = 22.6 Hz), 108.2 (d, J = 21.1 Hz), 92.5, 90.7, 89.3, 79.4, 62.2 (d, J = 28.4 Hz), 60.7 (d, J = 27.9 Hz), 60.3, 44.8, 23.0 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -107.49 – -107.77 (m), -140.95 – -141.59 (m). HRMS: [APCI+] [M+H]+calc. for C24H19O3N5F2⁷⁹Br³²S, 574.0355, observed, 574.0363. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-(4-methoxy-1H-pyrazol-1-yl)prop-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)- one (1622-455) 1622-455 was prepared according to General Procedure X. White solid, 12%.1H NMR (600 MHz, CDCl3) δ 8.26 (s, 1H), 7.89 (dd, J = 6.6, 2.2 Hz, 1H), 7.58 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.32 (t, J = 8.4 Hz, 1H), 5.19 (s, 2H), 4.77 (d, J = 15.4 Hz, 1H), 4.62 (dd, J = 19.4, 9.6 Hz, 1H), 4.55 – 4.45 (m, 2H), 4.37 (dd, J = 20.2, 11.3 Hz, 1H), 4.25 – 4.17 (m, 1H), 3.92 (s, 3H), 1.83 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.74 (d, J = 3.2 Hz), 164.19, 159.89, 158.23, 156.47, 148.45, 147.60, 140.46, 135.36, 131.15 (d, J = 7.6 Hz), 130.80, 127.84, 120.81, 117.37, 115.73 (d, J = 22.4 Hz), 113.47, 108.23 (d, J = 21.1 Hz), 90.76, 90.69, 89.33, 78.04, 62.23 (d, J = 28.7 Hz), 60.71 (d, J = 28.1 Hz), 59.02, 44.85, 43.17, 22.98 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -102.64 – -112.28 (m), -135.29 – -146.43 (m). HRMS: [APCI+] [M+H]+calc. for C25H21O3N5F2⁷⁹Br³²S, 588.0511, observed, 588.0521. Preparation of 1-(3-(5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1- yl)-2-oxoethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)prop-2-yn-1-yl)-1H-pyrazole- 3-carbonitrile (1622-456) 1622-456 was prepared according to General Procedure X. White solid, 15%.1H NMR (600 MHz, DMSO-d6) δ 10.50 (dd, J = 9.5, 6.2 Hz, 1H), 8.60 (s, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.90 – 7.77 (m, 1H), 7.71 (dd, J = 9.6, 7.7 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.41 (s, 2H), 4.93 – 4.80 (m, 2H), 4.58 – 4.38 (m, 2H), 4.16 – 3.98 (m, 2H), 1.66 (d, J = 22.0 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 206.82, 167.55, 166.36 (d, J = 2.8 Hz), 158.16, 157.20, 156.55, 150.66, 133.00, 132.93, 131.88, 131.59 (d, J = 9.1 Hz), 130.09 (d, J = 4.6 Hz), 130.00, 129.16, 126.49, 123.58, 118.87, 114.73, 112.16, 103.46 (d, J = 22.0 Hz), 91.78, 90.44, 61.38 (d, J = 27.6 Hz), 60.10 (d, J = 27.2 Hz), 56.51, 54.91, 46.50, 22.41 (d, J = 25.0 Hz)..19F NMR (565 MHz, DMSO-d6) δ -97.03 (t, J = 6.9 Hz), -139.00 (dq, J = 41.3, 20.5 Hz). HRMS: [APCI+] [M+H]+calc. for C25H18O2N6F2⁷⁹Br³²S, 583.0358, observed, 583.0368. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-(3-methoxy-1H-pyrazol-1-yl)prop-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)- one (1622-457) 1622-457 was prepared according to General Procedure X. White solid, 36%.1H NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.70 (dd, J = 6.6, 2.2 Hz, 1H), 7.40 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 7.14 (t, J = 8.5 Hz, 1H), 5.69 (d, J = 2.4 Hz, 1H), 4.92 (s, 2H), 4.60 (d, J = 15.4 Hz, 1H), 4.44 (dd, J = 19.2, 9.4 Hz, 1H), 4.38 – 4.27 (m, 2H), 4.19 (dd, J = 20.2, 11.3 Hz, 1H), 4.03 (dd, J = 17.3, 12.8 Hz, 1H), 3.87 (s, 3H), 1.65 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.74 (d, J = 3.2 Hz), 164.43, 164.17, 159.92, 158.27, 