Tricyclic ube2k modulators and methods for their use

Abstract

Provided are compounds of Formula (I): and pharmaceutically acceptable salts and compositions thereof, which are useful for treating neurological disorders.

Description

Docket No.: 119992-22820 UBE2K MODULATORS AND METHODS FOR THEIR USE RELATAPPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 528,459, filed July 24, 2023, the entire contents of which are incorporated herein by reference. BACKGROUND

[0002] Neurological disorders have become a large and increasing global burden with nearly one and six people suffering from a neurological disorder. Indeed, according to a 2017 study, neurological disorders are the world's largest cause of disability-adjusted life years (DALYs) or years of healthy life lost to due to death or disability.

[0003] Huntington’s disease (HD) is an inherited neurological disorder that causes the progressive breakdown (degeneration) of nerve cells in the brain. Most people with HD experience problems with thinking, behavior, and movements. Symptoms usually worsen over the course of 10 to 25 years and affect the ability to reason, walk, and talk. Currently, there is no treatment to stop or reverse HD, however there are some medications that can help keep symptoms under control.

[0004] The cause of HD arises from a polyglutamine (poly(Q)) triplet repeat expansion in the gene encoding the huntingtin (Htt) protein. The N-terminal region of Htt is characterized by a high incidence of post-translational modifications and is the source of modified fragments that are commonly found as intracellular and intranuclear aggregates. Htt is known to be ubiquitinated in its N-terminal region and suggested to play a role in multiple sub- cellular systems and pathways. Htt interacts with many proteins but one of particular interest is the E2 ubiquitin-conjugating enzyme UBE2K, which had previously been identified through a yeast two-hybrid screen as Huntingtin-interacting protein-2 (Hip2) and shown to be involved in the ubiquitination of Htt. SUMMARY

[0005] It has now been found that small molecule modulators allosterically targeting the function and activity of UBE2K demonstrate dose dependent decrease in the induction of chemical stressors in HD patient derived fibroblasts. See e.g., FIG. 1 where inventive compound 26 reversed epoxomicin induced cytotoxicity of Huntingtin fibroblast and rescued fibroblasts from cell death.

[0006] Provided herein, therefore, are UBE2K modulators having the Formula I: 1ME149145978v.1Docket No.: 119992-22820and pharmaceutically acceptable salts and compositions thereof, wherein R1, R2, p, Z1, Z2, R3, Y and Z are as described herein, and their use in treating various neurological disorders such as Huntington’s disease. The disclosed compounds and compositions modulate (e.g., inhibit) UBE2K and modified forms of UBE2K namely but not limited to mono ubiquitinated UBE2K, di,tri and tetra ubiquitinated UBE2K. BRIEFDESCRIPTION OF THEFIGURES

[0007] FIG. 1 shows the effects on mHTT containing HD subjects (HD fibroblasts) treated with epoxomicin and epoxomicin with compound 26. DETAILEDDESCRIPTION1. General Description of Compounds

[0008] Provided herein is a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein Z1and Z2are each independently N or CH; R1is (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, or –NRcRd, wherein two available hydrogen atoms on said halo(C1-C6)alkyl and halo(C1-C6)alkoxy may be taken together to which the carbon atoms they are attached to form a 3- to 6-membered cycloalkyl optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, halo(C1- C6)alkyl, (C1-C6)alkoxy, and halo(C1-C6)alkoxy; R2is CN, halo, OH, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, or halo(C1- C6)alkoxy; or R1and R2, when on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered oxygen containing heterocyclyl optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, and halo(C1- C6)alkyl; R3is hydrogen, (C1-C6)alkyl, or halo(C1-C6)alkyl; Y is CH2, -CHRa, -CRaRb, S, or SO; p is 0 or 1; 2ME149145978v.1Docket No.: 119992-22820 Raand Rbare each independently halo, (C1-C6)alkyl, or halo(C1-C6)alkyl; or Raand Rbtogether with the carbon atom they are bound for a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclyl, each of which are optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, (C1- C6)alkylOH, (C1-C6)alkylO(C1-C6)alkyl, and OH; Rcand Rdare each independently hydrogen (C1-C6)alkyl, halo(C1-C6)alkyl, (C1- C6)alkylO(C1-C6)alkyl, halo(C1-C6)alkylO(C1-C6)alkyl, (C1-C6)alkyl-O-halo(C1-C6)alkyl, halo(C1-C6)alkyl-O-halo(C1-C6)alkyl, or (C1-C6)alkylOH; or Rcand Rdtogether with the nitrogen atom they are bound form a 4- to 7-membered heterocyclyl optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, and oxo; Z is a tricyclic fused ring having the formula:ring A is aromatic; the wavy bond denotes the point of attachment to Y; X, X1, and X2are each, as valency permits, independently selected from -CR7, N, O, and S; the dotted line in ring B represents a single or double bond; R4and R5are each independently selected from hydrogen, (C1-C6)alkyl, halo(C1- C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, -S(C1-C6)alkyl, -SH, OH, (C3-C6)cycloalkyl, (C4-C7)heterocyclyl, and –NReRf, wherein said (C3-C6)cycloalkyl and (C4-C7)heterocyclyl are each optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, halo(C1- C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, and oxo; or R4and R5together at the carbon to which they are attached form =O or =S; R6is hydrogen or (C1-C6)alkyl when the dotted line in ring B is a single bond, or R6is absent when the dotted line in ring B is a double bond; d, d1, d2and d3are each independently selected from CR8and N; Reand Rfare each independently hydrogen, (C1-C4)alkyl, (C1-C4)alkylNH(C1- C4)alkyl, (C1-C4)alkylN[(C1-C4)alkyl]2, (C1-C4)alkylO(C1-C4)alkyl; R7is hydrogen or (C1-C6)alkyl; and R8is halogen, hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, CN, or OH. 2. Definitions 3ME149145978v.1Docket No.: 119992-22820

[0009] When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which is defined. For example, -NH(C1-C6)alkyl means that the point of attachment for this group is on the nitrogen atom.

[0010] The terms “halo” and “halogen” refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0011] The term “alkyl” when used alone or as part of a larger moiety, such as “haloalkyl”, means saturated straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1-4 carbon atoms, i.e., (C1-C4)alkyl.

[0012] “Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by –O-alkyl. For example, “(C1-C4)alkoxy” includes methoxy, ethoxy, proproxy, and butoxy.

[0013] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0014] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., but are not limited to –OCHCF2or –OCF3.

[0015] “Oxo” refers to the divalent function group =O, i.e., an oxygen atom connected to another atom (typically carbon or sulfur) by a double bond.

[0016] The term “heteroaryl” refers to an aromatic ring of the specified size (e.g., 5-, 6-, 7-, 8-, or 9-membered ring) containing 1 to 4 heteroatoms independently selected from N, O, and S. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Bi-cyclic heteroaryl include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Nonlimiting examples include indolyl, imidazopyridinyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, pyrazolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, etc. When specified, optional substituents on a heteroaryl group may be present on any substitutable position.

[0017] The term “heterocyclyl” refers to a saturated or partially unsaturated monocyclic ring of the specified size (e.g., 3-, 4-, 5-, 6-, or 7-membered ring) containing 1 to 4 heteroatoms independently selected from N, O, and S. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without 4ME149145978v.1Docket No.: 119992-22820 limitation, oxiranyl, thiiranyl, aziridinyl, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. When specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached.

[0018] The term “cycloalkyl” refers to a monocyclic hydrocarbon of the specified size (e.g., 3-, 4-, 5-, 6-, or 7-membered ring). Cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. When specified, optional substituents on a cycloalkyl group may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl is attached.

[0019] The disclosed compounds exist in various tautomeric forms and are part of the present disclosure. The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds / substituents resulting from at least one formal migration of a hydrogen atom and at least one change in valency. All such isomeric forms of such compounds are expressly included. Thus, when a compound herein is represented by a structural formula or designated by a chemical name herein, all other tautomeric forms which may exist for the compound are encompassed by the structural formula. This includes e.g., tautomers that may exist depending on if the dashed line in Ring B for the Group Z is a single or double bond. For example:the like.

[0020] The compounds described herein may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds described herein refer to non-toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of the present teachings with 5ME149145978v.1Docket No.: 119992-22820 acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.

[0021] The terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0022] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some aspects, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a particular organism, or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

[0023] The term “pharmaceutically acceptable” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat. 6ME149145978v.1Docket No.: 119992-22820

[0024] The term “effective amount” or “therapeutically effective amount” refers to an amount of a compound described herein that will elicit a biological or medical response of a subject e.g., a dosage of between 0.01 - 100 mg / kg body weight / day. 3. Compounds

[0025] In a first embodiment, provided are compounds having the Formula I, and pharmaceutically acceptable salts thereof, wherein the variables are as described above.

[0026] In a second embodiment, the compound of Formula I is of the Formula II:or a pharmaceutically acceptable salt thereof, wherein the variable are as described above for Formula I.

[0027] In a third embodiment, R3in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula I.

[0028] In a fourth embodiment, Z1and Z2in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, are each CH, wherein the remaining variables are as described above for Formula I or the third embodiment.

[0029] In a fifth embodiment, Y in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is CH2, wherein the remaining variables are as described above for Formula I or the third or fourth embodiment.

[0030] In a sixth embodiment, p in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is 0, wherein the remaining variables are as described above for Formula I or any one of the third to fifth embodiments.

[0031] In a seventh embodiment, R1in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, or –NRcRd; and Rcand Rdtogether with the nitrogen atom they are bound form a 5- to 6- membered heterocyclyl optionally substituted with 1 to 3 halo, wherein the remaining variables are as described above for Formula I or any one of the third to sixth embodiments. Alternatively, as part of a seventh embodiment, R1in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is (C1-C3)alkyl, halo(C1-C3)alkyl, (C1-C3)alkoxy, or –NRcRd; and Rcand Rdtogether with the nitrogen atom they are bound form a 5- to 6- membered nitrogen containing heterocyclyl optionally substituted with 1 to 3 halo, wherein 7ME149145978v.1Docket No.: 119992-22820 the remaining variables are as described above for Formula I or any one of the third to sixth embodiments. In another alternative, as part of a seventh embodiment, R1in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is OCF3, OCHF2, OCH3, CH3, pyrrolidinyl, or piperidinyl, wherein said pyrrolidinyl, or piperidinyl are optionally substituted with 1 to 3 halo, wherein the remaining variables are as described above for Formula I or any one of the third to sixth embodiments.

[0032] In an eighth embodiment, X in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is N, wherein the remaining variables are as described above for Formula I or any one of the third to seventh embodiments.

[0033] In a ninth embodiment, X1in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is CH or N, wherein the remaining variables are as described above for Formula I or any one of the third to eighth embodiments.

[0034] In a tenth embodiment, X2in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is CH, N, S, or O, wherein the remaining variables are as described above for Formula I or any one of the third to ninth embodiments.

[0035] In an eleventh embodiment, X in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is N, X1is N, and X2is CH; X is N, X1is N, and X2is N; X is N, X1is CH, and X2is S; or X is N, X1is CH, and X2is O, wherein the remaining variables are as described above for Formula I or any one of the third to tenth embodiments.

[0036] In a twelfth embodiment, d in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is N or –CR8, wherein the remaining variables are as described above for Formula I or any one of the third to eleventh embodiments.

[0037] In a thirteenth embodiment, d2in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is N or –CR8, wherein the remaining variables are as described above for Formula I or any one of the third to twelfth embodiments.

[0038] In a fourteenth embodiment, d1in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is –CR8, wherein the remaining variables are as described above for Formula I or any one of the third to thirteenth embodiments.

[0039] In a fifteenth embodiment, d3in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is –CR8, wherein the remaining variables are as described above for Formula I or any one of the third to fourteenth embodiments. 8ME149145978v.1Docket No.: 119992-22820

[0040] In a sixteenth embodiment, Z in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is selected from,remaining variables are as described above for Formula I or any one of the third to fifteenth embodiments. Alternatively, as part of a sixteenth embodiment, Z in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is selected fromFormula I or any one of the third to fifteenth embodiments.

[0041] In a seventeenth embodiment, R8in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is hydrogen or halo, wherein the remaining variables are as described above for Formula I or any one of the third to sixteenth embodiments. Alternatively, as part of a seventeenth embodiment, R8in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula I or any one of the third to sixteenth embodiments.

[0042] In an eighteenth embodiment, R4in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, (C1-C6)alkyl, (C1- C6)alkoxy, (C3-C6)cycloalkyl, halo(C1-C6)alkyl, –NReRf, -SH, -S(C1-C6)alkyl, (C4- C7)heterocyclyl, and (C1-C6)alkylN[(C1-C6)alkyl]2, wherein said (C4-C7)heterocyclyl is optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, halo(C1-C6)alkyl, 9ME149145978v.1Docket No.: 119992-22820 (C1-C6)alkoxy, and halo(C1-C6)alkoxy, wherein the remaining variables are as described above for Formula I or any one of the third to seventeenth embodiments. Alternatively, as part of an eighteenth embodiment, R4in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, (C1-C3)alkyl, (C1- C3)alkoxy, (C3-C4)cycloalkyl, halo(C1-C3)alkyl, –NReRf, -SH, -S(C1-C3)alkyl, (C5- C6)heterocyclyl, and (C1-C3)alkylN[(C1-C3)alkyl]2, wherein said (C5-C6)heterocyclyl is optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, wherein the remaining variables are as described above for Formula I or any one of the third to seventeenth embodiments. In another alternative, as part of an eighteenth embodiment, R4in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, methyl, ethyl, isopropyl, methoxy, cyclopropyl, CF3, NH2, N(CH3)2, NCH3(CH2CH3), -SH, SCH3, morpholino, piperidinyl, pyrrolidinyl, CH3NH(CH2)2N(CH3)2, CH3NH(CH2)2OCH3, and piperazinyl optionally substituted with methyl, wherein the remaining variables are as described above for Formula I or any one of the third to seventeenth embodiments.

[0043] In a nineteenth embodiment, R5in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula I or any one of the third to eighteenth embodiments.

