Myosin modulators and methods of their use

Abstract

Described herein are compounds that are myosin motor protein modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of myosin motor protein activity.

Description

Docket No.: KMYXP001WOMYOSIN MODULATORS AND METHODS OF THEIR USE

[0001] This application claims the benefit of priority of U. S. Provisional Application No. 63 / 775,093, filed March 20, 2025, and U. S. Provisional Application No. 63 / 775,155, filed March 20, 2025, the disclosures of which are incorporated by reference in their entirety for all purposes.

[0002] Myosins make up a superfamily of ATP-dependent motor proteins and are involved in several motility and contractile processes. Motor proteins are a class of molecular motors that can move along the surface of a suitable substrate. Motor proteins are powered by the hydrolysis of ATP and are responsible for substrate-based motility. In this way, myosin motor proteins can move along the actin cytoskeleton thus enabling a myriad of cellular functions including cytokinesis, locomotion, and cargo transport, among other cellular processes.Myosin proteins and protein isoforms are found in most eukaryotic organisms, including pathogens such as parasites, and are important in maintaining motility, cellular division, and cellular homeostasis. In some instances, there is sufficient differentiation between animal and parasite myosins to enable selective modulation of one over the other.

[0003] Numerous classes of myosin exist, and specialized myosins have been discovered. Myosin-XIV is a myosin subgroup found in the Apicomplexa phylum, which includes the parasitic protozoa responsible for coccidiosis and cryptosporidiosis. Coccidiosis is a disease of various animals in which the intestinal mucosa is invaded and damaged by the protozoa. The economic effects of coccidiosis can be especially severe in the poultry industry where intensive housing of birds favors the spread of the disease. Infection by coccidial protozoa is, for the most part, species specific. Numerous species, however, can infect a single host. For example, there are seven species of coccidial protozoa which infect chickens, six of which are considered to be moderately to severely pathogenic. There is an urgent need of inhibitors with new mechanism of action given the rapid rise of parasite resistance to the current standard of care.

[0004] Cryptosporidiosis is a diarrheal disease caused by the multiplication of protozoan parasites in the small intestine. Cryptosporidiosis is most commonly caused by the intracellular apicomplexan parasites C. parvum and C. hominis and can affect the respiratory tract in both immunocompetent and immunocompromised individuals. It can also be transmitted to other animals including cattle, sheep, pigs, horses, goats, and geckos.Nitazoxanide is the current standard of care for cryptosporidiosis, but the drug only exhibits partial efficacy in children and is no more effective than placebo in patients with AIDS. TheDocket No.: KMYXP001WOzoonotic C. parvum in particular is highly prevalent in young calves. In 2007, environmentally robust C. spp. oocysts were found in 84% of Estonian dairy cattle herds. Despite the fact that the parasite is shed by 24% of calves younger than 3 months of age, it is rarely diagnosed or treated. There are no FDA-approved drugs for treatment or prevention of cryptosporidiosis in livestock in the US and is a major unmet need in animal health.

[0005] As such, there is a need for small molecule effectors capable of modulating myosin proteins with the aim of treating diseases caused by apicomplexan parasites. Described herein are compounds that target myosin proteins in the cytoskeleton of parasites.SUMMARY OF THE INVENTION

[0006] Provided herein is a compound of Formula (I)R3R1aR1bor a salt or tautomer thereof, wherein,L is chosen from -SO2- and cycloprop- 1,1 -diyl;each of A, B, and D is independently selected from N, NR4, O, S, and CR5; provided thatat least one of A, B, and D is N or NR4; andno more than one of A, B, and D is O or S;Rlaand Rlbare independently selected from H, deuterium, and Ci-C4alkyl;R2is Ci-C6alkyl or TJ-R9;L1is absent or chosen from Ci-Cealkylene and C2-6alkenylene;R9is aryl, heteroaryl, or Cs-Cscycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 groups independently chosen from Ci-Cealkyl, Ci-Cealkoxy, haloalkyl, haloalkoxy, alkynyl, aryl, aryl(Ci-Cealkyl), benzyl, aryloxy, benzyloxy, heteroaryl, heteroaryl(Ci-C6alkyl), heteroaryloxy, -C(CHs)2OH, - CO2R7, -CH2CO2R7, -C(O)N(R7)2, -N(R7)2, -O(CH2)nR7, oxo, cyano, and halo; n is chosen from 1, 2, or 3;R3is a 5- or 6-membered heteroaryl, each of which is optionally substituted with one or two groups independently chosen from halogen, hydroxy, and Ci-Cealkyl; R4is H or Ci-Cealkyl;R5is H or Ci-Cealkyl; andDocket No.: KMYXP001WOeach R7is independently selected from H, Ci-Cealkyl, Ci-Cealkoxy, -N(CH₃)₂, and -C(O)N(CH₃)₂; or two R7on the same N atom are taken together with the N atom to which they are attached to form an N-containing heterocycle.

[0007] Also provided is a pharmaceutical formulation comprising a compound as recited herein, or a salt or tautomer thereof, together with a pharmaceutically acceptable carrier.

[0008] Also provided is a method of inhibiting myosin protein activity, comprising contacting a myosin protein with a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein.

[0009] Also provided is a method of treating or preventing coccidiosis or cryptosporidiosis in a subject that would benefit from the modulation of coccidial protozoa myosin protein activity or cryptosporidial protozoa myosin activity, comprising administering to the subject in need thereof a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein.

[0010] Also provided is a method of treating or preventing coccidiosis or cryptosporidiosis in a subject, comprising administering to the subject a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, that selectively inhibits coccidial protozoa myosin activity or cryptosporidial protozoa myosin activity relative to subject myosin activity.

[0011] Also provided is a method of preventing or reducing susceptibility to infection by a coccidial or cryptosporidial protozoa, comprisingadministering to a subject a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, that selectively inhibits coccidial protozoa myosin activity or cryptosporidial protozoa myosin activity relative to subject myosin activity; andexposing the subject to the coccidial or cryptosporidial protozoa.

[0012] Also provided is a method of treating or preventing coccidiosis or cryptosporidiosis in a subject comprising administering a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, that inhibits coccidial or cryptosporidial protozoa myosin ATPase activity.

[0013] Also provided is a feed supplement or medicated feed comprising ground dry vegetable- or animal-based feed, with or without additives such as proteins, vitamins, and minerals, and a compound as recited herein, or a salt or tautomer thereof.Docket No.: KMYXP001WO

[0014] Also provided is a feed additive composition for preventing or ameliorating coccidiosis, comprising a compound as recited herein, or a salt or tautomer thereof, as an active ingredient.

[0015] Also provided is a feed additive composition for preventing or ameliorating cryptosporidiosis, comprising a compound as recited herein, or a salt or tautomer thereof, as an active ingredient.

[0016] Also provided is a pharmaceutical formulation for control of coccidiosis in poultry, comprising a coccidiostatically effective amount of a compound as recited herein, or a salt or tautomer thereof, and a pharmaceutically acceptable carrier.

[0017] Also provided is a pharmaceutical formulation for control of cryptosporidiosis in cattle, comprising a cryptosporidiostatically effective amount of a compound as recited herein, or a salt or tautomer thereof, and a pharmaceutically acceptable carrier.

[0018] Also provided is a method of treating or preventing a disease caused by an Apicomplexa parasite in a subject, comprising administering to a subject a compound as recited herein, or a salt or tautomer thereof, a pharmaceutical formulation as recited herein, or a feed supplement as recited herein, that selectively inhibits Apicomplexa parasite myosin activity relative to subject myosin activity.

[0019] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.DETAILED DESCRIPTION

[0020] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0021] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, asDocket No.: KMYXP001WO“including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0022] Reference throughout this specification to “one embodiment” or “an embodiment” or “some embodiments” or “a certain embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” or “in some embodiments” or “in a certain embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment.Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0023] Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise.

[0024] When ranges of values are disclosed, and the notation “from m... to ” or “between... and ” is used, where m and are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 pM (micromolar),” which is intended to include 1 M, 3 pM, and everything in between to any number of significant figures (e.g., 1.255 pM, 2.1 pM, 2.9999 pM, etc.).

[0025] As used herein, “about” means ± 20% of the stated value, and includes more specifically values of ± 10%, ± 5%, ± 2% and ± 1% of the stated value.

[0026] The term “alkoxy”, and, interchangeably, “(alkyl)oxy”, as used herein, refers to an alkyl radical attached to a molecule by oxygen.

[0027] The term “alkyl,” as used herein, refers to a straight-chain or branched-chain saturated, hydrocarbon radical containing from 1 to 20 carbon atoms. In some embodiments, alkyl will comprise from 1 to 10 carbon atoms. In some embodiments, alkyl will comprise from 1 to 8 carbon atoms.

[0028] The term “alkynyl,” as used herein, refers to a straight-chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises from 2 to 4 carbon atoms

[0029] The term "aryl," as used herein, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together.Docket No.: KMYXP001WO

[0030] The term “aryloxy,” as used herein, refers to an aryl group attached to the parent molecular moiety through an oxygen atom.

[0031] The term “benzyl”, as used herein, refers to a phenyl group attached to the parent molecular moiety through a methylene group.

[0032] The term “benzyloxy”, as used herein, refers to a benzyl group attached to the parent molecular moiety through an oxygen atom.

[0033] The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein, refers to a saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members. In some embodiments, cycloalkyl will comprise from 5 to 7 carbon atoms. In some embodiments, cycloalkyl will comprise a spirocyclic ring system. “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, as well as the multicyclic (multicentered) saturated type.

[0034] The term “halo,” or “halogen,” as used herein, refers to fluorine, chlorine, bromine, or iodine.

[0035] The term "heteroaryl," as used herein, refers to a 3 to 15 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom chosen from N, O, and S. In some embodiments, heteroaryl will comprise from 1 to 4 heteroatoms as ring members. In some embodiments, heteroaryl will comprise from 1 to 2 heteroatoms as ring members. In some embodiments, heteroaryl will comprise from 5 to 7 atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings wherein heteroaryl rings are fused with other heteroaryl rings wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings.

[0036] The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” as used herein, refers to a saturated, partially unsaturated, or fully unsaturated (but nonaromatic) monocyclic; saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) bridged; saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) bicyclic; or saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) tricyclic heterocyclic group containing at least one heteroatom as a ring member wherein each heteroatom may be independently chosen from nitrogen, oxygen, and sulfur.

[0037] In some embodiments, heterocycloalkyl will comprise a spirocyclic ring system. In some embodiments, heterocycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In some embodiments, heterocycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In some embodiments, heterocyclo alkyl will comprise from 3 to 8 ring members inDocket No.: KMYXP001WOeach ring. In some embodiments, heterocycloalkyl will comprise from 3 to 7 ring members in each ring. In some embodiments, heterocycloalkyl will comprise from 5 to 6 ring members in each ring. “Heterocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl or heteroaryl group, as defined herein, or an additional heterocycle group.

[0038] The term “oxo,” as used herein, refers to =0.

[0039] Asymmetric centers exist in the compounds and pharmaceutically acceptable salts thereof, disclosed herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1 -isomers, and mixtures thereof. Individual stereoisomers of compounds, and pharmaceutically acceptable salts thereof, can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds, and pharmaceutically acceptable salts thereof, of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.Additionally, the compounds, and pharmaceutically acceptable salts thereof, disclosed herein may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0040] Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0041] The term “bond” refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.

[0042] The term “chlorinating agent,” as used herein, refers to a compound or salt that adds a chlorine atom or atoms to an organic compound in a chemical reaction.Docket No.: KMYXP001WO

[0043] The term “reducing agent”, as used herein, refers to a compound that effects the reduction of an organic compound in a chemical reaction (also known as an “reduction reaction” or a “reduction”)

[0044] As used herein, "administering to a subject" refers to the process of introducing a composition or dosage form into the subject via an art-recognized means of introduction.

[0045] The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the animal to have a reduced duration or quality of life.

[0046] The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0047] The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a desired endpoint. The precise therapeutically effective amount for a subject may depend upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of one of skill in the art.

[0048] As used herein, the terms “prevent”, “preventing”, or “prevention” are meant to encompass administration to animals which may or may not carry a causative organism of coccidiosis but are considered “at risk” of developing coccidiosis. The terms may also encompass amelioration (as opposed to elimination) of symptoms of the disease. For example, in experiments described below, administration of a compound as recited herein, or a salt or tautomer thereof, to animals already infected with Eimeria, i.e., a causative agent of coccidiosis, but who had not yet developed coccidiosis, may be effective in ameliorating symptoms of the disease, although not necessarily in eliminating those symptoms.Docket No.: KMYXP001WO

[0049] As used herein, the term “treat,” “treating”, or “treatment” means the administration of therapy to an individual who already manifests at least one symptom of a disease or condition or who has previously manifested at least one symptom of a disease or condition. For example, “treating” can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. For example, the term “treating” in reference to a disorder means a reduction in severity of one or more symptoms associated with that particular disorder.Therefore, treating a disorder does not necessarily mean a reduction in severity of all symptoms associated with a disorder and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with a disorder.

[0050] As used herein, the term “subject” refers to an animal. In some embodiments, the subject is a mammal, bird, or fish. In some embodiments, the subject is a companion animal, including but not limited to dogs, cats, rabbits, and horses. In some embodiments, the subject is a livestock animal.

[0051] As used herein, the term “livestock animal” refers to any farmed animal, including but not limited to ruminants such as cattle (e.g. cows or bulls, including calves), mono-gastric animals such as poultry, pigs (including piglets), birds, aquatic animals such as fish, agastric fish, gastric fish, freshwater fish such as salmon, cod, trout and carp, e.g. koi carp, marine fish such as sea bass, and crustaceans such as shrimps, mussels and scallops), horses (including race horses), goats, and sheep (including lambs). Poultry includes domestic poultry raised for egg, meat, and / or feathers. Examples of poultry include broilers, chickens, turkeys, ducks, geese, quail, pheasants, doves, pigeons, emu, ostriches and swans.

[0052] As used herein, the term “coccidial protozoa” refers to a single-celled parasitic eukaryote capable of causing coccidiosis in animals.

[0053] As used herein, the term “coccidiosis” refers to a disease produced by protozoa parasites of microscopic size. Included in the phylum Apicomplexa are the family Eimeriidae and considered several genera, e.g. Eimeria, Isospora, etc., which invade epithelial cells of the gut or other organs of infected animals, causing destruction of host cells, e.g. enterocytes, etc. This disease affects most animals raised commercially for food purposes, e.g., birds (e.g., chickens, chickens, chickens, chickens, turkeys, ducks, geese, etc.), mammals (e.g., sheep, goats, cows, pigs, rabbits, horses, water buffalos, etc.), fish, etc., or for other commercialDocket No.: KMYXP001WOpurposes (e.g., dogs, cats, marsupials, etc.). Disease is transmitted by contact with feces or ingestion of infected tissues. The primary symptom is diarrhea, which can become bloody in severe cases. Most coccidium-infected animals are asymptomatic; however, young or immunodeficient individuals can suffer from severe symptoms, including death.

[0054] As used herein, the term " Eimeria" refers to any species of the genus Eimeria, including but not limited to species infecting birds (e.g. chickens, chickens, chickens, capons, paints (Guinea pigs), flea, turkey, duck, oak, pheasants, partridge, quail, ostrich, etc.), mammals (e.g. sheep, goats, cows, pigs, rabbits, horses, dogs, cats, etc.), and fish (e.g. eyelashes, rabbits, anchovy or bokerons, herring, sardines, tents, cod, haddocks, bass, bass, jureles, raps, etc.). Non-limiting examples of Eimeria species include E.tenella, E. acervulina, E. brunetti, E. hagani, E. maxima, E. mitis, E. mivati, E. necatrix, E. praecox, E. adenoeides, E. gallopavonis, E. innocua, E. meleagridis, E. meleagrimitis, E. subrotunda, E. alectoreae, E. Caucasian, E. gonzalezcastroi, E. kofoidi, E. phasiani, E. cotumicis, E. lettyae, E. colchici, E. duodenalis, E. langeroni, E. megalovirus, E. pacifera, E. phasiani, E. landana, E. gorkhpuri, E. grenieri, E. numidae, E. anatis, E. aythyae, E. battakhi, E. danailovi, E. krtovi, E. stigmosa, E. truncata, E. bovis, E. zuernii, E. ellipsoidalis, E. cylindrica, E. aubumensis, E. alabamensis, E. subspherica, E. wyomingensis E. arioingi, E. christenseni, E. ninakohlyakimovae, E. alijevi, E. hirci, E. caprine, E. caprovina, E. pallide, E. jolchijevi, E. apsheronica, E. ahsata, E. bakuensis, E.crandallis, E.faurei, E. intricata, E. marsica, E. ovinoidalis, E. pallide, E. parva, E. weybridgensis, E. gilruthi, E. gonzalezi, E. granulose, E. punctata, E. scabra, E. porci, E. polita, E. suis, E. stiedae, E. irresidua, E. magna, E. media, E. periorans, E. leuckarti, E. solipedum, and E. iniungulsti.

[0055] As used herein, the terms “cryptosporidial protozoa” or “cryptosporidium" refer to a single-celled parasitic eukaryote capable of causing cryptosporidiosis in animals.

[0056] As used herein, the term “cryptosporidiosis” refers to a disease caused by microscopic parasites called cryptosporidium. There are numerous species of these parasites, including, but not limited to, C. parvum and C. hominis. Cryptosporidiosis may also be caused by C. canis, C. felis, C. meleagridis, and C. muris.

[0057] Those skilled in the art will appreciate that the invention(s) described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention(s) includes all such variations and modifications. The invention(s) also includes all the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of steps or features unless specifically stated otherwise.Docket No.: KMYXP001WO

[0058] The present invention(s) is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention(s), as described herein.

[0059] It is appreciated that certain features of the invention(s), which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention(s), which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0060] Provided herein is a compound of Formula (I), or a salt or tautomer thereofR3R1aR1bFormula (I)wherein,L is chosen from -SO2- and cycloprop- 1,1 -diyl;each of A, B, and D is independently selected from N, NR4, O, S, and CR5; provided thatat least one of A, B, and D is N or NR4; andno more than one of A, B, and D is O or S;Rlaand Rlbare independently selected from H, deuterium, and Ci-C4alkyl;R2is Ci-C6alkyl or -iJ-R9;L1is absent or chosen from Ci-Cealkylene and C2-6alkenylene;R9is aryl, heteroaryl, or Cs-Cscycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 groups independently chosen from Ci-Cealkyl, Ci-Cealkoxy, haloalkyl, haloalkoxy, alkynyl, aryl, aryl(Ci-Cealkyl), benzyl, aryloxy, benzyloxy, heteroaryl, heteroaryl(Ci-C6alkyl), heteroaryloxy, -C(CHs)2OH, - CO2R7, -CH2CO2R7, -C(O)N(R7)2, -N(R7)2, -O(CH2)nR7, oxo, cyano, and halo; n is chosen from 1, 2, or 3;R3is a 5- or 6-membered heteroaryl, each of which is optionally substituted with one or two groups independently chosen from halogen, hydroxy, and Ci-Cealkyl; R4is H or Ci-Cealkyl;R5is H or Ci-Cealkyl; andDocket No.: KMYXP001WOeach R7is independently selected from H, Ci-Cealkyl, Ci-Cealkoxy, -N(CH₃)₂, and -C(O)N(CH₃)₂; or two R7on the same N atom are taken together with the N atom to which they are attached to form an N-containing heterocycle.

[0061] In some embodiments, L is cycloprop- 1, 1 -diyl.

[0062] In some embodiments, R2is l R9and L1is absent.

[0063] In some embodiments, R9is phenyl optionally substituted with 1 or 2 groups independently chosen from halogen and Ci-Cealkoxy.

[0064] In some embodiments, R9is phenyl optionally substituted with methoxy, ethoxy, propoxy, or chloro.

[0065] In some embodiments, R9is phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, or 2-chlorophenyl.

[0066] In some embodiments, L is -SO2-.

[0067] In some embodiments, R2is Ci-Cealkyl.

[0068] In some embodiments, R2is methyl, ethyl, or propyl.

[0069] In some embodiments, R2is -iJ-R9and L1is -CH2- or -CH2CH2-.

[0070] In some embodiments, R2is -iJ-R9and L1is -CH2-, -CH2CH2-, or -CH=CH-.

[0071] In some embodiments, L1is -CH2- or -CH=CH-.

[0072] In some embodiments, R9is aryl or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 groups independently chosen from Ci-Cealkyl, Ci-Cealkoxy, haloalkyl, haloalkoxy, Ci-Cethioalkyl, alkynyl, aryl, aryl(Ci-Cealkyl), benzyl, aryloxy, benzyloxy, heteroaryl, heteroaryl(Ci-C6alkyl), heteroaryloxy, -CfCH^OH, -CO2R7, -CH2CO2R7, -C(O)N(R7)2, -N(R7)2, -O(CH2)nR7, oxo, cyano, and halo.

[0073] In some embodiments, R9is phenyl optionally substituted with 1, 2, or 3 groups independently chosen from Ci-Cealkyl, Ci-Cealkoxy, haloalkyl, haloalkoxy, aryl(Ci-Cealkyl), alkynyl, aryloxy, benzyloxy, heteroaryl, heteroaryl(Ci-C6alkyl), heteroaryloxy, -CfCH^OH, -CO2R7, -CH2CO2R7, -C(O)N(R7)2, -N(R7)2, -O(CH2)nR7, cyano, and halo.

[0074] In some embodiments, R9is phenyl optionally substituted with 1, 2, or 3 groups independently chosen from methoxy, ethoxy, propoxy, isopropoxy, butoxy, trifluoromethoxy, thiomethyl, chloro, fluoro, methyl, ethyl, propyl, trifluoromethyl, phenoxy, benzyloxy, pyridinyloxy, methyl, ethynyl, (dimethylamino)ethoxy, 2-methoxyethoxy, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 2-hydroxypropyl, methyltriazole, dimethyloxazolyl, and imidazolyl.

[0075] In some embodiments, R9is phenyl optionally substituted with methoxy, ethoxy, propoxy, butoxy, chloro, fluoro, phenoxy, benzyloxy, methyl, (dimethylamino)ethoxy, 2-Docket No.: KMYXP001WOmethoxyethoxy, cyano, ethynyl, carboxy, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 2-hydroxypropyl, and imidazolyl.

[0076] In some embodiments, R9is phenyl.

[0077] In some embodiments, R2is -iJ-R9and L1is absent.

[0078] In some embodiments, R9is aryl or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 groups independently chosen from Ci-Cealkyl, Ci-Cealkoxy, alkynyl, aryl, benzyl, aryloxy, benzyloxy, heteroaryl, -CfCH^OH, -CO2R7, -CH2CO2R7, -C(O)N(R7)2, -N(R7)2, -O(CH2)nR7, oxo, cyano, and halo.

[0079] In some embodiments, R9is phenyl optionally substituted with 1, 2, or 3 groups independently chosen from Ci-Cealkyl, Ci-Cealkoxy, alkynyl, aryloxy, benzyloxy, heteroaryl, -C(CH3)2OH, -CO2R7, -CH2CO2R7, -C(O)N(R7)2, -N(R7)2, -O(CH2)nR7, cyano, and halo.

[0080] In some embodiments, R9is phenyl optionally substituted with 1, 2, or 3 groups independently chosen from methoxy, ethoxy, propoxy, butoxy, chloro, fluoro, methyl, ethyl, propyl, phenoxy, benzyloxy, methyl, ethynyl, (dimethylamino)ethoxy, 2-methoxyethoxy, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 2-hydroxypropyl, and imidazolyl.

[0081] In some embodiments, R9is chosen from phenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-ethylphenyl, 4-propylphenyl, 4-methylsulfylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-cyano-4-methoxyphenyl, 4-ethynylphenyl, 4-(2-hydroxyethyl)phenyl, 4-(prop-l-yn-l-yl)phenyl, or 4-(3-methylbut- 1 -yn- 1 -yl)phenyl.

[0082] In some embodiments, R9is chosen from 4-methoxyphenyl, 4-ethoxyphenyl, and 4-propoxyphenyl.

[0083] In some embodiments, R9is phenyl substituted with 4H-imidazol-4-yl.

[0084] In some embodiments, R9is pyridinyl or pyrimidinyl, each of which is optionally substituted with methoxy, methylamino, dimethylamino, ethyl(methyl)amino, and pyrrolidinyl.

[0085] In some embodiments, R9is pyridin-3-yl or pyrimidin-5-yl, each of which is optionally substituted with methoxy, methylamino, dimethylamino, ethyl(methyl)amino, and pyrrolidinyl.

[0086] In some embodiments, R9is pyrrolyl, imidazolyl or pyrazolyl, each of which is optionally substituted with one or two groups independently chosen from methyl, ethyl, benzyl, phenyl, pyridinyl, and pyrimidinyl.Docket No.: KMYXP001WO

[0087] In some embodiments, R9isoptionally substituted with one or two methyl groups.

[0088] In some embodiments, R9isoptionally substituted with methyl, ethyl, phenyl, benzyl, pyridinyl, or pyrimidinyl.

[0089] In some embodiments, R9isoptionally substituted with pyridinyl.

[0090] In some embodiments,U and V are independently O, S, NRC, or CH2; andeach Rcis independently selected from H, -CH3, or -CH2CH3;wherein R9is optionally substituted with one or two groups independently chosen from oxo and methyl.

[0092] In some embodiments,Y is O, S, or NRb, and Y1is CRbor N;or Y is CRbor N, and Y1is O, S, or NRb; andeach Rbis independently selected from H, -CH3, or -CH2CH3.Docket No.: KMYXP001WO

[0093] In some embodiments, R9is chosen from

[0094] In some embodiments, R2is 2,3-dihydrobenzo[b][l,4]dioxinyl, chromanyl, phenyl, thiazolyl, benzo[ ][l,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2-oxo-2,3-di hydrobenzo| |oxazoly I, pyrrolyl, pyridyl, pyrimidyl, pyrazyl, diazolyl, indolyl, indazolyl, benzimidazolyl, imidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, 3-oxo-dihydrobenzo[b][l,4]thiazinyl, or pyrazolyl, each of which is optionally substituted with one or two groups independently chosen from halogen, Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Cefluoroalkoxy, cyano, Ci-Cehydroxy alkyl, methylcarboxyl, carbamoyl, Ci-Cealkylamino, Ci-Cethioalkyl, Ci-Cealkoxy, and C2-Ceethynyl.

[0095] In some embodiments, R2is phenyl, which is optionally substituted with one or two groups independently chosen from halogen, Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Cefluoroalkoxy, cyano, Ci-Cehydroxyalkyl, Ci-Cethioalkyl, Ci-Cealkoxy, and C2-Ceethynyl.

[0096] In some embodiments, R2is phenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-ethylphenyl, 4-propylphenyl, 4-methylsulfylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifhioromethylphenyl, 4-trifluoromethoxyphenyl, 3-cyano-4-methoxyphenyl, 4-ethynylphenyl, 4-(2-hydroxyethyl)phenyl, 4-(prop-l-yn-l-yl)phenyl, or 4-(3-methylbut- 1 -yn- 1 -yl)phenyl.

[0097] In some embodiments, R2is 2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl, chroman-6-yl, 2,3-dihydrobenzo[b][l,4]dioxin-6-yl, 2,3-dihydrobenzofuran-5-yl, 2,2-dimethyl-2,3-dihydrobenzofuran-5-yl, benzo[d][l,3]dioxol-5-yl, quinolin-6-yl, 3-oxo-dihydrobenzo[b][l,4]thiazinyl, or 2-(ethylamino)thiazol-5-yl.

[0098] In some embodiments, R2is thiazolyl, pyrrolyl, pyridyl, quinolinyl, benzothiazolyl, or pyrazolyl, each of which is optionally substituted with one or two groups independently chosen from Ci-Cealkyl, Ci-Cehydroxy alkyl, methylcarboxyl, carbamoyl, Ci-Cealkylamino, and Ci-Cealkoxy.

[0099] In some embodiments, R2is lH-pyrazol-4-yl, pyridin-3-yl, quinolin-6-yl, benzothiazol-5-yl, pyrrol-4-yl, or thiazol-5-yl, each of which is optionally substituted with one or two groups independently chosen from ethyl, methoxy, methyl, methylcarboxyl, carbamoyl, 2-hydroxypropanyl, and ethylamino.

[0100] In some embodiments, R2is 1 -ethyl- lH-pyrazol-4-yl, 6-methoxypyridin-3-yl, quinolin-6-yl, benzothiazol-5-yl, l-methyl-2-methylcarboxyl-pyrrol-4-yl, l-methyl-2-carbamoyl-pyrrol-4-yl, l-methyl-2-(l -hydroxy- l,l-dimethyl-methyl)-pyrrol-4-yl, or 2-(ethylamino)thiazol-5-yl.Docket No.: KMYXP001WO

[0101] In some embodiments, Rlaand Rlbare independently selected from H, D and -CH3.

[0102] In some embodiments, Rlaand Rlbare H.

[0103] In some embodiments, A is NR4, B is N, and D is CR5.

[0104] In some embodiments, A is N, B is NR4and D is CR5.

[0105] In some embodiments, A is N, B is CR5, and D is O, S, or NR4.

[0106] In some embodiments, R4is H or -CH3.

[0107] In some embodiments, R4is -CH3.

[0108] In some embodiments, R4is H.

[0109] In some embodiments, R5is H or -CH3.

[0110] In some embodiments, R5is -CH3.

[0111] In some embodiments, R5is H.

[0112] In some embodiments, Rla, Rlb, R4, and R5are H.

[0114] In some embodiments, is HN

[0115] In some embodiments, R3is chosen from thienyl, furanyl, thiazolyl, imidazolyl, isothiazolyl, isooxazolyl, and thiadiazolyl, each of which is optionally substituted with one or two groups independently chosen from OH, F, Cl, B Qr, and -CH3.r^NN^\ N^\ S^NS^NYN[Ullb] in some embodiments, K is chosen tromj U“,CH3.Docket No.: KMYXP001WO

[0117] In some embodiments, R3is chosen from

[0119] In some embodiments, R3is

[0120] In some embodiments, R3is chosen from phenyl, pyridinyl, pyridazinyl, and pyrimidinyl, each of which is optionally substituted with one or two groups independently chosen from halogen and hydroxy.

[0121] In some embodiments, R3is phenyl, pyridin-4-yl, pyridin-3-yl, pyridazin-4-yl, pyrimidin-4-yl, and pyrimidin-5-yl, each of which is optionally substituted with one or two groups independently chosen from halogen and hydroxy.

[0122] In some embodiments, R3is phenyl, 4-fluorophenyl, pyridin-4-yl, pyridin-3-yl, 6-hydroxy-pyridin-3-yl, pyridazin-4-yl, pyrimidin-4-yl, and pyrimidin-5-yl.

[0123] In some embodiments, the compound has structural Formula (II):

[0124] In some embodiments, R3is chosen from pyridinyl, isothiazolyl, furanyl, and pyrimidinyl, each of which is optionally substituted with one or two groups chosen from methyl and fluoro.Docket No.: KMYXP001WO

[0126] In some embodiments, R9is phenyl optionally substituted with one or two groups chosen from alkyl and alkoxy.

[0127] In some embodiments, R9is chosen from 4-ethoxyphenyl, 4-methoxyphenyl, and 4-ethylphenyl.

[0128] In some embodiments, the compound of Formula (I) is chosen fromDocket No.: KMYXP001WO5Docket No.: KMYXP001WOCD JODocket No.: KMYXP001WO5Docket No.: KMYXP001WO5Docket No.: KMYXP001WODocket No.: KMYXP001WODocket No.: KMYXP001WODocket No.: KMYXP001WO

[0130] The compounds disclosed herein can exist as pharmaceutically acceptable salts. The present disclosure includes compounds listed herein in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0131] The term “pharmaceutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates;Docket No.: KMYXP001WOdecyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0132] Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, MN-di benzyl phenethyl amine, 1 -ephenamine, and AW -dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0133] While it may be possible for the compounds, and pharmaceutically acceptable salts thereof, of the subject disclosure to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation.

[0134] Also provided is a pharmaceutical formulation comprising a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound, or pharmaceutically acceptable salts thereof, of the subject disclosure or a pharmaceutically acceptable salt thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0135] Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient.Docket No.: KMYXP001WO

[0136] Compounds, or pharmaceutically acceptable salts thereof, may be administered at a dose of from 0.1 to 500 mg / kg per day. The dose range for a subject is generally from 5mg to 2 g / day. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0137] The compounds, or pharmaceutically acceptable salts thereof, can be administered in various modes. In some embodiments, the pharmaceutical formulation is formulated for oral administration.

[0138] In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt thereof) in combination with another therapeutic agent. By way of example only, the therapeutic effectiveness of one of the compounds described herein, or pharmaceutically acceptable salts thereof, may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the subject is enhanced). Or, by way of example only, the benefit of experienced by a subject may be increased by administering one of the compounds described herein, or pharmaceutically acceptable salts thereof, with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the subject may simply be additive of the two therapeutic agents or the subject may experience a synergistic benefit.

[0139] In any case, the multiple therapeutic agents (at least one of which is a compound disclosed herein, or a pharmaceutically acceptable salt thereof) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.

[0140] Also provided is a feed supplement or medicated feed comprising ground dry vegetable- or animal-based feed, with or without additives such as proteins, vitamins, and minerals, and a compound as recited herein, or a salt or tautomer thereof.

[0141] Also provided is a feed additive composition for preventing or ameliorating coccidiosis, comprising a compound as recited herein, or a salt or tautomer thereof, as an active ingredient.Docket No.: KMYXP001WO

[0142] Also provided is a method of inhibiting myosin protein activity, comprising contacting a myosin protein with a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, or a feed supplement as described herein.

[0143] In some embodiments, the myosin protein is chosen from myosin-I, myosin- VI, myosin-XII, myosin-XIII, myosin-XXI, myosin-XXII, myosin-XXIII, and myosin-XXIV.

[0144] In some embodiments, the myosin-XIV protein is chosen from MyoA, MyoB, MyoC, MyoD, MyoE, and MyoH.

[0145] In some embodiments, the myosin-XIV protein is MyoA.

[0146] In some embodiments, the myosin-XXII protein is MyoF.

[0147] In some embodiments, the myosin-XXIII protein is chosen from MyoG, MyoJ, and MyoK.

[0148] In some embodiments, the myosin-XXIV protein is Myol.

[0149] In some embodiments, the myosin protein is expressed in a coccidial protozoa.

[0150] In some embodiments, the myosin protein is expressed in a cryptosporidial protozoa.

[0151] In some embodiments, the myosin protein is expressed in a coccidial or cryptosporidial protozoa.

[0152] Also provided is a method of treating or preventing coccidiosis in a subject that would benefit from the modulation of coccidial protozoa myosin protein activity, comprising administering to the subject in need thereof a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, or a feed supplement as described herein.

[0153] In some embodiments, treating the coccidial protozoa comprises inhibiting its growth or replication.

[0154] In some embodiments, inhibiting the coccidial protozoa growth or replication comprises modulating coccidial protozoa cytoskeletal proteins.

[0155] In some embodiments, modulating coccidial protozoa cytoskeletal proteins comprises inhibiting myosin ATPase activity.

[0156] In some embodiments, modulating coccidial protozoa cytoskeletal proteins comprises inhibiting actin turnover.

[0157] In some embodiments, modulating coccidial protozoa cytoskeletal proteins comprises modulating the interaction between myosin and actin.

[0158] In some embodiments, the coccidiosis comprises infection with Isospora spp., Eimeria spp., Sarcocystis spp., or Neospora spp.Docket No.: KMYXP001WO

[0159] In some embodiments, the Isospora spp. comprises I. canis, I. ohioensis, I. burrowsi, I. neorivolta, I. felis, or I. rivolta.

[0160] In some embodiments, the Eimeria spp. comprises E. tenella, E. brunetti, E. necatrix, E. maxima, or E. acervuline.

[0161] In some embodiments, the Neospora spp. comprises N. caninum.

[0162] Also provided is a method of treating or preventing coccidiosis, comprising administering to the subject a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, or a feed supplement as described herein, that selectively inhibits coccidial protozoa myosin activity relative to subject myosin activity.

[0163] Also provided is a method of preventing or reducing susceptibility to infection by a coccidial protozoa, comprisingadministering to a subject a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, or a feed supplement as described herein, that selectively inhibits coccidial protozoa myosin activity relative to subject myosin activity; andexposing the subject to the coccidial protozoa.

[0164] In some embodiments, the coccidial protozoa is in the sexual, asexual, sporozoite, merozoite, gamete or oocyst stage in its life cycle.

[0165] In some embodiments, the coccidial protozoa myosin is Myo A.