156.49, 148.43, 140.40, 135.33, 131.14 (d, J = 7.5 Hz), 130.84 (d, J = 3.9 Hz), 130.54, 120.85, 117.50, 115.76 (d, J = 22.6 Hz), 108.27 (d, J = 21.3 Hz), 91.44, 90.85, 90.70, 89.34, 78.09, 62.25 (d, J = 28.6 Hz), 60.73 (d, J = 27.7 Hz), 56.53, 44.84, 42.39, 23.00 (d, J = 25.6 Hz).19F NMR (565 MHz, CDCl3) δ -105.18 – -113.55 (m), -138.81 – -145.38 (m). HRMS: [APCI+] [M+H]+calc. for C25H21O3N5F2⁷⁹Br³²S, 588.0511, observed 588.0514. Preparation of 5-(3-bromo-4-fluorophenyl)-6-(3-(3,3-difluoroazetidin-1-yl)prop-1- yn-1-yl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-458) 1622-458 was prepared according to General Procedure X. Off-white solid, 6.5%.1H NMR (800 MHz, CDCl3) δ 8.08 (s, 1H), 7.71 (dd, J = 6.5, 2.2 Hz, 1H), 7.42 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.17 (t, J = 8.4 Hz, 1H), 4.60 (d, J = 15.5 Hz, 1H), 4.44 (dd, J = 20.2, 8.9 Hz, 1H), 4.37 – 4.28 (m, 2H), 4.19 (dd, J = 20.2, 11.3 Hz, 1H), 4.03 (dd, J = 16.6, 10.5 Hz, 1H), 3.63 (t, J = 12.0 Hz, 4H), 3.60 (s, sH), 1.65 (d, J = 21.4 Hz, 3H).13C NMR (201 MHz, CDCl3) δ 165.76 (d, J = 3.3 Hz), 163.90, 159.73, 158.49, 156.50, 148.35, 139.93, 135.27, 131.21 (d, J = 7.4 Hz), 131.11 (d, J = 3.8 Hz), 120.96, 118.00, 117.34, 115.97, 115.79 (d, J = 22.4 Hz), 114.61, 108.28 (d, J = 21.4 Hz), 91.85, 90.54, 89.52, 77.96, 62.64, 62.52, 62.41, 62.25 (d, J = 28.6 Hz), 60.74 (d, J = 28.1 Hz), 45.41, 44.84, 22.99 (d, J = 25.7 Hz).19F NMR (753 MHz, CDCl3) δ -99.34 – -99.86 (m), -107.10 – -107.92 (m), -141.20 – -141.46 (m, J = 20.3 Hz). HRMS: [APCI+] [M+H]+calc. for C24H20O2N4F4⁷⁹Br³²S, 583.0421, observed, 583.0421. Preparation of 6-(cyclopropylethynyl)-5-(3,4-difluorophenyl)-3-(2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-463) 1622-463 was prepared according to General Procedure X. White solid, 60 %.1H NMR (600 MHz, CDCl3) δ 8.06 (s, 1H), 7.85 (ddd, J = 11.7, 7.6, 2.3 Hz, 1H), 7.54 – 7.50 (m, 1H), 7.25 (dd, J = 10.0, 8.4 Hz, 1H), 4.68 (d, J = 15.2 Hz, 1H), 4.57 (dd, J = 19.5, 9.7 Hz, 1H), 4.48 – 4.43 (m, 1H), 4.42 (d, J = 15.4 Hz, 1H), 4.25 (dd, J = 20.3, 11.3 Hz, 1H), 4.12 – 4.04 (m, 1H), 1.73 (d, J = 21.4 Hz, 3H), 1.59 – 1.53 (m, 1H), 0.96 – 0.92 (m, 2H), 0.92 – 0.90 (m, 2H).13C {1H} NMR (151 MHz, CDCl3) δ 165.8 (d, J = 3.1 Hz), 162.0, 156.5, 151.2, 151.0 (d, J = 12.6 Hz), 149.5 (dd, J = 42.3, 12.4 Hz), 147.8, 140.0, 129.9 (d, J = 7.3 Hz), 124.7 (dd, J = 6.3, 3.5 Hz), 124.3, 117.4 (dd, J = 50.1, 18.4 Hz), 114.4, 100.0, 90.6, 89.2, 69.6, 61.4 (dd, J = 256.4, 28.4 Hz), 44.6, 29.7, 22.9 (d, J = 25.5 Hz), 8.8 (d, J = 2.8 Hz).19F NMR (565 MHz, CDCl3) δ -136.30 – -136.45 (m,), -136.85 (ddd, J = 20.9, 11.8, 8.2 Hz,), -141.20 – -141.47 (m). HRMS: [APCI+] [M+H]+calc. for C₂₃H₁₉O₂N₃F₃³²S, 458.11446, observed, 458.1153. Preparation of 6-(cyclopropylethynyl)-5-(3-(difluoromethyl)-4-fluorophenyl)-3-(2-(3- fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-464) Prepared according to General Procedure X. White solid, 43%.1H NMR (600 MHz, CDCl3) δ 8.25 – 8.20 (m, 1H), 8.07 (s, 1H), 7.92 – 7.86 (m, 1H), 7.24 (t, J = 9.7 Hz, 1H), 6.97 (t, J = 54.9 Hz, 1H), 4.69 (d, J = 15.2 Hz, 1H), 4.57 (dd, J = 19.7, 9.9 Hz, 1H), 4.47 (dd, J = 16.9, 11.0 Hz, 1H), 4.42 (d, J = 15.2 Hz, 1H), 4.25 (dd, J = 20.2, 11.3 Hz, 1H), 4.09 (dd, J = 16.9, 11.0 Hz, 