[0044] In a twentieth embodiment, R6in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is selected from hydrogen and (C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the third to nineteenth embodiments. Alternatively, as part of a twentieth embodiment, R6in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is selected from hydrogen and methyl, wherein the remaining variables are as described above for Formula I or any one of the third to nineteenth embodiments.

[0045] In a twenty-first embodiment, R4and R5in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, together at the carbon to which they are attached form =O or =S, wherein the remaining variables are as described above for Formula I or any one of the third to seventeenth embodiments. Alternatively, as part of a twenty-first embodiment, R4and R5in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, together at the carbon to which they are attached form =S, wherein the remaining variables are as described above for Formula I or any one of the third to seventeenth embodiments. 10ME149145978v.1Docket No.: 119992-22820

[0046] Specific examples of compounds are provided in the EXEMPLIFICATION section and are included as part of a thirteenth embodiment herein. Pharmaceutically acceptable salts as well as the neutral forms of these compounds are also included.

[0047] Also provided herein are pharmaceutical compositions comprising a compound described herein; and a pharmaceutically acceptable carrier. 4. Uses, Formulation and Administration

[0048] Compounds and compositions described herein are generally useful for modulating the activity of UBE2K. In some aspects, the compounds and compositions described herein inhibit the activity of UBE2K.

[0049] In some aspects, the compounds and compositions described herein are useful in treating cancer. Thus, provided herein are methods of treating a neurological disorder, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising a disclosed compound or pharmaceutically acceptable salt thereof. Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a neurological disorder. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for use in treating a neurological disorder.

[0050] Neurological disorder treatable by the present methods include, but are not limited to Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Aneurysm, Back pain, Bell’s palsy, Birth defects of the brain and spinal cord, Brain injury, Brain tumor, Cerebral palsy, Chronic fatigue syndrome, Concussion, Dementia, Disc disease of neck and lower back, Dizziness, Epilepsy, Frontotemporal dementia, Guillain-Barré syndrome, Headaches and migraines, Huntington’s disease, Lewy body dementia, Mild cognitive impairment, Multiple sclerosis, Muscular dystrophy, Neuralgia, Neuropathy, Neuromuscular and related diseases, Parkinson’s disease, Primary progressive aphasia, Psychiatric conditions (severe depression, obsessive-compulsive disorder), Scoliosis, Seizures, Spinal cord injury, Spinal deformity and disorders, Spine tumor, Stroke, Sundown syndrome, Vascular dementia, and Vertigo. In one aspect, the neurological disorder treated herein is Huntington’s disease.

[0051] In certain aspects, a composition described herein is formulated for administration to a subject in need of such composition. Compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via 11ME149145978v.1Docket No.: 119992-22820 an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0052] A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the composition. EXEMPLIFICATION

[0053] Representative examples of the disclosed compounds are illustrated in the following non-limiting methods, schemes, and examples.

[0054] Synthesis of N-((5-ethylpyrazolo [1, 5-c] quinazolin-2-yl) methyl)-2- (trifluoromethoxy) benzamide (Compound 1):

[0055] Step 1: Synthesis of N-((1H-pyrazol-3-yl) methyl)-2- (trifluoro methoxy) benzamide.

[0056] To a stirred solution of 2-(trifluoro methoxy) benzoic acid (1) (25g, 0.121mmol) in DMF (250mL) at 0oC was added HATU (46.1g, 0.121), followed by (2H-pyrazol-3-yl) methanamine (11.7g, 0.1213) and DIPEA (39.1 g, 0.303mmol). Then the reaction was stirred at room temperature for 12h. The mixture was then diluted with water (2.5L) and extracted 12ME149145978v.1Docket No.: 119992-22820 with EtOAc (2 x 500mL). The combined organic layer was washed once with H2O (250mL), saturated NaHCO3 solution (250mL), and finally saturated NaCl solution (250mL). The organic layer was dried over Na2SO4and concentrated to obtain the crude product. It was then purified by flash column chromatography (eluent: 70% EtOAc / Pet ether) to afford N- ((1H-pyrazol-3-yl) methyl)-2-(trifluoro methoxy) benzamide (18.3g, 53.0 %) as off-white solid.1H NMR (400 MHz, DMSO) δ 12.69-12.58 (m, 1H), 8.92-8.82 (m, 1H), 7.76 – 7.50 (m, 3H), 7.49 – 7.27 (m, 2H), 6.15 (d, J = 12.1Hz, 1H), 4.42 (t, J = 11.1Hz, 2H). LC-MS m / z (M+H): 286.1.

[0057] Step 2: N-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) methyl)-2- (trifluoro methoxy) benzamide.

[0058] To a stirred solution of N-((1H-pyrazol-3-yl) methyl)-2-(trifluoro methoxy) benzamide (18.3g, 64.15mmol) in toluene (400mL) at room temperature was added 3,4- dihydro-2H-pyran (5.39 g, 64.1mmol). Then the mixture was heated at 80oC for 4h and concentrated. The residue was diluted with EtOAc (250mL), washed once with saturated NaHCO3 solution (100mL) and H2O (100mL). The organic layer was dried over Na2SO4 and concentrated. The crude product obtained was triturated with petroleum ether (200mL) and stirred for 12h, where the solid precipitated was filtered, dried under vacuum to afford N-((1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) methyl)-2-(trifluoro methoxy) benzamide (12.57g, 51.5 %) as off-white solid.1H NMR (400 MHz, DMSO) δ 8.87 (s, 1H), 7.80 (d, J = 2.2Hz, 1H), 7.57 (t, J = 7.0Hz, 2H), 7.46 – 7.38 (m, 2H), 6.20 (d, J = 2.2Hz, 1H), 5.32 (d, J = 10.3Hz, 1H), 4.38 (d, J = 5.9Hz, 2H), 3.90 (d, J = 11.0Hz, 1H), 3.67 – 3.52 (m, 1H), 2.07 (dd, J = 24.7, 11.0Hz, 1H), 1.98 – 1.80 (m, 2H), 1.65 (s, 1H), 1.51 (d, J = 3.5Hz, 2H); LC-MS m / z (M+H): 370.1.

[0059] Step 3: N-((5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) methyl)-2- (trifluoro methoxy) benzamide.

[0060] To a stirred solution of N-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) methyl)-2-(trifluoro methoxy) benzamide (18.2g, 49.30mmol) in dry THF (200mL) at -78oC was added 1.6M n-butyl lithium in hexane (6.31g, 98.61mmol) over a period of 10 min. Then the mixture was stirred at same temperature for 1h, followed by the addition of iodine (13.76g, 54.2mmol) in dry THF (200mL) over a period of 15min. After the complete addition of iodine, the reaction mixture was slowly allowed to warm up to -20oC over a period of 45 min. The reaction was then quenched with saturated NaHSO3 solution (200mL) and extracted with EtOAc (2 x 150mL). The combined organic layer was dried over Na2SO4, concentrated on rotavapor to get the crude compound. The crude compound was purified by 13ME149145978v.1Docket No.: 119992-22820 flash column chromatography (eluent: 20 % EtOAc + Pet ether) to N-((5-iodo-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazol-3-yl) methyl)-2-(trifluoro methoxy) benzamide (12.57g, 51.5 %) as off-white solid.1H NMR (400 MHz, DMSO) δ 8.91 (t, J = 5.6Hz, 1H), 7.63 – 7.53 (m, 2H), 7.46-7.41 (m, 2H), 6.43 (s, 1H), 5.33 (d, J = 9.8Hz, 1H), 4.36 (d, J = 5.6Hz, 2H), 3.90 (d, J = 10.9Hz, 1H), 3.61-3.58 (m, 1H), 3.56-3.53 (m, 1H), 2.31-2.22 (m, 1H), 1.97 (d, J = 12.3Hz, 1H), 1.83 (d, J = 12.1Hz, 1H), 1.67 (s, 1H), 1.50 (s, 2H); LC-MS m / z (M+H): 396.0.

[0061] Step 4: Synthesis of N-((5-(2-aminophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-3-yl) methyl)-2-(trifluoromethoxy) benzamide.

[0062] To a stirred solution of N-((5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) methyl)-2-(trifluoro methoxy) benzamide (6.64g, 13.40mmol) and (2-aminophenyl)boronic acid (2.20g, 16.08mmol) in 1,4-dioxane-water (61mL + 19mL ) was added Na2CO3 (3.55g, 33.49mmol). Then the mixture was degassed with argon for 10min and to it was added tetrakis(triphenylphosphine)palladium(0) (1.54g, 1.33mmol). The resultant mixture was heated at 100oC for 12h, then diluted with H2O (15mL) and extracted with EtOAc (2 x 50mL). The combined organic layer dried over Na2SO4 and concentrated. The crude product obtained was purified by flash column chromatography (eluent: 30% EtOAc + Hexane) to afford N-((5-(2-aminophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide as yellow gummy solid (4.6g, 74.5%). LC-MS m / z (M-H): 461.11.

[0063] Step-5: Synthesis of N-((5-ethylpyrazolo [1, 5-c] quinazolin-2-yl) methyl)-2- (trifluoromethoxy) benzamide.

[0064] To a stirred solution of N-((5-(2-aminophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-3-yl) methyl)-2-(trifluoromethoxy) benzamide (50mg, 0.108mmol) in DCM (5mL) at 0oC was added propionyl chloride (15.071mg, 0.162mmol), followed by TEA (32.72mg, 0.323mmol). Then the reaction was stirred at room temperature for 12h. It was then diluted with cold H2O (5mL), the organic layer was separated and dried over Na2SO4. Concentration and purification of the crude product by prep-TLC (eluent: 30% EtOAc in Hexane) afforded N-((5-ethylpyrazolo [1, 5-c] quinazolin-2-yl) methyl)-2-(trifluoromethoxy) benzamide as off- white solid (12.5mg, 27.93%).1H NMR (400 MHz, DMSO) δ 9.15 (s, 1H), 8.19 (d, J = 7.4Hz, 1H), 7.86 (d, J = 7.9Hz, 1H), 7.69 (t, J = 7.5Hz, 2H), 7.61 (dd, J = 13.5, 6.7Hz, 2H), 7.47 (dd, J = 17.4, 8.2Hz, 2H), 7.21 (s, 1H), 4.68 (d, J = 5.8Hz, 2H), 3.30 – 3.25 (m, 2H), 1.42 (t, J = 7.4Hz, 3H); LC-MS m / z (M)+: 414.9.

[0065] The following compounds were synthesized similarly to the above protocol. 14ME149145978v.1Docket No.: 119992-22820

[0066] Synthesis of N-(pyrazolo [1, 5-c] quinazolin-2-ylmethyl)-2-(trifluoromethoxy) benzamide (Compound 4):

[0067] Step 1: Synthesis of N-((5-(2-aminophenyl)-1H-pyrazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide.

[0068] To a stirred solution of N-((5-(2-aminophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-3-yl) methyl)-2-(trifluoromethoxy) benzamide (3.70g, 8.03mmol) in DCM (20mL) at 0oC was added HCl in 1,4-dioxane (4M, 30mL). Then the mixture was warmed up and stirred at room temperature for 12h. It was then concentrated and further co-distilled with DCM (2 x 25mL) to get the crude compound. The crude compound was diluted with H2O (25mL), basified with saturated NaHCO3 solution (25mL) and extracted with EtOAc (2 x 15 ME149145978v.1Docket No.: 119992-22820 25mL). The combined organic layer was dried over Na2SO4 and concentrated to afford N-((5- (2-aminophenyl)-1H-pyrazol-3-yl) methyl)-2-(trifluoromethoxy) benzamide as yellow gummy solid (4.75g); LC-MS m / z (M-H): 377.19.

[0069] Step 2: Synthesis of N-(pyrazolo [1, 5-c] quinazolin-2-ylmethyl)-2- (trifluoromethoxy) benzamide:

[0070] To a stirred solution of N-((5-(2-aminophenyl)-1H-pyrazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide (70mg, 0.186mmol) in acetonitrile (5mL) at room temperature was added triethylorthoformate (27.56mg, 0.186mmol). Then the reaction mixture was heated at 100oC for 2h and concentrated. The residue was treated with H2O (10mL) and extracted with EtOAc (2 x 10mL). The combined organic layer was dried over Na2SO4and concentrated. The crude product obtained was purified by prep-TLC (eluent: 50% EtOAc in Hexane) to afford N-(pyrazolo [1, 5-c] quinazolin-2-ylmethyl)-2-(trifluoromethoxy) benzamide as off-white solid (12mg, 16.69%).1H NMR (400 MHz, DMSO) δ 9.31 (s, 1H), 9.16 (s, 1H), 8.23 (d, J = 7.6Hz, 1H), 7.91 (d, J = 8.0Hz, 1H), 7.78 – 7.65 (m, 3H), 7.62-7.58 (m, 1H), 7.50-7.44 (m, 2H), 7.20 (s, 1H), 4.68 (d, J = 5.4Hz, 2H); LC-MS m / z (M)+: 386.9.

[0071] Synthesis of N-((5-methylpyrazolo [1, 5-c] quinazolin-2-yl) methyl)-2- (trifluoromethoxy) benzamide (Compound 5):

[0072] Step 1: Synthesis of N-((5-(2-acetamidophenyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-3-yl) methyl)-2-(trifluoromethoxy) benzamide.

[0073] To a stirred solution of N-((5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) methyl)-2-(trifluoro methoxy) benzamide (70mg, 0.141mmol) and (2-acetyl amino phenyl)boronic acid (30.35mg, 0.169mmol) in 1,4-dioxane-water (7mL+ 3mL) was added Na2CO3 (37.36mg, 0.352mmol). The resultant mixture was then degassed with argon for 10min and was added tetrakis(triphenylphosphine)palladium 0 (16.28mg, 0.014mmol). The resultant mixture was heated at 100oC for 12h, then diluted with H2O (10mL) and extracted with EtOAc (2 x 10mL). The combined organic layer was dried over Na2SO4 and concentrated to get the crude compound. It was then purified by flash column chromatography (eluent: 50 % EtOAc + Hexane) to afford N-((5-(2-acetamidophenyl)-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) methyl)-2-(trifluoromethoxy) benzamide as 16ME149145978v.1Docket No.: 119992-22820 yellow gummy solid (40mg, 56.45%).1H NMR (400 MHz, DMSO) δ 9.17 (s, 1H), 8.93 (t, J = 5.8Hz, 1H), 7.58 (t, J = 7.9Hz, 3H), 7.44 (dd, J = 14.1, 7.2Hz, 3H), 7.28 (d, J = 6.9Hz, 2H), 6.22 (s, 1H), 4.87 (d, J = 8.5Hz, 1H), 4.49 (dd, J = 15.2, 6.0Hz, 1H), 4.40 (dd, J = 15.3, 5.5Hz, 1H), 4.09 (q, J = 5.2Hz, 1H), 3.91 (d, J = 10.2Hz, 1H), 3.16 (d, J = 5.3Hz, 4H), 2.32 (s, 1H), 1.88 (s, 4H), 1.70 (d, J = 12.2Hz, 1H), 1.45 (s, 3H); LC-MS m / z (M+H): 502.9.