[0166] In some embodiments, the host myosin is chosen from cardiac muscle myosin, skeletal muscle myosin, and smooth muscle myosin.

[0167] In some embodiments, the compound selectively inhibits the coccidial protozoa myosin relative to the host myosin by at least 2-fold.

[0168] In some embodiments, the compound selectively inhibits the coccidial protozoa myosin relative to the host myosin by at least 10-fold.

[0169] In some embodiments, the compound selectively inhibits the coccidial protozoa myosin relative to the host myosin by at least 100-fold.

[0170] Also provided is a method of treating or preventing coccidiosis in a subject comprising administering a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, that inhibits coccidial protozoa myosin ATPase activity.

[0171] In some embodiments, the myosin is MyoA.

[0172] Also provided is a method of treating a disease or condition in a subject that would benefit from the modulation of cryptosporidial protozoa myosin protein activity, comprisingDocket No.: KMYXP001WOadministering to the subject in need thereof a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, or a feed supplement as described herein.

[0173] In some embodiments, the disease or condition is cryptosporidiosis.

[0174] In some embodiments, the subject in need thereof is pregnant, immunocompromised, or any combination thereof.

[0175] In some embodiments, treating cryptosporidiosis comprises inhibiting cryptosporidial protozoa growth or replication.

[0176] In some embodiments, inhibiting cryptosporidial protozoa growth or replication comprises modulating cryptosporidial protozoa cytoskeletal proteins.

[0177] In some embodiments, modulating cryptosporidial protozoa cytoskeletal proteins comprises inhibiting myosin ATPase activity.

[0178] In some embodiments, modulating cryptosporidial protozoa cytoskeletal proteins comprises inhibiting actin turnover.

[0179] In some embodiments, modulating cryptosporidial protozoa cytoskeletal proteins comprises modulating the interaction between myosin and actin.

[0180] In some embodiments, the cryptosporidiosis comprises infection with Cryptosporidium spp.

[0181] In some embodiments, the Cryptosporidium spp. comprises C. hominis and C. parvum.

[0182] Also provided is a method of treating cryptosporidiosis in a subject, comprising administering to the subject a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, or a feed supplement as described herein, that selectively inhibits cryptosporidial protozoa myosin activity relative to subject myosin activity.

[0183] Also provided is a method of preventing or reducing susceptibility to infection by a cryptosporidial protozoa, comprisingadministering to a subject a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, or a feed supplement as described herein, that selectively inhibits cryptosporidial protozoa myosin activity relative to subject myosin activity; andexposing the subject to the cryptosporidial protozoa.

[0184] In some embodiments, the cryptosporidial protozoa is in the sexual, asexual, sporozoite, merozoite, gamete or oocyst stage in its life cycle.Docket No.: KMYXP001WO

[0185] In some embodiments, the cryptosporidial protozoa myosin is MyoA.

[0186] In some embodiments, the host myosin is chosen from cardiac muscle myosin, skeletal muscle myosin, and smooth muscle myosin.

[0187] In some embodiments, the compound selectively inhibits cryptosporidial protozoa myosin relative to the host myosin by at least 2-fold.

[0188] In some embodiments, the compound selectively inhibits cryptosporidial protozoa myosin relative to the host myosin by at least 10-fold.

[0189] In some embodiments, the compound selectively inhibits cryptosporidial protozoa myosin relative to the host myosin by at least 100-fold.

[0190] Also provided is a method of treating or preventing cryptosporidiosis in a subject comprising administering a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, that inhibits cryptosporidial protozoa myosin ATPase activity.

[0191] Also provided is a method of treating a disease or condition in a subject that would benefit from the modulation of coccidial or cryptosporidial protozoa myosin protein activity, comprising administering to the subject in need thereof a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, or a feed supplement as described herein.

[0192] In some embodiments, the disease or condition is coccidiosis or cryptosporidiosis.

[0193] In some embodiments, treating coccidiosis or cryptosporidiosis comprises inhibiting coccidial or cryptosporidial protozoa growth or replication.

[0194] In some embodiments, inhibiting coccidial or cryptosporidial protozoa growth or replication comprises modulating coccidial or cryptosporidial protozoa cytoskeletal proteins.

[0195] In some embodiments, modulating coccidial or cryptosporidial protozoa cytoskeletal proteins comprises inhibiting myosin ATPase activity.

[0196] In some embodiments, modulating coccidial or cryptosporidial protozoa cytoskeletal proteins comprises inhibiting actin turnover.

[0197] In some embodiments, modulating coccidial or cryptosporidial protozoa cytoskeletal proteins comprises modulating the interaction between myosin and actin.

[0198] Also provided is a method of treating coccidiosis or cryptosporidiosis in a subject, comprising administering to the subject a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, or a feed supplement as described herein, that selectively inhibits coccidial or cryptosporidial protozoa myosin activity relative to subject myosin activity.Docket No.: KMYXP001WO

[0199] Also provided is a method of preventing or reducing susceptibility to infection by a coccidial or cryptosporidial protozoa, comprisingadministering to a subject a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, or a feed supplement as described herein, that selectively inhibits coccidial or cryptosporidial protozoa myosin activity relative to subject myosin activity; andexposing the subject to the coccidial or cryptosporidial protozoa.

[0200] In some embodiments, the coccidial or cryptosporidial protozoa is in the sexual, asexual, sporozoite, merozoite, gamete or oocyst stage in its life cycle.

[0201] In some embodiments, the coccidial or cryptosporidial protozoa myosin is MyoA.

[0202] In some embodiments, the host myosin is chosen from cardiac muscle myosin, skeletal muscle myosin, and smooth muscle myosin.

[0203] In some embodiments, the compound selectively inhibits coccidial or cryptosporidial protozoa myosin relative to the host myosin by at least 2-fold.

[0204] In some embodiments, the compound selectively inhibits coccidial or cryptosporidial protozoa myosin relative to the host myosin by at least 10-fold.

[0205] In some embodiments, the compound selectively inhibits coccidial or cryptosporidial protozoa myosin relative to the host myosin by at least 100-fold.

[0206] Also provided is a method of treating or preventing coccidiosis or cryptosporidiosis in a subject comprising administering a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, that inhibits coccidial or cryptosporidial protozoa myosin ATPase activity.

[0207] Also provided is a method of treating or preventing a disease caused by an Apicomplexa parasite in a subject, comprising administering to a subject a compound as recited herein, or a salt or tautomer thereof, or a pharmaceutical formulation as recited herein, or a feed supplement as recited herein, that selectively inhibits Apicomplexa parasite myosin activity relative to subject myosin activity.

[0208] In some embodiments, the Apicomplexa parasite is a Babesia spp., an Eimeria spp., a Cryptosporidium spp., a Cystoisospora spp., a Theileria spp., or a Toxoplasma spp.

[0209] In some embodiments, the Babesia spp. is Babesia bovis, Babesia bigemina, Babesia canis, or Babesia caballi.

[0210] In some embodiments, the Cystoisospora spp. is Cystoisospora canis.

[0211] In some embodiments, the Theileria spp. is Theileria equi.

[0212] In some embodiments, the Toxoplasma spp. is Toxoplasma gondii.Docket No.: KMYXP001WO

[0213] In some embodiments, the disease caused by an Apicomplexa parasite is coccidiosis, babesiosis, piroplasmosis, cystoisosporiasis, or toxoplasmosis.

[0214] In some embodiments, the disease caused by an Apicomplexa parasite is poultry coccidiosis, cryptosporidiosis, small ruminant coccidiosis, cattle babesiosis, dog babesiosis, equine piroplasmosis, dog cystoisosporiasis, or cat toxoplasmosis.

[0215] Also provided is a poultry feed supplement or medicated poultry feed for the control of coccidiosis in poultry, comprising ground dry vegetable- and / or animal-based poultry feed, with or without additives such as proteins, vitamins, and minerals, and a coccidiostatically effective amount of a compound as recited herein, or a salt or tautomer thereof.

[0216] Also provided is a pharmaceutical formulation for the control of coccidiosis in poultry, comprising a coccidiostatically effective amount of a compound as recited herein, or a salt or tautomer thereof, and a pharmaceutically acceptable carrier.

[0217] Also provided herein is a cattle feed supplement or medicated cattle feed for the control of cryptosporidiosis in cattle, comprising ground dry vegetable- and / or animal-based cattle feed, with or without additives such as proteins, vitamins, and minerals, and a cryptosporidiostatically effective amount of a compound as recited herein, or a salt or tautomer thereof.

[0218] Also provided is a pharmaceutical formulation for the control of cryptosporidiosis in cattle, comprising a cryptosporidiostatically effective amount of a compound as recited herein, or a salt or tautomer thereof, and a pharmaceutically acceptable carrier.

[0219] In some embodiments, the pharmaceutically acceptable carrier is water.

[0220] In some embodiments, the compounds and salts described herein are modulators of myosin expressed in coccidial protozoa. In some embodiments, the compounds and salts described herein preferentially modulate myosin expressed in coccidial protozoa over host organism myosin. In some embodiments, the compounds and salts described herein are amenable to oral administration to a subject in need of treatment or disease prevention with a myosin modulator. In some embodiments, the subject in need of treatment is infected with a coccidial protozoa or has coccidiosis. In some embodiments, the subject in need of treatment or prevention is immunocompromised, infected, or pregnant. In some embodiments, the subject in need of using a myosin modulator is undergoing chemoprophylaxis to prevent coccidiosis.

[0221] In some embodiments, the compounds and salts described herein are modulators of myosin expressed cryptosporidial protozoa. In some embodiments, the compounds and salts described herein preferentially modulate myosin expressed in cryptosporidial protozoa overDocket No.: KMYXP001WOthe host organism myosin. In some embodiments, the compounds and salts described herein are amenable to oral administration to a subject in need of treatment or disease prevention with a myosin modulator. In some embodiments, the subject in need of treatment is infected with a cryptosporidial protozoa or has cryptosporidiosis. In some embodiments, the subject in need of treatment or prevention is immunocompromised, infected, or pregnant. In some embodiments, the subject in need of using a myosin modulator is undergoing chemoprophylaxis to prevent cryptosporidiosis.

[0222] In some embodiments, myosin modulators described herein have therapeutic utility. In some embodiments, myosin modulators described herein are used in the treatment or prevention of coccidiosis in a subject. In some embodiments, myosin modulators described herein are used in the treatment or prevention of acute coccidiosis. In some embodiments, myosin modulators described herein are used in the treatment or prevention of chronic coccidiosis.

[0223] In some embodiments, myosin modulators described herein inhibit the growth, replication, motility, or transmission of a coccidial protozoa. In some embodiments, the compounds are used to inhibit myosin ATPase activity. In some embodiments, the compounds selectively inhibit coccidial protozoa myosin ATPase activity by at least 2-fold, at least 5-fold, at least 10-fold, at least 50-fold, or at least 100-fold relative to host myosin. In some embodiments, the compounds modulate the interaction between myosin and actin. In some embodiments, the myosin modulators interact with myosin-XIV and subtypes thereof, including but not limited to MyoA, MyoB, MyoC, MyoD, MyoE, MyoH, or any combination thereof. In some embodiments, the myosin modulators interact with myosin-XXII and subtypes thereof, including but not limited to MyoF. In some embodiments, the myosin modulators interact with myosin-XXIII and subtypes thereof, including but not limited to MyoG, MyoJ, or MyoK, or any combination thereof. In some embodiments, the myosin modulators interact with myosin-XXIV and subtypes thereof, including but not limited to Myol. In some embodiments, the myosin modulators interact with myosin-XII and subtypes thereof. In some embodiments, the myosin modulators interact with myosin-XX and subtypes thereof. In some embodiments, the myosin modulators interact with myosin-XXI and subtypes thereof.

[0224] In some embodiments, the compounds and salts described herein are used to treat or prevent coccidiosis in animals, including but not limited to livestock and companion animals.

[0225] In some embodiments, a myosin modulator is used in the treatment or chemoprophylaxis of coccidiosis caused by infection with a coccidial protozoa such as, butDocket No.: KMYXP001WOnot limited to: a) species of Isospora including Isospora canis, Isospora ohioensis, Isospora burrowsi, Isospora neorivolta, Isospora felis, Isospora rivolta, b) species of Eime ria including Eimeria tenella, Eimeria brunetti, Eimeria necatrix, Eimeria maxima, and Eimeria acervulina, c) species of Sarcocystis, or d) species of Neospora including Neospora caninum.

[0226] In some embodiments, myosin modulators described herein have therapeutic utility. In some embodiments, myosin modulators described herein are used in the treatment or prevention of a variety of diseases or conditions such as, but not limited to, cryptosporidiosis. In some embodiments, myosin modulators described herein are used in the treatment or prevention of cryptosporidiosis in a subject. In some embodiments, myosin modulators described herein are used in the treatment or prevention of acute cryptosporidiosis. In some embodiments, myosin modulators described herein are used in the treatment or prevention of chronic cryptosporidiosis.

[0227] In some embodiments, myosin modulators described herein inhibit the growth, replication, motility, or transmission of a cryptosporidial protozoa. In some embodiments, the compounds are used to inhibit myosin ATPase activity. In some embodiments, the compounds selectively inhibit cryptosporidial protozoa myosin ATPase activity by at least 2-fold, at least 5-fold, at least 10-fold, at least 50-fold, or at least 100-fold relative to host myosin. In some embodiments, the compounds modulate the interaction between myosin and actin. In some embodiments, the myosin modulators interact with myosin-XIV and subtypes thereof, including but not limited to MyoA, MyoB, MyoC, MyoD, MyoE, MyoH, or any combination thereof. In some embodiments, the myosin modulators interact with myosin-XXII and subtypes thereof, including but not limited to MyoF. In some embodiments, the myosin modulators interact with myosin-XXIII and subtypes thereof, including but not limited to MyoG, MyoJ, or MyoK, or any combination thereof. In some embodiments, the myosin modulators interact with myosin-XXIV and subtypes thereof, including but not limited to Myol. In some embodiments, the myosin modulators interact with myosin-XII and subtypes thereof. In some embodiments, the myosin modulators interact with myosin-XX and subtypes thereof. In some embodiments, the myosin modulators interact with myosin-XXI and subtypes thereof.

[0228] In some embodiments, the compounds and salts described herein are used to treat or prevent cryptosporidiosis in animals, including but not limited to livestock and companion animals.

[0229] In some embodiments, a myosin modulator is used in the treatment or chemoprophylaxis of cryptosporidiosis caused by infection with cryptosporidial protozoa suchDocket No.: KMYXP001WOas, but not limited to, Cryptosporidium parvum, Cryptosporidium hominis, Cryptosporidium anis, Cryptosporidium felis, Cryptosporidium meleagridis, or Cryptosporidium muris.

[0230] Further embodiments include the embodiments disclosed in the following Schemes, which are not to be construed as limiting in any way.SCHEMESScheme I101 102 103 Formula la

[0231] Referring to Scheme I, Step 1, to a solution of the compound of Formula 101 in a polar solvent, such as ethanol, is added semicarbazide hydrochloride, and a base, such as sodium acetate. The mixture is stirred, optionally at elevated temperatures. In some embodiments, the mixture is stirred for 2-6 h. The product, a compound of Formula 102, is isolated and purified using methods known in the art.

[0232] Referring to Scheme I, Step 2, to a solution of the compound of Formula 102 in an polar aprotic solvent, such as dimethylformamide, is added POCh. The mixture is stirred, optionally at elevated temperatures. In some embodiments, the mixture is stirred between 4-8 h. The product, a compound of Formula 103, is isolated and purified using methods known in the art.

[0233] Referring to Scheme I, Step 3, to a solution of the compound of Formula 103 in a polar solvent, such as methanol, is added a compound of Formula 104, a mild acid, such as acetic acid, and a reducing agent, such as sodium cyanoborohydride. The resulting mixture is stirred, optionally at ambient temperature. In some embodiments, the mixture is stirred for 12- 24 h. The product, a compound of Formula la, is isolated and purified using methods known in the art. Individual enantiomers can be separated by using methods known in the art, such as chiral chromatography.Scheme IIDocket No.: KMYXP001WOXStep 1 Step 2 H2N NH2204R3OEt Cl Steps 3-4 201 202 203 205206 207 Formula lb

[0234] Referring to Scheme II, Step 1, to a solution of a compound of Formula 201 in diethylcarbonate is added a strong non-nucleophilic base, such as sodium hydride. The mixture is stirred, optionally at elevated temperature. In some embodiments, the mixture is stirred for 12-24 h. The product, a compound of Formula 202, is isolated and purified using methods known in the art.

[0235] Referring to Scheme II, Step 1, to a solution of a compound of Formula 202 in an organic solvent, such as dichloromethane, is added a chlorinating agent, such as sulfuryl chloride. The mixture is stirred, optionally at reduced temperature. In some embodiments, the mixture is stirred for 1-2 h. The product, a compound of Formula 203, is isolated and purified using methods known in the art.

[0236] Referring to Scheme II, Steps 3-4, to a solution of a compound of Formula 203 in a polar solvent, such as ethanol, is added a compound of Formula 204 (where X is chosen from O and S). The mixture is stirred, optionally at elevated temperature. In some embodiments, the mixture is stirred for 2-4 h. The product is isolated and purified using methods known in the art, then dissolved in an acidic solvent, such as hypophosphorous acid, along with NaNCh.The resulting mixture is stirred for between 1-2 h at reduced temperature. The product, a compound of Formula 205, is isolated and purified using methods known in the art.

[0237] Referring to Scheme II, Step 5, to a solution of the compound of Formula 205 in a polar aprotic solvent, such as tetrahydrofuran, is added a reducing agent, such as lithium aluminum hydride. The mixture is stirred, optionally at reduced temperatures. In some embodiments, the mixture is stirred for 1-3 h. The product, a compound of Formula 206, is isolated and purified using methods known in the art.

[0238] Referring to Scheme II, Step 6, to a solution of the compound of Formula 206 in an organic solvent, such as dichloromethane, is added a chlorinating agent, such as thionyl chloride. The resulting mixture is stirred, optionally under elevated temperatures. In someDocket No.: KMYXP001WOembodiments, the mixture is stirred under elevated temperatures for 1-2 h. The product, a compound of Formula 207, is isolated and purified using methods known in the art.

[0239] Referring to Scheme II, Step 7, to a solution of a compound of Formula 207 in a polar aprotic solvent, such as dimethylformamide, is added a base, such as potassium carbonate and / or diisopropylethylamine, and a compound of Formula 104. The mixture is stirred, optionally at ambient temperature. In some embodiments, the mixture is stirred for 16-24 h. The product, a compound of Formula lb, is isolated and purified using methods known in the art. Individual enantiomers can be separated by using methods known in the art, such as chiral chromatography.Scheme IIIStep 1 Step 2 Steps 3-4304ORBocHN-B^0R305Steps 5-6 Step 7 R3306 Formula la

[0240] Referring to Scheme III, Step 1, to a compound of Formula 301 is added N, N-dimethylformamide dimethyl acetal. The mixture is stirred, optionally at elevated temperature. In some embodiments, the mixture is stirred for 1-2 h. The product, a compound of Formula 302, is isolated and purified using methods known in the art.

[0241] Referring to Scheme III, Step 2, to a solution of the compound of Formula 302 in an organic solvent, such as ethanol, is added hydrazine hydrochloride. The mixture is stirred, optionally at elevated temperature. In some embodiments, the mixture is stirred for 1-2 h. The product, a compound of Formula 303, is isolated and purified using methods known in the art.

[0242] Referring to Scheme III, Steps 3-4, to a solution of the compound of Formula 303 in a polar protic solvent, such as DMF, is added a halogenating agent, such as N-iodosuccinimide. The mixture is stirred, optionally at ambient temperature. In some embodiments, the mixture is stirred for 16-24 h. The product is isolated and purified using methods known in the art, then treated using any method or methods of installing protectingDocket No.: KMYXP001WOgroups known in the art. The product, a compound of Formula 304 (X = Cl, Br, or I; and PG = protecting group, such as tetrahydropyranyl), is isolated and purified using methods known in the art.

[0243] Referring to Scheme III, Steps 5-6, to a solution of the compound of Formula 304 in a polar solvent, such as a mixture of dioxane, water, and acetonitrile, is added a compound of Formula 305 (R = alkyl, such as methyl, or hydrogen, or in combination with a second R group forms a heterocycloalkyl, such as pinacol borane), a base, such as potassium phosphate, and a palladium catalyst, such as bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloride palladium (II). The mixture is stirred, optionally at elevated temperature. In some embodiments, the mixture is stirred for 16-24 h. The product is isolated and purified using methods known in the art, then treated using any method or methods of removing protecting groups known in the art. The product, a compound of Formula 306, is isolated and purified using methods known in the art.

[0244] Referring to Scheme III, Step 7, to a solution of the compound of Formula 306 in an organic solvent, such as dichloromethane, is added a compound of Formula 307 and a base, such as triethylamine. The mixture is stirred, optionally at ambient temperature. In some embodiments, the mixture is stirred for 1-2 h. The product, a compound of Formula la, is isolated and purified using methods known in the art. Individual enantiomers can be separated by using methods known in the art, such as chiral chromatography.Scheme IVR3R3Q-NH2Step 2 CIZ R404Step 1 401 402 403 Formula Ic

[0245] Referring to Scheme IV, Step 1, to a solution of the compound of Formula 401 in a polar organic solvent, such as ethanol or THF, is added a compound of Formula Q-NH2 (Q = - OH or -S(O)C(CHS)3) and either a base, such as sodium acetate, or a Lewis acid, such as Ti(OEt)4. The mixture is stirred, optionally at ambient temperature. In some embodiments, the mixture is stirred at elevated temperature. In some embodiments, the mixture is stirred for 2-4 h. In some embodiments, the mixture is stirred for 16-24 h. The product, a compound of Formula 402, is isolated and purified using methods known in the art.

[0246] Referring to Scheme IV, Step 2, the compound of Formula 402 is added to an acidic solution, such as HC1 in dioxane or water. In some embodiments, a metal, such as zinc, is also added. The mixture is stirred, optionally at reduced temperature. In some embodiments, theDocket No.: KMYXP001WOmixture is stirred for 2-24 h. The product, a compound of Formula 403, is isolated and purified using methods known in the art. If Q = -S(O)C(CHs)3, the compound of Formula 402 is first dissolved in a polar organic solvent, such as THF, treated with a reducing agent, such as diisobutylaluminum hydride, and stirred at ambient temperature, optionally for 16-24 h.

[0247] Referring to Scheme IV, Step 3, to a solution of the compound of Formula 403 in an organic solvent, such as dichloromethane, is added a compound of Formula 404 and a base, such as triethylamine. The mixture is stirred, optionally at ambient temperature. In some embodiments, the mixture is stirred for 1-2 h. The product, a compound of Formula Ic, is isolated and purified using methods known in the art. Individual enantiomers can be separated by using methods known in the art, such as chiral chromatography.

[0248] Examples of embodiments of the present disclosure are provided in the following examples. The following examples are presented only by way of illustration and to assist one of ordinary skill in using the disclosure. The examples are not intended in any way to otherwise limit the scope of the disclosure.EXAMPLESExample 1: Synthesis of l-(4-methoxyphenyl)-N-((3-(thiophen-2-yl)-lH-pyrazol-4-yl) methyl) cyclopropan-1 -amine (Compound 1)NH2CONHNH2HCI, AcONa, EtOH Step-1IM EtMgBr in THF, Ti(OEt)4, BF3Et2O, THF_Step-45 4

[0249] Step 1: (E)-2-(l-(thiophen-2-yl)ethylidene)hydrazine-l-carboxamide: In a 3-neck 1 liter round-bottom flask under nitrogen atmosphere, l-(thiophen-2-yl)ethan-l-one (28.9 g, 0.229 mol) was dissolved in ethanol: H2O (1:1) (578 mL) at 25 °C. After 5 min stirring, semicarbazide hydrochloride (38.3 g, 0.343 mol) was added followed by sodium acetate (18.78 g, 0.229 mol) at 25 °C, and the reaction mixture stirred at 80 °C for 4 h.Completion of reaction was confirmed by TLC using 60% ethyl acetate in n-hexane as mobile phase. The reaction mixture was allowed to go to room temperature and then filtered. The collected precipitates were washed with water (100 mL), dried under reduced pressure toDocket No.: KMYXP001WOobtain the desired product as a white solid. (36.0 g, 86%). LCMS: (Method-C2): RT = 2.27 min, m / z 184 [M+l],

[0250] Step 2: 5-(thiophen-2-yl)-lH-pyrazole-4-carbaldehyde: In a 3-neck 500 mL round-bottom flask under nitrogen atmosphere, POCh (31.0 mL, 0.338 mol) was added dropwise to dry DMF (52.0 mL, 0.677 mol) at 0 °C. After stirring 1 h, (E)-2-(l-(thiophen-2-yl)ethylidene)hydrazine- 1 -carboxamide (31.0 g, 0.169 mol) was added portion wise at 25 °C and the reaction mixture stirred at 50 °C for 6 h. Completion of reaction was confirmed by TLC using 60% ethyl acetate in n-hexane as mobile phase. The reaction was quenched with ice water (300 mL) and, then basified with 3M aqueous NaOH to pH ~ 10. The product was extracted with ethyl acetate (200 mL x 3), and the combined organics were washed with water (300 mL), and brine (300 mL). After drying over Na2SC>4 the mixture was evaporated under reduced pressure and the crude product purified over silica gel (60-120) using 65% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an off-white solid (28.3 g, 94%). LCMS: (Method-C2): RT = 2.50 min, m / z 179.0 [M+l],

[0251] Step 3: l-(4-methoxyphenyl)-N-((3-(thiophen-2-yl)-lH-pyrazol-4-yl) methyl) cyclopropan-1 -amine: In a 10 mL round-bottom flask under nitrogen atmosphere, 3-(thiophen-2-yl)-l / / -pyrazole-4-carbaldehyde (0.200 g, 0.0011 mol) and l-(4-methoxyphenyl) cyclopropan-1 -amine (0.183 g, 0.0011 mol) were dissolved in methanol (2.00 mL) at 25 °C. After 5 min stirring, acetic acid (0.132 mL, 0.0022 mol) was added drop wise, and the reaction mixture was stirred for 2 h at 25 °C. The reaction was cooled to 0 °C, and sodium cyanoborohydride (0.204 g, 0.0033 mol) was added portion wise. The reaction mixture was stirred at 25 °C for 16 h at which point completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with water (10 mL), and the product was extracted with ethyl acetate (10 mL x 3). The combined organics were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4. After evaporation under reduced pressure, the crude product (0.960 g) was purified by reversed phase prep HPLC, purification method- 1, to afford the desired product as a white solid (0.280 g, 77%). LCMS: (Method-C2): RT = 1.04 min, m / z 326.29 [M+l],

[0252] Step 4: l-(4-methoxyphenyl) cyclopropan-l-amine: In a 250 mL 3-neck round-bottom flask under nitrogen atmosphere, titanium (IV) isopropoxide (11.7 mL, 0.040 mol) was added drop wise to a solution of 4-methoxybenzonitrile (5.00 g, 0.037 mol) in dry THF (50 mL) at -78 °C. After 10 min stirring, lAf ethyl magnesium bromide in THF (75.0 mL, 0.075 mol) was added drop wise at -78 °C. After 1 h stirring, BF3. OEt2 (9.300 mL, 0.075 mol) was added drop wise at -78 °C. The reaction mixture was then allowed to go to 25 °C andDocket No.: KMYXP001WOstirred for 4 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with 1N HCl (50.0 mL) at 0 °C and basified with ammonium hydroxide (40.0 mL) to pH ~ 10. The product was extracted with ethyl acetate (100 mL x 3), and the combined organic layers were washed with water (150 mL) and brine (150 mL) and dried over Na2SC>4. Following evaporation under reduced pressure, the crude product was purified over silica gel (60-120) using 3% methanol in dichloromethane as the mobile phase to afford the desired product as a brown liquid (1.80 g, 29%). LCMS: (Method-C2): RT= 0.95 min, m / z 164.01 [M+l],Example 2: Synthesis of l-(4-methoxyphenyl)-N-((l-methyl-3-(thiophen-2-yl)-lH- pyrazol-4-yl)methyl)cyclopropan-l-amine (Compound 2) & Example 3: Synthesis of 1- (4-methoxyphenyl)-N-((l-methyl-5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)cyclopropan- 1 -amine (Compound 3)

[0253] Step 1: l-methyl-3-(thiophen-2-yl)-lH-pyrazole-4-carbaldehyde: In a 25 mL one-neck round-bottom flask under nitrogen atmosphere, 3-(thiophen-2-yl)-lH- pyrazole-4-carbaldehyde (0.400 g, 0.002 mol) was dissolved in DMF (5.00 mL) followed by addition of potassium carbonate (0.390 g, 0.0028 mol) at 25 °C. After 5 min stirring, methyl iodide (0.72 mL, 0.011 mol) was added dropwise at 25 °C, and the reaction mixture was stirred at 60 °C for 6 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with water (10 mL) and the product extracted with ethyl acetate (20 mL x 3). The organic layer was washed with water (30 mL) and brine (30 mL), dried over Na2SC>4, and evaporated under reduced pressure. The crude product (0.400 g) was purified over silica gel (60-120) using 60% ethyl acetate in n-Docket No.: KMYXP001WOhexane as the mobile phase to afford the desired product as a white solid (Fraction- 1: 0.230 g, 53%) and (Fraction-2: 0.060 g, 14%). Fraction-1: LCMS: (Method-C2): RT= 1.08 min, m / z 193.24 [M+l], Fraction-2: LCMS: (Method-C2): RT= 1.13 min, m / z 193.26 [M+l], Note: Fraction- 1 and Fraction-2 were confirmed as 6 and 7, respectively, by NOE experiment.

[0254] Step 2: l-(4-methoxyphenyl)-N-((l-methyl-3-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)cyclopropan-l-amine: The title compound was prepared using the reaction conditions in example- 1 (Step 3), with l-methyl-3-(thiophen-2-yl)-l / / -pyrazole-4-carbaldehyde (0.100 g, 0.0005 mol) and l-(4-methoxyphenyl) cyclopropan-1 -amine (0.084 g, 0.0005 mol) as reagents. The crude product (0.210 g) was purified by reversed phase prep HPLC, purification method-4, to afford the desired product as a white solid (0.050 g, 28%). LCMS: (Method-C2): RT= 1.07 min, m / z 340.27 [M+l],

[0255] Step 2A:l-(4-methoxyphenyl)-N-((l-methyl-5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)cyclopropan-l-amine: The title compound was prepared using the reaction conditions in example- 1 (Step 3), with l-methyl-5-(thiophen-2-yl)-l / / -pyrazole-4-carbaldehyde (0.050 g, 0.0002 mol) and l-(4-methoxyphenyl) cyclopropan-1 -amine (0.050 g, 0.0003 mol) as reagents. The crude product (0.090 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.021 g, 24%). LCMS: (Method-C2): RT= 1.06 min, m / z 340.17 [M+l],Example 4: Synthesis of 2-(4-methoxyphenyl)-N-((3-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)propan-2-amine (Compound 4)3 Step-1 Compound 4

[0256] Step 1: 2-(4-methoxyphenyl)-N-((3-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)propan-2-amine: The title compound was prepared using the reaction conditions in example- 1 (Step 3), with 3-(thiophen-2-yl)-l / / -pyrazole-4-carbaldehyde (0.100 g, 0.0005 mol) and 2-(4-methoxyphenyl) propan-2-amine (0.082 g, 0.0005 mol) as reagents. The crude product (0.150 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.029 g, 16%). LCMS: (Method-C2): RT= 1.06 min, m / z 328.26 [M+l],Docket No.: KMYXP001WOExample 5: Synthesis of l-phenyl-N-((3-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)cyclopropan-l-amine (Compound 5)

[0257] Step 1: l-phenyl-N-((3-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)cyclopropan-l-amine: The title compound was prepared using the reaction conditions in example- 1 (Step 3), with 3-(thiophen-2-yl)-l / / -pyrazole-4-carbaldehyde (0.100 g, 0.0005 mol) and 1-phenylcyclopropan-1 -amine (0.074 g, 0.0005 mol) as reagents. The crude product (0.200 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.060 g, 36%). LCMS: (Method-C2): RT= 1.02 min, m / z 296.3 [M+l],Example 6: Synthesis of l-(4-chlorophenyl)-N-((3-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)cyclopropan-l-amine (Compound 6)Compound 6

[0258] Step 1: l-(4-chlorophenyl)-N-((3-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)cyclopropan-l-amine: The title compound was prepared using the reaction conditions in example- 1 (Step 3), with 3-(thiophen-2-yl)-l / / -pyrazole-4-carbaldehyde (0.100 g, 0.0005 mol) and l-(4-chlorophenyl)cyclopropan-l-amine (0.083 g, 0.0005 mol) as reagents. The crude product (0.235 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.066 g, 36%). LCMS: (Method-C2): RT = 1.07 min, m / z 328.28 [M-l],Example 7: Synthesis of l-(3-chlorophenyl)-N-((3-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)cyclopropan-l-amine (Compound 7)Docket No.: KMYXP001WO

[0259] Step 1: l-(3-chlorophenyl)-N-((3-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)cyclopropan-l-amine: The title compound was prepared using the reaction conditions in example- 1 (Step 3), with 3-(thiophen-2-yl)-l / / -pyrazole-4-carbaldehyde (0.100 g, 0.0005 mol) and l-(3-chlorophenyl)cyclopropan-l-amine (0.083 g, 0.0005 mol) as reagents. The crude product (0.150 g) was purified by reversed phase prep HPLC, purification method-3, to afford the desired product as a white solid (0.030 g, 16%). LCMS: (Method-C2): RT = 1.11 min, m / z 330.11 [M+l],Example 8: Synthesis of l-(2-chlorophenyl)-N-((3-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)cyclopropan-l-amine (Compound 8)

[0260] Step 1: l-(2-chlorophenyl)-N-((3-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)cyclopropan-l-amine: The title compound was prepared using the reaction conditions in example- 1 (Step 3), with 3-(thiophen-2-yl)-l / / -pyrazole-4-carbaldehyde (0.100 g, 0.0005 mol) and l-(2-chlorophenyl)cyclopropan-l-amine (0.083 g, 0.0005 mol) as reagents. The crude product (0.250 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.025 g, 14%). LCMS: (Method-H3): RT =1.08 min, m / z 330.17 [M+l],Example 9: Synthesis of l-(3-methoxyphenyl)-N-((3-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)cyclopropan-l-amine (Compound 9)Docket No.: KMYXP001WOCompound 9

[0261] Step 1: l-(3-methoxyphenyl)-N-((3-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)cyclopropan-l-amine: The title compound was prepared using the reaction conditions in example- 1 (Step 3), with 3-(thiophen-2-yl)-l / / -pyrazole-4-carbaldehyde (0.100 g, 0.0005 mol) and l-(3-methoxyphenyl)cyclopropan-l-amine (0.081 g, 0.0005 mol) as reagents. The crude product (0.240 g) was purified by reversed phase prep HPLC, purification method-1, to afford the desired product as a white solid (0.070 g, 38%). LCMS: (Method-C2): RT= 1.06 min, m / z 326.14 [M+l],Example 10: Synthesis of l-(4-methoxyphenyl)-N-((4-(thiophen-2-yl)thiazol-5- yl)methyl)cyclopropan-l -amine (Compound 10)Diethyl carbonate, SO2CI2, Thiourea, NaNO2, H2O, NaH (60%) CHCI3OEtEt0Hr50% H3PO2Step-1 Step-2 Step-3 Step-4 18 201M LAH in SOCI2;THF, THF DCM Step-5 Step-6 K2CO3, DMF Step-7

[0262] Step 1: ethyl 3-oxo-3-(thiophen-2-yl) propanoate: In a 250 mL 3-neck roundbottom flask under nitrogen atmosphere, NaH (60%) (3.23 g, 0.135 mol) was added portion wise to a solution of l-(thiophen-2-yl)ethan-l-one (10.0 g, 0.0792 mol) in diethyl carbonate (100 mL) at 0 °C. The reaction mixture was stirred at 85 °C for 16 h. Completion of reaction was confirmed by TLC using 10% ethyl acetate in n-hexane as the mobile phase. The reaction mixture was allowed to go to 25 °C and quenched with ice water (20 mL) at 0 °C. The product was extracted with ethyl acetate (100 mL x 2), and the combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SC>4, and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 5% ethyl acetate in n- hexane as the mobile phase to afford the desired product as an oil (5.80 g, 37%). LCMS:(Method-C2): RT= 1.19 min, m / z 198.98 [M+l],Docket No.: KMYXP001WO

