Bicyclic heteroaryl compounds

Abstract

Provided herein are novel compounds (e.g., Formula I), pharmaceutical compositions, and methods of use for treating a variety of diseases or disorders, such as cancer. (I)

Description

METHODS AND SYSTEMS FOR REMEDIATING FILTERCAKE IMPAIRMENT AROUND A SUBSEA INJECTION WELL CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 602,719, entitled “METHODS AND SYSTEMS FOR REMEDIATING FILTERCAKE IMPAIRMENT AROUND A SUBSEA INJECTION WELL,” having a filing date of November 27, 2023, the disclosure of which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION

[0002] The techniques described herein relate to the field of subsea production operations. More specifically, the techniques described herein relate to methods for increasing the performance of injector wells in a subsea production environment. BACKGROUND OF THE INVENTION

[0003] This section is intended to introduce various aspects of the art, which may be associated with embodiments of the present techniques. This discussion is believed to assist in providing a framework to facilitate a better understanding of particular aspects of the present techniques. Accordingly, it should be understood that this section should be read in this light, and not necessarily as admissions of prior art.

[0004] More than two-thirds of the earth is covered by oceans. As the petroleum industry continues its search for hydrocarbons, it is finding that more and more of the untapped hydrocarbon reservoirs are located beneath the oceans. Such reservoirs are referred to as “offshore reservoirs.”

[0005] A typical system used to produce hydrocarbons from offshore reservoirs uses hydrocarbon-producing wells located on the ocean floor. This type of production system, often referred to as a subsea production system (SPS), generally includes a subsea tree, manifolds, intervention systems, subsea processing systems, and the corresponding pipeline system. The SPS is placed on the ocean floor to direct the flow of production fluids from the producing wells, often referred to as “producers” or “subsea production wells,” towards the flowlines, to isolate the flow from the wells, and to allow access to perform workovers and interventions. Moreover, the produced hydrocarbons are transported to a host production facility.

[0006] The drilling and maintenance of remote offshore wells is expensive. In an effort to reduce drilling and maintenance expenses, remote offshore wells are often drilled in clusters. A grouping of wells in a clustered subsea arrangement is sometimes referred to as a “subsea wellsite.”A subsea wellsite typically includes wells for at one or more “pay zones.”

[0007] The grouping of remote of production fluids into a local production manifold. Fluids the manifold through the jumpers. From the manifold, theto the host production facility through the flowlines and riser. For wellsites that are in deeper waters, the gathering and separating facility is typically a floating production, storage, and offloading vessel (FPSO).

[0008] One challenge facing offshore production operations is maintaining sufficient pressure in the subsea reservoir over time to ensure efficient production of hydrocarbons. Injection wells may be used to inject fluid into the subsea reservoir at strategic locations to increase formation pressure. Injection wells may be used to inject either water or gases into the subsurface formation in order to maintain sufficient pressure to produce hydrocarbons from the formation.

[0009] When drilling subsea wells, it is a typical practice to bring expensive equipment, such as a drilling rig, to the drilling site, then to remove that equipment once drilling is completed. Mud filtercake is deliberately created during drilling to prevent losses. It forms virtually instantaneously as the drill exposes fresh permeable rock. A filtercake can build up during injection, but this is composed of injected solids rather than mud.

[0010] When injection wells are first placed into operation, residual mud filtercake may block injectors from being able to provide fluid at sufficient volume. Water injector impairment caused by the filtercake buildup can place limits on the ability to provide long-term pressure support for producing wells.

[0011] An FPSO in a deepwater operation may support producing wells, water injection wells, gas injection wells, and / or water-alternating-gas (WAG) injection wells. When an injection well is drilled and completed with an oil-based mud, an open hole sweep containing a cleaning additive compromised of solvents, surfactants and water wetting agents is circulated to displace the mud and leave things in a water wet state. The efficacy of this treatment is typically not known until the injection well comes online. When the injection well is brought online, pressure transient analysis (PTA) and modeling assessments can ascertain how much of the wellbore is contributing to the overall injectivity. If the analysis shows that the cleanup up was ineffective, it may indicate that a mud filtercake was left in place during lower completion operations causing injector impairment.

[0012] One way to remediate an injection well is through subsea well intervention. Such subsea well intervention requires again bringing expensive equipment that is adapted to perform theintervention to the SPS. Examples of such equipment include a light well intervention vessel (LWIV) or a drilling rig. Additional cleanup additives may be pumped to change the wettability of the mud filtercake followed by acids and chelating agents to dissolve or disaggregate barite in the filtercake and restore injectivity. The cost of these jobs may be prohibitive though given the challenges around planning (for field wide usage), mobilization, and execution especially at the infancy of the life of a field.

[0013] Further, subsea well intervention using acid and chelating agents has often not proved to be highly effective and the efficacy of the treatment is not readily detectable prior to removal of the equipment needed to perform the intervention. Accordingly, known filtercake remediation methods are often not highly effective. An improved method of removing or remediating residual filtercake around injectors in subsea wells is desirable. SUMMARY OF THE INVENTION

[0014] An embodiment provided herein relates to a method for remediating filtercake buildup in a subsea injection well. The method includes injecting a chemical solution into a riser tie-in connection using a chemical injection pump downstream of a water injection pump of an offshore production facility. The method also includes pumping, with the chemical injection pump, at least a portion of the chemical solution through a riser connected to the riser tie-in connection and to an injector region of an injection well connected to the riser. The injector region is in fluid communication with filtercake that is impairing the injector region, so that at least a portion of the chemical solution makes contact with the filtercake. The method further includes waiting at least a remediation time for the filtercake to be in contact with the chemical solution to cause remediation in the impairing of the injector region.

[0015] Another embodiment well system. The injection well system includes an injector well impaired with filtercake. The injection well system also includes a of a water injection pump of an offshore production facility. to a riser via a riser tie- in connection. The riser is in fluidThe riser receives a chemical solution pumped from the chemical injection pump so that a portion of the chemical solution makes contact with the filtercake. Further, at least a portion of the chemical solution is left in contact with the filtercake for at least a remediation time to cause remediation in the filtercake impairing of the injector region.

[0016] A further embodiment provided herein relates to a well system. The well system includes an injector well that has an injector region that is impaired with filtercake. The well system also includes a chemical injection pump downstream of a water injection pump of an offshore production facility. The chemical injection pump is connected to a riser via a riser tie-in connection. The riser is in fluid communication with the injector region. The riser receives a chemical solution pumped from the chemical injection pump so that a portion of the chemical solution makes contact with the filtercake. A portion of the chemical solution is left in contact with the filtercake for at least a remediation time to cause remediation in the filtercake impairing of the injector region. The well system further includes a computing system that calculates an aspect of the chemical solution to provide an input to remediating the filtercake.

[0017] These and other features and attributes of the disclosed embodiments of the present techniques and their advantageous applications and / or uses will be apparent from the detailed description that follows. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] To assist those of ordinary skill in the relevant art in making and using the subject matter described herein, reference is made to the appended drawings, where:

[0019] FIG.1 is a schematic view of an exemplary subsea production system including subsea production equipment;

[0020] FIG.2 is a schematic view of an exemplary injector well that may be remediated according to the present techniques;

[0021] FIG.3 is a schematic view of an injector region of an injector well that illustrates filtercake plugging as described herein;

[0022] FIG.4 is a diagram showing infrastructure of an offshore production facility, including a riser tie-in connection for injecting a low concentration chemical solution for remediation of filtercake according to the present techniques;

[0023] FIG.5 is a process flow diagram of an exemplary method for remediating filtercake in a subsea injection well according to the present techniques;

[0024] FIG.6 is a block diagram of an exemplary cluster computing system that may be utilized to implement at least a portion of the present techniques; and

[0025] FIG.7 is a block diagram of an exemplary non-transitory, computer-readable storage medium that may be used for the storage of data and modules of program instructions for implementing at least a portion of the present techniques.

[0026] It should be noted that the figures are merely examples of the present techniques and are not intended to impose limitations on the scope of the present techniques. Further, the figures are generally not drawn to scale, but are drafted for purposes of convenience and clarity in illustrating various aspects of the techniques. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] In the following detailed description section, the specific examples of the present techniques are described in connection with preferred embodiments. However, to the extent that the following description is specific to a particular embodiment or a particular use of the present techniques, this is intended to be for exemplary purposes only and simply provides a description of the embodiments. Accordingly, the techniques are not limited to the specific embodiments described below, but rather, include all alternatives, modifications, and equivalents falling within the true spirit and scope of the appended claims. Terminology

[0028] At the outset, and for ease of reference, certain terms used in this application and their meanings as used in this context are set forth. To the extent a term used herein is not defined below, it should be given the broadest definition those skilled in the art have given that term as reflected in at least one printed publication or issued patent. Further, the present techniques are not limited by the usage of the terms shown below, as all equivalents, synonyms, new developments, and terms or techniques that serve the same or a similar purpose are considered to be within the scope of the present claims.

[0029] As used herein, the singular forms “a,” “an,” and “the” mean one or more when applied to any embodiment described herein. The use of “a,” “an,” and / or “the” does not limit the meaning to a single feature unless such a limit is specifically stated.

[0030] The terms “about” and “around” mean a relative amount of a material or characteristic that is sufficient to provide the intended effect. The exact degree of deviation allowable in some cases may depend on the specific context, e.g., ±1%, ±5%, ±10%, ±15%, etc. It should be understood by those of skill in the art that these terms are intended to allow a description of certain features described and claimed without restricting the scope of these features to the precise numerical ranges provided. Accordingly, these terms should be interpreted as indicating that insubstantial or inconsequential modifications or alterations of the subject matter described are considered to be within the scope of the disclosure.

[0031] The term “and / or” placed between a first entity and a second entity means one of (1) the first entity, (2) the second entity, and (3) the first entity and the second entity. Multiple entities listed with “and / or” should be construed in the same manner, i.e., “one or more” of the entities so conjoined. Other entities may optionally be present other than the entities specifically identified by the “and / or” clause, whether related or unrelated to those entities specifically identified. Thus, as a non-limiting example, a reference to “A and / or B,” when used in conjunction with open-ended language such as “including,” may refer, in one embodiment, to A only (optionally including entities other than B); in another embodiment, to B only (optionally including entities other than A); in yet another embodiment, to both A and B (optionally including other entities). These entities may refer to elements, actions, structures, steps, operations, values, and the like.

[0032] As used herein, the term “any” means one, some, or all of a specified entity or group of entities, indiscriminately of the quantity.

[0033] The phrase “at least one,” in reference to a list of one or more entities, should be understood to mean at least one entity selected from any one or more of the entities in the list of entities, but not necessarily including at least one of each and every entity specifically listed within the list of entities, and not excluding any combinations of entities in the list of entities. This definition also allows that entities may optionally be present other than the entities specifically identified within the list of entities to which the phrase “at least one” refers, whether related or unrelated to those entities specifically identified. Thus, as a non-limiting example, “at least one of A or B” (or, equivalently, “at least one of A and B,” or, equivalently, “at least one of A and / or B”) may refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including entities other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including entities other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other entities). In other words, the phrases “at least one,” “one or more,” and “and / or” are open-ended expressions that are both conjunctive and disjunctive in operation. For example, each of the expressions “at least one of A, B, and C,” “at least one of A, B, or C,” “one or more of A, B, and C,” “one or more of A, B, or C,” and “A, B, and / or C” may mean A alone, B alone, C alone, A and B together, A and C together, B and C together, A, B, and C together, and optionally any of the above in combination with at least one other entity.

[0034] As used herein, the phrase “based on” does not mean “based only on,” unless expressly specified otherwise. In other words, the phrase “based on” means “based only on,” “based at least on,” and / or “based at least in part on.”

[0035] As used herein, the terms “example,” exemplary,” and “embodiment,” when used with reference to one or more components, features, structures, or methods according to the present techniques, are intended to convey that the described component, feature, structure, or method is an illustrative, non-exclusive example of components, features, structures, or methods according to the present techniques. Thus, the described component, feature, structure, or method is not intended to be limiting, required, or exclusive / exhaustive; and other components, features, structures, or methods, including structurally and / or functionally similar and / or equivalent components, features, structures, or methods, are also within the scope of the present techniques.

[0036] As used herein, the term “fluid” refers to gases and liquids, as well as to combinations of gases and liquids, combinations of gases and solids, combinations of liquids and solids, and combinations of gases, liquids, and solids.

[0037] A “hydrocarbon” is an organic compound that primarily includes the elements hydrogen and carbon, although nitrogen, sulfur, oxygen, metals, or any number of other elements may be present in small amounts. As used herein, the term “hydrocarbon” generally refers to components found in raw natural gas and oil.

[0038] The term “manifold” refers to an item of subsea production equipment that gathers production fluids from one or more subsea trees and delivers those fluids to a production line, either directly or through a jumper line.

[0039] As used herein, the term “production fluids” refers to fluids removed from a subsurface formation, including hydrocarbon fluids removed from an offshore reservoir.

[0040] The term “production facility” refers to any facility for receiving production fluids. The production facility may be a ship-shaped vessel located over a subsea wellsite, a floating production, storage, and offloading vessel (FPSO) located over or near a subsea wellsite, a near-shore separation facility, or an onshore separation facility.

[0041] As used herein, the term “resiliency” refers to the extent to which a particle is capable of volumetrically contracting in response to pressure increases and then subsequently recovering the lost volume in response to pressure decreases.

[0042] The term “subsea production system (SPS)” refers to an assembly of production equipment placed in a marine body. The marine body may be an ocean or a deep, freshwater lake,for example. Similarly, the term “subsea” both an ocean body and a deep, freshwater lake.

[0043] The term “subsea production of equipment placed proximate the bottom of a marine body, of an SPS.

[0044] The term “subsea well” a a the bottom of a marine body, such as an ocean floor. Similarly, the term “subsea tree” refers to any collection of valves disposed over a wellhead in a marine body.

[0045] The term “substantially,” when used in reference to a quantity or amount of a material, or a specific characteristic thereof, refers to an amount that is sufficient to provide an effect that the material or characteristic was intended of deviation allowable may depend, in some cases, on the specific

[0046] The terms “riser” and structure or collection of lines for transporting production fluidsas an FPSO.

[0047] The term “umbilical” refers to any line that contains a collection of smaller lines. An umbilical may also be referred to as an “umbilical line” or an “umbilical cable.”

[0048] Certain embodiments and features are described herein using a set of numerical upper limits and a set of numerical lower limits. It should be appreciated that ranges from any lower limit to any upper limit are contemplated unless otherwise indicated. All numerical values are “about” or “approximately” the indicated value, and account for experimental errors and variations that would be expected by

[0049] that are presented in a values explicitly recitedranges encompassed within that range, as if each numerical value and sub-range were explicitly recited. For example, a disclosed numerical range of 1 to 200 should be interpreted to include, not only the explicitly-recited limits of 1 and 200, but also individual values, such as 2, 3, 4, 197, 198, 199, etc., as well as sub-ranges, such as 10 to 50, 20 to 100, etc. Overview

[0050] As described above, filtercake hampers efficient operation of subsea injector wells during offshore production operations. However, to-date, suitable solutions to this issue are still lacking. The present techniques provide a remediation method that can be used in a deepwater environment when an FPSO is on location. Moreover, the present techniques may be performed with equipmenton the FPSO, rather than requiring the relocation of resources to the site of the injection well to be remediated.

[0051] The present techniques from filtercake left in place during lower completion operations practices. Such filtercakeimpairment may prevent the full injectivity. Exemplary Subsea Production System and Corresponding Subsea Production Equipment

[0052] The producing wells are in fluid communication with the host production facility via a system of pipes that transport the hydrocarbons from the subsea wells on the ocean floor to the host production facility. This system of pipes typically includes a collection of jumpers, flowlines, and risers (among other subsea production equipment). Jumpers include pipes that lie on the ocean floor and are used to lie on the ocean floor and are The riser extends from the In many instances, the top offlexible hose for delivering production fluids from the riser to the production facility.

[0053] FIG.1 is a schematic view of an exemplary subsea production system (SPS) 100 including subsea production equipment. The SPS 100 is configured to produce hydrocarbons from an offshore reservoir. The exemplary SPS 100 utilizes a single production line, including a production riser 102, although multiple could be used. Oil, gas, and, typically, water, which are generally are produced through the riser 102. In some embodiments, the production line. However, other sizes may be used.

[0054] The SPS 100 includes one or more subsea wells. For example, in the arrangement shown in FIG. 1, three subsea wells 104, 106, and 108 are included. In some embodiments, the subsea wells 104, 106, and 108 may include at least one production well and at least one injection well. However, in the arrangement shown in FIG. 1, at least one of the three subsea wells 104, 106, and 108 is an injection well, which may be remediated to reduce filtercake buildup as described herein.

[0055] Each subsea well 104, 106, and 108 includes a subsea tree 110 located on a marine floor 112, e.g., an ocean floor. Each subsea fluids to a jumper 114. The jumpers 114 then deliver the production is configured to comingle the production fluids and export the through a subsea flowline118 and the riser 102. Together, the a single production line.

[0056] The riser 102 ties back to a production facility 120. The production facility 120, sometimes referred to as a “host facility” or a “gathering facility,” is any facility where production fluids are collected. The production facility may be, for example, a ship-shaped vessel capable of self-propulsion in a marine body 122, e.g., the ocean, having a marine surface 124 and the marine floor 112. The production facility may alternatively be fixed to land and reside near shore or immediately onshore. Another type of leg platform (TLP).

[0057] In the exemplary facility 120 is a floating production, storage, and offloading body 122. As explained herein, the production facility 120 isfiltercake buildup.

[0058] As shown in FIG.1, the SPS 100 may include a production sled 126 for connecting the flowline 118 to the riser 102. In addition, the SPS 100 includes a utility umbilical 128, which is an integrated electrical / hydraulic control line. In particular, the utility umbilical 128 typically includes conductive wires for providing power to subsea production equipment. A control line within the utility umbilical 128 may carry hydraulic fluid used for controlling items of subsea production equipment, such as a subsea distribution unit (SDU) 130, the manifold 116, and the subsea trees 110 connected to the of closure mechanisms

[0059] The is to include all of the componentsshown in FIG.1. Rather, any number of components may be omitted from the SPS 100 or added to the SPS 100, depending on the details of the specific implementation.

[0060] FIG.2 is a schematic view of an exemplary injector well that may be remediated for filtercake buildup according to the present techniques. FIG.2 shows an injection well 200 that may be used to inject fluids such as water into a subsea reservoir 210 to maintain pressure in the subsea reservoir 210. Operation of the well 200 be controlled by a control unit 202.

[0061] The injection well 200 beneath the ocean floor 112 (FIG.1) into the subsea reservoir through the wellbore 204. Production tubing 208 extends more pumps in the productionfacility 120 may be used to pump as an injector region 212 and into the subsea reservoir 210.

[0062] FIG.3 is a schematic view of the injector region 212 of the injection well 200. FIG. 3 illustrates filtercake plugging as described herein. As shown in FIG. 3, the injector region 212 isplugged with filtercake 300, impeding or preventing the injector region 212 from being able to efficiently deliver injection fluids 214 into the subsea reservoir 210.

[0063] The filtercake 300 is typically deposited during the drilling of the injection well 200. Moreover, the is not cleaned up

[0064] The be used to deliverchemicals could be introduced upstream of the water injection pumps of the production facility 120 and delivered downhole to the injector region 212 (FIG. 2) have a concentration of about 100 parts per million (ppm). Other exemplary concentrations may be used, including concentrations of about 50 ppm, about 250 ppm, about 500 ppm, about 750 ppm, about 1,000 ppm, about 2,500 ppm, about 5,000 ppm, about 7,500 ppm or about limiting examples. Remediation of the filtercake 300 using injection pumps may, however, be undesirable for a number of a mud filtercake, concentrations greater than 10,000 ppmof about 1%) could be needed.

[0065] The chemicals used according to the techniques described herein are less aggressive as compared to acids and chelating agents that cannot be pumped directly from the FPSO. Those types of chemicals may have adverse side effects to the riser, flowlines, jumpers, manifolds, seals, tubing, etc. When an acid is pumped to remediate a well, a drilling rig or a LWIV should be deployed to the site and latched up directly to the wellhead. The treatment according to the present techniques avoids this effort and expense.

[0066] Even if the water injection 120 could deliver the concentration requirements, there may amount of chemical that may be discharged if the well being treateddischarging undiluted chemicals would need to be managed. In addition, there could be chemical compatibility considerations when injecting chemicals using the water injection pumps of the production facility 120. The pumps may not be rated to take certain chemicals at higher concentrations due to elastomer seal components that may exist inside of the pump. The elastomers may not be compatible with the chemical in the ranges required.

[0067] The present techniques exploit the notion that low concentration, less aggressive chemicals may be used to remediate the presence of the mud filtercake 300 using the existing infrastructure of the production facility 120. Moreover, the present techniques may be performedusing the 120 without the need to move such as a rig or LWIV to the filtercake 300.

[0068] including a of filtercake 300 according to the present techniques. As used herein, the term “low concentration” means a concentration in the range of 0.5% to 5%. Specific examples of low concentrations include approximately 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5% and 5.0%, to name just a few examples. Further, examples of chemicals that may be used for filtercake remediation include surfactants, such as water soluble ethoxylated alcohols balanced with oil soluble components, such as calcium or amine salts of such as dioctyl sulfo succinate.

[0069] As shown in FIG.4, the a water injection pump 402 for pumping water to the injection welltie-in connection 404 is provided on the downstream side of the water injection pump 402. The riser tie-in connection 404 is an input port that may receive fluids to be pumped into the riser 102 by a chemical injection pump 406. The chemical injection pump 406 is typically smaller in capacity and pressure than the water injection pump 402 with the ability to deliver a low concentration chemical solution at riser pressure to remediate the filtercake 300 from the injector region 212 (FIG.2) of the injection well 200 as described herein.

[0070] pump(s) 402, pumps The practitionerinto the tie-in connection 404.

[0071] According to the present techniques, the filtercake 300 may be removed from the injector region 212 by injecting a low concentration chemical solution into the riser 102 (FIG.1) via the riser tie-in connection 404. The low concentration chemical solution may be pumped down through the riser 102, flowline, tubing and lower completion until it comes in contact with the mud filtercake 300 impairing the injector region 212. The injection well 200 should then be shut-in allowing the low concentration chemical solution to break down the mud filtercake 300 before being brought back online.

[0072] In an exemplary embodiment of the present techniques, the composition of the chemical solution is designed to change the wettability of the filtercake 300 to assist in breaking down the filtercake 300. By way of example, if the filtercake 300 is an emulsion, the composition of the chemical solution may be designed to break down the integrity of the emulsion.

[0073] In one example, a low concentration chemical solution is pumped into the riser tie-in connection 404 at some percentage of the water injection rate until a pill of some specific calculated volume is formed in the riser 102 and flowline. The low concentration of the chemical solution could be in a range described previously herein. The volume of the pill could be approximately 1,000 barrels in one non-limiting example. Other non-limiting examples of pill size include approximately 500 barrels, approximately 2,000 barrels, approximately 3,000 barrels, approximately 4,000 barrels, approximately 5,000 barrels, approximately 6,000 barrels, approximately 7,000 barrels, approximately 8,000 barrels, approximately 9,000 barrels, or approximately 10,000 barrels, to name just a few examples.

[0074] The pill may have a length that is longer than or greater than the length of the injector region 212. This will allow treatment to take place multiple times as the pill is repeatedly moved into position along the injector region 212 multiple times to bring fresh chemical solution into contact with the filtercake 300. The fresh chemical solution is allowed to soak the filtercake 300 for at least the remediation time for each of the multiple times the pill is moved. The pill may be pumped has been brought into contact with the

[0075] into the riser tie-in connection 404ceases and the water injection rate is ramped up to deliver the chemical to the injector region 212 (FIG. 2). The water injection rate to deliver the pill could be performed by the water injection pump 402. The chemical injection pump 406 that goes into the riser tie-in connection 404 is no longer needed after all the chemical is pumped into the riser. At that point, the main water injection pump(s) 402 continue(s) to pump the pill through the riser 102, flowline, manifold, jumper, etc. until it reaches the lower completion.

[0076] Once a desired amount of pill volume reaches the injector region 212, injection isshut-in, and the low concentration chemical soaks the filtercake 300 for a prescribed period of time. The period of time to soak the filtercake 300 in the low concentration chemical is referred to herein as the remediation time. The remediation time is the time period in which disaggregation of the filtercake 300 begins to take place. In one example, the remediation time is a time in the rangebetween 24 hours and 48 hours. the remediation time could range between one day and three days, one day and day and five days, one day and six days, one day toseven days, or one day to 30 days, to name a few non-limiting examples.

[0077] Water injection into the subsea reservoir 210 may then resume at a specified ramp-up rate to introduce fresh low concentration chemical from the original pill to the filtercake 300. The injection well 200 should be shut-in once again and allowed to soak the filtercake 300 with the fresh low concentration chemical. This procedure could be repeated several times until the total pill of low concentration chemical has been injected into the injector region 212 to soak the filtercake 300. At that time, full scale injection of fluids into the subsea reservoir 210 may slowly be brought back online, and pressures may be monitored.

[0078] The practitioner will appreciate that the present techniques employ the chemical solution to change the wettability of the oil-based mud from “oil wet” to “water wet.” After some period of time, the wettability of the mud filtercake is changed to water wet, and with the expected relative permeability benefit, the residual mud may be injected away into the subsea reservoir. In one example, the present techniques may be used in treatment of a desulfated seawater injector drilled with barite-based oil-based mud. The treatment makes the barite water wet, allowing the water, undersaturated with barium sulfate (BaSO4), to dissolve the barite. The remaining barite may then dissolve over time in the desulfated treated seawater that is injected. Injectivity performance should improve and could be confirmed by performing a series of step rate tests and pressure transient analysis.

[0079] flow diagram of an exemplary method 500 for remediating filtercake in a to the present techniques. Calculations about various aspects of theat least in part, by one or more computing systems including one or more processors, such as the cluster computing system described with respect to FIG. 6, or any suitable variation(s) thereof. In some embodiments, such computing system(s) (or a portion of such computing systems) may be across a number of locations.

[0080] The method 500 begins solution is injected into the riser tie-in connection 404 using is downstream of the water injection pump 402 of an offshoreAs explained herein, the present techniques exploit the fact that a low concentration of chemicals may be used to treat filtercake buildup using existing infrastructure of an FPSO without the need to bring in expensiveresources, such as an LWIV or a drilling rig.

[0081] At block 502, the method 500 continues with the pumping by the chemical injection pump 406 of at least a portion of the chemical solution through the riser 102 connected to the riser tie-in connection 404 and to the injector region 212 of the injection well 200 connected to the riser 102. Filtercake 300 that is impairing the injector region 212 is in fluid communication therewith, such that at least a portion of the chemical solution is in contact with the filtercake 300.

[0082] Once the chemical solution is in contact with the filtercake 300, at least a remediation time is allowed to pass for the chemical solution to begin to disaggregate the filtercake 300. By soaking the filtercake, the solids (barite) in the mud start to disaggregate. Wettability is changed and that allows the residual mud to be swept away and the remaining barite to dissolve over time. The remediation time is indicated at block 506. The practitioner may determine the specific length of the remediation time based on conditions in the field, such as composition of the chemical solution and the extent to which the filtercake 300the injector region 212. As chemical solution may be pumped into contact with the filtercake 300 in may continue until the filtercake 300 has been exposed to sufficientthe filtercake 300 from the injector region 212.

[0083] FIG.6 is a block diagram of an exemplary cluster computing system 600 that may be utilized to implement at least a portion of the present techniques. As noted, the cluster computing system 600 may be used to compute aspects of the present techniques such as composition of the chemical solution, the size of a pill made up of thebe time to wait once the chemical solution is brought into contact with thethe injector region 212.

[0084] The exemplary cluster computing system 600 shown in FIG.6 has four computing units 602A, 602B, 602C, and 602D, each of which may perform calculations for a portion of the present techniques. However, one of ordinary skill in the art will system 600 is not limited to this configuration, as any number may be selected. For example, a smaller analysis may be run on a workstation, while a large calculation may be run on a clustertens, hundreds, or even more computing units.

[0085] The cluster computing system 600 may be accessed from any number of client systems 604A and 604B over a network 606, for example, through a high-speed network interface 608. Thecomputing units 602A to 602D may also function as support and access to the wider cluster computing

[0086] The network 606 may include a local area , the Internet, or any combinations thereof. Each clientmore non-transitory, computer-readable storage media for storing the operating code and program techniques, as described further media of FIG.7. For example, each and 610B, which may include the like. Each client system604A may a may include any number of hard drives, optical drives, flash drives, or the like.

[0087] The high-speed network interface 608 may be coupled to one or more buses in the cluster computing system 600, such as a communications bus 614. The communication bus 614 may be used to storage system rate between

[0088] In some embodiments, the one or more non-transitory, computer-readable storage media of the cluster storage system 616 include storage arrays 620A, 620B, 620C and 620D for the storage of models, data. visual representations, results (such as graphs, charts, and the like used to convey results obtained using the and other information concerning the implementation of at techniques. The storage arrays 620A to 620D may include any combinations drives, flash drives, or the like.

[0089] Eachat least one processor 622A, 622B, 622C and 622D and associated local non-transitory, computer-readable storage media, such as a memory device 624A, 624B, 624C and 624D and a storage device 626A, 626B, 626C and 626D, for example. Each processor 622A to 622D may be a multiple core unit, such as a multiple core central processing unit (CPU) or a graphics processing unit (GPU). Each memory device 624A to 624D may include ROM and / or RAM used to store program instructions for directing the corresponding processor 622A to 622D to implement at least a portion of the present techniques. Each storagedevice 626A to 626D may include one or more hard drives, optical drives, flash drives, or the like. In addition, each storage device 626A to 626D may be used to provide storage for models, intermediate results, data, images, or code used to implement at least a portion of the present techniques.

[0090] The present techniques are not limited to the architecture or unit configuration illustrated in FIG. 6. For example, any suitable processor-based device may be utilized for implementing at least a portion of the embodiments described herein, including (without limitation) personal computers, laptop computers, computer workstations, mobile devices, and multi-processor servers or workstations with (or without) shared memory. Moreover, the embodiments described herein may be implemented, at least in part, on application specific integrated circuits (ASICs) or very-large-scale integrated (VLSI) circuits. In fact, those skilled in the art may utilize any number of suitable structures capable of executing logical operations according to the embodiments described herein.

[0091] FIG.7 is a block diagram of an exemplary non-transitory, computer-readable storage medium 700 that may be used for the storage of data and modules of program instructions for implementing at least a portion of the present techniques. The non-transitory, computer-readable storage medium 700 may include a memory device, a hard disk, and / or any number of other devices, as described herein. A processor 702 may access the non-transitory, computer-readable storage medium 700 over a bus or network 704. While the non-transitory, computer-readable storage medium 700 may include any number of modules for implementing the present techniques, in some embodiments, the non-transitory, computer-readable storage medium 700 includes a filtercake remediation calculation module 706 for performing the techniques described herein (and / or any suitable variations thereof). Moreover, the filtercake remediation calculation module 706 may be adapted to analyze data to determine the composition and amount of low concentration chemical solution to be delivered to the injector region 212 of the injection well 200 in order to remediate filtercake buildup as described herein, or the remediation time to leave the chemical solution in contact with the filtercake 300. Embodiments of Present Techniques

[0092] In one or more embodiments, the present techniques may be susceptible to various modifications and alternative forms, such as the following embodiments as noted in paragraphs 1 to 55: 1. A method for remediating filtercake buildup in a subsea injection well, the method comprising: injecting a chemical solution into a riser tie-in connection using a chemical injection pump downstream of a water injection pump of an offshore production facility; pumping, with thechemical injection pump, at least a portion of the chemical solution through a riser connected to the riser tie-in connection and to an injector region of an injection well connected to the riser, the injector region being in fluid communication with filtercake that is impairing the injector region, so that at least a portion of the chemical solution makes contact with the filtercake; and waiting at least a remediation time for the in contact with the chemical solution to cause remediation in the impairing of the 2. The method recited in the chemical solution comprises a surfactant.3. The method recited in the surfactant a water soluble ethoxylated alcohol balanced with an oil soluble component. 4. The method recited in any of paragraph 3, wherein includes a calcium salt or an amine salt of dodecylbenzene sulfonates.5. The method recited in any of paragraphs 1 to 4, wherein the chemical solution comprises a wetting agent. 6. The method recited in any of paragraph 5, agent comprises a dioctyl sulfo succinate.7. The method recited in any of paragraphs 1 to 6, wherein the chemical solution is a low concentration chemical solution. 8. The method recited in any of paragraphs 1 to 7, wherein composition is designed to change wettability of the filtercake. 9. The method recited in paragraph 8, wherein the filtercake is an the chemical solution is designed to break down integrity of the emulsion.10. The method recited in any of paragraphs 1 to 9, wherein the chemical solution forms a pill of predetermined size in the riser. 11. The method recited in paragraph 10, wherein the pill has a length greater than the length of the injector region, and wherein the pill is pumped into contact with the injector region multiple times until the length of the pill has been brought into contact with the filtercake, waiting at least the remediation time between each of the multiple times. 12. The method recited in any of paragraphs 1 to 11, comprising shutting in the injection well during the remediation time. 13. The method recited in any of paragraphs 1 to 12, wherein the remediation time is determined based on sufficiency of the chemical solution to disaggregate at least a portion of the filtercake during the remediation time.14. The method recited in any of 1 to wherein the offshore production facility comprises a floating production, . 15. The method recited in any of tie-in connection is located on the offshore production facility. 16. The method recited in any of the pumping at least a portion of the chemical solution and 17. The method recited in any oftime comprises a time in the range between 24 hours and 48 hours. 18. An injection well system, comprising: an injector well having an injector region that is impaired with filtercake; a chemical injection pump downstream of a water injection pump of an offshore production facility, the chemical injection pump connected to a riser via a riser tie-in connection, the riser being in fluid communication with the injector region; wherein the riser receives a chemical solution pumped from the chemical injection pump so that at least a portion of the chemical solution makes contact with the filtercake; and wherein at least a portion of the chemical solution is left in contact with the filtercake for at least a remediation time to cause remediation in the filtercake impairing of the injector region. 19. The well system recited in paragraph 18, wherein the chemical solution comprises a surfactant. 20. The well system recited in paragraphs 18 or 19, wherein the surfactant comprises a water soluble ethoxylated alcohol balanced with an oil soluble component. 21. The well system recited in any of paragraph 20, wherein the oil soluble component includes a calcium salt or an amine salt of dodecylbenzene sulfonates. 22. The well system recited in any of paragraphs 18 to 21, wherein the chemical solution comprises a wetting agent. 23. The well system recited in paragraph 22, wherein the wetting agent comprises a dioctyl sulfo succinate. 24. The well system recited in any of paragraphs 18 to 23, wherein the chemical solution is a low concentration chemical solution. 25. The well system recited in any of paragraphs 18 to 24, wherein composition of the chemical solution is designed to change wettability of the filtercake. 26. The well system recited in paragraph 25, wherein the filtercake is an emulsion and composition of the chemical solution is designed to break down integrity of the emulsion. 27. The well system recited in any of paragraphs 18 to 26, wherein the chemical solution forms a pillof predetermined size in the riser. 28. The 27, wherein the pill has a length greater than the length of the the pill is pumped into contact with the injector region multiple times has been brought into contact with the filtercake, waiting at least the of the multiple times.29. The well system recited in any of paragraphs 18 to 28, wherein the injection well is shut in during the remediation time. 30. The well system recited in any of paragraphs 18 to 29, wherein the remediation time is determined based on sufficiency of the chemical solution to disaggregate at least a portion of the filtercake during the remediation time. 31. The well system recited in any of paragraphs 18 to 30, wherein the offshore production facility comprises a floating production, . 32. The well system recited in any the riser tie-in connection is located on the offshore production 33. The well system recited in anythe pumping at least a portion of the chemical solution and waiting for at least the remediation time are repeated. 34. The well system recited in any of paragraphs 18 to 33, wherein the remediation time comprises a time in the range between 24 hours and 48 hours. 35. A well system, comprising: an injector well having an injector region that is impaired with filtercake; a chemical injection pump downstream of a water injection pump of an offshore production facility, the chemical injection pump connected to a riser via a riser tie-in connection, the riser being in fluid communication with the injector region; wherein the riser receives a chemical solution pumped from the chemical injection pump so that at least a portion of the chemical solution makes contact with the filtercake; wherein the at least a portion of the chemical solution is left in contact with the filtercake for at least a remediation time to cause remediation in the filtercake impairing of the injector region; and a computing system that calculates an aspect of the chemical solution to provide an input to remediating the filtercake. 36. The well system recited in paragraph 35, wherein the chemical solution comprises a surfactant. 37. The well system recited in paragraphs 35 or 36, wherein the surfactant comprises a water soluble ethoxylated alcohol balanced with an oil soluble component. 38. The well system recited in paragraph 37, wherein the oil soluble component includes a calcium salt or an amine salt of dodecylbenzene sulfonates.39. The well system recited in any of paragraphs 35 to 38, wherein the chemical solution comprises a wetting agent. 40. The well system recited in paragraph 39, wherein the wetting agent succinate. 41. The well system recited in any of paragraphs 35 to 40, wherein the concentration chemical solution.42. The composition of the chemical solution 43. The is an emulsion and compositionof the the emulsion. 44. The well system recited in any of paragraphs 35 to 43, wherein the chemical solution forms a pill of predetermined size in the riser. 45. The well system recited in pill has a length greater than the length of the injector region, and wherein with the injector region multiple times until the length of the pill with the filtercake, waiting at least theremediation time between each of the multiple times. 46. The well system recited in any of paragraphs 35 to 45, wherein the injection well is shut in during the remediation time. 47. The well system recited in any of paragraphs 35 to 46, wherein the remediation time is determined based on sufficiency of the chemical solution to disaggregate at least a portion of the filtercake during the remediation time. 48. The well system recited in any of paragraphs 35 to 47, wherein the facility comprises a floating production, storage, and offloading vessel (FPSO). 49. The well system recited in any of paragraphs 35 to 48, wherein the riseris located 50. The of the 51. The solution 52. The solution53. The well system recited in any of paragraphs 35 to 52, wherein the computing system calculatesthe remediation time. 54. The well system recited in any of paragraphs 35 to 53, wherein the a size of a pill to include the chemical solution. 55. The well system recited in any of paragraphs 35 to 54, wherein the atime in 24 hours and 48 hours.