[0074] Step 2: Synthesis of N-((5-methylpyrazolo [1, 5-c] quinazolin-2-yl) methyl)-2- (trifluoromethoxy) benzamide.

[0075] To a stirred solution of N-((5-(2-acetamidophenyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-3-yl) methyl)-2-(trifluoromethoxy) benzamide (40mg, 0.079mmol) in DCM (5mL) at 0oC was added 1,4-dioxane-HCl (5mL). Then the reaction mixture was stirred at room temperature for 12h. It was then concentrated, diluted with cold H2O (5mL), basified with saturated NaHCO3 solution (5mL) and extracted with EtOAc (2 x10mL). The combined organic layer was dried over Na2SO4and concentrated to get the crude compound. It was then purified by prep-TLC (eluent: 40% EtOAc in Hexane) to afford N-((5-methylpyrazolo [1, 5- c] quinazolin-2-yl) methyl)-2-(trifluoromethoxy) benzamide as off-white solid (29.5mg, 93.27 %).1H NMR (400 MHz, DMSO) δ 9.16 (s, 1H), 8.18 (d, J = 7.8Hz, 1H), 7.84 (d, J = 7.6Hz, 1H), 7.70-7.66 (m, 2H), 7.63 – 7.56 (m, 2H), 7.47 (dd, J = 16.8, 8.3Hz, 2H), 7.21 (s, 1H), 4.68 (d, J = 5.7Hz, 2H), 2.88 (s, 3H); LC-MS m / z (M+H): 401.31.

[0076] The following compound was synthesized according to the protocol described above:

[0077] Synthesis of 2-(trifluoromethoxy)-N-((5-(trifluoromethyl) pyrazolo [1, 5-c] quinazolin-2-yl) methyl) benzamide (Compound 7): 17ME149145978v.1Docket No.: 119992-22820

[0078] To a stirred solution of N-((5-(2-aminophenyl)-1H-pyrazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide (50mg, 0.132mmol) in DCM (5mL) at 0oC was added trifluoroacetic anhydride (27.72mg, 0.131mmol), followed by TEA (33.33mg, 0.33mmol). Then the reaction mixture was stirred at room temperature for 4h. The mixture was then diluted with cold H2O (5mL), organic layer was separated, dried over Na2SO4and concentrated to obtain N-((5-(2-(2, 2, 2-trifluoroacetamido) phenyl)-1H-pyrazol-3-yl) methyl)-2-(trifluoromethoxy) benzamide as brown gummy solid (60mg). It was then dissolved in DCM (5mL) and to it was added HCl in 1,4-dioxane (5mL) and stirred at room temperature for 12h. The solvent was distilled off and the mixture was diluted with cold H2O (5mL), basified with saturated NaHCO3 solution (5mL) and extracted with EtOAc (2 x10mL). The combined organic layer was dried over Na2SO4and concentrated to get the crude compound. It was then purified by prep-TLC (eluent: 40% EtOAc in hexane) to afford 2-(trifluoromethoxy)-N-((5-(trifluoromethyl) pyrazolo [1, 5-c] quinazolin-2-yl) methyl) benzamide as off-white solid (12.5mg, 30.98%)NMR (400 MHz, DMSO) δ 9.23 (s, 1H), 8.37 (s, 1H), 8.06 (s, 1H), 7.84 (d, J = 3.7Hz, 2H), 7.67 (d, J = 11.8Hz, 1H), 7.61 (t, J = 6.5Hz, 1H), 7.56 – 7.41 (m, 2H), 7.40 (s, 1H), 4.71 (d, J = 5.7Hz, 2H); LC-MS m / z (M+H): 455.15.

[0079] Synthesis of N-((5-methylpyrazolo[1,5-c]pyrido[3,2-e]pyrimidin-2-yl)methyl)- 2-(trifluoromethoxy)benzamide (Compound 8):18ME149145978v.1Docket No.: 119992-22820

[0080] Step 1: Synthesis of N-((5-(2-aminopyridin-3-yl)-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy) benzamide.

[0081] To a stirred solution of N-[(5-iodo-1-tetrahydropyran-2-yl-pyrazol-3-yl)methyl]- 2-(trifluoromethoxy)benzamide (300mg, 0.60mmol) and (2-((tert-butoxycarbonyl) amino) pyridin-3-yl) boronic acid (216.24mg, 0.90mmol) in 1, 4 dioxane- H2O (10mL + 2.5mL) was added Na2CO3(192.6mg, 1.8mmol). To the resulting mixture, under argon atmosphere was added tetrakis(triphenylphosphine)palladium (0) (69.96mg, 0.04mmol) and the entire mixture was heated at 100oC for 12h. It was then partitioned between EtOAc (20mL) and water (10mL), the organic layer was separated, dried and evaporated. The resultant crude product was purified by flash column chromatography to afford the target compound as pale yellow solid (200mg, 71.62%). LC-MS (ESI): m / z 462.11 (M+H)+

[0082] Step 2: Synthesis of N-((5-(2-acetamidopyridin-3-yl)-1-acetyl-1H-pyrazol-3- yl) methyl)-2-(trifluoromethoxy) benzamide.

[0083] To a stirred solution of N-((5-(2-aminopyridin-3-yl)-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (60mg, 0.130) in anhydrous dichloromethane (10mL ) were added TEA (39.43mg, 0.39mmol) and acetyl chloride (8.1mg, 0.10mmol) and the resultant mixture was stirred at room temperature for 12h. The reaction mixture was then diluted with aqueous NaHCO3 solution (10mL) and extracted EtOAc (2 x 10mL). The combined organic layer was dried over Na2SO4and concentrated under vacuum to afford the target compound as pale-yellow solid (90mg).

[0084] Step-3: Synthesis of N-((5-methylpyrazolo[1,5-c]pyrido[3,2-e]pyrimidin-2- yl)methyl)-2-(trifluoromethoxy)benzamide.

[0085] To a stirred to solution of N-((5-(2-acetamidopyridin-3-yl)-1-acetyl-1H-pyrazol-3- yl) methyl)-2-(trifluoromethoxy) benzamide (90mg, 0.17mmol) in dichloromethane (5mL) at 00C was added HCl in 1, 4-dioxane (4.0M, 4mL). The resultant reaction mixture was stirred at room temperature for 12h. It was then diluted with aqueous NaHCO3solution (10mL) and extracted with DCM (2 x 10mL). The combined organic layer was dried over Na2SO4 and concentrated. The resultant crude product was purified by prep-TLC to afford the target product as off- white solid (25mg, 34.8%).NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.87 (d, J = 2.8Hz, 1H), 8.68 (d, J = 7.6Hz, 1H), 7.68-7.58 (m, 3H), 7.50-7.44 (m, 2H), 7.33 (s, 1H), 4.69 (d, J = 5.6Hz, 2H), 2.92 (s, 3H); LC-MS (ESI): m / z 401.9 (M+H)+

[0086] Synthesis of N-((5-methyl-[1, 2, 4] triazolo [1, 5-c] quinazolin-2-yl) methyl)-2- (trifluoromethoxy) benzamide (Compound 9): 19ME149145978v.1Docket No.: 119992-22820

[0087] Step 1: Synthesis of N-(cyanomethyl)-2-(trifluoromethoxy) benzamide.

[0088] To a stirred solution of 2-(trifluoromethoxy) benzoic acid (5g, 25mmol) in DMF (20mL) at 0oC was added of HATU (15.1 g, 39.8mmol), DIPEA (10.3 g, 79mmol) and 2- aminoacetonitrile.HCl (2.4g, 26mmol). The resulting reaction mixture was stirred at room temperature for 16h. The reaction mixture diluted with ice-cold water (50mL) and extracted with EtOAc (2 x 50mL). The organic layer was washed with ice-cold water (3 x 100mL), brine (2 x 100mL), dried over Na2SO4and concentrated. The crude product obtained was dissolved in diethyl ether (50mL) and then triturated with pentane (2 x 50mL), the solid precipitated was filtered, dried under vacuum to afford N-(cyanomethyl)-2- (trifluoromethoxy) benzamide (3.5g, Yield~58%) as off-white solid. LC-MS m / z (M-H): 245.2.

[0089] Step 2: Synthesis of N-((5-(2-nitrophenyl)-1H-1, 2, 4-triazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide.

[0090] To a stirred solution of N-(cyanomethyl)-2-(trifluoromethoxy) benzamide (300mg, 1.22mmol) in n-butanol at room temperature were added, 2-nitrobenzohydrazide (222.5mg, 1.22mmol) and K2CO3(84.8mg, 0.61mmol). The resultant mixture was stirred at 1650C under microwave condition for 1h. It was then diluted with water, and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product obtained was purified by flash column chromatography to afford the target compound as off-white solid. (70mg, 14%).1H NMR (400 MHz, DMSO): δ 14.22 (s, 1H), 9.11 (t, J = 5.6Hz, 1H), 7.99 (d, J = 8Hz, 1H), 7.84 (d, J = 8Hz, 1H), 7.75-7.70 (m, 2H), 20ME149145978v.1Docket No.: 119992-22820 7.65-7.58 (m, 2H), 7.48 (t, J = 5.6Hz, 1H), 7.42 (d, J = 8Hz, 1H), 4.56 (d, J = 5.6Hz, 2H); LC-MS m / z (M+H): 408.08.

[0091] Step 3: Synthesis of N-((5-(2-aminophenyl)-1H-1, 2, 4-triazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide.

[0092] To a stirred solution of N-((5-(2-nitrophenyl)-1H-1, 2, 4-triazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide (105mg, 0.25mmol) in methanol (20mL) was added Pd / C (105mg) and the resultant mixture was stirred at room temperature under hydrogen atmosphere for 12h. The mixture was filtered through a celite bed and washed with methanol. The filtrate obtained was dried over Na2SO4 and concentrated under vacuum to afford the target compound as brown solid.(30mg). LC-MS (ESI): m / z 378.1 (M+H).

[0093] Step 4: Synthesis of N-((5-(2-acetamidophenyl)-1-acetyl-1H-1, 2, 4-triazol-3- yl) methyl)-2-(trifluoromethoxy) benzamide.

[0094] A mixture of N-((5-(2-aminophenyl)-1H-1,2,4-triazol-3-yl)methyl)-2- (trifluoromethoxy) benzamide (30mg, 0.079mmol) in acetic anhydride (1mL) was stirred at 800C for 12h. The mixture was then diluted with ice-cold water and extracted with ethyl acetate. The organic layer was dried over MgSO4and concentrated under vacuum to afford the target compound as yellow viscous liquid (30mg). LC-MS (ESI): m / z 462.2 (M+H).

[0095] Step 5: Synthesis of N-((5-(2-acetamidophenyl)-1H-1, 2, 4-triazol-3-yl) methyl)-2-(trifluoromethoxy) benzamide.

[0096] To a stirred solution of N-((5-(2-acetamidophenyl)-1-acetyl-1H-1, 2, 4-triazol-3- yl) methyl)-2-(trifluoromethoxy) benzamide (100mg, 0.21mmol), in methanol (2mL) was added, K2CO3 (14.96mg, 0.10mmol) and the resultant mixture was stirred at 700C for 4h. The mixture was concentrated, then diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated under vacuum to afford the target compound as yellow viscous liquid. (50mg). LC-MS (ESI): m / z 420.1(M+H)+.

[0097] Step 6: Synthesis of N-((5-methyl-[1, 2, 4] triazolo [1, 5-c] quinazolin-2-yl) methyl)-2-(trifluoromethoxy) benzamide.

[0098] A mixture of N-((5-(2-acetamidophenyl)-1H-1, 2, 4-triazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide (80mg, 0.19mmol and HCl (4.0M in 1,4-dioxane, 4mL) was stirred at room temperature for 12h. The mixture was then basified with aqueous NH4CO3(10mL) and extracted with ethyl acetate (2 x 10mL). The combined organic layer was washed with brine (10mL), dried over Na2SO4 and concentrated. The crude product thus obtained was purified by prep-TLC to afford N-((5-methyl-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide as an off-white solid (16mg, 20.88%).1H NMR 21ME149145978v.1Docket No.: 119992-22820 (400 MHz, DMSO): δ 9.18 (t, J = 5.6Hz, 1H), 8.38(d, J = 8Hz, 1H), 7.99 (d, J = 8Hz, 1H), 7.92-7.88(m, 1H), 7.77 (t, J = 7.6Hz, 1H), 7.68-7.65 (m, 1H), 7.63-7.58 (m, 1H), 7.51-7.44 (m, 2H), 4.77(d, J = 5.6Hz, 2H), 2.92 (s 3H). LC-MS (ESI): m / z 402.1 (M+H)+.

[0099] Synthesis of N-[(5-methylpyrazolo[1,5-c]quinazolin-2-yl)methyl]-2- pyrrolidin-1-yl-benzamide (Compound 10):

[0100] Step 1: Synthesis of ethyl 4-(2-nitrophenyl)-2,4-dioxobutanoate.