[0263] Step 2: ethyl 2-chloro-3-oxo-3-(thiophen-2-yl)propanoate: In a 250 mL 3-neck round-bottom flask under nitrogen atmosphere, SO2CI2 (4.02 g, 0.0297 mol) was added drop wise to a solution of ethyl 3-oxo-3-(thiophen-2-yl)propanoate (5.90 g, 0.0297 mol) in dichloromethane (59.0 mL) at 0 °C. The reaction mixture was stirred at the same temperature for 2 h. Completion of reaction was confirmed by TLC using 30% ethyl acetate in n-hexane as the mobile phase. The reaction mixture was quenched with ice water (50 mL), and the product extracted with dichloromethane (100 mL x 2). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SC>4, and evaporated under reduced pressure to afford the crude product. (6.00 g crude, 88%). LCMS: (Method-C2): RT= 1.26 min, m / z 233.0 [M+l],

[0264] Step 3: ethyl 2-amino-4-(thiophen-2-yl)thiazole-5-carboxylate: In a 100 mL one-neck round-bottom flask under nitrogen atmosphere, thiourea (1.93 g, 0.0254 mol) was added portion wise to a solution of ethyl 2-chloro-3-oxo-3-(thiophen-2-yl)propanoate (5.90 g, 0.0254 mol) in ethanol (20.0 mL) at 25 °C and the reaction mixture stirred at 80 °C for 16 h. Completion of reaction was confirmed by TLC using 20% ethyl acetate in n-hexane as the mobile phase. The reaction was quenched with ice water (10 mL), and the product was extracted with dichloromethane (30 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SC>4, and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 5% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an oil (5.80 g, 91%). LCMS: (Method-C2): RT= 1.22 min, m / z 255 [M+l],

[0265] Step 4: ethyl 4-(thiophen-2-yl)thiazole-5-carboxylate: In a 25 mL 3-neck round-bottom flask under nitrogen atmosphere, NaNO2 (0.267 g 0.0039 mol) was added portion wise to a solution of ethyl 2-amino-4-(thiophen-2-yl)thiazole-5-carboxylate (0.500 g, 0.0019 mol) in 50% H3PO2 aqueous solution (10.0 mL) at 0 °C. The reaction mixture was stirred at the same temperature for 2 h. Completion of reaction was confirmed by TLC using 20% ethyl acetate in n-hexane as the mobile phase. The reaction was quenched with 10% NaOH aqueous solution (10 mL), and the product was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 15% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an oil (0.070 g, 14%). LCMS: (Method-C2): RT= 1.32 min, m / z 240[M+l],Docket No.: KMYXP001WO

[0266] Step 5: (4-(thiophen-2-yl)thiazol-5-yl)methanol: In a 10 mL one-neck roundbottom flask under nitrogen atmosphere, I A / lithium aluminum hydride in THF (0.167 mL, 0.000162 mol) was added drop wise to a solution of ethyl 4-(thiophen-2-yl)thiazole-5-carboxylate (0.040 g, 0.00016 mol) in dry THF (0.800 mL) at -78 °C. The reaction mixture was stirred for 2 h at the same temperature. Completion of reaction was confirmed by TLC using 30% ethyl acetate in n-hexane as the mobile phase. The reaction was quenched with water (5 mL) followed by 10% NaOH aqueous solution (5mL) and diluted with ethyl acetate (20 mL) and filtered. The organic layer was separated and washed with brine (10 mL), dried over Na2SO4 and evaporated under reduced pressure to afford the crude product. (0.030 g crude, 91%). LCMS: (Method-C2): RT= 1.06 min, m / z 198 [M+l],

[0267] Step 6: 5-(chloromethyl)-4-(thiophen-2-yl)thiazole: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, thionyl chloride (0.072 g, 0.00060 mol) was added drop wise to a solution of (4-(thiophen-2-yl)thiazol-5-yl)methanol (0.030 g, 0.00015 mol) in dry dichloromethane (0.600 mL) at 0 °C. The reaction mixture was stirred at 45 °C for 2 h. Completion of reaction was confirmed by TLC using 30% ethyl acetate in n-hexane as the mobile phase. The reaction solvent was evaporated under reduced pressure to afford the crude desired product as a solid. (0.030 g, 91%). LCMS: (Method-C2): RT= 1.28 min, m / z 215.8 [M+l],

[0268] Step 7: l-(4-methoxyphenyl)-N-((4-(thiophen-2-yl)thiazol-5-yl)methyl)cyclopropan-l-amine: In a 10 mL round-bottom flask under nitrogen atmosphere, potassium carbonate (0.077 g, 0.0055 mol) and DIPEA (0.048 mL, 0.00027 mol) were added simultaneously to a solution of l-(4-methoxyphenyl)cyclopropan-l -amine (0.025 g, 0.00015 mol) in dry DMF (1.100 mL) at 0 °C. After 20 min stirring, 5-(chloromethyl)-4-(thiophen-2-yl)thiazole (0.030 g, 0.00013 mol) in dry DMF (0.150 mL) was added drop wise at 0 °C and the reaction mixture stirred at 25 °C for 16 h. Completion of reaction was confirmed by TLC using 60% ethyl acetate in n-hexane as the mobile phase. The reaction was quenched with water (10 mL) and the product extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.045 g) was purified by reversed phase prep HPLC, purification method-1, to afford the desired product (0.012 g, 25%).LCMS: (Method-C2): RT= 1.14 min, m / z 343.02 [M+l],Example 11: Synthesis of l-(4-methoxyphenyl)-N-((4-(thiophen-2-yl)-lH-imidazol-5- yl)methyl)cyclopropan-l -amine (Compound 11)Docket No.: KMYXP001WOCompound 11

[0269] Step 1: ethyl 4-(thiophen-2-yl)-lH-imidazole-5-carboxylate: In a 30 mL sealed tube, ethyl 2-chloro-3-oxo-3-(thiophen-2-yl)propionate (1.30 g, 0.0055 mol) was added to formamide (3.00 mL) at 25 °C. After 5 min stirring, H2O (0.5 mL) was added and the reaction mixture stirred while sealed at 140 °C for 12 h. Completion of reaction was confirmed by TLC using 50% ethyl acetate in n-hexane as the mobile phase. The reaction mixture was allowed to go to 25 °C and quenched with ice water (20 mL). The product was extracted with ethyl acetate (40 mL x 2), and the combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 20% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an oil (0.250 g, 20%). LCMS: (Method- C2): RT = 1.09 min, m / z 223.12 [M+l],

[0270] Step 2: (4-(thiophen-2-yl)-lH-imidazol-5-yl)methanol: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, IM lithium aluminum hydride in THF (2.24 mL, 0.0022 mol) was added drop wise to a solution of ethyl 4-(thiophen-2-yl)-lH-imidazole- 5-carboxylate (0.250 g, 0.0011 mol) in dry THF (2.50 mL) at -78 °C. The reaction mixture was stirred for 2 h at the same temperature. Completion of reaction was confirmed by TLC using 50% ethyl acetate in n-hexane as the mobile phase. The reaction was quenched with IN HC1 solution (10 mL) followed by water (5 mL). The product was extracted with ethyl acetate (20 mL x 2), and the combined organic layers were washed brine (50 mL), dried over Na2SC>4 and evaporated under reduced pressure to afford the crude product (0.110 g, 54%). LCMS: (Method-C2): RT= 0.72 min, m / z 181.0 [M+l],

[0271] Step 3: 5-(chloromethyl)-4-(thiophen-2-yl)-lH-imidazole: In a 10 mL one- neck round-bottom flask under nitrogen atmosphere, thionyl chloride (0.290 g, 0.0024 mol) was added drop wise to a solution of (4-(thiophen-2-yl)-l / / -imidazol-5-yl) methanol (0.110 g, 0.00061 mol) in dry dichloromethane (1.10 mL) at 0 °C. The reaction mixture was stirred at 45 °C for 2 h. Completion of reaction was confirmed by TLC using 40% ethyl acetate in n-Docket No.: KMYXP001WOhexane as the mobile phase. The reaction solvent was evaporated under reduced pressure to afford the desired crude product as a solid (0.110 g crude, 90%). LCMS: (Method-C2): RT = 0.97 min, m / z 163.03 [M+- Cl],

[0272] Step 4: l-(4-methoxyphenyl)-N-((4-(thiophen-2-yl)-lH-imidazol-5-yl)methyl)cyclopropan-l-amine: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, potassium carbonate (0.306 g, 0.0022 mol) and DIPEA (0.190 mL, 0.0011 mol) were added simultaneously to a solution of l-(4-methoxyphenyl)cyclopropan-l -amine (0.099 g, 0.00060 mol) in dry DMF (1.10 mL) at 0 °C. After 20 min stirring, 5 -(chloromethyl) -4-(thiophen-2-yl)- 1 H-imidazole (0.110 g, 0.00055 mol) in dry DMF (0.550 mL) was added drop wise at 0 °C, and the reaction mixture was stirred at 25 °C for 16 h. Completion of reaction was confirmed by TLC using 70% ethyl acetate in n-hexane as the mobile phase. The reaction was quenched with water (10 mL) and the product extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4F and evaporated under reduced pressure. The crude product (0.200 g) was purified by reversed phase prep HPLC, purification method- 1, to afford the desired product as a paleyellow oil (0.025 g, 7.6%). LCMS: (Method-C2): RT= 1.05 min, m / z 326.06 [M+l],Example 12: Synthesis of N-((3-(5-chlorothiophen-2-yl)-lH-pyrazol-4-yl)methyl)-l-(4- methoxyphenyl)cyclopropan-l-amine (Compound 12)0 NH2CONHNH2HCI, AcONa, EtOH ci Step-1 NaBH3CN,32 AcOH, MeOH Step-3

[0273] Step 1: (E)-2-(l-(5-chlorothiophen-2-yl)ethylidene)hydrazine-l-carboxamide: In a 100 mL 3-neck round-bottom flask under nitrogen atmosphere, l-(5-chlorothiophen-2-yl)ethan-l-one (1.00 g, 0.006 mol) was dissolved in ethanol: H2O (1:1) (10 mL) at 25 °C. After 5 min stirring, semicarbazide hydrochloride (0.920 g, 0.008 mol) followed by sodium acetate (0.49 g, 0.006 mol) were added at 25 °C and the reaction mixture stirred at 80 °C for 4 h. Completion of reaction was confirmed by TLC using 60% ethyl acetate in n-Docket No.: KMYXP001WOhexane as the mobile phase. The reaction mixture was allowed to go to 25 °C and filtered. The precipitates were washed with water (100 mL) and dried under reduced pressure to obtain the desired product as a white solid. (1.2 g, 89%). LCMS: (Method-C2): RT= 1.09 min, m / z 217.67 [M+l],

[0274] Step 2: 3-(5-chlorothiophen-2-yl)-lH-pyrazole-4-carbaldehyde: In a 3-neck 100 mL round-bottom flask under nitrogen atmosphere, POCh (0.650 mL, 0.006 mol) was added dropwise to dry DMF (2.40 mL, 0.013 mol) at 0 °C. After 1 h stirring, (E)-2-(l-(5- chlorothiophen-2-yl)ethylidene)hydrazine-l -carboxamide (0.700 g, 0.003 mol) was added portion wise at 25 °C and the reaction mixture stirred at 50 °C for 6 h. Completion of reaction was confirmed by TLC using 60% ethyl acetate in n-hexane as the mobile phase. The reaction was quenched with ice water (50 mL), then basified with 3M aqueous NaOH to pH ~ 10. The product was extracted with ethyl acetate (100 mL x 3) and the combined organic layers washed with water (100 mL) and brine (100 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 65% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an off-white solid (0.250 g, 37%). LCMS: (Method-C2): RT=1.07 min, m / z 196.92 [M+l],

[0275] Step 3: N-((3-(5-chlorothiophen-2-yl)-lH-pyrazol-4-yl)methyl)-l-(4- methoxyphenyl)cyclopropan-l-amine: The title compound was prepared using the reaction conditions in example- 1 (Step 3), with 3-(5-chlorothiophen-2-yl)-l / / -pyrazole-4-carbaldehyde (0.100 g, 0.0005 mol) and l-(4-methoxyphenyl)cyclopropan-l-amine (0.081 g, 0.0005 mol) as reagents. The crude product (0.250 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.030 g, 18%). LCMS: (Method-C2): RT= 1.15 min, m / z 359.91 [M+],Example 13: Synthesis of N-((3-(5-chlorofuran-2-yl)-lH-pyrazol-4-yl)methyl)-l-(4- methoxyphenyl)cyclopropan-l -amine (Compound 13)Step-3Docket No.: KMYXP001WO

[0276] Step 1: (E)-2-(l-(5-chlorofuran-2-yl)ethylidene)hydrazine-l-carboxamide: In a 100 mL 3-neck round-bottom flask under nitrogen atmosphere, l-(5-chlorofuran-2-yl)ethan-l-one (1.00 g, 0.006 mol) was dissolved in ethanol:H2O (1:1) (10 mL) at 25 °C. After 5 min stirring, semicarbazide hydrochloride (0.920 g, 0.008 mol) followed by sodium acetate (0.49 g, 0.006mol) were added at 25 °C and the reaction mixture stirred at 80 °C for 4 h. Completion of reaction was confirmed by TLC using 60% ethyl acetate in n-hexane as the mobile phase. The reaction mixture was allowed to go to 25 °C and then filtered. The precipitates were washed with water (100 mL) and dried under reduced pressure to obtain the desired product as a white solid. (1.2 g, 89%). LCMS: (Method-C2): RT= 1.09 min, m / z 217.67 [M+l],

[0277] Step 2: 3-(5-chlorofuran-2-yl)-lH-pyrazole-4-carbaldehyde: In a 3-neck 100 mL round-bottom flask under nitrogen atmosphere, POCh (0.650 mL, 0.006 mol) was added dropwise to dry DMF (2.40 mL, 0.013 mol) at 0 °C. After 1 h stirring, (E)-2-(l-(5-chlorothiophen-2-yl)ethylidene)hydrazine-l -carboxamide (0.700 g, 0.003 mol) was added portion wise at 25 °C and the reaction mixture stirred at 50 °C for 6 h. Completion of reaction was confirmed by TLC using 60% ethyl acetate in n-hexane as the mobile phase. The reaction was quenched with ice water (50 mL), then basified with 3M aqueous NaOH to pH - 10. The product was extracted with ethyl acetate (100 mL x 3), and the combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 65% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an off-white solid (0.250 g, 37%). LCMS: (Method-C2): RT=1.07 min, m / z 196.92 [M+l],

[0278] Step 3: N-((3-(5-chlorofuran-2-yl)-lH-pyrazol-4-yl)methyl)-l-(4-methoxyphenyl)cyclopropan-l-amine: The title compound was prepared using the reaction conditions in example-1, with 3-(5-chlorofuran-2-yl)-l / / -pyrazole-4-carbaldehyde (0.100 g, 0.0005 mol) and l-(4-methoxyphenyl)cyclopropan-l-amine (0.081 g, 0.0005 mol) as reagents. The crude product (0.120 g) was purified by reversed phase prep HPLC, purification method-1, to afford the desired product as a white solid (0.009 g, 5%). LCMS: (Method-C2): RT= 1.09 min, m / z 344.16 [M+l],Example 14: Synthesis of l-(4-methoxyphenyl)-N-((5-methyl-3-(thiophen-2-yl)-lH- pyrazol-4-yl)methyl)cyclopropan-l -amine (Compound 14)Docket No.: KMYXP001WOStep-4

[0279] Step 1: 3-bromo-5-methyl-lH-pyrazole-4-carbaldehyde: In a 3-neck 100 mL round-bottom flask under nitrogen atmosphere, POBr? (3.400 mL, 0.033 mol) was added dropwise to dry DMF (10.2 mL, 0.132 mol) at 0 °C. After 1 h stirring, 5-methyl-2,4-dihydro- 3 / / -pyrazol-3-one (1.00 g, 0.010 mol) was added portion wise at 25 °C and the reaction mixture stirred at 50 °C for 6 h. Completion of reaction was confirmed by TLC using 60% ethyl acetate in n-hexane as the mobile phase. The reaction was quenched with ice water (50 mL), then basified with 3M aqueous NaOH to pH ~ 10. The product was extracted with ethyl acetate (90 mL x 3), and the combined organic layers were washed with water (90 mL) and brine (90 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 65% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an off-white solid (0.500 g, 26%). LCMS: (Method-C2): RT = 1.04 min, m / z 188.9 [M+l],

[0280] Step 2: 3-bromo-5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-4- carbaldehyde: In 30 mL sealed tube under nitrogen atmosphere, p-toluenesulfonic acid (0.015 g, 0.00007 mol) was added to solution of 3-bromo-5-methyl-l / / -pyrazole-4- carbaldehyde (0.150 g, 0.0007 mol) in THF at 0 °C. After 10 min stirring, 3,4-dihydro-2 / 7- pyran (0.200 g, 0.0023 mol) was added portion wise at 25 °C and the reaction mixture stirred at 60 °C for 2 h. Completion of reaction was confirmed by TLC using 60% ethyl acetate in n- hexane as the mobile phase. The reaction was quenched with water (20 mL). The product was then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 65% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an off-white solid (0.100 g, 46%).

[0281] LCMS: (Method-C2): RT= 1.21 min, m / z 273.13 [M+l],Docket No.: KMYXP001WO

[0282] Step 3: 5-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-(thiophen-2-yl)-lH-pyrazole-4-carbaldehyde: In a 30 mL sealed tube under argon atmosphere, 2M sodium carbonate (1.482 mL g, 0.0029 mol) was added to a solution of 3-bromo-5-methyl-l-(tetrahydro-2 / / -pyran-2-yl)-l / / -pyrazole-4-carbaldehyde (0.270 g, 0.00098 mol) and thiophen-2-ylboronic acid (0.379 g, 0.0029 mol) in 1,4-dioxane (2.70 mL) at 25 °C. The reaction mixture was degassed with argon for 10 min. Pd(dppf)C12, (0.072 g, 0.00009 mol) was added and the reaction mixture was stirred while sealed for 3 h at 70 °C. Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as mobile phase. The reaction mixture was allowed to go to 25 °C, then diluted with water (20 mL) and the product extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.350 g) was purified over silica gel (60-120) using 60% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.210 g, 77%). Note: Compound was confirmed by1H-NMR.

[0283] Step 4: l-(4-methoxyphenyl)-N-((5-methyl-l-(tetrahydro-2H-pyran-2-yl)-3- (thiophen-2-yl)-lH-pyrazol-4-yl)methyl)cyclopropan-l-amine: In a 10 mL one roundbottom flask under nitrogen atmosphere, 5-methyl-l-(tetrahydro-2 / / -pyran-2-yl)-3-(thiophen-2-yl)-l / / -pyrazole-4-carbaldehyde (0.140 g, 0.0005 mol) and l-(4-methoxyphenyl)cyclopropan- 1 -amine (0.081 g, 0.0005 mol) were dissolved in methanol (1.400 mL mL) at 25 °C. After 5 min stirring, acetic acid (0.057 mL, 0.0010 mol) was added drop wise and the reaction mixture stirred for 2 h at 25 °C. The reaction was cooled to 0 °C, sodium cyanoborohydride (0.204 g, 0.0033 mol) was added portion wise, and the reaction mixture stirred at 25 °C for 16 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.200 g) was purified over silica gel (60-120) using 70% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.100 g, 47%). LCMS: (Method-C2): RT = 1.19 min, m / z 424.19 [M+l],

[0284] Step 5: l-(4-methoxyphenyl)-N-((5-methyl-3-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)cyclopropan-l-amine: In a 25 mL one-neck round-bottom flask under nitrogen atmosphere, l-(4-methoxyphenyl)-N-((5-methyl-l-(tetrahydro-2 / / -pyran-2-yl)-3-(thiophen-2-yl)-l / / -pyrazol-4-yl)methyl)cyclopropan-l -amine (0.100 g, 0.008 mol) was dissolved in methanol (1.00 mL) and the mixture cooled to 0 °C. After 5 min stirring, 4M HCl in dioxaneDocket No.: KMYXP001WO(2.00 mL) was added dropwise at 0 °C and the reaction mixture stirred for 4 h at the same temperature. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with water (20 mL), and the product was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.180 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.026 g, 32%). LCMS: (Method-C2): RT = 1.02 min, m / z 340.4 [M+l],Example 15: Synthesis of l-(4-methoxyphenyl)-N-((3-(5-methylfuran-2-yl)-lH-pyrazol-4- yl)methyl)cyclopropan-l -amine (Compound 15)

[0285] Step 1: (E)-2-(l-(5-methylfuran-2-yl)ethylidene)hydrazine-l-carboxamide:In a 250 mL 3-neck round-bottom flask under nitrogen atmosphere, l-(5-methylfuran-2-yl)ethan-l-one (5.00 g, 0.040 mol) was dissolved in ethanol:H2O (1:1) (50 mL) at 25 °C. After 5 min stirring, semicarbazide hydrochloride (6.70 g, 0.060 mol) followed by sodium acetate (5.40 g, 0.040 mol) were added at 25 °C and the reaction mixture stirred at 80 °C for 4 h.Completion of reaction was confirmed by TLC using 60% ethyl acetate in n-hexane as the mobile phase. The reaction mixture was allowed to go to 25 °C and filtered. The collected precipitates were washed with water (300 mL) and dried under reduced pressure to obtain the desired product as a white solid. (6.00 g, 82%). LCMS: (Method-C2): RT= 1.03 min, m / z 182.25 [M+l],

[0286] Step 2: 3-(5-methylfuran-2-yl)-lH-pyrazole-4-carbaldehyde: In a 3-neck 100 mL round-bottom flask under nitrogen atmosphere, POCh (1.0 mL, 0.011 mol) was added dropwise to dry DMF (2.0 mL, 0.022 mol) at 0 °C. After 1 h stirring, (E)-2-(l-(5-methylfuran-2-yl)ethylidene)hydrazine-l -carboxamide (1.0 g, 0.005 mol) was added portion wise at 25 °C and the reaction mixture stirred at 50 °C for 6 h. Completion of reaction wasDocket No.: KMYXP001WOconfirmed by TLC using 40% ethyl acetate in n-hexane as the mobile phase. The reaction was quenched with ice water (90 mL), then basified with 3M aqueous NaOH to pH ~ 10. The product was then extracted with ethyl acetate (70 mL x 3). The combined organic layers were washed with water (80 mL) and brine (80 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 65% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an off-white solid (0.300 g, 31%). LCMS: (Method-C2): RT=1.08 min, m / z 177.23 [M+l],

[0287] Step 3: l-(4-methoxyphenyl)-N-((3-(5-methylfuran-2-yl)-lH-pyrazol-4- yl)methyl)cyclopropan-l-amine: The title compound was prepared using the reaction conditions in example- 1 (Step 3), with 3-(5-methylfuran-2-yl)-l / / -pyrazole-4-carbaldehyde (0.100 g, 0.0005 mol) and l-(4-methoxyphenyl)cyclopropan-l-amine (0.081 g, 0.0005 mol) as reagents. The crude product (0.174 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.040 g, 22%). LCMS: (Method-C2): RT= 1.08 min, m / z 324.17 [M+l],Example 16: Synthesis of 4-methoxy-N-(l-(5-(thiophen-2-yl)-lH-pyrazol-4- yl)ethyl)benzenesulfonamide (Compound 16)

[0288] Step 1: (E)-2-methyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methylene)propane- 2-sulfinamide: In a 50 mL one-neck round-bottom flask under nitrogen atmosphere, Ti(OEt)4 (2.81 g, 0.012 mol) was added drop wise to a solution of 5-(cyclopenta-2,4-dien-l-yl)-lH- pyrazole-4-carbaldehyde (1.00 g, 0.0056 mol) and 2-methylpropane-2-sulfinamide (0.834 g, 0.0061 mol) and in THF (10.0 mL) at 25 °C. The reaction mixture was stirred at 75 °C (external temperature) for 16 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction mixture was allowed to go to 25 °C and then quenched with water (120 mL) and diluted with ethyl acetate (30 mL). The slurry was filteredDocket No.: KMYXP001WOthrough Celite and washed with ethyl acetate (20 mL x 2). The organic layer was separated and washed with brine (50 mL), dried over Na2SC>4 and evaporated under reduced pressure. (1.25 g, 71%). LCMS: (Method-C2): RT= 1.17 min, 282.34 m / z [M+l],

[0289] Step 2: (Z)-2-methyl-N-((l-(phenylsulfonyl)-5-(thiophen-2-yl)-lH-pyrazol- 4-yl)methylene)propane-2-sulfinamide: In a 25 mL one-neck round-bottom flask under nitrogen atmosphere, benzenesulfonyl chloride (0.310 g, 0.0017 mol) was added portion wise to a solution of (£’)-2-methyl-N-((5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methylene)propane-2-sulfinamide (0.500 g, 0.0017 mol) and triethylamine (0.230 mL, 0.0017 mol) in acetonitrile (5.000 mL) at 0 °C. The reaction mixture was stirred for 16 h at 80 °C. Completion of reaction was confirmed by TLC using 30% ethyl acetate in n-hexane as mobile phase. The reaction mixture was diluted with water (10 mL) and ethyl acetate (30 mL). The organic layer was separated and washed with water (20 mL) and brine (30 mL), dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 15% ethyl acetate in n-hexane as the mobile phase to afford the desired product (0.330 g, 44%). LCMS: (Method-C2): RT= 1.32 min, 423.69 m / z [M+2],

[0290] Step 3: 2-methyl-N-(l-(l-(phenylsulfonyl)-5-(thiophen-2-yl)-lH-pyrazol-4-yl)ethyl)propane-2-sulfinamide: In a 25 mL one-neck round-bottom flask under nitrogen atmosphere, IM methyl magnesium bromide in THF (2.56 mL, 0.00064 mol) was added drop wise to a solution of (Z)-2-methyl-N-((l-(phenylsulfonyl)-5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methylene)propane-2-sulfinamide (0.270 g, 0.0025 mol) in dry THF (2.70 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. Completion of reaction was confirmed by TLC using 30% ethyl acetate in n-hexane as mobile phase. The reaction was quenched with IN HC1 (5.00 mL) and diluted with ethyl acetate (10.0 mL). The organic layer was separated and washed with water (10 mL) and brine (10 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 65% ethyl acetate in n-hexane as the mobile phase to afford the desired product (0.170 g, 93%). LCMS: (Method-C2): RT= 1.29 min, 438.15 m / z [M+l],

[0291] Step 4: 2-methyl-N-(l-(5-(thiophen-2-yl)-lH-pyrazol-4-yl)ethyl)propane-2-sulfinamide: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, activated magnesium powder (0.037 g, 0.0015 mol) was added portion wise to a solution of 2-methyl-N-(l-(l-(phenylsulfonyl)-5-(thiophen-2-yl)-l / / -pyrazol-4-yl)ethyl)propane-2-sulfinamide (0.170 g, 0.00038 mol) in methanol (1.70 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. Completion of reaction was confirmed by TLC using 30% ethyl acetate in n-hexane as mobile phase. The reaction was quenched with IN HC1 (10 mL) at 0 °C and dilutedDocket No.: KMYXP001WOwith ethyl acetate (20 mL). The organic layer was separated and washed with water (10 mL) and brine (10 mL), dried over Na2SC>4 and evaporated under reduced pressure to afford the crude product. (0.170 g, 100%). LCMS: (Method-H2): RT= 2.33 min, 298 m / z [M+l].

[0292] Step 5: l-(5-(thiophen-2-yl)-lH-pyrazol-4-yl)ethan-l-amine: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, 4M HCl in dioxane (0.850 mL, 5 volumes) was added drop wise to a solution of 2-methyl-N-(l-(l-(phenylsulfonyl)-5-(thiophen-2-yl)-l / / -pyrazol-4-yl)ethyl)propane-2-sulfinamide (0.170 g, 0.0057 mol) in methanol (1.70 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction mixture was evaporated, quenched with IN NaOH (2.00 mL) at 0 °C and the product extracted with ethyl acetate (10 mL x 2). The combined organic layers were separated and washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 5% methanol in dichloromethane as mobile phase to afford the desired product (0.102 g, 92%). LCMS: (Method-C2): RT= 2.33 min, 176.93 m / z [M-16].

[0293] Step 6: 4-methoxy-N-(l-(5-(thiophen-2-yl)-lH-pyrazol-4-yl)ethyl)benzenesulfonamide: In a 10 mL round-bottom flask under nitrogen atmosphere, triethylamine (0.159 mL, 0.0011 mol) was added drop wise to a solution of (l-(5-(thiophen-2-yl)-IT / -pyrazol-4-yl)ethan-l -amine (0.110 g, 0.000056 mol) in dichloromethane (1.10 mL) at 25 °C. 4-methoxybenzenesulfonyl chloride (0.129 g, 0.00062 mol) was added drop wise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.150 g) was purified by reversed phase prep HPLC, purification method-3, to afford the desired product as a white solid (0.020 g, 10%). LCMS: (Method-C2): RT= 1.155 min, m / z 364.08 [M+l],Example 17: Synthesis of l-(4-methoxyphenyl)-N-((3-(thiophen-2-yl)isothiazol-4- yl)methyl)cyclopropan-l -amine (Compound 17)Docket No.: KMYXP001WO

[0294] Step 1: 5-(thiophen-2-yl)-l,3,4-oxathiazol-2-one: In a 3-neck assembly under nitrogen atmosphere, chloro carbonylsulfenyl chloride (2.61 mL, 0.0314 mol) was added to a solution of thiophene-2-carboxamide (2.0 g, 0.0157 mol) in toluene (20.0 mL) at 0 °C. The reaction mixture was stirred at 100 °C for 16 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction solvent was evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 10% ethyl acetate in n-hexane as mobile phase to afford the desired product as an oil (1.10 g, 38%). This product was confirmed by NMR analysis.

[0295] Step 2: methyl 3-(thiophen-2-yl)isothiazole-4-carboxylate: In a 30 mL roundbottom flask under nitrogen atmosphere, 5-methyl propiolate (0.772 mL, 0.0086 mol) was added drop wise to a solution of (thiophen-2-yl)-l,3,4-oxathiazol-2-one (1.10 g, 0.0059 mol) in 1,3 -dichlorobenzene (11.0 mL) at 25 °C. The reaction mixture was stirred at 150 °C for 16 h. Completion of reaction was confirmed by TLC using 10% ethyl acetate in n-hexane as mobile phase. The reaction was quenched with water (10.0 mL) and the product extracted with dichloromethane (20 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 5% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an oil (0.500 g, 37%). LCMS: (Method-C2): RT= 1.318 min, m / z 226 [M+l],

[0296] Step 3: (3-(thiophen-2-yl) isothiazol-4-yl) methanol: In a 10 mL one-neck roundbottom flask under nitrogen atmosphere, IM lithium aluminum hydride in THF (1.95 mL, 0.0019 mol) was added drop wise to a solution of methyl 3-(thiophen-2-yl)isothiazole-4-carboxylate (0.220 g, 0.00097 mol) in dry THF (4.40 mL) at -78 °C and the reaction mixture stirred for 1 h at the same temperature. Completion of reaction was confirmed by TLC usingDocket No.: KMYXP001WO10% ethyl acetate in n-hexane as the mobile phase. The reaction was quenched with diluted IN HC1 solution (10.0 mL) followed by water (5.00 mL). The product was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 30% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an oil (0.190 g, 97%). LCMS: (Method-C2): RT= 1.122 min, 198 m / z [M+l],

[0297] Step 4: 3-(thiophen-2-yl) isothiazole-4-carbaldehyde: In a 10 mL round-bottom flask under nitrogen atmosphere, (3-(thiophen-2-yl)isothiazol-4-yl)methanol (0.150 g, 0.00076 mol) was dissolved in dry dichloromethane (3.00 mL) and the mixture cooled to 0 °C. After 5 min stirring, Dess-Martin periodinane (0.645 g, 0.0015 mol) was added portion wise at 0 °C and the reaction mixture stirred for 2 h at the same temperature. Completion of reaction was confirmed by TLC using 30% ethyl acetate in hexane as mobile phase. The reaction was quenched with water (5.00 mL) and the product extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 10% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an oil (0.115 g 77%). LCMS: (Method-C2): RT= 1.122 min, 196 m / z [M+l],

[0298] Step 5: l-(4-methoxyphenyl)-N-((3-(thiophen-2-yl)isothiazol-4-yl)methyl)cyclopropan-l-amine: In a 10 mL round-bottom flask under nitrogen atmosphere, a mixture of 3-(thiophen-2-yl) isothiazole-4-carbaldehyde (0.115 g 0.000587 mol) and l-(4-methoxyphenyl)cyclopropan- 1 -amine (0.106 g, 0.00064 mol) in dry methanol (0.805 mL) was treated with acetic acid (0.345 mL) and stirred at 25 °C for 5 h. The reaction mixture was cooled to 0 °C and sodium cyanoborohydride (0.074 g, 0.0011 mol) was added portion wise. The reaction mixture was stirred at 25 °C for 16 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with water (5.00 mL) and the product extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.150 g) was purified by reversed phase prep HPLC, purification method-3, to afford the desired product (0.055 g, 27%).LCMS: (Method-C2): RT= 1.143 min, 343 m / z [M+l],Example 18: Synthesis of l-(4-ethoxyphenyl)-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)cyclopropan-l -amine (Compound 18)Docket No.: KMYXP001WOTi(OiPr)4, EtMgBr, BF3Et2O, THF Step-166 Step-2 Compound 18

[0299] Step 4: l-(4-ethoxyphenyl) cyclopropan-1 -amine: In a 250 mL 3-neck roundbottom flask under nitrogen atmosphere, titanium (IV) isopropoxide (1.00 mL, 0.0037 mol) was added drop wise to a solution of 4-ethoxybenzonitrile (0.500 g, 0.0033 mol) in dry THF (15 mL) at -78 °C. After 10 min stirring, 3M ethyl magnesium bromide in THF (2.2 mL, 0.0067 mol) was added drop wise at -78 °C. After 1 h stirring, BFs. OEt2 (0.860 mL, 0.0067 mol) was added drop wise at -78 °C. The reaction mixture was stirred at 25 °C for 4 h.Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with IN HC1 (40.0 mL) at 0 °C and basified with ammonium hydroxide (20.0 mL) to pH 10. The product was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (150 mL) and brine (150 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 3% methanol in dichloromethane as the mobile phase to afford the desired product as a brown liquid (0.300 g, 29%). LCMS: (Method-H2): RT = 0.97 min, m / z 177.12 [M+l],

[0300] Step 3: l-(4-ethoxyphenyl)-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)cyclopropan-l-amine: The title compound was prepared using the reaction conditions in example-1 (Step 3), with 5-(thiophen-2-yl)-l / / -pyrazole-4-carbaldehyde (0.100 g, 0.0005 mol) and l-(4-ethoxyphenyl)cyclopropan-l -amine (0.088 g, 0.0005 mol) as reagents. The crude product (0.150 g) was purified by reversed phase prep HPLC, purification method-3, to afford the desired product as a white solid (0.065 g, 22%). LCMS: (Method-C2): RT= 1.10 min, m / z 340.16 [M+l],Example 19: Synthesis of 4-methoxy-N-((3-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 19)Docket No.: KMYXP001WO

[0301] Step 1: (E)-5-(thiophen-2-yl)-lH-pyrazole-4-carbaldehyde oxime: In a 3-neck one liter round-bottom flask under nitrogen atmosphere, 5-(thiophen-2-yl)- IH-pyrazole-4-carbaldehyde (21.1 g, 0.119 mol) was dissolved in ethanol (423 mL) at 25 °C. After 5 min stirring, sodium acetate (11.71 g, 0.142 mol) followed by hydroxylamine hydrochloride (9.92 g, 0.142 mol) were added at 25 °C and the reaction mixture stirred at 25 °C for 3 h.Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as mobile phase. The reaction was quenched with water (200 mL) and the product extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over Na2SO4 and evaporated under reduced pressure to obtain the desired product as a yellowish solid. (21.5 g, 94 %). LCMS: (Method-H2): RT= 2.607 min, m / z 194.0 [M+l],

[0302] Step 2: (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine: In a 3-neck 250 mL round-bottom flask under nitrogen atmosphere, (£’)-5-(thiophen-2-yl)-l / / -pyrazole-4-carbaldehyde oxime (15 g, 0.070 mol) was added in 35% HC1 solution (75 mL) and the reaction mixture cooled to 0 °C. After 10 min, activated zinc dust (24.4 g, 0.372 mol) was added portion wise at 0 °C. The reaction mixture was stirred 0 °C for 2 h. Completion of reaction was confirmed by TLC. The reaction mixture was diluted with milli-Q water (100 mL) and basified with ammonium hydroxide to pH 10 at 0 °C. The product was extracted with 30% IPA / CHCh (150 mL x 3) and the solvents evaporated under reduced pressure to obtain the desired product as a yellowish semi solid (13.8 g, 99%). LCMS: (Method-H2): RT = 2.085 min, m / z 180 [M+l],