[0093] embodiments described herein are well-calculated to achieve the advantages set that such embodiments are susceptible to modification, variation, and changefrom the spirit thereof. In other words, the particular embodiments described herein are illustrative only, as the teachings of the present techniques may be modified and practiced in different but equivalent manners apparent to those skilled in the benefit of the teachings herein. Furthermore, no limitations are intended on the details construction, or design herein shown, other than as described in the claimsthe systems and methods illustratively disclosed herein may suitably be practiced in the absence of any element that is not specifically disclosed herein and / or any optional element disclosed herein. While compositions and methods are described in terms of “comprising” or “including” various components or steps, the compositions and methods can also “consist essentially of” or “consist of” the various components and steps. Indeed, the present techniques all alternatives, modifications, and equivalents falling within the true spirit andthe appended claims.

[0068] Exemplified L2-R2suitable for Formula I (e.g., any of the applicable subformulae) include any of those respective groups as shown in the specific compounds listed in Table 1 herein.

[0069] For example, in some embodiments, unless otherwise specified or contrary from context, in Formula I (e.g., any of the applicable subformulae), L2-R2can be, etc. In some embodiments, unless otherwise specified or contrary from context, in Formula I (e.g., any of the applicable subformulae), L2-R2can bespecified or contrary from context, in Formula I (e.g., any of the applicable subformulae), L2-

[0070] In some preferred embodiments, L2is a substituted cyclopropylene, and the compound of Formula I can be characterized as having a structure according to Formula I-D,Formula I-D, wherein: q is 1 or 2;R101is F or methyl optionally substituted with F or R101is F, C1-2 alkyl optionally substituted with F (e.g., CH3, CH2F, CHF2, or CF3), CN, C2-3 alkynyl optionally substituted with F, or C 1-4 heteroalkyl optionally substituted with F (e.g., CH2OCH3); andJ1, J2, J3, J4, J5, J6, J7, Js, L1, R1, and R2are defined herein. Exemplary definitions of the variables for Formula I-D are also shown in enumerated embodiments Bl-43. Typically, in such embodiments, R101is F. In some embodiments, R101is Ci -4 heteroalkyl optionally substituted with F. For example, in some embodiments, R101is CH2OCH3. In some embodiments, R101is CH2CH2OCH3. In some embodiments, q is 1. In some embodiments, the moietycan have a stereochemistry selected fromthe two R101groups are the same, for example, both are F. Typically, in Formula I-D, R2is hydrogen, F, C1-2 alkyl optionally substituted with F (e.g., CH3, CEFF, CHF2, or CF3), CN, cyclopropyl, or C2-3 alkynyl optionally substituted with F, such as. Forexample, in some embodiments, the moietysome embodiments, the moietycan besome embodiments, the moietycan be, moietybicyclic heteroaryl moiety as defined in Formula I- 1 , 1-2, 1-3, I-la, I- Lb, I-lc, I-2a, I-2b, I-3a, I-3b, I-la-1, 1-la-2, 1-2a-l, I-2a-2, 1-3a-l, I-3a-2, I-lb-1, I- lb-2, I-2b-l, I-2b-2, 1-3b- 1, or I-3b-2.

[0071] In some embodiments, the compound of Formula I-D can be characterized as having a structure according to Formula I-X:Formula I-X, wherein:R101is F, Ci-2 alkyl optionally substituted with F (e.g., CH3, CFFF, CHF2, or CF3), CN, C2-3 alkynyl optionally substituted with F, or C 1-4 heteroalkyl optionally substituted with F (e.g., CH2CH2OCH3, orCH2OCH3); andJ1, J2, J3, J4, J5, J6, J7, J8, L1, R1, and R2are defined herein. Exemplary definitions of the variables for Formula I-X are also shown in enumerated embodiments Dl-26. Without wishing to be bound by theories, it is believed that compounds having stereochemistry as drawn in Formula I-X are better than the other possible stereoisomers for inhibiting PARG activities and / or for inhibiting cancer cell growth. As exemplified in the Examples section, compounds having the as-drawn stereochemistry may be synthesized through chiral starting material or through chiral separation using SFC or HPLC.

[0072] In some preferred embodiments, R101in Formula I-X is a C 1-4 heteroalkyl optionally substituted with F (e.g., CH2CH2OCH3, or CFEOCH3). For example, in some embodiments, R101is CH2OCH3. In some embodiments, R101is CH2CH2OCH3.

[0073] R2in Formula I-X is typically methyl. Other suitable R2include those defined herein.

[0074] In some preferred embodiments, the compound of Formula I-X can be characterized as having a structure according to Formula I-Xa:Formula I-Xa, wherein J1, J2, J3, J4, J5, J6, J7, J8, L1, and R1are defined herein.

[0075] In some embodiments according to Formula I-X, the bicyclic heteroaryl moietycan be a bicyclic heteroaryl moiety as defined in Formula I- 1, 1-2, 1-3, 1- la, I-lb, I-lc, I-2a, I-2b, I-3a, I-3b, I-la-1, 1-la-2, 1-2a-l, I-2a-2, 1-3a-l, I-3a-2, 1-lb-1, 1-lb- 2, 1-2b-l , I-2b-2, 1-3h-l, or I-3b-2.

[0076] For example, in some preferred embodiments, the compound of Formula I-X can be characterized as having a structure according to Formula I-Xb:Formula I-Xb, wherein L1, R1, R4and R5are defined herein.

[0077] In embodiments, the compound of Formula I-X can be characterized as having a structure according to Formula I-Xc:Formula I-Xc, wherein L1, R1, R4and R5are defined herein.

[0078] For example, typically, in Formula I-Xb or I-Xc, R4is hydrogen or halogen, preferably, R4is hydrogen, F or Cl. Typical definitions of L1, R1, and R5for Formula I-Xb or I-Xc are described in enumerated embodiments D12-26.

[0079] In Formula I and its subformulae, J3is typically CRS, wherein Rsis defined herein.

[0080] In some embodiments, R5can be hydrogen, halogen (e.g., Cl), or OH.

[0081] In some embodiments, R5can be L3-G2A, wherein I is an optionally substituted g2A - = _ |C2-4 alkynylene. For example, in some embodiments, R5can be > , wherein G~Ais defined herein, for example, G2Ais a CM heteroalkyl, e.g., CH2OCH3 or CH2CH2OCH3.

[0082] In some embodiments, R5can be G2, and G2is an optionally substituted 3-14 membered ring, preferably, a heteroaryl or heterocyclic ring.

[0083] In some embodiments, R5can be an optionally substituted 4-12 membered heterocyclic ring having 1-4 ring heteroatoms independently selected from N, O, and S, wherein the S atom is optionally oxidized. The 4-12 membered heterocyclic ring is typically a monocyclic ring (typically has 4-7 ring members with 1 or 2 ring heteroatoms) or a bicyclicring (typically has 5- 12 ring members with 1 -3 ring heteroatoms), which can be a fused, spiro, or bridged bicyclic ring.

[0084] In some embodiments, R5can be an optionally substituted 4-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O, and S, wherein the S atom is optionally oxidized (e.g., S(O), SO2, S(=NH)(=O)) for example, a monocyclic 5 or 6 membered heterocyclic ring having 1 or 2 ring heteroatoms, such as a pyrrolidine, piperidine, or piperazine ring. For example, in some embodiments, R5is a ringeach of which is optionally substituted. When substituted, the 4-7 membered heterocyclic ring can be typically substituted with 1-3 substituents each independently oxo, halogen (e.g.,wherein GAat each occurrence is an optionally substituted group independently selected from (i) C1-4 alkyl; (ii) C 1-4 heteroalkyl; and (iii) a 3-10 membered ring, or two GAtogether with the intervening atom(s) are joined to form an optionally substituted 4-10 membered heterocyclic ring; wherein when substituted, the C1-4 alkyl or Ci -i heteroalkyl is preferably substituted with 1-3 substituents each independently (1) halogen (preferably F), CN, OH, or NH2, (2) C1-4 heteroalkyl optionally substituted with F; or (3) an optionally substituted 3-10 membered ring; and when substituted, the 3-10 membered ring or the 4-10 membered heterocyclic ring is preferably substituted with 1-3 substituents independently (1) oxo (as applicable), halogen (e.g., F, Cl), CN, OH, or NH2; (2) C1-4 alkyl optionally substituted with F; (3) C1-4 heteroalkyl optionally substituted with F; or (4) a 3-6 membered ring optionally substituted 1-3 substituents independently selected from oxo, F, Cl, CN, OH, CM alkyl optionally substituted with F, and C 1.4 heteroalkyl optionally substituted with F.

[0085] In some more specific embodiments, R5can have a structure according to F-l, F-2, or F-3 below:wherein: n is an integer of 0-4,(a) R10at each occurrence is independently oxo, halogen (e.g., F), OH, CN, GA, OGA,or(b) two R10are joined to form an optionally substituted 3-6 membered ring (e.g., cyclopropyl, cyclobutyl, or oxetane ring), and any remaining R10are as defined in (a); or(c) one R10and R11are joined to form an optionally substituted 3-6 membered ring, and any remaining R10are as defined in (a);R11is hydrogen, GA, C(O)GA, SO2GA, C(O)OGA, C(O)NHGA, C(O)NGAGA, SO2NHGA, S(=NH)(=O)GA, S(=N-GA)(=O)GA, or SO2NGAGA, or defined in (c) above; wherein GAat each occurrence is an optionally substituted group independently selected from (i) Ci -4 alkyl; (ii) CM heteroalkyl; and (iii) a 3-10 membered ring, or two GAtogether with the intervening atom(s) are joined to form an optionally substituted 4-10 membered heterocyclic ring; wherein when substituted, the C alkyl or C heteroalkyl is preferably substituted with 1-3 substituents each independently (1) halogen (preferably F), CN, OH, or NH2, (2) C 1-4 heteroalkyl optionally substituted with F; or (3) an optionally substituted 3-10 membered ring; and when substituted, the 3-10 membered ring or the 4-10 membered heterocyclic ring is preferably substituted with 1-3 substituents independently (1) oxo (as applicable), halogen (e.g., F, Cl), CN, OH, or NH2; (2) C alkyl optionally substituted with F; (3) C 1-4 heteroalkyl optionally substituted with F; or (4) a 3-6 membered ring optionally substituted 1-3 substituents independently selected from oxo, F, Cl, CN, OH, CM alkyl optionally substituted with F, and C 1-4 heteroalkyl optionally substituted with F.To be clear, when it is said that two R10are joined to form a ring structure, the two R10can be attached to the same carbon, two adjacent carbon atoms, or two non-adjacent carbon atoms, thus, the ring formed can be a spiro ring, a fused ring, or a bridged ring. Similarly, when it is said that one R10and R11are joined to form a ring structure, the R10can be attached to a carbon atom adjacent to the nitrogen atom of (NR11) or a non-adjacent carbon atom, thus forming a fused ring or a bridged ring.

[0086] In some embodiments, in F-l, F-2, or F-3, n is 0, 1, or 2; R10at each occurrence is independently CN or GA, and R11is hydrogen, GA, C(O)GA, SO2GA, C(O)OGA, C(O)NHGA, C(O)NGAGA, SO2NHGA, S(=NH)(=O)GA, S(=N-GA)(=O)GA, or SO2NGAGA, wherein GAis defined herein. In some embodiments, GAat each occurrence is independently:(1) a Ci-4 alkyl optionally substituted with 1-3 substituents each independently F, OH, Ci-4 alkoxy optionally substituted with 1-3 F, NH(CI-4 alkyl), or N(CI-3 alkyl)(Ci-3 alkyl); or(2) a 3-10 membered ring, (CM alkylene)-(3-10 membered ring), or (Ci-4heteroalkylene)- (3-10 membered ring), preferably, the 3-10 membered ring is a 3-6 membered ring selected from C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5 or 6-membered heteroaryl, or phenyl, wherein the 3-10 membered ring is optionally substituted with 1-3 substituents independently selected from oxo, F, Cl, OH, CN, C1-4 alkyl optionally substituted with F, Ci -4 alkoxy optionally substituted with F, and optionally substituted 3-5 membered ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.).

[0087] In some embodiments, in F-l, F-2, or F-3, n is 0, 1, or 2; R10at each occurrence is independently CN, cyclopropyl, C1-4 alkyl optionally substituted with F (e.g., CH3) or CM heteroalkyl optionally substituted with F (e.g., CH2OCH3), and R11is hydrogen, GA, C(O)GA, SO2GA, C(O)OGA, C(O)NHGA, C(O)NGAGA, SO2NHGA, S(=NH)(=O)GA, S(=N- GA)(=O)GA, or SO2NGAGA, wherein GAis defined herein.

[0088] In some embodiments, in F-l, F-2, or F-3, n is 0. For example, in some embodiments, in Formula I (or any of the applicable subformulae herein), Rsis characterized as having a structureis defined herein.

[0089] In some embodiments, in F-l, F-2, or F-3, n is 1. For example, in some embodiments, in connection with Formula I (or any of the applicable subformulae herein), R5is characterized as having a structurewherein R10and R11are defined herein. Typically, R10in F-7 is F, OH, or GA(as defined herein). In some embodiments, in connection with Formula I (or any of the applicable subformulae herein), R5is characterized as having a structurewherein R11is defined herein.

[0090] In some embodiments, in connection with Formula I (or any of the applicable subformulae herein), R5is characterized as having a structure, wherein R10and R11are defined herein. Typically, R10in F-8 is GA(as defined herein). For example, in some embodiments, R10in F-8 is a C1-4 alkyl optionally substituted with F, e.g., CH3, CH2F, CHF2, or CF3. In some embodiments, R10in F-8 is a C1-4 heteroalkyl optionally substituted with deuterium and / or F. For example, in some embodiments, R10in F-8 is methoxymethyl group, CH2OCH3, e.g., having a structure of. In some embodiments, in connection with Formula I (or any of the applicable subformulae herein), R5is characterized as having a structurewherein R11is defined herein. In some embodiments, in connection with Formula I (or any of the applicable subformulae herein), Rsis characterized as having a structure of F-8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R or F-8c-S,

[0091] In some embodiments, in F-l, F-2, or F-3, n is 2. For example, in some embodiments, in connection with Formula I (or any of the applicable subformulae herein), R5is characterized as having a structurewherein R10and R11are defined herein. In some embodiments, each R10in F-9 is independently F, OH, or GA(as defined herein). In some embodiments, two R10in F-9 are joined to form a 3-6 membered ring, such as a cyclopropyl ring. For example, in some embodiments, in connection with Formula I (or any of the applicable subformulae herein), R5is characterized as having a structurewherein R11is defined herein. In some embodiments, in connection with Formula I (or any of the applicable subformulae herein), R5is characterized as having a structurewhereinR11is defined herein.

[0092] In some embodiments, in connection with Formula I (or any of the applicable subformulae herein), Rsis characterized as having a structure of F-10,10), wherein R10and R11are defined herein. In some embodiments, each R10in F-10 is independently C1-4 alkyl optionally substituted with F, e.g., CH3, CH2F, CHF2, or CF3. In some embodiments, each R10in F-10 is independently a C1-4 heteroalkyl optionally substituted with deuterium and / or F. In some embodiments, two R10in F-10 are joined to form a 3-6 membered ring, such as a cyclopropyl ring. For example, in some embodiments, in connection with Formula I (or any of the applicable subformulae herein), R5is characterized as having a structurewherein R11is defined herein. In some embodiments, the two methyl groups in F-lOa are cis to each other, ,6...'' N '<IR (F-10a-l). In some embodiments, the two methyl groups in F-lOa are trans toAI each other, e.g., R (F-10a-2). In some embodiments, in connection with Formula I(or any of the applicable subformulae herein), R5is characterized as having a structure of F-C10b, R11(F-lOb), wherein R11is defined herein. In some preferred embodiments, in connection with Formula I (or any of the applicable subformulae herein), R5isR1C) A N "R1OR11(F-lOc), wherein R10and R11are defined herein - without wishing to bebound by theories, it is believed that the disubstituted piperazine in this configuration is more preferred than the other possible stereoisomers. In some preferred embodiments, in connection with Formula I (or any of the applicable subformulae herein),(F-10a-2), wherein R11is defined herein.

[0093] In some embodiments, in F-l, F-2, or F-3, two R10are joined to form an optionally substituted 3-6 membered ring (e.g., cyclopropyl, cyclobutyl, or oxetane ring), and any remaining R10are independently C alkyl optionally substituted with F or CM heteroalkyl optionally substituted with F. For example, in some embodiments, R5can have a m(R10)\^ y structure according to n I R 11 (F-la),- lb), wherein m is 0, 1, or 2,R10at each occurrence is independently CM alkyl optionally substituted with F or CM heteroalkyl optionally substituted with F, R11is defined herein.

[0094] In some embodiments, in F-l, F-2, or F-3, one R10and R11are joined to form an optionally substituted 3-6 membered ring, and any remaining R10are independently CM alkyl optionally substituted with F or CM heteroalkyl optionally substituted with F. For example, in some embodiments, R5can have a structure according t-lc), wherein m is 0, 1, or 2, R10at each occurrence is independently CM alkyl optionally substituted with F or C 1-4 heteroalkyl optionally substituted with F.

[0095] In some embodiments, in F-l, F-2, or F-3, or in F-4, F-5, F-6, F-7, F-7a, F-7b, F-8, F-8a, F-8b, F-8c, F-8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l, F-9a-2, F- 10, F-lOa, F-10a-l, F-10a-2, F-lOb, F-lOc, F-la, or F-lb, R11is C(O)GA, SO2GA, C(O)OGA, C(O)NHGA, C(O)NGAGA, SO2NHGA, S(=NH)(=O)GA, S(=N-GA)(=O)GA, or SO2NGAGA, wherein GAis defined herein. For example, in some embodiments, R11is C(O)GA, SO2GA, C(O)OGA, C(O)NHGA, C(O)NGAGA, SO2NHGA, S(=NH)(=O)GA, S(=N-GA)(=O)GA, or SO2NGAGA, and GAat each occurrence is independently (1) a CM alkyl optionallysubstituted with 1 -3 substituents each independently F, OH, CM alkoxy optionally substituted with 1-3 F, NH(CI-4 alkyl), or N(CI-3 alkyl)(Ci-3 alkyl) or (2) a 3-6 membered ring selected from C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5 or 6-membered heteroaryl, or phenyl, wherein the 3-6 membered ring is optionally substituted with 1-3 substituents independently selected from oxo, F, Cl, OH, CN, C alkyl optionally substituted with F, CM alkoxy optionally substituted with F, and optionally substituted 3-5 membered ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.).

[0096] In some embodiments, in F-l, F-2, or F-3, or in F-4, F-5, F-6, F-7, F-7a, F-7b, F- 8, F-8a, F-8b, F-8c, F-8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l, F-9a-2, F- 10, F-lOa, F-10a-l, F-10a-2, F-lOb, F-lOc, F-la, or F-lb, R11can be C(O)GA1, C(O)OGA1, SO2GA1, C(O)NHGA1, or C(O)NGA1GA1, wherein GA1at each occurrence is independently Ci- 4 alkyl optionally substituted with F, such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, in F-l, F-2, or F-3, or in F-4, F-5, F-6, F-7, F-7a, F-7b, F-8, F-8a, F-8b, F-8c, F-8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l , F-9a-2, F-10, F-lOa, F-10a-l , F-10a-2, F-lOb, F-lOc, F-la, or F-lb, R11can be C(O)GA2, SO2GA2, C(O)NHGA2or SO2NHGA2, wherein GA2is a 3-6 membered ring selected from C3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl), 4-6 membered heterocyclyl (e.g., oxetanyl or azetidinyl), 5 or 6- membered heteroaryl, or phenyl, wherein the 3-6 membered ring is optionally substituted with 1-3 substituents independently selected from oxo, F, Cl, OH, CN, CM alkyl optionally substituted with F, C alkoxy optionally substituted with F, and optionally substituted 3-5 membered ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.). In some embodiments, GA2can be a C3-6 cycloalkyl, such as cyclopropyl or cyclobutyl, which is optionally substituted with 1 or 2 substituents each independently F, OH, CN, or CH3. In some embodiments, GA2can be a cyclopropyl or cyclobutyl, which is optionally substituted with 1 or 2 substituents each independently F, OH, CN, NH2, or CH3. In some embodiments, GA2can be a 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms, such as pyrrolidine, piperidine, piperazine, etc., which is optionally substituted with 1 or 2 substituents each independently F, OH, CN, or CH3. In some embodiments, GA2can be an oxetanyl or azetidinyl, which is optionally substituted with 1 or 2 substituents each independently F, OH, OCH3, CN, or CH3.

[0097] In some specific embodiments, in F-l, F-2, or F-3, or in F-4, F-5, F-6, F-7, F-7a,F-7b, F-8, F-8a, F-8b, F-8c, F-8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l, F- 9a-2, F-10, F-lOa, F-10a-l, F-10a-2, F-lOb, F-lOc, F-la, or F-lb, R11can be selected from:Typically, in such embodiments, n is 0, 1, or 2, and R10at each occurrence is independently CN, cyclopropyl, CM alkyl optionally substituted with F (e.g., CH3) or C 1-4 heteroalkyl optionally substituted with F (e.g., CH2OCH3).

[0098] In some embodiments, in F-l, F-2, or F-3, or in F-4, F-5, F-6, F-7, F-7a, F-7b, F- 8, F-8a, F-8b, F-8c, F-8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l, F-9a-2, F- 10, F-lOa, F-10a-l, F-10a-2, F-lOb, F-lOc, F-la, or F-lb, R11can be C(O)GA1, C(O)NHGA1, or C(O)NGA1GA1, wherein GA1is defined herein.

[0099] In some embodiments, in F-l, F-2, or F-3, or in F-4, F-5, F-6, F-7, F-7a, F-7b, F- 8, F-8a, F-8b, F-8c, F-8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l, F-9a-2, F- 10, F-lOa, F-10a-l, F-10a-2, F-lOb, F-lOc, F-la, or F-lb, R11can be C(O)GA2, wherein GA2is defined herein.

[0100] In some embodiments, in F-l, F-2, or F-3, or in F-4, F-5, F-6, F-7, F-7a, F-7b, F- 8, F-8a, F-8b, F-8c, F-8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l, F-9a-2, F- 10, F-lOa, F-10a-l, F-10a-2, F-lOb, F-lOc, F-la, or F-lb, R11can be hydrogen.

[0101] In some embodiments, in F-l, F-2, or F-3, or in F-4, F-5, F-6, F-7, F-7a, F-7b, F-8, F-8a, F-8b, F-8c, F-8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l, F-9a-2, F-10, F-lOa, F-10a-l, F-10a-2, F-lOb, F-lOc, F-la, or F-lb, R11can

[0102] In some embodiments, in F-l, F-2, or F-3, or in F-4, F-5, F-6, F-7, F-7a, F-7b, F-8, F-8a, F-8b, F-8c, F-8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l, F-9a-2, F-10, F-lOa, F-10a-l, F-10a-2, F-lOb, F-lOc, F-la, or F-lb, R11can be selected from:

[0103] In some embodiments, in F-l, F-2, or F-3, or in F-4, F-5, F-6, F-7, F-7a, F-7b, F-8, F-8a, F-8b, F-8c, F-8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l, F-9a-2, F-10, F-lOa, F-10a-l, F-10a-2, F-lOb, F-lOc, F-la, or F-lb, R11can be GA, wherein GAis defined herein. For example, in some embodiments, R11can be an optionally substituted 5 or6-membered heteroaryl, which is optionally substituted, preferably, when substituted, the 5 or6-membered heteroaryl is substituted with 1-3 substituents independently selected from F, Cl,OH, CN, Ci-4 alkyl optionally substituted with F, Ci-4 alkoxy optionally substituted with F, and optionally substituted 3-5 membered ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.). Typically, in such embodiments, n is 0, 1, or 2, and R10at each occurrence is independently CN, cyclopropyl, Ci-4 alkyl optionally substituted with F (e.g., CH3) or CM heteroalkyl optionally substituted with F (e.g., CH2OCH3). In some embodiments, R11can be optionally substituted 5 or 6-membered heteroaryl having 2 or 3 heteroatoms each independently N, O, or S, such as optionally substituted imidazole or thiadiazole. For example, in some embodiments, R11can

[0104] In some embodiments, R5can be an optionally substituted 5-12 membered, such as 7-12 membered, heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O, and S, wherein the S atom is optionally oxidized, for example, a 7-12 membered bicyclic heterocyclic ring which can be a spiro, fused, or bridged bicyclic heterocyclic ring.

[0105] In some embodiments, R5can be a 7-12 membered spiro bicyclic heterocyclic ring having 1-3 ring heteroatoms each independently N, O, and S, wherein the S atom is optionally oxidized. For example, in some embodiments, R5can be a spiro bicyclic heterocyclic ring having one ring being a 4, 5, or 6 membered ring and the other being a 3, 4 or 5 membered ring, such as the following:, which is optionally substituted, e.g., with one or more R10groups as defined herein.In some embodiments, when substituted, the substituents are each independently halogen (e.g., F), CN, cyclopropyl, Ci-4 alkyl optionally substituted with F (e.g., CH3) or C1-4 heteroalkyl optionally substituted with F (e.g., CH2OCH3).

[0106] In some preferred embodiments, R5can have a spiro oxetane ring, for example, in( A) some embodiments, R5can be represented by the structure of O , wherein ring A is a 4-8 membered carbocyclic or heterocyclic ring, which shares a single ring carbon atom with§ 9 the oxetane ring. In some specific embodiments, R5can be O or O .

[0107] In some embodiments, R5can include a spiro oxidized thietane ring, for example, in some embodiments, R5can be represented by the structure, wherein ring A is a 4-8 membered carbocyclic or heterocyclic ring, which shares a single ring carbon atom with the oxidized thietane ring.

[0108] In some embodiments, R5can be a 7-10 membered fused bicyclic heterocyclic ring having 1-3 ring heteroatoms each independently N, O, and S. For example, in some embodiments, R5can be a 4,5-fused, 4,6-fused, 4,7-fused, 5,5-fused, 5,6-fused, 5,7-fused, or6,6-fused bicyclic heterocyclic ring, such as the following:substituted, e.g., with one or more R10groups as defined herein. In some embodiments, when substituted, the substituents are each independently halogen (e.g., F), CN, cyclopropyl, Ci-4 alkyl optionally substituted with F (e.g., CH3) or C 1-4 heteroalkyl optionally substituted with F (e.g., CH2OCH3).

[0109] In some embodiments, R5can be a 7-10 membered bridged bicyclic heterocyclic ring having 1-3 ring heteroatoms each independently N, O, and S, such as a 2,1,1-bridged bicyclic, 2,2,1 -bridged bicyclic, 2,2,2-bridged bicyclic, 2,3,1-bridged bicyclic, 2,4,1-bridged bicyclic, for example, R5can be selected from the following:which is optionally substituted, e.g., with one or more R10groups as defined herein. In some embodiments, when substituted, the substituents are each independently halogen (e.g., F), CN, cyclopropyl, CM alkyl optionally substituted with F (e.g., CH3) or C 1-4 heteroalkyl optionally substituted with F (e.g., CH2OCH3).

[0110] In some embodiments, R5can also be a 5 or 6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, such as imidazole, pyrazole, thiadiazole, etc., which can be optionally substituted. When substituted, the 5 or 6 membered heteroaryl is preferably substituted with 1-3 substituents each independently halogen (e.g., F),at each occurrence is independently selected from (i) CM alkyl optionally substituted with 1-3 F; (ii) Ci 4 heteroalkyl optionally substituted with 1-3 F; and (iii) a 3-7 membered ring, which is optionally substituted with 1-3 substituents independently selected from oxo, halogen (e.g.,F), OH, CN, Ci-2 alkyl optionally substituted with F, and C 1-4 heteroalkyl having 1 or 2 heteroatoms independently O, N, or S, wherein the S is optionally oxidized, wherein the CM heteroalkyl is optionally substituted with 1-3 F, or two GBtogether with the intervening atom(s) are joined to form an optionally substituted 4-7 membered heterocyclic ring,. For example, in some embodiments, R5can be an optionally substituted 5 or 6 membered heteroaryl, e.g., pyrazole, when substituted, the 5 or 6 membered heteroaryl is preferably substituted with 1-3 substituents independently (1) halogen (e.g., F, Cl), CN, OH, or NH2; (2) CM alkyl optionally substituted with F; (3) CM heteroalkyl optionally substituted with F; or (4) a 3-6 membered ring optionally substituted 1-3 substituents independently selected from oxo, F, Cl, CN, OH, CM alkyl optionally substituted with F, and C M heteroalkyl optionally substituted with F. In some embodiments, the C heteroalkyl has 1 or 2 heteroatoms independently O, N, or S, wherein the S is optionally oxidized.

[0111] In some embodiments, R5can also be L3-G2, wherein L3is O, NH, CO, C(O)NH, C(O)N(Ci-4 alkyl), SO2, SO2NH, SO2N(Ci-4 alkyl), an optionally substituted CM alkylene, an optionally substituted C2-4 alkenylene, an optionally substituted C2-4 alkynylene, or an optionally substituted CM heteroalkylene, and G2is an optionally substituted 3-14 membered ring, for example, any of the monocyclic or bicyclic heterocyclic ring as described herein.-For example, in some embodiments, R can be, wherein G7is defined herein., nIn some embodiments, R can be, wherein G is a 3-8 membered heterocyclic ring having 1-3 ring heteroatoms independently N, O, or S, wherein the sulfur atom is optionally oxidized, for example, an oxetanyl or azetidinyl ring, and the 3-8 membered heterocyclic ring is optionally substituted with one or more substituents, e.g., 1-3 substituents, each independently oxo, F, Cl, CN, OH, CM alkyl optionally substituted with F, or Ci -4 heteroalkyl optionally substituted with F.

[0112] In some specific embodiments, R5can have a structure according to any of those corresponding Rsgroups described in Table 1.