1H), 1.73 (d, J = 21.4 Hz, 3H), 1.57 – 1.53 (m, 1H), 0.95 – 0.85 (m, 4H).13C {1H} NMR (151 MHz, CDCl3) δ 165.8 (d, J = 3.1 Hz), 162.0, 160.1 (d, J = 255.0 Hz), 156.6, 147.8, 140.2, 132.6 (d, J = 8.4 Hz), 129.7 (d, J = 3.7 Hz), 127.0 – 126.7 (m), 124.3, 122.2 (d, J = 12.9 Hz), 116.4 (d, J = 21.1 Hz), 114.5, 111.9 (d, J = 5.1 Hz), 110.3 (d, J = 5.3 Hz), 108.8, 99.9, 90.6, 89.2, 69.5, 62.3 (d, J = 28.5 Hz), 60.6 (d, J = 28.0 Hz), 44.6, 22.9 (d, J = 25.5 Hz), 8.7 (d, J = 2.3 Hz), 1.0.19F NMR (565 MHz, CDCl3) δ -114.41 (d, J = 54.9 Hz), -118.78– -118.86 (m), -141.19 – -141.47 (m). HRMS: [APCI+] [M+H]+ calc. for C₂₄H₂₀O₂N₃F₄³²S, 490.12069, observed, 490.12021. Preparation of 5-(6-(cyclopropylethynyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (1622-465) Prepared according to General Procedure X. White solid, 97%.1H NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.75 (dd, J = 6.7, 2.2 Hz, 1H), 7.44 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.17 (t, J = 8.5 Hz, 1H), 4.62 (d, J = 15.4 Hz, 1H), 4.60 – 4.53 (m, 1H), 4.49 – 4.44 (m, 1H), 4.36 (d, J = 15.2 Hz, 1H), 4.28 – 4.21 (m, 1H), 4.11 – 4.05 (m, 1H), 1.67 (d, J = 21.5 Hz, 3H), 1.45 – 1.38 (m, 1H), 0.99 – 0.94 (m, 2H), 0.80 – 0.76 (m, 2H).13C {1H} NMR (151 MHz, CDCl3) δ 165.8 (d, J = 5.6 Hz), 163.0, 158.7 (d, J = 248.3 Hz), 156.4, 147.7, 138.1, 135.3, 131.2 (d, J = 7.3 Hz), 131.0 (d, J = 3.9 Hz), 124.3, 120.6, 116.9 (d, J = 20.1 Hz), 115.3 (d, J = 22.6 Hz), 113.4, 107.7, 103.1, 102.0, 100.7, 90.6, 69.3, 67.6, 62.1 (d, J = 28.5 Hz), 60.6 (d, J = 28.0 Hz), 44.7, 22.8 (d, J = 25.7 Hz), 9.1.19F NMR (565 MHz, CDCl3) δ -106.0 – -105.1 (m, Hz), -141.2 – -141.5 (m, Hz). HRMS: [APCI+] [M+H]+ calc. for C₂₄H₁₉O₂N₄F₂³²S, 465.11913, observed, 465.11905. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-morpholinoprop-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-466) 1622-466 was prepared according to General Procedure X.1H NMR (800 MHz, CDCl3) δ 8.07 (s, 1H), 7.73 (dd, J = 6.6, 2.2 Hz, 1H), 7.41 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.17 (t, J = 8.4 Hz, 1H), 4.60 (d, J = 15.4 Hz, 1H), 4.44 (ddd, J = 19.5, 9.7, 1.5 Hz, 1H), 4.37 – 4.29 (m, 2H), 4.22 – 4.16 (m, 1H), 4.06 – 4.00 (m, 1H), 3.71 (t, J = 4.7 Hz, 4H), 3.47 (s, 2H), 2.48 (t, J = 4.6 Hz, 4H), 1.63 (d, J = 5.5 Hz, 3H). Preparation of 6-(cyclopropylethynyl)-5-(3-(difluoromethoxy)-4-fluorophenyl)-3-(2- (3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-467) Prepared according to General Procedure X. White solid, 47%.1H NMR (800 MHz, CDCl3) δ 8.04 (s, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.61 – 7.59 (m, 1H), 7.24 (t, J = 9.2 Hz, 1H), 6.62 (t, J = 73.2 Hz, 1H), 4.66 (d, J = 15.2 Hz, 1H), 4.54 (dd, J = 19.5, 9.7 Hz, 1H), 4.44 (dd, J = 17.0, 9.7 Hz, 1H), 4.39 (d, J = 15.2 Hz, 1H), 4.22 (dd, J = 20.2, 11.3 Hz, 1H), 4.06 (dd, J = 17.4, 11.3 Hz, 1H), 1.70 (d, J = 21.4 Hz, 3H), 1.55 – 1.51 (m, 1H), 0.92 – 0.88 (m, 2H), 0.87 –0.84 (m, 2H).13C {1H} NMR (201 MHz, CDCl3) δ 166.2 (d, J = 3.5 Hz), 162.3, 156.9, 155.1, 153.8, 148.1, 140.4, 138.4 (d, J = 12.5 Hz), 130.3 (d, J = 3.8 Hz), 127.2 (d, J = 7.1 Hz), 124.7, 123.3, 117.7 (d, J = 19.3 Hz), 117.3, 116.0, 114.8, 114.7, 100.4, 90.8, 89.8, 69.9, 62.6 (d, J = 28.6 Hz), 60.9 (d, J = 27.8 Hz), 44.9, 