[0303] Step 3: 4-methoxy-N-((3-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: In a 10 mL round-bottom flask under nitrogen atmosphere, triethylamine (0.156 mL, 0.0011 mol) was added drop wise to a solution of (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine (0.100 g, 0.00055 mol) in dichloromethane (1.0 mL) at 25 °C. The reaction mixture was cooled to 0 °C, and 4-methoxybenzenesulfonyl chloride (0.126 g, 0.00061 mol) was added portion wise. The reaction mixture was stirred at 25 °C for 1 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over Na2SO4L and evaporated under reduced pressure. The crude product (0.110 g) was purified by reversed phase prep HPLC, purification method-3, to afford the desired product as a white solid (0.025 g, 22%). LCMS: (Method-C2): RT= 1.168 min, m / z 350.2 [M+l],Docket No.: KMYXP001WOExample 20: Synthesis of 4-ethoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 20)69 Compound 20

[0304] Step 1: 4-ethoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.200 g, 0.0011 mol) and 4-ethoxybenzenesulfonyl chloride (0.270 g, 0.0012 mol) as reagents. The crude product (0.220 g) was purified over silica gel (60-120) using 80% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.080 g, 20%). LCMS: (Method-H3): RT= 2.873 min, m / z 364.0 [M+],Example 21: Synthesis of 4-isopropoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl) methyl) benzenesulfonamide (Compound 21)

[0305] Step 1: 4-isopropoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl) methyl) benzenesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and 4-isopropoxybenzenesulfonyl chloride (0.164 g, 0.00092 mol) as reagents. The crude product (0.220 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.050 g, 16%). LCMS: (Method-C3): RT= 1.256 min, m / z 378.18 [M+l],Example 22: Synthesis of 4-phenoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 22)Docket No.: KMYXP001WOTEA, DCMStep-169

[0306] Step 1: 4-phenoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.050 g, 0.00027 mol) and 4-phenoxybenzenesulfonyl chloride (0.074 g, 0.00027 mol) as reagents. The crude product (0.140 g) was purified over silica gel (60-120) using 70% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.030 g, 26%). LCMS: (Method-C2): RT= 1.284 min, m / z 412.2 [M+],Example 23: Synthesis of 4-methoxy-3,5-dimethyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 23)TEA, DCMStep-169

[0307] Step 1: 4-methoxy-3,5-dimethyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and 4-methoxy-3,5-dimethylbenzenesulfonyl chloride (0.216 g, 0.00092 mol) as reagents. The crude product (0.220 g) was purified over silica gel (60-120) using 70% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.050 g, 16%). LCMS: (Method-H3): RT= 2.288 min, m / z 378.0 [M+],Example 24: Synthesis of N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 24)Docket No.: KMYXP001WOTEA, DCMStep-1

[0308] Step 1: N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and benzenesulfonyl chloride (0.162 g, 0.00092 mol) as reagents. The crude product (0.113 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.042 g, 16%). LCMS: (Method-C2): RT= 1.12 min, m / z 320.63 [M+l],Example 25: Synthesis of N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)chromane-6- sulfonamide (Compound 25)TEA, DCMStep-1

[0309] Step 1: N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)chromane-6-sulfonamide:The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and chromane-6-sulfonyl chloride (0.212 g, 0.00091 mol) as reagents. The crude product (0.140 g) was purified over silica gel using 70% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.021 g, 6.7%). LCMS: (Method-C2): RT= 1.182 min, m / z 376.12 [M+],Example 26: Synthesis of N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-2,3- dihydrobenzo[b][l,4]dioxine-6-sulfonamide (Compound 26)Docket No.: KMYXP001WO

[0310] Step 1: N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-2,3-dihydrobenzo[b][l,4]dioxine-6-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and 2,3-dihydrobenzo[b][l,4]dioxine-6-sulfonyl chloride (0.214 g, 0.00091 mol) as reagents. The crude product (0.146 g) was purified by reversed phase prep HPLC, purification method- 1, to afford the desired product as a white solid (0.022 g, 6.9%). LCMS: (Method-C2): RT= 1.179 min, m / z 378.14 [M+l],Example 27: Synthesis of N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)quinoline-6- sulfonamide (Compound 27)

[0311] Step 1: N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and quinoline-6- sulfonyl chloride (0.209 g, 0.00092 mol) as reagents. The crude product (0.146 g) was purified by reversed phase prep HPLC, purification method- 1, to afford the desired product as a white solid (0.068 g, 27%). LCMS: (Method-C2): RT= 1.100 min, m / z 371.15 [M+l],Example 28: Synthesis of 3-methoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 28)

[0312] Step 1: 3-methoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.100 g, 0.00055 mol) and 3-methoxybenzenesulfonyl chloride (0.126 g, 0.000612 mol) asDocket No.: KMYXP001WOreagents. The crude product (0.056 g) was purified by reversed phase prep HPLC, purification method-3, to afford the desired product as a white solid (0.023 g, 12%). LCMS: (Method-C2): RT= 1.172 min, m / z 350.25 [M+l],Example 29: Synthesis of 6-methoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)pyridine-3-sulfonamide (Compound 29)TEA, DCMStep-1

[0313] Step 1: 6-methoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)pyridine-3-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine (0.080 g, 0.00044 mol) and 6-methoxypyridine-3-sulfonyl chloride (0.101 g, 0.00049 mol) as reagents. The crude product (0.057 g) was purified by reversed phase prep HPLC, purification method- 1, to afford the desired product as a white solid (0.025 g, 16%). LCMS: (Method-C2): RT= 1.105 min, m / z 351.01 [M+l],Example 30: Synthesis of N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)cyclohexanesulfonamide (Compound 30)o 'o 80TEA, DCMCompound 30Step-169

[0314] Step 1: N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)cyclohexanesulfonamide:The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and cyclohexane sulfonyl chloride (0.167 g, 0.00092 mol) as reagents. The crude product (0.200 g) was purified by reversed phase prep HPLC, purification method- 1, to afford the desired product as a white solid (0.018 g, 6.7%). LCMS: (Method-C2): RT=1.160 min, m / z 325.77 [M+],Docket No.: KMYXP001WOExample 31: Synthesis of N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)methane sulfonamide (Compound 31)

[0315] Step 1: N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)methane sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine (0.100 g, 0.00055 mol) and methane sulfonyl chloride (0.070 g, 0.00061 mol) as reagents. The crude product (0.060 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.029 g, 20%). LCMS: (Method-C2): RT= 1.01 min, m / z 258.13 [M+l],Example 32: Synthesis of N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)propane-l- sulfonamide (Compound 32)69

[0316] Step 1: N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)propane-l-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine (0.10 g, 0.00055 mol) and propane- 1- sulfonyl chloride (0.0872 g, 0.00061 mol) as reagents. The crude product was purified over silica gel using 50% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.020 g, 13%). LCMS: (Method-C2): RT= 1.101 min, m / z 286.15 [M+l],Example 33: Synthesis of l-phenyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)methanesulfonamide (Compound 33)Docket No.: KMYXP001WO69

[0317] Step 1: l-phenyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)methanesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.100 g, 0.00055 mol) and phenylmethanesulfonyl chloride (0.116 g, 0.00061 mol) as reagents. The crude product (0.0 g) was purified over silica gel using 50% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.050 g, 27%). LCMS: (Method-C2): RT= 1.159 min, m / z 334.19 [M+l],Example 34: Synthesis of N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)pyridine-2- sulfonamide (Compound 34)

[0318] Step 1: N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)pyridine-2-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine (0.10 g, 0.00055 mol) and pyridine-2-sulfonyl chloride (0.109 g, 0.00061 mol) as reagents. The crude product (0.295 g) was purified over silica gel using 50% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.024 g, 13%). LCMS: (Method-C2): RT= 1.066 min, m / z 321.10 [M+l],Example 35: Synthesis of N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)pyridine-3- sulfonamide (Compound 35)Docket No.: KMYXP001WO

[0319] Step 1: N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)pyridine-3-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine (0.100 g, 0.00055 mol) and pyridine-3-sulfonyl chloride (0.108 g, 0.00061 mol) as reagents. The crude product (0.150 g) was purified over silica gel using 50% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.038 g, 21%). LCMS: (Method-C2): RT= 1.049 min, m / z 321.15 [M+l],Example 36: Synthesis of 3-phenoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 36)

[0320] Step 1: 3-phenoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.070 g, 0.00039 mol) and 3-phenoxybenzenesulfonyl chloride (0.115 g, 0.00042 mol) as reagents. The crude product (0.90 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.021 g, 13%). LCMS: (Method-C2): RT= 1.292 min, m / z 412.32 [M+l],Example 37: Synthesis of 4-propoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 37)

[0321] Step 1: 4-propoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and 4-propoxybenzenesulfonyl chloride (0.215 g, 0.00092 mol) asDocket No.: KMYXP001WOreagents. The crude product (0.220 g) was purified over silica gel (60-120) using 80% ethyl acetate in n-hexane as the mobile phase afford the desired product as a white solid (0.070 g, 22%). LCMS: (Method-H3): RT= 3.046 min, m / z 378.0 [M+l],Example 38: Synthesis of 4-isobutoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 38)

[0322] Step 1: 4-isobutoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.10 g, 0.00055 mol) and 4-isobutoxybenzenesulfonyl chloride (0.150 g, 0.00061 mol) as reagents. The crude product (0.180 g) was purified over silica gel using 50% ethyl acetate in hexane as the mobile phase to afford the desired product as a white solid (0.115 g, 53%). LCMS: (Method-C2): RT= 1.316 min, m / z 392.20 [M+l],Example 39: Synthesis of 4-(benzyloxy)-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 39)69

[0323] Step 1: 4-(benzyloxy)-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.1 g, 0.00055 mol) and 4-(benzyloxy)benzenesulfonyl chloride (0.173 g, 0.00061 mol) as reagents. The crude product (0.90 g) was purified by reversed phase prep HPLC, purificationDocket No.: KMYXP001WOmethod-1, to afford the desired product as a white solid (0.027 g, 11%). LCMS: (Method-C2): RT= 1.312 min, m / z 426.10 [M+l],Example 40: Synthesis of 4-(2-(dimethylamino)ethoxy)-N-((5-(thiophen-2-yl)-lH- pyrazol-4-yl)methyl)benzenesulfonamide (Compound 40)90

[0324] Step 1: 4-(2-(dimethylamino)ethoxy)benzenesulfonyl chloride: In a 30 mL sealed tube under nitrogen atmosphere, chlorosulfonic acid (0.641 mL, 0.0096 mol) was added drop wise to a solution of N, N-dimethyl-2-phenoxyethan-l-amine (0.400 g, 0.0024 mol) in dichloromethane (5.00 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 3 h. Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as mobile phase. The reaction was quenched with ice water (10 mL) and aqueous sodium carbonate solution (0.5 g in water 5 mL). The product was extracted with dichloromethane (10 mL x 3). The organic layer was separated and dried over Na2SO4 and evaporated under reduced pressure to afford the crude product. (0.370 g, 58%). LCMS: (Method-H2): RT = 1.096 min, m / z 264 [M+l],

[0325] Step 2: 4-(2-(dimethylamino)ethoxy)-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.251 g, 0.0014 mol) and 4-(2-(dimethyl amino)ethoxy)benzenesulfonyl chloride (0.367 g, 0.0014 mol) as reagents. The crude product (0.330 g) was purified by reversed phase prep HPLC, purification method- 1, to afford the desired product as a white solid (0.023 g, 6.0%). LCMS: (Method-C2): RT= 0.966 min, m / z 407.14 [M+l],Example 41: Synthesis of 4-(2-methoxyethoxy)-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 41)Docket No.: KMYXP001WOCompound 41

[0326] Step 1: 4-(2-methoxyethoxy)-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.10 g, 0.00055 mol) and 4-(2-methoxyethoxy)benzenesulfonyl chloride (0.153 g, 0.00061 mol) as reagents. The crude product (0.323 g) was purified over silica gel using 50% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.050 g, 23%). LCMS: (Method-H3): RT= 2.620 min, m / z 394 [M+l],Example 42: Synthesis of N, N-dimethyl-2-(4-(N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)sulfamoyl)phenoxy)acetamide (Compound 42)

[0327] Step 1: N, N-dimethyl-2-(4-(N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)sulfamoyl)phenoxy)acetamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.100 g, 0.00055 mol) and 4-(2-(dimethylamino)-2-oxoethoxy)benzenesulfonyl chloride (0.170 g, 0.00061 mol) as reagents. The crude product (0.189 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.080 g, 34%). LCMS: (Method-C2): RT= 1.05 min, m / z 421.21 [M+l],Example 43: Synthesis of 3-fluoro-4-methoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 43)Docket No.: KMYXP001WOCompound 43

[0328] Step 1: 3-fluoro-4-methoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.200 g, 0.0011 mol) and 3-fluoro-4-methoxybenzenesulfonyl chloride (0.275 g, 0.0012 mol) as reagents. The crude product (0.400 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.200 g, 49%). LCMS: (Method-H3): RT= 2.71 min, m / z 368.00 [M+l],Example 44: Synthesis of 3-chloro-4-methoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 44)

[0329] Step 1: 3-chloro-4-methoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.200 g, 0.0011 mol) and 3-chloro-4-methoxybenzenesulfonyl chloride (0.289 g, 0.0012 mol) as reagents. The crude product (0.500 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.210 g, 49%). LCMS: (Method-C2): RT= 1.18 min, m / z 383.4 [M+],Example 45: Synthesis of l-methyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-lH- imidazole-4-sulfonamide (Compound 45)Docket No.: KMYXP001WOTEA, DCMStep-169

[0330] Step 1: l-methyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-lH-imidazole-4-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and 1 -methyl- IH-imidazole-4-siilfonyl chloride (0.181 g, 0.010 mol) as reagents. The crude product (0.095 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.026 g, 9.7%). LCMS: (Method-C2): RT= 0.97 min, m / z 323.62 [M+l],Example 46: Synthesis of l,2-dimethyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)- lH-imidazole-4-sulfonamide (Compound 46)TEA, DCMStep-1

[0331] Step 1: l,2-dimethyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-lH-imidazole-4-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and 1,2-dimethyl- IH-imidazole-4-siilfonyl chloride (0.155g, 0.00080 mol) as reagents. The crude product (0.160 g) was purified over silica gel (60-120) using 2% methanol in dichloromethane as the mobile phase to afford the desired product as a white solid (0.111 g, 39%). LCMS: (Method-H3): RT= 2.04 min, m / z 338.0 [M+l],Example 47: Synthesis of l-methyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-lH- pyrazole-4-sulfonamide (Compound 47)Docket No.: KMYXP001WOTEA, DCMStep-169 Compound 47

[0332] Step 1: l-methyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-lH-pyrazole-4-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and 1 -methyl- IH-pyrazole-4-siilfonyl chloride (0.144g, 0.00080 mol) as reagents. The crude product (0.323 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.025 g, 9.6%). LCMS: (Method-H3): RT= 2.15 min, m / z 324.0 [M+l],Example 48: Synthesis of 4-methyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-3,4- dihydro-2H-benzo[b][l,4]oxazine-6-sulfonamide (Compound 48)Compound 48

[0333] Step 1: 4-methyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine-6-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)- IH-pyrazol-4-yl)methanamine (0.100 g, 0.00055 mol) and 4-methyl-3,4-dihydro-2 / / -benzo[b][l,4]oxazine-6-sulfonyl chloride (0.142 g, 0.00061 mol) as reagents. The crude product (0.140 g) was purified by reversed phase prep HPLC, purification method- 1, using to afford the desired product as a white solid (0.090 g, 43%). LCMS: (Method-C2): RT= 1.15 min, m / z 390.67 [M+],Example 49: Synthesis of 2,2-dimethyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)- 2,3-dihydrobenzofuran-5-sulfonamide (Compound 49)Docket No.: KMYXP001WO69

[0334] Step 1: 2,2-dimethyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-2,3-dihydrobenzofuran-5-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and 2,2-dimethyl-2,3-dihydrobenzofuran-5-sulfonyl chloride (0.196 g, 0.00080 mol) as reagents. The crude product (0.267 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.080 g, 26%). LCMS: (Method-H3): RT= 2.94 min, m / z 390.0 [M+l],Example 50: Synthesis of 2-oxo-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-2,3- dihydrobenzo[d]oxazole-5-sulfonamide (Compound 50)

[0335] Step 1: 2-oxo-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-2,3-dihydrobenzo[d]oxazole-5-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)- IH-pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and 2-oxo-2,3-dihydrobenzo[d]oxazole-5-sulfonyl chloride (0.186 g, 0.00080 mol) as reagents. The crude product (0.280 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.027 g, 9.0%). LCMS: (Method-H3): RT= 2.15 min, m / z 377.0 [M+l],Example 51: Synthesis of 3-methyl-2-oxo-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)- 2,3-dihydrobenzo[d]oxazole-5-sulfonamide (Compound 51)Docket No.: KMYXP001WOTEA, DCM Step-169

[0336] Step 1: 3-methyl-2-oxo-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-2,3-dihydrobenzo[d]oxazole-5-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)- IH-pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and 3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-sulfonyl chloride (0.197 g, 0.00080 mol) as reagents. The crude product (0.092 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.020 g, 6.4%). LCMS: (Method-C2): RT= 1.10 min, m / z 391.07 [M+l],Example 52: Synthesis of N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzo[d]isoxazole-5-sulfonamide (Compound 52)69 Compound 52

[0337] Step 1: N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzo[d]isoxazole-5-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and benzo[d]isoxazole-5-sulfonyl chloride (0.173 g, 0.00083 mol) as reagents. The crude product (0.293 g) was purified by reversed phase prep HPLC, purification method-4, to afford the desired product as a white solid (0.020 g, 6.7%). LCMS: (Method-C2): RT= 1.15 min, m / z 361.07 [M+l],Example 53: Synthesis of 4-propyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 53)Docket No.: KMYXP001WO

[0338] Step 1: 4-propyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and 4-propylbenzenesulfonyl chloride (0.174 g, 0.00083 mol) as reagents. The crude product (0.235 g) was purified by reversed phase prep HPLC, purification method-3, to afford the desired product as a white solid (0.057 g, 19%). LCMS: (Method-H2): RT= 1.26 min, m / z 361.84 [M+l],Example 54: Synthesis of 4-cyano-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 54)69 Step-1

[0339] Step 1: 4-cyano-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and 4-cyanobenzenesulfonyl chloride (0.168 g, 0.00080 mol) as reagents. The crude product (0.130 g) was purified over silica gel (60-120) using 2% MeOH in dichloromethane as the mobile phase to afford the desired product as an off-white solid (0.067 g, 23%). LCMS: (Method-H3): RT= 2.66 min, m / z 345.0 [M+l],Example 55: Synthesis of ethyl 4-(N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)sulfamoyl)benzoate (Compound 55)Docket No.: KMYXP001WOO

[0340] Step 1: ethyl 4-(N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)sulfamoyl)benzoate: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and ethyl 4-(chlorosulfonyl)benzoate (0.198 g, 0.00083 mol) as reagents. The crude product (0.090 g) was purified by reversed phase prep HPLC, purification method-1, to afford the desired product as a white solid (0.036 g, 11%). LCMS: (Method-C2): RT= 1.21 min, m / z 392.0 [M+l],Example 56: Synthesis of l-ethyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-lH- pyrazole-4-sulfonamide (Compound 56)TEA, DCM69 Step-1

[0341] Step 1: l-ethyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-lH-pyrazole- 4-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and l-ethyl-l / / -pyrazole-4-sulfonyl chloride (0.155 g, 0.00083 mol) as reagents. The crude product (0.250 g) was purified by reversed phase prep HPLC, purification method-3, to afford the desired product as a white solid (0.090 g, 32%). LCMS: (Method-C2): RT= 1.03 min, m / z 337.86 [M+l],Example 57: Synthesis of l-benzyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-lH- pyrazole-4-sulfonamide (Compound 57)Docket No.: KMYXP001WOTEA, DCM69 Step 1: l-benzyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-lH-pyrazole-4-sulfonamide:

[0342] The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine (0.150 g, 0.00083 mol) and 1-benzyl-l / / -pyrazole-4-sulfonyl chloride (0.204 g, 0.00083 mol) as reagents. The crude product (0.300 g) was purified by reversed phase prep HPLC, purification method- 1, to afford the desired product as a white solid (0.116 g, 35%). LCMS: (Method-H3): RT= 2.75 min, m / z 400.00 [M+l],Example 58: Synthesis of N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzo[d][l,3]dioxole-5-sulfonamide (Compound 58)

[0343] Step 1: N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzo[d][l,3]dioxole- 5-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine (0.100 g, 0.00055 mol) and benzo[d][l,3]dioxole-5-sulfonyl chloride (0.135 g, 0.00061 mol) as reagents. The crude product (0.150 g) was purified by reversed phase prep HPLC, purification method-3, to afford the desired product as a white solid (0.056 g, 28%). LCMS: (Method-C2): RT= 1.14 min, m / z 396.02 [M+l],Example 59: Synthesis of N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzo[d]thiazole-6-sulfonamide (Compound 59)Docket No.: KMYXP001WO

[0344] Step 1: N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzo[d]thiazole-6-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-lH-pyrazol-4-yl)methanamine (0.100 g, 0.00055 mol) and benzo[d]thiazole-6-sulfonyl chloride (0.142 g, 0.00061 mol) as reagents. The crude product (0.140 g) was purified by reversed phase prep HPLC, purification method- 1, to afford the desired product as a white solid (0.090 g, 43%). LCMS: (Method-C2): RT= 1.076 min, m / z 376.93 [M+l],Example 60: Synthesis of 2-oxo-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-2,3- dihydrobenzo[d]oxazole-6-sulfonamide (Compound 60)

[0345] Step 1: 2-oxo-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.100 g, 0.00055 mol) and 2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonyl chloride (0.142 g, 0.00061 mol) as reagents. The crude product (0.150 g) was purified by reversed phase prep HPLC, purification method-3, to afford the desired product as a white solid (0.018 g, 8.6%). LCMS: (Method-C2): RT= 1.075 min, m / z 376.72 [M+l],Example 61: Synthesis of 3-methyl-2-oxo-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)- 2,3-dihydrobenzo[d]oxazole-6-sulfonamide (Compound 61)Docket No.: KMYXP001WO

[0346] Step 1: 3-methyl-2-oxo-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)- IH-pyrazol-4-yl)methanamine (0.100 g, 0.00055 mol) and 3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonyl chloride (0.151 g, 0.00061 mol) as reagents. The crude product (0.180 g) was purified by reversed phase prep HPLC, purification method-4, to afford the desired product as a white solid (0.014 g, 6.4%). LCMS: (Method-C2): RT= 1.13 min, m / z 390.99 [M+l],Example 62: Synthesis of 3-oxo-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-3,4- dihydro-2H-benzo[b][l,4]oxazine-6-sulfonamide (Compound 62)

[0347] Step 1: 3-oxo-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-3,4-dihydro- 2H-benzo[b][l,4]oxazine-6-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.100 g, 0.00055 mol) and 3-oxo-3,4-dihydro-2 / / -benzo[b][l,4]oxazine-6-sulfonyl chloride (0.151 g, 0.00061 mol) as reagents. The crude product (0.300 g) was purified by reversed phase prep HPLC, purification method- 1, to afford the desired product as a white solid (0.084 g, 39%). LCMS: (Method-C2): RT=1.10 min, m / z 391.03 [M+l],Example 63: Synthesis of 2,3-dioxo-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)- 1.2.3.4- let rahydroquinoxali ne-6-sul fonamide (Compound 63)Docket No.: KMYXP001WO

[0348] Step 1: 2,3-dioxo-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-l,2,3,4- tetrahydroquinoxaline-6-sulfonamide: The title compound was prepared using the reaction conditions in example-25 (Step 3), with (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.100 g, 0.00055 mol) and 2,3-dioxo-l,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride (0.158 g, 0.00061 mol) as reagents. The crude product (0.280 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.025 g, 11%). LCMS: (Method-C2): RT= 0.94 min, m / z 403.81 [M+l],Example 64: Synthesis of 4-ethynyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 64)K2CO3, HN^ / 0MeOH AStep-3 s J Compound 64

[0349] Step 1: 4-bromo-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide: In a 30 mL vial under nitrogen atmosphere, triethylamine (0.69 mL, 0.00501 mol) was added drop wise to a solution of (5-(thiophen-2-yl)-l / / -pyrazol- 4-yl)methanamine (0.300 g, 0.00167 mol) in dichloromethane (3.00 mL) at 25 °C. The reaction mixture was cooled to 0 °C and 4-bromobenzenesulfonyl chloride (0.427 g, 0.00167 mol) added portion wise. The reaction mixture was stirred at 25 °C for 1 h. Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as mobile phase. The reaction was quenched with water (10 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 3% methanol in dichloromethane as the mobile phase to afford the desiredDocket No.: KMYXP001WOproduct as a white solid (0.450 g, 67%). LCMS: (Method-C2): RT= 1.226 min, m / z 400 [M+2],

[0350] Step 2: N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-4- ((trimethylsilyl)ethynyl)benzenesulfonamide: In a 30 sealed tube, 4-bromo-N-((5-(thiophen-2-yl)-l / / -pyrazol-4yl)methyl)benzenesulfonamide (0.400 g, 0.0010) and ethynyltrimethylsilane (0.147 g, 0.0015 mol) were added in THF (4.00 mL) and degassed with argon for 10 min. DIPEA (0.380 mL, 0.0022 mol), Pd(PPhs)2C12 (0.0439 g 0.00006 mol) and Cui (0.01142 g, 0.00006 mol) were added, and the reaction vessel was sealed and the mixture stirred for 12 h at 80 °C. Completion of reaction was confirmed by TLC using 50% ethyl acetate in n-hexane as mobile phase. The reaction mixture was allowed to go to 25 °C and diluted with water (40 mL). The product was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and evaporated under reduced pressure to afford the solid product. The crude product (0.270 g) was purified over silica gel (60-120) using 35% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a brownish solid (0.125 g, 30 %). LCMS:(Method-H2): RT= 3.581 min, m / z 416.0 [M+l],

[0351] Step 3: 4-ethynyl-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: In a 10 mL vial under nitrogen atmosphere, potassium carbonate (0.062 g, 0.00045 mol) was added portion wise to a solution of N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)-4-((trimethylsilyl)ethynyl)benzenesulfonamide (0.125 g, 0.00030 mol) in dry methanol (1.25 mL) at 0 °C and the reaction mixture stirred at 25 °C for 2 h. Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as mobile phase. The reaction was quenched with water (10 mL) and the product extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with water (15 mL) and brine (15 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.090 g) was purified on silica gel (60-120) using 25% ethyl acetate in n-hexane as a mobile to afford desired product as a white solid (0.020 g, 58%). LCMS: (Method-C2): RT= 1.161 min, m / z 344.29 [M+l],Example 65: Synthesis of 4-(N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)sulfamoyl)benzoic acid (Compound 65)Docket No.: KMYXP001WOLiOH. H2O, THF, H2O Step-1

[0352] Step 1: 4-(N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)sulfamoyl)benzoic acid:In a 10 mL round-bottom flask, lithium hydroxide monohydrate (0.032 g, 0.00076 mol) in water (0.300 mL) was added dropwise to solution of ethyl 4-(N-((5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methyl)sulfamoyl)benzoate (0.100 g, 0.00025 mol) in dry THF (1.00 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 4 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction solvent was evaporated and the residue dissolved in water (5. 00 mL). The aqueous layer was washed with diethyl ether (10.0 mL) and acidified using 35% hydrochloric acid to pH 2-3 at 0 °C. The product was extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.120 g) was purified over silica gel (60-120) using 3% methanol in dichloromethane as the mobile phase to afford the desired product as an off-white solid (0.038 g, 41%). LCMS: (Method-C2): RT = 1.11 min, m / z 363.96.Example 66: Synthesis of 4-(N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)sulfamoyl)benzamide (Compound 66)NH4OH Step-1

[0353] Step 1: 4-(N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)sulfamoyl)benzamide:In a 10 mL round-bottom flask, ammonium hydroxide (3.00 mL) was added drop wise to ethyl 4-(N-((5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methyl)sulfamoyl)benzoate (0.150 g, 0.00038 mol) at 25 °C. The reaction mixture was stirred at 100 °C for 3 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction was quenched with water (10 mL) and the product extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and evaporated under reduced pressure. The crude product (0.300 g) was purified byDocket No.: KMYXP001WOreversed phase prep HPLC, purification method- 1, to afford the desired product as a white solid (0.116 g, 35%). LCMS: (Method-C2): RT= 1.03 min, m / z 362.99 [M+l],Example 67: Synthesis of N-methyl-4-(N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)sulfamoyl)benzamide (Compound 67)2 / WTMA in Toluene, 2M CH3NH2in THF, Toluene Step-1

[0354] Step 1: N-methyl-4-(N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)sulfamoyl)benzamide: In a 10 mL round-bottom flask under nitrogen atmosphere, 2M trimethyl aluminum in toluene (0.255 mL, 0.00051 mol) was added dropwise to solution of ethyl 4-(N-((5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methyl)sulfamoyl)benzoate (0.100 g, 0.00025 mol) and 2M CH3NH2 in THF (0.255 mL, 0.00051 mol) in dry toluene (1.00 mL) at 0 °C. The reaction mixture was stirred at 100 °C for 6 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction mixture was warmed to 25 °C, quenched with ice water (10 mL) and the product extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.150 g) was purified by reversed phase prep HPLC, purification method- 1, to afford the desired product as a white solid (0.022 g, 23%). LCMS: (Method-C2): RT= 1.03 min, m / z 377.06 [M+l],Example 68: Synthesis of N, N-dimethyl-4-(N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)sulfamoyl)benzamide (Compound 68)2M TMA in Toluene, 2M CH3NHCH3 in THF, Toluene Step-1

[0355] Step 1: N, N-dimethyl-4-(N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)sulfamoyl)benzamide: The title compound was prepared using the reaction conditions in example-74, with ethyl 4-(N-((5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methyl)sulfamoyl)benzoate (0.100 g, 0.00025 mol) and 2M CH3NHCH3 in THF (0.255 mL,Docket No.: KMYXP001WO0.00051 mol) as reagents. The crude product (0.160 g) was purified by reversed phase prep HPLC, purification method-1, to afford the desired product as a white solid (0.078 g, 78%). LCMS: (Method-C2): RT= 1.00 min, m / z 391.01 [M+l],Example 69: Synthesis of 4-(2-hydroxypropan-2-yl)-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide (Compound 69)

[0356] Step 1: 4-(2-hydroxypropan-2-yl)-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)benzenesulfonamide: In a 10 mL round-bottom flask under nitrogen atmosphere, lAf CHsMgBr in THF (1.021 mL, 0.0010 mol) was added dropwise to a solution of ethyl 4- (N-((5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methyl)sulfamoyl)benzoate (0.100 g, 0.00025 mol) in dry THF (1.00 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 3 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction was quenched with IN HC1 solution (10 mL) and the product extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure to obtain the desired product as a solid. The crude product (0.130 g) was purified over silica gel (60-120) using 60% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an off- white solid (0.035 g, 36%). LCMS: (Method-H3): RT= 2.44 min, m / z 376.0 [M-l],Example 70: Synthesis of 2-methoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)pyrimidine-5-sulfonamide (Compound 70)

[0357] Step 1: 2-chloro-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)pyrimidine-5- sulfonamide: In a 30 mL sealed tube under nitrogen atmosphere, 2-chloropyrimidine-5- sulfonyl chloride (0.522 g, 0.0024 mol) was dissolved in THF (8.0 mL) and cooled to -78 °C.After 5 min stirring, (5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methanamine (0.400 g, 0.0022 mol)Docket No.: KMYXP001WOfollowed by N, N-diisopropylethylamine (0.768 mL, 0.044 mol) were added at -78 °C. The reaction mixture was slowly allowed to go to 25 °C and stirred for 1 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction was quenched with water (20 mL) and the product extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with water (60 mL) and brine (60 mL), dried over Na2SC>4 and evaporated under reduced pressure to obtain the desired product as a solid. (0.420 g, 53%). LCMS: (Method-C2): RT= 1.124 min, m / z 356.03 [M+],

[0358] Step 2: 2-methoxy-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)pyrimidine-5-sulfonamide: In a 10 mL sealed tube under nitrogen atmosphere, 2-chloro-N-((5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methyl) pyrimidine-5- sulfonamide (0.100 g, 0.00028 mol) was dissolved in methanol (1.00 mL) and cooled to 0 °C. After 5 min stirring, 25% sodium methoxide in methanol (0.060 mL, 0.00056 mol) was added drop wise at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction was quenched with water (10 mL) and the product extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.048 g) was purified by reversed phase prep HPLC, purification method-3, to afford the desired product as a white solid (0.025 g, 25%). LCMS: (Method-C3): RT= 1.088 min, m / z 352.20 [M+l],Example 71: Synthesis of 2-(methylamino)-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)pyrimidine-5-sulfonamide (Compound 71)

[0359] Step 1: 2-(methylamino)-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)pyrimidine-5-sulfonamide: In a 10 mL sealed tube under nitrogen atmosphere, triethylamine (0.094 mL, 0.00056 mol) was added drop wise to a solution of methylamine hydrochloride (0.038 g, 0.00056) in methanol (1.200 mL) at 0 °C. After 5 min stirring, 2-chloro-N- ((5- (thiophen- 2-yl)- 1 H-py razo I -4-y I )met hy I )py i m id i ne-5- sulfonamide (0.120 g, 0.00028 mol) in methanol (0.600 mL) was added drop wise at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. Completion of reaction was confirmed by TLC using 10% methanolDocket No.: KMYXP001WOin dichloromethane as the mobile phase. The reaction was quenched with water (10 mL) and the product extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.250 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.022 g, 22%). LCMS: (Method-C2): RT= 1.019 min, m / z 351.03 [M+l],Example 72: Synthesis of 2-(dimethylamino)-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)pyrimidine-5-sulfonamide (Compound 72)

[0360] Step 1: 2-(dimethylamino)-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)pyrimidine-5-sulfonamide: The title compound was prepared using the reaction conditions in example-78, with 2-chloro-N-((5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methyl)pyrimidine-5-sulfonamide (0.050 g, 0.00014 mol) and 2M Dimethylamine in THF (0.140 mL, 0.00028 mol) as reagents. The crude product (0.130 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.005 g, 3.8%). LCMS: (Method-C2): RT= 1.152 min, m / z 365.03 [M+l],Example 73: Synthesis of 2-(ethyl(methyl)amino)-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)pyrimidine-5-sulfonamide (Compound 73)

[0361] Step 1: 2-(ethyl(methyl)amino)-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)pyrimidine-5-sulfonamide: The title compound was prepared using the reaction conditions in example-78, with 2-chloro-N-((5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methyl)pyrimidine-5-sulfonamide (0.100 g, 0.00028 mol) and N-methylethanamine (0.033 g, 0.00056 mol) as reagents. The crude product (0.143 g) was purified by reversed phase prepDocket No.: KMYXP001WOHPLC, purification method-3, to afford the desired product as a white solid (0.007 g, 6.6%). LCMS: (Method-C2): RT= 1.153 min, m / z 379.04 [M+],Example 74: Synthesis of 2-(pyrrolidin-l-yl)-N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)pyrimidine-5-sulfonamide (Compound 74)

[0362] Step 1: 2-(pyrrolidin-l-yl)-N-((5-(thiophen-2-yl)-lH-pyrazol-4-yl)methyl)pyrimidine-5-sulfonamide: The title compound was prepared using the reaction conditions in example-78, with 2-chloro-N-((5-(thiophen-2-yl)-l / / -pyrazol-4-yl)methyl)pyrimidine-5-sulfonamide (0.200 g, 0.00056 mol) and Pyrrolidine (0.043 g, 0.00061 mol) as reagents. The crude product (0.185 g) was purified by reversed phase prep HPLC, purification method-1, to afford the desired product as a white solid (0.010 g, 4.6%). LCMS: (Method-C2): RT= 1.130 min, m / z 391.05 [M+l],Example 75: Synthesis of ethyl 2-(4-(N-((5-(thiophen-2-yl)-lH-pyrazol-4- yl)methyl)sulfamoyl)-lH-pyrazol-l-yl)acetate (Compound 75)BnSH, Xantphos,BrCH2COOEt, Pd2(dba)3, DIPEA, CS2CO3, DMF Dioxane Step-1 Step-2124

[0363] Step 1: ethyl 2-(4-iodo-lH-pyrazol-l-yl)acetate: In a 3-neck 250 mL round-bottom flask under nitrogen atmosphere, 4-iodo- 1 H-pyrazole (5.0 g, 0.0259 mol) was dissolved in DMF (50 mL) at 25 °C. After 5 min stirring, ethyl 2-bromoacetate (6.18 mL, 8.6 g, 0.0518 mol) followed by cesium carbonate (12.2 g, 0.037 mol) were added at 25 °C and the reaction mixture stirred at 25 °C for 3 h. Completion of reaction was confirmed by TLC using 5% methanol in dichloro methane as the mobile phase. The reaction was quenched with iceDocket No.: KMYXP001WOcold water (150 mL) and the product extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (150 mL) and brine (200 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 40% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (4.5 g, 62%). LCMS: (Method-C2): RT= 1.225 min, m / z 280.89 [M+l],

[0364] Step 2: ethyl 2-(4-(benzylthio)-17 / -pyrazol-l-yl)acetate: In a 30 mL sealed tube under nitrogen atmosphere, DIPEA (1.23 mL, 0.0071 mol) was added drop wise to a solution of ethyl 2-(4-iodo-177-pyrazol-l-yl)acetate (1.00 g, 0.0035 mol) and phenylmethanethiol (0.442 g, 0.0035 mol) in dioxane (10.0 mL) at 25 °C. The reaction mixture was degassed with argon for 15 min. Xantphos (0.113 g, 0.000196 mol) followed by Pd2(dba)3 (0.081 g, 0.000089 mol) were added at 25 °C and the reaction mixture stirred at 90 °C for 2 h. Completion of reaction was confirmed by TLC using 30% ethyl acetate in n-hexane as the mobile phase. The reaction was quenched with ice cold water (15.0 mL) and the product extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with water (20.0 mL) and brine (20.0 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 15% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.550 g, 56%). LCMS: (Method-C2): RT= 1.365 min, m / z 277.00 [M+l],

[0365] Step 3: ethyl 2-(4-(chlorosulfonyl)-17 / -pyrazol-l-yl)acetate: In a 30 mL sealed tube under nitrogen atmosphere, ethyl 2-(4-(benzylthio)- 177-pyrazol- l-yl)acetate (0.550 g, 0.0019 mol) was dissolved in chloroform (5.50 mL) and water (5.50 mL) at 25 °C. After 5 min stirring, Ch gas was purged until saturation for 10 min, and the reaction mixture was stirred while sealed at 25 °C for 15 min. Completion of reaction was confirmed by TLC using 30% ethyl acetate in n-hexane as the mobile phase. The reaction was quenched with water (10 mL) and the product extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4 and evaporated under reduced pressure to afford the crude desired product (0.500 g, 99%).