[0113] In some embodiments, the present disclosure also provides the following enumerated embodiments A 1-29:Embodiment Al. A compound of Formula I-A, or a pharmaceutically acceptable salt thereof:Formula LA, wherein:R100is hydrogen, F, CN, an optionally substituted alkyl, such as a C1-4 alkyl optionally substituted with deuterium or F (e.g., CH3, CD3, CH2F, CHF2, etc.), or an optionally substituted heteroalkyl, such as a CM heteroalkyl (e.g., CH2OCH3), optionally substituted with deuterium or F; preferably, R100is hydrogen, F, CN, or methyl optionally substituted with deuterium or F (e.g., CH3, CD3, CH2F, CHF2, etc.); andJ1, J2, J3, J4, J5, J6, J7, J8, L1, L2, and R2are defined herein.Embodiment A2. The compound of embodiment Al, or a pharmaceutically acceptable salt thereof, wherein R100is F or CN.Embodiment A3. The compound of embodiment Al or 2, or a pharmaceuticallyF acceptable salt thereof, wherein L2isO—, and R2is hydrogen, F, C1-2 alkyl optionally substituted with F (e.g., CH3, CH2F, CHF2, or CF3), CN, cyclopropyl, or C2-3 alkynyl optionally substituted with F, suchEmbodiment A4. The compound of embodiment A2, or a pharmaceutically acceptable salt thereof, wherein L2-R2isEmbodiment A5. The compound of any of embodiments A 1-4, or a pharmaceutically acceptable salt thereof, wherein J3is CR5, wherein R5is defined herein.Embodiment A6. The compound of any of embodiments A 1-4, or a pharmaceutically acceptable salt thereof, whereinwherein R4is hydrogen or halogen, preferably, R4is hydrogen, F or Cl, wherein R5is defined herein.Embodiment A7. The compound of any of embodiments A 1-4, or a pharmaceutically acceptable salt thereof, whereinwherein R5is defined herein.Embodiment A8. The compound of any of embodiments A 1-4, or a pharmaceutically acceptable salt thereof, whereinwherein R5is defined herein.Embodiment A9. The compound of any of embodiments A 1-4, or a pharmaceutically acceptable salt thereof, whereinwherein R4is hydrogen or halogen, preferably, R4is hydrogen, F or Cl, wherein R5is defined herein.Embodiment A10. The compound of any of embodiments A 1-4, or a pharmaceutically acceptable salt thereof, whereinwherein R5is defined herein.Embodiment All. The compound of any of embodiments A 1-4, or a pharmaceutically acceptable salt thereof, whereinwherein R4is hydrogen or halogen, preferably, R4is hydrogen, F or Cl, wherein R5is defined herein.Embodiment A12. The compound of any of embodiments A 1-4, or a pharmaceutically acceptable salt thereof, wherein, wherein R5is defined herein.Embodiment A13. The compound of any of embodiments Al-12, or a pharmaceutically acceptable salt thereof, wherein L1is an optionally substituted Ci-6 alkylene, an optionally substituted C2-6 alkenylene, an optionally substituted C2-6 alkynylene, or an optionally substituted 3-8 membered ring.Embodiment A14. The compound of any of embodiments Al-12, or a pharmaceutically acceptable salt thereof, wherein L1is an optionally substituted 5- membered heteroaryl ring, such as an optionally substituted ring selected from thiazole, oxazole, imidazole, oxadiazole, or thiadiazole.Embodiment A15. The compound of any of embodiments Al-12, or apharmaceutically acceptable salt thereof, wherein L1is NHEmbodiment A16. The compound of any of embodiments Al-12, or a pharmaceutically acceptable salt thereof, wherein, wherein the attaching point meta to the S atom is attached to the cyclopropyl ring in Formula I-A.Embodiment A17. The compound of any of embodiments Al-12, or a pharmaceutically acceptable salt thereof, wherein L1is an optionally substituted 6- membered heteroarylene having 1 or 2 ring nitrogens, such as an optionally substituted pyridylene or optionally substituted pyridazylene.Embodiment A18. The compound of any of embodiments Al-12, or a pharmaceutically acceptable salt thereof, wherein L1isEmbodiment A19. The compound of any of embodiments A5- 18, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted 4-12 membered heterocyclic ring having 1-4 ring heteroatoms independently selected from N, O, and S, wherein the S atom is optionally oxidized.Embodiment A20. The compound of any of embodiments A5-18, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted monocyclic 5 or 6 membered heterocyclic ring having 1 or 2 ring heteroatoms.Embodiment A21. The compound of any of embodiments A5- 18, or a pharmaceutically acceptable salt thereof, wherein R5has a structure according to F- 1 , F-2, or F-3, or R5has a structure according to F-4, F-5, F-6, F-7, F-7a, F-7b, F-8, F- 8a, F-8b, F-8c, F-8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l, F-9a-2, F-10, F-lOa, F-10a-l, F-10a-2, or F-lOb, or F-lOc, as defined herein.Embodiment A22. The compound of any of embodiments A5-18, or a pharmaceutically acceptable salt thereof, wherein Rshas a structure according to F- 1 , F-2, or F-3, wherein R11is selected from:and wherein n is 0, 1, or 2, and R10at each occurrence is independently CN, cyclopropyl,Ci-4 alkyl optionally substituted with F (e.g., CH3) or C 1-4 heteroalkyl optionally substituted with F (e.g., CH2OCH3); or R5has a structure according to F-4, F-5, F-6, F-7, F-7a, F-7b, F-8, F-8a, F-8b, F-8c, F-8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l, F-9a-2, F-10, F-lOa, F-10a-l, F-10a-2, or F-lOb, or F-lOc, wherein R11is(i) hydrogen;(ii) selected from:defined herein.Embodiment A23. The compound of any of embodiments A5-18, or a pharmaceutically acceptable salt thereof, wherein R5has a structure according to F-l, F-2, or F-3, wherein R11is an optionally substituted 5 or 6-membered heteroaryl having 2 or 3 heteroatoms each independently N, O, or S, such as optionally substituted imidazole or thiadiazole, and wherein n is 0, 1, or 2, and R10at each occurrence is independently CN, cyclopropyl, C 1-4 alkyl optionally substituted with F (e.g., CH3) or Ci -4 heteroalkyl optionally substituted with F (e.g., CH2OCH3).Embodiment A24. The compound of any of embodiments A5-18, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted 7-12 membered spiro bicyclic heterocyclic ring having 1-3 ring heteroatoms each independently N, O, and S, wherein the S atom is optionally oxidized, such as selected from:which is optionally substituted.Embodiment A25. The compound of any of embodiments A5-18, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted 7-10 membered fused bicyclic heterocyclic ring having 1-3 ring heteroatoms each independently N, O, and S, such as selected from:substituted.Embodiment A26. The compound of any of embodiments A5- 18, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted 7-10 membered bridged bicyclic heterocyclic ring having 1-3 ring heteroatoms each independently N, O, and S, such as selected from:is optionally substituted.Embodiment A27. The compound of any of embodiments A5-18, or a pharmaceutically acceptable salt thereof, wherein R5is a 5 or 6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, such as imidazole, pyrazole, thiadiazole, etc., which is optionally substituted.Embodiment A28. The compound of any of embodiments A5- 18, or a pharmaceutically acceptable salt thereof, whereinEmbodiment A29. The compound of any of embodiments A5-18, or a pharmaceutically acceptable salt thereof, wherein R5is any of the corresponding R5groups in Table 1.

[0114] In some embodiments, the present disclosure also provides the following enumerated embodiments Bl-43:Embodiment Bl. A compound of Formula I-D, or a pharmaceutically acceptable salt thereof:Formula I-D, wherein: q is 1 or 2;R101at each occurrence is independently F or methyl optionally substituted with F; or R101at each occurrence is independently F, C1-2 alkyl optionally substituted with F (e.g., CH3, CH2F, CHF2, or CF3), CN, C2-3 alkynyl optionally substituted with F, or C 1-4 heteroalkyl optionally substituted with F (e.g., CH2OCH3); andJ1, J2, J3, J4, J5, J6, J7, J8, L1, R1, and R2are defined herein.Embodiment B2. The compound of embodiment B 1 , or a pharmaceutically acceptable salt thereof, wherein R101at each occurrence is independently F or Ci-4 heteroalkyl optionally substituted with F (e.g., CH2CH2OCH3, orCFFOCFT).Embodiment B3. The compound of embodiment B 1 or 2, or a pharmaceutically acceptable salt thereof, wherein q is 1.Embodiment B4. The compound of embodiment B 1 or 2, or a pharmaceutically acceptable salt thereof, wherein q is 2.Embodiment B5. The compound of any of embodiments B 1-4, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen, F, C1-2 alkyl optionally substituted with F (e.g., CH3, CH2F, CHF2, or CF3), CN, cyclopropyl, or C2-3 alkynyl optionally substituted with F, suchEmbodiment B6. The compound of embodiment B 1 , or a pharmaceutically acceptable salt thereof, wherein the moietyEmbodiment B7. The compound of any of embodiments Bl -6, or a pharmaceutically acceptable salt thereof, wherein J3is CR5, wherein Rsis defined herein.Embodiment B8. The compound of any of embodiments B 1-6, or a pharmaceuticallywherein R4is hydrogen or halogen, preferably, R4is hydrogen, F or Cl, wherein R5is defined herein.Embodiment B9. The compound of any of embodiments B 1 -6, or a pharmaceutically acceptable salt thereof, whereinwherein Rsis defined herein.Embodiment BIO. The compound of any of embodiments B 1-6, or a pharmaceutically acceptable salt thereof, whereinwherein R5is defined herein.Embodiment Bll. The compound of any of embodiments Bl-6, or a pharmaceutically acceptable salt thereof, whereinwherein R4is hydrogen or halogen, preferably, R4is hydrogen, F or Cl, wherein R5is defined herein.Embodiment B12. The compound of any of embodiments Bl-6, or a pharmaceutically acceptable salt thereof, whereinwherein Rsis defined herein.Embodiment B13. The compound of any of embodiments B 1 -6, or a pharmaceutically acceptable salt thereof, whereinwherein R4is hydrogen or halogen, preferably, R4is hydrogen, F or Cl, wherein R5is defined herein.Embodiment B14. The compound of any of embodiments B 1 -6, or a pharmaceutically acceptable salt thereof, wherein, wherein R5is defined herein.Embodiment B15. The compound of any of embodiments Bl-14, or a pharmaceutically acceptable salt thereof, wherein L1is an optionally substituted Ci-6 alkylene, an optionally substituted C2-6 alkenylene, an optionally substituted C2-6 alkynylene, or an optionally substituted 3-8 membered ring, and R1is an optionally substituted 3-8 membered ring.Embodiment B16. The compound of embodiment B 15, or a pharmaceutically acceptable salt thereof, wherein L1is an optionally substituted 5-membered heteroaryl ring, such as an optionally substituted ring selected from thiazole, oxazole, imidazole, oxadiazole, or thiadiazole.Embodiment B17. The compound of embodiment B 15, or a pharmaceutically acceptable salt thereof, wherein L1isEmbodiment B18. The compound of embodiment B 15, or a pharmaceutically acceptable salt thereof, wherein, wherein the attaching point meta to the S atom is attached to R1.Embodiment B19. The compound of any of embodiments Bl-14, or a pharmaceutically acceptable salt thereof, wherein L1is an optionally substituted 6- membered heteroarylene having 1 or 2 ring nitrogens, such as an optionally substituted pyridylene or optionally substituted pyridazylene.Embodiment B20. The compound of embodiment B 19, or a pharmaceutically acceptable salt thereof, wherein L1isEmbodiment B21. The compound of any of embodiments B 15-20, or a pharmaceutically acceptable salt thereof, wherein R1is 3-4 membered ring, such ascyclopropyl or cyclobutyl, optionally substituted with 1 -3 substituents each independently selected from deuterium, F, OH, CN, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 heteroalkyl, wherein the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, or C1-4 heteroalkyl is optionally substituted with 1-3 substituents independently selected from F and OH.Embodiment B22. The compound of any of embodiments Bl 5-20, or a pharmaceutically acceptable salt thereof, wherein R1is an optionally substituted cyclopropyl, preferably, when substituted, the cyclopropyl is substituted with 1-3 substituents each independently selected from F, OH, CN, or C 1-2 alkyl optionally substituted with 1-3 F, more preferably, when substituted, the cyclopropyl is substituted with one or two substituents (e.g., one substituent) each independently selected from F, CN, or methyl optionally substituted with 1-3 F, for example, R1isEmbodiment B23. The compound of any of embodiments Bl- 14, or a pharmaceutically acceptable salt thereof, wherein L1is an optionally substituted 7-12 membered bicyclic ring structure; and R1is hydrogen, deuterium, halogen, CN, OH, NH2, an optionally substituted C1-4 alkyl, an optionally substituted C2-4 alkenyl, an optionally substituted C2-4 alkynyl, an optionally substituted CM heteroalkyl, or an optionally substituted 3-6 membered ring.Embodiment B24. The compound of embodiment B23, or a pharmaceutically acceptable salt thereof, wherein L1is an optionally substituted 8-10 membered fused bicyclic ring structure, which has a first and second constituent ring, wherein the first constituent ring is a 5 -membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O, and S, and the second constituent ring is an aryl, heteroaryl, carbocyclic, or heterocyclic ring.Embodiment B25. The compound of embodiment B23, or a pharmaceutically acceptable salt thereof, wherein L1is an optionally substituted 8 or 9 membered fused bicyclic heteroaryl having a first and second constituent ring, wherein the first constituent ring is a 5 -membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O, and S, and the second constituent ring is phenyl, a 5-membered heteroaryl, or a 6-membered heteroaryl.Embodiment B26. The compound of embodiment B24 or 25, or a pharmaceutically acceptable salt thereof, wherein the first constituent ring is a thiazole ring,Embodiment B27. The compound of embodiment B23, or a pharmaceutically acceptable salt thereof, wherein L1is a fused bicyclic heteroaryl having a structure ofEmbodiment B28. The compound of any of embodiments B23-27, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, deuterium, halogen (preferably F or Cl), OH, CN, C alkyl, C2-4 alkenyl, C2-4 alkynyl, or C 1-4 heteroalkyl, wherein the C1-4 alkyl, C2-4 alkenyl, C24 alkynyl, or C1-4 heteroalkyl is optionally substituted with 1-3 substituents independently selected from F and OH.Embodiment B29. The compound of any of embodiments B 1 -14, or a pharmaceutically acceptable salt thereof, wherein L1is null and R1is an optionally substituted 5-membered heteroaryl having 1-3 ring heteroatoms independently selected from S, N, and O, for example, an optionally substituted ring selected from thiazole, oxazole, imidazole, oxadiazole, or thiadiazole, or R1is an optionally substituted 6-membered heteroarylene having 1 or 2 ring nitrogens, such as an optionally substituted pyridylene or optionally substituted pyridazylene.Embodiment B30. The compound of embodiment B29, or a pharmaceutically acceptable salt thereof, wherein R1is thiazole, oxazole, imidazole, oxadiazole, or thiadiazole, each of which is optionally substituted with a C1-2 alkyl optionally substituted with F, such as CF2H, CH3, CF3, etc.Embodiment B31. The compound of embodiment B30, or a pharmaceuticallyEmbodiment B32. The compound of any of embodiments Bl -14, or a pharmaceutically acceptable salt thereof, wherein L'-R1is any of the corresponding L'-R1groups in Table 1.Embodiment B33. The compound of any of embodiments B7-32, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted 4-12 membered heterocyclic ring having 1-4 ring heteroatoms independently selected from N, O, and S, wherein the S atom is optionally oxidized.Embodiment B34. The compound of any of embodiments B7-32, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted monocyclic 5 or 6 membered heterocyclic ring having 1 or 2 ring heteroatoms.Embodiment B35. The compound of any of embodiments B7-32, or a pharmaceutically acceptable salt thereof, wherein Rshas a structure according to F- 1 , F-2, or F-3, or R5has a structure according to F-4, F-5, F-6, F-7, F-7a, F-7b, F-8, F- 8a, F-8b, F-8c, F-8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l, F-9a-2,F-10, F-lOa, F-10a-l, F-10a-2, or F-lOb, or F-lOc, as defined herein.Embodiment B36. The compound of any of embodiments B7-32, or a pharmaceutically acceptable salt thereof, wherein R5has a structure according to F- 1 , F-2, or F-3, wherein R11is selected from:and wherein n is 0, 1, or 2, and R10at each occurrence is independently CN, cyclopropyl,Ci-4 alkyl optionally substituted with F (e.g., CH3) or C 1-4 heteroalkyl optionally substituted with F (e.g., CH2OCH3); or R5has a structure according to F-4, F-5, F-6, F-7, F-7a, F-7b, F-8, F-8a, F-8b, F-8c, F- 8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l, F-9a-2, F-10, F-lOa, F-10a-l, F-10a-2, or F-lOb, or F-lOc, wherein R11is(i) hydrogen;(ii) selected from:defined herein.Embodiment B37. The compound of any of embodiments B7-32, or a pharmaceutically acceptable salt thereof, wherein R5has a structure according to F-l, F-2, or F-3, wherein R11is an optionally substituted 5 or 6-membered heteroaryl having 2 or 3 heteroatoms each independently N, O, or S, such as optionally substituted imidazole or thiadiazole, and wherein n is 0, 1, or 2, and R10at eachoccurrence is independently CN, cyclopropyl, C1-4 alkyl optionally substituted with F (e.g., CH3) or Ci -4 heteroalkyl optionally substituted with F (e.g., CH2OCH3).Embodiment B38. The compound of any of embodiments B7-32, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted 7-12 membered spiro bicyclic heterocyclic ring having 1-3 ring heteroatoms each independently N, O, and S, wherein the S atom is optionally oxidized.Embodiment B39. The compound of any of embodiments B7-32, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted 7-10 membered fused bicyclic heterocyclic ring having 1-3 ring heteroatoms each independently N, O, and S.Embodiment B40. The compound of any of embodiments B7-32, or a pharmaceutically acceptable salt thereof, wherein Rsis an optionally substituted 7-10 membered bridged bicyclic heterocyclic ring having 1-3 ring heteroatoms each independently N, O, and S.Embodiment B41. The compound of any of embodiments B7-32, or a pharmaceutically acceptable salt thereof, wherein R5is a 5 or 6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, such as imidazole, pyrazole, thiadiazole, etc., which is optionally substituted.Embodiment B42. The compound of any of embodiments B7-32, or a pharmaceutically acceptable salt thereof, whereinEmbodiment B43. The compound of any of embodiments B7-32, or a pharmaceutically acceptable salt thereof, wherein R5is any of the corresponding R5groups in Table 1.

[0115] In some embodiments, the present disclosure also provides the following enumerated embodiments Cl-26:Embodiment Cl. A compound of Formula I-B, or a pharmaceutically acceptable salt thereof:Formula I-B wherein:Ring B is an optionally substituted 5 or 6 membered heterocyclyl or heteroaryl ring having 1-3 ring heteroatoms independently N, O, or S;R1is hydrogen, deuterium, halogen, CN, OH, NH , an optionally substituted CM alkyl, an optionally substituted CM heteroalkyl, or an optionally substituted 3-6 membered ring; andJ1, J2, J3, J4, J5, J6, J7, J8, L1, L2, and R2are defined herein.Embodiment C2. The compound of embodiment C 1 , or a pharmaceutically acceptable salt thereof, wherein ring B is an optionally substituted 6-membered heteroaryl, such as an optionally substituted pyridine, for example,can have a structureEmbodiment C3. The compound of embodiment Cl, or a pharmaceutically acceptable salt thereof, wherein ring B is an optionally substituted 6-memberedheterocyclic ring, for example,can have a structurewhich is optionally substituted.Embodiment C4. The compound of any of embodiments Cl -3, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, deuterium, halogen (preferably F or Cl), OH, CN, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, or CM heteroalkyl, wherein the CM alkyl, C2-4 alkenyl, C2-4 alkynyl, or C 1-4 heteroalkyl is optionally substituted with 1-3 substituents independently selected from F and OH.Embodiment C5. The compound of embodiment C 1 , or a pharmaceutically acceptable salt thereof, whereinEmbodiment C6. The compound of any of embodiments Cl -5, or a pharmaceuticallyCH ,, CH2F, CHF2, or CF3), CN, cyclopropyl, or C2-3 alkynyl optionally substituted with F, suchEmbodiment C7. The compound of embodiment C6, or a pharmaceutically acceptable salt thereof, wherein L2-R2isEmbodiment C8. The compound of any of embodiments Cl-7, or a pharmaceutically acceptable salt thereof, wherein J3is CR5, wherein R5is defined herein.Embodiment C9. The compound of any of embodiments Cl -7, or a pharmaceutically acceptable salt thereof, whereinwherein R4is hydrogen or halogen, preferably, R4is hydrogen, F or Cl, wherein R5is defined herein.Embodiment CIO. The compound of any of embodiments Cl-7, or a pharmaceutically acceptable salt thereof, whereinwherein R5is defined herein.Embodiment Cll. The compound of any of embodiments Cl-7, or a pharmaceutically acceptable salt thereof, whereinwherein Rsis defined herein.Embodiment C12. The compound of any of embodiments Cl-7, or a pharmaceutically acceptable salt thereof, whereinwherein R4is hydrogen or halogen, preferably, R4is hydrogen, F or Cl, wherein R5is defined herein.Embodiment C13. The compound of any of embodiments Cl -7, or a pharmaceutically acceptable salt thereof, whereinwherein R5is defined herein.Embodiment C14. The compound of any of embodiments Cl -7, or a pharmaceutically acceptable salt thereof, whereinwherein R4is hydrogen or halogen, preferably, R4is hydrogen, F or Cl, wherein R5is defined herein.Embodiment C15. The compound of any of embodiments Cl -7, or a pharmaceutically acceptable salt thereof, wherein, wherein R5is defined herein.Embodiment C16. The compound of any of embodiments C8-15, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted 4-12 membered heterocyclic ring having 1-4 ring heteroatoms independently selected from N, O, and S, wherein the S atom is optionally oxidized.Embodiment C17. The compound of any of embodiments C8-15, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted monocyclic 5 or 6 membered heterocyclic ring having 1 or 2 ring heteroatoms.Embodiment C18. The compound of any of embodiments C8-15, or a pharmaceutically acceptable salt thereof, wherein R5has a structure according to F-l, F-2, or F-3, or R5has a structure according to F-4, F-5, F-6, F-7, F-7a, F-7b, F-8, F-8a, F-8b, F-8c, F-8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l , F-9a-2, F-10, F-lOa, F-10a-l, F-10a-2, or F-lOb, or F-lOc, as defined herein.Embodiment C19. The compound of any of embodiments C8-15, or a pharmaceutically acceptable salt thereof, wherein R5has a structure according to F-l, F-2, or F-3, wherein R11is selected from:and wherein n is 0, 1, or 2, and R10at each occurrence is independently CN, cyclopropyl, Ci-4 alkyl optionally substituted with F (e.g., CH3) or C1-4 heteroalkyl optionally substituted with F (e.g., CH2OCH3); or R5has a structure according to F-4, F-5, F-6, F-7, F-7a, F-7b, F-8, F-8a, F-8b, F-8c, F- 8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l, F-9a-2, F-10, F-lOa, F-10a-l, F-10a-2, or F-lOb, or F-lOc, wherein Rnis(i) hydrogen;(ii) selected from:; or(iii) selected fromwhen applicable, R10is defined herein.Embodiment C20. The compound of any of embodiments C8-15, or a pharmaceutically acceptable salt thereof, wherein R5has a structure according to F-l, F-2, or F-3, wherein R11is an optionally substituted 5 or 6-membered heteroaryl having 2 or 3 heteroatoms each independently N, O, or S, such as optionally substituted imidazole or thiadiazole, and wherein n is 0, 1, or 2, and R10at each occurrence is independently CN, cyclopropyl, Ci-4 alkyl optionally substituted with F (e.g., CH3) or Ci -4 heteroalkyl optionally substituted with F (e.g., CH2OCH3).Embodiment C21. The compound of any of embodiments C8-15, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted 7-12 membered spiro bicyclic heterocyclic ring having 1-3 ring heteroatoms each independently N, O, and S, wherein the S atom is optionally oxidized, such as selected from:which is optionally substituted.Embodiment C22. The compound of any of embodiments C8-15, or a pharmaceutically acceptable salt thereof, wherein Rsis an optionally substituted 7-10 membered fused bicyclic heterocyclic ring having 1-3 ring heteroatoms each independently N, O, and S, such as selected from:, which is optionally substituted.Embodiment C23. The compound of any of embodiments C8-15, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted 7-10 membered bridged bicyclic heterocyclic ring having 1-3 ring heteroatoms each independently N, O, and S, such as selected from:is optionally substituted.Embodiment C24. The compound of any of embodiments C8-15, or a pharmaceutically acceptable salt thereof, wherein R5is a 5 or 6 membered heteroaryl having 1 -3 ring heteroatoms independently selected from N, O, and S, such as imidazole, pyrazole, thiadiazole, etc., which is optionally substituted.Embodiment C25. The compound of any of embodiments C8-15, or a pharmaceutically acceptable salt thereof, whereinEmbodiment C26. The compound of any of embodiments C8-15, or a pharmaceutically acceptable salt thereof, wherein R5is any of the corresponding R5groups in Table 1.

[0116] In some embodiments, the present disclosure also provides the following enumerated embodiments DI -26:Embodiment DI. A compound of Formula I-X, or a pharmaceutically acceptable salt thereof:Formula I-X, wherein:R101is F, Ci-2 alkyl optionally substituted with F (e.g., CH3, CH2F, CHF2, or CF3), CN, C2-3 alkynyl optionally substituted with F, or C 1-4 heteroalkyl optionally substituted with F (e.g., CH2CH2OCH3, orCH2OCH3); andJ1, J2, J3, J4, J5, J6, J7, J8, L1, R1, and R2are defined herein.Embodiment D2. The compound of embodiment DI, or a pharmaceutically acceptable salt thereof, characterized as having a structure of Formula I-Xa:Formula I-Xa.Embodiment D3. The compound of embodiment DI or D2, or a pharmaceutically acceptable salt thereof, characterized as having a structure of Formula 1-Xb:Formula I-Xb, wherein R4and R5are defined herein.Embodiment D4. The compound of embodiment DI or D2, or a pharmaceutically acceptable salt thereof, characterized as having a structure of Formula I-Xc:Formula I-Xc, wherein R4and R5are defined herein.Embodiment D5. The compound of embodiment D3 or D4, wherein R4is hydrogen or halogen, preferably, R4is hydrogen, F or Cl.Embodiment D6. The compound of embodiment DI or D2, or a pharmaceutically acceptable salt thereof, wherein the moiety, wherein R5is defined herein.Embodiment D7. The compound of embodiment DI or D2, or a pharmaceutically acceptable salt thereof, wherein the moietywherein R5is defined herein.Embodiment D8. The compound of embodiment DI or D2, or a pharmaceutically acceptable salt thereof, wherein the moiety, wherein R4is hydrogen or halogen, preferably, R4is hydrogen, F or Cl, wherein R5is defined herein.Embodiment D9. The compound of embodiment DI or D2, or a pharmaceutically acceptable salt thereof, wherein the moiety, wherein R5is defined herein.Embodiment DIO. The compound of embodiment DI or D2, or a pharmaceuticallyCl, wherein R5is defined herein.Embodiment Dll. The compound of embodiment DI or D2, or a pharmaceutically acceptable salt thereof, wherein the moiety, wherein R5is defined herein.Embodiment D12. The compound of any of embodiments DI- 11, or a pharmaceutically acceptable salt thereof, wherein L1is an optionally substituted 5-membered heteroaryl ring, such as an optionally substituted ring selected from thiazole, oxazole, imidazole, oxadiazole, or thiadiazole.Embodiment D13. The compound of embodiment DI 2, or a pharmaceutically acceptable salt thereof, wherein L1isEmbodiment D14. The compound of embodiment D12 or D13, or a pharmaceutically acceptable salt thereof, wherein R1is an optionally substituted cyclopropyl, preferably, when substituted, the cyclopropyl is substituted with 1-3 substituents each independently selected from F, OH, CN, or C1-2 alkyl optionally substituted with 1-3 F, more preferably, when substituted, the cyclopropyl is substituted with one or two substituents (e.g., one substituent) each independently selected from F, CN, or methyl optionally substituted with 1-3 F, for example, R1is, , Embodiment D15. The compound of any of embodiments D 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein L1is null and R1is an optionally substituted 5-membered heteroaryl having 1-3 ring heteroatoms independently selected from S, N, and O, for example, an optionally substituted ring selected from thiazole, oxazole, imidazole, oxadiazole, or thiadiazole, or R1is an optionally substituted 6-membered heteroarylene having 1 or 2 ring nitrogens, such as an optionally substituted pyridylene or optionally substituted pyridazylene.Embodiment D16. The compound of embodiment DI 5, or a pharmaceutically acceptable salt thereof, wherein R1is thiazole, oxazole, imidazole, oxadiazole, or thiadiazole, each of which is optionally substituted with a C1-2 alkyl optionally substituted with F, such as CF2H, CH3, CF3, etc.Embodiment D17. The compound of embodiment DI 6, or a pharmaceutically acceptable salt thereof, whereinEmbodiment D18. The compound of any of embodiments DI -1 1 , or a pharmaceutically acceptable salt thereof, wherein L'-R1is any of the corresponding L'-R1groups in Table 1.Embodiment D19. The compound of any of embodiments D3- 18, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted 4-12 membered heterocyclic ring having 1-4 ring heteroatoms independently selected from N, O, and S, wherein the S atom is optionally oxidized.Embodiment D20. The compound of any of embodiments D3- 18, or a pharmaceutically acceptable salt thereof, wherein Rsis an optionally substituted monocyclic 5 or 6 membered heterocyclic ring having 1 or 2 ring heteroatoms.Embodiment D21. The compound of any of embodiments D3-18, or a pharmaceutically acceptable salt thereof, wherein Rshas a structure according to F-l, F-2, or F-3, or R5has a structure according to F-4, F-5, F-6, F-7, F-7a, F-7b, F-8, F- 8a, F-8b, F-8c, F-8a-R, F-8a-S, F-8b-R, F-8b-S, F-8c-R, F-8c-S, F-9, F-9a-l , F-9a-2, F-10, F-lOa, F-10a-l, F-10a-2, F-lOb, or F-lOc, as defined herein.Embodiment D22. The compound of any of embodiments D3-18, or a pharmaceutically acceptable salt thereof, wherein R5has a structure according to F- 1 , F-2, or F-3, wherein R11is selected from:and wherein n is 0, 1, or 2, and R10at each occurrence is independently CN, cyclopropyl, Ci-4 alkyl optionally substituted with F (e.g., CHp or C 1-4 heteroalkyl optionally substituted with F (e.g., CH2OCH3).Embodiment D23. The compound of any of embodiments D3-18, or a pharmaceutically acceptable salt thereof, wherein R5has a structure according to F-4, F-5, F-6, F-7, F-7a, F-7b, F-8, F-8a, F-8b, F-8c, F-8a-R, F-8a-S, F-8b-R, F-8b-S, F- 8c-R, F-8c-S, F-9, F-9a-l, F-9a-2, F-10, F-lOa, F-10a-l, F-10a-2, F-lOb, or F-lOc, wherein R11is (i) hydrogen;(ii) selected from:is defined herein.Embodiment D24. The compound of embodiments D23, or a pharmaceutically acceptable salt thereof, wherein R5has a structure according to F-lOa, preferably, F- 10a-2, preferably, R11in F-lOa or F-10a-2 is hydrogen.Embodiment D25. The compound of embodiments D23, or a pharmaceutically acceptable salt thereof, whereinEmbodiment D26. The compound of any of embodiments D3- 18, or a pharmaceutically acceptable salt thereof, wherein Rsis any of the corresponding R5groups in Table 1.

[0117] In some embodiments, the present disclosure also provides a compound selected from Table 1 below, a deuterated analog thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:Table 1. List of Compounds

[0118] In some embodiments, to the extent applicable, the genus of compounds described herein also excludes any specifically known single compounds prior to this disclosure. In some embodiments, to the extent applicable, any sub-genus or species of compounds prior to this disclosure that are entirely within a genus of compounds described herein can also be excluded from such genus herein.Method of Synthesis

[0119] The compounds of the present disclosure can be readily synthesized by those skilled in the art in view of the present disclosure. Exemplified syntheses are also shown in the Examples section.

[0120] In some embodiments, the present disclosure also provides novel synthetic intermediates described herein, e.g., those novel intermediates in the Examples section.

[0121] As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in “Protective Groups in Organic Synthesis”, 4thed. P. G. M. Wuts; T. W. Greene, John Wiley, 2007, and references cited therein. The reagents for the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (Wiley, 7thEdition), and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999), and any of available updates as of this filing.Pharmaceutical Compositions

[0122] Certain embodiments are directed to a pharmaceutical composition comprising one or more compounds of the present disclosure.

[0123] The pharmaceutical composition can optionally contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula 1-1, 1-2, 1- 3, 1-la, I-lb, Lie, L2a, L2b, I-3a, L3b, Lla-1, Lla-2, L2a-1, 1-2a-2, 1-3a-l, I-3a-2, 1-lb-1, 1- lb-2, 1-2b-l, I-2b-2, 1-3b-l, I-3b-2, 1-A, I-Al, I-A2, 1-B, LC, I-D, I-X, I-Xa, LXb, or I-Xc),any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are known in the art. Non-limiting suitable excipients include, for example, encapsulating materials or additives such as antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. See also Remington’s The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof.

[0124] The pharmaceutical composition can include any one or more of the compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, e.g., in a therapeutically effective amount. In any of the embodiments described herein, the pharmaceutical composition can comprise a therapeutically effective amount (e.g., for treating a cancer herein) of a compound selected from any of Examples 1-266, or any of the specific compounds disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof. In some preferred embodiments, the pharmaceutical composition can comprise a compound selected from the compounds according to Examples 1-266 that have an IC50 value less than 100 nM, more preferably, less than 50 nM, as measured according to Biological Example 1.

[0125] The pharmaceutical composition herein can be formulated for delivery via any of the known routes of delivery, which include but not limited to administering orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally or parenterally.

[0126] In some embodiments, the pharmaceutical composition can be formulated for oral administration. The oral formulations can be presented in discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients for the preparationof compositions for oral administration are known in the art. Non-limiting suitable excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, com starch, com oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer’s solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0127] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (such as intravenous injection or infusion, subcutaneous or intramuscular injection). The parenteral formulations can be, for example, an aqueous solution, a suspension, or an emulsion. Excipients for the preparation of parenteral formulations are known in the art. Non-limiting suitable excipients include, for example, 1,3- butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.

[0128] Compounds of the present disclosure can be used alone, in combination with each other, or in combination with one or more additional therapeutic agents, e.g., in combination with an additional anticancer therapeutic agent, such as a chemotherapeutic agent described herein, or those chemotherapeutic agents described in WO2023 / 057389, WO2021 / 055744, and WO2023 / 057394.

[0129] When used in combination with one or more additional therapeutic agents, compounds of the present disclosure or pharmaceutical compositions herein can be administered to the subject either concurrently or sequentially in any order with such additional therapeutic agents. In some embodiments, the pharmaceutical composition can comprise one or more compounds of the present disclosure and the one or more additional therapeutic agents in a single composition. In some embodiments, the pharmaceutical composition comprising one or more compounds of the present disclosure can be included ina kit which also comprises a separate pharmaceutical composition comprising the one or more additional therapeutic agents.

[0130] The pharmaceutical composition can include various amounts of the compounds of the present disclosure, depending on various factors such as the intended use and potency and selectivity of the compounds. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present disclosure and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound of the present disclosure is an amount effective to treat a disease or disorder as described herein, such as a cancer herein, which can depend on the recipient of the treatment, the disorder, condition or disease being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered.Method of Treatment / Use

[0131] Compounds of the present disclosure have various utilities. For example, compounds of the present disclosure can be used as therapeutic active substances for the treatment and / or prophylaxis of a disease or disorder in which PARG activity is implicated. Accordingly, some embodiments of the present disclosure are also directed to methods of using one or more compounds of the present disclosure or pharmaceutical compositions herein for treating or preventing a disease or disorder in which PARG activity is implicated in a subject in need thereof, such as for treating cancer in a subject in need thereof.