[0101] To a stirred solution of 2-nitroacetophenone (10g, 60.60mmol) in dry THF (100mL) at -78oC was added a solution of LiHMDS (1M in THF, 121mL, 120mmol) and stirred at same temperature for 30 min. To the resultant solution was then added diethyl oxalate (9.73 g, 66.66mmol) and the mixture was warmed up and stirred at room temperature for 5h. The reaction was quenched with 2N HCl solution (50mL) and extracted with EtOAc (2 x 50mL). The combined organic layer was dried over Na2SO4and concentrated to obtain the crude product. It was then purified by flash column chromatography to afford ethyl 4-(2- nitrophenyl)-2,4-dioxobutanoate (8.0 g, 49.77 %) as pale yellow solid.1H NMR (400 MHz, CDCl3) δ 13.89 (s, 1H), 8.04 (d, J = 8.0Hz, 1H), 7.75 (t, J = 7.5Hz, 1H), 7.69 (dd, J = 11.0, 4.5Hz, 1H), 7.60 (d, J = 7.5Hz, 1H), 6.65 (s, 1H), 4.38 (q, J = 7.1Hz, 2H), 1.39 (t, J = 7.1Hz, 3H).

[0102] Step 2: Synthesis of ethyl 3-(2-nitrophenyl)-1H-pyrazole-5-carboxylate.

[0103] To a stirred to solution of ethyl 4-(2-nitrophenyl)-2,4-dioxobutanoate in acetic acid (150mL) was added hydrazine hydrate (25mL) and the reaction mixture was stirred at 22ME149145978v.1Docket No.: 119992-22820 room temperature for 16h. After the completion of reaction, it was quenched with ice cold water (300mL) and stirred for 15min. The precipitated solid was filtered and air dried to afford ethyl 3-(2-nitrophenyl)-1H-pyrazole-5-carboxylate (8.3 g, 84.19 %) as pale pink solid.1H NMR (400 MHz, CDCl3) δ 14.19 (brs, 1H), 7.88 (brs, 1H), 7.81 (brs, 1H), 7.73 (brs, 1H), 7.61 (brs, 1H), 7.09 (brs, 1H), 4.32 (q, J = 7.2Hz, 2H), 1.30 (t, J = 6.8Hz, 3H).

[0104] Step 3: Synthesis of ethyl 3-(2-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazole-5-carboxylate.

[0105] To a stirred to solution ethyl 3-(2-nitrophenyl)-1H-pyrazole-5-carboxylate (4g, 15.7mmol) in toluene (40mL) were added 3, 4-dihydro-2H-pyran (10mL) and TFA (catalytic). Then the reaction mixture was heated at 80oC for 4h and concentrated. The residue was then diluted with EtOAc (25mL), washed once with H2O (25mL) and saturated NaHCO3 solution (25mL). The organic layer was dried over Na2SO4 and concentrated to obtain the crude product. It was then purified by flash column chromatography to afford ethyl 3-(2-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylate as red liquid (2.5g, 47%).1H NMR (400 MHz, DMSO) δ 8.00 – 7.77 (m, 2H), 7.73 (t, J = 7.4Hz, 1H), 7.62 (t, J = 7.1Hz, 1H), 7.27 (s, 1H), 6.16 (d, J = 8.8Hz, 1H), 4.33 (q, J = 7.0Hz, 2H), 3.84 (d, J = 11.9Hz, 2H), 3.71 (s, 1H), 3.58 (s, 2H), 3.40 (s, 1H), 2.17 (d, J = 11.4Hz, 1H), 1.89 (d, J = 13.2Hz, 1H), 1.31 (t, J = 7.2Hz, 3H).

[0106] Step 4: Synthesis of ethyl 3-(2-aminophenyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazole-5-carboxylate.

[0107] To a stirred to solution ethyl 3-(2-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazole-5-carboxylate (1 g, 2.897mmol) in methanol (10mL) was added 10% Pd-C (200mg, 20%). Then the reaction mixture was stirred under hydrogen atmosphere at 50Psi for 4h at room temperature. The reaction mixture was then filtered through celite and the filtrate was concentrated to obtain ethyl 3-(2-aminophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5- carboxylate (5) as off-white solid (600mg, 66%).1H NMR (400 MHz, DMSO) δ 7.58 (d, J = 7.0Hz, 1H), 7.38 (s, 1H), 7.03 (t, J = 7.2Hz, 1H), 6.75 (d, J = 8.1Hz, 1H), 6.57 (t, J = 7.1Hz, 1H), 6.24 (s, 2H), 6.13 (d, J = 9.3Hz, 1H), 4.33 (q, J = 6.4Hz, 2H), 3.93 (d, J = 10.5Hz, 1H), 3.60 (s, 1H), 2.30 (d, J = 12.1Hz, 1H), 1.98 (s, 2H), 1.68 (s, 1H), 1.54 (s, 2H), 1.33 (t, J = 7.1Hz, 3H).

[0108] Step 5: Synthesis ethyl 3-(2-acetamidophenyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazole-5-carboxylate.

[0109] To a stirred to solution ethyl 3-(2-aminophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazole-5-carboxylate (600mg, 1.904mmol) in DCM (10mL) at 0oC was added TEA 23ME149145978v.1Docket No.: 119992-22820 (0.8mL, 5.712mmol), followed by acetyl chloride (220mg, 2.85mmol). The resultant mixture was stirred at room temperature for 5h. It was then quenched with H2O (10mL) and extracted with DCM (2x 10mL). The combined organic layer was dried over Na2SO4and concentrated to obtain the crude compound. It was then purified by flash column chromatography(eluting 35% EtOAc in hexane) to afford ethyl 3-(2-acetamidophenyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazole-5-carboxylate (6) as off white solid (500mg, 73.47%).1H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 8.28 (d, J = 8.3Hz, 1H), 7.86 (d, J = 6.8Hz, 1H), 7.49 (s, 1H), 7.34 (t, J = 7.5Hz, 1H), 7.16 (t, J = 7.3Hz, 1H), 6.17 (d, J = 9.8Hz, 1H), 4.36 (q, J = 5.6Hz, 2H), 4.02 – 3.88 (m, 1H), 3.63 (bs, 1H), 2.34-2.29 (m, 1H), 2.13 (s, 2H), 2.09-2.00 (m, 2H), 1.70 (bs, 1H), 1.55 (bs, 2H), 1.34 (t, J = 7.1Hz, 3H).

[0110] Step 6: Synthesis ethyl 5-methylpyrazolo [1, 5-c] quinazoline-2-carboxylate.

[0111] To a stirred to solution ethyl 3-(2-acetamidophenyl)-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazole-5-carboxylate (500mg, 1.27mmol) in DCM (10mL) at 0oC was added HCl (4.0M in 1,4-dioxane, 10mL). The resultant mixture was stirred at room temperature for 4h. It was then concentrated, and the residue was basified with saturated NaHCO3 solution(10mL) and extracted with EtOAc (2 x 20mL). The combined organic layer was dried over Na2SO4and concentrated. The crude product obtained was purified by flash column chromatography (eluting 35% EtOAc in hexane) to afford ethyl 5-methylpyrazolo [1, 5-c] quinazoline-2- carboxylate as off-white solid (200mg, 99%).1H NMR (400 MHz, DMSO) δ 8.38 (d, J = 7.7Hz, 1H), 7.98 – 7.80 (m, 2H), 7.74 (t, J = 7.6Hz, 1H), 7.67 (t, J = 7.5Hz, 1H), 4.41 (q, J = 7.2Hz, 2H), 2.92 (s, 3H), 1.37 (t, J = 6.7Hz, 3H).

[0112] Step 7: Synthesis of (5-methylpyrazolo [1, 5-c] quinazolin-2-yl) methanol.

[0113] To a stirred to solution ethyl 5-methylpyrazolo [1, 5-c] quinazoline-2-carboxylate (300mg, 1.176mmol) in THF (10mL) at 0oC was added LAH (178mg, 4.705mmol) and the reaction mixture was heated to stir at 60oC for 16h. The reaction mixture was then cooled and quenched with saturated NH4Cl solution at 0oC and extracted with EtOAc (2 x 15mL). The combined organic layer was dried over Na2SO4and concentrated to obtain the crude target compound. It was then purified by flash column chromatography (eluting 50% EtOAc in hexane) to afford (5-methylpyrazolo [1, 5-c] quinazolin-2-yl) methanol as off-white solid (200mg, 66 %).

[0114] Step 8: Synthesis of (5-methylpyrazolo [1, 5-c] quinazolin-2-yl) methyl methanesulfonate.

[0115] To a stirred to solution (5-methylpyrazolo [1, 5-c] quinazolin-2-yl) methanol (8) (200mg, 0.934mmol) in DCM (10mL) at 0oC was added TEA (283mg, 2.803mmol), 24ME149145978v.1Docket No.: 119992-22820 followed by methane sulfonyl chloride (160mg, 1.401mmol). Then the reaction mixture was stirred at room temperature for 3h. It was then quenched with H2O (10mL) and extracted with DCM (2 x 10mL). The combined organic layer was dried over Na2SO4and concentrated to afford (5-methylpyrazolo [1, 5-c] quinazolin-2-yl) methyl methane sulfonate (250mg) as yellow liquid.1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.5Hz, 1H), 7.91 (d, J = 7.9Hz, 1H), 7.68 (t, J = 7.6Hz, 1H), 7.58 (t, J = 7.6Hz, 1H), 7.13 (s, 1H), 5.52 (s, 2H), 3.09 (s, 3H), 3.00 (s, 3H).

[0116] Step 9: Synthesis of 2-(azidomethyl)-5-methylpyrazolo [1, 5-c]quinazoline.

[0117] To a stirred to solution (5-methylpyrazolo [1, 5-c] quinazolin-2-yl) methyl methanesulfonate (250mg, 0.859mmol) in DMF (5mL) at 0oC was added NaN3(223mg, 3.436mmol) and the resultant mixture was stirred at room temperature for 3h. It was then quenched with H2O (15mL) and extracted with EtOAc (2 x 10mL). The combined organic layer was washed once each with H2O (10mL) and brine solution (10mL), dried over Na2SO4and concentrated to afford 2-(azidomethyl)-5-methylpyrazolo [1,5-c]quinazoline (200mg) as red liquid.1H NMR (400 MHz, DMSO) δ 8.27 (d, J = 7.8Hz, 1H), 7.85 (d, J = 8.1Hz, 1H), 7.71 (t, J = 7.6Hz, 1H), 7.63 (t, J = 7.4Hz, 1H), 7.39 (s, 1H), 4.73 (s, 2H), 2.88 (s, 3H).

[0118] Step 10: Synthesis of (5-methylpyrazolo [1, 5-c] quinazolin-2- yl)methanamine.

[0119] To a stirred to solution 2-(azidomethyl)-5-methylpyrazolo [1,5-c]quinazoline (200mg, 0.840mmol) in 1,4-dioxane-H2O (5mL + 1mL) at 0oC was added Zn-dust (215mg, 3.36mmol), followed by NH4Cl (178mg, 3.36mmol) and the resultant mixture was stirred at room temperature for 4h. The mixture was then filtered through celite and the filtrate was extracted with EtOAc (2 x 15mL). The combined organic layer was dried over Na2SO4and concentrated to afford (5-methylpyrazolo [1, 5-c] quinazolin-2-yl) methanamine (100mg) as yellow liquid.1H NMR (400 MHz, DMSO) δ 8.19 (d, J = 8.1Hz, 1H), 7.82 (d, J = 7.7Hz, 1H), 7.68 (s, 1H), 7.61 (d, J = 7.5Hz, 1H), 7.29 (s, 1H), 3.99 (s, 2H), 2.86 (s, 3H).

[0120] Step 11: Synthesis of N-((5-methylpyrazolo [1, 5-c] quinazolin-2-yl) methyl)- 2-(pyrrolidin-1-yl) benzamide.

[0121] To a stirred solution of 2-(pyrrolidin-1-yl) benzoic acid (50mg, 0.261mmol) in DCM (5mL) were added EDC.HCl (74mg, 0.387mmol) and HOBt (53mg, 0.392mmol) at 0°C. The resultant mixture was stirred for 15min at 0 °C and to it were added (5- methylpyrazolo [1, 5-c] quinazolin-2-yl) methanamine (66mg, 0.311mmol) and TEA (0.11mL, 1.089mmol). It was then stirred at room temperature for 12h and concentrated. The residue was diluted with H2O (10mL) and extracted with EtOAc (2 x 10mL). The combined 25ME149145978v.1Docket No.: 119992-22820 organic layer was dried over Na2SO4 and concentrated. The crude product obtained was purified by column chromatography (eluent: 50% EtOAc in hexane) to afford N-((5- methylpyrazolo [1, 5-c] quinazolin-2-yl) methyl)-2-(pyrrolidin-1-yl) benzamide as off-white solid (3.6mg, 3.6%).1H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.25 (d, J = 7.7Hz, 1H), 7.83 (d, J = 7.7Hz, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.30-7.19 (m, 3H), 6.80 – 6.60 (m, 2H), 4.66 (s, 2H), 3.17 (s, 4H), 2.87 (s, 3H), 1.79 (s, 4H); LC-MS m / z (M+H): 386.0.

[0122] The following compound was synthesized according to the above protocol.

[0123] Synthesis of N-((5-aminopyrazolo [1, 5-c] quinazolin-2-yl) methyl)-2- (trifluoromethoxy) benzamide (Compound 12):

[0124] To a stirred solution of N-((5-(2-aminophenyl)-1H-pyrazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide (50mg, 0.132mmol) in ethanol (5mL) was added CNBr (13.98mg, 0.132mmol) at 0oC . Then the reaction mixture was then warmed up and stirred at room temperature for 48h. The mixture was then concentrated, diluted with H2O (15mL) and extracted with EtOAc (2 x 15mL). The combined organic layer was dried over Na2SO4, and concentrated. The crude product obtained was purified by prep-TLC (eluent: 50 % EtOAc in Hexane) to afford N-((5-aminopyrazolo [1, 5-c] quinazolin-2-yl) methyl)-2- (trifluoromethoxy) benzamide as off-white solid (7mg, 13.21 %).1H NMR (400 MHz, DMSO) δ 9.13 (s, 1H), 7.97 (d, J = 8.1Hz, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 7.55 – 7.40 (m, 6H), 7.27 (s, 1H), 7.07 (s, 1H), 4.66 (s, 2H); LC-MS m / z (M+H): 402.25. 26ME149145978v.1Docket No.: 119992-22820

[0125] Synthesis of N-((5-oxo-5,6-dihydropyrazolo[1,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (Compound 13):

[0126] To a stirred solution of N-((5-(2-aminophenyl)-1H-pyrazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide (70mg, 0.186mmol) in THF (5mL) was added TEA (56.35mg, 0.557mmol), followed by triphosgene (27.59mg, 0.93mmol). Then the reaction mixture was stirred at room temperature for 12h. The solvent was distilled off and the residue was diluted with cold H2O (10mL) and extracted with EtOAc (2 x 10mL). The combined organic layer was dried over Na2SO4and concentrated. The crude product thus obtained obtained was purified by prep-TLC to afford N-((5-oxo-5,6-dihydropyrazolo[1,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide as off-white solid (5mg, 7 %).1H NMR (400 MHz, DMSO) δ 11.80 (s, 1H), 9.12 (s, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 7.60 (s, 1H), 7.50 (s, 2H), 7.34 (s, 1H), 7.08 (s, 1H), 4.58 (s, 2H); LC-MS m / z (M)+: 402.9.