[0366] Step 4: ethyl 2-(4-(N-((5-(thiophen-2-yl)-17 / -pyrazol-4-yl)methyl)sulfamoyl)-177-pyrazol-l-yl)acetate: In a 10 mL round-bottom flask under nitrogen atmosphere, triethylamine (0.463 mL, 0.0033 mol) was added drop wise to a solution of (5-(thiophen-2-yl)-177-pyrazol-4-yl)methanamine (0.300 g, 0.0016 mol) in dichloromethane (5 mL) at 0 °C. After 5 min stirring, ethyl 2-(4-(chlorosulfonyl)-177-pyrazol-l-yl)acetate (0.500 g, 0.0020 mol) added portion wise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobileDocket No.: KMYXP001WOphase. The reaction was quenched with water (10 mL) and the product extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 3% methanol in dichloromethane as the mobile phase to afford the desired product as a white solid (0.300 g, 42%). LCMS: (Method-C2): RT= 1.149 min, m / z 396.02 [M+l],Example 76O,=A^-((3-(l,3,4-Thiadiazol-2-yl)-lH-pyrazol-4-yl)methyl)-4-methoxybenzenesulfonamide

[0367] Step 1: 2-Bromo-l,3,4-thiadiazole: In a 100 mL one neck round-bottom flask under nitrogen atmosphere, l,3,4-thiadiazol-2-amine (3.00 g, 0.0296 mol) dissolved in 48% aqueous in HBr (30.0 mL): water (30.0 mL) and the reaction mixture was cooled to 0°C. Copper(I) bromide (0.425 g, 0.0029 mol) followed by sodium nitrite (1.360 g, 0.0296 mol) in water (48.0 mL) was added dropwise over 45 minutes at 0°C and the reaction mixture was stirred for Ih at the same temperature. Completion of reaction was confirmed by TLC using 30% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with saturated sodium bicarbonate (150 mL) and the product was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (3.50 g) was purified over silica gel (60-120) using 30% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as a solid (2.00 g, 40.86%).

[0368] Step 2: l-(l,3,4-Thiadiazol-2-yl)ethan-l-one: In a 100 mL sealed tube under argon atmosphere, 2-bromo-l,3,4-thiadiazole (2.0 g, 0.0121 mol) and tributyl(l -ethoxy vinyl) stannane (5.25 g, 0.0145 mol) were added in toluene (60.0 mL) at 25°C and the reactionDocket No.: KMYXP001WOmixture was degassed for 15 minutes with argon. Tetrakis (1.39 g, 0.0012 mol) was added and the reaction mixture was stirred for Ih at 110°C. Completion of reaction was confirmed by TLC using 30% ethyl acetate in zi-hexane as mobile phase. The reaction mixture was diluted with water (200 mL). The product was extracted with ethyl acetate (200 mL x 2). The combined organics were washed with brine (200 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (2.00 g) was dissolved in tetrahydrofuran (20.0 mL) and cooled to 0°C then 4Af HC1 in dioxane (10.0 mL) was added dropwise. The reaction mixture was stirred for Ih at the same temperature. Completion of reaction was confirmed by TLC using 30% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with saturated sodium bicarbonate (200 mL) and the product was extracted with ethyl acetate (200 mL x 3). The combined organic layer washed with brine (200 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (2.00 g) was purified over silica gel (60-120) using 30% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an oil (0.650 g, 41.85%). LCMS: (Method-H3): RT= 1.53 min, m / z 129 [M+l], 92.59%.

[0369] Step 3: (E)-3-(Dimethylamino)-l-(l,3,4-thiadiazol-2-yl)prop-2-en-l-one: In a 10 mL one neck round-bottom flask under nitrogen atmosphere, N,N-dimethylformamide dimethyl acetal (6.50 mL) was added dropwise to l-(l,3,4-thiadiazol-2-yl)ethan-l-one (0.650 g, 0.0050 mol) at 25°C. The reaction mixture was stirred at 70°C for Ih. Completion of reaction was confirmed by TLC using 30% ethyl acetate in zi-hexane as mobile phase. The reaction solvent was evaporated under reduced pressure to afford the desired product as a solid which was used in the next step without further purification (0.750 g, 80.7%). Mass: m / z 184 [M+l],

[0370] Step 4: 2-(lH-Pyrazol-3-yl)-l,3,4-thiadiazole: In a 25 mL one-neck roundbottom flask under nitrogen atmosphere, hydrazine hydrochloride (0.870 g, 0.0127 mol) was added portionwise to a solution of (E)-3-(dimethylamino)-1-(1,3,4-thiadiazol-2-yl)prop-2-en-1-one (0.750 g, 0.0040 mol) in ethanol (7.50 mL) at 25°C. The reaction mixture was stirred atDocket No.: KMYXP001WO50°C for 2h. Completion of reaction was confirmed by TLC using 30% ethyl acetate in n-hexane as mobile phase. The reaction was quenched with water (70 mL) and saturated sodium bicarbonate solution (70 mL) then extracted with ethyl acetate (70 mL x 3). Combined organics were washed with brine (70 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.750 g) was purified over silica gel (60-120) using 30% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an oil (0.220 g, 35.3%). LCMS: (Method-C3): RT= 1.181 min, m / z 153.01 [M+l], 99.1%.

[0371] Step 5: 2-(4-Iodo-lH-pyrazol-3-yl)-l,3,4-thiadiazole: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, N-iodosuccinimide (0.480 g, 0.002170 mol) was added portionwise to a solution of 2-(l / / -pyrazol-3-yl)-l,3,4-thiadiazole (0.220 g, 0.0014 mol) in DMF (2.20 mL) at 25°C. The reaction mixture was stirred at 25°C for 16h.Completion of reaction was confirmed by TLC using 50% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). Combined organics were washed with saturated sodium thiosulfate (30 mL), water (30 mL), brine (30 mL) and dried over sodium sulfate and evaporated under reduced pressure. The crude product (0.300 g) was purified over silica gel (60-120) using 30% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a solid (0.280 g, 69.65%). LCMS: (Method-C3): RT= 1.333 min, m / z 279 [M+l], 91.4%.

[0372] Step 6: 2-(4-Iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)-l,3,4-thiadiazole: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, / ^-toluene sulfonic acid (0.022 g, 0.0001 mol) was added to solution of 2-(4-iodo-l / / -pyrazol-3-yl)-1,3,4-thiadiazole (0.280 g, 0.0010 mol) in tetrahydrofuran (2.80 mL) at 0°C. After 10 min stirring, 3,4-dihydro-2 / / -pyran (0.254 g, 0.0030 mol) was added portionwise at 0°C and the reaction mixture stirred at 70°C for 2h. Completion of reaction was confirmed by TLC using 50% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with water (30Docket No.: KMYXP001WOmL) and extracted with ethyl acetate (30 mL x 3). Combined organics were washed with brine (30 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.450 g) was purified over silica gel (60-120) using 30% ethyl acetate in zi-hexane as a mobile phase to afford the desired product as a solid (0.350 g, 100%). LCMS: (Method-C3): RT= 1.568 min, m / z 362.79 [M+l], 91.7%.Q

[0373] Step 7: / er / -Butvl((l-(tetrahvcho-2 / / -pyran-2-yl)-3-(1.3.4-thiadiazol-2-yl)-lH-pyrazol-4-yl)methyl)carbamate: In a 30 mL sealed tube under argon atmosphere, potassium phosphate (0.451 g, 0.0020 mol) was added to a solution of 2-(4-iodo-l-(tetrahydro-2 / / -pyran-2-yl)-l / / -pyrazol-3-yl)-l,3,4-thiadiazole (0.250 g, 0.0006 mol) and added tert-butyl ((4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methyl) carbamate (0.213 g, 0.0008 mol) in dioxane (2.00 mL), acetonitrile (2.00 mL) and water (1.00 mL) at 25°C. The reaction mixture was degassed with argon for 15 minutes followed by addition of bis(di-tert-butyl(4-dimethylaminophenyl) phosphine) dichloride palladium(II) (0.048 g, 0.00006 mol). The reaction mixture was stirred at 80°C for 16h. Completion of reaction was confirmed by TLC using 50% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). Combined organics were washed with brine (30 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.500 g) was purified over silica gel (60-120) using 30% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an oil (0.250 g, 99.1%). LCMS: (Method-C3): RT= 1.537 min, m / z 366 [M+l], 31.2%.

[0374] Step 8: (3-(l,3,4-Thiadiazol-2-yl)-lH-pyrazol-4-yl)methanamine: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, 4 / V HC1 in dioxane (0.125 mL) was added dropwise to a solution of terLbutyl((l-(tetrahydro-2 / / -pyran-2-yl)-3-(l,3,4-thiadiazol-2-yl)-l / / -pyrazol-4-yl) methyl) carbamate (0.250 g, 0.00068 mol) in methanol (0.250 mL) at 0°C. The reaction mixture was stirred at 25°C for 16h. Completion of reaction was confirmed byDocket No.: KMYXP001WOTLC using 50% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with saturated sodium bicarbonate (20 mL) and the product was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.250 g) was purified over silica gel (60-120) using 50% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an oil (0.070 g, 47.0%). LCMS: (Method-H3): RT= 0.931 min, m / z 182 [M+l], 24.4%.

[0375] Step 9: A-((3-(l,3,4-Thiadiazol-2-yl)-lH-pyrazol-4-yl)methyl)-4-methoxybenzenesulfonamide: In a 10 mL round-bottom flask under nitrogen atmosphere, 4-methoxybenzenesulfonyl chloride (0.079 g, 0.0003 mol) was added portionwise to a solution of (3-(l,3,4-thiadiazol-2-yl)-l / / -pyrazol-4-yl)methanamine (0.070 g, 0.0003 mol) and triethylamine (0.161 mL, 0.0011 mol) in dichloromethane (0.700 mL) at 0°C. The reaction mixture was stirred at 25°C for Ih. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.110 g) was purified by reversed phase purification, using 0.1% ammonia in o water and 100% acetonitrile as a mobile phase and column (C18 spherical, 40-60 pm, 100A, 12g) on a CombiFlash®, to afford the desired product as a white solid (0.009 g, 7.96%).LCMS: (Method-C2): RT= 1.336 min, m / z 352.16 [M+l], 98.4%.Example 77O 7=II / A-((3-(l,2,4-Thiadiazol-5-yl)-lH-pyrazol-4-yl)methyl)-4-methoxybenzenesulfonamideDocket No.: KMYXP001WO

[0376] Step 1: 5-Bromo-l,2,4-thiadiazole: In a 250 mL one-neck round-bottom flask under nitrogen atmosphere, l,2,4-thiadiazol-5-amine (2.00 g, 0.0197 mol) dissolved in 48% aqueous in HBr (20.0 mL): water (20.0 mL), and the reaction mixture was cooled to 0°C. Copper(I) bromide (0.283 g, 0.00197 mol) was added followed by sodium nitrite (1.360 g, 0.0197 mol) in water (48.0 mL) dropwise over 45 minutes at 0°C. The reaction mixture was stirred for Ih at the same temperature. Completion of reaction was confirmed by TLC using 30% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with saturated sodium bicarbonate (150 mL) and the product extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (3.50 g) was purified over silica gel (60-120) using 30% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as a solid (0.800 g, 24.5%).

[0377] Step 2: l-(l,2,4-Thiadiazol-5-yl)ethan-l-one: In a 100 mL sealed tube under argon atmosphere, 5-bromo-l,2,4-thiadiazole (0.800 g, 0.00484 mol) and tributyl(l-ethoxyvinyl)stannane (2.10 g, 0.0058 mol) were added in toluene (24.0 mL) at 25°C and the reaction mixture was degassed for 15 minutes with argon. Pd(Phs)4 (0.560 g, 0.00048 mol) was added, and the reaction mixture was stirred for Ih at 110°C. Completion of reaction was confirmed by TLC using 30% ethyl acetate in zi-hexane as mobile phase. The reaction mixture was diluted with water (200 mL). The product was extracted with ethyl acetate (200 mL x 2). The combined organics were washed with brine (200 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (2.00 g) dissolved in tetrahydrofuran (12.0 mL) and cooled to 0°C then 4M HC1 in dioxane (6.00 mL) was added dropwise. The reaction mixture was stirred for Ih at the same temperature. Completion of reaction was confirmed by TLC using 30% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with saturated sodium bicarbonate (120 mL) and the product was extracted with ethyl acetate (120 mL x 3). The combined organic layers were washed with brine (120 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (1.20 g) was purified over silica gel (60-120) using 30% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an oil (0.800 g, 128.8%).ODocket No.: KMYXP001WO

[0378] Step 3: (E)-3-(Dimethylamino)-l-(l,2,4-thiadiazol-5-yl)prop-2-en-l-one: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, N,N-dimethylformamide dimethyl acetal (8.00 mL) was added dropwise on l-(l,2,4-thiadiazol-5-yl)ethan-l-one (0.800 g, 0.0062 mol) at 25°C. The reaction mixture was stirred at 70°C for Ih. Completion of reaction was confirmed by TLC using 30% ethyl acetate in zi-hexane as mobile phase. The reaction mixture was evaporated under reduced pressure to afford the desired product as a solid which was used in the next step without further purification (0.800 g, 69.9%). LCMS: (Method-C): RT= 1.292 min, m / z 184 [M+l], 96.9%.

[0379] Step 4: 5-(lH-Pyrazol-3-yl)-l,2,4-thiadiazole: In a 25 mL one-neck roundbottom flask under nitrogen atmosphere, hydrazine hydrochloride (0.890 g, 0.0131 mol) was added portionwise to a solution of (£)-3-(dimethylamine)-l-(l,2,4-thiadiazol-5-yl)prop-2-en-1-one (0.800 g, 0.0043 mol) in ethanol (8.00 mL) at 25°C. The reaction mixture was stirred at 50°C for 2h. Completion of reaction was confirmed by TLC using 30% ethyl acetate in n-hexane as mobile phase. The reaction was quenched with water (70 mL) and extracted with ethyl acetate (70 mL x 3). Combined organics were washed with brine (70 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.750 g) was purified over silica gel (60-120) using 30% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an oil (0.220 g, 35.3%). LCMS: (Method-C3): RT= 1.181 min, m / z 153.01 [M+l], 99.1%.

[0380] Step 5: 5-(4-Iodo-lH-pyrazol-3-yl)-l,2,4-thiadiazole: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, N-iodosuccinimide (0.310 g, 0.0014 mol) was added portionwise to a solution of 5-(l / / -pyrazol-3-yl)-l,2,4-thiadiazole (0.180 g, 0.0011 mol) in MN-dimethylformamide (1.80 mL) at 25°C. The reaction mixture was stirred at 25°C for 16h. Completion of reaction was confirmed by TLC using 50% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with water (30 mL) and extracted with ethyl acetateDocket No.: KMYXP001WO(30 mL x 3). Combined organics were washed with saturated sodium thiosulfate (30 mL), water (30 mL), brine (30 mL) and dried over sodium sulfate and evaporated under reduced pressure. The crude product (0.300 g) was purified over silica gel (60-120) using 30% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a solid (0.200 g, 60.81%). LCMS: (Method-C): RT= 1.432 min, m / z 279 [M+l], 95.1%.

[0381] Step 6: 5-(4-Iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)-l,2,4-thiadiazole: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, / ^-toluene sulfonic acid (0.015 g, 0.00007 mol) was added to solution of 5-(4-iodo-l / / -pyrazol-3-yl)-1,2,4-thiadiazole (0.200 g, 0.0007 mol) in tetrahydrofuran (2.00 mL) at 0°C. After 10 min stirring, 3,4-dihydro-2 / / -pyran (0.181 g, 0.0021 mol) was added at 0°C, and the reaction mixture stirred at 70°C for 2h. Completion of reaction was confirmed by TLC using 50% ethyl acetate in / ?-hexane as mobile phase. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and evaporated under reduced pressure. The crude product (0.450 g) was purified over silica gel (60-120) using 30% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an oil (0.180 g, 69.1%). LCMS: (Method-C): RT= 1.737 min, m / z 363.1 [M+l], 89.5%.

[0382] Step 1: tert-Butyl((l-(tetrahydro-2H-pyran-2-yl)-3-(l,2,4-thiadiazol-5-yl)-lH-pyrazol-4-yl) methyl) Carbamate: In a 30 mL sealed tube under argon atmosphere, potassium phosphate (0.324 g, 0.0014 mol) was added to a solution of 5-(4-iodo-l-(tetrahydro-2 / / -pyran-2-yl)-l / / -pyrazol-3-yl)-l,2,4-thiadiazole (0.180 g, 0.0004 mol) andDocket No.: KMYXP001WOadded tert-butyl ((4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) methyl) carbamate (0.153 g, 0.0005 mol) in dioxane (1.80 mL), acetonitrile (1.80 mL) and water (0.600 mL) at 25°C. The reaction mixture was degassed with argon for 15 minutes followed by addition of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.038 g, 0.00004 mol). The reaction mixture was stirred at 80°C for 16h. Completion of reaction was confirmed by TLC using 50% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). Combined organics were washed with brine (30 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.500 g) was purified over silica gel (60-120) using 30% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an oil (0.084 g, 46.2%). LCMS: (Method-C): RT= 1.792 min, m / z 366 [M+l], 65.7%.

[0383] Step 8: (3-(l,2,4-Thiadiazol-5-yl)-lH-pyrazol-4-yl)methanamine: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, N HC1 in dioxane (0.400 mL) was added dropwise to a solution of terLbutyl((l-(tetrahydro-2 / / -pyran-2-yl)-3-(l,2,4-thiadiazol-5-yl)-l / / -pyrazol-4-yl) methyl) carbamate (0.084 g, 0.0002 mol) in methanol (0.800 mL) at 0°C. The reaction mixture was stirred at 25°C for 16h. Completion of reaction was confirmed by TLC using 50% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with saturated sodium bicarbonate (20 mL) and the product was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.100 g) was purified over silica gel (60-120) using 50% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an oil (0.035 g, 69.9%). LCMS: (Method-H3): RT= 1.436 min, m / z 182 [M+l], 45.5%.HN~sV VoV\^N

[0384] Step 9: 2V-((3-(l,2,4-Thiadiazol-5-yl)-lH-pyrazol-4-yl)methyl)-4-methoxybenzenesulfonamide: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, 4-methoxybenzenesulfonyl chloride (0.040 g, 0.00019 mol) was addedDocket No.: KMYXP001WOportionwise to a solution of (3-(l,2,4-thiadiazol-5-yl)-l / / -pyrazol-4-yl)methanamine (0.035 g, 0.00019 mol) and triethylamine (0.080 mL, 0.00057 mol) in dichloromethane (0.350 mL) at 0°C. The reaction mixture was stirred at 25°C for Ih. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (10 mL) and product was extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.080 g) was purified over silica gel (40-60) using 40% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as a white solid (0.003 g, 5.31%). LCMS: (Method-C3): RT= 1.445 min, m / z 352.09 [M+l], 100%.2V-((3-(l,2,4-Thiadiazol-3-yl)-lH-pyrazol-4-yl) methyl)-4-methoxybenzenesulfonamide

[0385] Step 1: l-(l,2,4-Thiadiazol-3-yl)ethan-l-one In a 100 mL sealed tube under argon atmosphere, 5-bromo-l,2,4-thiadiazole (0.980 g, 0.0059 mol) and tributyl(l-ethoxyvinyl) stannane (2.57 g, 0.0071 mol) were added in toluene (29.0 mL) at 25°C and the reaction mixture was degassed for 15 minutes with argon. Pd(Phs)4 (0.686 g, 0.0005 mol) was added and the reaction mixture stirred for Ih at 110°C. Completion of reaction was confirmed by TLC using 30% ethyl acetate in zi-hexane as mobile phase. The reaction mixture was diluted with water (200 mL) and product was extracted with ethyl acetate (200 mL x 2). The combined organics were washed with brine (200 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (2.00 g) dissolved in tetrahydrofuran (12.0 mL) and cooled to 0°C then 4Af HC1 in dioxane (6.00 mL) was added dropwise. The reaction mixture was stirred for Ih at the same temperature. Completion of reaction was confirmed by TLC using 30% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with saturated sodium bicarbonate (120 mL) and the product was extracted with ethyl acetate (120 mL x 3). The combined organic layers were washed with brine (120 mL),Docket No.: KMYXP001WOdried over sodium sulfate and evaporated under reduced pressure. The crude product (1.20 g) was purified over silica gel (60-120) using 30% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an oil (0.380 g, 49.9%). LCMS: (Method-C): RT= 1.121 min, m / z 129 [M+l], 96.8%.

[0386] Step 2: (E)-3-(Dimethylamino)-l-(l,2,4-thiadiazol-3-yl)prop-2-en-l-one In a 10 mL one-neck round bottom flask under nitrogen atmosphere, N, N-dimethylformamide dimethyl acetal (3.80 mL) was added dropwise on l-(l,2,4-thiadiazol-3-yl)ethan-l-one (0.380 g, 0.0029 mol) at 25°C. The reaction mixture was stirred at 70°C for Ih. Completion of reaction was confirmed by TLC using 30% ethyl acetate in zi-hexane as mobile phase. The reaction solvent was evaporated under reduced pressure to afford the desired product as a solid (0.400 g, 73.6%). LCMS: (Method-C): RT= 1.222 min, m / z 184 [M+l], 100%.

[0387] Step 3: 3-(lH-Pyrazol-3-yl)-l,2,4-thiadiazole In a 25 mL one-neck round bottom flask under nitrogen atmosphere, hydrazine hydrochloride (0.445 g, 0.0065 mol) was added portionwise to a solution of (£)-3-(dimethylamine)-l-(l,2,4-thiadiazol-5-yl)prop-2-en-l-one (0.400 g, 0.0021 mol) in ethanol (4.00 mL) at 25°C. The reaction mixture was stirred at 50°C for 2h. Completion of reaction was confirmed by TLC using 30% ethyl acetate in / ?- hexane as mobile phase. The reaction was quenched with water (70 mL) and extracted with ethyl acetate (70 mL x 3). Combined organics were washed with brine (70 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.750 g) was purified over silica gel (60-120) using 30% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an oil (0.380 g, 114%).

[0388] Step 4: 3-(4-Iodo-lH-pyrazol-3-yl)-l,2,4-thiadiazole In a 10 mL one-neck round bottom flask under nitrogen atmosphere, N-iodosuccinimide (0.683 g, 0.00303Docket No.: KMYXP001WOmol) was added portionwise to a solution of 3-(l / / -pyrazol-3-yl)-l,2,4-thiadiazole (0.380 g, 0.0025 mol) in WN-dimethylformamide (3.80 mL) at 25°C. The reaction mixture was stirred at 25°C for 16h. Completion of reaction was confirmed by TLC using 50% ethyl acetate in n-hexane as mobile phase. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). Combined organics were washed with saturated sodium thiosulfate (30 mL), water (30 mL), brine (30 mL) and dried over sodium sulfate and evaporated under reduced pressure. The crude product (0.420 g) was purified over silica gel (60-120) using 30% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as a solid (0.380 g, 54.7%). LCMS: (Method-C): RT= 1.390 min, m / z 279 [M+l], 94.7%.

[0389] Step 5: 3-(4-Iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)-l,2,4-thiadiazole In a 10 mL one-neck round bottom flask under nitrogen atmosphere, / ^-toluene sulfonic acid (0.028 g, 0.0001 mol) was added to a solution of 3-(4-iodo-l / / -pyrazol-3-yl)-1,2,4-thiadiazole (0.380 g, 0.0013 mol) in tetrahydrofuran (3.80 mL) at 0°C. After 10 min stirring, 4-dihydro-2 / / -pyran (0.344 g, 0.0041 mol) was added dropwise at 0°C and the reaction mixture stirred at 70°C for 2h. Completion of reaction was confirmed by TLC using 50% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with Water (30 mL) and extracted with ethyl acetate (30 mL x 3). Combined organics were washed with brine (30 mL), dried over sodium sulfate and evaporated under reduced pressure. The crude product (0.500 g) was purified over silica gel (60-120) using 30% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an oil (0.350 g, 70.7%). LCMS: (Method-C): RT= 1.604 min, m / z 363.1 [M+l], 97.3%.Step 6: 7ert-Butyl((l-(tetrahydro-2H-pyran-2-yl)-3-(l,2,4-thiadiazol-3-yl)-lH-pyrazol-4-yl) methyl)Docket No.: KMYXP001WO

[0390] carbamate In a 30 mL sealed tube under argon atmosphere, potassium phosphate (0.630 g, 0.0028 mol) was added to a solution of 3-(4-iodo-l-(tetrahydro-2 / / -pyran-2-yl)-lH-pyrazol-3-yl)-l,2,4-thiadiazole (0.350 g, 0.0009 mol) and added tert-butyl ( (4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) methyl) carbamate (0.297 g, 0.0011 mol) in dioxane (2.80 mL), acetonitrile (2.80 mL) and water (1.40 mL) at 25°C. The reaction mixture was degassed with argon for 15 minutes then was added bis(di-tert-butyl(4-dimethylaminophenyl) phosphine) dichloropalladium(II) (0.068 g, 0.00009 mol) was added under argon and the reaction mixture was stirred at 80°C for 16h. Completion of reaction was confirmed by TLC using 50% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). Combined The reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). Combined organics were washed with brine (30 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.450 g) was purified over silica gel (60-120) using 30% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an oil (0.060 g, 17.0%). LCMS: (Method-C3): RT= 1.578 min, m / z 366 [M+l], 31.2%.

[0391] Step 7: (3-(l,2,4-Thiadiazol-3-yl)-lH-pyrazol-4-yl)methanamine In a 10 mL one-neck round bottom flask under nitrogen atmosphere, 4 / V HC1 in dioxane (0.300 mL) was added dropwise to a solution of terLbutyl((l-(tetrahydro-2 / / -pyran-2-yl)-3-(l,2,4-thiadiazol-3-yl)-l / / -pyrazol-4-yl) methyl) carbamate (0.060 g, 0.0001 mol) in methanol (0.600 mL) at 0°C. The reaction mixture was stirred at 25°C for 16h. Completion of reaction was confirmed by TLC using 50% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with saturated sodium bicarbonate (20 mL) and product was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.090 g) was purified over silica gel (60-120) using 50% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an oil (0.012 g, 40.3%).Docket No.: KMYXP001WO

[0392] Step 8: 2V-((3-(l,2,4-Thiadiazol-3-yl)-lH-pyrazol-4-yl) methyl)-4-methoxybenzenesulfonamide In a 10 mL one-neck round bottom flask under nitrogen atmosphere, 4-methoxybenzenesulfonyl chloride (0.0136 g, 0.000066 mol) was added portionwise to a solution of (3-(l,2,4-thiadiazol-3-yl)-l / / -pyrazol-4-yl)methanamine (0.012 g, 0.00006 mol) and triethylamine (0.030 mL, 0.0002 mol) in dichloromethane (0.350 mL) at 0°C. The reaction mixture was stirred at 25°C for Ih. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.025 g) was purified over silica gel (40-60) using 40% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as a white solid (0.002 g, 4.30%). LCMS: (Method-C3): RT= 1.389 min, m / z 352.16 [M+l], 95.4%.2V-((3-(Isothiazol-5-yl)-lH-pyrazol-4-yl)methyl)-l-(pyridin-2-yl)-lH-pyrazole-4- sulfonamideO

[0393] Step 1: (E)-3-(Dimethylamino)-l-(isothiazol-5-yl)prop-2-en-l-one In a 250 mL one-neck round bottom flask under nitrogen atmosphere, MN-dimethylformamide dimethyl acetal (100 mL) was added dropwise on l-(isothiazol-5-yl)ethan-l-one (10.0 g, 0.0029 mol) at 25°C. The reaction mixture was stirred at 70°C for Ih. Completion of reaction was confirmed by TLC using 50% ethyl acetate in zi-hexane as mobile phase. The reaction mixture was evaporated under reduced pressure to afford the desired product as a solid, which was used in the next step without any further purification (12.1 g, 84.4%). LCMS: (Method-C): RT= 0.957 min, m / z 183 [M+l], 100%.Docket No.: KMYXP001WOHN IN^VSV

[0394] Step 2: 5-(lH-Pyrazol-3-yl)isothiazole: In a 250 mL one-neck round bottom flask under nitrogen atmosphere, hydrazine hydrochloride (13.54 g, 0.199 mol) was added portionwise to a solution of (£)-3-(dimethylamino)-l-(isothiazol-5-yl)prop-2-en- 1-one (12.1 g, 0.0663 mol) in ethanol (120.0 mL) at 25°C. The reaction mixture was stirred at 70°C for 3h. Completion of reaction was confirmed by TLC using 50% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with water (400 mL) followed by saturated sodium bicarbonate solution (400 mL) then extracted with ethyl acetate (200 mL x 3). Combined organics were washed with brine (400 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (15.0 g) was purified over silica gel (60-120) using 50% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an oil (9.60 g, 95.6%). LCMS: (Method-C): RT= 0.971 min, m / z 151.9 [M+l], 98.6%.^ 4HN ]L /

[0395] Step 3: 5-(4-Iodo-lH-pyrazol-3-yl) isothiazole: In a 250 mL one-neck round bottom flask under nitrogen atmosphere, / V-iodosiiccinimide (17.1 g, 0.0761 mol) was added to a solution of 5-(l / / -pyrazol-3-yl) isothiazole (9.60 g, 0.0634 mol) in N, N-dimethylformamide (96.0 mL). The reaction mixture was stirred at 25°C for 16h.Completion of reaction was confirmed by TLC using 70% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with water (400 mL) and extracted with ethyl acetate (200 mL x 3). Combined organics were washed with saturated sodium thiosulfate (400 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (20.0 g) was purified over silica gel (60-120) using 80% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an oil (15.0 g, 85.3%). LCMS: (Method-C): RT= 1.455 min, m / z 278 [M+l], 98.7%.

[0396] Step 4: Methyl 3-(isothiazol-5-yl)-lH-pyrazole-4-carboxylate: In a 500 mL Hydrogenator under nitrogen atmosphere, Pd(OAc)2 (0.114 g, 0.00108 mol) and triethylamineDocket No.: KMYXP001WO(4.68 mL, 0.0324 mol) were added to the solution of 5-(4-iodo-l / / -pyrazol-3-yl)isothiazole (3.00 g, 0.0108 mol) in methanol (30.0 mL) at 25°C. The reaction mixture was stirred for 10 minutes then flushed with 5 Kg pressure carbon monoxide twice. The reaction mixture was stirred for 6h at 70°C under 20 Kg pressure (CO). Completion of reaction was confirmed by TLC using 50% ethyl acetate in zi-hexane as mobile phase. The reaction was evaporated under reduced pressure, residue was quenched with water (lOOmL) and extracted with ethyl acetate (100 mL x 2). The combined organic was dried over sodium sulfate and evaporated under reduced pressure. The crude product (3.50 g) was purified over silica gel (60-120) using 70% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as a solid (1.60 g, 70.6%). LCMS: (Method-C2): RT= 1.032 min, 210.07 m / z [M+l], 94.5%.

[0397] Step 5: (3-(Isothiazol-5-yl)-lH-pyrazol-4-yl)methanol: In a 250 mL three-neck round-bottom flask under nitrogen atmosphere, lAf lithium aluminum hydride in THF (15.29 mL, 0.0152 mol) was added dropwise to a solution of methyl 3-(isothiazol-5-yl)-l / 7-pyrazole-4-carboxylate (1.60 g, 0.0009 mol) in dry THF (160 mL) at 0°C and the reaction mixture stirred for 3h at 25°C. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction was quenched with diluted IN HC1 solution (100 mL) followed by water (100 mL) and the product was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (2.40 g) was purified over silica gel (60-120) using 80% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as a solid (1.28 g, 92.4%). LCMS: (Method-C2): RT= 0.855 min, 181.97 m / z [M+l], 100%.N=\%+

[0398] Step 6: 5-(4-(Azidomethyl)-lH-pyrazol-3-yl)isothiazole: In a 100 mL one-neck round-bottom flask under nitrogen atmosphere, diphenylphosphorylazide (1.82 g, 0.0066 mol) was added dropwise to a solution of (3-(isothiazol-5-yl)-l / / -pyrazol-4-yl)methanol (0.600 g, 0.0033 mol) in THF (6.00 mL) at 0°C. After 10 minutes stirring, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.840 mL, 0.0056 mol) was added dropwise at 0°C and the reaction mixture was stirred at 25°C for 16h. Completion of reaction was confirmed by TLCDocket No.: KMYXP001WOusing 50% ethyl acetate in zi-hexane as mobile phase. The reaction was quenched with water (50 mL) and extracted (40 mL x 32). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over sodium sulfate and solvent was evaporated under reduced pressure. The crude product (1.30 g) was purified over silica gel (60-120) using 40% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as a solid (0.580 g, 84.9%). LCMS: (Method-C2): RT= 1.440 min, m / z 205 [M-l], 84.4%.

[0399] Step 7: (3-(Isothiazol-5-yl)-lH-pyrazol-4-yl)methanamine: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, H2O (0.500 mL) was added dropwise to a solution of 5-(4-(azidomethyl)-l / / -pyrazol-3-yl)isothiazole (0.200 g, 0.0009 mol) in THF (2.00 mL) at 25°C. After 10 minutes stirring, triphenylphosphine (0.380 g, 0.0014 mol) was added at 25°C and the reaction mixture was stirred at 25°C for 16h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction was quenched with water (30 mL) and extracted (20 mL x 3). The combined organic layers were washed with water (20 mL) dried over sodium sulfate and evaporated under reduced pressure. The crude product (0.310 g) was purified over silica gel (60-120) using 10% methanol in dichloromethane as the mobile phase to afford the desired product as a solid (0.050 g, 84.9%).