[0132] In some embodiments, the present disclosure provides a method of inhibiting PARG enzyme activity in a cell, the method comprising contacting the cell with an effective amount of the compound of present disclosure (e.g., a compound of Formula I (e.g., Formula 1-1, 1-2, 1-3, 1-la, I- lb, I-lc, I-2a, I-2b, I-3a, I-3b, I-la-1, 1-la-2, 1-2a-l, I-2a-2, 1-3a-l, I-3a-2, I-lb-1, 1-lb-2, 1-2b-l, I-2b-2, 1-3b-l, I-3b-2, 1-A, I-Al, I-A2, 1-B, I-C, I-D, I-X, I-Xa, I-Xb, or I-Xc), any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof). In some embodiment, contacting the cell occurs in vitro. In some embodiment, contacting the cell occurs in vivo. In some embodiments, the method selectively inhibits PARG enzyme activity over PARP1 or ARH3 enzyme activity.

[0133] In some embodiments, the present disclosure provides a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting the cell with an effectiveamount of the compound of present disclosure (e.g., a compound of Formula I (e.g., Formula 1-1, 1-2, 1-3, 1-la, Lib, I-lc, L2a, L2b, L3a, I-3b, I-la-1, Lla-2, L2a-1, 1-2a-2, 1-3a-l, I-3a-2, Llb-1, 1-lb-2, 1-2b-l, L2b-2, L3b-1, 1-3b-2, 1-A, LAI, LA2, 1-B, LC, LD, I-X, LXa, I-Xb, or LXc), any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof).

[0134] In some embodiments, the present disclosure provides a method of treating a disease or disorder in which PARG activity is implicated in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of present disclosure (e.g., a compound of Formula I (e.g., Formula 1-1, 1-2, 1-3, 1- la, Lib, I-lc, L2a, L2b, L3a, L3b, Lla-1, Lla-2, L2a-1, L2a-2, L3a-1, L3a-2, Llb-1, 1-lb- 2, L2b-1, L2b-2, L3b-1, L3b-2, LA, LAI, LA2, LB, LC, LD, LX, LXa, I-Xb, or LXc), any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition as defined herein. In some embodiments, the disease or disorder in which PARG activity is implicated is a proliferative disorder described herein. In some embodiments, the disease or disorder in which PARG activity is implicated is a cancer described herein. In some embodiments, the cancer can be selected from ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, lung cancer (such as small cell lung carcinoma (SCLC)), colorectal cancer, melanoma, sarcoma, and gastric cancer.

[0135] In some embodiments, the present disclosure provides a method of treating a proliferative disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of present disclosure (e.g., a compound of Formula I (e.g., Formula 1-1, 1-2, 1-3, Lla, Lib, Lie, L2a, L2b, L3a, L3b, Lla- 1, Lla-2, L2a-1, L2a-2, L3a-1, L3a-2, Llb-1, Llb-2, L2b-1, L2b-2, L3b-1, L3b-2, LA, I- Al, LA2, LB, LC, LD, LX, LXa, I-Xb, or LXc), any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition as defined herein. Examples of proliferative conditions include, but are not limited to, pre- malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumours, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin.

[0136] Preferably, the proliferative disorder is cancer. Thus, in some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of present disclosure (e.g., a compound of Formula I (e.g., Formula 1-1, 1-2, 1-3, 1- la, Lib, Lie, I-2a, I-2b, I-3a, L3b, I-la-1, 1-la-2, 1-2a-l, I-2a-2, L3a-1, I-3a-2, Lib- 1, 1-lb- 2, 1-2b-l, L2b-2, 1-3b- 1, 1-3b-2, 1-A, LAI, LA2, LB, LC, LD, LX, I-Xa, I-Xb, or LXc), any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition as defined herein. In some embodiments, the cancer can be selected from ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, lung cancer (such as small cell lung carcinoma (SCLC)), colorectal cancer, melanoma, sarcoma, and gastric cancer. In a particular embodiment, the cancer is human cancer.

[0137] Compounds of the present disclosure can be used in the methods herein as a monotherapy or in a combination therapy. For example, in some embodiments, the compound of the present disclosure may be used in combination with conventional surgery or radiotherapy or chemotherapy. In some embodiments, such chemotherapy may include one or more of the following anti-tumour agents, (i) antiproliferative / antineoplastic drugs and combinations thereof, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracy clines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5oc-reductase such as finasteride; (iii) anti-invasion agents [for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin- 1 -yl)ethoxy]-5- tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341 ), N-(2-chloro-6- methylphenyl)-2-{6-[4-(2- hydroxyethyl)piperazin-l -yl]-2- methylpyrimidin-4-ylamino} thiazole- 5 -carboxamide (dasatinib, BMS- 354825; J. Med. Chem., 2004, 47, 6658-6661 ) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase]; (iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB 1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stem et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, ppll -29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro- 4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)-quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (for example Ras / Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifamib (R1 15777) and lonafarnib (SCH66336)), inhibitors of cell signalling through MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZDI 152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors; (v) anti angiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU1 1248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5- yloxy)-6- methoxy-7-(3-pyrrolidin-l - ylpropoxy)quinazoline (AZD2171 ; Example 240 within WO00 / 47212), compounds such as those disclosed in International Patent Applications W097 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin (Xvp3 function and angiostatin)]; (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213; (vii) an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan; (viii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; (ix) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi - drug resistance gene therapy; and (x) immunotherapy approaches, including for example ex- vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine- transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies. Agents that may be combined with a PARG inhibitor also include those described in WO2023 / 057389, WO2021 / 055744, and WO2023 / 057394.

[0138] As understood herein, the term "combination" refers to simultaneous, separate or sequential administration. In one aspect of the invention "combination" refers to simultaneous administration. In another aspect of the invention "combination" refers to separate administration. In a further aspect of the invention "combination" refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0139] Dosing regimen including doses for the methods described herein can vary and be adjusted, which can depend on the recipient of the treatment, the disorder, condition or disease being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered.Definitions

[0140] It is meant to be understood that proper valences are maintained for all moieties and combinations thereof.

[0141] It is also meant to be understood that a specific embodiment of a variable moiety herein can be the same or different as another specific embodiment having the same identifier.

[0142] Suitable groups for the variables in compounds of Formula I, or a subformula thereof, as applicable, are independently selected. Non-limiting useful groups for the variables in compounds of Formula I, or a subformula thereof, as applicable, include any of the respective groups, individually or in any combination, as shown in the Examples or in the specific compounds described in Table 1 herein. In addition, it is to be understood that the definition of a variable in Formula I can have the same definition for the variable defined in a subformula of Formula I. Similarly, unless otherwise specified or contrary from context, the definition of a variable in a subformula of Formula I can have the same definition for the variable defined in connection with Formula I or another subformula of Formula I.

[0143] The described embodiments of the present disclosure can be combined. Such combination is contemplated and within the scope of the present disclosure. For example, it is contemplated that the definition(s) of any one or more of J1, J2, J3, J4, J5, J6, J7, J8, L1, L2, R1, and R2of Formula I can be combined with the definition of any one or more of the other(s) of J1, J2, J3, J4, J5, J6, J7, J8, L1, L2, R1, and R2, as applicable, and the resulted compounds from the combination are within the scope of the present disclosure.

[0144] The symbol, -~w. when displayed perpendicular to (or otherwise crossing) a bond, indicates the point at which the displayed moiety is attached to the remainder of the molecule. It should be noted that for a divalent structure (or multivalent structure), the immediately connected group or groups or appropriate variable(s) shown in a formula may be shown in the divalent structure (or multivalent structure) beyond the symbol, to indicate direction of attachment. When the immediately connected group(s) or variable is not shown for either of the two attaching points of a divalent structure, it should mean that either direction of attachment to the remainder of the molecule is allowed, unless otherwise specified or obviously contrary from context.

[0145] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry’, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modem Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987. The disclosure is not intended to be limited in any manner by the exemplary listing of substituents described herein.

[0146] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC), chiral supercritical fluid chromatograph (SFC), and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al. , Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et cd., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers including racemic mixtures. When a stereochemistry is specifically drawn, unless otherwise contradictory from context, it should be understood that with respect to that particular chiral center or axial chirality, the compound can exist predominantly as the as-drawn stereoisomer, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer(s), for example, the compound can have an enantiomeric excess of greater than 60%, greater than 80%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%. The presence and / or amounts of stereoisomers can bedetermined by those skilled in the art in view of the present disclosure, including through the use of a chiral HPLC or chiral SFC. As understood by those skilled in the art, when a is shown in the chemical structures herein, unless otherwise contradictory from context, it is to designate that the corresponding chiral center is enantiomerically pure or enriched in either of the configurations or is enantiomerically pure or enriched in the as-dawn configuration, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer(s). Also, when no stereochemistry is specifically drawn, and no is used in the chemical structures, unless otherwise contradictory from context, it should be understood that such structures include the corresponding compound in any stereoisomeric forms, including individual isomers substantially free of other isomers and mixtures of various isomers including racemic mixtures.

[0147] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example “Ci-e” is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-6, C1-5, Ci^t, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6.

[0148] As used herein, the term “compound(s) of the present disclosure” refers to any of the compounds described herein according to Formula I (e.g., I- 1, 1-2, 1-3, 1-la, Lib, Lie, I- 2a, L2b, L3a, L3b, Lla-1, Lla-2, L2a-1, L2a-2, L3a-1, L3a-2, Llb-1, Llb-2, L2b-1, L2b-2, L3b-1, L3b-2, LA, LAI, LA2, LB, LC, LD, LX, I-Xa, I-Xb, or I-Xc), any of Examples 1- 266, or any of the specific compounds disclosed in Table 1 herein, isotopically labeled compound(s) thereof (such as a deuterated analog wherein one or more of the hydrogen atoms is / are substituted with a deuterium atom with an abundance above its natural abundance, e.g., a CD3 analog when the compound has a CH3 group), possible regioisomers, possible geometric isomers, possible stereoisomers thereof (including diastereoisomers, enantiomers, and racemic mixtures), tautomers thereof, conformational isomers thereof, pharmaceutically acceptable esters thereof, and / or possible pharmaceutically acceptable salts thereof (e.g., acid addition salt such as HC1 salt or base addition salt such as Na salt). In some embodiments, the compounds of the present disclosure can be selected from any of the enumerated embodiments A 1-29. In some embodiments, the compounds of the present disclosure can be selected from any of the enumerated embodiments Bl-43. In some embodiments, the compounds of the present disclosure can be selected from any of the enumerated embodiments Cl-26. In some embodiments, the compounds of the presentdisclosure can be selected from any of the enumerated embodiments DI -26. Hydrates and solvates of the compounds of the present disclosure are considered compositions of the present disclosure, wherein the compound(s) is in association with water or solvent, respectively.

[0149] Compounds of the present disclosure can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to2H,3H,13C,14C,15N,180,32P, 35S,18F,36C1, and125I. Compounds that contain other isotopes of these and / or other atoms are within the scope of this invention.

[0150] As used herein, the phrase “administration” of a compound, “administering” a compound, or other variants thereof means providing the compound or a prodrug of the compound to the individual in need of treatment.

[0151] As used herein, the term "alkyl" as used by itself or as part of another group refers to a straight- or branched-chain aliphatic saturated hydrocarbon. In some embodiments, the alkyl can include one to twelve carbon atoms (i.e., C1-12 alkyl) or the number of carbon atoms designated. In one embodiment, the alkyl group is a straight chain C1-10 alkyl group. In another embodiment, the alkyl group is a branched chain C3-10 alkyl group. In another embodiment, the alkyl group is a straight chain C1-6 alkyl group. In another embodiment, the alkyl group is a branched chain C3-6 alkyl group. In another embodiment, the alkyl group is a straight chain CM alkyl group. For example, a C1-4 alkyl group includes methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and iso-butyl. As used herein, the term "alkylene" as used by itself or as part of another group refers to a divalent radical derived from an alkyl group. For example, non-limiting straight chain alkylene groups include -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, and the like.

[0152] As used herein, the term "alkenyl" as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one or more, for example, one, two or three carbon-to-carbon double bonds. In one embodiment, the alkenyl group is a C2-6 alkenyl group. In another embodiment, the alkenyl group is a C2-4 alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0153] As used herein, the term "alkynyl" as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one or more, for example, one to three carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-carbon triple bond. In one embodiment, the alkynyl group is a C2-6 alkynyl group. In another embodiment, the alkynyl group is a C2-4 alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0154] As used herein, the term "alkoxy" as used by itself or as part of another group refers to a radical of the formula ORal, wherein Ralis an alkyl.

[0155] As used herein, the term "cycloalkoxy" as used by itself or as part of another group refers to a radical of the formula ORal, wherein Ralis a cycloalkyl.

[0156] As used herein, the term "haloalkyl" as used by itself or as part of another group refers to an alkyl substituted with one or more fluorine, chlorine, bromine and / or iodine atoms. In preferred embodiments, the haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, the haloalkyl group is a Ci-10 haloalkyl group. In one embodiment, the haloalkyl group is a C1-6 haloalkyl group. In one embodiment, the haloalkyl group is a C1-4 haloalkyl group.

[0157] As used herein, the term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched-chain alkyl group, e.g., having from 2 to 14 carbons, such as 2 to 10 carbons in the chain, in which one or more of the carbons has been replaced by a heteroatom selected from S, O, P and N, and wherein the nitrogen, phosphine, and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom(s) S, O. P and N may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. When the heteroalkyl is said to be substituted, the substituent(s) can replace one or more hydrogen atoms attached to the carbon atom(s) and / or the heteroatom(s) of the heteroalkyl. In some embodiments, the heteroalkyl is a C 1-4 heteroalkyl, which refers to the heteroalkyl defined herein having 1-4 carbon atoms. Examples of C1-4 heteroalkyl include, but are not limited to, C4 heteroalkyl such as -C^-CHi-NfCHq-CHi, C3 heteroalkyl such as -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2- S(O)-CH3, -CH2-CH2-S(O)2-CH3, C2heteroalkyl such as -CH2-CH2-OH, -CH2-CH2-NH2, - CH2-NH(CH3), -O-CH2-CH3 and Ci heteroalkyl such as, -CH2-OH, -CH2-NH2, -O-CH3. Preferably, the C1-4 heteroalkyl (or CM heteroalkylene) herein contains 1 or 2 heteroatoms,such as one oxygen, one nitrogen, two oxygens, two nitrogens, or one oxygen and one nitrogen. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2- CH2-O-CH2-CH2- and -O-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R or the like.

[0158] In some preferred embodiments, unless otherwise specified or contrary from context, a C1-6 heteroalkyl herein can be a C1-6 alkoxy, NH(CI-6 alkyl), N(CM alkyl)(Ci-4 alkyl), -(C1-5 alkylene)-O-(Ci-5 alkyl), -(C1-5 alkylene)-NH(Ci-5 alkyl), -(C 1-4 alkylene) -N(C 1-4 alkyl)(Ci-4alkyl), -(C1-5 alkylene)-S-(Ci-5alkyl), -(C1-5 alkylene)-SO2-(Ci-5alkyl), SO2(Ci-6alkyl), P(0)(CM alkyI)(Ci-4 alkyl), SO2NH(CI-6 alkyl), S02N(C alkyl)(Cw alkyl), -(C1-5 alkylene)-SO2NH-(Ci-5 alkyl), or -(C alkylene)-S02N(Ci4 alkyl )(C alkyl), provided that the total number of carbons are no greater than 6, not counting any optional substituents.

[0159] In some preferred embodiments, unless otherwise specified or contrary from context, a CM heteroalkyl herein can be a C alkoxy, NH(C alkyl), N(Ci-3 alkyl) (C 1-3 alkyl), -(C1-3 alkylene)-O-(Ci-3 alkyl), -(Ci-3 alkylene)-NH(Ci-3 alkyl), -(C1-2 alkylene) -N(C 1-2 alkyl)(Ci-2 alkyl), -(C1-3 alkylene)-S-(Ci-3 alkyl), -(C1-3 alkylene)-SO2-(Ci-3 alkyl), S02(CM alkyl), P(O)(Ci-3alkyl)(Ci-3alkyl), SO2NH(CM alkyl), SO2N(Ci-3alkyl)(Ci-3alkyl), -(C1.3 alkylene)-SO2NH-(Ci-3 alkyl), or -(C1-2 alkylene)-SO2N(Ci-2 alkyl)(Ci-2 alkyl), provided that the total number of carbons are no greater than 4, not counting any optional substituents.

[0160] “Carbocyclyl” or “carbocyclic” as used by itself or as part of another group refers to a radical of a non-aromatic cyclic hydrocarbon group having at least 3 carbon atoms, e.g., from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”), and zero heteroatoms in the non- aromatic ring system. The carbocyclyl group can be either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. Non-limitingexemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbomyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl. As used herein, the term "carbocyclylene" as used by itself or as part of another group refers to a divalent radical derived from the carbocyclyl group defined herein.

[0161] In some embodiments, “carbocyclyl” is fully saturated, which is also referred to as cycloalkyl. In some embodiments, the cycloalkyl can have from 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In preferred embodiments, the cycloalkyl is a monocyclic ring. As used herein, the term "cycloalkylene" as used by itself or as part of another group refers to a divalent radical derived from a cycloalkyl group, for example,, etc.

[0162] Unless otherwise defined or contrary from context, a heteroatom herein refers to an atom selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon.

[0163] “Heterocyclyl” or “heterocyclic” as used by itself or as part of another group refers to a radical of a 3-membered or larger, such as 3- to 14-membered, non-aromatic ring system having ring carbon atoms and at least one ring heteroatom, such as 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system, such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings, and the point of attachment can be on any ring. As used herein, the term "heterocyclylene" as used by itself or as part of another group refers to a divalent radical derived from the heterocyclyl group defined herein. The heterocyclyl or heterocylylene can be optionally linked to the rest of the molecule through a carbon or nitrogen atom.

[0164] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydro furanyl, dihydrofuranyl, tetrahydrothiophenyl, dihydro thiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclylgroups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7- membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5- membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0165] “Aryl” as used by itself or as part of another group refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2- naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“CM aryl”; e.g., anthracyl). As used herein, the term "arylene" as used by itself or as part of another group refers to a divalent radical derived from the aryl group defined herein.

[0166] “Aralkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more aryl groups, preferably, substituted with one aryl group. Examples of aralkyl include benzyl, phenethyl, etc. When an aralkyl is said to be optionally substituted, either the alkyl portion or the aryl portion of the aralkyl can be optionally substituted.

[0167] “Heteroaryl” as used by itself or as part of another group refers to a radical of a 5- 14 membered monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and at least one, preferably,1-4, ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. In bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g. , indolyl, quinolinyl, and the like), the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). As used herein, the term "heteroarylene" as used by itself or as part of another group refers to a divalent radical derived from the heteroaryl group defined herein.

[0168] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0169] “Heteroaralkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more heteroaryl groups, preferably, substituted with one heteroaryl group. When a heteroaralkyl is said to be optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl can be optionally substituted.

[0170] As used herein, unless specified or otherwise contrary, a "ring structure", "cyclic structure", or simply "ring", with a designated number of ring members, such as a "3-10 membered ring structure", a "3-12 membered ring structure", or a "5- or 6-membered ring", should be understood as encompassing any ring structure (e.g., carbocyclic, heterocyclic, aryl, heteroaryl, etc.) having the designated number of ring members, which can be (1) monocyclic or polycyclic (as chemically feasible), such as a monocyclic ring or a bicyclic ring (including fused, spiro, and bridged bicyclic ring, and those ring systems where two monocyclic rings are connected through a single or double bond); (2) aromatic, partially unsaturated, or fully saturated; and in the case of a polycyclic structure, each ring can be independently aromatic, partially unsaturated, or fully saturated; and (3) containing no heteroatom (i.e., all ring members are carbon atoms) or 1-4 heteroatoms; or in the case of a polycyclic structure, each ring can independently have no ring heteroatom or 1-4 ring heteroatoms (e.g., O, N, S, etc.). When a ring is said to contain a ring sulfur or nitrogen atom, the sulfur or nitrogen atom can he optionally oxidized. One or more ring carbon atoms in a ring structure can be present as C(=O). A fully saturated ring refers to a ring in which none of the ring carbon atom(s) and any present ring heteroatom(s) (e.g., nitrogen) forms a double bond or triple bond with any other atom. The ring structure can be optionally substituted with one or more substituents described herein. The substituents of a ring structure herein can also have a cyclic structure, and in some cases, two substituents of a ring structure may be said to be joined to form a cyclic structure.

[0171] As commonly understood in the art, for clarity, when a structure can be characterized in multiple ways, as long as one such characterization falls within the scope of the definition of a variable herein, it can be said that the structure is a suitable definition for the variable. For example, when a monovalent variable is defined as an optionally substituted6-membered ring, the variable encompasses, among other structures, (a) the structure ofwhich can be viewed as a 6-membered monocyclic or bicyclic ring substituted with a phenyl group; and (b) the structure of, which can beviewed as a 6-membered ring, wherein two substituents are joined to form a cyclopropyl ring; but the variable would not encompassbecause the attaching ring is not a 6- membered ring under any characterization of the structure. To further explain, when the variable is instead defined as an optionally substituted monocyclic 6-membered ring, then theX variable does not encompass, but encompasses the structure of -wlvv . And if the variable is defined as a 6-membered ring optionally substituted with halogen, then the variable can encompass structures such as,as each of which can be viewed as a 6-membered ring that is unsubstituted or substituted with 1 or two fluorine atoms.

[0172] As commonly understood in the art, alkylene, alkenylene, alkynylene, heteroalkylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene refer to the corresponding divalent radicals of alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, respectively.

[0173] An “optionally substituted” group, such as an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refers to the respective group that is unsubstituted or substituted. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwiseindicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent can be the same or different at each position. Typically, when substituted, the optionally substituted groups herein can be substituted with 1-5 substituents. Substituents can be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent or a sulfur atom substituent, as applicable, each of which can be optionally isotopically labeled, such as deuterated. Two of the optional substituents can join to form a ring structure, such as an optionally substituted cycloalkyl, heterocylyl, aryl, or heteroaryl ring. Substitution can occur on any available carbon, oxygen, or nitrogen atom, and can form a spirocycle. Typically, substitution herein does not result in an O-O, 0-N, S-S, S-N (except SO2-N bond), heteroatom-halogen, or -C(O)-S bond or three or more consecutive heteroatoms, with the exception of O-SO2-O, O-SO2-N, and N-SO2-N, except that some of such bonds or connections may be allowed if in a stable aromatic system.

[0174] In a broad aspect, the permissible substituents herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a cycloalkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, an aryl, or a heteroaryl, each of which can be substituted, if appropriate.

[0175] Exemplary substituents include, but not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, - alkynylene-heteroaryl, — OH, hydroxyalkyl, haloalkyl, — O-alkyl, — O-haloalkyl, -alkylene- O-alkyl, — O-aryl, — O-alkylene-aryl, — O-heteroaryl, — O-alkylene-heteroaryl, — O- cycloalkyl, — O-heterocycloalkyl, acyl, — C(O)-alkyl, — C(O)-haloalkyl, — C(O)-aryl, — C(O)-alkylene-aryl, — C(O)-heteroaryl, — C(O)-alkylene-heteroaryl, — C(O)-cycloalkyl, —C(O)-heterocycloalkyl, halo, — NO2, — CN, — SF5, — C(O)OH, — C(O)O-alkyl, — C(0)0- aryl, —C(0)0— alkylene-aryl, — S(O)-alkyl, — S(O)2-alkyl, — S(O)-haloalkyl, — S(0)2- haloalkyl, — S(O)-aryl, — S(O)2-aryl, — S(O)-heteroaryl, — S(O)2-heteroaryl, — S-alkyl, — S- aryl, — S-heteroaryl, — S-alkylene-aryl, — S-alkylene-heteroaryl, — S(O)2-alkylene-aryl, — S(O)2-alkylene-heteroaryl, — S-cycloalkyl, — S-heterocycloalkyl, — S(O)-cycloalkyl, — S(O)-heterocycloalkyl, — S(O)2-cycloalkyl, — S(O)2-heterocycloalkyl, — S(O)(=NH)-alkyl, — S(O)(=NH)-haloalkyl, — S(O)(=NH)-aryl, — S(O)(=NH)-alkylene-aryl, — S(O)(=NH)- heteroaryl, — S(O)(=NH)-alkylene-heteroaryl, — S(O)(=NH)-cycloalkyl, — S(O)(=NH)- heterocycloalkyl, — S(O)(=Nalkyl)-alkyl, — S(O)(=Nalkyl)-haloalkyl, — S(O)(=Nalkyl)- aryl, — S(O)(=Nalkyl)-alkylene-aryl, — S(O)(=Nalkyl)-heteroaryl, — S(O)(=Nalkyl)- alkylene-heteroaryl, — S(O)(=Nalkyl)-cycloalkyl, — S(O)(=N alkyl) -heterocycloalkyl, cycloalkyl, heterocycloalkyl, — O — C(O)-alkyl, — O — C(O)-aryl, — O — C(O)-cycloalkyl, — C(=N— CN)— NH2, — C(=NH)— NH2, — C(=NH)— NH(alkyl), — N(Yi)(Y2), -alkylene- N(YI)(Y2), — C(O)N(Y I)(Y2) and — S(O)2N(YI)(Y2), wherein Y 1 and Y2can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, -alkylene-aryl, heteroaryl, -alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, and Y1 and Y2 with the nitrogen they linked can form a heterocyclic ring.

[0176] Some examples of suitable substituents include, but not limited to, (Ci-C8)alkyl groups, (C2-C8)alkenyl groups, (C2-C8)alkynyl groups, (C3-Cio)cycloalkyl groups, halogen (F, Cl, Br or I), halogenated (Ci-C8)alkyl groups (for example but not limited to — CF3), — O— (Ci-Cs)alkyl groups, —OH, — S— (Ci-Cs)alkyl groups, — SH, — NH(Ci-C8)alkyl groups, — N((Ci-Cs)alkyl)2groups, — NH2, — C(O)NH2, — C(O)NH(Ci-C8)alkyl groups, — C(O)N((Ci-C8)alkyl)2, — NHC(O)H, — NHC(O) (Ci-Cs)alkyl groups, — NHC(O) (C3- C8)cycloalkyl groups, — N((Ci-C8)alkyl)C(O)H, — N((Ci-C8)alkyl)C(O)(Ci-C8)alkyl groups, — NHC(O)NH2, — NHC(O)NH(Ci-C8)alkyl groups, — N((Ci-C8)alkyl)C(O)NH2groups, — NHC(O)N((Ci-C8)alkyl)2groups, — N((Ci-C8)alkyl)C(O)N((Ci-C8)alkyl)2groups, — N((Ci- C8)alkyl)C(O)NH((Ci-C8)alkyl), — C(O)H, — C(O)(Ci-C8)alkyl groups, — CN, — NO2, — S(O)(Ci-C8)alkyl groups, — S(O)2(Ci-C8)alkyl groups, — S(O)2N((Ci-C8)alkyl)2 groups, — S(O)2NH(Ci-C8)alkyl groups, — S(O)2NH(C3-C8)cycloalkyl groups, — S(O)2NH2groups, — NHS(O)2(Ci-C8)alkyl groups, — N((Ci-C8)alkyl)S(O)2(Ci-C8)alkyl groups, — (Ci-Cs)alkyl- O — (Ci-Cs)alkyl groups, — O — (Ci-C8)alkyl-0 — (Ci-C8)alkyl groups, — C(O)OH, —C(O)O(Ci-Cs)alkyl groups, NHOH, NHO(Ci-Cs)alkyl groups, — O-halogenated (Ci-Cs)alkyl groups (for example but not limited to — OCF3), — S(O)2-halogenated (Ci-Cs)alkyl groups (for example but not limited to — S(O)2CF3), — S -halogenated (Ci-Cs)alkyl groups (for example but not limited to — SCF3), — (Ci-Ce) heterocycle (for example but not limited to pyrrolidine, tetrahydrofuran, pyran or morpholine), — (Ci-Ce) heteroaryl (for example but not limited to tetrazole, imidazole, furan, pyrazine or pyrazole), -phenyl, — NHC(O)O — (Ci- Ce)alkyl groups, — N((Ci-C6)alkyl)C(O)O — (Ci-Ce)alkyl groups, — C( — NH) — (Ci-Ce)alkyl groups, — C( — NOH) — (Ci-C6)alkyl groups, or — C( — N — O — (Ci-C6)alkyl)-(Ci-C6)alkyl groups.

[0177] Exemplary carbon atom substituents include, but are not limited to, deuterium, halogen, -CN, -NO2, -N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkyl amino, dialkyl amino, amide, sulfonamide, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, etc. For example, exemplary carbon atom substituents can include F, Cl, -CN, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -NH2, -N(CI-6 alkyl)2, -NH(CI-6alkyl), -SH, -SCi_6alkyl, -C(=O)(Ci_6alkyl), -CO2H, -CO2(Ci_6alkyl), -OC(=O)(Ci-6 alkyl), -OCO2(Ci-6alkyl), -C(=O)NH2, -C(=O)N(CI-6alkyl)2, -OC(=O)NH(CI-6alkyl), - NHC(=O)(CI-6alkyl), -N(CI-6alkyl)C(=O)( Ci-6alkyl), -NHCO2(CI-6alkyl), - NHC(=O)N(CI-6 alkyl)2, -NHC(=O)NH(CI-6alkyl), -NHC(=O)NH2, -NHSO2(CI-6alkyl), - SO2N(Ci-6 alkyl)2, -SO2NH(CI_6alkyl), -SO2NH2,-SO2CI^ alkyl, -SO2OC-6 alkyl, - OSO2C1-6 alkyl, -SOC1-6 alkyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal substituents can be joined to form =0.

[0178] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, acyl groups, esters, sulfone, sulfoxide, Ci-10 alkyl, Ci-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two substituent groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein. In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as anamino protecting group). Nitrogen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated by reference herein. Exemplary nitrogen protecting groups include, but not limited to, those forming carbamates, such as Carbobenzyloxy (Cbz) group, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, tertButyloxycarbonyl (BOC) group, Troc, 9-Fluorenylmethyloxycarbonyl (Fmoc) group, etc., those forming an amide, such as acetyl, benzoyl, etc., those forming a benzylic amine, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, etc., those forming a sulfonamide, such as tosyl, Nosyl, etc., and others such as p-methoxyphenyl.

[0179] Exemplary oxygen atom substituents include, but are not limited to, acyl groups, esters, sulfonates, Ci-io alkyl, Ci-io haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein. In certain embodiments, the oxygen atom substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, those forming alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyls such as 4-methoxybenzyl, methoxylmethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), etc., those forming silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t- butyldimethylsilyl (TBDMS), etc., those forming acetals or ketals, such as tetrahydropyranyl (THP), those forming esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxy acetate, etc., those forming carbonates or sulfonates such as methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts), etc.

[0180] Unless expressly stated to the contrary, combinations of substituents and / or variables are allowable only if such combinations are chemically allowed and result in a stable compound. A “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).

[0181] Unless otherwise specified or contrary from context, the optionally substituted groups as referred to herein can be (A) unsubstituted; (B) substituted with one or more substituents each independently deuterium, halogen, CN, or Q’-Q2-Q3-Q4, wherein Q1, Q2, and Q3are each independently null, O, NQ4, C(O), S, SO, SO2, S(O)(=NQ4), CM alkylene optionally substituted with deuterium, F, and / or OH, or P(O)Q4, wherein Q4at each occurrence is independently hydrogen, C1-6 alkyl optionally substituted with one or more Q10, C2-6 alkenyl optionally substituted with one or more Q10, C2-6 alkynyl optionally substituted with one or more Q10, C1-6 heteroalkyl optionally substituted with one or more Q10, or 3-14 membered ring optionally substituted with one or more Q10, wherein Q10at each occurrence is independently deuterium, halogen, oxo (as applicable), CN, or Q20-Q21-Q22-Q23, wherein Q20, Q21, and Q22are each independently null, O, NQ23, C(O), S, SO, SO2, S(O)(=NQ23), C1-4 alkylene optionally substituted with deuterium, F, and / or OH, or P(O)Q23, wherein Q23at each occurrence is independently hydrogen, C1-6 alkyl optionally substituted with one or more Q30, C2-6 alkenyl optionally substituted with one or more Q30, C2-6 alkynyl optionally substituted with one or more Q30, C1-6 heteroalkyl optionally substituted with one or more Q30, or 3-8 membered ring optionally substituted with one or more Q30, wherein Q30at each occurrence is independently deuterium, halogen, oxo (as applicable), CN, OH, NH2, C1-4 alkyl optionally substituted with one or more Q31, C1-4 heteroalkyl optionally substituted with one or more Q31, or 3-5 membered ring optionally substituted with one or more Q31, wherein Q31at each occurrence is independently deuterium, F, OH, C1-4 alkyl optionally substituted with deuterium and / or F, or C1-4 heteroalkyl optionally substituted with deuterium and / or F; or (C) two or more substituents of the respective optionally substituted group, and / or one of the substituents of the respective optionally substituted group and another variable herein, are joined to form a ring (e.g., a spiro ring, a fused ring, or a bridged ring), which is optionally substituted with one or more substituents as defined in (B), and any remaining substituents of the respective optionally substituted group are as defined in (B). In some preferred embodiments, the optionally substituted groups as defined in connection with a formula herein can be unsubstituted or substituted with one or more substituents as defined in (B). The combination of Q1, Q2, and Q3is not particularly limited, which can preferably be (a) a linker of O, NQ4, C(O), S, SO, SO2, or P(O)Q4, when two of Q1, Q2, and Q3are null, or (b) a linker of amide (C(O)NQ4), ester (C(O)O), sulfonamide (SO2NQ4), etc., when one of Q1, Q2, and Q3is null, or (c) a linker of carbamate (OC(O)NQ4), urea (NQ4C(O)NQ4),sulfamoylamino (NQ4SO2NQ4), etc., when none of Q1, Q2, and Q3is null. The combination of Q20, Q21, and Q22should be understood similarly.

[0182] Unless otherwise specified or contrary from context, when a group herein is defined as being optionally substituted with one or more substituents selected from a defined list or simply a defined list of substituents, the group is typically unsubstituted or substituted with 1, 2, 3, or 4 substituents as defined, although in some embodiments, the group can also be substituted with more than 4 substituents. For example, an alkyl group optionally substituted with one or more substituents independently selected from deuterium, F, and OH can be typically unsubstituted or substituted with 1-4 substituents each independently deuterium, F, or OH. Similarly, an alkyl group optionally substituted with deuterium and / or F is typically unsubstituted or substituted with 1-4 substituents each independently deuterium or F.

[0183] Unless otherwise specified or contrary from context, a 3-x membered ring herein, wherein x is an integer of 6 or greater, e.g., 3-14 membered, 3-8 membered ring, etc., can be a (i) 3-x membered carbocyclic ring, (ii) 4-x membered heterocyclic ring having 1-3 ring heteroatoms each independently O, S, and N, wherein the sulfur atom, if present, is optionally oxidized; (iii) phenyl ring, or phenyl or naphthyl ring when x is 10 or greater; (iv) a 5 or 6- membered heteroaryl ring having 1-4 ring heteroatoms each independently O, S, and N, or a 5 or 6-membered heteroaryl ring or bicyclic heteroaryl ring having 1-4 ring heteroatoms each independently O, S, and N, when x is 9 or greater.