[0127] Synthesis of N-((5-oxo-5,6-dihydropyrazolo[1,5-c]pyrido[3,2-e]pyrimidin-2- yl)methyl)-2-(trifluoromethoxy)benzamide (Compound 14):

[0128] Step 1: N-((5-(2-aminopyridin-3-yl)-1H-pyrazol-3-yl)methyl)-2- (trifluoromethoxy) benzamide.

[0129] To a stirred to solution of N-((5-(2-aminopyridin-3-yl)-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (80mg, 0.17mmol) in dichloromethane (5mL) at 00C was added HCl in 1, 4-dioxane (4.0 M, 4mL). The reaction mixture was stirred at room temperature for 4h. To the mixture was then added aqueous NaHCO3 (10mL) and extracted with CH2Cl2 (10mL). The organic layer was separated, dried (Na2SO4) and concentrated to obtain the crude product which was purified flash column chromatography to afford the target compound as off- white solid (60mg, 92.30%).1H NMR (400 MHz, DMSO): δ 12.95 (s, 1H), 9.01 (s, 1H), 7.89 (d, J = 4.0Hz, 1H), 7.77 (d, J = 7.1Hz, 27ME149145978v.1Docket No.: 119992-22820 1H), 7.66 (d, J = 7.6Hz, 1H), 7.59 (t, J = 7.6Hz, 1H), 7.49-7.42 (m, 2H), 7.01 (bs, 2H), 6.65 (s, 1H), 6.63 – 6.54 (m, 1H), 4.50 (d, J = 5.4Hz, 2H); LC-MS (ESI): m / z 377.9 (M)+

[0130] Step 2: Synthesis of N-((5-oxo-5,6-dihydropyrazolo[1,5-c]pyrido[3,2- e]pyrimidin-2-yl)methyl)-2-(trifluoromethoxy)benzamide.

[0131] To a stirred solution of N-((5-(2-aminopyridin-3-yl)-1H-pyrazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide (64mg, 0.169mmol) in dry THF (10mL) were added triphosgene (25.18, 0.08mmol) followed by Et3N (42.86mg, 0.42mmol and the resultant mixture was allowed stir at room temperature for 6h. It was then concentrated and diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated under vacuum to obtain the crude product which was purified by prep-HPLC to afford the target compound as off-white solid (30mg, 43.85).1H NMR (400 MHz, DMSO): δ 12.29 (s, 1H), 9.14 (s, 1H), 8.50 (s, 1H), 8.45 (d, J = 7.7Hz, 1H), 7.67-7.58 (m, 2H), 7.50- 7.43 (m, 2H), 7.34 (s, 1H), 7.17 (s, 1H), 4.59 (d, J = 4.9Hz, 2H); LC-MS (ESI): m / z 403.9 (M)+.

[0132] Synthesis of N-((5-thioxo-5,6-dihydropyrazolo[1,5-c]quinazolin-2-yl)methyl)- 2-(trifluoromethoxy)benzamide (Compound 15):

[0133] To a stirred solution of N-((5-(2-aminophenyl)-1H-pyrazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide (4.75g, 12.62mmol) in pyridine (110mL) and H2O (30mL) was added carbon disulfide (110mL) at room temperature. Then the reaction mixture heated at 100oC for 12h. It was then diluted with cold H2O (500mL), the solid precipitated was filtered and air-dried to obtain the crude compound. It was then purified by prep-HPLC to afford N- ((5-thioxo-5,6-dihydropyrazolo[1,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide as off-white solid(1.6g, 30.30%).1H NMR (400 MHz, DMSO) δ 13.52 (s, 1H), 9.17 (t, J = 5.8Hz, 1H), 8.07 (d, J = 7.8Hz, 1H), 7.76 – 7.65 (m, 1H), 7.62- 7.56 (m, 3H), 7.51 – 7.36 (m, 3H), 7.23 (s, 1H), 4.64 (d, J = 5.9Hz, 2H); LC-MS m / z (M+H): 419.26.

[0134] Synthesis of N-((6-methyl-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide (Compound 16): 28ME149145978v.1Docket No.: 119992-22820

[0135] Step 1: Synthesis of N-((5-(2-(methylamino) phenyl)-1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazol-3-yl) methyl)-2-(trifluoromethoxy) benzamide.

[0136] To a stirred solution of N-[(5-iodo-1-tetrahydropyran-2-yl-pyrazol-3-yl)methyl]- 2-(trifluoromethoxy)benzamide (250mg, 0.504mmol) and (2-(methylamino) phenyl)boronic acid (91.45mg, 0.605mmol) in 1,4-dioxane-water (8mL + 2mL ) was added Na2CO3(133.56mg, 1.26mmol). The resultant mixture was thoroughly degassed with argon for 10min and to it was added tetrakis(triphenylphosphine)palladium(0) (58.21mg, 0.050mmol). The mixture was then heated at 100oC for 12h, then diluted with H2O (15mL) and extracted the mixture with EtOAc (2 x 15mL). The combined organic layer dried over Na2SO4and concentrated to obtain the crude product. It was then purified by flash column chromatography (eluent: 40% EtOAc in hexane) to afford N-((5-(2-(methylamino) phenyl)-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) methyl)-2-(trifluoromethoxy) benzamide as off- white solid (80mg, 33.45%);(400 MHz, CDCl3) δ 8.01 (s, 1H), 7.68 (s, 1H), 7.49 (s, 2H), 7.41-7.30 (m, 2H), 7.14 (s, 2H), 6.75-6.67 (m, 2H), 6.29 (s, 1H), 4.96 (s, 1H), 4.75 (s, 1H), 4.68 (s, 1H), 4.07 (s, 2H), 3.49 (s, 1H), 2.80 (s, 3H), 2.47 (s, 1H), 2.02 (s, 1H), 1.74 (s, 2H), 1.25 (s, 2H). LC-MS m / z (M)+: 474.9.

[0137] Step 2: Synthesis of N-((5-(2-(methylamino) phenyl)-1H-pyrazol-3-yl) methyl)-2-(trifluoromethoxy) benzamide.

[0138] To a stirred solution of N-((5-(2-(methylamino) phenyl)-1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazol-3-yl) methyl)-2-(trifluoromethoxy) benzamide (80mg, 0.168mmol) in DCM (5mL) at 0oC was added HCl (4.0 M in 1,4-dioxane, 5mL). Then the reaction mixture was stirred at room temperature for 12h. The mixture was concentrated and the residue was co- distilled with DCM (2 x 25mL) and the resultant residue was diluted with H2O (5mL), basified with saturated NaHCO3 solution (5mL) and extracted with EtOAc (2 x 10mL). The combined organic layer was dried over Na2SO4and concentrated to afford N-((5-(2- 29ME149145978v.1Docket No.: 119992-22820 aminophenyl)-1H-pyrazol-3-yl) methyl)-2-(trifluoromethoxy) benzamide as yellow gummy solid (40mg, 60.99%).1H NMR (400 MHz, MeOD) δ 7.93 (d, J = 7.8Hz, 1H), 7.67 (s, 1H), 7.64 – 7.51 (m, 4H), 7.51 – 7.37 (m, 3H), 6.87 (s, 1H), 3.66 (s, 2H), 3.08 (d, J = 12.9Hz, 3H); LC-MS m / z (M+H): 390.9.

[0139] Step 3: Synthesis of N-((6-methyl-5-oxo-5,6-dihydropyrazolo[1,5- c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide.

[0140] To a stirred solution of N-((5-(2-aminophenyl)-1H-pyrazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide (40mg, 0.102mmol) in THF (5mL) at 0oC were added TEA (25.75mg, 0.255mmol) and triphosgene (15.21mg, 0.051mmol). The resultant mixture was heated at 100oC for 12h. The solvent was distilled off, the residue was diluted with H2O (10mL) and extracted with EtOAc (2 x 10mL). The combined organic layer was dried over Na2SO4 and concentrated. The crude product obtained was prep-HPLC to afford N-((6- methyl-5-oxo-5, 6-dihydropyrazolo [1, 5-c] quinazolin-2-yl) methyl)-2-(trifluoromethoxy) benzamide as off-white solid (10mg, 23.54 %).1H NMR (400 MHz, DMSO) δ 9.13 (s, 1H), 8.06 (d, J = 7.6Hz, 1H), 7.78 – 7.54 (m, 4H), 7.47 (d, J = 9.5Hz, 2H), 7.38 (s, 1H), 7.10 (s, 1H), 4.60 (s, 2H), 3.69 (s, 3H); LC-MS m / z (M)+: 416.9.

[0141] Synthesis of N-((6-methyl-5-thioxo-5,6-dihydropyrazolo[1,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide (Compound 17):

[0142] To a stirred solution of N-((5-(2-aminophenyl)-1H-pyrazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide (90mg, 0.23mmol) in THF (5mL) at 0oC were added TEA (0.1mL, 0.692mmol) and thiophosgene (0.026mL, 0.345mmol). Then the reaction mixture was stirred at room temperature for 6h and concentrated. The residue was diluted with H2O (10mL) and extracted with EtOAc (2 x 10mL). The combined organic layer was dried over Na2SO4 and concentrated. The crude product obtained was purified by flash column chromatography (eluent: 40% EtOAc in hexane) to afford N-((6-methyl-5-thioxo-5, 6- dihydropyrazolo [1, 5-c] quinazolin-2-yl) methyl)-2-(trifluoromethoxy) benzamide as off- white solid (15mg, 15 %).1H NMR (400 MHz, DMSO) δ 9.16 (s, 1H), 8.17 (d, J = 7.8Hz, 1H), 7.79 (d, J = 8.9Hz, 1H), 7.70 (d, J = 7.6Hz, 2H), 7.59 (d, J = 6.4Hz, 1H), 7.56 – 7.38 (m, 3H), 7.25 (s, 1H), 4.63 (d, J = 6.0Hz, 2H), 4.30 (s, 3H); LC-MS m / z (M)+: 432.8. 30ME149145978v.1Docket No.: 119992-22820

[0143] Synthesis of N-((5-oxo-5,6-dihydropyrazolo[1,5-c]pyrido[3,2-e]pyrimidin-2- yl)methyl)-2-(trifluoromethoxy)benzamide (Compound 18):

[0144] Step 1: Synthesis of N-((5-(2-aminopyridin-3-yl)-1H-pyrazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide.

[0145] To a stirred solution of N-((5-(2-aminopyridin-3-yl)-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazol-3-yl) methyl)-2-(trifluoromethoxy)benzamide (400mg, 0.86mmol) in DCM (5mL) at 0oC was added HCl (4.0M in 1,4-dioxane, 5mL). The mixture was warmed up and stirred at room temperature for 12h. It was then concentrated and co-distilled with DCM (2 x 30mL). The residue was diluted with H2O (5mL), basified with NaHCO3solution (10mL) and extracted with EtOAc (2 x 25mL). The combined organic layer was dried over Na2SO4and concentrated to obtain N-((5-(2-aminopyridin-3-yl)-1H-pyrazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide as yellow viscous solid (300mg, 93%).1H NMR (400 MHz, DMSO) δ 12.93 (s, 1H), 9.00 (s, 1H), 7.88 (s, 1H), 7.76 (d, J = 6.4Hz, 1H), 7.55-7.66 (m, 2 H), 7.42-7.48 (m, 2 H), 7.00 (s, 2H), 6.60 (s, 1H), 6.58 (s, 1H), 4.50 (d, J = 5.2Hz, 2H); LC- MS m / z (M)+: 377.9.

[0146] Step 2: Synthesis of N-((5-oxo-5,6-dihydropyrazolo[1,5-c]pyrido[3,2- e]pyrimidin-2-yl)methyl)-2-(trifluoromethoxy)benzamide.

[0147] To a stirred solution of N-((5-(2-aminopyridin-3-yl)-1H-pyrazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide (120mg, 0.318mmol) in THF (10mL) at 0oC were added TEA (80.29mg, 0.795mmol) and triphosgene (47.22mg, 0.159mmol). The resultant mixture was heated at 100oC for 12h and concentrated. The residue was diluted with H2O (10mL) and extracted with EtOAc (2 x 10mL). The combined organic layer was dried over Na2SO4 and concentrated. The crude product obtained was purified by prep-HPLC to afford N-((5-oxo- 5,6-dihydropyrazolo[1,5-c]pyrido[3,2-e]pyrimidin-2-yl)methyl)-2- (trifluoromethoxy)benzamide as off white solid (15mg, 11.69%).1H NMR (400 MHz, DMSO) δ 9.13 (s, 1H), 8.49 (d, J = 3.6Hz, 1H), 8.44 (d, J = 7.6Hz, 1H), 7.65 (d, J = 8.4Hz, 1H), 7.59 (t, J = 7.6Hz, 1H), 7.43-7.49 (m, 2H), 7.34 (t, J = 7.6Hz, 1H), 7.17 (s, 1H), 4.58 (d, J = 5.6Hz, 2H); LC-MS m / z (M)+: 403.8.