[0400] Step 8: 2V-((3-(Isothiazol-5-yl)-lH-pyrazol-4-yl)methyl)-l-(pyridin-2-yl)-lH-pyrazole-4-sulfonamide: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, l-(pyridin-2-yl)-l / / -pyrazole-4-sulfonyl chloride (0.067 g, 0.0002 mol) was added portionwise to a solution of ((3-(isothiazol-5-yl)-l / / -pyrazol-4-yl)methanamine (0.050 g, 0.0002 mol) and triethylamine (0.120 mL, 0.0008 mol) in dichloromethane (0.500 mL) at 0°C. The reaction mixture was stirred at 25°C for Ih. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.075 g) was purified over silica gel (40-60) using 40%Docket No.: KMYXP001WOethyl acetate in / ?-hexane as the mobile phase to afford the desired product as a white solid (0.045 g, 84.9%). LCMS: (Method-C2): RT= 1.421 min, m / z 388.14 [M+l], 98.0%.Example 804-(lH-Imidazol-4-yl)-2V-((3-(isothiazol-5-yl)-lH-pyrazol-4-yl) methyl)benzenesulfonamide

[0401] Step 1: 4-Bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-imidazole: In 25 mL one-neck round-bottom flask under nitrogen atmosphere, / ^-toluene sulfonic acid (0.120 g, 0.0006 mol) was added to solution of 4-bromo- l / 7-imidazole (1.000 g, 0.0068 mol) in THF (10.0 mL) at 0°C. After 10 min stirring, 3,4-dihydro-2 / 7-pyran (1.787 g, 0.0204 mol) was added portionwise at 25 °C and the reaction mixture stirred at 60°C for 2h. Completion of reaction was confirmed by TLC using 60% ethyl acetate in zi-hexane as the mobile phase. The reaction was quenched with water (20 mL) and the product was then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (1.50 g) was purified over silica gel (60-120) using 50% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an off-white solid (1.20 g, 80%). LCMS: (Method-C2): RT= 1.70 min, m / z 233.03 [M+2], 100%.

[0402] Step 2: l-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l H-imidazole: In a 30 mL sealed tube under argon atmosphere, potassium carbonate (0.476 g, 0.0034 mol) was added to a solution of 4-bromo- l-(tetrahydro-2H-pyran-2-yl)-lH-imidazole (0.400 g, 0.0017 mol) and Bis(pinacolato)diboron (0.139 g, 0.0018 mol) in 1,4-dioxane (4.00 mL) at 25°C. The reaction mixture was degassed with argon for 10 minutes. X-Phos Pd G4 (0.015 g, 0.00001 mol) was added, and the reaction mixtureDocket No.: KMYXP001WOwas stirred for 3h at 120°C. Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as mobile phase. The reaction mixture was allowed to 25 °C then diluted with water (30 mL). The product was extracted with ethyl acetate (40 mL x 2). The combined organics were washed with water (30 mL), brine (30 mL), dried over sodium sulfate, and evaporated under reduced pressure to afford the crude product (1.0 g) as a brown solid which was used in the next step without further purification. (0.600 g, 125%).

[0403] Step 3: 4-Bromo-2V-((3-(isothiazol-5-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, 4-bromobenzenesulfonyl chloride (0.255 g, 0.0099 mol) was added portionwise to a solution of (3-(isothiazol-5-yl)-l / / -pyrazol-4-yl)methanamine (0.200 g, 0.0011 mol) and trimethylamine (0.224 mL, 0.0022 mol) in dichloromethane (2.00 mL) at 0°C. The reaction mixture was stirred at 25°C for Ih. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.500 g) was purified over silica gel (40-60) using 40% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.480 g, 108%). LCMS: (Method-C3): RT= 1.51 min, m / z 401.01 [M], 75.6%.

[0404] Step 4: 2V-((3-(Isothiazol-5-yl)-lH-pyrazol-4-yl)methyl)-4-(l-(tetrahydro- 2H-pyran-2-yl)-lH-imidazol-4-yl)benzenesulfonamide: In a 30 mL sealed tube under argon atmosphere, potassium carbonate (0.137 g, 0.0010 mol) in water (2.00 mL) was added to a solution of 4-bromo-N-((3-(isothiazol-5-yl)-l / / -pyrazol-4-yl)methyl)benzenesulfonamide (0.200 g, 0.0005 mol) and l-(tetrahydro-2 / / -pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l / / -imidazole (0.139 g, 0.0005 mol) in dioxane (4.00 mL) at 25°C. The reaction mixture was degassed with argon for 10 minutes then Pd(dppf)C12 (0.041 g, 0.00005Docket No.: KMYXP001WOmol) was added. The reaction mixture was stirred for 3h at 70 °C. Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as mobile phase. The reaction mixture was allowed to 25 °C and then diluted with water (20 mL). The product was extracted with ethyl acetate (30 mL x 2). The combined organics were washed with water (30 mL), brine (30 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.200 g) was purified over silica gel (60-120) using 5% methanol in dichloromethane as the mobile phase to afford the desired product as a white solid (0.030 g, 13.0%).

[0405] Step 5: 4-(lH-Imidazol-4-yl)-2V-((3-(isothiazol-5-yl)-lH-pyrazol-4-yl) methyl)benzenesulfonamide: In a 25 mL one-neck round-bottom flask under nitrogen atmosphere, N-( (3-(isothiazol-5-yl)-l / / -pyrazol-4-yl) methyl)-4-(l-(tetrahydro-2 / / -pyran-2-yl)-lH-imidazol-4-yl)benzenesulfonamide (0.030 g, 0.00006 mol) was dissolved in methanol (0.300 mL) and the reaction mixture was cooled to 0°C. After 5 minutes stirring, 4M HCl in dioxane (0.300 mL) was added dropwise at 0°C and the reaction mixture stirred for 4h at the same temperature. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with water (20 mL), and the product was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.040 g) was purified by reversed phase prep HPLC, purification method-1, to afford the desired product as a white solid (0.004 g, 16.2%). LCMS: (Method-C2): RT= 1.27 min, m / z 387.2 [M+l], 100%.Example 812V-((3-(Isothiazol-5-yl)-lH-pyrazol-4-yl) methyl)- l-(pyrimidin-2-yl)-lH-pyrazole-4- sulfonamideDocket No.: KMYXP001WOBr

[0406] Step 1: 2-(4-Bromo-lH-pyrazol-l-yl)pyrimidine: In a 30 mL microwave vial under nitrogen atmosphere, potassium carbonate (0.870 g, 0.0063 mol), copper iodide (0.053 g, 0.0002 mol) and L-proline (0.072 g, 0.0006 mol) were added to a solution of 2-chloropyrimidine (0.405 g, 0.0035 mol) and 4-bromo-l / / -pyrazole (0.400 g, 0.0027 mol) in DMSO (4.00 mL) at 25°C. The reaction mixture was stirred in a microwave at 140 C for 2h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (30 mL) and extracted with dichloromethane (20 mL x 3). Combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.900 g) was purified over silica gel (60-120) using 40% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as a solid. (0.700 g, 89.7%). LCMS: (Method-C3): RT= 1.41 min, m / z 227.06 [M+l], 96.2%.

[0407] Step 2: 2-(4-(Benzylthio)-lH-pyrazol-l-yl)pyrimidine: In a 30 mL sealed tube under nitrogen atmosphere, M N-diisopropylethylamine (0.460 mL, 0.0026 mol) was added dropwise to a solution of 2-(4-bromo-l / / -pyrazol-l-yl) pyrimidine (0.300 g, 0.0013 mol) and phenylmethanethiol (0.160 g, 0.0013 mol) in dioxane (6.00 mL) at 25°C. The reaction mixture was degassed with argon for 15 minutes. Xantphos (0.038 g, 0.0006 mol) and Pd2(dba)3 (0.030 g, 0.00003 mol) were added at 25°C. The reaction mixture was stirred at 90°C for 2h. Completion of reaction was confirmed by TLC using 10% ethyl acetate in n-hexane as the mobile phase. The reaction was quenched with ice cold water (15.0 mL) and the product extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with water (20.0 mL) and brine (20.0 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.250 g) was purified over silica gel (60-120) using 10% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an oil (0.220 g, 62.8%). LCMS: (Method-C3): RT= 1.630 min, m / z 269.40 [M+l], 93.3%.Cl-SiiODocket No.: KMYXP001WO

[0408] Step 3: l-(Pyrimidin-2-yl)-lH-pyrazole-4-sulfonyl chloride: In a 30 mL sealed tube under nitrogen atmosphere, 2-(4-(benzylthio)-l / / -pyrazol-l-yl)pyrimidine (0.220 g, 0.0008 mol) was dissolved in acetonitrile (2.00 mL) at 25°C. Then was added mixture of acetic acid: water (0.400 mL:1.00 mL) and the reaction mixture was cooled to 0°C. After 5 minutes stirring, A-chloro succinimide (0.130 g, 0.0009 mol) was added at 0°C. The stirred the reaction mixture at the same temperature for 2h. Completion of reaction was confirmed by TLC using 30% ethyl acetate in zi-hexane as the mobile phase. The reaction solvent was evaporated to afford a crude product which was used in the next step without further purification. (0.194 g, 97.0%).

[0409] Step 4: 2V-((3-(Isothiazol-5-yl)-lH-pyrazol-4-yl) methyl)-l-(pyrimidin-2-yl)-lH-pyrazole-4-sulfonamide: In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, trimethylamine (0.463 mL, 0.0033 mol) was added dropwise to a solution of (3-(isothiazol-5-yl)-l / / -pyrazol-4-yl)methanamine (0.100 g, 0.0006 mol) in dichloromethane (5.00 mL) at 0°C. After 5 minutes stirring, l-(pyrimidin-2-yl)-l / / -pyrazole-4-sulfonyl chloride (0.194 g, 0.0007 mol) added portionwise at 0°C. The reaction mixture was stirred at 25°C for Ih. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction was quenched with water (10 mL) and the product extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.300 g) was purified over silica gel (60-120) using 3% methanol in dichloromethane as the mobile phase to afford the desired product as a white solid (0.018 g, 6.20%). LCMS: (Method-C2): RT= 1.336 min, m / z 389.14 [M+l], 99.2%.Docket No.: KMYXP001WO2V-((3-(Isothiazol-5-yl)-lH-pyrazol-4-yl)methyl)-l-(pyridin-2-yl)-lH-pyrrole-3- sulfonamideIIN

[0410] Step 1: 2-(lH-Pyrrol-l-yl)pyridine: In a 30 mL one-neck round-bottom flask under nitrogen atmosphere, cesium carbonate (7.276 g, 0.0223 mol) and copper oxide (0.112 g, 0.0014 mol) were added to a solution of l / 7-pyrrole (1.00 g, 0.01490 mol) and 2-iodopyridine (3.673 g, 0.0179 mol) in dimethylsulfoxide (10.0 mL) at 25°C. The reaction mixture was stirred at 100°C 16h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (30 mL) and extracted with dichloromethane (10 mL x 3). Combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (1.00 g) was purified over silica gel (60-120) using 5% methanol in dichloromethane as the mobile phase to afford the desired product as white solid (0.900 g, 41.9%). LCMS: (Method-C): RT= 1.600 min, m / z 145.1 [M+l], 93.4%.SiiO

[0411] Step 2: l-(Pyridin-2-yl)-lH-pyrrole-3-sulfonyl chloride: In a 30 mL sealed tube under nitrogen atmosphere, chlorosulfonic acid (0.802 g, 0.0069 mol) was added dropwise to a solution of 2-(l / / -pyrrol-l-yl)pyridine (0.500 g, 0.0034 mol) was dissolved in acetonitrile (5.00 mL) at 0°C. The reaction mixture was stirred at 25°C for 16h. Thionyl chloride (0.301 mL, 0.0041 mol) was added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at 80°C for 3h. Completion of reaction was confirmed by TLC using 30% ethyl acetate in zi-hexane as the mobile phase. The reaction was quenched with water (10 mL) and the product extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and evaporated under reduced pressure to afford the desired crude product (0.250 g, 29.8%). LCMS: (Method-C): RT= 1.740 min, m / z 243.00 [M+l], 57.9%.Docket No.: KMYXP001WO

[0412] Step 3: V-((3-(Isothiazol-5-yl)-lH-pyrazol-4-yl)methyl)-l-(pyridin-2-yl)-lH-pyrrole-3-sulfonamide: In a 10 mL one neck round-bottom flask under nitrogen atmosphere, trimethylamine (0.283 mL, 0.0020 mol) was added dropwise to a solution of (3-(isothiazol-5-yl)-l / / -pyrazol-4-yl)methanamine (0.186 g, 0.0010 mol) in dichloromethane (2.50 mL) at 0°C. After 5 minutes stirring, l-(pyridin-2-yl)-l / / -pyrrole-3-sulfonyl chloride (0.250 g, 0.0010 mol) was added portionwise at 0°C. The reaction mixture was stirred at 25°C for Ih. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction was quenched with water (10 mL) and the product extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.190 g) was purified over silica gel (60-120) using 3% methanol in dichloromethane as the mobile phase to afford the desired product as a white solid (0.027 g, 6.78%). LCMS: (Method-C2): RT= 1.435 min, m / z 387.17 [M+l], 100%.2V-((3-(lH-Imidazol-l-yl)-lH-pyrazol-4-yl)methyl)-4-methoxybenzenesulfonamide

[0413] Step 1: 3-(l-Imidazolyl)-l-(tetrahydro-2H-pyran-2-yl)-4-pyrazolecarbonitrile: In a 30 mL microwave vial under nitrogen atmosphere, potassium carbonate (1.251 g, 0.0089 mol), copper iodide (0.047 g, 0.0002 mol) and L-proline (0.103 g,Docket No.: KMYXP001WO0.0008 mol) were added to a solution of 3-iodo-l-(tetrahydro-2 / / -pyran-2-yl)-4-pyrazolecarbonitrile (1.500 g, 0.0049 mol) and I / / -imidazole (0.302 g, 0.0044 mol) in DMSO (10.0 mL) at 25°C. The reaction mixture was stirred at 140°C in microwave for 2 h.Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). Combined organic layer were washed with water (10.0 mL), brine (10.0 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.350 g) was purified over silica gel (60-120) using 5% methanol in dichloromethane as the mobile phase to afford the desired product as a solid. (0.204 g, 20.0%). LCMS: (Method-H3): RT= 2.392 min, m / z 244.00 [M], 71.3%.N

[0414] Step 2: (3-(lH-Imidazol-l-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)methanamine: In a 10 mL one neck round-bottom flask under nitrogen atmosphere, sodium borohydride (0.184 g, 0.0048 mol) was added portionwise to a solution of 3-(l-imidazolyl)-l-(tetrahydro-2 / / -pyran-2-yl)-4-pyrazolecarbonitrile (0.200 g, 0.0008 mol) and nickel(II) chloride hexahydrate (0.040 g, 0.0001 mol) in methanol (2.00 mL) at 0°C. The reaction mixture was stirred at 25°C for Ih. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction was quenched with water (20 mL) and the product extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure to afford a crude product which was used in the next step without further purification (0.120 g, 57.7%). LCMS: (Method-H3): RT= 1.739 min, m / z 248.02 [M+l], 32.7%.N

[0415] Step 3: 2V-((3-(lH-Imidazol-l-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)methyl)-4-methoxybenzenesulfonamide: In a 10 mL one neck round-bottomDocket No.: KMYXP001WOflask under nitrogen atmosphere, trimethylamine (0.200 mL, 0.0014 mol) was added dropwise to a solution of (3-(l / / -imidazol-l-yl)-l-(tetrahydro-2 / / -pyran-2-yl)-l / / -pyrazol-4-yl)methanamine (0.120 g, 0.0004 mol) in dichloromethane (1.20 mL) at 0°C. After 5 minutes stirring, 4-methoxybenzenesulfonyl chloride (0.090 g, 0.0004 mol) was added portionwise at 0°C. The reaction mixture was stirred at 25°C for Ih. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction was quenched with water (10 mL) and the product extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.250 g) was purified over silica gel (60-120) using 3% methanol in dichloromethane as the mobile phase to afford the desired product as a white solid (0.056 g, 27.6%). LCMS: (Method-C2): RT= 1.149 min, m / z 418.0 [M+l], 31.8%.

[0416] Step 4: 2V-((3-(lH-Imidazol-l-yl)-lH-pyrazol-4-yl)methyl)-4-methoxybenzenesulfonamide: In a 25 mL one-neck round-bottom flask under nitrogen atmosphere, A-((3-(l / / -imidazol-l-yl)-l-(tetrahydro-2 / / -pyran-2-yl)-l / / -pyrazol-4-yl)methyl)-4-methoxybenzenesulfonamide (0.056 g, 0.0001 mol) was dissolved in methanol (0.25 mL) and cooled to 0°C. After 5 minutes stirring, 4Af HC1 in dioxane (0.250 mL) was added dropwise at 0°C and the reaction mixture stirred for Ih at the same temperature.Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with water (20 mL) and product was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.060 g) was purified over silica gel (60-120) using 100% ethyl acetate as the mobile phase to afford the desired product as an off-white solid (0.012 g, 26.8%). LCMS: (Method-H3): RT= 2.121 min, m / z 334.0 [M+l], 95.1%.Example 84Docket No.: KMYXP001WO\-((3-(Isothiazol-3-yl)-l / / -pyrazol-4-yl)niethyl)-l -phenyl- l / / -pyrazole-4-sulfonaniideH

[0417] Step 1: (E)-2-(l-(Isothiazol-3-yl)ethylidene)hydrazine-l-carboxamide: In a 25 mL one-neck round-bottom flask under nitrogen atmosphere, semicarbazide hydrochloride (1.31 g, 0.01181 mol) followed by sodium acetate (0.645 g, 0.00787 mol) were added to the solution of l-(isothiazol-3-yl)ethan-l-one (1.00 g, 0.00787 mol) in ethanol (10.0 mL) at 25°C. The reaction mixture stirred at 25°C for 16h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. Solid product was filtered and was washed with ethanol (15 mL), / ?-hexane (20 mL) and dried under reduced pressure to afford the desired product as a white solid. (1.50 g, 100%). LCMS: (Method-C3): RT= 1.299, m / z 185.03 [M+l], 100%.

[0418] Step 2: 3-(Isothiazol-3-yl)-lH-pyrazole-4-carbaldehyde: In a 50 mL three-neck round-bottom flask under nitrogen atmosphere, POCh (3.03 mL, 0.0325 mol) was added dropwise to dry DMF (15.0 mL) at 0°C. After 1 h stirring, (£’)-2-(l-(isothiazol-3-yl)ethylidene)hydrazine- 1 -carboxamide (1.5 g, 0.0081 mol) was added portionwise at 0°C and the reaction mixture stirred at 70°C for 16h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction was quenched with ice water (50 mL) then basified with 3M aqueous NaOH up to pH ~ 10. The product was then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (2.00 g) was purified over silica gel (40-60) using 80% ethylDocket No.: KMYXP001WOacetate in zi-hexane as the mobile phase to afford the desired product as a yellow oil (0.140 g, 9.59%). LCMS: (Method-C2): RT=0.958 min, m / z 180.05 [M+l], 96.2%.

[0419] Step 3: (E)- / V-((3-(Isothiazol-3-yl)-lH-pyrazol-4-yl) methylene)-2-methylpropane-2-sulfinamide: In a 10 mL one neck round-bottom flask under nitrogen atmosphere, Ti(OEt)4 (0.693 g, 0.0030 mol) was added dropwise to a solution of 3-(isothiazol-3-yl)-l / / -pyrazole-4-carbaldehyde (0.140 g, 0.0007 mol) and 2-methylpropane-2-sulfinamide (0.129 g, 0.0010 mol) in THF (1.400 mL) at 25°C. The reaction mixture was stirred at 75 °C for 16h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction mixture was allowed to 25 °C and quenched by water (20 mL) and diluted with ethyl acetate (30 mL x 2). The organic layer was washed with brine (30 mL), dried over sodium sulfate, and evaporated under reduced pressure to afford a crude product which was used in the next step without further purification (0.300 g, 100%). LCMS:(Method-C2): RT= 1.110 min, m / z 283.1 [M+l], 60.7%.

[0420] Step 4: 2V-((3-(Isothiazol-3-yl)-lH-pyrazol-4-yl) methyl)-2-methylpropane- 2-sulfinamide: In a 50 mL one neck round-bottom flask under nitrogen atmosphere, 1M diisobutylaluminum hydride in THF (5.67 mL, 0.0056 mol) was added dropwise to a solution of (£’)-N-((3-(isothiazol-3-yl)- 1 H-py razol-4-y 1) methylene)-2-methylpropane-2-sulfinamide (0.400 g, 0.0014 mol) in dry THF (4.00 mL) at 0°C. The reaction mixture was stirred at 25°C for 16h. Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as mobile phase. The reaction was quenched with IN HC1 up to pH~7 at 0°C and extracted by 10% IPA: Chloroform (50 mL x 2). The organic layer was separated and washed with brine (50 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to afford the desired product (0.180 g, 59.6%). LCMS: (Method-C2): RT= 1.023 min, m / z 285.17 [M+l], 81.9%.Docket No.: KMYXP001WO

[0421] Step 5: (3-(Isothiazol-3-yl)-lH-pyrazol-4-yl)methanamine: In a 10 mL one neck round-bottom flask under nitrogen atmosphere, 4M HCl in dioxane (0.900 mL) was added dropwise to a solution of N-((3-(isothiazol-3-yl)-l / / -pyrazol-4-yl) methyl)-2-methylpropane-2-sulfinamide (0.180 g, 0.00063 mol) in methanol (1.80 mL) at 0°C. The reaction mixture was allow stirred at 25 °C for 16h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction mixture was quenched with IN NaOH (4.00 mL) at 0°C and the product extracted with ethyl acetate (30 mL x 2). The combined organic layers were separated and washed with brine (30.0 mL), dried over sodium sulfate, and evaporated under reduced pressure to afford the desired product which was used in the next step without further purification (0.110 g, 80.2%). LCMS:(Method-H): RT= 1.435 min, m / z 180.8 [M], 100%.

[0422] Step 6: 2V-((3-(Isothiazol-3-yl)-lH-pyrazol-4-yl)methyl)-l-phenyl-lH-pyrazole-4-sulfonamide: In a 10 mL one neck round-bottom flask under nitrogen atmosphere, triethyl amine (0.060 mL, 0.0004 mol) was added dropwise to a solution of (3-(isothiazol-3-yl)-l / / -pyrazol-4-yl)methanamine (0.030 g, 0.0001 mol) in dichloromethane (0.300 mL) at 25°C. 1 -phenyl- IH-pyrazole-4-siilfonyl chloride (0.033 g, 0.0001 mol) was added dropwise at 0°C. The reaction mixture was stirred at 25°C for Ih. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with water (10.0 mL) and extracted with dichloromethane (10.0 mL x 3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.050 g) was purified by reversed phase chromatography using 0.1% ammonia in water and 100% acetonitrile as a mobile phase and column (Cl 8 spherical 40-60 um 100 A 12 g) on a CombiFlash® to afford the desired product as a white solid (0.009 g, 16.8%). LCMS:(Method-C3): RT= 1.508 min, m / z 387.17 [M+l], 98.3%.Docket No.: KMYXP001WOExample 85Izz- / \ Zxc zn- zI OOcn==l-Ethvl- \-((3-(isothiazol-3-yl)-l / / -pyrazol-4-yl) methyl)-lH-pyrazole-4-sulfonamide

[0423] The title compound was prepared using the reaction conditions of Example 83 (Step 6), with (3-(isothiazol-3-yl)-l / / -pyrazol-4-yl)methanamine hydrochloride (0.030 g, 0.0001 mol) and l-ethyl-l / / -pyrazole-4-sulfonyl chloride (0.027 g, 0.0001 mol) as reagents. The crude product (0.060 g) was purified over silica gel (40-60) using 5% methanol in dichloromethane as the mobile phase afford the desired product as a white solid (0.016 g, 34.1%). LCMS: (Method-C): RT= 1.384 min, m / z 339.12 [M+l], 100%. HPLC: (Method-59): RT= 3.720 min, 93.6%.

[0424] Examples in the following table were prepared using similar conditions as described for those of the previous examples from the appropriate starting materials.Table 1. Example CompoundsEx. Structure IUPAC Name m / z No.04-methoxy-N - { [3 -(5-methylfuran-2- 348.0 / =\ / HNVHA / 0yl)- 1 H-pyrazol-4-yl] methyl } benzene- 8601- sulfonamideC °4-ethoxy-N- { [3-( 1,2-thiazol-5-yl)- 1H- 365.1 pyrazol-4-yl] methyl } benzene- 1 - 87sulfonamideDocket No.: KMYXP001WOEx. Structure IUPAC Name m / z No.4-propoxy-N-{[3-(l,2-thiazol-5-yl)- 379.1 1 H-pyrazol-4-yl]methyl } benzene- 1 - 88 sulfonamideN-((3-(isothiazol-5-yl)-lH-pyrazol-4- 397.2 yl)methyl)- [1,1 '-biphenyl] -4- 89 vX ° sulfonamideN^VSA'NN-((3-(isothiazol-5-yl)-lH-pyrazol-4- 411.2 o yl)methyl)-2'-methyl- [1,1 '-biphenyl] - o. Ij 4- sulfonamide90 Z\HN ] H b 0N^ X^x OOW== AD1^ zS4Z C)-^fA / . _ N-((3-(isothiazol-5-yl)-lH-pyrazol-4- 385.2 zzz.- - I T q. X / X?,s v=^ / yl)methyl)- 1 -phenyl- lH-pyrazole-4- 91 HN7^ / P| 'bsulfonamide'NC Vb-N4-methoxy-N - ( (3 - (3 -methylthiophen- 364.0 2-yl)- lH-pyrazol-4- 92 yl)methyl)benzenesulfonamide\^° 4-(2,5-dimethyloxazol-4-yl)-N-((3- 416.1(isothiazol-5-yl)-lH-pyrazol-4- AJ yl)methyl)benzenesulfonamide93HN7^ / H 0Nx^xsvDocket No.: KMYXP001WOEx. Structure IUPAC Name m / z No.I N-((3-(isoxazol-5-yl)-lH-pyrazol-4- 362.1 zN yl)methyl)-2-oxo-2,3- 94 dihydrobenzo [d] oxazole- 5 - X c\<o sulfonamideN-((3-(isothiazol-3-yl)-lH-pyrazol-4- 349.2 XX o yl)methyl)-4- 95 HN^ j fj 0 methoxybenzenesulfonamide'N%NL sN-N N-((3-(isothiazol-5-yl)-lH-pyrazol-4- 402.2 oyl)methyl)-4-( 1 -methyl- 1H- 1,2,3- A O ZI96 Z\ °,-S JQJ triazol-4-yl)benzenesulfonamideHN7^ / P| 0N^V==\ h Csxr 0 ° N-((3-(isoxazol-5-yl)-lH-pyrazol-4- 335.1 yl)methyl)-4- z97 IHl / ^f H 'O methoxybenzenesulfonamide°vN-((3-(isothiazol-4-yl)-lH-pyrazol-4- 351.0 yl)methyl)-4- 98 methoxybenzenesulfonamideN-((3-(isothiazol-5-yl)-lH-pyrazol-4- 414.1 %£y v yl)methyl)-4-(pyridin-2- 99 nN7^ / Pj o yloxy)benzenesulfonamideNX^\Qb-NDocket No.: KMYXP001WOEx. Structure IUPAC Name m / z No.N-((3-(isothiazol-5-yl)-lH-pyrazol-4- 389.0 yl)methyl)-4- q. IjF100 (trifluoromethyl)benzenesulfonamideH 0NS=V==\C VN-((3-(isoxazol-4-yl)-lH-pyrazol-4- 335.0 yl)methyl)-4- 101 f| 'b methoxybenzenesulfonamideJr,oN(E)-N-((3-(isothiazol-5-yl)-lH- 347.0 pyrazol-4-yl)methyl)-2-phenylethene- 102 [j 0 1- sulfonamidesvN-((3-(isothiazol-5-yl)-lH-pyrazol-4- 405.0 yl)methyl)-4- 103 [j 'b (trifluoromethoxy)benzenesulfonamideNSY===\SVExample 104l-(4-Methoxyphenyl)-N-((4-phenylthiazol-5-yl)methyl)cyclopropan-l-amineStep 14-Bromothiazole-5-carbaldehydeDocket No.: KMYXP001WO

[0425] In a 25 mL one-neck round-bottom flask under nitrogen atmosphere, (4-bromothiazol- 5-yl)methanol (0.900 g, 0.0046 mol) dissolved in dry dichloromethane (18.0 mL) and the reaction mixture was cooled to 0 °C. After 5 min stirring, Dess-Martin periodinane (3.90 g, 0.0091 mol) was added portion wise at 0 °C, and the reaction mixture was stirred for 3 h at the same temperature. Completion of reaction was confirmed by TLC using 30% ethyl acetate in n-hexane as mobile phase. The reaction was quenched with water (50 mL) and the product was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.950 g) was purified over silica gel (60-120) using 60% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an oil (0.600 g, 67.4%).LCMS: (Method-C2): RT= LOO min, m / z 191.90 [M+l], 100%.Step 2SN4-Phenylthiazole-5-carbaldehyde

[0426] In a 30 mL sealed tube under argon atmosphere, sodium carbonate (0.492 g, 0.0046 mol) in water (1.00 mL) was added to a solution of 5-bromothiazole-4-carbaldehyde (0.300 g, 0.0015 mol) and phenylboronic acid (0.378 g, 0.0031 mol) in dioxane (4.00 mL) at 25 °C. The reaction mixture was degassed with argon for 10 min. Pd(dppf)C12 (0.114 g, 0.00015 mol) was added, and the reaction mixture was stirred for 3 h at 70 °C. Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as mobile phase. The reaction mixture was allowed to cool to 25 °C and then diluted with water (20 mL). The product was extracted with ethyl acetate (30 mL x 2). The combined organics were washed with water (30 mL) and brine (30 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.500 g) was purified over silica gel (60-120) using 60% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.200 g, 67.65%).LCMS: (Method-C2): RT= 1.21 min, m / z 189.89 [M+l], 100%.Step 3Docket No.: KMYXP001WOl-(4-Methoxyphenyl)-N-((4-phenylthiazol-5-yl)methyl)cyclopropan-l-amine

[0427] In a 10 mL round-bottom flask under nitrogen atmosphere, 4-phenylthiazole-5-carbaldehyde (0.100 g, 0.0005 mol) and l-(4-methoxyphenyl) cyclopropan-1 -amine (0.081 g, 0.0005 mol) were dissolved in methanol (1.00 mL) at 25 °C. After 5 min stirring, acetic acid (0.060 mL, 0.0010 mol) was added drop wise and the reaction mixture was stirred for 2 h at 25 °C. Sodium cyanoborohydride (0.099 g, 0.0015 mol) was added portion wise at 0 °C, and the reaction mixture was stirred at 25 °C for 16 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with water (10 mL) and the product was extracted with ethyl acetate (10 mL x 3). The combined organics were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.150 g) was purified by reversed phase prep HPLC using method- 1 to afford the desired product as a white solid (0.023 g, 12.9%).LCMS: (Method-C2): RT= 1.138 min, m / z 336.94 [M+l], 100%.HPLC: (Method-59): RT= 3.69 min, 99.69%.Example 1054-Methoxy-N-((4-phenylthiazol-5-yl)methyl)benzenesulfonamideStep 1(E)-4-Phenylthiazole-5-carbaldehyde oxime

[0428] In a 25 ml round-bottom flask under nitrogen atmosphere, 4-phenylthiazole-5-carbaldehyde (0.230 g, 0.0012 mol) was dissolved in ethanol (6 mL) at 25 °C. After 5 min stirring, sodium acetate (0.118 g, 0.0014 mol) followed by hydroxylamine hydrochloride (0.082 g, 0.0012 mol) were added at 25 °C and the reaction mixture stirred at 25 °C for 3 h. Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as mobile phase. The reaction was quenched with water (30 mL) and the product extracted withDocket No.: KMYXP001WOethyl acetate (30 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure to obtain the desired product as a yellowish solid. (0.230 g, 92.65 %).LCMS: (Method-C2): RT= 1.20 min, m / z 205.04 [M+l], 67.4%.Step 2(4-Phenylthiazol-5-yl)methanamine

[0429] In a 25 mL 1-neck round-bottom flask under nitrogen atmosphere, (E)-4-phenylthiazole-5-carbaldehyde oxime (0.210 g, 0.0010 mol) was added in 35% HC1 solution (5 mL) and the reaction mixture cooled to 0 °C. After 10 min, activated zinc dust (0.312 g, 0.0048 mol) was added portion wise at 0 °C. The reaction mixture was stirred 0 °C for 2 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction mixture was diluted with milli-Q water (100 mL) and basified with ammonium hydroxide to pH ~ 10 at 0 °C. The product was extracted with 30% IPA / CHCh (50 mL x 3) and the solvents evaporated under reduced pressure to obtain the desired product as a yellowish semi solid (0.100 g, 51.1%).LCMS: (Method-C2): RT= 0.83 min, m / z 190.06 [M+], 85.45%.4-Methoxy-N-((4-phenylthiazol-5-yl)methyl)benzenesulfonamide

[0430] In a 10 mL round-bottom flask under nitrogen atmosphere, triethylamine (0.151 mL, 0.0011 mol) was added drop wise to a solution of (4-phenylthiazol-5-yl)methanamine (0.100 g, 0.00052 mol) in dichloromethane (1.0 mL) at 25 °C. 4-methoxybenzenesulfonyl chloride (0.225 g, 0.0011 mol) was added portion wise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crudeDocket No.: KMYXP001WOproduct (0.110 g) was purified by using C-18 high performance reversed phase column (50 g) from RediSep and 0-40% acetonitrile in 0.1M aqueous ammonia solution in as a mobile phase to afford the desired product as a white solid (0.028 g, 14.8%).LCMS: (Method-C2): RT= 1.224 min, m / z 361.27 [M], 100%.HPLC: (Method-59): RT= 4.63 min, 97.53%.Example 106N-((3-(4-Fluorophenyl)-lH-pyrazol-4-yl)methyl)-l-(4-methoxyphenyl)cyclopropan-l- amineFStep 1O NH2N-NH(E)-2-(l-(4-Fluorophenyl)ethylidene)hydrazine-l-carboxamide

[0431] In a 100 mL 3-neck round-bottom flask under nitrogen atmosphere, l-(4-fhiorophenyl)ethan-l-one (3.00 g, 0.021 mol) was dissolved in ethanol: H2O (1:1) (30 mL) at 25 °C. After 5 min stirring, semicarbazide hydrochloride (3.20 g, 0.028 mol) followed by sodium acetate (2.80 g, 0.021 mol) were added at 25 °C and the reaction mixture stirred at 80 °C for 4 h. Completion of reaction was confirmed by TLC using 40% ethyl acetate in n-hexane as the mobile phase. The reaction mixture was allowed to cool to 25 °C and filtered. The precipitate was washed with ethanol (30 mL) and n-hexane (30 mL) and dried under reduced pressure to afford the desired product as a white solid. (2.50 g, 59.0%).LCMS: (Method-C2): RT= 1.08 min, m / z 196.25 [M+l], 100%.3-(4-Fluorophenyl)-lH-pyrazole-4-carbaldehyde

[0432] In a 25 mL 3-neck round-bottom flask under nitrogen atmosphere, POCI3 (1.9 mL, 0.020 mol) was added dropwise to dry DMF (3 mL, 0.040 mol) at 0 °C. After 1 h stirring, (£)-Docket No.: KMYXP001WO2-(l-(4-fluorophenyl) ethylidene)hydrazine- 1 -carboxamide (2 g, 0.010 mol) was added portion wise at 0 °C and the reaction mixture stirred at 50 °C for 6 h. Completion of reaction was confirmed by TLC using 60% ethyl acetate in n-hexane as the mobile phase. The reaction mixture was poured portion wise on crushed ice (100 mL) and basified with 3M aqueous NaOH up to pH ~ 10. The product was then extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 65% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an off-white solid (0.800 g, 41.1%).LCMS: (Method-C2): RT= 1.10 min, m / z 190.87[M+l], 88.6%.Step 3FN-((3-(4-Fluorophenyl)-lH-pyrazol-4-yl)methyl)-l-(4-methoxyphenyl)cyclopropan-l-amine

[0433] The title compound was prepared using the reaction conditions in Example 1 (Step 3), with 3-(4-fluorophenyl)-lH-pyrazole-4-carbaldehyde (0.200 g, 0.001 mol) and l-(4-methoxyphenyl)cyclopropan- 1 -amine (0.162 g, 0.001 mol) as reagents. The crude product (0.500 g) was purified by reversed phase prep HPLC, purification method 2, to afford the desired product as a white solid (0.098 g, 27.6%).LCMS: (Method-H3): RT= 3.104 min, m / z 338.2 [M+l], 100%.HPLC: (Method-59): RT= 3.82 min, 99.24%.Example 1074-Methoxy-N-((3-phenyl-lH-pyrazol-4-yl)methyl)benzenesulfonamideStep 1Docket No.: KMYXP001WONH2(E)-2-(l -Phenylethylidene)hydrazine- 1 -carboxamide