[0184] Unless otherwise specified or contrary from context, a 3-6 membered ring herein can be a (1) 3-6 membered carbocyclic ring, e.g., cyclopropyl, cyclobutyl, etc., (ii) 4-6 membered heterocyclic ring having 1-2 ring heteroatoms each independently O, S, and N, wherein the sulfur atom, if present, is optionally oxidized, e.g., oxetane, azetidine, etc.; (iii) a 5-membered heteroaryl ring having 1-4 ring heteroatoms each independently O, S, and N; (iv) a 6- membered heteroaryl ring having 1 or 2 ring nitrogen atoms; or (v) a phenyl ring.

[0185] Unless otherwise specified or contrary from context, a 3-5 membered ring herein can be a (i) 3-5 membered carbocyclic ring, e.g., cyclopropyl, cyclobutyl, etc., (ii) 4-5 membered heterocyclic ring having 1-2 ring heteroatoms each independently O, S, and N, wherein the sulfur atom, if present, is optionally oxidized, e.g., oxetane, azetidine, etc.; or (iii) a 5- membered heteroaryl ring having 1-4 ring heteroatoms each independently O, S, and N.

[0186] In some embodiments, the “optionally substituted” alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, carbocyclic, carbocyclylene, cycloalkyl, cycloalkylene,alkoxy, cycloalkoxy, heterocyclyl, or heterocyclylene herein can each he independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, -OH, protected hydroxyl, oxo (as applicable), NHz, protected amino, NH(CI-4 alkyl) or a protected derivative thereof, N(CM alkyl((Ci-4 alkyl), C alkyl, C24 alkenyl, C2-4 alkynyl, C alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, 3- 7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from deuterium, F, -OH, oxo (as applicable), C alkyl, fluorosubstituted CM alkyl (e.g., CF3), CM alkoxy and fluoro-substituted CM alkoxy. In some embodiments, the “optionally substituted” aryl, arylene, heteroaryl or heteroarylene group herein can each be independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, -OH, -CN, NH2, protected amino, NH(CM alkyl) or a protected derivative thereof, N(CM alkyl((Ci-4 alkyl), -S(=O)(CM alkyl), -SOz(Ci- 4 alkyl), CM alkyl, C2-4 alkenyl, C2-4 alkynyl, CM alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1 , 2 or 3 ring heteroatoms independently selected from O, S, and N, 3-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from deuterium, F, -OH, oxo (as applicable), CM alkyl, fluoro-substituted CM alkyl, CM alkoxy and fluoro-substituted CM alkoxy.

[0187] “Halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0188] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0189] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from tautomerization. The exact ratio of the tautomers depends on several factors, including for example temperature, solvent, and pH. Tautomerizations areknown to those skilled in the art. Exemplary tautomerizations include keto-to-enol, amide-to- imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations .

[0190] The term “subject” (alternatively referred to herein as “patient”) as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0191] As used herein, the terms "treat," "treating," "treatment," and the like refer to eliminating, reducing, or ameliorating a disease or condition, and / or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. As used herein, the terms "treat," "treating," "treatment," and the like may include "prophylactic treatment," which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0192] The term "effective amount" refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, prophylaxis or treatment of diseases. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells and / or tissues. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

[0193] As used herein, the singular form “a”, “an”, and “the”, includes plural references unless it is expressly stated or is unambiguously clear from the context that such is not intended.

[0194] The term “and / or” as used in a phrase such as “A and / or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0195] Headings and subheadings are used for convenience and / or formal compliance only, do not limit the subject technology, and are not referred to in connection with the interpretation of the description of the subject technology. Features described under one heading or one subheading of the subject disclosure may be combined, in various embodiments, with features described under other headings or subheadings. Further it is not necessarily the case that all features under a single heading or a single subheading are used together in embodiments.Examples

[0196] The various starting materials, intermediates, and compounds of embodiments herein can be isolated and purified where appropriate using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds can be performed using conventional methods such as by melting point, mass spectrum, nuclear magnetic resonance, and various other spectroscopic analyses. The examples herein may use a solvent, such as an HPLC solvent, containing certain acids (such as formic acid) for the purification of target compounds. In these examples, the target compounds may exist as an acid addition salt, which may be a partial salt or a stoichiometric salt (full salt) with the acids in the solvent, such as HPLC solvent. For example, when an HPLC solvent containing formic acid is used for the purification of a target compound, it is expected that the isolated target compound may contain some residual formic acid. It is to be noted that the signals in an NMR spectrum of the target compound due to formic acid may or may not be reported herein. In such cases, an ordinarily skilled person in the art would understand that the isolated target compound may for example exist in a free form (no salt formation, residual formic acid considered an impurity), a partial salt, or a full salt, depending on vacuum drying conditions. It should be understood that the enantiomeric excesses ("ee") reported herein are only representative from the exemplified procedures herein and not limiting; those ordinarily skilled in the art wouldunderstand that such enantiomers with a different ee, such as a higher ee, can be obtained in view of the present disclosure. The abbreviations used in the Examples section should be understood as having their ordinary meanings in the art unless specifically indicated otherwise or obviously contrary from context. The examples are illustrative only and do not limit the claimed invention in any way.

[0197] Exemplary embodiments of steps for performing the synthesis of products described herein are described in greater detail infra.Intermediate A2-(5-(benzylthio)-7-chloropyrazolo[l,5-a]pyridin-3-yl)-5-(difluoromethyl)-l,3,4-thiadiazole

[0198] Step 1: 5-bromo-7-chloropyrazolo[l,5-a]pyridine (A-l)

[0199] To a solution of 5-bromopyrazolo[l,5-a]pyridine (3 g, 15.2 mmol) in dry THF (70 mL) was added LiHMDS (1 M in THF solution, 18.3 mL, 18.3 mmol) dropwise at -78 °C under N2. After stirring for 2 hrs, a solution of C2CI6 (3.24 g, 13.7 mmol) in dry THF (5 mL) was added drop wise at -78 °C under N2 atmosphere. Then the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 6 hrs. LCMS showed the reaction completed. The reaction mixture was worked up with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give a crude product which was purified by flash column chromatography on silica gel (eluting with 8% EtOAc in PE) to afford 5-bromo-7-chloro-pyrazolo[l,5-a]pyridine (2.7 g). LCMS (ESI, m / z): [M+H]+= 230.9.

[0200] Step 2: 5-(benzylthio)-7-chloropyrazolo[l,5-a]pyridine (A-2)

[0201] To a solution of 5-bromo-7-chloro-pyrazolo[l ,5-a]pyridine (2.9 g, 12.5 mmol) and phenylmethanethiol (1.87 g, 15.0 mmol) in 1,4-dioxane (100 mL) was added DIEA (1.62 g, 12.5 mmol, 2.18 mL), Xantphos (1.45 g, 2.51 mmol) and Pd2(dba)s (1.15 g, 1.25 mmol) under N2. The reaction mixture was degassed, then stirred at 100 °C for 3 hrs under N2 atmosphere. LCMS showed the reaction completed. The reaction mixture was worked up with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 13% EtOAc in PE) to afford 5-benzylsulfanyl-7-chloro-pyrazolo[l,5-a]pyridine (700 mg). LCMS (ESI, m / z): [M+H]+= 274.9.

[0202] Step 3: 5-(benzylthio)-7-chloro-3-iodopyrazolo[l,5-a]pyridine (A-3)

[0203] To a solution of 5-benzylsulfanyl-7-chloro-pyrazolo[l,5-a]pyridine (587 mg, 2.14 mmol) in acetonitrile (15 mL) was added NIS (514.3 mg, 2.29 mmol) at room temperature under N2. The reaction mixture was stirred at room temperature for 1 hr. LCMS showed the reaction completed. The reaction mixture was worked up with water and extracted by EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 15% EtOAc in PE) to afford 5- benzylsulfanyl-7-chloro-3-iodo-pyrazolo[l,5-a]pyridine (788 mg). LCMS (ESI, m / z): [M+H]+= 400.8.

[0204] Step 4: 5-(benzylthio)-7-chloro-3-(trimethylstannyl)pyrazolo[l,5-a]pyridine (A-4)

[0205] To a solution of 5-benzylsulfanyl-7-chloro-3-iodo-pyrazolo[l,5-a]pyridine (600 mg, 1.5 mmol) in 1,4-dioxane (10 mL) was added trimethyl(trimethylstannyl)stannane (588 mg, 1.8 mmol) and Pd(PPlt3)4 (86 mg, 0.075 mmol) under N2. The reaction mixture was degassed with N2, then stirred at 100 °C for 1.5 hrs. LCMS showed the reaction completed. The reaction mixture was concentrated under reduced pressure to afford the crude product which was used directly for the next step without further purification. LCMS (ESI, m / z): [M+H]+= 437.0.

[0206] Step 5: 2-(5-(benzylthio)-7-chloropyrazolo[l,5-a]pyridin-3-yl)-5-(difluoromethyl)- 1,3,4-thiadiazole (A)

[0207] To a solution of (5-benzylsulfanyl-7-chloro-pyrazolo[l,5-a]pyridin-3-yl)- trimethyl-stannane (300 mg, 0.69 mmol) in DMF (10 mL) was added 2-bromo-5-(difluoromethyl)- 1 ,3, 4-thiadiazole (162 mg, 0.75 mmol) and Pd(PPhs)4 (80 mg, 0.068 mmol) under N2. The reaction mixture was degassed, then stirred at 100 °C for 5 hrs under N2 atmosphere. LCMS showed the reaction completed. Then the reaction mixture was worked up with water and extracted with EtOAc. The organic layers were washed with saturated brine, dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 5% - 10% EtOAc in PE) to afford 2-(5-(benzylthio)-7-chloropyrazolo[l,5-a]pyridin-3-yl)-5- (difluoromethyl)-l, 3, 4-thiadiazole (230 mg). LCMS (ESI, m / z): [M+H]+= 409.1.Intermediate B7-chloro-N-(l-cyanocyclopropyl)-3-(5-(difluoromethyl)-l,3,4-thiadiazol-2- y l)pyrazolo [ 1 , 5 -a]pyridine- 5 - sulfonamide (B)

[0208] Step 1: 7-chloro-3-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)pyrazolo[l,5- a]pyridine-5-sulfonyl chloride (B-l)

[0209] To a solution of 2-(5-benzylsulfanyl-7-chloro-pyrazolo[l,5-a]pyridin-3-yl)-5-(difluoromethyl)-l, 3, 4-thiadiazole (500 mg, 1.22 mmol) in H2O (0.9 mL), HCOOH (1.9 mL) and DCM (5 mL) was added NCS (653 mg, 4.89 mmol) at 0 °C under N2. The mixture was stirred at room temperature for 1.5 hrs. LCMS showed the reaction completed. The reaction mixture was worked up with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous N 2SO4, filtered, and concentrated to afford the crude product (420 mg) which was used directly in the next step without further purification. LCMS (ESI, m / z): [M+H]+= 385.1.

[0210] Step 2: 7-chloro-N-(l-cyanocyclopropyl)-3-(5-(difluoromethyl)-l,3,4-thiadiazol- 2-yl)pyrazolo [ 1 ,5 -a]pyridine-5-sulfonamide (B)

[0211] To a solution of 1 -aminocyclopropanecarbonitrile hydrochloride.7 mg, 0.234 mmol) in DCM (1 mL) was added TEA (79 mg, 0.779 mmol, 0.109 mL). After stirring for 5 mins, 7-chloro-3-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]pyrazolo[l,5-a]pyridine-5- sulfonyl chloride (100 mg, 0.260 mmol) in DCM (ImL) was added at 0 °C under N2. Thereaction mixture was stirred at 0 °C for 2 hrs. LCMS showed the reaction completed. The reaction mixture was worked up with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous NazSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 5% MeOH in DCM) to afford 7-chloro-N-(l- cyanocyclopropyl)-3-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]pyrazolo[l,5-a]pyridine-5- sulfonamide (12 mg). LCMS (ESI, m / z): [M+H]+= 431.0.Intermediate C2-bromo-5 -( 1 -fluorocyclopropyl)- 1 ,3 ,4-thiadiazole(C)step1step 2C-1 C

[0212] Step 1: 5-(l-fluorocyclopropyl)-l,3,4-thiadiazol-2-amine (C-1)

[0213] To a solution of 1 -fluorocyclopropanecarboxylic acid (2 g, 19.2 mmol) in POCh (20 mL) was added aminothiourea (1.75 g, 19.2 mmol) under N2. The mixture was stirred at 80 °C for 1 hr. LCMS showed the reaction completed. The reaction mixture was cooled to room temperature, poured into water carefully, then neutralized with saturated aqueous NaHCCL to pH = 7~8. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to afford 5-(l-fluorocyclopropyl)-l,3,4-thiadiazol-2-amine (2.17 g). LCMS (ESI, m / z): [M+H]+= 160.0.

[0214] Step 2: 2-bromo-5-(l-fluorocyclopropyl)-l,3,4-thiadiazole (C)

[0215] To a solution of 5-(l-fluorocyclopropyl)-l,3,4-thiadiazol-2-amine (2.17 g, 13.6 mmol) in ACN (50 mL) was added CuB (4.57 g, 20.5 mmol) and tert-butyl nitrite (1.72 g, 16.6 mmol, 1.98 mL) at -20 °C under N2. The mixture was stirred at -20 °C for 5 hrs. LCMS showed the reaction completed. The reaction mixture was worked up with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 13% EtOAc in PE) toafford 2-bromo-5-(l -fluorocyclopropyl)-! ,3,4-thiadiazole (1.4 g). LCMS (ESI, m / z): [M+H]+= 222.8.Intermediate D2-bromo-4-(difluoromediyl)thiazole(D)step 1D

[0216] To a solution of 2-bromothiazole-4-carbaldehyde (2.0 g, 10.4 mmol) in DCM (20 mL) was added DAST (6.72 g, 41.7 mmol) at 0 °C under N2. The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was quenched with saturated aqueous NaHCCh, then extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na^SO i. filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 5% EtOAc in PE) to afford 2-bromo-4-(difluoro methyl) thiazole (1.5 g).1H NMR (400 MHz, DMSO-tfo) 6 8.18 (s 1H), 7.07 (t, J = 54.0 Hz, 1H).Intermediate E isopropyl piperazine- 1 -carboxylate hydrochloride (E)

[0217] Step 1: 1 -(tert-butyl) 4-isopropyl piperazine- 1 ,4-dicarboxylate (E-l)

[0218] To a mixture of / er / -butyl piperazine- 1 -carboxylate (1 g, 5.37 mmol) and TEA (1.63 g, 16.1 mmol, 2.25 mL) in DCM (10 mL) was added isopropyl carbonochloridate (790 mg, 6.44 mmol) at room temperature under N2. The mixture was stirred at room temperature for 3 hrs. After completion, the reaction mixture was worked up with water and extracted with DCM. The combined organic layers were washed with aqueous HC1 (I M) and then withsaturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 1 -(tert- butyl) 4-isopropyl piperazine- 1,4-dicarboxylate (1.3 g).

[0219] Step 2: isopropyl piperazine- 1 -carboxylate hydrochloride (E)

[0220] 1 -(tert-butyl) 4-isopropyl piperazine- 1,4-dicarboxylate (1 g, 3.67 mmol) was added to a solution of HC1 in 1,4-dioxane solution (4.0 M, 11 mL). The reaction mixture was stirred for 1 hr at room temperature. LCMS showed the reaction completed. The reaction mixture was concentrated under reduced pressure to give isopropyl piperazine- 1 -carboxylate hydrochloride (750 mg) which was used directly in the next step without further purification.Intermediate F(l-methylcyclobutyl)(piperazin-l-yl)methanone hydrochloride (F)

[0221] Step 1: tert-butyl 4-(l-methylcyclobutanecarbonyl)piperazine-l-carboxylate (F-l)

[0222] To a solution of 1 -methylcyclobutanecarboxylic acid (505 mg, 4.42 mmol), tertbutyl piperazine- 1 -carboxylate (750 mg, 4.03 mmol) and DIPEA (1.56 g, 12.1 mmol, 2.10 mL) in DMF (5 mL) was added HATU (1.68 g, 4.42 mmol) under N2. The reaction mixture was stirred at room temperature for 3 hrs. LCMS showed the reaction completed. The reaction mixture was worked up with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 0-30% EtOAc in PE) to give / -butyl 4-(l- methylcyclobutanecarbonyl)piperazine-l -carboxylate (0.95 g).

[0223] Step 2: (l-methylcyclobutyl)-piperazin-l-yl-methanone hydrochloride salt (F)

[0224] tert-butyl 4-(l-methylcyclobutanecarbonyl)piperazine-l -carboxylate (300 mg,1.06mmol) was added to HC1 in 1,4-dioxane (4 M, 6 mL) at 0 °C. The mixture was warmed to room temperature and stirred for 3 hrs under N2 atmosphere. TLC showed the reaction completed. The reaction mixture was concentrated to afford (l-methylcyclobutyl)(piperazin- l-yl)methanone hydrochloride (200 mg). LCMS (ESI, m / z): [M+H]+= 183.1.Intermediate G2-methyl-5-(piperazin-l-yl)-l,3,4-thiadiazole hydrochloride (G)

[0225] Step 1: tert-butyl 4-(5-methyl-l,3,4-thiadiazol-2-yl)piperazine-l-carboxylate (G- 1)

[0226] To a solution of 2-bromo-5-methyl-l,3,4-thiadiazole (500 mg, 2.79 mmol) and DIPEA (256 mg, 5.58 mmol) in 1,4-dioxane (7 mL) was added tert-butyl piperazine-1- carboxylate (520 mg, 2.79 mmol) at room temperature under N2. The reaction mixture was stirred at 110 °C for 5 hrs. LCMS showed the reaction completed. The reaction mixture was cooled to room temperature and worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous NaiSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc in PE) to afford tert-butyl 4-(5- methyl-l,3,4-thiadiazol-2-yl)piperazine-l-carboxylate (680 mg). LCMS (ESI, m / z): [M+H]+= 285.4.

[0227] Step 2: 2-methyl-5-piperazin-l-yl-l,3,4-thiadiazole hydrochloride (G)

[0228] tert-butyl 4-(5-methyl-l,3,4-thiadiazol-2-yl)piperazine-l-carboxylate (680 mg,2.39 mmol) was added to a solution of HC1 in 1,4 dioxane (4 M, 4 mL). The mixture was stirred at room temperature for 2 hrs. LCMS showed the reaction completed. The reaction mixture was concentrated under reduced pressure to afford 2-methyl-5-piperazin-l-yl-l,3,4- thiadiazole hydrochloride (520 mg). LCMS (ESI, m / z): [M+H]+= 184.26.Intermediate H(S)-(3-fluoropyrrolidin-l-yl)(piperazin-l-yl)methanone hydrochloride (H)

[0229] Step 1: tert-butyl (S)-4-(3-fluoropyrrolidine-l-carbonyl) piperazine- 1 -carboxylate (H-1)

[0230] To a solution of tert-butyl piperazine- 1 -carboxyl ate (1.92 g, 10.3 mmol) and bis(trichloromethyl) carbonate (1.53 g, 5.17 mmol) in DCM (40 mb) was added DIEA (4.01 g, 30.9 mmol, 5.40 mL) dropwise at 0 °C under Nz. The mixture was stirred at room temperature for 3 hrs under Nz atmosphere. Then (S)-3-fluoropyrrolidine (920 mg, 10.3 mmol) was added and stirred for another 30 min. After completion, the reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous NazSO4, filtered, and concentrated under reduced pressure. The residue was purified via prep-HPLC (0.05% NH4HCO3) to afford tert-butyl (S)- 4-(3-fluoropyrrolidine-l-carbonyl) piperazine- 1 -carboxylate (800 mg). LCMS (ESI, m / z): [M+H-tBu]+= 246.2.

[0231] Step 2: (S)-(3-fluoropyrrolidin-l-yl) (piperazin- 1-yl) methanone (H)

[0232] To a solution of tert-butyl (S)-4-(3-fluoropyrrolidine-l-carbonyl) piperazine- 1- carboxylate (500 mg, 1.66 mmol) in MeOH (5 mL) was added HC1 (4.0 M in 1,4-dioxane, 2.5 mL). The mixture was stirred at room temperature for 3 hrs. After completion, the mixture was concentrated under reduced pressure to afford (S)-(3-fluoropyrrolidin-l- yl)(piperazin-l-yl)methanone hydrochloride (330 mg). LCMS (ESI, m / z): [M+H]+= 202.3.Intermediate I2-methyl-5-(piperazin- 1-yl)- 1,3,4-oxadiazole hydrochloride (I)Boc

[0233] Step 1: tert-butyl 4-(5-methyl-l, 3, 4-oxadiazoL2-yl)piperazine-l -carboxylate (1-1)

[0234] To a solution of 2-bromo-5-methyl- 1,3,4-oxadiazole (500 mg, 3.07 mmol) in 1,4- dioxane (7 mL) were added tert-butyl piperazine- 1 -carboxylate (571 mg, 3.07 mmol) and DIEA (786 mg, 6.14 mmol) at room temperature. The mixture was stirred at 110 °C for 5 hrs under N2 atmosphere. LCMS showed the reaction completed. The reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SOr, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc in PE) to afford rert-butyl 4-(5-methyl-l,3,4-oxadiazol-2-yl)piperazine-l- carboxylate (650 mg). LCMS (ESI, m / z): [M+H]+= 269.2.

[0235] Step 2: 2-methyl-5-piperazin-l-yl-l,3,4-oxadiazole (I)

[0236] A mixture of tert-butyl 4-(5-methyl-l,3,4-oxadiazol-2-yl)piperazine-l-carboxylate(300 mg, 1.12 mmol) in a solution of HC1 (4.0 M in 1,4-dioxane, 4 mL) was stirred at room temperature for 2 hrs. LCMS showed the reaction completed. The reaction mixture was concentrated under reduced pressure to afford 2-methyl-5-(piperazin-l-yl)-l,3,4-oxadiazole hydrochloride (230 mg) which was used directly for the next step without further purification. LCMS (ESI, m / z): [M+H]+= 169.1.Intermediate J5-bromo-3-(difluoromethyl)-l,2,4-thiadiazole (J)

[0237] Step 1 : 2, 2-difluoroacetimidamide hydrochloride (J-1)

[0238] To a stirred suspension of NH4CI (8.2 g, 153 mmol) in dry toluene (6 mL) at 0 °C was added trimethylaluminum (10.4 g, 143.8 mmol) under N2 and stirred until effervescence ceased. Then Methyl 2,2-difluoroacetate (4.8 g, 43.6 mmol) was added. The resulting mixture was stirred overnight at 80 °C under N2 atmosphere. After completion, the reaction mixture was cooled to 0 °C and quenched with methanol dropwise. The resulting mixture was stirred for 90 minutes at 0 °C until the solid formed. The mixture was filtered through celite, then the filtrate was concentrated under reduced pressure to afford 2, 2-difluoroacetimidamide hydrochloride (2.2 g).

[0239] Step 2: (E)-N'-chloro-2, 2-difluoroacetimidamide (J-2)

[0240] To a solution of 2, 2-difluoroacetimidamide hydrochloride (2.2 g, 16.9 mmol) in water (30 mL) was added aqueous NaCIO (w / w% = 7.5%, 12 mL). The mixture was stirred at 0 °C for 30 mins. LCMS showed the reaction completed. The reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SC>4, filtered, and concentrated to give N'-chloro- 2,2-difluoro-acetamidine (500 mg). LCMS (ESI, m / z): [M+H]+= 128.9.

[0241] Step 3: 3-(difluoromethyl)-l,2,4-thiadiazol-5-amine (J-3)

[0242] A solution of N'-chloro-2,2-difluoro-acetamidine (500 mg, 3.9 mmol) in methanol (9 mL) was treated with thiocyanic acid (230 mg, 3.9 mmol) for 5 min at 0 °C, followed by the addition of ytterbium(III) trifluoromethanesulfonate hydrate (242 mg, 0.39 mmol) inportions at room temperature for 5 hrs under N2. LCMS showed the reaction completed. The reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous NazSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 0-5% MeOH in DCM) to afford 3- (difluoromethyl)-l,2,4-thiadiazol-5-amine (300 mg). LCMS (ESI, m / z): [M+H]+= 151.9. 'H NMR (400 MHz, DMSO-c / 6) 5 8.26 (s, 2H), 6.78 (t, 7= 52 Hz, 1H).

[0243] Step 4: 5-bromo-3-(difluoromethyl)-l,2,4-thiadiazole (J)

[0244] To a solution of 3-(difluoromethyl)-l,2,4-thiadiazol-5-amine (300 mg, 1.98 mmol) in CH3CN (3 mL) was added CuBr2 (532 mg, 2.38 mmol), followed by rert-Butyl nitrite (266 mg, 2.58 mmol) at room temperature. The reaction mixture was stirred at 45 °C for 4 hrs.LCMS showed the reaction completed. The reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 0-10% EtOAc in PE) to give 5-bromo-3-(difluoromethyl)-l,2,4-thiadiazole (100 mg). LCMS (ESI, m / z): [M+H]+= 214.8.Intermediate K[(3S)-3 -hydroxypyrrolidin- 1 -yl] -piperazin- 1 -yl-methanone (K)

[0245] Step 1: tert-butyl 4-[(3S)-3-hydroxypyrrolidine-l-carbonyl] piperazine- 1- carboxylate (K-l)

[0246] To a solution of tert-butyl piperazine- 1 -carboxyl ate (1.92 g, 10.3 mmol) and bis(trichloromethyl) carbonate (1.53 g, 5.17 mmol) in DCM (40 mL) was added DIEA (4.01 g, 31.0 mmol) dropwise at 0 °C under N2. The reaction mixture was allowed to warm to room temperature and stirred for 3 hrs. TLC indicated the total consumption of the starting material. (3S)-pyrrolidin-3-ol (900 mg, 10.3 mmol) was added to the mixture at 0 °C underN2- The reaction mixture was stirred at room temperature for 30 mins. LCMS showed the reaction completed. The reaction mixture was worked up with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified prep- HPLC(0.05% NH4HCO3) to afford tert-butyl 4-[(3S)-3-hydroxypyrrolidine-l-carbonyl] piperazine- 1 -carboxylate (800 mg). LCMS (ESI, m / z): [M+H]+= 300.3.

[0247] Step 2: [(3S)-3-hydroxypyrrolidin-l-yl]-piperazin-l-yl-methanone (K)

[0248] To a solution of tert-butyl 4-[(3S)-3-hydroxypyrrolidine-l-carbonyl] piperazine- 1- carboxylate (500 mg, 1.67 mmol) in MeOH (5 mL) was added HC1 (4.0 M in 1,4-dioxane, 1.25 ml, 5.0 mmol). The reaction mixture was stirred at room temperature for 3 hrs. LCMS indicated the total consumption of the starting material. The reaction mixture was concentrated under reduced pressure to afford (S)-(3-hydroxypyrrolidin-l-yl)(piperazin-l- yl)methanone hydrochloride (400 mg). LCMS (ESI, m / z): [M+H]+= 200.3.Intermediate L2-bromo-4H-pyrano[3,4-d]thiazol-7(6H)-one (L) Cstep 1 step 2

[0249] Step 1 : 2-amino-4H-pyrano[3,4-d] thiazol-7(6H)-one (L-l)

[0250] 3-hydroxy-2H-pyran-5-one (5 g, 43.8 mmol) and anhydrous Sodium acetate (5.4 g, 65.8 mmol) were suspended in acetic acid (50 mL) with stirring. Br2(7 g, 43.8 mmol) was added dropwise at room temperature under N2. The reaction is stirred at room temperature for 2 hrs, then Thiourea (3.34 g, 43.8 mmol) was added under N2. After heating at 100 °C for 16 hrs, the reaction mixture was cooled and concentrated under reduced pressure. The residue was slurried with water, then with hot EtOAc. After drying in vacuum, 2-amino-4H- pyrano[3,4-d] thiazol-7-one (5.5 g) was obtained. LCMS (ESI, m / z): [M+H]+= 171.1.

[0251] Step 2 : 2-bromo-4H-pyrano[3,4-d] thiazol-7(6H)-one (L)

[0252] To a solution of 2-amino-4H-pyrano[3,4-d] thiazol-7-one (5 g, 29.3 mmol) in ACN (50 mL) was added tert-Butyl nitrite (6.06 g, 58.8 mmol) dropwise at 0 °C followed by addition of CuBr2(13.1 g, 58.7 mmol). The mixture was stirred at 80 °C for 16 hrs under N2.The reaction mixture was worked up with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 25% EtOAc in PE) to afford 2-bromo-4H- pyrano[3,4-d] thiazol-7-one (2.3 g). LCMS (ESI, m / z): [M+H]+= 233.9.Intermediate M1 -(5 -bromo- 1 ,3 ,4-thiadiazol-2-yl)cyclobutan- 1 -ol (M)

[0253] Step 1: l-(5-amino-l,3,4-thiadiazol-2-yl)cyclobutanol (M-l)

[0254] To a solution of 1-hydroxycyclobutanecarboxylic acid (1.00 g, 8.61 mmol) in phosphoryl trichloride (5.30 mL) was added aminothiourea (785 mg, 8.61 mmol) under N2. The mixture was stirred at 80 °C for 1 hr under N2 atmosphere. After completion, the reaction mixture was quenched by adding into water carefully, then neutralized with saturated aqueous NaHCCh to pH = 8-9. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford l-(5-amino-l,3,4-thiadiazol-2-yl)cyclobutanol (796 mg). LCMS (ESI, m / z): [M+H]+= 172.1.

[0255] Step 2: l-(5-bromo-l,3,4-thiadiazol-2-yl)cyclobutanol (M)

[0256] To a mixture of tert-butyl nitrite (2.53 g, 24.5 mmol) and CuBr2 (4.11 g, 18.4 mmol) in MeCN (84 mL) was added l-(5-amino-l,3,4-thiadiazol-2-yl)cyclobutanol (2.10 g, 12.3 mmol). The mixture was stirred at 80 °C for 1 hr. After completion, the reaction mixture was worked up with aqueous saturated NH4CI, then extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 20% EtOAc in PE) to afford l-(5-bromo- 1,3,4- thiadiazol-2-yl)cyclobutanol (183 mg). LCMS (ESI, m / z): [M+H]+= 235.0.Intermediate N l-(5-bromo-l,3,4-thiadiazol-2-yl)cyclopropane-l-carbonitrile (N)Step 1 H2N Step 2N-1 N

[0257] Step 1: l-(5-amino-l,3,4-thiadiazol-2-yl) cyclopropane- 1 -carbonitrile (N-1)

[0258] To a solution of 1 -cyanocyclopropanecarboxylic acid (10 g, 90.0 mmol) in POCh (100 mL) was added amino thiourea (8.20 g, 90.0 mmol) under N2. The mixture was stirred at 80 °C for 30 mins under N2 atmosphere. LCMS showed the reaction completed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM, then neutralized by saturated aqueous NaHCCh till pH 8~9. Then the resulting mixture was extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford l-(5- amino-l,3,4-thiadiazol-2-yl) cyclopropane carbonitrile (3.4 g). LCMS (ESI, m / z): [M+H]+= 167.1.

[0259] Step 2: l-(5-bromo-l,3,4-thiadiazol-2-yl) cyclopropane- 1 -carbonitrile (N)

[0260] To a solution of l-(5-amino-l,3,4-thiadiazol-2-yl) cyclopropane carbonitrile (3.84 g, 23.1 mmol) in ACN (200 mL) was added rert-butyl nitrite (2.91 g, 28.2 mmol) and CuB (7.74 g, 34.7 mmol) under N2. The mixture was stirred at -20 °C for 5 hrs under N2 atmosphere. LCMS showed the reaction completed. The reaction mixture was worked up with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SC>4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 9% EtOAc in PE) to afford l-(5-bromo-l,3,4-thiadiazol-2-yl) cyclopropane carbonitrile (1.2 g). LCMS (ESI, m / z): [M+H]+= 300.0.Intermediate O l-(lH-pyrazol-4-yl)cyclopropane-l -carbonitrile (O)-

[0261] Step 1: l-tetrahydropyran-2-ylpyrazole-4-carbaldehyde (O-l)

[0262] To a mixture of lH-pyrazole-4-carbaldehyde (2 g, 20.8 mmol) in THF (60 mL) was added 3,4-dihydro-2H-pyran (3.50 g, 41.6 mmol) and 4-methylbenzenesulfonic acid (358 mg, 2.08 mmol). The mixture was stirred at 60 °C for 2 hrs. After completion, the reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 50% EtOAc in PE) to give l-tetrahydropyran-2-ylpyrazole-4-carbaldehyde (3.27 g). LCMS (ESI, m / z): [M+H]+= 181.2.

[0263] Step 2: 2-(l-tetrahydropyran-2-ylpyrazol-3-yl)acetonitrile (O-2)

[0264] To a solution of TosMIC (3.64 g, 18.6 mmol) in 1,2-Dimethoxyethane (22.6 mL) was added a solution of KOtBu (1 M in THF, 35.5 mL, 35.5 mmol) dropwise at -50 °C under N . The mixture was stirred at -50 °C for 20 mins. Then a solution of l-tetrahydropyran-2- ylpyrazole-3-carbaldehyde (3.2 g, 17.8 mmol) in 1,2-Dimethoxyethane (22.6 mL) was added dropwise. The reaction mixture was stirred at -50 °C for 30 mins under N2 atmosphere. After completion, MeOH (22.6 mL) was added to the reaction mixture, then stirred at 80 °C for 1 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was worked up with water, then acidified to pH = 5-6 with AcOH. The resulting mixture was extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elutingwith 33% EtOAc in PE) to give 2-(l-tetrahydropyran-2-ylpyrazol-3-yl)acetonitrile (2.1 g). LCMS (ESI, m / z): [M+H]+= 108.2.

[0265] Step 3: l-(l-tetrahydropyran-2-ylpyrazol-4-yl)cyclopropanecarbonitrile (0-3)

[0266] To a solution of Diisopropylamine (2.97 g, 29.3 mmol) in THF (34 mL) was added n-BuLi (1.6 M in hexane, 16.7 mL, 26.7 mmol) dropwise at -30 °C under N2. The mixture was stirred at room temperature for 1 hr. Then 2-(l-tetrahydropyran-2-ylpyrazol-4- yl) acetonitrile (1.70 g, 8.89 mmol) in THF (8.5 mL) was added to the mixture at 0 °C under N2. The mixture was stirred at room temperature for 1 hr. Then BrClLCfLBr (5.12 g, 26.7 mmol) was added at 0 °C. The reaction mixture was stirred for an additional 1 hr at 0 °C under N2 atmosphere. After completion, the reaction mixture was quenched with saturated aqueous NH4CI, then extracted with DCM. The combined organic layes were washed with saturated brine, dried over anhydrous NaiSCL, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 33% EtOAc in PE) to give l -(l-tetrahydropyran-2-ylpyrazol-4- yl)cyclopropanecarbonitrile (1.0 g). LCMS (ESI, m / z): [M+H-THP]+= 134.2.