23.2 (d, J = 25.8 Hz), 10.0 (d, J = 3.4 Hz), 1.0, 0.5.19F NMR (753 MHz, CDCl3) δ -81.41 (d, J = 73.9 Hz), -128.61 – -128.66 (m), -141.25 – -141.46 (m, J = 20.1 Hz). HRMS: [APCI+] [M+H]+ calc. for C₂₄H₂₀O₃N₃F₄³²S, 506.1156, observed, 506.11623. Preparation of 1-(3-(5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1- yl)-2-oxoethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)prop-2-yn-1-yl)-1H-pyrazole- 4-carbonitrile (1622-468) 1622-476 was prepared according to General Procedure X. White solid, 27%.1H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.90 (d, J = 0.7 Hz, 1H), 7.82 (d, J = 0.7 Hz, 1H), 7.69 (dd, J = 6.5, 2.2 Hz, 1H), 7.39 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.18 (t, J = 8.4 Hz, 1H), 5.15 (s, 2H), 4.60 (d, J = 15.4 Hz, 1H), 4.48 – 4.41 (m, 1H), 4.35 (d, J = 15.4 Hz, 1H), 4.34 – 4.28 (m, 1H), 4.20 (dd, J = 20.2, 11.3 Hz, 1H), 4.03 (dd, J = 16.6, 12.0 Hz, 1H), 1.65 (d, J = 21.4 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 165.64 (d, J = 3.2 Hz), 164.54, 160.08, 158.42, 156.45, 148.75, 143.01, 141.42, 135.20, 133.98, 131.10 (d, J = 7.3 Hz), 130.68 (d, J = 3.9 Hz), 120.89, 116.37, 115.93 (d, J = 22.6 Hz), 113.06, 108.43 (d, J = 21.1 Hz), 93.48, 90.70, 89.33, 88.19, 79.93, 62.23 (d, J = 28.7 Hz), 60.74 (d, J = 28.2 Hz), 44.85, 43.33, 22.99 (d, J = 25.5 Hz).19F NMR (565 MHz, CDCl3) δ -104.65 – -108.24 (m), -139.33 – -143.14 (m). HRMS: [APCI+] [M+H]+calc. for C25H18O2N6F2⁷⁹Br³²S, 583.0358, observed, 583.0361. Preparation of 5-(3-chloro-4-fluorophenyl)-6-(cyclopropylethynyl)-3-(2-(3-fluoro-3- methylazetidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-469) 1622-469 was prepared according to General Procedure X. Off-white solid, 35%.1H NMR (600 MHz, CDCl3) δ 8.05 (s, 1H), 7.57 (dd, J = 7.1, 2.2 Hz, 1H), 7.36 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.16 (t, J = 8.8 Hz, 1H), 4.58 (d, J = 15.4 Hz, 1H), 4.43 (dd, J = 19.4, 9.6 Hz, 1H), 4.36 – 4.27 (m, 2H), 4.18 (dd, J = 20.2, 11.2 Hz, 1H), 4.02 (dd, J = 17.3, 11.2 Hz, 1H), 1.64 (d, J = 21.4 Hz, 3H), 1.39 (tt, J = 8.3, 5.0 Hz, 1H), 0.93 – 0.84 (m, 2H), 0.78 – 0.70 (m, 2H).13C NMR (151 MHz, CDCl3) δ 165.88 (d,4JC-F = 3.0 Hz), 163.12, 158.65, 157.00, 156.46, 147.84, 138.33, 132.64, 130.78 (d,4JC-F= 4.1 Hz), 130.53 (d,3JC-F= 7.3 Hz), 120.76, 119.86 (d,2JC-F= 17.8 Hz), 119.86, 115.58 (d,2JC-F= 21.1 Hz), 103.15, 90.69, 89.33, 67.72, 62.19 (d,2JC-F= 28.5 Hz), 60.67 (d,2JC-F= 28.0 Hz), 44.85, 22.93 (d,2JC-F = 25.5 Hz), 9.17, 0.63.19F NMR (565 MHz, CDCl3) δ -107.72 – -120.12 (m), -136.27 – -151.21 (m). HRMS: [APCI+] [M+H]+calc. for C23H19N3O2F235Cl32S, 474.0849, observed 474.0859. Preparation of 5-(3-bromo-4-fluorophenyl)-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2- oxoethyl)-6-(3-fluoroprop-1-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one (1622-470) 1622-470 was prepared using 1622-AEA as a precursor, with the fluorine atom in the CH2F group installed via a DAST reaction. Off-white solid, 22%.1H NMR (600 MHz, CDCl3) δ 8.09 (s, 1H), 7.72 (dd, J = 6.6, 2.2 Hz, 1H), 7.43 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.17 (t, J = 8.5 Hz, 1H), 5.10 (d, J = 47.5 Hz, 2H), 4.61 (d, J = 15.4 Hz, 1H), 4.45 (dd, J = 19.1, 9.9 Hz, 1H), 4.38 – 4.28 (m, 2H), 4.24 – 4.15 (m,...