[0434] In a 100 mL 3-neck round-bottom flask, acetophenone (3.00 g, 0.0250 mol) was dissolved in ethanol:H2O (1:1) (25 mL) at 25 °C. After 5 min stirring, semicarbazide hydrochloride (4.16 g, 0.0375 mol) followed by sodium acetate (2.05 g, 0.0250 mol) were added at 25 °C and the reaction mixture stirred at 80 °C for 4 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction mixture was allowed to cool to 25 °C and filtered. The solid product was washed with ethanol (20.0 mL) and zi-hexane (20.0 mL). The solid product was dried under reduced pressure to afford the desired product as a white solid. (3.9 g, 88.1%).LCMS: (Method-C2): RT= 1.12 min, m / z 178.15 [M+l], 100%.Step 23-Phenyl-lH-pyrazole-4-carbaldehyde-pyrazole-4-carbaldehyde

[0435] In a 50 mL 3-neck round-bottom flask under nitrogen atmosphere, POCl3 (9.9 mL, 0.0453 mol) was added dropwise to dry DMF (8 mL) at 0 °C. After 1 h stirring, (E)-2-(l-phenylethylidene)hydrazine-l -carboxamide (3.90 g, 0.0226 mol) was added portion wise at 25 °C and the reaction mixture stirred at 50 °C for 6 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction mixture was poured portion wise on crushed ice (80 mL) and basified with 3M aqueous NaOH up to pH ~ 10. The product was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (150 mL) and brine (150 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 70% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an off-white solid (3.5 g, 92.4%).LCMS: (Method-C2): RT=1.13 min, m / z 172.96 [M+l], 90.97%.Step 3Docket No.: KMYXP001WO(E)-3-Phenyl-lH-pyrazole-4-carbaldehyde oxime

[0436] In a 25 ml 1-neck round-bottom flask under nitrogen atmosphere, 3-phenyl-lH-pyrazole-4-carbaldehyde (1.00 g, 0.0058 mol) was dissolved in ethanol (15 mL) at 25 °C. After 5 min stirring, sodium acetate (0.475 g, 0.0058 mol) followed by hydroxylamine hydrochloride (0.484 g, 0.0069 mol) were added at 25 °C and the reaction mixture stirred at 25 °C for 3 h. Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as mobile phase. The reaction was quenched with water (50 mL) and the product extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SC>4 and evaporated under reduced pressure to afford the desired product as a yellowish solid. (0.800 g, 73.6%).LCMS: (Method-C2): RT= 1.09 min, m / z 187.93 [M+l], 77.91%.Step 4(3-Phenyl-lH-pyrazol-4-yl)methanamine

[0437] In a 25 mL 3-neck round-bottom flask under nitrogen atmosphere, (E)-3-phenyl-1H-pyrazole-4-carbaldehyde oxime (0.500 g, 0.0026 mol) was added in 35% HC1 solution (5 mL) and the reaction mixture cooled to 0 °C. After 5 min, activated zinc dust (0.834 g, 0.0128 mol) was added portion wise at 0 °C and the reaction mixture was stirred at the same temperature for 2 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction mixture was diluted with milli-Q water (30 mL) and basified with ammonium hydroxide to pH ~ 10 at 0 °C. The product was extracted with 30% IPA / CHCh (30 mL x 3) and the solvents evaporated under reduced pressure to afford the desired product as a yellowish semi solid (0.250 g, 54.0%).LCMS: (Method-C2): RT= 0.86 min, m / z 174.92 [M+l], 89.03%.Step 5Docket No.: KMYXP001WO4-Methoxy-N-((3-phenyl-lH-pyrazol-4-yl)methyl)benzenesulfonamide

[0438] In a 10 mL round-bottom flask under nitrogen atmosphere, triethylamine (0.144 mL, 0.001 mol) was added drop wise to a solution of (3-phenyl-lH-pyrazol-4-yl)methanamine (0.100 g, 0.0005 mol) in dichloromethane (1.0 mL) at 25 °C. The reaction mixture was cooled to 0 °C, and 2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl sulfurochloridite (0.130 g, 0.0006 mol) was added portion wise. The reaction mixture was allowed to stir at 25 °C for 1 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (10 mL), and the product was extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and evaporated under reduced pressure. The crude product (0.106 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.100 g, 50.4%).LCMS: (Method-C2): RT= 1.136 min, m / z 344.19 [M+l], 100%.HPLC: (Method-59): RT= 4.30 min, 99.66%.Example 1084-Methoxy-N-((5-phenylthiazol-4-yl)methyl)benzenesulfonamideStep 1OMethyl 5-phenylthiazole-4-carboxylate

[0439] In a 30 mL sealed tube under argon atmosphere, sodium carbonate (1.400 g, 0.0135 mol) was added to a solution of 4-bromothiazole-5-carbaldehyde (1.00 g, 0.0045 mol) andDocket No.: KMYXP001WOphenylboronic acid (0.550 g, 0.0045 mol) in dry THF (10 mL) at 25 °C. The reaction mixture was degassed with argon for 10 min. Pd(PPh3)4 (0.520 g, 0.00045 mol) was added under argon atmosphere and the reaction mixture was stirred for 3 h at 70 °C. Completion of reaction was confirmed by TLC using 50% ethyl acetate in hexane as mobile phase. The reaction mixture was cooled to 25 °C and diluted with water (20 mL). The product was extracted with ethyl acetate (50 mL x 2). The combined organics were washed with water (50 mL) and brine (50 mL), dried over Na2SC>4, and evaporated under reduced pressure. The crude product (1.20 g) was purified over silica gel (60-120) using 30% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.800 g, 81.0%).LCMS: (Method-C2): RT= 1.14 min, m / z 220.04 [M+l], 99.68%.Step 2S5-Phenylthiazole-4-carbaldehyde

[0440] In a 50 mL 1-neck round-bottom flask under nitrogen atmosphere, 1M diisobutylaluminum hydride in THF (7.2 mL, 0.0072 mol) was added drop wise to a solution of methyl 5-phenylthiazole-4-carboxylate (0.800 g, 0.0036 mol) in dry THF (10 mL) at -78 °C. The reaction mixture was stirred at 25 °C for 16 h. Completion of reaction was confirmed by TLC using 40% ethyl acetate in n-hexane as mobile phase. The reaction was quenched with 1N HCl solution (5.00 mL) and diluted with ethyl acetate (40.0 mL). The organic layer was separated and washed with aqueous solution potassium sodium tartrate (50 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.800 g) was purified over silica gel (60-120) using 50% ethyl acetate in n-hexane as the mobile phase to afford the desired product (0.600 g, 76.0%).LCMS: (Method-C2): RT= 1.14 min, 190.06 m / z [M+l], 100.0%.N(E)-5-Phenylthiazole-4-carbaldehyde oxime

[0441] In a 25 ml 1-neck round-bottom flask under nitrogen atmosphere, 5-phenylthiazole-4-carbaldehyde (0.600 g, 0.0031 mol) was dissolved in ethanol (9.00 mL) at 25 °C. After 5 minDocket No.: KMYXP001WOstirring, sodium acetate (0.260 g, 0.0031 mol) followed by hydroxylamine hydrochloride (0.264 g, 0.0038 mol) were added at 25 °C and the reaction mixture stirred at 25 °C for 3 h. Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as mobile phase. The reaction was quenched with water (30 mL) and the product extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.700 g) was purified over silica gel (60-120) using 90% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an off-white solid (0.550 g, 84.9%).LCMS: (Method-C2): RT= 1.12 min, m / z 205.11 [M+l], 77.91%.Step 4NH(5-Phenylthiazol-4-yl) methanamine

[0442] In a 25 mL 1-neck round-bottom flask under nitrogen atmosphere, (£)-5-phenylthiazole-4-carbaldehyde oxime (0.200 g, 0.00097 mol) was added in 35% HC1 solution (2.00 mL) and the reaction mixture cooled to 0 °C. After 5 min, activated zinc dust (0.320 g, 0.0048 mol) was added portion wise at 0 °C, and the reaction mixture was stirred same temperature for 3 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction mixture was diluted with milli-Q water (25 mL) and basified with ammonium hydroxide to pH ~ 10 at 0 °C. The product was extracted with 30% IPA / CHCh (40 mL x 3) and solvents evaporated under reduced pressure. The crude product (0.250 g) was purified over basic alumina using 5-10% methanol in dichloromethane as the mobile phase to afford the desired product as thick oil (0.100 g, 53.7%).LCMS: (Method-C2): RT= 0.907 min, m / z 191.00 [M+l], 97.87%.Step 54-Methoxy-N-((5-phenylthiazol-4-yl)methyl)benzenesulfonamide

[0443] In a 10 mL 1-neck round-bottom flask under nitrogen atmosphere, triethylamine (0.147 mL, 0.0010 mol) was added drop wise to a solution of (5-phenylthiazol-4-Docket No.: KMYXP001WOyl)methanamine (0.100 g, 0.00052 mol) in dichloromethane (1.0 mL) at 25 °C. 4-methoxybenzenesulfonyl chloride (0.119 g, 0.00057 mol) was added portion wise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.106 g) was purified by silica gel (100-200) and 30% ethyl acetate in n-hexane as a mobile phase to afford the desired product as a white solid (0.090 g, 47.5%). LCMS: (Method-C2): RT= 1.265 min, m / z 362.0 [M+2], 100%.HPLC: (Method-60): RT= 4.831 min, 99.41%.Example 1094-Methoxy-N-((3-(pyrimidin-5-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamideStep 1CN3-Iodo-lH-pyrazole-4-carbonitrile

[0444] In a 1-liter 3-neck round-bottom flask under nitrogen atmosphere, 3-amino-lH-pyrazole-4-carbonitrile (34.0 g, 0.314 mol) was dissolved in cone. HC1 (420 mL) and reaction mixture cooled to -5 °C. After 5 min stirring, sodium nitrite (43.0 g, 0.629 mol) in water (60.0 mL) was added drop wise below at 0 °C. After 15 min stirring, potassium iodide (130 g, 0.785 mol) in water (60.0 mL) was added drop wise below at 0 °C. The reaction mixture was stirred at 0 to 5 °C temperature for 3 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with water (400 mL) and the product extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with saturated solution of Na2S2O5 (300 mL), water (300 mL) and brine (300 mL). Organic layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product (50 g) was purified over silica gel (60-120) using 50% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid. (30.0 g, 43.6%).Docket No.: KMYXP001WOLCMS: (Method-C-2): RT= 1.01 min, m / z 217.96 [M+l], 85.59%.Step 23-Iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-4-carbonitrile

[0445] In a 250 mL 3-neck round-bottom flask under nitrogen atmosphere, 3-iodo-lH-pyrazole-4-carbonitrile (17.0 g, 0.0783 mol) was dissolved in THF (160 mL) followed by slowly addition of 3,4-dihydro-2H-pyran (19.7 g, 0.0138 mol) at 25 °C. After 10 min stirring, 4-methylbenzenesulfonic acid (1.63 g, 0.0086 mol) was added portion wise at 25 °C and the reaction mixture was stirred at 70 °C for 16 h. Completion of reaction was confirmed by TLC using 30% ethyl acetate in hexane as mobile phase. The reaction was quenched with water (200 mL) and the product extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with water (300 mL) and brine (300 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (40.0 g) was purified over silica gel (60-120) using 40% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a yellow liquid. (23 g, 97.7%).LCMS: (Method-C-2): RT= 1.14 min, m / z 303.12 [M+l], 93.43%.Step 33-(Pyrimidin-5-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-4-carbonitrile

[0446] In a 30 mL sealed tube under argon atmosphere, 5-(tributylstannyl) pyrimidine (1.94 g, 0.0052 mol) followed by sodium carbonate (1.03 g, 0.0099 mol) were added to a solution of 3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-4-carbonitrile (0.500 g, 0.0033 mol) in dioxane (5.00 mL) at 25 °C. The reaction mixture was degassed with argon for 10 min.Pd(OAc)2 (0.051 g, 0.00023 mol) was added under argon atmosphere and the reaction mixture was stirred for 3 h at 70 °C. Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as mobile phase. The reaction mixture was cooled to 25 °C and diluted with water (20 mL). The product was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried overDocket No.: KMYXP001WONa2SO4 and evaporated under reduced pressure. The crude product (0.500 g) was purified over silica gel (60-120) using 60% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.200 g, 47.5%).LCMS: (Method-C2): RT= 1.10 min, m / z 256.16 [M+l], 84.66%.Step 4NH(3-(Pyrimidin-5-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl) methanamine

[0447] In a 10 mL 1-neck round-bottom flask under nitrogen atmosphere, Raney nickel (0.093 g, 0.0015 mol) was added portion wise to a solution of 3-(pyrimidin-5-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-4-carbonitrile (0.080 g, 0.00031 mol) in methanol (4.00 mL) at 25 °C. After 5 min stirring, ammonium hydroxide (4.00 mL) was added dropwise at 25 °C, and the reaction mixture was stirred under hydrogen balloon pressure at room temperature for 6 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction mixture was filtered carefully through Celite and washed with methanol (10 mL x 3). Combined organic layers were evaporated under reduced pressure. The crude product (0.100 g) was purified over silica gel (60-120) using 5% methanol in dichloromethane as the mobile phase to afford the desired product as a liquid. (0.030 g, 36.9%).LCMS: (Method-C2): RT= 0.877 min, m / z 260.17 [M+l], 83.25%.Step 5O II HN-S- -1O4-Methoxy-N-((3-(pyrimidin-5-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)methyl)benzene sulfonamide

[0448] In a 10 mL round-bottom flask under nitrogen atmosphere, triethylamine (0.031 mL, 0.00022 mol) was added drop wise to a solution of (3-(pyrimidin-5-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)methanamine (0.030 g, 0.00011 mol) in dichloromethane (1.0Docket No.: KMYXP001WOmL) at 25 C. 4-methoxybenzenesulfonyl chloride (0.028 g, 0.00013 mol) was added portion wise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (30 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over NaiSCL and evaporated under reduced pressure. The crude product (0.060 g) was purified over silica gel (60-120) using 5% methanol in dichloromethane as the mobile phase to afford the desired product as a liquid. (0.030 g, 60.4%).LCMS: (Method-C2): RT= 1.13 min, m / z 430.24 [M], 68.69%.Step 6O II / / =\ \N= / 4-Methoxy-N-((3-(pyrimidin-5-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide

[0449] In a 10 mL 1-neck round-bottom flask under nitrogen atmosphere, 4N HC1 in dioxane (0.150 mL, 5 volume) was added drop wise to a solution of 4-methoxy-N-((3-(pyrimidin-5-yl)- l-(tetrahydro-2H-pyran-2-yl)- lH-pyrazol-4-yl)methyl)benzenesulfonamide (0.030 g, 0.00006 mol) in methanol (0.300 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with INNaOH aq. (0.500 mL) at 0 °C and the product extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.025 g) purified by using C-18 high performance reversed phase column (50 g) from RediSep and 0-40% acetonitrile in O.lAf aqueous ammonia solution in as a mobile phase to afford the desired product as a white solid (0.003 g, 12.4%).LCMS: (Method-C2): RT= 1.018 min, 346.13 m / z [M+l], 96.55%.HPLC: (Method-72): RT= 3.318 min, 98.73%.Example 1104-Methoxy-N-((3-(pyrimidin-4-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamideDocket No.: KMYXP001WOStep 13-(Pyrimidin-4-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-4-carbonitrile

[0450] In a 30 mL sealed tube under argon atmosphere, cesium fluoride (1.09 g, 0.0072 mol) was added to a solution of 3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-4-carbonitrile (0.500 g, 0.0033 mol) and 4-(tributylstannyl) pyrimidine (1.94 g, 0.0052 mol) in dioxane (5.00 mL) at 25 °C. The reaction mixture was degassed with argon for 10 min. Pd(t-BusP)2 (0.050 g, 0.00009 mol) was added under argon atmosphere and the reaction mixture was stirred for 3 h at 70 °C. Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as a mobile phase. The reaction mixture was cooled to 25 °C and diluted with water (20 mL). The product was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SC>4, and evaporated under reduced pressure. The crude product (0.560 g) was purified over silica gel (60-120) using 60% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as a white solid (0.180 g, 42.7%).LCMS: (Method-C2): RT= 1.14 min, m / z 256.16 [M+l], 74.29%.Step 2NH2(3-(Pyrimidin-5-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl) methanamine

[0451] In a 10 mL 1-neck round-bottom flask under nitrogen atmosphere, Raney nickel (0.201 g, 0.0033 mol) was added portion wise to a solution of 3-(pyrimidin-4-yl)-l-(tetrahydro-2H-Docket No.: KMYXP001WOpyran-2-yl)-lH-pyrazole-4-carbonitrile (0.180 g, 0.0007 mol) in methanol (15.0 mL) at 25 °C. After 5 min stirring, aqueous ammonia (9 mL) was added dropwise at 25 °C and the reaction mixture stirred under hydrogen balloon pressure at room temperature for 6 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction mixture was filtered carefully through Celite and washed with methanol (10 mL x 3). The combined organic layers were evaporated under reduced pressure. The crude product (0.150 g) was purified over silica gel (60-120) using 5% methanol in dichloromethane as the mobile phase to afford the desired product as a liquid. (0.060 g, 32.8%).LCMS: (Method-C2): RT= 0.92 min, m / z 260.17 [M+l], 68.23%.Step 3OiiHN-S / IIO4-methoxy-N-((3-(pyrimidin-4-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4- yl)methyl)benzene sulfonamide

[0452] In a 10 mL 1-neck round-bottom flask under nitrogen atmosphere, triethylamine (0.060 mL, 0.00046 mol) was added drop wise to a solution of (3-(pyrimidin-5-yl)-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)methanamine (0.060 g, 0.00023 mol) in dichloromethane (1.00 mL) at 25 °C. 4-methoxybenzenesulfonyl chloride (0.027 g, 0.0002 mol) was added portion wise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h.Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (20 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and evaporated under reduced pressure. The crude product (0.060 g) was purified over silica gel (60-120) using 5% methanol in dichloromethane as the mobile phase to afford the desired product as a liquid. (0.050 g, 50.3%).LCMS: (Method-C2): RT= 1.24 min, m / z 430.24 [M+l], 70.77%.Step 4HN-S / IIODocket No.: KMYXP001WO4-Methoxy-N-((3-(pyrimidin-4-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide

[0453] In a 10 mL 1-neck round-bottom flask under nitrogen atmosphere, 4N HC1 in dioxane (0.25 mL, 5 volume) was added drop wise to a solution of 4-methoxy-N-((3-(pyrimidin-5-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide (0.050 g, 0.00011 mol) in methanol (0.5 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h.Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with INNaOH aq. (0.200 mL) at 0 °C and the product extracted with ethyl acetate (10 mL x 2). Combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.012 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.004 g, 9.95%).LCMS: (Method-C2): RT= 1.034 min, 346.14 m / z [M+l], 99.62%.HPLC: (Method-72): RT= 3.568 min, 97.13%.Example 1112-Oxo-N-((3-(pyridin-3-yl)-lH-pyrazol-4-yl)methyl)-2,3-dihydrobenzo[d]oxazole-5- sulfonamideStep 11 -(6-Methoxypyridin-3-yl)ethan- 1 -one

[0454] In a 50 mL 1-neck round-bottom flask under nitrogen atmosphere, l-(6-hydroxypyridin-3-yl)ethan-l-one (2.50 g, 0.0182 mol) was dissolved in DMSO (15 mL) at 25 °C. After 5 min stirring, potassium carbonate (4.00 g, 0.0728 mol), followed by methyl iodide (1.39 ml, 0.0218 mol), were added slowly at 25 °C and the reaction mixture stirred at room temperature for 8 h. Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as the mobile phase. The reaction was quenched with ice water (50 mL) and the product extracted with ethyl acetate (75 mL x 3). The combined organic layers wereDocket No.: KMYXP001WOwashed with water (50 mL) and brine (50 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 80% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an off-white solid (2.30 g, 83.5%).LCMS: (Method-C2): RT= 1.02 min, m / z 151.77 [M+l], 100%.Step 2oy— NH2N-NHQ(Z)-2-(l-(6-Methoxypyridin-3-yl)ethylidene)hydrazine-l-carboxamide

[0455] In a 100 mL round-bottom flask under nitrogen atmosphere, l-(6-methoxypyridin-3-yl)ethan-l-one (2.30 g, 0.0152 mol) was dissolved in ethanokfhO (1:1) (50 mL) at 25 °C. After 5 min stirring, semicarbazide hydrochloride (2.6- g, 0.0228 mol), followed by sodium acetate (1.24 g, 0.0152 mol), were added at 25 °C and the reaction mixture stirred at 80 °C for 4 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction mixture was allowed to go to 25 °C and filtered. The collected precipitate was washed with ethanol (20 mL), zi-hexane (20 mL) and dried under reduced pressure to afford the desired product as a white solid. (2.80 g, 88.4%).LCMS: (Method-C2): RT= 1.24 min, m / z 209.11 [M+l], 100%.Step 3Cl3-(6-Chloropyridin-3-yl)-lH-pyrazole-4-carbaldehyde

[0456] In a 50 mL 3-neck round-bottom flask under nitrogen atmosphere, POCh (2.50 mL, 0.0269 mol) was added dropwise to dry DMF (6.00 mL) at 0 °C. After 1 h stirring, (Z)-2-(l-(6-methoxypyridin-3-yl)ethylidene)hydrazine-l -carboxamide (2.80 g, 0.0134 mol) was added portion wise at 25 °C and the reaction mixture stirred at 50 °C for 6 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction mixture was poured portion wise onto crushed ice (40 mL) and basified with 3M aqueous NaOH up to pH ~ 10. The product was extracted with ethyl acetate (50 mL x 3), andDocket No.: KMYXP001WOthe combined organic layers were washed with water (60 mL) and brine (60 mL), dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 70% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as an off-white solid (0.700 g, 25.1%).LCMS: (Method-C2): RT=1.02 min, m / z 207.91 [M+l], 98.50%.Step 4Cl(E)-3-(6-Chloropyridin-3-yl)-lH-pyrazole-4-carbaldehyde oxime

[0457] In a 25 mL 1-neck round-bottom flask under nitrogen atmosphere, 3-(6-chloropyridin-3-yl)-lH-pyrazole-4-carbaldehyde (0.700 g, 0.0033 mol) was dissolved in ethanol (10 mL) at 25 °C. After 5 min stirring, sodium acetate (0.275 g, 0.0033 mol) followed by hydroxylamine hydrochloride (0.280 g, 0.0040 mol) were added at 25 °C and reaction mixture stirred at 25 °C for 3 h. Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as mobile phase. The reaction was quenched with water (50 mL) and the product extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SC>4 and evaporated under reduced pressure to afford the desired product as a yellowish solid. (0.750 g, 99.9%).LCMS: (Method-C2): RT= 0.98 min, m / z 223.02 [M+l], 100%.Step 5HN^\ ^NH2N^ / f )N=Z(3-(Pyridin-3-yl)-lH-pyrazol-4-yl)methanamine

[0458] In a 25 mL 1-neck round-bottom flask under nitrogen atmosphere, (E)-3-(6-chloropyridin-3-yl)-lH-pyrazole-4-carbaldehyde oxime (0.300 g, 0.0022 mol) was added in 35% HC1 solution (5 mL) and the reaction mixture cooled to 0 °C. After 10 min stirring, activated zinc dust (0.690 g, 0.0107 mol) was added portion wise at 0 °C. The reaction mixture was stirred 0 °C for 2 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction mixture was diluted with milli-Q water (100 mL) and basified with ammonium hydroxide to pH ~ 10 at 0 °C. The product wasDocket No.: KMYXP001WOextracted with 30% IPA / CHCh (25 mL x 3), and the solvents evaporated under reduced pressure to afford the desired product as a yellowish semi solid (0.120 g, 51.1%).LCMS: (Method-C2): RT= 0.26 min, m / z 175.08 [M+l], 93.70%.Step 62-Oxo-N-((3-(pyridin-3-yl)-lH-pyrazol-4-yl)methyl)-2,3-dihydrobenzo[d]oxazole-5-sulfonamide

[0459] In a 10 mL 1-neck round-bottom flask under nitrogen atmosphere, triethylamine (0.192 mL, 0.0013 mol) was added drop wise to a solution of (3-(pyridin-3-yl)-lH-pyrazol-4-yl)methanamine (0.120 g, 0.0006 mol) in dichloromethane (1.0 mL) at 25 °C. 2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl sulfurochloridite (0.167 g, 0.00072 mol) was added portion wise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.142 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.022 g, 8.60%).LCMS: (Method-C2): RT= 0.893 min, m / z 372.13 [M+l], 95.5%.HPLC: (Method-72): RT= 8.54 min, 95.93%.Example 1124-Methoxy-N-((3-(pyrimidin-4-yl) -lH-pyrazol-4-yl)methyl)benzenesulfonamideStep 1Docket No.: KMYXP001WO3-(Pyridin-4-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-4-carbonitrile

[0460] In a 30 mL sealed tube under argon atmosphere, cesium fluoride (0.398 g, 0.0026 mol) was added to a solution of 3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-4-carbonitrile (0.380 g, 0.0012 mol) and 4-(tributylstannyl) pyridine (0.647 g, 0.0017 mol) in dioxane (5.00 mL) at 25 °C. The reaction mixture was degassed with argon for 10 min. Pd(t-BusP)2 (0.018 g, 0.000036 mol) was added under argon atmosphere and the reaction mixture stirred for 3 h at 70 °C. Completion of reaction was confirmed by TLC using 5% methanol in dichloromethane as mobile phase. The reaction mixture was allowed to go to 25 °C and diluted with water (20 mL). The product was extracted with ethyl acetate (30 mL x 2). The combined organics were washed with water (30 mL) and brine (30 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.560 g) was purified over silica gel (60-120) using 60% ethyl acetate in zi-hexane as the mobile phase to afford the desired product as a white solid (0.100 g, 31.4%).LCMS: (Method-C2): RT= 1.05 min, m / z 255.16 [M+l], 92.48%.Step 2(3-(Pyridin-4-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl) methanamine

[0461] In a 10 mL 1-neck round-bottom flask under nitrogen atmosphere, nickel chloride hexahydrate (0.083 g, 0.00003 mol) was added to the solution of 3-(pyridin-4-yl)-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazole-4-carbonitrile (0.090 g, 0.00035 mol) in methanol (2 mL) at 25 °C and the reaction mixture cooled to 0 °C. After 5 min stirring, sodium borohydride (0.077 g, 0.0021 mol) was added portion wise at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with water (10 mL) and product was extracted with ethyl acetate (30 mL x 3). The organic layers wereDocket No.: KMYXP001WOwashed with water (30 mL) and brine (30 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.800 g) was purified over silica gel (60-120) using 5% methanol in dichloromethane as the mobile phase to afford the desired product as a liquid. (0.060 g, 65.6%).LCMS: (Method-H3): RT= 1.86 min, m / z 259.1 [M+l], 56.47%.Step 3OiiHN-S- / HO4-Methoxy-N-((3-(pyridin-4-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)methyl)benzene sulfonamide

[0462] In a 10 mL 1-neck round-bottom flask under nitrogen atmosphere, triethylamine (0.067 mL, 0.00046 mol) was added drop wise to a solution of (3-(pyridin-4-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)methanamine (0.060 g, 0.00023 mol) in dichloromethane (1.0 mL) at 25 °C. 4-methoxybenzenesulfonyl chloride (0.047 g, 0.00023 mol) was added portion wise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (20 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.060 g) was purified over silica gel (60-120) using 5% methanol in dichloromethane as the mobile phase to afford the desired product as a liquid. (0.070 g, 70.3%).LCMS: (Method-C2): RT= 1.08 min, m / z 429.18 [M+l], 87.84%.Step 4HN-S / II-J O4-Methoxy-N-((3-(pyrimidin-4-yl) -lH-pyrazol-4-yl)methyl)benzenesulfonamide

[0463] In a 10 mL 1-neck round-bottom flask under nitrogen atmosphere, 4 / V HC1 in dioxane (0.350 mL, 5 volume) was added drop wise to a solution of 4-methoxy-N-((3-(pyridin-4-yl)-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide (0.070 g, 0.00016Docket No.: KMYXP001WOmol) in methanol (0.500 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with INNaOH (0.500 mL) at 0 °C and the product extracted with ethyl acetate (10 mL x 2). The combined organic layers were separated and washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.124 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.026 g, 46.2%).LCMS: (Method-H3): RT= 2.245 min, 345.0 m / z [M+l], 100%.HPLC: (Method-60): RT= 3.549 min, 97.24%.Example 1132-Oxo-N-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)-2,3-dihydrobenzo[d]oxazole-5- sulfonamideStep 1O NH2N-NH(Z)-2-(l-(Pyridin-4-yl)ethylidene)hydrazine-l-carboxamide

[0464] In a 100 mL 3-neck round-bottom flask under nitrogen atmosphere, l-(6-methoxypyridin-3-yl)ethan-l-one (5.00 g, 0.0412 mol) was dissolved in ethanol: H2O (1:1) (50.0 mL) at 25 °C. After 5 min stirring, semicarbazide hydrochloride (6.80 g, 0.0619 mol) followed by sodium acetate (4.90 g, 0.0412 mol) were added at 25 °C and the reaction mixture stirred at 80 °C for 4 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction mixture was allowed to go to 25 °C and filtered. The collected precipitate was washed with ethanol (15 mL) and zi-hexane (15 mL) and dried under reduced pressure to afford the desired product as a white solid. (6.00 g, 81.6%).LCMS: (Method-C2): RT= 0.26 min, m / z 179.0 [M+l], 99.86%.Docket No.: KMYXP001WOStep 2NN3-(Pyridin-4-yl)-lH-pyrazole-4-carbaldehyde

[0465] In a 100 mL 3-neck round-bottom flask under nitrogen atmosphere, POCh (6.40 mL, 0.0674 mol) was added dropwise to dry DMF (15.0 mL) at 0 °C. After 1 h stirring, (Z)-2-(l-(pyridin-4-yl)ethylidene)hydrazine-l -carboxamide (6.00 g, 0.0337 mol) was added portion wise at 25 °C and the reaction mixture stirred at 50 °C for 6 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction was quenched with ice water (100 mL) and basified with 3M aqueous NaOH up to pH ~ 10. The product was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (3.50 g) was purified over silica gel (60-120) using 80% ethyl acetate in n-hexane as the mobile phase to afford the desired product as a white solid (0.650 g, 7.36%).LCMS: (Method-C2): RT=0.280 min, m / z 174.03 [M+l], 89.95%.Step 3N(E)-2-Methyl-N-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methylene)propane-2-sulfinamide

[0466] In a 50 mL 100 mL 1-neck round-bottom flask under nitrogen atmosphere, Ti(OEt)4 (3.37 g, 0.0148 mol) was added drop wise to a solution of 3-(pyridin-4-yl)-lH-pyrazole-4-carbaldehyde (0.650 g, 0.0037 mol) and 2-methylpropane-2-sulfinamide (0.636 g, 0.0052 mol) and in THF (15.0 mL) at 25 °C. The reaction mixture was stirred at 75 °C (external temperature) for 16 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction mixture was allowed to go to 25 °C, quenched with water (50 mL) and diluted with ethyl acetate (100 mL). This slurry was filtered through Celite and washed with ethyl acetate (50 mL x 2). The organic layer was separated and washed with brine (60 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude productDocket No.: KMYXP001WOwas punfied over silica gel (60-120) using 80% ethyl acetate in n-hexane as the mobile phase to afford the desired product as an orange liquid (0.900 g, 86.8%).LCMS: (Method-C2): RT= 0.900 min, 277.14 m / z [M+l], 98.97%.Step 42-Methyl-N-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)propane-2-sulfinamide

[0467] In a 25 mL 1-neck round-bottom flask under nitrogen atmosphere, 1M diisobutylaluminum hydride in THF (13 mL, 0.0130 mol) was added drop wise to a solution of (E)-2-methyl-N-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methylene)propane-2-sulfinamide (0.900 g, 0.0032 mol) in dry THF (10.0 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. Completion of reaction was confirmed by TLC using 50% ethyl acetate in n-hexane as mobile phase. The reaction was quenched with IN HC1 (5.00 mL) at 0 °C and diluted with ethyl acetate (40 mL). The organic layer was separated and washed with saturated potassium sodium tartrate solution (10.0 mL), water (10 mL), and brine (10 mL). Organic layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product (1.10 g) was purified over silica gel (60-120) using 70% ethyl acetate in zi-hexane as the mobile phase to afford the desired product (0.700 g, 77.2%).LCMS: (Method-C2): RT= 0.82 min, 279.16 m / z [M+l], 98.0%.Step 5HN^ / NH2N^ / O(3-(Pyridin-4-yl)-lH-pyrazol-4-yl)methanamine

[0468] In a 20 mL one-neck round-bottom flask under nitrogen atmosphere, 4 / V HC1 in dioxane (3.50 mL, 5 volume) was added drop wise to a solution of 2-methyl-N-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)propane-2-sulfinamide (0.700 g, 0.0057 mol) in methanol (3.50 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as mobile phase. The reaction was quenched with IN NaOH (4.00 mL) at 0 °C and the product extracted with ethyl acetateDocket No.: KMYXP001WO(30 mL x 2). The combined organic layers were separated and washed with water (30 mL) and brine (30 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product was purified over silica gel (60-120) using 5% methanol in dichloromethane as mobile phase to afford the desired product (0.280 g, 63.9%).LCMS: (Method-H2): RT= 3.40 min, 175.2 m / z [M-16], 95.5%.Step 62-Oxo-N-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)-2,3-dihydrobenzo[d]oxazole-5-sulfonamide

[0469] In a 10 mL round-bottom flask under nitrogen atmosphere, triethylamine (0.461 mL, 0.0032 mol) was added drop wise to a solution of (3-(pyridin-4-yl)-lH-pyrazol-4-yl)methanamine (0.280 g, 0.0016 mol) in dichloromethane (1.00 mL) at 25 °C. 2-Oxo-2,3-dihydrobenzo[d]oxazol-5-yl sulfurochloridite (0.412 g, 0.0017 mol) was added portion wise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (30 mL) and the product extracted with dichloromethane (70 mL x 3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.106 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.022 g, 8.60%). LCMS: (Method-C2): RT= 0.889 min, m / z 372.12 [M+l], 100%.HPLC: (Method-59): RT= 2.81 min, 95.84%.Example 1144-Ethoxy-N-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide

[0470] The title compound was prepared using the reaction conditions in Example 10 (Step 6), with (3-(pyridin-4-yl)-lH-pyrazol-4-yl)methanamine (0.150 g, 0.00086 mol) and 4-Docket No.: KMYXP001WOethoxybenzenesulfonyl chloride (0.228 g, 0.0010 mol) as reagents. The crude product (0.160 g) was purified by reversed phase prep HPLC, purification method-3, to afford the desired product as a white solid (0.106 g, 34.3%).LCMS: (Method-C2): RT= 0.997 min, m / z 359.52 [M+l], 100%.HPLC: (Method-59): RT= 3.28 min, 100%.Example 1154-Isopropoxy-N-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamideHN— S- / iiO

[0471] The title compound was prepared using the reaction conditions in Example 10 (Step 6), with (3-(pyridin-4-yl)-lH-pyrazol-4-yl)methanamine (0.150 g, 0.00086 mol) and 4-isopropoxybenzenesulfonyl chloride (0.242 g, 0.0010 mol) as reagents. The crude product (0.162 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.095 g, 29.6%).LCMS: (Method-C2): RT= 1.038 min, m / z 372.97 [M+l], 100%.HPLC: (Method-59): RT= 3.49 min, 96.28%.Example 1164-Propoxy-N-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamideHN— S- / H-J O

[0472] The title compound was prepared using the reaction conditions in Example 10 (Step 6), with (3-(pyridin-4-yl)-lH-pyrazol-4-yl)methanamine (0.150 g, 0.00086 mol) and 4-propoxybenzenesulfonyl chloride (0.242 g, 0.0010 mol) as reagents. The crude product (0.145 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.064 g, 20.0%).LCMS: (Method-C2): RT= 1.058 min, m / z 373.42 [M+l], 100%.HPLC: (Method-60): RT= 4.154 min, 99.83%.Example 117Docket No.: KMYXP001WOl-Ethyl-N-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)-lH-pyrazole-4-sulfonamide

[0473] The title compound was prepared using the reaction conditions in Example 10 (Step 6), with (3-(pyridin-4-yl)-lH-pyrazol-4-yl)methanamine (0.150 g, 0.00086 mol) and 1-ethyl-lH-pyrazole-4-sulfonyl chloride (0.201 g, 0.0010 mol) as reagents. The crude product (0.145 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.046 g, 16.1%).LCMS: (Method-C2): RT= 0.857 min, m / z 333.11 [M+l], 100%.HPLC: (Method-60): RT= 2.985 min, 98.49%.Example 1184-Ethyl-N-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide O HN-S- / H-J O