[0148] Synthesis of N-((5-thioxo-5,6-dihydropyrazolo[1,5-c]pyrido[3,2-e]pyrimidin- 2-yl)methyl)-2-(trifluoromethoxy)benzamide (Compound 19): 31ME149145978v.1Docket No.: 119992-22820

[0149] To a stirred solution of N-((5-(2-aminopyridin-3-yl)-1H-pyrazol-3-yl) methyl)-2- (trifluoromethoxy) benzamide (90mg, 0.24mmol) in mixture of pyridine (4mL) and H2O (0.5mL) was added carbon disulfide (1.5mL). Then the reaction mixture was stirred at 120oC for 12h. It was then diluted with H2O (10mL) and extracted with EtOAc (2 x 10mL). The combined organic layer was dried over Na2SO4 and concentrated. The crude product obtained was purified by prep-HPLC to afford of N-((5-thioxo-5,6-dihydropyrazolo[1,5-c]pyrido[3,2- e]pyrimidin-2-yl)methyl)-2-(trifluoromethoxy)benzamide as brown solid (2mg, 2%).1H NMR (400 MHz, DMSO) δ 13.92 (s, 1H), 9.17 (d, J = 2.8Hz, 1H), 8.53-8.60 (m, 2H), 7.68 (d, J = 6.0Hz, 1H), 7.58-7.60 (m, 1H), 7.443-7.48 (m, 3H), 7.32 (s, 1H), 4.62 (d, J = 4.4Hz, 2H); LC-MS m / z (M)+: 419.8.

[0150] Synthesis of N-((5-(methylthio) pyrazolo [1, 5-c] quinazolin-2-yl) methyl)-2- (trifluoromethoxy) benzamide (Compound 20):

[0151] To a stirred solution of N-((5-thioxo-5,6-dihydropyrazolo[1,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide (1.1g, 2.62mmol) in DMF (10mL) at 0oC was added K2CO3 (906.6mg, 6.56mmol) followed by methyl iodide (559.2mg, 3.93mmol). Then the reaction was stirred at room temperature for 12h. To the reaction mixture was added H2O (100mL), the resultant precipitate was filtered, washed with water and dried to obtain the crude target compound. It was then purified by prep-TLC (eluent: 50 % EtOAc in hexane) to afford N-((5-(methylthio) pyrazolo [1, 5-c] quinazolin-2-yl) methyl)-2-(trifluoromethoxy) benzamide as pale yellow solid (810mg, 59.5 %). LC-MS m / z (M+H): 433.17.

[0152] Synthesis of N-((5-morpholinopyrazolo [1, 5-c] quinazolin-2-yl) methyl)-2- (trifluoromethoxy) benzamide (Compound 21): 32ME149145978v.1Docket No.: 119992-22820

[0153] A mixture of N-((5-(methylthio) pyrazolo [1, 5-c] quinazolin-2-yl) methyl)-2- (trifluoromethoxy) benzamide (100mg, 2.231mmol) in morpholine (1mL) was heated at 130oC for 12h. It was then diluted with H2O (10mL) and extracted with EtOAc (2 x 15mL). The combined organic layer was dried over Na2SO4 and concentrated to obtain the crude product. It was then purified by flash column chromatography (eluent: 50 % EtOAc in hexane) to afford N-((5-morpholinopyrazolo [1, 5-c] quinazolin-2-yl) methyl)-2-(trifluoromethoxy) benzamide as off-white solid (7.2mg, 6.61%).1H NMR (400 MHz, DMSO) δ 9.13 (t, J = 5.8Hz, 1H), 8.08 (d, J = 8.0Hz, 1H), 7.67 (dd, J = 7.6, 1.7Hz, 1H), 7.65 – 7.55 (m, 3H), 7.51- 7.39 (m, 3H), 7.15 (s, 1H), 4.66 (d, J = 5.9Hz, 2H), 3.91 (d, J = 4.9Hz, 4H), 3.86 – 3.77 (m, 4H); LC-MS m / z (M+H): 472.3.

[0154] The following compounds were synthesized according to the protocol described above: 33ME149145978v.1Docket No.: 119992-22820

[0155] Synthesis of N-((5-(dimethylamino) pyrazolo [1,5-c]quinazolin-2-yl)methyl)- 2-(trifluoromethoxy)benzamide (Compound 25):34ME149145978v.1Docket No.: 119992-22820

[0156] To a stirred solution of N-((5-(methylthio)pyrazolo[1,5-c]quinazolin-2-yl)methyl)- 2-(trifluoromethoxy) benzamide (50mg, 0.115mmol) in dichloromethane (5mL) at 0oC was added m-CPBA (49.7mg, 0.289mmol). Then the reaction mixture was stirred at room temperature for 3h followed by the addition of dimethylamine hydrochloride (18.8mg, 0.231mmol) and Et3N (0.1mL, 0.693mmol). The resultant mixture was allowed stir at room temperature for 12h, then the mixture was diluted with H2O (10mL) and extracted with dichloromethane (2 x 15mL). The combined organic layer was washed once with saturated NaHCO3 (10mL), dried over Na2SO4 and concentrated to obtain the crude product. It was purified by flash column chromatography (eluent: 40% EtOAc in hexane) to afford N-((5-((2- methoxyethyl)(methyl)amino)pyrazolo[1,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy) benzamide as off-white solid (15mg, 30.37%).1H NMR (400 MHz, DMSO) δ 9.13 (t, J = 4.0Hz, 1H), 8.02 (d, J = 7.2Hz, 1H), 7.67 (d, J = 7.6Hz, 1H), 7.45 – 7.63 (m, 5H), 7.34 (t, J = 6.4Hz, 1H), 7.11 (s, 1H), 4.65 (d, J = 6.0Hz, 2H), 3.36 (s, 6H); LC-MS m / z (M+H): 430.33.

[0157] Synthesis of 2-(difluoromethoxy)-N-((5-thioxo-5,6-dihydro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)methyl)benzamide (Compound 26):

[0158] Step 1: Synthesis of N-(cyanomethyl)-2-(difluoromethoxy) benzamide.

[0159] To a stirred solution of 2-(difluoromethoxy) benzoic acid (5.0g, 26.58mmol) in N, N-dimethyl formamide (15mL) were added HATU (11.10g, 29.23mmol) and DIPEA (5.15g, 39.87mmol) at 00C and the mixture was stirred for 10min. To the mixture was added 2- aminoacetonitrile hydrochloride and it was further stirred at room temperature for 12h. The reaction mixture was diluted with H2O (20mL), extracted with EtOAc (2 x 20mL) and washed with sodium bicarbonate solution. The organic layer was separated, dried over Na2SO4 and concentrated to obtain the crude product. It was then purified by flash column chromatography to obtain N-(cyanomethyl)-2-(difluoromethoxy) benzamide (7.96g, 99%).1H 35ME149145978v.1Docket No.: 119992-22820 NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 7.56 (t, J = 7.9Hz, 2H), 7.34 (dd, J = 11.7, 4.1Hz, 1H), 7.29 – 6.96 (m, 2H), 4.30 (d, J = 5.6Hz, 2H); LC-MS m / z (M-H): 225.2.

[0160] Step 2: Synthesis of 2-(difluoromethoxy)-N-((5-(2-nitrophenyl)-1H-1, 2, 4- triazol-3-yl) methyl) benzamide.

[0161] To a stirred solution of N-(cyanomethyl)-2-(difluoromethoxy) benzamide (2.0g, 8.84mmol) in n-butanol (5mL) were added potassium carbonate (0.6g, 4.42mmol) and 2- nitrobenzo hydride (1.6g, 8.84mmol) at 0 °C. The resultant mixture was stirred for 10min at 0 °C and then at 165 °C for 1h under microwave irradiation. The mixture was then diluted with H2O (4 x 20mL) and extracted with EtOAc (4 x 20mL). The combined organic layer was dried over Na2SO4and concentrated to afford 2-(difluoromethoxy)-N-((5-(2- nitrophenyl)-1H-1, 2, 4-triazol-3-yl) methyl) benzamide as brown oil (1.07g, 58.15%). LC- MS m / z (M+H): 390.1.

[0162] Step 3: Synthesis of N-((5-(2-aminophenyl)-1H-1,2,4-triazol-3-yl)methyl)-2- (difluoromethoxy) benzamide

[0163] To a stirred solution of 2-(difluoromethoxy)-N-((5-(2-nitrophenyl)-1H-1,2,4- triazol-3-yl) methyl) benzamide (1.07g, 2.748mmol) in methanol (100mL) was added 10% palladium on carbon (1.0g ) at room temperature and the mixture was stirred for 10min. The resultant mixture was then stirred at room temperature under hydrogen atmosphere for 3h, then filtered through celite and washed with methanol (50mL). The filtrate was concentrated to obtain N-((5-(2-aminophenyl)-1H-1, 2, 4-triazol-3-yl) methyl)-2-(difluoro methoxy) benzamide as brown solid. (901mg, 98.76%). LC-MS m / z (M+H): 360.1.

[0164] Step 4: Synthesis of 2-(difluoromethoxy)-N-((5-thioxo-5,6-dihydro- [1,2,4]triazolo[1,5-c] quinazol in-2-yl)methyl)benzamide.

[0165] To a stirred solution of N-((5-(2-aminophenyl)-1H-1,2,4-triazol-3-yl)methyl)-2- (difluoromethoxy) benzamide (720mg, 2.00mmol) in a sealed tube in pyridine (20mL) was added carbon disulfide (20mL) and water (6mL) at 0°C and the resultant mixture was stirred at 100°C for 16h. The mixture was then quenched with ice-cold water (200mL), stirred for 15min and precipitate that was formed was collected by filtration to obtain the crude product. It was then purified by prep-HPLC to afford 2-(difluoromethoxy)-N-((5-thioxo-5,6-dihydro- [1,2,4]triazolo[1,5-c] quinazolin-2-yl)methyl)benzamide as pale green solid (441mg, 54.83%).1H NMR (400 MHz, DMSO) δ 14.02 (s, 1H), 9.02 (t, J = 5.8Hz, 1H), 8.20 (d, J = 7.1Hz, 1H), 7.88 – 7.73 (m, 1H), 7.65 (dd, J = 10.7, 4.8Hz, 2H), 7.54 (td, J = 7.2, 2.8Hz, 2H), 7.35 (t, J = 7.2Hz, 1H), 7.30 – 7.22 (m, 2H), 4.72 (d, J = 5.8Hz, 2H); LC-MS m / z (M+H): 402.15. 36ME149145978v.1Docket No.: 119992-22820

[0166] Synthesis of 2-(difluoromethoxy)-N-((5-thioxo-5,6-dihydro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)methyl)benzamide (Compound 26): Alternative route

[0167] Step 1: Synthesis of methyl (2-(difluoromethoxy) benzoyl) glycinate.

[0168] To a stirred to solution of 2-(difluoromethoxy) benzoic acid (20g, 106.32mmol) in DCM (250mL) were added EDC.HCl (30.57g, 159mmol), HOBt (21.55g, 154mmol) and TEA (44.82mL, 318mmol) at 00C. The resulting mixture was stirred for 10min and methyl glycinate (20g, 159mmol) was added. The entire mixture was stirred at room temperature for 12h, then diluted with ice-cold water (100mL) and extracted with EtOAc (2 x 20mL). The combined organic layer was dried over Na2SO4and concentrated under vacuum. The crude product obtained was purified by flash column chromatography (eluent: 40% ethyl acetate in hexane) to afford methyl (2-(difluoromethoxy) benzoyl) glycinate as off-white solid (25g, 91%).1H NMR (400 MHz, DMSO): δ 8.69 (s, 1H), 7.59-7.52 (m, 2H), 7.35-6.97 (m, 3H), 4.01 (d, J = 5.6Hz 2H), 3.66 (s, 3H); LC-MS (ESI): m / z 260 (M+H)+.

[0169] Step 1a: Synthesis of 2-isothiocyanatobenzonitrile.

[0170] To a stirred mixture of Na2CO3 (27g, 254mmol) in DCM: H2O at 0oC was added thiophosgene (15mL, 190mmol) and the mixture was stirred for 10min. Then a solution of 2- aminobenzonitrile (15g, 127mmol) in DCM (150mL) was added at 0°C and continued stirring for another for 30 min. It was then diluted with cold water and extracted with DCM (2 x 250mL). The combined organic layer dried over Na2SO4and concentrated to afford 2- isothiocyanatobenzonitrile as off-white solid (10g, 49%).1H NMR (400 MHz, DMSO): δ 7.65 – 7.57 (m, 2H), 7.37 – 7.34 (m, 2H).

[0171] Step 2: Synthesis of 2-(difluoromethoxy)-N-(2-hydrazinyl-2-oxoethyl) benzamide. 37ME149145978v.1Docket No.: 119992-22820

[0172] To a stirred solution of methyl (2-(difluoro methoxy) benzoyl) glycinate (25g, 96.5mmol) in ethanol (250mL) at room temperature was added hydrazine hydrate (40mL) and the mixture was stirred at 80oC for 12h. It was then concentrated and the crude compound was triturated with petroleum ether to afford 2-(difluoro methoxy)-N-(2- hydrazinyl-2-oxoethyl) benzamide 3 as off-white solid (15.5g, 62%).1H NMR (400 MHz, DMSO): δ 9.08 (s, 1H), 8.47 (t, J = 5.2Hz, 1H), 7.66 (d, J = 6.4Hz, 1H), 7.54 (t, J = 6Hz, 1H), 7.39-7.01 (m, 4H), 4.25 (s, 2H), 3.85 (d, J = 5.6Hz, 2H); LC-MS (ESI): m / z 260.0 (M+H)+.

[0173] Step 3: Synthesis of 2-(difluoromethoxy)-N-((5-thioxo-5,6-dihydro- [1,2,4]triazolo[1,5-c] quinazolin-2-yl) methyl) benzamide.