[0267] Step 4: l-(lH-pyrazol-4-yl)cyclopropanecarbonitrile (O)

[0268] To a solution of l-(l-tetrahydropyran-2-ylpyrazol-4-yl)cyclopropanecarbonitrile(900 mg, 4.14 mmol) in 1,4-dioxane (10 mL) was added HC1 (4 M in 1,4-dioxane, 3.1 mL, 12.4 mmol) dropwise. The mixture was stirred at room temperature for 1 hr. After completion, the reaction mixture was filtered to get the filter cake which was further washed with a mixture of PE and EtOAc (10:1). The solid was dispensed in saturated aqueous sodium bicarbonate, then extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give l-(lH-pyrazol-4- yl)cyclopropanecarbonitrile (506 mg). LCMS (ESI, m / z): [M+H]+= 134.1.Intermediate P5-chloro-l-iodoimidazo[l,5-a]pyridine-7-sulfonyl chloride (P)

[0269] Step 1: (4-bromo-6-chloropyridin-2-yl)methanamine (P-1)

[0270] o a so]U|on of 4-bromo-6-chloro-pyridine-2-carbonitrile (6 g, 27.6 mmol) in DCM (100 mL) was added DIBAL-H (1.0 mol / L in n-hexane, 82.8 mL, 82.8 mmol) dropwise at 0 °C under N2. The reaction solution was stirred at 0 °C for 2 hrs. LCMS showed the reaction completed. The mixture was worked up with satd. aq. ammonium chloride solution, then was extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude product which was used directly for the next step without further purification. LCMS (ESI, m / z): [M+H]+= 221.0.

[0271] Step 2: N-((4-bromo-6-chloropyridin-2-yl)methyl)formamide (P-2)

[0272] o a sojuqon of (4-bromo-6-chloro-2-pyridyl)methanamine (6 g, 27.1 mmol) in formic acid (80 mL) was added acetic anhydride (16 mL) under N2. The reaction mixture was stirred at 80 °C for 16 hrs. LCMS showed the reaction completed. The mixture was concentrated to give the crude product which was used directly for the next step without further purification. LCMS (ESI, m / z): [M+H]+= 249.0.

[0273] Step 3: 7-bromo-5-chloro-imidazo[l,5-a]pyridine (P-3)

[0274] To a solution of N-[(4-bromo-6-chloro-2-pyridyl)methyl]formamide (7.1 g, 28.5 mmol) in toluene (60 mL) was added POCI3 (6 mL) under N2. The reaction solution was stirred at 80 °C for 3 hrs. LCMS showed the reaction completed. The mixture was concentrated and worked up with water. The solution was neutralized to pH=8 by aqueous saturated NaHCCL and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to give aresidue. The residue was purified by flash column chromatography on silica gel (eluting with 10% EtOAc in PE) to give 7-bromo-5-chloro-imidazo[l,5-a]pyridine (4.35 g). LCMS (ESI, m / z): [M+H]+= 233.1.

[0275] Step 4: 7-benzylsulfanyl-5-chloro-imidazo[l,5-a]pyridine (P-4)

[0276] To a solution of 7-bromo-5-chloro-imidazo[l,5-a]pyridine (4.35 g, 18.8 mmol) in 1,4-dioxane (60 mL) was added phenylmethanethiol (1.87 g, 15.0 mmol), DIEA (2.43 g, 18.8 mmol), Xantphos (2.17 g, 3.76 mmol) and Pd2(dba)3 (593 mg, 0.648 mmol) under N2. The reaction solution was degassed, then stirred at 80 °C for 3 hrs under N2 atmosphere. LCMS showed the reaction completed. The reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel (eluting with 25% EtOAc in PE) to give 7-benzylsulfanyl-5-chloro-imidazo[l,5-a]pyridine (3.7 g). LCMS (ESI, m / z): [M+H]+= 275.1.

[0277] Step 5: 7-(benzylthio)-5-chloro-l-iodoimidazo[l,5-a]pyridine (P-5)

[0278] To a solution of 7-benzylsulfanyl-5-chloro-imidazo[l,5-a]pyridine (1.5 g, 5.46 mmol) in THF (20 mL) was added NIS (1.84 g, 8.19 mmol) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 2 hrs. LCMS showed the reaction completed. The reaction was worked up with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude. The crude was purified by flash column chromatography on silica gel (eluting with 25% EtOAc in PE) to give 7-benzylsulfanyl-5-chloro-l-iodo- imidazo[l,5-a]pyridine (1.66 g). LCMS (ESI, m / z): [M+H]+= 401.0.

[0279] Step 6: 5-chloro-l-iodoimidazo[l,5-a]pyridine-7-sulfonyl chloride (P)

[0280] To a solution of 7-benzylsulfanyl-5-chloro-l-iodo-imidazo[l,5-a]pyridine (1.66 g, 4.14 mmol) in dichloromethane was added acetic acid (9.5 mL), water (3.0 mL) and NCS (1.66 g, 12.4 mmol) portion-wise at 0 °C. The mixture was stirred at 25 °C for 2 hrs. LCMS showed the reaction completed. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography on silica gel (eluting with 10%EtOAc in PE) to give 5-chloro-l -iodo-imidazo[l ,5-a]pyridine-7-sulfonyl chloride (950 mg).LCMS (ESI, m / z): [M+H]+= 376.9.Intermediate Q2-(6-(benzylthio)-4-chloro-lH-indazol-l-yl)-5-(difluoromethyl)-l,3,4-thiadiazole (Q)

[0281] Step 1: 6-(benzylthio)-4-chloro-lH-indazole (Q-l)

[0282] To a mixture of 6-bromo-4-chloro-lH-indazole (5.0 g, 21.6 mmol), phenyl methanethiol (8.05 g, 64.8 mmol) and DIEA (8.38 g, 64.8 mmol) in 1,4-dioxane (50 ml) was added Xantphos (1.25 g, 2.16 mmol) and Pd2(dba)3-CHCh (1.12 g, 1.08 mmol) under N2. The mixture was degassed, stirred at 100 °C for 3 hrs under N2 atmosphere. TLC indicated the total consumption of the starting material. The reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 10% EtOAc in PE) to afford the product 6-benzylsulfanyl-4-chloro-lH-indazole (5.5 g). LCMS (ESI, m / z): [M+H]+= 275.1.

[0283] Step 2: 2-(6-(benzylthio)-4-chloro-l H-indazol-1 -yl)-5-(difluoromethyl)-l ,3,4- thiadiazole (Q)

[0284] To a mixture of 6-benzylsulfanyl-4-chloro-lH-indazole (3.3 g, 12.0 mmol) and 2- bromo-5-(difluoromethyl)-l,3,4-thiadiazole (3.87 g, 18.0 mmol) in DMF (50 ml) was added CS2CO3 (5.87 g, 18.0 mmol). The mixture was stirred at 60 °C for 2 hrs under N2 atmosphere. After completion, the mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 1% EtOAc in PE) to afford 2-(6-benzylsulfanyl-4- chloro-indazol-l-yl)-5-(difluoromethyl)-l,3,4-thiadiazole (4.0 g). LCMS (ESI, m / z): [M+H]+= 409.2.Intermediate R6-bromo-8-chloro-7-fluoroimidazo[ l,2-a]pyridine (R)

[0285] Step 1: 5-bromo-3-chloro-4-fluoro-pyridin-2-amine (R-1)

[0286] To a solution of 5-bromo-4-fluoro-pyridin-2-amine (7 g, 36.7 mmol) in MeCN (84.0 mL) was added NCS (4.99 g, 37.4 mmol) at room temperature. After stirring for 24 hrs, the reaction mixture was poured into sat. aq. sodium bicarbonate, then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSC , filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 11% EtOAc in PE) to afford 5-bromo-3-chloro-4-fluoro-pyridin-2- amine (5.59 g). LCMS (ESI, m / z): [M+H]+= 225.0; ’H NMR (400 MHz, CDCh) 5 8.09-8.01 (m, 1H), 5.05 (s, 2H).

[0287] Step 2: 6-bromo-8-chloro-7-fluoro-imidazo[l,2-aJpyridine (R)

[0288] A reaction mixture of 5-bromo-3-chloro-4-fluoro-pyridin-2-amine (2.00 g, 8.87 mmol) and 2-chloroacetaldehyde (40% in water, 5.92 g, 30.2 mmol) in ethanol was stirred at 100 °C for 1 hr. When the reaction completed, the precipitate was collected by filtration. The solid was dispersed in sat. aq. sodium bicarbonate solution, then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 50% EtOAc in PE) to afford intermediate R (1.30 g). LCMS (ESI, m / z): [M+H]+= 248.9.Intermediate S8-chloro-3 - [5 -( 1 -cyanocyclopropyl)- 1 ,3 ,4-thiadiazol-2-yl]-A- [ 1 - (fluoromethyl)cyclopropyl]imidazo[l,2-a]pyridine-6-sulfonamide (S)

[0289] Step 1 : 6-(benzylthio)-8-chloroimidazo[l ,2-a]pyridine (S-l)

[0290] To a mixture of 6-bromo-8-chloroimidazo[l,2-a]pyridine (5.0 g, 21.6 mmol) in 1,4-dioxane (50 mL) was added phenyl methanethiol (2.95 g, 23.8 mmol), DIPEA (8.38 g, 64.8 mmol), Xantphos (1.25 g, 2.16 mmol) and Pd2(dba)3-CHCh (1.12 g, 1.08 mmol) under N2. The reaction mixture was degassed, then stirred at 100 °C for 3 hrs under N2 atmosphere. After completion, the reaction was treated with water, then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with DCM) to afford 6-(benzylthio)-8-chloroimidazo[l,2-a]pyridine (5.9 g). LCMS (ESI, m / z): [M+H]+= 275.1.

[0291] Step 2: 6-(benzylthio)-8-chloro-3-iodoimidazo[l,2-a]pyridine (S-2)

[0292] To a mixture of 6-benzylsulfanyl-8-chloro-imidazo[l,2-a]pyridine (5.0 g, 18.2 mmol) in ACN (50 mL) was added NIS (4.50 g, 20.0 mmol) in portions at 0 °C for 30 min. After stirring at room temperature for 16 hrs, the reaction mixture was treated with water, then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 15 % EtOAc in PE) to afford 6- (benzylthio)-8-chloro-3-iodoimidazo[l,2-a]pyridine (7.26 g). LCMS (ESI, m / z): [M+H]+= 401.0.

[0293] Step 3: (6-benzylsulfany]-8-chloro-imidazo[l ,2-a]pyridin-3-yl)-tributyl-stannane (S-3)

[0294] o a so] utionof 6-benzylsulfanyl-8-chloro-3-iodo-imidazo[l ,2-a]pyridine (2 g, 4.99 mmol) in THF (40 mL) was added z-PrMgCl-LiCl (1.3 M in THF, 4.22 mL, 5.49 mmol) dropwise at -15 °C under N . After stirring at -15 °C for 15 min, tributyl(chloro)stannane (1.79 g, 5.49 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hr, then was worked up with saturated aqueous NH4CI solution, and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo to afford (6-benzylsulfanyl-8-chloro-imidazo[l,2-a] pyridin-3-yl)-tributyl-stannane (2.5 g). LCMS (ESI, m / z): [M+H]+= 565.3

[0295] Step 4: l-[5-(6-benzylsulfanyl-8-chloro-imidazo[l,2-a] pyridin-3-yl)-l,3,4- thiadiazol-2-yl]cyclopropanecarbonitrile (S-4)

[0296] To a solution of (6-benzylsulfanyl-8-chloro-imidazo[l,2-a]pyridin-3-yl)-tributyl- stannane (2.5 g, 4.43 mmol) and intermediate N (1.02 g, 4.43 mmol) in 1,4-dioxane (100 mL) was added Pd(PPti3)4 (512 mg, 0.443 mmol) under N2. The mixture was degassed, then stirred at 100 °C for 12 hrs under N2 atmosphere. After completion, the mixture was treated with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc in PE) to afford l-[5-(6-benzylsulfanyl-8-chloro- imidazo[l,2-a] pyridin-3-yl)-l,3,4-thiadiazol-2-yl]cyclopropanecarbonitrile (1.5 g). LCMS (ESI, m / z): [M+H]+= 424.3.

[0297] Step 5: 8-chloro-3-[5-(l-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl]imidazo[l,2- a]pyridine-6-sulfonyl chloride (S-5)

[0298] To a mixture of l-[5-(6-benzylsulfanyl-8-chloro-imidazo[l,2-a]pyridin-3-yl)- l,3,4-thiadiazol-2-yl]cyclopropanecarbonitrile (700 mg, 1.65 mmol), formic Acid (3.04 g, 66.1 mmol) and water (1.19 g, 66.1 mmol) in DCM (10 mL) was added NCS (1.49 g, 11.1 mmol) in portions at 0 °C. The mixture was stirred at room temperature for 2 hrs. After completion, the reaction was treated with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residuewas purified by flash column chromatography on silica gel (eluting with 30% EtOAc in PE) to afford 8-chloro-3-[5-(l-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl]imidazo[l,2- a]pyridine-6-sulfonyl chloride (600 mg). LCMS (ESI, m / z): [M+H]+= 400.2.

[0299] Step 6: 8-chloro-3-[5-(l-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl]-N-[l-(fluoromethyl)cyclopropyl]imidazo[ 1 ,2-a]pyridine-6-sulfonamide (S)

[0300] A solution of 8-chloro-3-[5-(l-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl] imidazo[l,2-a] pyridine-6-sulfonyl chloride (600 mg, 1.50 mmol) and 1- (fluoromethyl)cyclopropanamine hydrochloride (282 mg, 2.25 mmol) in pyridine (10 mL) was stirred at room temperature for 2 hrs under Nz. The reaction mixture was concentrated to dryness. The residue was purified by flash column chromatography on silica gel (eluting with 35% EtOAc in PE) to afford the product which was further purified on prep- HPLC (0.1% FA) to give intermediate S (400 mg). LCMS (ESI, m / z): [M+H]+= 453.3.

[0301] The intermediates in the table below were synthesized using conditions analogous to that used to synthesize intermediate S from commercially available starting materials or synthesized based on literatures.Intermediate Y8-(4-acetylpiperazin-l-yl)-7V-(l-cyanocyclopropyl)-3-iodo-imidazo[l,2-a]pyridine-6- sulfonamide (Y)

[0302] Step 1: 6-amino-5-bromo-pyridine-3-sulfonyl chloride (Y-l)

[0303] A solution of 3-bromopyridin-2-amine (2 g, 11.6 mmol) in chlorosulfuric acid (8 mL) was stirred at 140 °C for 1 hr. The reaction mixture was cooled to 0 °C, then poured into ice- water. The precipitates were collected by filtration, triturated by PE: EtOAc (1:1) and dried under reduced pressure. Then the solid was triturated by 4 M HCI in 1,4-dioxane for 1 hr, filtered to give 6-amino-5-bromo-pyridine-3-sulfonyl chloride (2.8 g) which was used in the next step without further purification.

[0304] Step 2: 6-amino-5-bromo- V-( l-cyanocyclopropyl)pyridine-3 -sulfonamide (Y-2)

[0305] To a solution of 6-amino-5-bromo-pyridine-3-sulfonyl chloride (1.8 g, 6.63 mmol) in pyridine (10 mL) was added 1 -amino- 1 -cyclopropanecarbonitrile hydrochloride (943 mg, 7.96 mmol) under N2. After stirring at room temperature for 16 hrs, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 20% EtOAc in PE) to give 6-amino-5- bromo- / V-(l-cyanocyclopropyl)pyridine-3-sulfonamide (900 mg). LCMS (ESI, m / z): [M+H]+= 317.0.

[0306] Step 3: 8-bromo-. / V-(l-cyanocyclopropyl)imidazo[ L2-a]pyridine-6-sulfonamide (Y-3)

[0307] A solution of 6- amino- 5 -bromo- A-( l-cyanocyclopropyl)pyridine-3-sulfonamide(828 mg, 2.61 mmol) in 2-chloroacetaldehyde (40% in H2O, 8 mL) was stirred at 100 °C for 1 hr. After completion, the reaction mixture was treated with water, the extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 10% EtOAc in PE) to give 8-bromo-AA I - cyanocyclopropyl)imidazo[l,2-a]pyridine-6-sulfonamide (700 mg). LCMS (ESI, m / z): [M+H]+= 341.0.

[0308] Step 4: 8-(4-acetylpiperazin-l-yl)-M( l-cyanocyclopropyl)imidazo[ l,2-a]pyridine- 6-sulfonamide (Y-4)

[0309] To a solution of 8-bromo-AA 1 -cyanocyclopropyl )imidazo[ 1 ,2-a]pyridine-6- sulfonamide (300 mg, 0.879 mmol) and 1 -piperazin -1 -ylethanone (338 mg, 2.64 mmol) in 1,4-dioxane (25 mL) was added CS2CO3 (859 mg, 2.64 mmol) and Pd-PEPPSLIHept Cl (85.5 mg, 0.088 mmol) under N2. The mixture was degassed, then stirred at 100 °C for 2 hrs under N2 atmosphere. When LC-MS shown reaction completed, the reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 10% MeOH in DCM) to afford 8-(4-acetylpiperazin-l-yl)-A-(l- cyanocyclopropyl)imidazo-[l,2-a]pyridine-6-sulfonamide (220 mg). LCMS (ESI, m / z): [M+H]+= 389.3.

[0310] Step 5: 8-(4-acetylpiperazin-l-yl)- / V-(l-cyanocyclopropyl)-3-iodo-imidazo[l,2- a]pyridine-6-sulfonamide (Y)

[0311] To a mixture of 8-(4-acetylpiperazin- 1 -yl)-A-(l -cyanocyclopropyl )imidazo[ 1 ,2- a]pyridine-6-sulfonamide (140 mg, 0.36 mmol) in ACN (10 mL) was added NIS (122 mg, 0.54 mmol) in portions at 0 °C under N2. After stirring at room temperature for 2 hrs, the reaction mixture was treated with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography onsilica gel (eluting with 50% EtOAc in PE) to afford intermediate Y (100 mg). LCMS (ESI, m / z): [M+H]+= 515.2.

[0312] Intermediate Z in the table below was synthesized using conditions analogous to the preparation of intermediate Y-3 with commercially available chemical reagents. Others (AA to AD) were synthesized using conditions analogous to the synthesis of intermediate Y with commercially available or known chemical reagents.Intermediate AF tert-butyl 4-[6-[tert-butoxycarbonyl-[l-(fluoromethyl)cyclopropyl]sulfamoyl]-7-fluoro-3- iodo-imidazo[l,2-a]pyridin-8-yl]piperazine- 1 -carboxylate (AF)

[0313] Stepl: tert-butyl 4-[6-[tert-butoxycarbonyl-[l- (fluoromethyl)cyclopropyl]sulfamoyl]-3-iodo-imidazo[l,2-a]pyridin-8-yl]piperazine-l- carboxylate (AF-1)

[0314] To a solution of intermediate AC (170 mg, 0.293 mmol) and DMAP (7.2 mg, 0.059 mmol) in DCM (3 mL) was added BOC2O (0.096 g, 0.44 mmol) under N2. After stirring at room temperature for 2 hrs, the reaction mixture was treated with water, then extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous NazSCU, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 14 % EtOAc in PE) to afford tertbutyl 4-[6-[tert-butoxycarbonyl-[l-(fluoromethyl)cyclopropyl]sulfamoyl]-3-iodo- imidazo[l,2-a]pyridin-8-yl]piperazine-l-carboxylate (157 mg). LCMS (ESI, m / z): [M+H]+= 680.0.

[0315] Step 2: tert-butyl 4-[6-[tert-butoxycarbonyl-[l - (fluoromethyl)cyclopropyl]sulfamoyl]-7-fluoro-3-iodo-imidazo[l,2-a]pyridin-8- yl]piperazine-l -carboxylate (AF)

[0316] To a solution of tert-butyl 4-[6-[tert-butoxycarbonyl-[l- (fluoromethyl)cyclopropyl]sulfamoyl]-3-iodo-imidazo[l,2-a]pyridin-8-yl]piperazine-l- carboxylate (100 mg, 0.147 mmol) in DMF (10 mL) was added selectfluor (52.1 mg, 0.147 mmol) under N2. After stirring at room temperature for 1 hr, the reaction mixture was treated with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc in PE) to afford intermediate AF (80 mg). LCMS (ESI, m / z): [M+H]+= 698.2.Intermediate AG tert-butyl 4-(3-iodo-6-(A-(l-methylcyclobutyl)sulfamoyl)imidazo[l,2-a]pyridin-8- yl)piperidine- 1 -carboxylate (AG)

[0317] Intermediate AG was synthesized from Intermediate Z following the strategy of Intermediate Y, via Suzuki coupling, subsequent hydrogenation, and iodination. LCMS (ESI, m / z): [M+H]+= 575.0.Intermediate AH tert-butyl 4-(6-(JV-(1 -(fluoromethyl)cyclopropyl)sulfamoyl)-3-iodoimidazo[l ,2-a]pyridin- 8-yl)piperidine- 1 -carboxy late (AH)

[0318] Intermediate AH was synthesized using conditions analogous to the synthesis of intermediate AG from commercially available chemical reagents. LCMS (ESI, m / z): [M+H]+= 578.7.

[0319] Intermediates Al and AJ in the tables below were synthesized using conditions analogous to the synthesis of 37-7 from commercially available starting materials.Intermediate AK(27?)-2-(methoxymethyl)-l-methylcyclopropan-l-amine hydrochloride (AK)

[0320] Step 1: ethyl (2R)-2-(methoxymethyl)-l -methylcyclopropane- 1 -carboxylate (AK-1)

[0321] To a solution of ethyl 2-diethoxyphosphorylpropanoate (5.30 g, 22.3 mmol) in DME (40 mL) in a sealed tube was added n-BuLi solution (2.5 M in hexane, 9. 12 mL, 22.8 mmol) slowly at room temperature under N2, followed by addition of (2R)-2- (methoxymethyl)oxirane (980 mg, 11.1 mmol). The reaction mixture was stirred at 130 °C for 20 hrs. When reaction completed, it was cooled to rt, then worked up with saturated aqueous NH4CI solution and extracted with ethyl ether. The combined organic layers were dried over anhydrous MgSOr, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 4% EtOAc in PE) to give ethyl (2R)-2-(methoxymethyl)-l-methylcyclopropane-l-carboxylate (5 g).

[0322] Step 2: ( 2R)-2-(methoxymethy 1 )- 1 -methylcyclopropane- 1 -carboxy lie acid (AK-2)

[0323] To a solution of ethyl (2 / ? )-2-( methoxy methyl )- 1 -melhylcyclopropane- 1 - carboxylate (2.3 g, 13.4 mmol) in THF (25 mL) was added aqueous NaOH (3 N, 25 mL, 75 mmol) under N2. The reaction mixture was refluxed for 6 hrs. After cooling to room temperature, the mixture was treated with water, acidified to pH = 1 with aqueous HCI solution (3 N), then extracted with EtOAc. The combined organic layers were washed withbrine, dried over anhydrous Na2SO4, filtered, and concentrated to give (2 / ?)-2- (methoxymethyl)-l-methylcyclopropane-l -carboxylic acid which was used directly in the next step without further purification.

[0324] Step 3: tert-butyl ((21?)-2-(methoxymethyl)-l -methylcyclopropyl )carbamate (AK- 3)

[0325] yo a so]ution of (27?)-2-(methoxymethyl)-l-methylcyclopropane-l-carboxylic acid (1.3 g, 9.02 mmol) in 2-methylpropan-2-ol (25 mL) was added DPPA (3.72 g, 13.5 mmol) under N2. The reaction mixture was stirred at rt for 2 hrs, then heated to 75 °C and stirred for another 16 hrs. After completion, the reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 0 -10% EtOAc in PE) to afford tert -butyl ((2 ?)-2-(methoxymethyl)-l-methylcyclopropyl)carbamate (1 g). H NMR (400 MHz, DMSO-^6) 5 7.10 (s, 1 H), 3.29 (d, 7 = 3.2 Hz, 2H), 3.24 (s, 3H), 1.44-1.31 (m, 9H), 1.21 (s, 3H), 1.12-1.08 (m, 1H), 0.76 (dd, J = 9.6 Hz, 5.0 Hz, 1H), 0.31 (dd, J = 6.4 Hz, 5.0 Hz, 1H).

[0326] Step 4: ( 2Af)-2-( methoxy methyl)- 1 -methylcyclopropan- 1 -amine hydrochloride (AK)

[0327] To a solution of tert-butyl ((27?)-2-(methoxymethyl)-l- methylcyclopropyl)carbamate (1 g, 4.64 mmol) in 1,4-dioxane (15 mL) was added HC1 (4.0 M in 1,4-dioxane, 5 mL). After stirring at room temperature for 3 hrs, the reaction mixture was concentrated to give intermediate AK (400 mg). LCMS (ESI, m / z): [M+H]+= 116.1.

[0328] Intermediates AL and AM were synthesized using conditions analogous to the synthesis of intermediate Y-2 from commercially available chemical reagents.Intermediate AN8-bromo-3-[5-(l-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl]-A-(l- methylcyclopropyl)imidazo[l,2-a]pyridine-6-sulfonamide (AN)

[0329] Step 1: l-[5-[(E)-2-ethoxyvinyl]-l,3,4-thiadiazol-2-yl]cyclopropanecarbonitrile (AN-1)

[0330] To a solution of intermediate N (4.2 g, 18.3 mmol) in 1,4-dioxane (84 mL) and water (8.4 mL) was added 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyLl,3,2-dioxaborolane (8.68 g, 43.8 mmol), Pd(dppf)Ch (1.34 g, 1.83 mmol) and K2CO3 (6.31 g, 45.6 mmol) under N2. The reaction mixture was degassed, then stirred at 100 °C for 2 hrs under N2. Due to incompletion of the reaction, another portion of 2-[(£')-2-ethoxyvinyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (8.68 g, 43.8 mmol) and K2CO3 (6.31 g, 45.6 mmol) was added, degassed, and the reaction mixture was stirred at 100 °C for another 2 hrs under N2. After completion, the reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluting with 20% EtOAc in PE) to obtain 1- [5-[(£')-2- ethoxyvinyl]-l,3,4-thiadiazol-2-yl]cyclopropanecarbonitrile (2.14 g). LCMS (ESI, m / z): [M+H]+= 222.1.

[0331] Step 2: 8-bromo-3-[5-(l-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl]-A-(l- methylcyclopropyl)imidazo[ 1 ,2-a]pyridine-6-sulfonamide (AN)

[0332] To a stirred solution of l-[5-[(£)-2-ethoxyvinyl]-l,3,4-thiadiazol-2- yl]cyclopropanecarbonitrile (970 mg, 4.38 mmol) in 1,4-dioxane (35 mL) and water (11.8 mL) was added 1 -bromopyrrolidine-2, 5-dione (780 mg, 4.38 mmol) at 0 °C. After stirring at room temperature for 1 hr, intermediate AL (1.34 g, 4.38 mmol) was added, and the reaction mixture was stirred at 85 °C for 2 hrs. After completion, the mixture was treated with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purifiedby flash column chromatography on silica gel (eluting with 0-100% EtOAc in PE) to afford intermediate AN (1.62 g). LCMS (ESI, m / z): [M+H]+= 479.1.

[0333] Intermediates AO and AP in the table below were synthesized using conditions analogous to the synthesis of intermediate AN from chemical reagents commercially available, or prepared from commercially available reagents using conventional reactions well known in the art.Intermediate AU6-bromo-4-chloro-5-fluoro- l / 7-indazole (AU)

[0334] Step 1: 4-bromo-2-chloro-3,6-difluoro-benzaldehyde (AU-1)

[0335] To a solution of l-bromo-3-chloro-2,5-difluoro-benzene (10 g, 44.0 mmol) in THF (150 mL) was added with LDA (2.0 M in THF, 26.5 mL, 52.8 mmol) dropwise at -68 °C under N2. After stirring for 30 mins, DMF (3.54 g, 48.4 mmol) was added into the mixture. After stirring at -68 °C under N2 for 1 hr, the reaction mixture was worked up with water below -50 °C, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with 4% EtOAc in PE) to afford 4-bromo-2-chloro-3,6-difluoro-benzaldehyde (6.4 g). LCMS (ESI, m / z): [M+H]+= 254.6.

[0336] Step 2: 6-bromo-4-chloro-5-fluoro-l H-indazole (AU)

[0337] To a solution of 4-bromo-2-chloro-3,6-difluoro-benzaldehyde (1 g, 3.91 mmol) in ethylene glycol (10 mL) was added hydrazine hydrate (85% in water, 922 mg, 15.7 mmol) in a microwave tube. The mixture was irradiated under microwave at 180 °C for 1 hr under N2. When completed, the reaction mixture was worked up with water, then extracted with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 5%- 15% EtOAc in PE) to afford Intermediate AU (0.4 g). LCMS (ESI, m / z): [M+H]+= 248.9.Intermediate AV l-(5-(6-(benzylthio)-4-chloro-5-fluoro-lH-indazol-l-yl)-l,3,4-thiadiazol-2- yl)cyclopropane- 1 -carbonitrile (AV)

[0338] Intermediate AV was synthesized using conditions analogous to the synthesis of intermediate Q from Intermediate AU. LCMS (ESI, m / z): [M+H]+= 442.1

[0339] Intermediates AW and AX in the table below were synthesized using conditions analogous to the synthesis of intermediate N from commercially available starting materials.Intermediate AY ethyl 5-(l-cyanocyclopropyl)-l,3,4-thiadiazole-2-carboxylate (AY)

[0340] Step 1: l-(5-(l-ethoxyvinyl)-l,3,4-thiadiazol-2-yl)cyclopropane-l-carbonitrile (AY-1)

[0341] To a solution of l-(5-bromo-l,3,4-thiadiazol-2-yl)cyclopropanecarbonitrile (8.3 g, 36.1 mmol) and tributyl(l-ethoxyvinyl)stannane (26 g, 72 mmol) in 1,4-dioxane (100 mL) was added Pd(PPh3)2Ch (1.01 g, 1.44 mmol) under N2. The mixture reaction mixture was degassed, and then was stirred at 110 °C for 3 hrs under N2 atmosphere. When completed, the reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 25% EtOAc in PE) to afford l-[5-(l-ethoxyvinyl)- l,3,4-thiadiazol-2-yl]cyclopropanecarbonitrile (6 g).

[0342] Step 2: ethyl 5-(l-cyanocyclopropyl)-l,3,4-thiadiazole-2-carboxylate (AY)

[0343] To a mixture of l-[5-(l-ethoxyvinyl)-l,3,4-thiadiazol-2- yl]cyclopropanecarbonitrile (12 g, 54 mmol) in MeOH (500 mL) was bubbled with ozone at - 78 °C until the mixture turned blue. The reaction mixture was worked up with aqueous Na2S20s dropwise at -10 °C, then was extracted with EtOAc. The combined organic layers were washed by saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 25% EtOAc in PE) to afford intermediate AY (9 g). LCMS (ESI, m / z): [M+H]+= 224.1; ’H NMR (400 MHz, CDCh) 5 4.50 (q, J = 7.2 Hz, 2H), 2.17-2.09 (m, 2H), 2.06-1.98 (m, 2H), 1.44 (t, 7= 7.2 Hz, 3H).

[0344] Intermediates AZ and BA in the table below were synthesized using conditions analogous to the synthesis of intermediate AY. All other starting materials were either prepared as described in the intermediates section, commercially available, or prepared from commercially available reagents using conventional reactions well known in the art.Intermediate BB methyl 5 -(1 -cyanocyclopropyl) picolinate (BB)

[0345] Step 1: l-(6-chloropyridin-3-yl)cyclopropane-l-carbonitrile (BB-1)

[0346] To a solution of 2-(6-chloro-3-pyridyl) acetonitrile (1.0 g, 6.55 mmol) in THF (30 mL) was added NaH (60% dispersion in oil, 655 mg, 16.4 mmol) at 0 °C under N2. After stirring for 10 mins, 1,2-dibromoethane (2.95 g, 15.7 mmol) was added dropwise over 15 mins under N2. After stirring at room temperature for 1 hr, the reaction mixture was worked up with water, then extracted with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous NazSCU. filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 45% DCM in PE) to afford l-(6-chloropyridin-3-yl)cyclopropane-l -carbonitrile (800 mg). LCMS (ESI, m / z): [M+H]+= 179.0

[0347] Step 2: methyl 5-(l-cyanocyclopropyl) picolinate (BB)

[0348] To a solution of l-(6-chloropyridin-3-yl)cyclopropane-l-carbonitrile (2 g, 11.2 mmol) in MeOH (20 mL) was added TEA (1 mL) and Pd(dppf)Ch (1.64 g, 2.24 mmol) under N2. The reaction mixture was degassed, then stirred at 100 °C for 3 hrs under CO (10 atm). When completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with 50% EtOAc in PE) to give intermediate BB (1.3 g). LCMS (ESI, m / z): [M+H]+= 203.1

[0349] Intermediates BC, BD and BE in the table below were synthesized using conditions analogous to the synthesis of 39-9. All other starting materials were either prepared as described in the intermediates section, commercially available, or prepared from commercially available reagents using conventional reactions well known in the art.Intermediate BF3-bromo-5-[(4- / er / -butylphenyl)methylsulfanyl]pyridine-2-carbonitrile (BF)

[0350] To a solution of 3-bromo-5-fluoro-pyridine-2-carbonitrile (20 g, 99.5 mmol) in DMF (130 mL) was added CS2CO3 (64.8 g, 199 mmol) and (4-terr-butylphenyl)methanethiol (17.9 g, 99.3 mmol) under N2. After stirring at 60 °C for 1 hr, the reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 5% EtOAc in PE) to afford Intermediate BF (33 g). LCMS (ESI, m / z): [M+H]+= 361.0.Intermediate BG and Intermediate BH8-chloro-3 -(5 -( 1 -cyanocyclopropyl)- 1 ,3 ,4-thiadiazol-2-yl)-A-( 1 - (fluoromethyl)cyclopropyl)imidazo[l,5-a]pyridine-6-sulfonamide (BG) and 1,8-dichloro-3-(5-(l-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl)-j'V-(l-(fluoromethyl)cy clopropyl)imidazo [1,5- a]pyridine- 6- sulfonamide (BH)

[0351] Step: l 5-((4-(rerr-butyl)benzyl)thio)-3-chloropicolinonitrile (BG-1)

[0352] To a solution of 5-bromo-3-chloro-pyridine-2-carbonitrile (10 g, 46mmol) in 1 ,4- dioxane (190 mL) was added (4-ter / -butylphenyl)methanethiol (8.29 g, 46 mmol), Pd2(dba)3 (4.21 g, 4.60 mmol), Xantphos (5.32 g, 9.20 mmol) and DIPEA (17.8 g, 138 mmol ) at room temperature under N2 atmosphere. The reaction mixture was degassed, then stirred at 100 °C for 2 hrs under N2. When completed, the reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous NazSO-i, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 10 % EtOAc in PE) to give 5-[(4-rert-butylphenyl)methylsulfanyl]-3-chloro-pyridine-2-carbonitrile (4.6 g). LCMS (ESI, m / z): [M+H]+= 317.2

[0353] Step:2 (5-((4-(terf-butyl)benzyl)thio)-3-chloropyridin-2-yl)methanamine (BG-2)

[0354] To a stirred solution of 5-[(4- / er / -butylphenyl)methylsulfanyl]-3-chloro-pyridine-2-carbonitrile (4.6 g, 14.5 mmol) in DCM (50 mL) was added DIBAL-H (1.0 M in heptane,43.5 mL, 43.5 mmol) dropwise at -78 °C under N2. After stirring for 1 hr, the reaction mixture was worked up with water followed by 15% NaOH aq. solution, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous NaiSC , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting 0-10% MeOH in DCM) to afford [5-[(4-tert- butylphenyl)methylsulfanyl]-3-chloro-2-pyridyl]methanamine (2.8 g). LCMS (ESI, m / z): [M+H]+= 321.3.