Claims

1. CLAIMS We claim:

1. A compound of Formula I or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof:Formula I wherein W is selected from O, S, and NR2; wherein Y is selected from O, S, and NR3; wherein Z is –C(R4R5)–; wherein Q is N or CR6; wherein T is N or CR7; wherein U1and U2are independently C or N; wherein V is selected from S, O, N, NR8, and CR9; wherein X is C or N; wherein G1, G2, G3, and G4are independently CH or N; wherein n is 0 or 1; wherein when n is 0, m is an integer selected from 0 to 6; wherein when n is 1, m is an integer selected from 0 to 8; wherein o is an integer selected from 1 to 5; wherein RAis selected from hydrogen, deuterium, methyl, CHF2, CH2F, CF3, CD3, CN, SF5, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (carbocyclyl)alkyl, optionally substituted (heterocyclyl)alkyl, optionally substituted (aryl)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted acyl, optionally substituted amide, and Si-substituted silyl; wherein RBand RC, in each occurrence, are independently selected from halogen, nitro, cyano, hydroxyl, formyl, carboxyl, sulfamoyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, halo(arylalkyl), alkylaryl, halo(alkylaryl), alkyloxy, haloalkyloxy, aryloxy, haloaryloxy, alkylcarbonyl, (haloalkyl)carbonyl, arylcarbonyl, (haloaryl)carbonyl, alkylcarbonyloxy, (haloalkyl)carbonyloxy, arylcarbonyloxy, (haloaryl)carbonyloxy, alkyloxycarbonyl, (haloalkyl)oxycarbonyl, aryloxycarbonyl, (haloaryl)oxycarbonyl, primary amino, alkylamino, haloalkylamino, alkylammonium, haloalkylammonium, alkylcarbonylamino, (haloalkyl)carbonylamino, arylcarbonylamino, (haloaryl)carbonylamino, carbamoyl, N-alkylcarbamoyl, N-(haloalkyl)carbamoyl, alkylthio, (haloalkyl)thio, alkylsulfinyl, (haloalkyl)sulfinyl, alkylsulfonyl, (haloalkyl)sulfonyl, N- alkylsulfamoyl, and N-(haloalkyl)sulfamoyl; wherein R2and R3are independently selected from hydrogen, hydroxyl, alkyl, haloalkyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, halo(arylalkyl), alkylaryl, halo(alkylaryl), alkyloxy, haloalkyloxy, aryloxy, and haloaryloxy; wherein R4and R5are independently selected from hydrogen, halogen, cyano, alkyl, and haloalkyl; wherein R6, R7, and R9are independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, formyl, carboxyl, sulfamoyl, alkyl, haloalkyl, hydroxylalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, hydroxylcarbocyclyl, heterocyclyl, haloheterocyclyl, hydroxylheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, halo(arylalkyl), alkylaryl, halo(alkylaryl), alkyloxy, haloalkyloxy, aryloxy, haloaryloxy, alkylcarbonyl, (haloalkyl)carbonyl, arylcarbonyl, (haloaryl)carbonyl, alkylcarbonyloxy, (haloalkyl)carbonyloxy, arylcarbonyloxy, (haloaryl)carbonyloxy, alkyloxycarbonyl, (haloalkyl)oxycarbonyl, aryloxycarbonyl, (haloaryl)oxycarbonyl, primary amino, alkylamino, haloalkylamino, alkylammonium, haloalkylammonium, alkylcarbonylamino, (haloalkyl)carbonylamino, arylcarbonylamino, (haloaryl)carbonylamino, carbamoyl, N- alkylcarbamoyl, N-(haloalkyl)carbamoyl, alkylthio, (haloalkyl)thio, alkylsulfinyl, (haloalkyl)sulfinyl, alkylsulfonyl, (haloalkyl)sulfonyl, N-alkylsulfamoyl, and N- (haloalkyl)sulfamoyl; and wherein R8is independently selected from hydrogen, alkyl, haloalkyl, hydroxylalkyl, carbocyclyl, halocarbocyclyl, hydroxylcarbocyclyl, heterocyclyl, haloheterocyclyl,hydroxylheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, halo(arylalkyl), alkylaryl, halo(alkylaryl), alkylcarbonyl, (haloalkyl)carbonyl, arylcarbonyl, (haloaryl)carbonyl, alkyloxycarbonyl, (haloalkyl)oxycarbonyl, aryloxycarbonyl, (haloaryl)oxycarbonyl, carbamoyl, N-alkylcarbamoyl, N-(haloalkyl)carbamoyl, alkylsulfinyl, (haloalkyl)sulfinyl, alkylsulfonyl, (haloalkyl)sulfonyl, N-alkylsulfamoyl, and N-(haloalkyl)sulfamoyl.