[0174] To a stirred solution of 2-(difluoro methoxy)-N-(2-hydrazinyl-2-oxoethyl) benzamide (16g, 61.71mmol) in ethanol (160mL) at room temperature was added 2- isothiocyanatobenzonitrile (11.86g, 74mmol) and the mixture was stirred at 90oC for 12h. It was concentrated and the crude product obtained was triturated with acetonitrile (20mL) and stirred for 15 minutes. The resultant precipitate was collected by filtration and vacuum dried to obtain 2-(difluoromethoxy)-N-((5-thioxo-5,6-dihydro-[1,2,4]triazolo[1,5-c] quinazolin-2- yl) methyl) benzamide as off-white solid (15g, 60%).1H NMR (400 MHz, DMSO): δ 14.02 (s, 1H), 9.02 (t, J = 5.6Hz, 1H) 8.20 (d, J = 8Hz, 1H), 7.79 (t, J = 8.4Hz, 1H), 7.65 (t, J = 8.8Hz, 2H), 7.56-7.51 (m, 2H), 7.42-7.05 (m, 3H), 4.72 (d, J = 5.6Hz, 2H); LC-MS (ESI): m / z 402.27 (M+H)+.

[0175] Synthesis of 2-(difluoromethoxy)-N-((5-methoxy-[1, 2, 4] triazolo [1, 5-c] quinazolin-2-yl) methyl) benzamide (Compound 27):

[0176] To a stirred to solution of N-((5-(2-aminophenyl)-1H-1,2,4-triazol-3-yl)methyl)-2- (difluoro methoxy) benzamide (150mg, 0.417mmol) in toluene (10mL) was added tetra methoxymethane (142mg, 1.043mmol) and the reaction mixture was heated at 80oC for 16h. The solvent was distilled off, diluted with H2O (10mL) and extracted with EtOAc (2 x 15mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum to get the crude compound. It was then purified by prep-TLC (eluent: 3% MeOH in DCM) to afford 2-(difluoromethoxy)-N-((5-methoxy-[1, 2, 4] triazolo [1, 5-c] quinazolin-2-yl) methyl) 38ME149145978v.1Docket No.: 119992-22820 benzamide as an off-white solid (70mg, 41.9%).1H NMR (400 MHz, DMSO) δ 9.02 (t, J = 5.8Hz, 1H), 8.30 (d, J = 7.1Hz, 1H), 7.84 (d, J = 4.8Hz, 2H), 7.62 (dd, J = 10.7, 4.8Hz, 2H), 7.54 (td, J = 7.2, 2.8Hz, 2H), 7.35 (t, J = 7.2Hz, 1H), 7.30 – 7.22 (m, 2H), 4.72 (d, J = 5.8Hz, 2H); LC-MS m / z (M+H): 400.1.

[0177] Synthesis of 2-(difluoro methoxy) -N-((5-(methylthio)-[1,2,4] triazolo[1,5-c] quinazolin-2-yl) methyl) benzamide (Compound 28) and 2-(difluoromethoxy)-N-((5- morpholino-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methyl)benzamide (Compound 29):

[0178] Synthesis of 2-(difluoro methoxy)-N-((5-(methylthio)-[1,2,4] triazolo[1,5-c] quinazolin-2-yl) methyl) benzamide.

[0179] To a stirred solution of 2-(difluoromethoxy)-N-((5-thioxo-5,6-dihydro- [1,2,4]triazolo[1,5-c] quinazolin-2-yl) methyl) benzamide (2g, 4.98mmol) in DMF(15mL) were added K2CO3(1.38g, 9.97mmol) and Iodomethane (0.46mL, 7.48mmol) at 0oC and stirred at that temperature for 10min. The mixture was warmed up to room temperature and stirred for 3h. It was then diluted with cold water (70mL) and the precipitated solid was filtered and vacuum dried to afford the 2-(difluoro methoxy) -N-((5-(methylthio)-[1,2,4] triazolo[1,5-c] quinazolin-2-yl) methyl) benzamide as off-white solid (1.99g, 96%).1H NMR (400 MHz, DMSO): δ 9.07(t, J = 5.6Hz, 2H), 8.36 (d, J = 8Hz, 1H), 7.96 (d, J = 8Hz, 1H), 7.89 (t, J = 7.2Hz, 1H), 7.71 (t, J = 8Hz, 1H), 7.65 (d, J = 7.6Hz, 1H), 7.55 (t, J = 7.6Hz, 1H), 7.38-7.01 (m, 3H), 4.77 (d, J = 5.6Hz, 2H),2.78 (s, 3H); LC-MS (ESI): m / z 416.23 (M+H)+.

[0180] Step-2: 2-(difluoromethoxy)-N-((5-morpholino-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)methyl)benzamide.

[0181] A mixture of 2-(difluoro methoxy)-N-((5-(methylthio)-[1,2,4] triazolo[1,5-c] quinazolin-2-yl) methyl) benzamide (100mg, 0.24mmol) and morpholine (2mL) was heated at 90oC for 16h. The resultant mixture was diluted with water (20mL) and extracted with EtOAc (2 x 15mL). The combined organic layer was washed once each with brine (15mL) and water (15 m). It was then dried over Na2SO4and concentrated to obtain the crude compound. The crude product was purified by flash column chromatography (eluent: 70% ethyl acetate in hexane) to afford 2-(difluoro methoxy) -N-((5-morpholino -[1,2,4] triazolo 39ME149145978v.1Docket No.: 119992-22820 [1,5-c] quinazolin-2-yl) methyl) benzamide (30mg, 27%) as an off-white solid.1H NMR (400 MHz, DMSO): δ 9.01(t, J = 5.6Hz, 2H), 8.26 (d, J = 8Hz, 1H), 7.78-7.70 (m, 2H), 7.61 (d, J = 7.6Hz, 1H), 7.56-7.48 (m, 2H), 7.38-7.01 (m, 3H), 4.74 (d, J = 5.6Hz, 2H), 3.97 (d, J = 3.6Hz, 4H), 3.81 (d, J = 4.4Hz, 4H); LC-MS (ESI): m / z 455.40 (M+H)+.

[0182] The following compounds were synthesized according to the protocol described above:40ME149145978v.1Docket No.: 119992-22820

[0183] Synthesis of 2-(difluoromethoxy)-N-((5-(dimethylamino)-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)methyl)benzamide (Compound 33):

[0184] To a stirred solution of 2-(difluoromethoxy) -N-((5-(methylthio)-[1, 2, 4] triazolo [1, 5-c] quinazolin-2-yl) methyl) benzamide (200mg, 0.481mmol) in DCM (10mL) at 0oC was added mCPBA (207mg, 1.204mmol). The reaction mixture was stirred at room temperature for 3h followed by the addition of dimethylamine hydrochloride (78mg, 0.963mmol) and TEA (0.32mL, 2.409mmol) The resultant mixture was stirred at room temperature for 12h. Water (10mL) was added to the mixture, organic layer separated and aqueous layer was extracted with DCM (2 x 15mL). The combined organic layer was washed once with saturated NaHCO3 (10mL), dried over Na2SO4 and concentrated. The crude product obtained was purified by flash column chromatography (eluent: 40% EtOAc in hexane) to obtain 2-(difluoromethoxy)-N-((5-(dimethylamino)-[1, 2, 4] triazolo [1, 5-c] quinazolin-2-yl) methyl) benzamide as off-white solid (170mg, 85 %);1H NMR (400 MHz, DMSO) δ 9.00-9.02 (m, 1H), 8.22 (t, J = 6.8Hz, 1H), 7.62-7.75 (m, 3H), 7.55 – 7.58 (m, 1H), 7.01 – 7.46 (m, 4H), 4.75 (t, J = 5.6Hz, 2H), 3.42 (d, J = 5.6Hz, 3H), 3.33 (d, J = 6.0Hz, 3H); LC-MS m / z (M+H): 413.0.

[0185] The following compound was synthesized according to the protocol described above:41ME149145978v.1Docket No.: 119992-22820

[0186] Synthesis of 2-methoxy-N-((5-thioxo-5,6-dihydro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)methyl)benzamide (Compound 35:

[0187] Step 1: Synthesis of methyl (2-methoxybenzoyl) glycinate.

[0188] To a stirred to solution of 2-methoxybenzoic acid (500mg, 3.286mmol) in DCM (10mL) were added EDC.HCl (944mg, 4.929mmol), HOBt (666mg, 4.929mmol) and TEA (1.4mL, 9.858mmol) at 00C. The resulting mixture was stirred for 10min followed by the addition of methyl glycinate.HCl (618mg, 4.929mmol) and the mixture was stirred at room temperature for 12h. It was then concentrated, diluted with ice-cold water (15mL) and extracted with EtOAc (2 x 10mL). The combined organic layer was dried over Na2SO4and concentrated. The crude product obtained was purified by flash column chromatography (eluent: 40% ethyl acetate in hexane) to obtain methyl (2-methoxybenzoyl) glycinate as an 42ME149145978v.1Docket No.: 119992-22820 off white solid (388mg, 52.92%).1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 7.87 – 7.85 (m, 1H), 7.52 (ddd, J = 8.6, 3.0, 1.5Hz, 1H), 7.18 (d, J = 8.4Hz, 1H), 7.07 (t, J = 7.5Hz, 1H), 4.07 (d, J = 5.6Hz, 2H), 3.93 (d, J = 1.1Hz, 3H), 3.67 (d, J = 1.1Hz, 3H).

[0189] Step 2: Synthesis of N-(2-hydrazinyl-2-oxoethyl)-2-methoxybenzamide.

[0190] To a stirred solution of methyl (2-methoxybenzoyl) glycinate (388mg, 1.739mmol) in ethanol (10mL) at room temperature was added hydrazine hydrate (0.5mL, 2.087mmol) and the mixture was stirred at 95oC for 12h. It was concentrated and the crude product obtained was triturated with petroleum ether to afford N-(2-hydrazinyl-2-oxoethyl)- 2-methoxybenzamide as off-white solid (145mg, 35.77 %).1H NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 8.55 (s, 1H), 7.92 – 7.84 (m, 1H), 7.57 – 7.48 (m, 1H), 7.19 (d, J = 8.2Hz, 1H), 7.06 (dd, J = 10.4, 4.6Hz, 1H), 4.27 (s, 2H), 3.99 – 3.86 (m, 5H); LC-MS (ESI): m / z 224.1 (M+H)+.

[0191] Step 3: Synthesis of 2-methoxy-N-((5-thioxo-5,6-dihydro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)methyl)benzamide.

[0192] To a stirred solution of N-(2-hydrazinyl-2-oxoethyl)-2-methoxybenzamide (145mg, 0.649mmol) in ethanol (10mL) at room temperature was added 2- isothiocyanatobenzonitrile (124mg, 0.779mmol) and the mixture was stirred at 90oC for 12h. The mixture was concentrated and the crude product obtained was triturated with acetonitrile (15mL), stirred for 15min, the precipitate was collected by filtration and vacuum dried to obtain 2-methoxy-N-((5-thioxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)methyl)benzamide as off-white solid (130mg, 39.7%).1H NMR (400 MHz, DMSO) δ 14.03 (s, 1H), 9.04 (s, 1H), 8.23 (d, J = 8.0Hz, 1H), 7.91 (d, J = 7.6Hz, 1H), 7.81 (t, J = 7.7Hz, 1H), 7.68 (d, J = 8.3Hz, 1H), 7.55 (t, J = 7.7Hz, 2H), 7.22 (d, J = 8.5Hz, 1H), 7.09 (t, J = 7.5Hz, 1H), 4.80 (t, J = 2.4Hz, 2H), 4.02 (d, J = 3.1Hz, 3H). LC-MS (ESI): m / z 364.39 (M-H)+.

[0193] The following compounds were synthesized according to the protocol described above:43ME149145978v.1Docket No.: 119992-22820

[0194] Synthesis of 2-(difluoromethoxy)-N-((5-thioxo-5,6-dihydropyrazolo[1,5- c]quinazolin-2-yl)methyl)benzamide (Compound 38):

[0195] Step 1: Synthesis of (3-(2-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-5-yl) methanol.

[0196] To a stirred solution of ethyl 3-(2-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazole-5-carboxylate (5.5g, 15.94mmol) in methanol (250mL) at 0oC was added NaBH444ME149145978v.1Docket No.: 119992-22820 (2.4g, 63.76mmol) and the mixture was stirred at room temperature for 12 h. The mixture was concentrated and was diluted with water and extracted with EtOAc. The organic layer dried dried over Na2SO4and concentrated. The crude product thus obtained was purified by flash column chromatography (eluent 35% EtOAc + hexane) to obtain 3-(2-nitrophenyl)-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl) methanol as thick liquid (2.1g, 43 %).1H NMR (400 MHz, DMSO) δ 7.79 (dd, J = 5.4, 4.0Hz, 2H), 7.67 (t, J = 7.6Hz, 1H), 7.54 (t, J = 7.7Hz, 1H), 6.51 (s, 1H), 5.52 (dd, J = 8.7, 2.8Hz, 1H), 5.41 (s, 1H), 4.61 – 4.50 (m, 2H), 3.81 (d, J = 11.2Hz, 1H), 3.67 – 3.53 (m, 2H), 3.46 – 3.33 (m, 2H), 2.23 – 2.10 (m, 1H), 2.08 – 1.99 (m, 1H), 1.83 (d, J = 13.5Hz, 1H); LC-MS m / z (M+H): 304.2.

[0197] Step 2: Synthesis of (3-(2-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-5-yl) methyl methane sulfonate.

[0198] To a stirred solution of 3-(2-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-5-yl) methanol (2g, 6.60mmol) in DCM (20mL) at 0oC were added methanesulfonyl chloride (982mg, 8.54mmol) and followed by TEA (999mg, 9.90mmol). Then the reaction mixture was stirred at room temperature for 12h. The resultant mixture was diluted with cold H2O (20mL), the organic layer was separated, dried over Na2SO4and concentrated to obtain (3-(2-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl) methyl methane sulfonate as pale green liquid. (2.50g, 99%).

[0199] Step 3: Synthesis of 5-(azidomethyl)-3-(2-nitrophenyl)-1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazole.