[0355] Step:3 tert-butyl ((5-((4-(tert-butyl)benzyl)thio)-3-chloropyridin-2- yl)methyl)carbamate (BG-3)

[0356] To a mixture of (5-((4-(tert-butyl)benzyl)thio)-3-chloropyridin-2-yl)methanamine(750 mg, 2.3 mmol) and DIPEA (906 mg, 7.0 mmol) in DCM (10 mL) was added (Boc)2O (612 mg, 2.8 mmol) at 0 °C under N2. After stirring at room temperature for 4 hrs, the reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 10% EtOAc in PE) to afford tert-butyl / V-| |5-| (4- tert-butylphenyl)methylsulfanyI]-3-chloro-2-pyridyl]methyl]carbamate (800 mg). LCMS (ESI, m / z): [M+H]+= 421.3.

[0357] Step:4 tert-butyl ((3-chloro-5-(chlorosulfonyl)pyridin-2-yl)methyl)carbamate(BG-4)

[0358] To a mixture of terf-butyl / / -[[5-[(4-tert-butylphenyl)methylsulfanyl]-3-chloro-2- pyridyl]methyl]carbamate (10 g, 23.8 mmol), formic acid (36 mL) and H2O (17 mL) in DCM (500 mL) was added NCS (12.7 g, 95.0 mmol) in portions at 0 °C under N2. After stirring at room temperature for 2 hrs, the mixture was worked up with water, then extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 20% EtOAc in PE) to afford tert-butyl 7\7-[(3- chIoro-5-chlorosuIfonyl-2-pyridyI)methyI]carbamate (8.1 g).

[0359] Step 5: tert-butyl ((3-chloro-5-(Ar-( l - (fluoromethyl)cycIopropyI)suIfamoyl)pyridin-2-yl)methyl)carbamate (BG-5)

[0360] To a solution of l-(fluoromethyl)cyclopropan-l -amine hydrochloride (9.38 g, 75 mmol) in pyridine (45 mL) was added a solution of tert-butyl N-[(3-chloro-5-chlorosulfonyL2-pyridy])methyl]carbamate (17 g, 50 mmol) in DCM (45 mL) under N2. After stirring at room temperature for 4 hrs, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 16% EtOAc in PE) to afford tert-butyl A -[[3-chloro-5- [[ l-(fhioromethyl)cyclopropyl Jsulfamoyl ]- 2-pyridyl]methyl]carbamate (10.4 g). LCMS (ESI, m / z): [M+H]+= 394.1.

[0361] Step 6: 6-(aminomethyl)-5-chloro- -(l-(fluoromethyl)cyclopropyl)pyridine-3- sulfonamide (BG-6)

[0362] To a solution of tert-butyl ((3-chloro-5-(? / -(l-(lluoromethyl)cyclopropyl)sulfamoyl)pyridin-2-yl)methyl)carbamate (40 g, 102 mmol) in DCM (250 mL) was added HC1 (4.0 M in 1,4-dioxane, 50 mL). After stirring at room temperature for 1 hr, the reaction mixture was concentrated to give the product as HC1 salt which was used in the next step without further purification. LCMS (ESI, m / z): [M+H]+=294.1.

[0363] Step 7: 7V-((3-chloro-5-(7V-(l -(fluoromethyl)cyclopropy])sulfamoyl)pyridin-2- yl)methyl)-5-(l-cyanocyclopropyl)-l,3,4-thiadiazole-2-carboxamide (BG-7)

[0364] To a solution of 6-(aminomethyl)-5-chloro-7V-[ 1-(fluoromethyl)cyclopropyl]pyridine-3-sulfonamide HC1 salt (8.7 g, 26.3 mmol) in MeOH (50 mL) was added ethyl 5-(l-cyanocyclopropyl)-l,3,4-thiadiazole-2-carboxylate (6.61 g, 29.6 mmol) and DIPEA (15.3 g, 118 mmol) under N2. After stirring at room temperature for 18 hrs, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel chromatography (eluting with 40% EtOAc in PE) to afford ?7-[[3-chloro-5-[[ l-(fluoromethyl)cyclopropyl]sulfamoyl ]-2-pyridyl]methyl]-5- (l-cyanocyclopropyl)-l,3,4-thiadiazole-2-carboxamide (8.5 g). LCMS (ESI, m / z): [M+H]+=471.1.

[0365] Step 8: 8-chloro-3-(5-(l-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl)-7V-(l-(fluoromethyl)cyclopropyl)imidazo[l,5-a]pyridine-6-sulfonamide (BG, Example 83)

[0366] To a solution of 7V-[[3-chloro-5-[[l-(fluoromethyl)cyclopropyl]sulfamoyl]-2- pyridyl]methyl]-5-(l-cyanocyclopropyl)-l,3,4-thiadiazole-2-carboxamide (8.5 g, 18 mmol) in 1,4-dioxane (160 mL) was added POCI3 (16.8 mL) under N2. After stirring at 120 °C for 6 hrs, the reaction mixture was concentrated under reduced pressure. The residue was washed with EtOH twice, filtered to give the filter cake, which was dried under reduced pressure to give intermediate BG (6.24 g). The crude product of intermediate BG was further purified viaprep-HPLC (0.1 % FA) to give high purity product example 83 for biology assay. LCMS (ESI, m / z): [M+H]+= 453.2 *H NMR (400 MHz, DMSO-tfc) 5 9.75 (s, 1H), 7.99 (s, 1H), 7.43 (s, 1H), 4.23 (d, / = 48.8 Hz, 2H), 2.21-2.15 (m, 2H), 2.01-1.95 (m, 2H), 0.90-0.73 (m, 4H).

[0367] Step 9: l,8-dichloro-3-(5-(l-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl)-jV-(l-(fluoromethyl)cyclopropyl)imidazo[l,5-a]pyridine-6-sulfonamide (BH, Example 113)

[0368] To a solution of 8-chloro-3-[5-(l-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl]- / V-[l-(fluoromethyl)cyclopropyl]imidazo[l,5-a]pyridine-6-sulfonamide (200 mg, 0.44 mmol) in DCM (20 mL) was added l,3-dichloro-5,5-dimethyl-imidazolidine-2, 4-dione (261 mg, 1.32 mmol) at 0 °C under N2. After stirring at room temperature for 30 mins, the reaction mixture was worked up with saturated aqueous solution ^2826)3, then extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na SO-i, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc in PE) to afford Intermediate BH (212 mg). Intermediate BH was further purified by prep-HPLC (0.1% FA) to give Example 113 for biology assay. LCMS (ESI, m / z): [M+H]+= 487.2; *H NMR (400 MHz, DMSO-A) 5 9.76 (s, 1H), 8.98 (brs, 1H), 7.43 (s, 1H), 4.26 (d, J = 48.8 Hz, 2H), 2.24-2.19 (m, 2H), 2.02- 1.97 (m, 2H), 0.91-0.78 (m, 4H).

[0369] Intermediates in the table below were synthesized using conditions analogous to the synthesize of intermediate BG or BH. For synthesis of intermediate BS, the last step was fluorination with selectfluor. All other starting materials were either prepared as described in the intermediates section, commercially available, or prepared from commercially available reagents using conventional reactions well known in the art.Intermediate BTN-( 1 -oxo- 1 ,4-thiazinan- 1 -ylidene)acetamide (BT)

[0370] Step 1: benzyl thiomorpholine-4-carboxylate (BT-1)

[0371] To a solution of thiomorpholine (2.2 g, 21.3 mmol) and NaHCOs (3.58 g, 42.6 mmol) in THF (20 mL) and Water (5 mL) was added benzyl carbonochloridate (5.46 g, 32 mmol) at 0 °C under N2. After stirring at room temperature for 16 hrs, the reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous N 2SC>4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc in PE) to afford benzyl thiomorpholine-4-carboxylate (4.6 g). LCMS (ESI, m / z): [M+H]+= 238.1.

[0372] Step 2: benzyl 1 -imino- 1 -oxo- 1 ,4-thiazinane-4-carboxylate (BT-2)

[0373] To a solution of benzyl thiomorpholine-4-carboxylate (2.5 g, 10.5 mmol) and ammonium carbamate (4.11 g, 52.7 mmol) in MeOH (40 mL) was added [acetoxy(phenyl)- iodanyl] acetate (17.0 g, 52.7 mmol) at portions at room temperature. After stirring at room temperature for 3 hrs, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 5% MeOH in DCM) to afford benzyl 1 -imino- 1 -oxo- l,4-thiazinane-4-carboxylate (2.4 g). LCMS (ESI, m / z): [M+H]+= 269.1.

[0374] Step 3: benzyl 1 -acetylimino- 1 -oxo- l,4-thiazinane-4-carboxylate (BT-3)

[0375] To a solution of benzyl 1 -imino- 1 -oxo- 1 ,4-thiazinane-4-carboxylate (2.4 g, 8.9 mmol) and TEA (1.81 g, 17.9 mmol) in DCM (20 mL) was added acetyl chloride (843 mg, 10.7 mmol) at 0 °C under N2. After stirring at room temperature for 3 hrs, the reaction mixture was worked up with water, then extracted with EtOAc. The combined organiclayers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 50% EtOAc in PE) to afford benzyl 1 -acetylimino- 1 -oxo- 1,4- thiazinane-4-carboxylate (2.5 g). LCMS (ESI, m / z): [M+H]+= 311.0.

[0376] Step 4: / V-(l-oxo-l,4-thiazinan-l-ylidene)acetamide (BT)

[0377] To a solution of benzyl 1 -acetylimino- 1 -oxo- 1 ,4-thiazinane-4-carboxylate (1.5 g, 4.83 mmol) in MeOH (20 mL) was added Pd / C (10% palladium on carbon, wetted with ca. 55%, water for safety, 200 mg) under N2. The reaction mixture was purged with H?, then stirred at room temperature for 12 hrs under H2 (1 atm). When completed, the reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to afford intermediate BT (700 mg). LCMS (ESI, m / z): [M+H]+= 177.0.Intermediate BY / -butyl (.S')-2-( lluoromethyl)pi perazine- 1 -carboxylate (BY)

[0378] Step 1: benzyl (.SJ-3-(hydroxymethyl)piperazine- 1 -carboxylate (BY-1)

[0379] To a solution of 4-benzyl 1 -(tert-butyl) (S)-2-(hydroxymethyl)piperazine-l,4- dicarboxylate (5.5 g, 15.7 mmol) in DCM (60 mL) was added TFA (30 mL). After stirring at room temperature for 1 hr, the reaction mixture was concentrated in vacuo. The residue was worked up with water, adjusted to pH = 9 with saturated aqueous Na^COr solution, then extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give benzyl (5)-3-(hydroxymethyl) piperazine- 1- carboxylate (3.5 g). LCMS (ESI, m / z): [M+H]+= 251.1.

[0380] Step 2: benzyl (3alS')-tetrahydro-[l,2,3]oxathiazolo[3,4-a]pyrazine-5(3 / / )- carboxylate 1 -oxide (BY-2)

[0381] To a solution of benzyl (5)-3-(hydroxymethyl) piperazine- 1 -carboxylate (2 g, 8.0 mmol), imidazole (1.63 g, 24 mmol) and TEA (2.02 g, 20.0 mmol) in DCM (40 mL) was added SOCh (1.14 g, 9.6 mmol) dropwise at 0 °C under N2. After stirring at room temperature for 16 hrs, the reaction mixture was treated with saturated aqueous NH4CI solution, then extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SC>4, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting with 15% EtOAc in PE) to afford benzyl (3a>S’)-tetrahydro-[l,2,3]oxathiazolo[3,4-a]pyrazine-5(3H)-carboxylate 1-oxide (2.3 g). LCMS (ESI, m / z): [M+H]+= 297.1.

[0382] Step 3: benzyl (5')-tetrahydro-[L2,3]oxathiazolo[3,4-a]pyrazine-5(3 / 7)-carboxylate 1,1 -dioxide (BY-3)

[0383] To a solution of benzyl (3aS)-tetrahydro-[ 1 ,2,3 ]oxathiazolo[3,4-a]pyrazine-5(377)- carboxylate 1-oxide (2.3 g, 7.8 mmol) and RuCh xFhO (32.2 mg, 0.15 mmol) in EtOAc (25 mL), acetonitrile (60 mL) and water (60 mL) was added NaIO4 (4.15 g, 19.4 mmol) in portions at 0 °C. After stirring at room temperature for 1 hr, the reaction mixture was worked with saturated aqueous NH4CI solution, then extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 15% EtOAc in PE) to afford benzyl (S)-tetrahydro- [l,2,3]oxathiazolo[3,4-a]pyrazine-5(377)-carboxylate 1,1-dioxide (1.7 g). LCMS (ESI, m / z): [M+H]+= 313.1.

[0384] Step 4: (S)-4-((benzyloxy)carbonyl)-2-(fluoromethyl)piperazine-l -sulfonic acid (BY-4)

[0385] To a solution of benzyl (S')-tetrahydro-[l,2,3]oxathiazolo[3,4-a]pyrazine-5(37 / )- carboxylate 1,1-dioxide (1 g, 3.2 mmol) in THF (40 mL) was added TBAF (1.0 M in THF, 8 mL, 8.0 mmol) under N2. After stirring at reflux for 1.5 hrs, the reaction mixture was concentrated in vacuo to give the product BY-4 which was used directly in the next step without further purification. LCMS (ESI, m / z): [M-H] = 331.2.

[0386] Step 5: benzyl (S)-3-(fluoromethyl)piperazine-l-carboxylate (BY-5)A mixture of (S)-4-((benzyloxy)carbonyl)-2-(fluoromethyl)piperazine-l -sulfonic acid (1 g, 3.0 mmol) in 1,4-dioxane (20 mL) was added HC1 solution (4.0 M in 1,4-dioxane, 10 mL) dropwise at 0 °C under N2. After stirring at room temperature for 1 hr, the reaction mixture was concentratedto give benzyl (S)-3-(fluoromethyl)piperazine-l -carboxylate which was used directly in the next step. LCMS (ESI, m / z): [M+H]+= 253.2.

[0387] Step 6: 4-benzyl 1 -( rt-butyl) (5)-2-( fluoromethyl )piperazine- 1 ,4-dicarboxyl ate (BY-6)

[0388] To a solution of benzyl CS')-3-( fluoromethyl (piperazine- 1 -carboxylate (870 mg, 3.45 mmol) in THF (30 mL) was added TEA (1.05 g, 10.4 mmol) and (BochO (828 mg, 3.8 mmol) under N2. After stirring at room temperature for 2.5 hrs, the reaction mixture was worked up with water, then extracted with DCM. The combined organic layers were washed with saturated aqueous NH4CI solution, dried over anhydrous NkoSOr, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 15% EtOAc in PE) to afford 4-benzyl 1 -(tert-butyl) (S)-2- (fluoromethyl)piperazine-l,4-dicarboxylate (1 g). LCMS (ESI, m / z): [M+H-56]+= 297.2.

[0389] Step 7: tert-butyl CS')-2-( 11 uoromethy I (piperazine- 1 -carboxy late (BY)

[0390] To a mixture of 4-benzyl l-(tert-butyl) i.S')-2-( fluoromethyl (piperazine- 1 ,4- dicarboxylate (800 mg, 2.27 mmol) in methanol (24 mL) was added Pd / C (10% palladium on carbon, wetted with ca. 55% water for safety, 800 mg) under N2. The mixture was purged with H2, then stirred at room temperature for 2 hrs under H2 atmosphere (1 atm). After completion, the reaction mixture was filtered through a Celite pad. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 0-4% MeOH in DCM) to afford intermediate BY (400 mg). LCMS (ESI, m / z): [M+H-56]+= 163.1.Intermediate BZ ter / -butyl ( / ?)-2-( fluoromethyl (piperazine- 1 -carboxylate (BZ)Boc BZ

[0391] Intermediate BZ was synthesized using conditions analogous to the synthesis of intermediate BY from commercially available chemical reagents. LCMS (ESI, m / z): |M+H- 56]+= 163.1.Intermediate CA(2S)-2-(difluoromethyl)piperazine (CA)

[0392] Step 1: rd / 7-bulyl (S)-3-(hydroxymethyl)-4-(4-methoxybenzyl)piperazine-l- carboxylate (CA-1)

[0393] A solution of tert-butyl ( 3S)-3-( hydroxy methy 1 )piperazine- 1 -carboxylate (5 g, 23 mmol), l-(chloromethyl)-4-methoxy-benzene (3.98 g, 25 mmol) and TEA (4.68 g, 46 mmol) in THF (15 mL) was stirred at reflux for 16 hrs under N2. After completion, the reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel to afford tert-butyl (3S)-3-(hydroxymethyl)-4-[(4- methoxyphenyl)methyl]piperazine-l -carboxylate (6 g). LCMS (ESI, m / z): [M+H]+= 337.4.

[0394] Step 2: tert-butyl (>S’)-3-formyl-4-(4-methoxybenzyl)piperazine- 1 -carboxylate (CA-2)

[0395] To a solution of oxalyl chloride (4.53 g, 36 mmol) in DCM (10 ml) was added DMSO (4.18 g, 54 mmol) in DCM (4.5 mL) dropwise at -65 °C. After stirring at -65 °C for 10 mins, tert-butyl (3S')-3-(hydroxymethyl)-4-[(4-methoxyphenyl)methyl]piperazine-l- carboxylate (6 g, 17.8 mmol) in DCM (7 ml) was added dropwise at -65 °C under N2. After stirring at -65 °C for 1.5 hrs, TEA (10.8 g, 107 mmol) was added to the mixture. The reaction mixture was warmed to 0 °C, then the reaction mixture was worked up with saturated aqueous NH4CI and extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford tert-butyl (3S)-3-formyl-4-[(4-methoxyphenyl)methyl]piperazine-l -carboxylate (5 g). LCMS (ESI, m / z): [M+H]+= 335.2.

[0396] Step 3: tert-butyl (5)-3-(difluoromethyl)-4-(4-methoxybenzyl)piperazine- 1 - carboxylate (CA-3)

[0397] To a solution of tert-butyl (3S)-3-formyl-4-[(4-methoxyphenyl)methyl ]piperazine- 1-carboxylate (6 g, 17.9 mmol) in DCM (16 mL) was added DAST (5.78 g, 36 mmol) at 0 °C under N2. After stirring at room temperature for 5 hrs, the reaction mixture was worked up with saturated aqueous NH4CI solution, then extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 35% EtOAc in PE) to afford tert-butyl (3S)-3- (difluoromethyl)-4-[(4-methoxyphenyl)methyl]piperazine-l -carboxylate (2.98 g). LCMS (ESI, m / z): [M+H]+= 357.4.

[0398] Step 4: (S)-2-(difluoromethyl)-l-(4-methoxybenzyl)piperazine (CA-4)

[0399] To a solution of tert-butyl (3S)-3-(difluoromethyl)-4-[(4- methoxyphenyl)methyl]piperazine-l -carboxylate (300 mg, 0.84 mmol) in DCM (2 mL) was added HC1 (4.0 M in 1,4-dioxane, 2 mL). After stirring at room temperature for 3 hrs, the reaction mixture was worked up with saturated aqueous NaiCCL solution, then extracted by DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 5% MeOH in DCM) to afford (25)-2- (difluoromethyl)-l-[(4-methoxyphenyl)methyl]piperazine (156 mg). LCMS (ESI, m / z): [M+H]+= 257.1.

[0400] Step 5: (2S’)-2-(difluoromethyl)piperazine (CA)

[0401] A solution of (2S)-2-(difluoromethyl)-l-[(4-methoxyphenyl)methyl]piperazine(1.4 g, 5.46 mmol) in TFA (10 mL) was stirred at 80 °C for 3 hrs. When the reaction completed, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 10% MeOH in DCM) to afford intermediate CA (415 mg).!H NMR (400 MHz, CDCh) 5 5.62 (td, J = 56.4 Hz, 5.6 Hz, 1H), 3.13-2.89 (m, 4H), 2.84-2.70 (m, 2H), 2.65 (m, 1H).Intermediate CB1 -(5 -Bromothiazol-2-yl)cyclopropane- 1 -carbonitrile (CB)

[0402] Step 1: 2-(Thiazol-2-yl)acetonitrile (CB-1)

[0403] To a stirred solution of tert-butyl 2-cyanoacetate (22.4 g, 159 mmol) in DMF (50 mL) was added NaH (60% dispersion in mineral oil, 5.85 g, 146 mmol) in portions at 0 °C under N2 atmosphere. After stirring at 0 °C for 10 min, 2-bromothiazole (20.0 g, 122 mmol) in DMF (50 mL) was added stepwise. The resulting mixture was stirred for an additional 15 mins at room temperature, then stirred for 2 hrs at 120 °C under N2. When the reaction completed, the reaction mixture was acidified to pH = 4 with aqueous HC1 solution (IN), then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in toluene (50 mL), then TsOH (2.10 g, 12 mmol) was added at room temperature. After stirring for an additional 2 hrs at 105 °C, the reaction mixture was worked up with saturated aqueous sodium bicarbonate, then extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 35% EtOAc in PE) to afford 2-(thiazoL2-yl)acetonitrile (6.86 g). LCMS (ESI, m / z): [M+H]+= 125.0; 'H NMR (400 MHz, CDC13) 5 7.81 (d, 7 = 3.2 Hz, 1H), 7.41 (d, 7 = 3.2 Hz, 1H), 4.18 (s, 2H).

[0404] Step 2: l-(thiazol-2-yl)cyclopropane-l -carbonitrile (CB-2)

[0405] To a stirred mixture of 2-(thiazol-2-yl)acetonitrile (6.86 g, 55 mmol) in THF (80 mL) was added NaH (60% dispersion in mineral oil, 2.65 g, 66 mmol), followed by 1,2- dibromoethane (15.6 g, 83 mmol) at 0 °C under N2. After stirring for 1 hr at room temperature under N2 atmosphere, the reaction mixture was quenched with saturated aqueous NH4CI solution, then was extracted with EtOAc. The combined organic layers were dried over anhydrous Na SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 12% EtOAc in PE) togive l -(thiazol-2-yl)cyclopropane-l -carbonitrile (5.34 g). LCMS (ESI, m / z): [M+H]+= 151.0; ’H NMR (400 MHz, DMS0-< / 6) 8 7.75 (d, J = 3.2 Hz, 1H), 7.70 (d, J= 3.2 Hz, 1H), 1.98 (m, 2H), 1.75 (m, 2H).

[0406] Step 3: l-(5-Bromothiazol-2-yl)cyclopropane-l -carbonitrile (CB)

[0407] A solution of l-(thiazol-2-yl)cyclopropane-l-carbonitrile (5.2 g, 34.6 mmol) and NBS (6.16 g, 34.6 mmol) in ACN was stirred for 2 hrs at 80 °C under N2 atmosphere. When reaction completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 5% EtOAc in DCM) to give intermediate CB (6.1 g). LCMS (ESI, m / z): [M+H]+= 228.9; H NMR (400 MHz, DMSO-6) 8 7.85 (s, 1H), 2.05-1.93 (m, 2H), 1.84-1.73 (m, 2H).Intermediate CC l,8-dichloro-3-(5-(l-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl)-A-(l- methylcyclopropyl)imidazo[l,5-a]pyridine-6-sulfonamide (CC)

[0408] Intermediate CC was synthesized from intermediate BI by using conditions analogous to the synthesize of intermediate BH. LCMS (ESI, m / z): [M+H]+= 469.1.Intermediate CD2-methyl-l-oxa-3,8-diazaspiro[4.5]dec-2-ene (CD)

[0409] Step 1 : tert-butyl 2-methyl-l-oxa-3,8-diazaspiro[4.5]dec-2-ene-8-carboxylate(CD-I)

[0410] To a solution of tert-butyl 4-(aminomethyl)-4-hydroxy-piperidine-l -carboxylate (4 g, 17.4 mmol) in MeOH (30 mL) was added KOH (1.58 g, 28.2 mmol), followed by a solution of ethyl ethanimidate hydrochloride (4.47 g, 36.2 mmol) in MeOH (10 mL) under N2 atmosphere at room temperature. After stirring at 80 °C for 16 hrs, the reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with water and saturated sodium sulfite solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 3-5% MeOH in DCM) to afford terr-butyl 2-methyl-l-oxa-3,8- diazaspiro[4.5]dec-2-ene-8-carboxylate (3.0 g). LCMS (ESI, m / z): [M+H]+= 255.3.

[0411] Step 2: 2-methyl-l-oxa-3,8-diazaspiro[4.5]dec-2-ene (CD)

[0412] A mixture of tert-butyl 2-methyl-l-oxa-3,8-diazaspiro[4.5]dec-2-ene-8- carboxylate (900 mg, 3.54 mmol) in l,l,l,3,3,3-hexafluoropropan-2-ol (10 mL) was stirred at 120 °C for 2 hrs under microwave. After completion, the reaction mixture was concentrated in vacuo to give a residue which was purified by silica gel column chromatography (eluting with 10% MeOH in DCM) to afford intermediate CD (100 mg). LCMS (ESI, m / z): [M+H]+= 155.3.Intermediate CE(J?)-2-(difluoromethyl)piperazine (CE)

[0413] Intermediate CE was synthesized using conditions analogous to the synthesis of intermediate CA from commercially available chemical reagents, ' l l NMR (400 MHz, DMSO-O 5 5.79 (td, J = 61.6 Hz, 5.2 Hz, 1H), 2.82-2.75 (m, 3H), 2.69-2.66 (m, 1H), 2.59- 2.55 (m, 1H), 2.45-2.38 (m, 2H).Intermediate CF rac-(17?,2R)-2-(2-methoxyethyl)-l-methylcyclopropan-l-amine (CF)chloro(triisopropoxy)titaniumACN, THF, -78 °C-rtCF-1 CF-2

[0414] Step 1: / 'ac-2-[(lR,27?)-2-amino-2-methyl-cyclopropyl]ethanol (CF-1)

[0415] To a solution of chloro(triisopropoxy)titanium (1.0 M in THF, 27.7 mmol, 27.7 mL) in THF (60 mL) was added chloro(cyclohexyl)magnesium (2.0 M in Et20, 69.4 mmol, 34.7 mL) dropwise at -78 °C under N2 atmosphere. After stirring at -78 °C for 45 mins, a mixture of but-3-en-l-ol (1 g, 13.9 mmol) and acetonitrile (1.14 g, 27.7 mmol, 1.45 mL) in THF (60 mL) was added. The reaction mixture was allowed to warm to room temperature (over approximately 1.5 hrs), stirred for an additional 16 hrs. The reaction mixture was worked up with 10% aqueous NaOH solution, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous NaiSCh, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with 20% MeOH in DCM) to afford rac-2-[(17?,2R)-2-amino-2- methyl-cyclopropyl]ethanol (350 mg).

[0416] Step 2: rac-tert-butyl ((lR,2R)-2-(2-hydroxyethyl)-l- methylcyclopropyl)carbamate (CF-2)

[0417] To a solution of rac-2-[(lR,2R)-2-amino-2-methyl-cyclopropyl]ethanol (1 g, 8.68 mmol) and TEA (1.05 g, 10.4 mmol) in DCM (20 mL) was added BOC2O (1.99 g, 9.12 mmol) under N2. After stirring at room temperature for 2 hrs, the reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 50% EtOAc in PE) to afford rac-2-[(lR,2R)-2-amino-2-methyl-cyclopropyl]ethanol (1.4 g). *H NMR (400 MHz, DMSO-d6) 5 6.82 (s, 1H), 4.43 (m, 1H), 3.56-3.39 (m, 2H), 1.58 (m, 1H), 1.37 (s, 9H), 1.25-1.16 (m, 4H), 0.70 (m, 1H), 0.55 (m, 1H), 0.28 (m, 1H).

[0418] Step 3: rac-rert-butyl ((lR,2R)-2-(2-methoxyethyl)-l- methylcyclopropyl)carbamate (CF-3)

[0419] To a solution of rac-2-[(17?,27?)-2-amino-2-methy]-cyclopropyl]ethanol (500 mg, 2.32 mmol) and Ag2O (861 mg, 3.72 mmol) in MeCN (15 mL) was added iodomethane (5.60 g, 39.5 mmol) under N2. After stirring at 80 °C for 16 hrs, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc in PE) to afford rac-tert-butyl (\R,2R)-2-(2- methoxyethyl)-l-methylcyclopropyl)carbamate (245 mg).1H NMR (400 MHz, DMSO-de) 8 6.83 (s, 1H), 3.37 (t, J = 6.8 Hz, 2H), 3.23 (s, 3H), 1.65 (m, 1H), 1.37 (s, 9H), 1.32-1.15 (m, 4H), 0.69 (m, 1H), 0.54 (m, 1H), 0.30 (m, 1H).

[0420] Step 4: rac-(17?,27?)-2-(2-methoxyethyl)-l-methylcyclopropan-l-amine (CF)

[0421] To a solution of rac-tert-butyl ((17?,2R)-2-(2-methoxyethyl)-l- methylcyclopropyl)carbamate (245 mg, 1.07 mmol) in DCM was added HC1 (4.0 M in 1,4- dioxane, 5 mL) under N2. After stirring at room temperature for 2 hrs, the reaction mixture was concentrated in vacuo to afford intermediate CF as HC1 salt (138 mg) which was use in the next step directly.Intermediate CG( 1. S', 2Afi-2-( methoxymethyl )- l-methylcyclopropan- l -amine (CG)

[0422] Intermediate CG-SM was synthesized following the referenceChim. Acta, 1989, 72, 1301.”

[0423] Step 1: (lS,5R)-l-(bromomethyl)-3-oxabicyclo[3.1.0]hexan-2-one (CG-1)

[0424] To a solution of (15',57?)-l-(hydroxymethyl)-3-oxabicyclo[3.1.0]hexan-2-one (1.0 g, 7.8 mmol) in DCM (10 mL) was added PBrs (2.11 g, 7.81 mmol) under N2 atmosphere.After stirring at room temperature for 1 hr, the reaction mixture was worked up with water, then extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (eluting with 25% EtOAc in PE) to afford ( 1 R,5R)- 1 - (bromomethyl)-3-oxabicyclo[3.1.0]hexan-2-one (600 mg).]H NMR (400 MHz, CDCh) 8 4.34 (dd, 7 = 9.2 Hz, 4.8 Hz, 1H), 4.16 (d, J = 9.2 Hz, 1H), 4.10 (d, 7 = 11.2 Hz, 1H), 3.29 (d, J = 11.2 Hz, 1H), 2.36 (m, 1H), 1.49 (m, 1H), 1.27 (t, J = 4.8 Hz, 1H).

[0425] Step 2: (lS,5R)-l-methyl-3-oxabicyclo[3.1.0]hexan-2-one (CG-2)

[0426] To a solution of (lR,5R)-l-(bromomethyl)-3-oxabicyclo[3.1.0]hexan-2-one (600 mg, 3.14 mmol) in MeOH (5 mL) was added DIPEA (487 mg, 3.77 mmol) and Pd / C (palladium on carbon, wetted with ca.55% water for safety, 67 mg) under N2 atmosphere. The mixture was degassed, then stirred at room temperature under H2 (1 atm) for 6 hrs. After completion, the mixture was filtered through a celite pad. The filtrate was concentrated in vacuo to give a residue which was purified by flash column chromatography on silica gel (eluting with 25% EtOAc in PE) to afford (18',5R)-l-methyl-3-oxabicyclo[3. L0]hexan-2-one (300 mg).]H NMR (400 MHz, CDCh) 6 4.26 (dd, J = 9.2 Hz, 4.8 Hz, 1H), 4.09 (d, J = 9.2 Hz, 1H), 2.05 (m, 1H), 1.38 (s, 3H), 1.06 (m, 1H), 0.90 (t, J = 4.6 Hz, 1H).

[0427] Step 3: methyl (lS,2R)-2-(methoxymethyl)-l-methylcyclopropane-l-carboxylate (CG-3)

[0428] To a solution of (1 S’, 5R)-l-methyl-3 -oxabicyclo [3.1.0]hexan-2-one (300 mg, 2.68 mmol) in MeOH (10 mL) was added trimethoxymethane (539 mg, 5.08 mmol) and concentrated H2SO4 (0.14 mL) under N2. After stirring at 60 °C for 2 hrs, the reaction mixture was concentrated, then partitioned between with water and DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 15% MeOH in DCM) to afford methyl (15',2R)-2-(methoxymethyl)-l-methyl-cyclopropanecarboxylate (200 mg). *H NMR (400 MHz, CDCh) 8 3.68 (s, 3H), 3.62 (dd, 7 = 10.6 Hz, 5.8 Hz, 1H), 3.38 (dd, 7 = 10.6 Hz, 8.2 Hz, 1H), 3.27 (s, 3H), 1.39-1.26 (m, 5H), 0.85 (m, 1H).

[0429] Intermediate CG was synthesized from CG-3 using conditions analogous to that used to synthesize intermediate AK, via hydrolysis, subsequent curtius reaction and Boc deprotection with >98% ee.]H NMR (400 MHz, DMSO-tfc) 8 8.49 (brs, 3H), 3.64-3.51 (m, 2H), 3.25 (s, 3H), 1.35 (s, 3H), 1.19 (m, 1H), 0.90-0.79 (m, 2H).

[0430] Intermediates in the table below were synthesized using conditions analogous to that used to synthesize intermediate Q from chemicals either commercially available or synthesized according to the literature.0431] Intermediates in the table below were synthesized using conditions analogous to that used to synthesize intermediate 39-9 from chemicals either commercially available or synthesized according to the literature or disclosed herein.rac-(12?,27?)-2-(5-bromo-l,3,4-thiadiazol-2-yl)cyclopropane-l-carbonitrile (CQ)

[0432] Intermediate CQ is prepared in racemic form. It should be noted that the two stereo-centers in CQ have the &1 designation because of their fixed relative configuration. Other compounds herein having the &1 designations should be understood similarly.