2. The compound of claim 1, wherein W is O.

3. The compound of claim 1, wherein W is NH or N(OH).

4. The compound of any one of claims 1–3, wherein Y is O.

5. The compound of any one of claims 1–3, wherein Y is NH or N(OH).

6. The compound of any one of claims 1–5, wherein Z is –CH2–.

7. The compound of claim 1, wherein W is O, Y is O, and Z is –CH2–.

8. The compound of any one of claims 1–7, wherein themoiety is selected from:.

9. The compound of any one of claims 1–8, wherein R6is hydrogen.

10. The compound of any one of claims 1–9, wherein R7is hydrogen.

11. The compound of claim 8, wherein themoiety is selected from:1 116. The compound of any one of claims 1–14, where R8is selected from hydrogen, alkyl, haloalkyl, hydroxylalkyl, carbocyclyl, halocarbocyclyl, hydroxylcarbocyclyl, heterocyclyl, haloheterocyclyl, hydroxylheterocyclyl, aryl, haloaryl, heteroaryl, and haloheteroaryl.

17. The compound of claim 16, wherein R8is selected from hydrogen, methyl, CHF2, CH2F, CF3, ethyl, isopropyl, cyclopropyl, cyclobutyl,, and .

18. The compound of any one of claims 1–14, wherein R9is selected from hydrogen, halogen, cyano, alkyl, haloalkyl, hydroxylalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl,halocarbocyclyl, hydroxylcarbocyclyl, heterocyclyl, haloheterocyclyl, hydroxylheterocyclyl, aryl, haloaryl, heteroaryl, and haloheteroaryl.

19. The compound of claim 18, wherein R9is selected from hydrogen, halogen, cyano, methyl, CHF2, CH2F, CF3, ethyl, isopropyl, cyclopropyl, cyclobutyl,, , , ,.

20. The compound of claim 8, wherein themoiety is.

21. The compound of claim 8, wherein themoiety is. 2 herein the,23. The compound of claim 8, wherein themoiety, .

24. The compound of any one of claims 1–23, wherein RB, in each occurrence, is independently selected from halogen, cyano, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, hydroxyl, alkyloxy, haloalkyloxy, primary amino, alkylamino, haloalkylamino, carbocyclyl, and halocarbocyclyl.

25. The compound of claim 24, wherein RB, in each occurrence, is independently selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, – OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy.

26. The compound of any one of claims 1–25, wherein: (i) G1is CH; or (ii) G2is CH.

27. The compound of any one of claims 1–25, wherein: (i) G1and G3are CH; (ii) G1and G2are CH; (iii) G2and G3are CH; or (iii) G2and G4are CH.

28. The compound of any one of claims 1–25, wherein: (i) G1, G2, and G3are CH; or (ii) G1, G2, and G4are CH.

29. The compound of any one of claims 1–25, wherein: (i) G3is N; or (ii) G4is N.

30. The compound of any one of claims 1–25, wherein: (i) G2and G4are N; (ii) G3and G4are N; (iii) G1and G4are N; or (iii) G1and G3are N.

31. The compound of any one of claims 1–25, wherein: (i) G1, G3, and G4are N; or (ii) G2, G3, and G4are N.

32. The compound of any one of claims 1–25, wherein G1, G2, G3, and G4are CH.

33. The compound of any one of claims 1–25, wherein:(i) G1, G2, and G3are CH, and G4is N; or (ii) G1, G2, and G4are CH, and G3is N.

34. The compound of any one of claims 1–25, wherein: (i) G1and G3are CH, and G2and G4are N; (ii) G1and G2are CH, and G3and G4are N; (iii) G2and G3are CH, and G1and G4are N; or (iii) G2and G4are CH, and G1and G3are N.