[0474] The title compound was prepared using the reaction conditions in Example 10 (Step 6), with (3-(pyridin-4-yl)-lH-pyrazol-4-yl)methanamine (0.100 g, 0.00057 mol) and 4-ethylbenzenesulfonyl chloride (0.141 g, 0.00068 mol) as reagents. The crude product (0.100 g) was purified on silica gel (60-120) using 3% methanol in dichloromethane as the mobile phase to afford the desired product as a white solid (0.023 g, 11.7%).LCMS: (Method-C2): RT= 1.012 min, m / z 343.20 [M+l], 100%.HPLC: (Method-59): RT= 3.45 min, 95.21%.Example 1194-Propyl-N-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamideHN-S / HODocket No.: KMYXP001WO

[0475] The title compound was prepared using the reaction conditions in Example 10 (Step 6), with (3-(pyridin-4-yl)-lH-pyrazol-4-yl)methanamine hydrochloride (0.100 g, 0.00047 mol) and 4-propylbenzenesulfonyl chloride (0.114 g, 0.00052 mol) as reagents. The crude product (0.150 g) was purified on silica gel (60-120) using 3% methanol in dichloromethane as the mobile phase to afford the desired product as a white solid (0.055 g, 32.5%).LCMS: (Method-C3): RT= 1.366 min, m / z 357.14 [M+l], 98.68%.HPLC: (Method-59): RT= 3.75 min, 95.01%.Example 1206-Methoxy-N-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)pyridine-3-sulfonamide

[0476] The title compound was prepared using the reaction conditions in Example 10 (Step 6), with (3-(pyridin-4-yl)-lH-pyrazol-4-yl)methanamine hydrochloride (0.108 g, 0.00047 mol) and 6-methoxypyridine-3-sulfonyl chloride (0.108 g, 0.00052 mol) as reagents. The crude product (0.147 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.080 g, 48.8%).LCMS: (Method-C2): RT= 0.902 min, m / z 347.28 [M+l], 100%.HPLC: (Method-59): RT= 2.88 min, 100%.Example 121N-((3-(Pyridin-4-yl)-lH-pyrazol-4-yl)methyl)chromane-6-sulfonamide

[0477] The title compound was prepared using the reaction conditions in Example 10 (Step 6), with (3-(pyridin-4-yl)-lH-pyrazol-4-yl)methanamine hydrochloride (0.120 g, 0.00052 mol) and chromane-6-sulfonyl chloride (0.159 g, 0.00068 mol) as reagents. The crude product (0.100 g) was purified on silica gel (60-120) using 3% methanol in dichloromethane as the mobile phase to afford the desired product as a white solid (0.035 g, 19.9%).LCMS: (Method-Cl): RT= 1.327 min, m / z 371.16 [M+l], 100%.Docket No.: KMYXP001WOHPLC: (Method-59): RT= 3.20 min, 100%.Example 122N-((3-(Pyridin-4-yl)-lH-pyrazol-4-yl)methyl)-2,3-dihydrobenzo[b][l,4]dioxine-6- sulfonamide

[0478] The title compound was prepared using the reaction conditions in example- 10 (Step-6), with (3-(pyridin-4-yl)-lH-pyrazol-4-yl)methanamine hydrochloride (0.100 g, 0.00047 mol) and 2,3-dihydrobenzo[b][l,4]dioxine-6-sulfonyl chloride (0.122 g, 0.00052 mol) as reagents. The crude product (0.147 g) was purified by reversed phase prep HPLC, purification method-2, to afford the desired product as a white solid (0.056 g, 31.7%).LCMS: (Method-Cl): RT= 1.300 min, m / z 373.16 [M+l], 100%.HPLC: (Method-60): RT= 3.516 min, 99.10%.Example 123N-((3-(Pyridin-4-yl)-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide

[0479] The title compound was prepared using the reaction conditions in Example 10 (Step 6), with (3-(pyridin-4-yl)-lH-pyrazol-4-yl)methanamine hydrochloride (0.100 g, 0.00047mol) and quinoline-6-sulfonyl chloride (0.118 g, 0.00052 mol) as reagents. The crude product (0.100 g) was purified on silica gel (60-120) using 5% methanol in dichloromethane as the mobile phase to afford the desired product as a white solid (0.021 g, 12.1%).LCMS: (Method-C3): RT= 1.229 min, m / z 366.20 [M+l], 100%.HPLC: (Method-59): RT= 2.73 min, 97.88%.Example 124A^-((3-(Pyridin-4-yl)-lH-pyrazol-4-yl)methyl)benzo[ ][l,3]dioxole-5-sulfonamideDocket No.: KMYXP001WO

[0480] In a 10 mL round-bottom flask under nitrogen atmosphere, triethylamine (0.081 mL, 0.00056 mol) was added drop wise to a solution of (3-(pyridin-4-yl)-l / / -pyrazol-4-yl)methanamine (0.050 g, 0.00028 mol) in dichloromethane (1.00 mL) at 25 °C. Benzo[d] [l,3]dioxole-5-sulfonyl chloride (0.063 g, 0.00028 mol) was added portion wise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (30 mL) and the product extracted with dichloromethane (70 mL x 3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SC>4 and evaporated under reduced pressure. The crude product (0.055 g) was purified by reversed phase prep HPLC, purification method-1, to afford the desired product as a white solid (0.010 g, 9.72%).LCMS: (Method-C3): RT= 1.27 min, m / z 359.2 [M+l], 100%.Example 1252,2-Dimethyl-2V-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)-2,3-dihydrobenzofuran-5- sulfonamide

[0481] In a 10 mL round-bottom flask under nitrogen atmosphere, triethylamine (0.136 mL, 0.00094 mol) was added drop wise to a solution of (3-(pyridin-4-yl)-l / / -pyrazol-4-yl)methanamine hydrochloride (0.100 g, 0.00047 mol) in dichloromethane (1.00 mL) at 25 °C. 2,2-Dimethyl-2,3-dihydrobenzofuran-5-sulfonyl chloride (0.117 g, 0.00047 mol) was added portion wise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction was quenched with water (30 mL) and the product extracted with dichloromethane (70 mL x 3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and evaporated under reduced pressure. The crude product (0.145 g) was purified by reversed phase purification, using 0.1% ammonia in water and 30% acetonitrile as a mobileDocket No.: KMYXP001WOphase and column (Cl 8 spherical, 40-60 pm, 100A, 12g) on a CombiFlash® to afford the desired product as a white solid (0.025 g, 13.7%).LCMS: (Method-C3): RT= 1.321 min, m / z 385.13 [M+l], 100%.Example 1262-(Ethylamino)-A-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)thiazole-5-sulfonamideA-(5-(A-((3-(Pyridin-4-yl)-lH-pyrazol-4-yl)methyl)sulfamoyl)thiazol-2-yl)acetamide

[0482] In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, trimethylamine (0.447 mL, 0.0034 mol) was added dropwise to a solution of (3-(pyridin-4-yl)-l / / -pyrazol-4-yl)methanamine (0.200 g, 0.0001 mol) in dichloromethane (2.00 mL) at 25°C. 2-Acetamidothiazole-5-sulfonyl chloride (0.276 g, 0.0001 mol) was added portionwise at 0°C. The reaction mixture was stirred at 25°C for Ih. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane. The reaction mixture was quenched with water (30 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude product (0.400 g) was purified over silica gel (40-60) using 10% methanol in dichloromethane as the mobile phase to afford the desired product as a white solid (0.310 g, 71.3%).LCMS: (Method-C3): RT= 1.210 min, m / z 379.21 [M+l], 85.5%.Step 2Docket No.: KMYXP001WO2-(Ethylamino)-A-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)thiazole-5-sulfonamide

[0483] In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, I A / lithium aluminum hydride in THF (1.53 mL, 0.0001 mol) was added dropwise to a solution of N-(5-(N-((3-(pyridin-4-yl)-l / / -pyrazol-4-yl)methyl)sulfamoyl)thiazol-2-yl)acetamide (0.290 g, 0.0007 mol) in dry THF (2.90 mL) at -78°C. The reaction mixture was stirred for 3h at the same temperature. Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as the mobile phase. The reaction was quenched with water (5 mL) followed by 10% NaOH aqueous solution (5.00 mL) was added dropwise at 0°C and stirred for 15 minutes then diluted with ethyl acetate (30 mL) and filtered. The organic layer was separated and washed with brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure to afford a crude product. The crude product (0.250 g) was purified by reversed phase purification, using 0.1% ammonia in water and 30% acetonitrile as a mobile phase and column (Cl 8 spherical, 40-60 pm, 100A, 12g) on CombiFlash*', to afford the desired product as a white solid (0.023 g, 8.24%).LCMS: (Method-C2): RT= 0.880 min, m / z 365.19 [M+l], 100%.Example 1274-Ethynyl-A-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide4-Bromo-A-((5-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamideDocket No.: KMYXP001WO

[0484] In a 25 mL one-neck round-bottom flask under nitrogen atmosphere, 4-bromobenzenesulfonyl chloride (0.880 g, 0.0034 mol) was added portionwise to a solution of (5-(pyridin-4-yl)-lH-pyrazol-4-yl)methanamine (0.805 g, 0.0028 mol) and triethylamine (0.500 g, 0.0057 mol) in dichloromethane (5.00 mL) at 0°C. The reaction mixture was stirred for Ih at 25°C. Completion of reaction was confirmed by TLC using 70% ethyl acetate in n-hexane as a mobile phase. The reaction was quenched with ice cold water (15 mL) and the product extracted with ethyl acetate (20 mL x 2). The combined organics were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. Crude product (0.990 g) was purified by using silica gel (60-120) and 70% ethyl acetate in zi-hexane as a mobile phase to afford a desired product (0.250 g, 22.15%).LCMS: (Method-C2): RT= 1.01 min, m / z 395.00 [M+2], 99.41%.Step 2o-s— < y — TMSII \ / O ' — 'A^-((5-(Pyridin-4-yl)-lH-pyrazol-4-yl)methyl)-4-((trimethylsilyl)ethynyl)benzenesulfonamide

[0485] In a 30 mL sealed tube under nitrogen atmosphere, 4-bromo-N-((5-(pyridin-4-yl)-l / / -pyrazol-4-yl) methyl) benzenesulfonamide (0.200 g, 0.0005 mol) was dissolved in THF (2.00 mL) at 25°C. After 5 minutes stirring, MN-Diisopropylethylamine (DIPEA) (0.194 mL, 0.145 g, 0.0011 mol), followed by ethynyltrimethylsilane (0.075 g, 0.0007 mol), were added at 25°C, and the reaction mixture was degassed with argon for 15 minutes. The mixture was then treated with Cui (0.005 g, 0.00003 mol) and Pd(PPh3)2Cl2(0.022 g, 0.00003 mol) at 25°C, and the reaction mixture was stirred at 80°C for 12h. Completion of reaction was confirmed by TLC using 70% ethyl acetate in zi-hexane as a mobile phase. The reaction was quenched with ice cold water (5 mL) and the product extracted with ethyl acetate (10 mL x 3). The combined organics were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, and evaporated under reduced pressure. Crude product (0.210 g) was purified over silica gel (60- 120) using 70% ethyl acetate in zi-hexane as a mobile phase to afford a desired product (0.090 g, 43.1%).LCMS: (Method-C2): RT= 1.21 min, / z 411.3 [M+l], 82%.Step 3Docket No.: KMYXP001WO4-Ethynyl-A^-((3-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)benzenesulfonamide

[0486] In a 10 mL one-neck round-bottom flask under nitrogen atmosphere, potassium carbonate (0.045 g, 0.0003 mol) was added portionwise to a solution of (N-((5-(pyridin-4-yl)-lH-pyrazol-4-yl)methyl)-4-((trimethylsilyl)ethynyl)benzenesulfonamide (0.090 g, 0.0002 mol) in methanol (1.80 mL) at 0°C. The reaction mixture was stirred at 25 °C for 2h.Completion of reaction was confirmed by TLC using 10% methanol in dichloromethane as a mobile phase. The reaction was quench...

Claims

Docket No.: KMYXP001WOCLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a salt or tautomer thereofR3R1aR1bFormula (I)wherein,L is chosen from -SO2- and cycloprop- 1,1 -diyl;each of A, B, and D is independently selected from N, NR4, O, S, and CR5; provided that at least one of A, B, and D is N or NR4; andno more than one of A, B, and D is O or S;Rlaand Rlbare independently selected from H, deuterium, and Ci-C4alkyl;R2is Ci-C6alkyl or -L^R9;L1is absent or chosen from Ci-Cealkylene and C2-ealkenylene;R9is aryl, heteroaryl, or Cs-Cscycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 groups independently chosen from Ci-Cealkyl, Ci-Cealkoxy, haloalkyl, haloalkoxy, alkynyl, aryl, aryl(Ci-C6alkyl), benzyl, aryloxy, benzyloxy, heteroaryl, heteroaryl(Ci-Cealkyl), heteroaryloxy, -C(CH₃)₂OH, -CO2R7, -CH2CO2R7, - C(O)N(R7)2, -N(R7)2, -O(CH2)nR7, oxo, cyano, and halo;n is chosen from 1, 2, or 3;R3is a 5- or 6-membered aryl or heteroaryl, each of which is optionally substituted with one or two groups independently chosen from halogen, hydroxy, and Ci-Cealkyl;R4is H or Ci-Cealkyl;R5is H or Ci-Cealkyl; andeach R7is independently selected from H, Ci-Cealkyl, Ci-Cealkoxy, -N(CH₃)₂, and -C(O)N(CH₃)₂; or two R7on the same N atom are taken together with the N atom to which they are attached to form an N-containing heterocycle.

2. The compound of any one of the preceding claims, or a salt or tautomer thereof, wherein L is cycloprop- 1,1 -diyl.

3. The compound of claim 2, or a salt or tautomer thereof, wherein R2is L!-R9and L1is absent.Docket No.: KMYXP001WO4. The compound of claim 3, or a salt or tautomer thereof, wherein R9is phenyl optionally substituted with 1 or 2 groups independently chosen from halogen and Ci-Cealkoxy.

5. The compound of claim 4, or a salt or tautomer thereof, wherein R9is phenyl optionally substituted with methoxy, ethoxy, propoxy, or chloro.

6. The compound of claim 5, or a salt or tautomer thereof, wherein R9is phenyl, 3- methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-chlorophenyl, 3- chlorophenyl, or 2 -chlorophenyl.

7. The compound of claim 1, or a salt or tautomer thereof, wherein L is -SO2-.

8. The compound of claim 7, or a salt or tautomer thereof, wherein R2is Ci-Cealkyl.

9. The compound of claim 8, or a salt or tautomer thereof, wherein R2is methyl, ethyl, or propyl.

10. The compound of claim 7, or a salt or tautomer thereof, wherein R2is -L!-R9and L1is -CH2-, -CH2CH2-, or -CH=CH-.

11. The compound of claim 10, or a salt or tautomer thereof, wherein L1is -CH2- or -CH=CH-.

12. The compound of claim 11, or a salt or tautomer thereof, wherein R9is phenyl optionally substituted with methoxy, ethoxy, propoxy, butoxy, chloro, fluoro, phenoxy, benzyloxy, methyl, (dimethylamino)ethoxy, 2-methoxyethoxy, cyano, ethynyl, carboxy, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 2-hydroxypropyl, and imidazolyl.

13. The compound of claim 12, or a salt or tautomer thereof, wherein R9is phenyl.

14. The compound of claim 7, or a salt or tautomer thereof, wherein R2is -L!-R9and L1is absent.

15. The compound of claim 14, or a salt or tautomer thereof, wherein R9is aryl or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 groups independently chosen from Ci-Cealkyl, Ci-Cealkoxy, haloalkyl, haloalkoxy, Ci-Cethioalkyl, alkynyl, aryl, aryl(Ci- Cealkyl), benzyl, aryloxy, benzyloxy, heteroaryl, heteroaryl(Ci-C6alkyl), heteroaryloxy, - C(CH3)2OH, -CO2R7, -CH2CO2R7, -C(O)N(R7)2, -N(R7)2, -O(CH2)nR7, oxo, cyano, and halo.

16. The compound of claim 15, or a salt or tautomer thereof, wherein R9is phenyl optionally substituted with 1, 2, or 3 groups independently chosen from Ci-Cealkyl, Ci-Cealkoxy, haloalkyl, haloalkoxy, aryl(Ci-C6alkyl), alkynyl, aryloxy, benzyloxy, heteroaryl, heteroaryl(Ci-C6alkyl), heteroaryloxy, -C(CH₃)₂OH, -CO2R7, -CH2CO2R7, -C(O)N(R7)2, - N(R7)2, -O(CH2)nR7, cyano, and halo.

17. The compound of claim 16, or a salt or tautomer thereof, wherein R9is phenyl optionally substituted with 1, 2, or 3 groups independently chosen from methoxy, ethoxy, propoxy,Docket No.: KMYXP001WOisopropoxy, butoxy, trifluoromethoxy, thiomethyl, chloro, fluoro, methyl, ethyl, propyl, trifluoromethyl, phenoxy, benzyloxy, pyridinyloxy, methyl, ethynyl, (dimethylamino)ethoxy, 2-methoxyethoxy, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 2-hydroxypropyl, methyltriazole, dimethyloxazolyl, and imidazolyl.

18. The compound of claim 17, or a salt or tautomer thereof, wherein R9is chosen from phenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-ethylphenyl, 4- propylphenyl, 4-methylsulfylphenyl, 4-chlorophenyl, 4-bromophenyl, 4- trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-cyano-4-methoxyphenyl, 4- ethynylphenyl, 4-(2-hydroxyethyl)phenyl, 4-(prop-l-yn-l-yl)phenyl, or 4-(3-methylbut-l-yn- l-yl)phenyl..

19. The compound of claim 17, or a salt or tautomer thereof, wherein R9is phenyl substituted with 4H-imidazol-4-yl.

20. The compound of claim 15, or a salt or tautomer thereof, wherein R9is pyridinyl or pyrimidinyl, each of which is optionally substituted with methoxy, methylamino, dimethylamino, ethyl(methyl)amino, and pyrrolidinyl.

21. The compound of claim 20, or a salt or tautomer thereof, wherein R9is pyridin-3-yl or pyrimidin-5-yl, each of which is optionally substituted with methoxy, methylamino, dimethylamino, ethyl(methyl)amino, and pyrrolidinyl.

22. The compound of claim 15, or a salt or tautomer thereof, wherein R9is pyrrolyl, imidazolyl or pyrazolyl, each of which is optionally substituted with one or two groups independently chosen from methyl, ethyl, benzyl, phenyl, pyridinyl, and pyrimidinyl.

23. The compound of claim 22, or a salt or tautomer thereof, wherein R9isoptionally substituted with one or two methyl groups.

24. The compound of claim 22, or a salt or tautomer thereof, wherein R9is\^NH optionally substituted with methyl, ethyl, phenyl, benzyl, pyridinyl, or pyrimidinyl.

25. The compound of claim 22, or a salt or tautomer thereof, wherein R9isoptionally substituted with pyridinyl.Docket No.: KMYXP001WO26. The compound of claim 15, or a salt or tautomer thereof, whereinU and V are independently O, S, NRC, or CH2; andeach Rcis independently selected from H, -CH3, or -CH2CH3;wherein R9is optionally substituted with one or two groups independently chosen from oxo and methyl.

27. The compound of claim 26, or a salt or tautomer thereof, wherein R9is chosen from28. The compound of claim 15, or a salt or tautomer thereof, whereinY is O, S, or NRb, and Y1is CRbor N;or Y is CRbor N, and Y1is O, S, or NRb; andeach Rbis independently selected from H, -CH3, or -CH2CH3.

29. The compound of claim 28, or a salt or tautomer thereof, wherein R9is chosen from30. The compound of claim 7, or a salt or tautomer thereof, wherein R2is 2,3- dihydrobenzo[b][l,4]dioxinyl, chromanyl, phenyl, thiazolyl, benzo[r / ][ 1,3]dioxolyl, 2,3- dihydrobenzofuranyl, 2-oxo-2,3-dihydrobenzo[r / ]oxazolyl, pyrrolyl, pyridyl, pyrimidyl, pyrazyl, diazolyl, indolyl, indazolyl, benzimidazolyl, imidazolyl, quinolinyl, isoquinolinyl,Docket No.: KMYXP001WOquinoxalinyl, benzothiazolyl, 3-oxo-dihydrobenzo[b][l,4]thiazinyl, or pyrazolyl, each of which is optionally substituted with one or two groups independently chosen from halogen, Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Cefluoroalkoxy, cyano, Ci-Cehydroxyalkyl, methylcarboxyl, carbamoyl, Ci-Cealkylamino, Ci-Cethioalkyl, Ci-Cealkoxy, and C2- Ceethynyl.

31. The compound of claim 30, or a salt or tautomer thereof, wherein R2is phenyl, which is optionally substituted with one or two groups independently chosen from halogen, Ci- Cealkyl, Ci-Cefluoroalkyl, Ci-Cefluoroalkoxy, cyano, Ci-Cehydroxy alkyl, Ci-Cethioalkyl, Ci-Cealkoxy, and C2-Ceethynyl.

32. The compound of claim 31, or a salt or tautomer thereof, wherein R2is phenyl, 4- methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-ethylphenyl, 4- propylphenyl, 4-methylsulfylphenyl, 4-chlorophenyl, 4-bromophenyl, 4- trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-cyano-4-methoxyphenyl, 4- ethynylphenyl, 4-(2-hydroxyethyl)phenyl, 4-(prop-l-yn-l-yl)phenyl, or 4-(3-methylbut-l-yn- l-yl)phenyl.

33. The compound of claim 30, or a salt or tautomer thereof, wherein R2is 2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl, chroman-6-yl, 2,3-dihydrobenzo[b][l,4]dioxin-6-yl, 2,3- dihydrobenzofuran-5-yl, 2,2-dimethyl-2,3-dihydrobenzofuran-5-yl, benzo[d][l,3]dioxol-5-yl, quinolin-6-yl, 3-oxo-dihydrobenzo[b][l,4]thiazinyl, or 2-(ethylamino)thiazol-5-yl.

34. The compound of claim 30, or a salt or tautomer thereof, wherein R2is thiazolyl, pyrrolyl, pyridyl, quinolinyl, benzothiazolyl, or pyrazolyl, each of which is optionally substituted with one or two groups independently chosen from Ci-Cealkyl, Ci-Cehydroxyalkyl, methylcarboxyl, carbamoyl, Ci-Cealkylamino, and Ci-Cealkoxy.

35. The compound of claim 34, or a salt or tautomer thereof, wherein R2is lH-pyrazol-4-yl, pyridin-3-yl, quinolin-6-yl, benzothiazol-5-yl, pyrrol-4-yl, or thiazol-5-yl, each of which is optionally substituted with one or two groups independently chosen from ethyl, methoxy, methyl, methylcarboxyl, carbamoyl, 2-hydroxypropanyl, and ethylamino.

36. The compound of claim 30, or a salt or tautomer thereof, wherein R2is 1 -ethyl- lH-pyrazol-4- yl, 6-methoxypyridin-3-yl, quinolin-6-yl, benzothiazol-5-yl, l-methyl-2-methylcarboxyl- pyrrol-4-yl, 1 -methyl-2-carbamoyl-pyrrol-4-yl, 1 -methyl-2-( 1 -hydroxy- 1, 1 -dimethyl- methyl)-pyrrol-4-yl, or 2-(ethylamino)thiazol-5-yl.

37. The compound of any one of claims 1-36, or a salt or tautomer thereof, whereinDocket No.: KMYXP001WORlaand Rlbare independently selected from H, D and -CH3.

38. The compound of claim 37, or a salt or tautomer thereof, wherein Rlaand Rlbare H.

39. The compound of any one of claims 1-38, or a salt or tautomer thereof, wherein A is NR4, B is N, and D is CR5.

40. The compound of any one of claims 1-38, or a salt or tautomer thereof, wherein A is N, B is NR4, and D is CR5.

41. The compound of any one of claims 1-38, or a salt or tautomer thereof, wherein A is N, B is CR5, and D is O, S, or NR4.

42. The compound of any one of claims 1-41, or a salt or tautomer thereof, wherein R4is H or - CH3.

43. The compound of claim 42, or a salt or tautomer thereof, wherein R4is -CH3.

44. The compound of claim 42, or a salt or tautomer thereof, wherein R4is H.

45. The compound of any one of claims 1-44, or a salt or tautomer thereof, wherein R5is H or - CH3.

46. The compound of claim 45, or a salt or tautomer thereof, wherein R5is -CH3.

47. The compound of claim 45, or a salt or tautomer thereof, wherein R5is H.

48. The compound of any one of claims 1-41, or a salt or tautomer thereof, wherein Rla, Rlb, R4, and R5are H.

49. The compound of any one of claims 1-38, or a salt or tautomer thereof, whereinB'N N50. The compound of claim 49, or a salt or tautomer thereof, wherein51. The compound of any one of claims 1-50, or a salt or tautomer thereof, wherein R3is chosen from thienyl, furanyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, and thiadiazolyl, each of which is optionally substituted with one or two groups independently chosen from OH, F, Cl, Br, and -CH3.Docket No.: KMYXP001WO52. The compound of claim 51, or a salt or tautomer thereof, wherein R3is chosen fromSG'Noptionally substituted with Cl or -CH3.

53. The compound of claim 52, or a salt or tautomer thereof, wherein R3is chosen fromN 1 SQNS-54. The compound of claim 53, or a salt or tautomer thereof, wherein R3is55. The compound of any one of claims 1-50, or a salt or tautomer thereof, wherein R3is chosen from phenyl, pyridinyl, pyridazinyl, and pyrimidinyl, each of which is optionally substituted with one or two groups independently chosen from halogen and hydroxy.

56. The compound of claim 55, or a salt or tautomer thereof, wherein R3is phenyl, pyridin-4-yl, pyridin-3-yl, pyridazin-4-yl, pyrimidin-4-yl, and pyrimidin-5-yl, each of which is optionally substituted with one or two groups independently chosen from halogen and hydroxy.

57. The compound of claim 56, or a salt or tautomer thereof, wherein R3is phenyl, 4- fluorophenyl, pyridin-4-yl, pyridin-3-yl, 6-hydroxy-pyridin-3-yl, pyridazin-4-yl, pyrimidin-4- yl, and pyrimidin-5-yl.

58. The compound of claim 1, or a salt or tautomer thereof, having structural Formula (II):HN-S-R\\ / II90Docket No.: KMYXP001WO59. The compound of claim 58, or a salt or tautomer thereof, wherein R3is chosen from pyridinyl, isothiazolyl, furanyl, and pyrimidinyl, each of which is optionally substituted with one or two groups chosen from methyl and fluoro.

60. The compound of claim 58 or 59, or a salt or tautomer thereof, wherein R3is chosen fromanci.

61. The compound of any one of claims 58 to 60, or a salt or tautomer thereof, wherein R9is phenyl optionally substituted with one or two groups chosen from alkyl and alkoxy.

62. The compound of any one of claims 58 to 61, or a salt or tautomer thereof, wherein R9is chosen from 4-ethoxyphenyl, 4-methoxyphenyl, and 4-ethylphenyl.

63. The compound of claim 1, wherein the compound of Formula (I) is chosen fromDocket No.: KMYXP001WODocket No.: KMYXP001WODocket No.: KMYXP001WODocket No.: KMYXP001WODocket No.: KMYXP001WODocket No.: KMYXP001WOthereof.

64. The compound of claim 1, wherein the compound of Formula I is chosen fromDocket No.: KMYXP001WODocket No.: KMYXP001WODocket No.: KMYXP001WO65. A pharmaceutical formulation comprising a compound as recited in of any one of claims 1- 64, or a salt or tautomer thereof, together with a pharmaceutically acceptable carrier.

66. The pharmaceutical formulation of claim 65, wherein the pharmaceutical formulation is formulated for oral administration.

67. A feed supplement or medicated feed comprising ground dry vegetable- or animal-based feed, with or without additives such as proteins, vitamins, and minerals, and a compound as recited in any one of claims 1-64, or a salt or tautomer thereof.

68. A method of inhibiting myosin protein activity, comprising contacting a myosin protein with a compound as recited in any one of claims 1-64, or a salt or tautomer thereof, a pharmaceutical formulation as recited claim 65 or 66, or a feed supplement as recited in claim 67.

69. The method of claim 68, wherein the myosin protein is chosen from myosin-I, myosin- VI, myosin-XII, myosin-XIII, myosin-XIV, myosin-XXI, myosin-XXII, myosin-XXIII, and myosin-XXIV.

70. The method of claim 69, wherein the myosin-XIV protein is chosen from MyoA, MyoB, MyoC, MyoD, MyoE, and MyoH.

71. The method of claim 70, wherein the myosin-XIV protein is MyoA.

72. The method of claim 69, wherein the myosin-XXII protein is MyoF.

73. The method of claim 69, wherein the myosin-XXIII protein is chosen from MyoG, MyoJ, and MyoK.

74. The method of claim 69, wherein the myosin-XXIV protein is Myol.Docket No.: KMYXP001WO75. The method of any one of claims 68-74, wherein the myosin protein is expressed in a coccidial or cryptosporidial protozoa.

76. The method of claim 75, wherein the coccidial or cryptosporidial protozoa is chosen from Isospora spp., Eimeria spp., Sarcocystis spp., Cryptosporidium spp. and Neospora spp.

77. A method of treating or preventing coccidiosis or cryptosporidiosis in a subject that would benefit from modulation of coccidial protozoa myosin protein activity or cryptosporidial protozoa myosin protein activity, comprising administering to the subject in need thereof a compound as recited in any one of claims 1-64, or a salt or tautomer thereof, a pharmaceutical formulation as recited in claim 65 or 66, or a feed supplement as recited in claim 67.

78. The method of claim 77, wherein the subject in need thereof is pregnant, immunocompromised, infected, or any combination thereof.

79. The method of claim 77, wherein treating the coccidiosis or cryptosporidiosis comprises inhibiting coccidial protozoa growth or replication or cryptosporidial protozoa growth or replication.

80. The method of claim 79, wherein inhibiting the coccidial or cryptosporidial protozoa growth or replication comprises modulating parasite cytoskeletal proteins.

81. The method of claim 80, wherein modulating coccidial or cryptosporidial protozoa cytoskeletal proteins comprises inhibiting myosin ATPase activity.

82. The method of claim 80, wherein modulating coccidial or cryptosporidial protozoa cytoskeletal proteins comprises inhibiting actin turnover.

83. The method of claim 80, wherein modulating coccidial or cryptosporidial protozoa cytoskeletal proteins comprises modulating an interaction between myosin and actin.

84. The method of claim 77, wherein the coccidiosis comprises infection with Isospora spp., Eimeria spp., Sarcocystis spp., o Neospora spp.

85. The method of claim 84, wherein the Isospora spp. comprises I. canis, I. ohioensis, I.burrowsi, I. neorivolta, I. felis, or I. rivolta.

86. The method of claim 84, wherein the Eimeria spp. comprises E. tenella, E. brunetti, E. necatrix, E. maxima, or E. acervuline.

87. The method of claim 84, wherein the Neospora spp. comprises N. caninum.

88. A method of treating or preventing coccidiosis or cryptosporidiosis in a subject, comprising administering to a subject a compound as recited in any one of claims 1-64, or a salt orDocket No.: KMYXP001WOtautomer thereof, a pharmaceutical formulation as recited in claim 65 or 66, or a feed supplement as recited in claim 67, that selectively inhibits coccidial protozoa myosin activity or cryptosporidial protozoa myosin activity relative to subject myosin activity.

89. A method of preventing or reducing susceptibility to infection by a coccidial or cryptosporidial protozoa, comprisingadministering to a subject a compound as recited in any one of claims 1-64, or a salt or tautomer thereof, a pharmaceutical formulation as recited in claim 65 or 66, or a feed supplement as recited in claim 67, that selectively inhibits coccidial protozoa myosin activity or cryptosporidial protozoa myosin activity relative to subject myosin activity; and exposing the subject to the coccidial or cryptosporidial protozoa.

90. The method of claim 89, wherein the coccidial or cryptosporidial protozoa is in a sexual, asexual, sporozoite, merozoite, gamete or oocyst stage in its life cycle.

91. The method of any one of claims 88-90, wherein the coccidial or cryptosporidial protozoa myosin is MyoA.

92. The method of any one of claims 88-90, wherein the subject myosin is chosen from cardiac muscle myosin, skeletal muscle myosin, and smooth muscle myosin.

93. The method of any one of claims 88-90, wherein the compound selectively inhibits the coccidial or cryptosporidial protozoa myosin relative to the subject myosin by at least 2-fold.

94. The method of any one of claims 88-90, wherein the compound selectively inhibits the coccidial or cryptosporidial protozoa myosin relative to the subject myosin by at least 10- fold.

95. The method of any one of claims 88-90, wherein the compound selectively inhibits the coccidial or cryptosporidial protozoa myosin relative to the subject myosin by at least 100- fold.

96. A method of treating or preventing coccidiosis or cryptosporidiosis in a subject comprising administering a compound as recited in any one of claims 1-64, or a salt or tautomer thereof, a pharmaceutical formulation as recited in claim 65 or 66, or a feed supplement as recited in claim 67, that inhibits coccidial protozoa myosin ATPase activity or cryptosporidial protozoa myosin ATPase activity.

97. The method of claim 96, wherein the myosin is MyoA.

98. A poultry feed supplement or medicated poultry feed for control of coccidiosis in poultry, comprising ground dry vegetable- and / or animal-based poultry feed, with or withoutDocket No.: KMYXP001WOadditives such as proteins, vitamins, and minerals, and a coccidiostatically effective amount of a compound as recited in any one of claims 1-64, or a salt or tautomer thereof.

99. A feed additive composition for preventing or ameliorating coccidiosis, comprising a compound as recited in any one of claims 1-64, or a salt or tautomer thereof.

100. A pharmaceutical formulation for control of coccidiosis in poultry, comprising a coccidiostatically effective amount of a compound as recited in any one of claims 1-64, or a salt or tautomer thereof, and a pharmaceutically acceptable carrier.

101. The pharmaceutical formulation of claim 100, wherein the pharmaceutically acceptable carrier is water.

102. A cattle feed supplement or medicated cattle feed for control of cryptosporidiosis in cattle, comprising ground dry vegetable- and / or animal-based feed, with or without additives such as proteins, vitamins, and minerals, and a cryptosporidiostatically effective amount of a compound as recited in any one of claims 1-64, or a salt or tautomer thereof.

103. A feed additive composition for preventing or ameliorating cryptosporidiosis, comprising a compound as recited in any one of claims 1-64, or a salt or tautomer thereof, as an active ingredient.

104. A pharmaceutical formulation for control of cryptosporidiosis in cattle, comprising a cryptosporidiostatically effective amount of a compound as recited in any one of claims 1- 64, or a salt or tautomer thereof, and a pharmaceutically acceptable carrier.

105. A method of treating or preventing a disease caused by an Apicomplexa parasite in a subject, comprising administering to a subject a compound as recited in any one of claims 1-64, or a salt or tautomer thereof, a pharmaceutical formulation as recited in claim 65 or 66, or a feed supplement as recited in claim 67, that selectively inhibits Apicomplexa parasite myosin activity relative to subject myosin activity.

106. The method of claim 105, wherein the Apicomplexa parasite is a Babesia spp., an Eimeria spp., a Cryptosporidium spp., a Cystoisospora spp., a Theileria spp., or a Toxoplasma spp.

107. The method of claim 106, wherein the Babesia spp. is Babesia bovis, Babesia bigemina, Babesia canis, or Babesia caballi.

108. The method of claim 106, wherein the Cystoisospora spp. is Cystoisospora canis.

109. The method of claim 106, wherein the Theileria spp. is Theileria equi.

110. The method of claim 106, wherein the Toxoplasma spp. is Toxoplasma gondii.

111. The method of claim 106, wherein the Cryptosporidium spp. is C. hominis or C. parvum.Docket No.: KMYXP001WO112. The method of claim 105, wherein the disease caused by an Apicomplexa parasite is coccidiosis, cryptosporidiosis, babesiosis, piroplasmosis, cystoisosporiasis, or toxoplasmosis.

113. The method of claim 105, wherein the disease caused by an Apicomplexa parasite is poultry coccidiosis, small ruminant coccidiosis, cattle babesiosis, dog babesiosis, equine piroplasmosis, dog cystoisosporiasis, or cat toxoplasmosis.

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