[0433] Intermediate CQ was synthesized using conditions analogous to the synthesis of intermediate N from commercially available starting materials. LCMS (ESI, m / z): [M+H]+= 229.9.Intermediate CR rac-ethyl 5-((lR,2R)-2-cyanocyclopropyl)-l,3,4-thiadiazole-2-carboxylate (CR)

[0434] Intermediate CR was synthesized from intermediate CQ using conditions analogous to the synthesis of intermediate AY. LCMS (ESI, m / z): [M+H]+= 224.1Intermediate CS rac-8-bromo-3-(5-((17?,27?)-2-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl)-jV-(l- methylcyclopropyl)imidazo[l,5-a]pyridine-6-sulfonamide (CS)

[0435] Intermediate CS was synthesized from intermediate CR using conditions analogous to the synthesis of intermediate BG. LCMS (ESI, m / z): [M+H]+= 479.1Intermediate CT l-(5-(8-bromo-6-((4-(terZ-butyl)benzyl)thio)imidazo[l,5-a]pyridin-3-yl)-l,3,4-thiadiazol-2- yl)cyclopropane- 1 -carbonitrile (CT)

[0436] Intermediate CT-SM was synthesized from intermediate BF using conditions analogous to the synthesize of intermediate BG-3. Intermediate CT was synthesized from intermediate CT-SM using conditions analogous to the synthesis of intermediate BG from BG-5. LCMS (ESI, m / z): [M+H]+=523.9.Intermediate CUtert-butyl ((8-bromo-l -chloro-3-(5-(l -cyanocyclopropyl)-] ,3,4-thiadiazol-2-yl)imidazo[l ,5- a|pyridin-6-yl)sullbnyl)(( I . S\2 / ?)-2-( methoxy methyl )- 1 -methylcyclopropyl )carbamate (CU)

[0437] Intermediate CU-2 was synthesized from intermediate CT using conditions(note: 5 eq. of NCS) analogous to the synthesis of intermediate BG-3. The protection of intermediate CU-2 with Boc was using conditions analogous to the synthesis of intermediate AF-1 to afford intermediate CU. LCMS (ESI, m / z): [M+H-56]+= 511.1.

[0438] Intermediates in the table below were synthesized using conditions analogous to that used to synthesize intermediate CU from chemicals either commercially available or synthesized according to the literature.intermediate AN or BN with conditions analogous to the synthesis of intermediate AF-1.Intermediate DA tert-butyl ((8-bromo-3-(5-(l-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl)-l-fluoroimidazo[l,5- a]pyridin-6-yl)sulfonyl)(l-methylcyclopropyl)carbamate (DA)DA

[0440] Intermediate DA was synthesized from intermediate CZ using conditions analogous to the synthesis of intermediate AF with selecfluor at 70 °C. LCMS (ESI, m / z): [M+H-56]+= 541.2Intermediate DB6-amino-5 -bromo-2V-(( 1.S',2 / ?)-2-( methoxy methyl )- 1 -methylcyclopropyl)pyridine-3 - sulfonamide (DB)

[0441] Intermediate DB was synthesized using conditions analogous to the synthesis of intermediate Y-2 from commercially available chemical reagents. LCMS (ESI, m / z): [M+H]+= 350.4.Intermediate DC8-bromo-3-(5-(l-cyanocyclopropyl)-l,3,4-thiadiazol-2-yl)- -((15',27?)-2-(methoxymethyl)-l- methylcyclopropyl)imidazo[l,2-a]pyridine-6-sulfonamide (DC)

[0442] Intermediate DC was synthesized using conditions analogous to the synthesis of intermediate AN from chemical reagents commercially available, or prepared from commercially available reagents using conventional reactions well known in the art. LCMS (ESI, m / z): [M+H]+= 523.1Example 13-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-7-(2-oxa-7- azaspiro [3.5 ] nonan-7-yl)pyrazolo [1,5- a]pyridine- 5 - s ulfonamide (1)

[0443] Step 1: 7-chloro-3-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)pyrazolo[l,5- a]pyridine-5-sulfonyl chloride (1-1)

[0444] To a suspension of 2-(5-benzylsulfanyl-7-chloro-pyrazolo[l,5-a]pyridin-3-yl)-5- (difluoromethyl)-l,3,4-thiadiazole (375 mg, 0.917 mmol), acetic acid (0.34 mL) and water (0.23 mL) in acetonitrile (9.2 mL) was added l,3-dichloro-5,5-dimethyl-imidazolidine-2,4- dione (271 mg, 1.38 mmol) portion wise at 0 °C under N2. The resulting mixture was stirred at 0 °C for 2 hrs. LCMS showed the reaction completed. The reaction mixture was concentrated to give the crude product which was used directly for the next step without further purification. LCMS (ESI, m / z): [M+H]+= 384.9.

[0445] Step 2: 7-chloro-3-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methyl cy clopropy l)py razolo [ 1 , 5 - a]py ridine- 5 - sulfonamide (1-2)

[0446] To a suspension of 1-methylcyclopropan-l -amine hydrochloride (195.8 mg, 1.82 mmol), TEA (462 mg, 4.57 mmol, 0.64 mL), DMAP (11.1 mg, 0.091 mmol) in DCM (5 mL) was added 7-chloro-3-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]pyrazolo[l,5-a]pyridine-5- sulfonyl chloride (352 mg, 0.914 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc in PE) to afford 7-chloro-3-(5- (difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)pyrazolo[l,5-a]pyridine-5- sulfonamide (90 mg). LCMS (ESI, m / z): [M+H]+= 420.2.

[0447] Step 3: 3-(5-(difluoromethyl)-l ,3,4-thiadiazol-2-yl)-N-(l -methylcyclopropyl)-7- (2-oxa-7 -azaspiro [3.5]nonan-7-yl)pyrazolo [ 1 ,5 -a]pyridine-5 -sulfonamide ( 1)

[0448] To a mixture of 2-oxa-7-azaspiro[3.5]nonane hemi-oxalate(54.5 mg, 0.317 mmol) and 7-chloro-3-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]-N-(l-methylcyclopropyl)- pyrazolo[l,5-a]pyridine-5-sulfonamide (90 mg, 0.215 mmol) in DMF (8 mL) was added TEA (173 mg, 1.71 mmol, 0.24 mL) under N2. The reaction mixture was stirred at 100 °C for 16 hrs. LCMS showed the reaction completed. The reaction mixture was worked up with water and extracted with EtOAc. The organic layers were washed with saturated brine, dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 5% MeOH in DCM) to afford the product which was further purified by prep-HPLC (0.05% NH4HCO3) to afford 3- (5-(difhioromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-7-(2-oxa-7- azaspiro[3.5]nonan-7-yl)pyrazolo[l,5-a]pyridine-5-sulfonamide. LCMS (ESI, m / z): [M+H]+= 51 1.2. H NMR (400 MHz, DMSO-cfe) 5 8.95 (s, 1H), 8.45 (s, 1H), 8.39 (s, 1 H), 7.66 (t, 7 = 52.0 Hz, 1H), 6.82 (s, 1H), 4.43 (s, 4H), 3.47-3.40 (m, 4H), 2.09-2.02 (m, 4H), 1.13 (s, 3H), 0.74-0.67 (m, 2H), 0.49-0.42 (m, 2H).

[0449] Examples 2-24 were prepared according to the general procedures herein forExample 1, and in an analogous manner to that used to synthesize the example compounds with the appropriate intermediates. The starting materials were either prepared as described in the Intermediates section, commercially available, or prepared from commercially available reagents using conventional reactions well known in the art.Example 253-(3-(difluoromethyl)-l,2,4-thiadiazol-5-yl)-N-(l-methylcyclopropyl)-7-(2-oxa-7- azaspiro[3.5]nonan-7-yl)pyrazolo[l,5-a]pyridine-5-sulfonamide (25)

[0450] Step 1: 7-chloro-3-iodopyrazolo[l,5-a]pyridine-5-sulfonyl chloride (25-1)

[0451] To a solution of 5-benzylsulfanyl-7-chloro-3-iodo-pyrazolo[l,5-a]pyridine (A-3, 403 mg, 1.01 mmol) in DCM (12 mL), formic acid (1.5 mL), and water (0.7 mL) was added NCS (537 mg, 4.02 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hr. LCMS showed the reaction completed. The reaction mixture was worked up with water, then extracted with DCM. The combined organic layers were washed with saturated brine,dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without further purification.

[0452] Step 2: 7-chloro-3-iodo-N-(l-methylcyclopropyl)pyrazolo[l,5-a]pyridine-5- sulfonamide(25-2)

[0453] To a solution of 1-methylcyclopropan-l -amine hydrochloride (102 mg, 0.95 mmol) in pyridine (6 mL) was added 7-chloro-3-iodo-pyrazolo[l,5-a]pyridine-5-sulfonyl chloride (360 mg, 0.95 mmol) at 0 °C under Nz. The mixture was stirred at room temperature for 30 mins. LCMS showed the reaction completed. The reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with water and saturated brine, dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 20% EtOAc in PE) to afford 7-chloro-3-iodo-N-(l-methylcyclopropyl)pyrazolo[l,5- a]pyridine-5-sulfonamide (290 mg). LCMS (ESI, m / z): [M+H]+= 411.9.

[0454] Step 3: 3-iodo-N-(l-methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonan-7- yl)pyrazolo [ 1 ,5 -a]pyridine-5 -sulfonamide (25-3)

[0455] To a mixture of 7-chloro-3-iodo-N-(l-methylcyclopropyl)pyrazolo[l,5- a]pyridine-5-sulfonamide (482 mg, 0.70 mmol) and 2-oxa-7-azaspiro[3.5]nonane hemioxalate (269 mg, 1.72 mmol) in DMF (5.0 mL) was added TEA (712 mg, 7.0 mmol) under N2. The mixture was stirred at 100 °C for 5 hrs. LCMS showed the reaction completed. The reaction mixture was worked up with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous NaiSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 50% EtOAc in PE) to afford 3-iodo-N-(l- methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrazolo[l,5-a]pyridine-5- sulfonamide (123 mg). LCMS (ESI, m / z): [M+H]+= 503.1.

[0456] Step 4: N-(l-methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-3

[0457] (trimethyllstannyl)pyrazolo[l,5-a]pyridine-5-sulfonamide (25-4)

[0458] To a solution of 3-iodo-N-(l-methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrazolo[l,5-a]pyridine-5-sulfonamide (100 mg, 0.20 mmol) in 1,4-dioxane (1 mL) were added trimethyl(trimethylstannyl)stannane (78 mg, 0.24 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) under N2. The reaction mixture was degassed, then stirred at 100 °C for 1.5 hrs under N2 atmosphere. After completion, the reaction mixture was worked up with water, thenextracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous NaiSO-i, filtered, and concentrated to afford the crude product which was used in the next step without further purification. LCMS (ESI, m / z): [M+H]+= 539.1.

[0459] Step 5: 3-(3-(difhioromethyl)-l,2,4-thiadiazol-5-yl)-N-(l-methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrazolo[l,5-a]pyridine-5-sulfonamide (25)

[0460] To a solution of N-(l-methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-3-(trimethylstannyl)pyrazolo[l,5-a]pyridine-5-sulfonamide (60 mg, 0.11 mmol) in 1,4-dioxane (40 mL) was added 5-bromo-3-(difluoromethyl)-l,2,4-thiadiazole (48 mg, 0.22 mmol) and Pd(PPti3)4 (13 mg, 0.01 mmol) under N2. The mixture was degassed, then stirred at 100 °C for 5 hrs under N2 atmosphere. LCMS showed the reaction completed. The reaction mixture was worked up with water, then extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% FA) to afford 3-(3- (difluoromethyl)-l ,2,4-thiadiazol-5-yl)-N-(l -methylcyclopropyl)-7-(2-oxa-7- azaspiro[3.5]nonan-7-yl)pyrazolo[l,5-a]pyridine-5-sulfonamide. LCMS (ESI, m / z): [M+H]+= 509.2. H NMR (400 MHz, DMSO-d6) 5 9.06 (s, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 7.30 (t, J = 54 Hz, 1H), 6.84 (s, 1H), 4.42 (s, 4H) 3.45-3.39 (m, 4H), 2.08-2.01 (m, 4H), 1.13 (s, 3H), 0.75-0.68 (m, 2H), 0.49-0.42 (m, 2H).Example 26 l-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]-N-(l-ethynylcyclopropyl)-4-[4-[(3S)-3- hydroxypyrrolidine-1 -carbonyl] piperazin- 1-yl] indazole-6-sulfonamide (26)

[0461] Step 1: 4-chloro-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-lH-indazole-6- sulfonyl chloride (26-1)

[0462] o a soiut£onof 2-(6-benzylsulfanyl-4-chloro-indazol-l-yl)-5-(difluoromethyl)-l,3,4- thiadiazole (2 g, 4.89 mmol) in MeCN (20 mL) was added AcOH (0.42 mL) and water (0.26 mL). 1, 3 -Dichloro-5, 5 -dimethylhydantoin (1.45 g, 7.36 mmol) was added portion wise at 0 °C under N2. The reaction mixture was stirred at 0 °C for 2 hrs. After completion, the reaction mixture was concentrated to give the crude product which was used for the next step directly without further purification. LCMS (ESI, m / z): [M+H]+= 385.3.

[0463] Step 2: 4-chloro-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- ethynylcyclopropyl)-lH-indazole-6-sulfonamide (26-2)

[0464] To a solution of 1-ethynylcyclopropan-l -amine hydrochloride (610 mg, 5.19 mmol) in pyridine (20 mL) was added 4-chloro-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)- lH-indazole-6-sulfonyl chloride (2.0 g, 5.19 mmol) portion wise under N2 at room temperature. The resulting mixture was stirred at room temperature for 12 hrs. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 35% EtOAc in PE) to afford 4-chloro-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-ethynylcyclopropyl)-lH- indazole-6-sulfonamide (1.1 g). LCMS (ESI, m / z): [M+H]+= 430.3.

[0465] Step 3: l-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]-N-(l-ethynylcyclopropyl)-4- [4-[(3S)-3-hydroxypyrrolidine-l -carbonyl]piperazin-l-yl]indazole-6-sulfonamide (26)

[0466] To a solution of 4-chloro-l -[5-(difluoromethyl)- l ,3,4-thiadiazol-2-yl]-N-(l - ethynylcyclopropyl) indazole-6-sulfonamide (100 mg, 0.233 mmol), [(3S)-3- hydroxypyrrolidin-l-yl]-piperazin-l-yl-methanone (69.5 mg, 0.349 mmol) and t-BuONa (44.7 mg, 0.465 mmol) in 1,4-dioxane (5 mL) was added Pd-PEPPSI-IPent catalyst (36.8 mg, 0.047 mmol) under N2. The mixture was degassed, then stirred at 100 °C for 2 hrs. The reaction mixture was worked up with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 10% MeOH in DCM) to afford the product which was further purified on prep-HPLC (0.1% FA) to afford l-[5-(difluoromethyl)-l,3,4- thiadiazol-2-yl]-N-(l-ethynylcyclopropyl)-4-[4-[(3S)-3-hydroxypyrrolidine-l- carbonyl]piperazin-l-yl]indazole-6-sulfonamide. LCMS (ESI, m / z): [M+H]+= 593.3.]H NMR (400 MHz, DMSO-tfe) 5 8.87 (s, 1H), 8.71 (br s, 1H), 8.43 (s, 1H), 7.54 (t, J= 52.0 Hz, 1H), 7.15 (s, 1H), 4.84 (br s, 1 H), 4.18-4.12 (m, 1 H), 3.50-3.29 (m, 8H), 3.28-3.24 (m, 3H), 3.10-3.04 (m, 1H), 2.60 (s, 1H), 1.82-1.66 (m, 2H), 1.13-1.08 (m, 2H), 0.95-0.90 (m, 2H).

[0467] Examples 27-33 were prepared according to the general procedures herein for Example 26, and in an analogous manner to that used to synthesize the example compounds with the appropriate intermediates. The starting materials were either prepared as described in the Intermediates section, commercially available, or prepared from commercially available reagents using conventional reactions well known in the art.Example 34 l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-5-(2-oxa-7- azaspiro[3.5]nonan-7-yl)imidazo[l,5-a]pyridine-7-sulfonamide (34)

[0468] Step 1: 5-chloro-l-iodo-N-(l-methylcyclopropyl)imidazo[l,5-a]pyridine-7- sulfonamide (34-1)

[0469] To a solution of 1-methylcyclopropan-l -amine hydrochloride (306 mg, 3.28 mmol) in pyridine (3 mL) was added 5-chloro-l-iodo-imidazo[l,5-a]pyridine-7-sulfonyl chloride (950 mg, 2.52 mmol) at room temperature under N2. The mixture was stirred at temperature for 1 hr. LCMS showed the reaction completed. The reaction was worked up with water and extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography on silica gel (eluting with 30% EtOAc in PE) to give 5-chloro-l-iodo-N-(l- methylcyclopropyl)imidazo[ l ,5-a]pyridine-7-sulfonamide (637 mg). LCMS (ESI, m / z): [M+H]+= 412.0.

[0470] Step 2: 5-chloro-N-(l-methylcyclopropyl)-l-(trimethylstannyl)imidazo[l,5- a]pyridine-7-sulfonamide (34-2)

[0471] To a solution of 5-chloro-l-iodo-N-(l-methylcyclopropyl)imidazo[l,5-a]pyridine-7-sulfonamide (637 mg, 1.55 mmol) in 1,4-dioxane (10 mL) was added trimethyl(trimethylstannyl)stannane (761 mg, 2.32 mmol) and Pd(PPh3)4 (179 mg, 0.155 mmol) under argon. The mixture was degassed and stirred at 100 °C for 2 hrs under argon atmosphere. LCMS showed the reaction completed. The resulting mixture was concentrated under reduced pressure to give the crude product which was directly used for the next step without purification. LCMS (ESI, m / z): [M+H]+= 450.1.

[0472] Step 3: 5-chloro-l -(5-(difluoromethyl)-l ,3,4-thiadiazoL2-yl)-N-(l - methylcyclopropyl)imidazo[l,5-a]pyridine-7-sulfonamide (34-3)

[0473] To a solution of 5-chloro-N-(l-methylcyclopropyl)-l-trimethylstannyl- imidazo[l,5-a]pyridine-7-sulfonamide (800 mg, 1.78 mmol) in DMF (10 mL) was added 2- bromo-5-(difluoromethyl)-l,3,4-thiadiazole (374 mg, 1.74 mmol) and Pd(PPh3)4 (155 mg, 0.133 mmol) under argon. The mixture was degassed, then stirred at 90 °C for 2 hrs under argon atmosphere. LCMS showed the desired product was detected. Water was added into the mixture and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous NazSC , filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography on silica gel (eluting with 50 % EtOAc in PE) to give 5 -chloro- 1 - [5-(difluoromethyl)- 1 ,3 ,4-thiadiazol-2-yl]-N-( 1 - methylcyclopropyl)imidazo[l,5-a]pyridine-7-sulfonamide (178 mg). LCMS (ESI, m / z): [M+H]+= 420.1.

[0474] Step 4: l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)imidazo[l,5-a]pyridine-7-sulfonamide (34)

[0475] To a solution of 5-chloro-l-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]-N-(l- methylcyclopropyl)imidazo[l,5-a]pyridine-7-sulfonamide (170 mg, 0.405 mmol) in DMAc (4 mL) was added 2-oxa-7-azaspiro[3.5]nonane (103 mg, 0.81 mmol) and DIPEA (157 mg, 1.21 mmol) under argon. The reaction mixture was stirred at 120 °C under microwave for 2 hrs under argon atmosphere. LCMS showed the reaction completed. Water was added and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by prep-HPLC (0.1% FA) to give l-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]-N-(l-methylcyclopropyl)-5-(2-oxa-7- azaspiro[3.5]nonan-7-yl)imidazo[l,5-a]pyridine-7-sulfonamide. LCMS (ESI, m / z): [M+H]+= 511.2. ’HNMR (400 MHz, DMSO-rfc) 5 8.56 (s, 1H), 8.33 (d, J = 1.6 Hz, 1H), 8.30 (br s, 1H), 7.57 (t, J = 53.6 Hz, 1H), 6.59 (d, 7 = 1.6 Hz, 1H), 4.35 (s, 4H), 3.06-3.03 (m, 4H), 2.03- 2.00 (m, 4H), 1.06 (s, 3H), 0.65-0.62 (m, 2H), 0.39-0.36 (m, 2H).Example 35 l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-(difluoromethyl)cyclopropyl)-5-(2-oxa-7- azaspiro[3.5]nonan-7-yl)imidazo[l,5-a]pyridine-7-sulfonamide (35)

[0476] Step 1: 5-chloro-N-(l-(difluoromethyl)cy...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof:provided that the bicyclic ring containing J1-J8is a heteroaryl ring, preferably, the ring of J1, J2, J6, J7, and J8has 1, 2, or 3 ring nitrogen atoms; L1is null, an optionally substituted C1-6 alkylene, an optionally substituted C2-6 alkenylene, an optionally substituted C2-6alkynylene, or an optionally substituted 3-8 membered ring, and R1is an optionally substituted 3-8 membered ring; or L1is null or an optionally substituted 7-12 membered bicyclic ring structure, and R1is hydrogen, deuterium, halogen, CN, OH, NH2, an optionally substituted C1-4alkyl, an optionally substituted C2-4 alkenyl, an optionally substituted C2-4 alkynyl, an optionally substituted C1-4heteroalkyl, or an optionally substituted 3-6 membered ring; L2is an optionally substituted C1-4 alkylene or an optionally substituted 3-5 membered carbocyclic or heterocyclic ring, R2is hydrogen, deuterium, halogen, CN, OH, an optionally substituted C1-4 alkyl, an optionally substituted C2-4alkenyl, or an optionally substituted C2-4alkynyl, or an optionally substituted 3-5 membered carbocyclic or heterocyclic ringR3is hydrogen, deuterium, halogen, CN, G1, OG1, NHG1, NG1G1, C(O)G1, C(O)NHG1, or C(O)NG1G1; R4is hydrogen, deuterium, halogen, CN, an optionally substituted C1-4 alkyl, an optionally substituted C2-4alkenyl, an optionally substituted C2-4alkynyl, an optionally substituted C1-4 heteroalkyl, OG1, NHG1, NG1G1, or an optionally substituted 3-6 membered ring; wherein G1at each occurrence is independently hydrogen, an optionally substituted C1-4 alkyl, an optionally substituted C2-4alkenyl, an optionally substituted C2-4alkynyl, an optionally substituted C1-4 heteroalkyl, or an optionally substituted 3-10 membered ring; or two G1together with the nitrogen atom they are both attached to are joined to form an optionally substituted 4-10 membered heterocyclic ring; R5is hydrogen, halogen, CN, OH, G2, or L3-G2, or R5is L3-G2A, wherein L3is O, NH, CO, C(O)NH, C(O)N(C1-4 alkyl), SO2, SO2NH, SO2N(C1-4 alkyl), an optionally substituted C1-4alkylene, an optionally substituted C2-4alkenylene, an optionally substituted C2-4 alkynylene, or an optionally substituted C1-4 heteroalkylene, and G2is an optionally substituted 3-14 membered ring; wherein G2Ais hydrogen, an optionally substituted C1-4 alkyl, or an optionally substituted C1-4 heteroalkyl; and R6and R7are each independently hydrogen, deuterium, halogen, CN, or an optionally substituted C1-4 alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula I-1:

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula I-2:

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula I-3:

5. The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein J1is N.

6. The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein J1is CR3, preferably, CH.

7. The compound of any of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein J2is N.

8. The compound of any of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein J2is CR4, preferably, R4is hydrogen or halogen, preferably, R4is hydrogen, F or Cl.

9. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein J4is CH or CF.

10. The compound of any of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein J5is CH.

11. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein J4and J5are both CH.

12. The compound of any of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein L1is an optionally substituted 5-membered heteroarylene having 1-3 ring heteroatoms independently selected from S, N, and O, for example, an optionally substituted ring selected from thiazole, oxazole, imidazole, oxadiazole, or thiadiazole, or L1is an optionally substituted 6-membered heteroarylene having 1 or 2 ring nitrogens, such as an optionally substituted pyridylene or optionally substituted pyridazylene.

13. The compound of any of claims 1-11, or a pharmaceutically acceptable salt thereof, , wherein the attaching point meta to the S atom is14. The compound of any of claims 1-11, or a pharmaceutically acceptable salt thereof, .

15. The compound of any of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R1is a 3-4 membered ring (e.g., cyclopropyl or cyclobutyl) optionally substituted with 1-3 substituents each independently selected from deuterium, F, OH, CN, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 heteroalkyl (e.g., CH2OCH3) , wherein the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, or C1-4 heteroalkyl is optionally substituted with 1-3 substituents independently selected from F and OH.

16. The compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R1is an optionally substituted cyclopropyl, preferably, when substituted, the cyclopropyl is substituted with 1-3 substituents each independently selected from F, OH, CN, or C1-2alkyl optionally substituted with 1-3 F, more preferably, when substituted, the cyclopropyl is substituted with one or two substituents (e.g., one substituent) each independently selected from F, CN, or methyl optionally substituted with 1-3 F, for .

17. The compound of any of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein L1is an optionally substituted 8-10 membered fused bicyclic ring structure having a first and second constituent ring, wherein the first constituent ring is a 5- membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O, and S, and the second constituent ring is an aryl, heteroaryl, carbocyclic, or heterocyclic ring.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein L1is an optionally substituted 8 or 9 membered fused bicyclic heteroaryl having a first and second constituent ring, wherein the first constituent ring is a 5-membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O, and S, and the second constituent ring is phenyl, a 5-membered heteroaryl, or a 6-membered heteroaryl.

19. The compound of claim 17 or 18, or a pharmaceutically acceptable salt thereof, wherein L1attaches to J7through a ring atom of the first constituent ring, and attaches to R1through a ring atom of the second constituent ring.

20. The compound of any of claims 17-19, or a pharmaceutically acceptable salt thereof, wherein the first constituent ring is a thiazole .

21. The compound of any of claims 17-20, or a pharmaceutically acceptable salt thereof, wherein the second constituent ring is a 5 or 6 membered heteroaryl, for example, L1is is drawn to show direction of attachment).

22. any of claims 17-21, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, deuterium, halogen (preferably, F or Cl), OH, CN, C1-4alkyl, C2-4alkenyl, C2-4 alkynyl, or C1-4 heteroalkyl, wherein the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, or C1-4heteroalkyl is optionally substituted with 1-3 substituents independently selected from F and OH.

23. The compound of any of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein L1-R1is selected from the following: ,24. The compound of any of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein L1-R1is selected from the following: .

25. The compound of any of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted 4-12 membered heterocyclic ring having 1-4 ringheteroatoms independently selected from N, O, and S, wherein the S atom is optionally oxidized.

26. The compound of any of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted 4-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O, and S, wherein the S atom is optionally oxidized, for example, R5 is a ring selected, each of which is optionally substituted.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R5is selected from the following: , wherein:n is an integer of 0-4, (a) R10at each occurrence is independently oxo, halogen (e.g., F), OH, CN, GA, OGA, C(O)GA, SO2GA, P(O)GAGA,C(O)NHGA, C(O)NGAGA, SO2NHGA,(b) two R10are joined to form an optionally substituted 3-6 membered ring (e.g., cyclopropyl, cyclobutyl, or oxetane ring), and any remaining R10are as defined in (a); or (c) one R10and R11are joined to form an optionally substituted 3-6 membered ring, and any remaining R10are as defined in (a); R11is hydrogen, GA, C(O)GA, SO2GA, C(O)OGA, C(O)NHGA, C(O)NGAGA, SO2NHGA, S(=NH)(=O)GA, S(=N-GA)(=O)GA, or SO2NGAGA, or defined in (c) above;wherein GAat each occurrence is an optionally substituted group independently selected from (i) C1-4alkyl; (ii) C1-4heteroalkyl; and (iii) a 3-10 membered ring, or two GAtogether with the intervening atom(s) are joined to form an optionally substituted 4-10 membered heterocyclic ring; wherein when substituted, the C1-4 alkyl or C1-4 heteroalkyl is preferably substituted with 1-3 substituents each independently (1) halogen (preferably F), CN, OH, or NH2, (2) C1-4 heteroalkyl optionally substituted with F; or (3) an optionally substituted 3-10 membered ring; and when substituted, the 3-10 membered ring or the 4-10 membered heterocyclic ring is preferably substituted with 1-3 substituents independently (1) oxo (as applicable), halogen (e.g., F, Cl), CN, OH, or NH2; (2) C1-4 alkyl optionally substituted with F; (3) C1-4heteroalkyl optionally substituted with F; or (4) a 3-6 membered ring optionally substituted 1-3 substituents independently selected from oxo, F, Cl, CN, OH, C1-4alkyl optionally substituted with F, and C1-4heteroalkyl optionally substituted with F.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein n is 0; or n is 1 or 2, for example, ,Nindependently F, OH, or GA, when R10is not a substituent of a ring carbon atom adjacent to a ring nitrogen, or (2) R10at each occurrence is independently GA, when R10is a substituent of a ring carbon atom adjacent to a ring nitrogen.

29. The compound of claim 27 or 28, or a pharmaceutically acceptable salt thereof, wherein GAat each occurrence is independently: (1) a C1-4 alkyl optionally substituted with 1-3 substituents each independently F, OH, C1-4 alkoxy optionally substituted with 1-3 F, NH(C1-4 alkyl), or N(C1-3 alkyl)(C1-3 alkyl); or (2) a 3-10 membered ring, (C1-4 alkylene)-(3-10 membered ring), or (C1-4 heteroalkylene)- (3-10 membered ring), preferably, the 3-10 membered ring is a 3-6 membered ring selected from C3-6 cycloalkyl (e.g., cyclopropyl or cyclobutyl), 4-6 membered heterocyclyl (e.g., azetidinyl, oxetanyl, pyrrolidinyl, etc.), 5 or 6-membered heteroaryl, or phenyl, wherein the 3-10 membered ring is optionally substituted with 1-3 substituents independently selected from oxo, F, Cl, OH, CN, C1-4 alkyl optionally substituted with F, C1-4 alkoxy optionally substituted with F, and optionally substituted 3-5 membered ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.).

30. The compound of any of claims 27-29, or a pharmaceutically acceptable salt thereof, wherein R11is C(O)GA, SO2GA, C(O)OGA, C(O)NHGA, C(O)NGAGA, SO2NHGA, S(=NH)(=O)GA, S(=N-GA)(=O)GA, or SO2NGAGA; or R11is hydrogen.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, where R11is selected from:or or32. The compound of any of claims 27-29, or a pharmaceutically acceptable salt thereof, wherein R11is GA, preferably, GAis an optionally substituted 5 or 6-membered heteroaryl.

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, where R11is .

34. The compound of any of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted 7-12 membered heterocyclic ring having 1-3 ringheteroatoms independently selected from N, O, and S, wherein the S atom is optionally oxidized.

35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein R5includes a spiro oxetane ring, for example, R5can be represented by the structure of , wherein ring A is a 4-8 membered carbocyclic or heterocyclic ring, which ring carbon atom with the oxetane ring.

36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein R5is selected from: .

37. The compound of any of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R5is an optionally substituted 5 or 6 membered heteroaryl, e.g., pyrazole, when substituted, the 5 or 6 membered heteroaryl is preferably substituted with 1-3 substituents independently (1) halogen (e.g., F, Cl), CN, OH, or NH2; (2) C1-4alkyl optionally substituted with F; (3) C1-4 heteroalkyl optionally substituted with F; or (4) a 3-6 membered ring optionally substituted 1-3 substituents independently selected from oxo, F, Cl, CN, OH, C1-4 alkyl optionally substituted with F, and C1-4 heteroalkyl optionally substituted with F.

38. The compound of any of claims 1-37, or a pharmaceutically acceptable salt thereof, orC1-2alkyl optionally substituted with F (e.g., CH3, CH2F, CHF2, or CF3), CN, C2-3 alkynyl optionally substituted with F, or C1-4heteroalkyl optionally substituted with F (e.g., .

39. any or a acceptable salt thereof, wherein R2is hydrogen, F, C1-2 alkyl optionally substituted with F (e.g., CH3, CH2F, CHF2, or CF3), CN, cyclopropyl, or C2-3alkynyl optionally substituted with F, such as ,40. The compound of any of claims 1-39, or a pharmaceutically acceptable salt thereof, as applicable, characterized as having a structure according to Formula I-A: ,wherein: R100is hydrogen, F, CN, an optionally substituted alkyl, such as a C1-4alkyl optionally substituted with deuterium or F (e.g., CH3, CD3, CH2F, CHF2, etc.), or an optionally substituted heteroalkyl, such as a C1-4heteroalkyl optionally substituted with deuterium or F.

41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, as defined in any of Embodiments A2-29 herein.

42. The compound of any of claims 1-39, or a pharmaceutically acceptable salt thereof, as applicable, characterized as having a structure according to Formula I-D:wherein: q is 1 or 2; and R101at each occurrence is independently F or methyl optionally substituted with F; or R101at each occurrence is independently F, C1-2alkyl optionally substituted with F (e.g., CH3, CH2F, CHF2, or CF3), CN, C2-3 alkynyl optionally substituted with F, or C1-4 heteroalkyl optionally substituted with F (e.g., CH2OCH3).

43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, as defined in any of Embodiments B2-43 herein.

44. The compound of any of claims 1-39, or a pharmaceutically acceptable salt thereof, as applicable, characterized as having a structure according to Formula I-B: ,wherein:Ring B is an optionally substituted 5 or 6 membered heterocyclyl or heteroaryl ring having 1-3 ring heteroatoms independently N, O, or S; and R1is hydrogen, deuterium, halogen, CN, OH, NH2, an optionally substituted C1-4 alkyl, an optionally substituted C1-4heteroalkyl, or an optionally substituted 3-6 membered ring.

45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, as defined in any of Embodiments C2-26 herein.

46. The compound of any of claims 1-39, or a pharmaceutically acceptable salt thereof, as applicable, characterized as having a structure according to Formula I-X:wherein: R101is F, C1-2 alkyl optionally substituted with F (e.g., CH3, CH2F, CHF2, or CF3), CN, C2-3alkynyl optionally substituted with F, or C1-4heteroalkyl optionally substituted with F (e.g., CH2CH2OCH3, or CH2OCH3).

47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, as defined in any of Embodiments D2-26 herein.

48. A compound selected from Table 1, or Example Nos.1-266, or a pharmaceutically acceptable salt thereof.

49. A pharmaceutical composition comprising the compound of any of claims 1-48, or a pharmaceutically acceptable salt thereof.

50. A method of treating a disease or disorder in which PARG activity is implicated, the method comprising administering an effective amount of the compound of any of claims1-48, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 49.

51. The method of claim 50, wherein the disease or disorder is cancer.