35. The compound of any one of claims 1–25, wherein: (i) G1, G3, and G4are N, and G2is CH; or (ii) G2, G3, and G4are N, and G1is CH.

36. The compound of any one of claims 1–35, wherein the carbon at the para position of Ring B is substituted by RB.

37. The compound of claim 36, wherein the carbon at the para position of Ring B is substituted by F.

38. The compound of any one of claims 1–37, wherein when G2is CH, its carbon is substituted by RB.

39. The compound of claim 38, wherein when G2is CH, its carbon is substituted by cyano, Cl, or Br.

40. The compound of any one of claims 1–39, wherein o is 1 or 2.

41. The compound of any one of claims 1–25, wherein themoiety iswherein p is an integer selected from 0 to 3.

42. The compound of claim 41, wherein G1, G3, and G4are CH.

43. The compound of claim 41, wherein: (i) G1is N, G3is CH, and G4is CH; (ii) G1is CH, G3is N, and G4is CH; or(iii) G1is CH, G3is CH, and G4is N.

44. The compound of claim 41, wherein: (i) G1is N, G3is N, and G4is CH; (ii) G1is CH, G3is N, and G4is N; or (iii) G1is N, G3is CH, and G4is N.

45. The compound of claim 41, wherein G1, G3, and G4are N.

46. The compound of any one of claims 41–45, wherein p is 0.

47. The compound of claim 41, wherein themoiety is selected from:.

48. The compound of any one of claims 41–47, wherein the RBsubstituent at the para position of Ring B is F.

49. The compound of any one of claims 41–48, wherein the RBsubstituent at the G2position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, and ethynyl.

50. The compound of claim 49, wherein the RBsubstituent at the G2position is cyano, Cl, or Br. :5 The compound of claim 47, wherein , themoiety is selected from:.

53. The compound of any one of claims 1–52, wherein n is 0.

54. The compound of any one of clams 1–53, wherein m is 1 or 2.

55. The compound of claim 53, wherein themoiety.

56. The compound of any one of claims 1–55, wherein RC, in each occurrence, is independently selected from halogen, cyano, alkyl, and haloalkyl.

57. The compound of claim 56, wherein RC, in each occurrence, is independently selected from halogen, cyano, methyl, CHF2, CH2F, CF3, ethyl, isopropyl, and cyclopropyl.

58. The compound of claim 55, wherein one RCis halogen, and the other RCis alkyl or haloalkyl.

59. The compound of claim 58, wherein one RCis F, and the other RCis selected from methyl, CHF2, CH2F, CF3, ethyl, isopropyl, and cyclopropyl.

60. The compound of claim 55, wherein themoiety.

61. The compound of any one of claims 1–60, wherein RAis selected from hydrogen, deuterium, methyl, CD3, CHF2, CH2F, CF3, CN, and SF5.

62. The compound of claim 61, wherein RAis selected from methyl, CD3, CHF2, CH2F, and CF3.

63. The compound of any one of claims 1–60, wherein RAis selected from optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

64. The compound of claim 63, wherein RAis selected from:

65. The compound of claim 64, wherein RAis.

66. The compound of claim 63, wherein RAis selected from:

68. The compound of claim 63, wherein RAis selected from:

670. The compound of any one of claims 1–60, wherein RAis selected from optionally substituted (carbocyclyl)alkyl, optionally substituted (heterocyclyl)alkyl, optionally substituted (aryl)alkyl, and optionally substituted (heteroaryl)alkyl.

71. The compound of claim 70, wherein RAis, wherein: RA1is selected from optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and RA2and RA3are (i) independently selected from hydrogen, halogen, cyano, alkyl, haloalkyl, hydroxyl, alkyloxy, haloalkyloxy, primary amino, alkylamino, and haloalkylamino, or (ii) join withthe carbon atom to which they are attached to form a 3–6 membered carbocycle, 3–6 membered halocarbocycle, 3–6 membered heterocycle, or 3–6 membered haloheterocycle.

72. The compound of claim 71, wherein RA2and RA3are independently selected from hydrogen, halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, hydroxyl, methoxy, trifluoromethoxy, –NH2, –NH(CH3), and –N(CH3)2.

73. The compound of claim 72, wherein: (i) RA2and RA3are hydrogen; (ii) RA2is F and RA3is hydrogen (iii) RA2is methyl and RA3is hydrogen; or (iv) RA2and RA3are methyl.

74. The compound of claim 71, wherein RA2and RA3join with the carbon atom to which they are attached to form a 3–6 membered carbocycle or 3–6 membered halocarbocycle.

75. The compound of claim 74, wherein RAis.

76. The compound of any one of claims 71–75, where RA1is optionally substituted carbocyclyl or optionally substituted aryl.

77. The compound of claim 76, wherein RA1is selected from:

78. The compound of claim 76, wherein RA1is selected from:.

79. The compound of claim 76, wherein RA1is selected from:.

80. The compound of any one of claims 71–75, where RA1is optionally substituted heterocyclyl.

81. The compound of claim 80, wherein RA1is selected from:

82. The compound of claim 80, wherein RA1is selected from:

83. The compound of any one of claims 71–75, where RA1is optionally substituted heteroaryl.

84. The compound of claim 83, wherein RA1is selected from:,86. The compound of claim 70, wherein RAis selected from optionally substituted (carbocyclyl)methyl, optionally substituted (heterocyclyl)methyl, optionally substituted (aryl)methyl, and optionally substituted (heteroaryl)methyl.

87. The compound of claim 86, wherein RAis optionally substituted (carbocyclyl)methyl or optionally substituted (aryl)methyl.

88. The compound of claim 87, wherein RAis selected from:.

89. The compound of claim 87, wherein RAis selected from:.

90. The compound of claim 86, wherein RAis optionally substituted (heterocyclyl)methyl.

91. The compound of claim 90, wherein RAis selected from:

993. The compound of claim 86, wherein RAis optionally substituted (heteroaryl)methyl.

94. The compound of claim 93, wherein RAis selected from:

95. The compound of claim 93, wherein RAis selected from:

96. The compound of claim 93, wherein RAis selected from:

97. The compound of any one of claims 1–60, wherein RAis optionally substituted acyl.

98. The compound of claim 97, wherein RAis selected from:.

99. The compound of claim 97, wherein RAis selected from:

100. The compound of any one of claims 1–60, wherein RAis optionally substituted amide.

101. The compound of claim 100, wherein RAis selected from:

102. The compound of any one of claims 1–60, wherein RAis optionally Si-substituted silyl.

103. The compound of claim 102, wherein RAis selected from:

104. A pharmaceutical formulation, comprising the compound of any one of claims 1–103 and a pharmaceutical acceptable excipient.

105. The pharmaceutical formulation of claim 104, wherein the pharmaceutical formulation is in the form of tablet, caplet, capsule, pill, gel, cream, granule, solution, suspension, emulsion, or nanoparticulate formulation.

106. The pharmaceutical formulation of claim 104, wherein the pharmaceutical formulation is an oral or intravenous formulation.

107. A method of treating a neurological disorder or condition, comprising administering an effective amount of the compound of any one of claims 1–103 or the pharmaceutical formulation of any one of claims 104–106 to a subject in need thereof.

108. The method of claim 107, wherein the compound or pharmaceutical formulation is administered orally, intravenously, intranasally, or intramuscularly.

109. The method of claim 107 or 108, wherein the neurological disorder or condition is selected from neurodegenerative disease or disorder, pain, epilepsy, essential tremor, movement disorder or impaired motor function, stroke, traumatic brain injury, transient ischemia, global ischemia, hypoxia, and spinal cord trauma.

110. The method of claim 109, wherein the neurological disorder or condition is neurodegenerative disease or disorder.

111. The method of claim 110, wherein the neurodegenerative disease or disorder is selected from Alzheimer’s disease, dementia, chronic traumatic encephalopathy, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, spinal muscular atrophy, bulbar muscular atrophy, spinocerebellar ataxia, familial spastic paraparesis, Machado Joseph disease, Friedreich’s ataxia, and Lewy body disease.

112. The method of claim 109, wherein the neurological disorder or condition is pain.

113. The method of claim 112, wherein the pain is neuropathic pain, inflammatory pain, perioperative pain, or nociceptive pain.

114. The method of claim 112, wherein the pain is chronic pain.

115. A method of treating a neuropsychiatric disorder or condition, comprising administering an effective amount of the compound of any one of claims 1–103 or the pharmaceutical formulation of any one of claims 104–106 to a subject in need thereof.

116. The method of claim 115, wherein the compound or pharmaceutical formulation is administered orally, intravenously, intranasally, or intramuscularly.

117. The method of claim 115 or 116, wherein the neuropsychiatric disorder or condition is selected from schizophrenia, depression, post-partum depression, post-traumatic stress disorder, bipolar disorder, fragile X syndrome, sleeping disorder, anxiety disorder, autism spectrum disorder, obsessive-compulsive disorder, addiction or use dependence, uncontrolled anger, cognitive deficit disorder, headache, migraine, eating disorder, and attention-deficit disorder.

118. The method of claim 117, wherein the neuropsychiatric disorder or condition is schizophrenia.

119. The method of claim 118, wherein the neuropsychiatric disorder or condition is depression.

120. The method of claim 119, wherein the depression is major depressive disorder, treatment- resistant depression, or bipolar depression.

121. The method of claim 117, wherein the neuropsychiatric disorder or condition is bipolar disorder.

122. The method of claim 117, wherein the neuropsychiatric disorder or condition is autism spectrum disorder.

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