[0200] To a stirred solution of (3-(2-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-5-yl) methyl methane sulfonate (2.5g, 6.56mmol) in DMF (20mL) at 0oC was added NaN3(640mg, 9.84mmol), Then the reaction mixture was stirred at room temperature for 12h. It was then diluted with cold H2O (75mL) and extracted with EtOAc (2x 50mL). The combined organic layer was dried over Na2SO4 and concentrated to obtain 5-(azidomethyl)- 3-(2-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole as pale brown solid (1.7g, 80%).1H NMR (400 MHz, DMSO) δ 7.81 (dd, J = 7.7, 6.9Hz, 2H), 7.70 (t, J = 7.6Hz, 1H), 7.57 (t, J = 7.7Hz, 1H), 6.71 (d, J = 10.3Hz, 1H), 5.54 (dd, J = 8.5, 2.8Hz, 1H), 4.70 – 4.62 (m, 2H), 3.91 – 3.76 (m, 1H), 3.76 – 3.50 (m, 2H), 2.20-2.10 (m, 1H), 2.08 – 1.92 (m, 1H), 1.94 – 1.81 (m, 1H), 1.79 – 1.64 (m, 1H).

[0201] Step 4: Synthesis of (3-(2-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-5-yl) methanamine.

[0202] To a stirred solution of 5-(azidomethyl)-3-(2-nitrophenyl)-1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazole (1.7g, 5.18mmol) in THF-H2O (20mL + 10mL) was added 45ME149145978v.1Docket No.: 119992-22820 triphenylphosphine (2.30g, 7.77mmol) at 0oC. Then the reaction mixture was stirred at room temperature for 12h. The mixture was concentrated, diluted with 1N HCl solution (20mL) and extracted with EtOAc (2 x 20mL). The aqueous layer was basified with 1N NaOH solution (20mL), and extracted with EtOAc (2 x 50mL). The combined organic layer was dried over Na2SO4 and concentrated to obtaiin (3-(2-nitrophenyl)-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazol-5-yl) methanamine as gummy solid (500mg, 32%).

[0203] Step 5: Synthesis of 2-(difluoromethoxy)-N-((3-(2-nitrophenyl)-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazol-5-yl) methyl) benzamide.

[0204] To a stirred solution of (3-(2-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-5-yl) methanamine (500mg, 1.65mmol) and 2-(difluoromethoxy)benzoic acid (341mg, 1.81mmol) in DCM (50mL) at 0oC were added EDC.HCl (483mg, 2.47mmol), HOBt (333mg, 2.47mmol) and TEA (499mg, 4.95mmol). Then the reaction mixture was warmed up and stirred at room tempreature for 12h. The resultant mixture was concentrated, diluted with cold H2O (10mL) and extracted with EtOAc (2x 10mL). The combined organic layer was washed once each with saturated NaHCO3 solution (20mL), sat.NH4Cl solution (20mL) and with brine (20mL), dried over Na2SO4and concentrated. The residue was subjected to flash column chromatography (eluent: 30% EtOAc+hexane) to obtain 2- (difluoromethoxy)-N-((3-(2-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl) methyl) benzamide as off-white solid (470mg, 60%).1H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 7.77 (dd, J = 18.0, 7.8Hz, 2H), 7.71 – 7.64 (m, 1H), 7.54 (dd, J = 16.7, 7.7Hz, 3H), 7.41 – 7.15 (m, 4H), 6.55 (s, 1H), 5.57 (d, J = 5.5Hz, 1H), 4.59 (dd, J = 10.0, 5.5Hz, 2H), 3.80 (s, 1H), 3.66 (s, 1H), 3.16 (d, J = 5.0Hz, 1H), 2.20 – 2.14 (m, 1H), 2.04 – 1.99 (m, 1H), 1.89 (s, 1H), 1.66 – 1.60 (m, 1H), 1.53 (s, 2H).

[0205] Step 6: Synthesis of 2-(difluoromethoxy)-N-((5-(2-nitrophenyl)-1H-pyrazol-3- yl) methyl) benzamide.

[0206] To a stirred solution of 2-(difluoromethoxy)-N-((3-(2-nitrophenyl)-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazol-5-yl) methyl) benzamide (470mg, 0.99mmol) in DCM (10mL) at 0oC was added HCl (4.0M in 1,4-dioxane, 10mL). Then the reaction mixture was warmed up and stirred at room temperature for 12h. It was concentrated, diluted with cold H2O (20mL), basified with saturated NaHCO3solution (10mL) and extracted with ethyl acetate (20mL x 3). The combined organic layer was dried over Na2SO4 and concentrated to afford 2- (difluoromethoxy)-N-((5-(2-nitrophenyl)-1H-pyrazol-3-yl) methyl) Benzamide as off-white solid (350mg, 92%). 46ME149145978v.1Docket No.: 119992-22820

[0207] Step 7: Synthesis of N-((5-(2-aminophenyl)-1H-pyrazol-3-yl) methyl)-2- (difluoromethoxy) benzamide.

[0208] To a stirred solution of 2-(difluoromethoxy)-N-((5-(2-nitrophenyl)-1H-pyrazol-3- yl) methyl) benzamide (350mg, 0.90mmol) in methanol (30mL) was added Pd-C (350mg, 10% wt / wt). The resultant mixture was stirred under hydrogen atmosphere at 50psi for 12h. The mixture was then filtered over celite bed and concentrated to afford N-((5-(2- aminophenyl)-1H-pyrazol-3-yl) methyl)-2-(difluoromethoxy) benzamide brown gummy solid (300mg, 93%). LC-MS m / z (M-H): 359.1.

[0209] Step-8: Synthesis of 2-(difluoromethoxy)-N-((5-thioxo-5,6- dihydropyrazolo[1,5-c]quinazolin-2-yl)methyl)benzamide.

[0210] To a stirred solution of N-((5-(2-aminophenyl)-1H-pyrazol-3-yl) methyl)-2- (difluoromethoxy) benzamide (300mg, 0.837mmol) in a mixture of pyridine-H2O (6mL+1.2mL) was added carbon disulfide (4.5mL). Then the reaction mixture was heated at 100oC for 12h. It was then diluted with cold H2O (20mL) and extracted with EtOAc (2 x 10mL). The organic layer was dried over Na2SO4 and concentrated. The crude product obtained was purified by prep-HPLC, to obtain 2-(difluoromethoxy)-N-((5-thioxo-5, 6- dihydropyrazolo [1, 5-c] quinazolin-2-yl) methyl) benzamide as off-white solid (58mg, 17%).1H NMR (400 MHz, DMSO) δ 13.53 (s, 1H), 9.01 (s, 1H), 8.05 (d, J = 8.1Hz, 1H), 7.65 (d, J = 7.6Hz, 1H), 7.64 – 7.50 (m, 3H), 7.44 (d, J = 14.0Hz, 1H), 7.36 (t, J = 7.6Hz, 1H), 7.31- 7.06 (m, 3H), 4.66 (d, J = 6.0Hz, 2H); LC-MS m / z (M+H): 401.23.

[0211] Synthesis of 2-(difluoromethoxy)-5-fluoro-N-((5-thioxo-5,6-dihydro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)methyl)benzamide (Compound 39):47ME149145978v.1Docket No.: 119992-22820

[0212] Step 1: Synthesis of methyl 5-fluoro-2-hydroxybenzoate.

[0213] To a stirred solution of 5-fluoro-2-hydroxybenzoic acid (5g, 0.390mmol) in MeOH (100mL) at 0oC was added concentrated H2SO4(1mL). Then the reaction mixture was refluxed at 80oC for 12h and concentrated. The residue was dissolved in EtOAc (50mL), washed with water (2 x 25mL), dried over Na2SO4 and concentrated to afford methyl 5-fluoro-2-hydroxybenzoate as off-white solid (4.5g, 80%).1H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 7.51 (dd, J = 9.0, 3.3Hz, 1H), 7.46 – 7.38 (m, 1H), 7.03 (dd, J = 9.1, 4.6Hz, 1H), 3.89 (s, 3H).

[0214] Step 2: Synthesis of methyl 2-(difluoromethoxy)-5-fluorobenzoate.

[0215] To a stirred solution of methyl 5-fluoro-2-hydroxybenzoate (2.5g, 14.69mmol) in DMF (10mL) at 0oC was added K2CO3 (5.0g, 36.72mmol), followed by chlorodifluoroacetic acid (2.3g, 17.63mmol). Then the reaction mixture was heated at 100oC for 2h. It was then diluted with cold H2O (50mL) and extracted with EtOAc (2 x 15mL). The combined organic layer was washed once H2O (15mL), dried over Na2SO4 and concentrated. The crude compound thus obtained was purified by flash column chromatography to afford methyl 2- (difluoromethoxy)-5-fluorobenzoate as pale-green liquid (650mg, 20%).1H NMR (400 MHz, CDCl3) δ 7.61 (dt, J = 8.4, 2.8Hz, 1H), 7.29 – 7.25 (m, 2H), 6.56 (t, J = 74.6Hz, 1H), 3.97 (s, 3H).

[0216] Step 3: Synthesis of 2-(difluoromethoxy)-5-fluorobenzoic acid.

[0217] To a stirred solution of methyl 2-(difluoromethoxy)-5-fluorobenzoate (750mg, 3.409mmol) in THF-H2O (10mL + 10mL)) at 0oC was added LiOH.H2O (572mg, 13.636mmol). Then the reaction mixture was stirred at room temperature for 12h. It was concentrated, diluted with H2O (10mL), acidified with saturated citric acid solution (10mL) and extracted with EtOAc (2 x 15mL). The combined organic layer was dried over Na2SO4 and concentrated to obtain 2-(difluoromethoxy)-5-fluorobenzoic acid as off-white solid (450mg, 64%).1H NMR (400 MHz, DMSO) δ 13.56 (brs, 1H), 7.66 – 7.62 (m, 1H), 7.55- 7.50 (m, 1H), 7.44-7.31 (m, 1H), 7.02-6.94 (m, 1H). GC-MS m / z (M+H): 206.0.

[0218] Step 4: Synthesis of N-(cyanomethyl)-2-(difluoromethoxy)-5- fluorobenzamide.

[0219] To a stirred solution of 2-(difluoromethoxy)-5-fluorobenzoic acid (550mg, 2.668mmol) in DMF (10mL) at 0oC were added HATU (1g, 2.668mmol), DIPEA (861mg, 6.674mmol) and aminoacetonitrile.HCl (270mg, 2.936mmol). The resultant mixture was stirred at room temperature for 12h. It was then diluted with H2O (50mL) and extracted with EtOAc (2 x 15mL). The combined organic layer was dried over Na2SO4 and concentrated to 48ME149145978v.1Docket No.: 119992-22820 obtain the crude product. It was purified by flash column chromatography to afford N- (cyanomethyl)-2-(difluoromethoxy)-5-fluorobenzamide as off-white solid (350mg, 53%).1H NMR (400 MHz, DMSO) δ 8.98 (t, J = 5.4Hz, 1H), 7.66 – 7.46 (m, 2H), 7.40 – 7.31 (m, 1H), 7.17 (t, J = 76.7Hz, 1H), 4.30 (d, J = 5.6Hz, 2H).

[0220] Step 5: Synthesis of 2-(difluoromethoxy)-5-fluoro-N-((5-(2-nitrophenyl)-1H- 1,2,4-triazol-3-yl)methyl)benzamide.

[0221] To a stirred solution of N-(cyanomethyl)-2-(difluoromethoxy)-5-fluorobenzamide (350mg, 1.433mmol) and 2-nitrobenzohydrazide (285mg, 1.576mmol) in n-butanol was added K2CO3 (99mg, 0.716mmol). Then the reaction mixture was heated at 130oC for 12h. The mixture was diluted with cold H2O (10mL) and extracted with EtOAc (2 x 15mL). The combined organic layer was dried over Na2SO4 and concentrated to obtain the crude compound. It was then purified by flash column chromatography to afford 2- (difluoromethoxy)-5-fluoro-N-((5-(2-nitrophenyl)-1H-1,2,4-triazol-3-yl)methyl)benzamide as off-white solid (60mg, 11%). LC-MS m / z (M+H): 408.08.

[0222] Step-6: Synthesis of N-((5-(2-aminophenyl)-1H-1, 2, 4-triazol-3-yl) methyl)-2- (difluoromethoxy)-5-fluorobenzamide.

[0223] To a stirred solution of 2-(difluoromethoxy)-5-fluoro-N-((5-(2-nitrophenyl)-1H- 1,2,4-triazol-3-yl)methyl)benzamide (60mg, 0.147mmol) in MeOH (5mL) was added Pd-C (60mg, 10% wt / wt). Then the reaction mixture was stirred under hydrogen atmosphere at 50 psi for 2h. The mixture was then filtered through celite and the filtrate was concentrated to obtain N-((5-(2-aminophenyl)-1H-1, 2, 4-triazol-3-yl) methyl)-2-(difluoromethoxy)-5- fluorobenzamide as brown solid (50mg). LC-MS m / z (M+H): 378.1.

[0224] Step-7: Synthesis of 2-(difluoromethoxy)-5-fluoro-N-((5-thioxo-5,6-dihydro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)methyl)benzamide.

[0225] To a stirred solution of N-((5-(2-aminophenyl)-1H-1, 2, 4-triazol-3-yl) methyl)-2- (difluoromethoxy)-5-fluorobenzamide (50mg, 0.13mmol) in a mixture of pyridine and H2O (1.32mL + 0.6mL) was added carbon disulfide (1.32mL). The resultant mixture was heated at 100oC for 12h. It was then diluted with cold H2O (20mL), the solid precipitated was collected by filtration and air dried to obtain the crude compound. It was then purified by prep-HPLC to obtain 2-(difluoromethoxy)-5-fluoro-N-((5-thioxo-5,6-dihydro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)methyl)benzamide as off-white solid (7.5mg, 13%).1H NMR (400 MHz, DMSO) δ 14.03 (s, 1H), 9.14 (t, J = 5.8Hz, 1H), 8.20 (d, J = 7.6Hz, 1H), 7.79 (t, J = 7.8Hz, 1H), 7.66 (d, J = 8.3Hz, 1H), 7.53 (t, J = 7.6Hz, 1H), 7.47 (dd, J = 8.5, 49ME149145978v.1Docket No.: 119992-22820 3.1Hz, 1H), 7.45 – 7.37 (m, 1H), 7.36 – 7.01 (m, 3H), 4.72 (d, J = 5.9Hz, 2H); LC-MS m / z (M+H): 420.17.

[0226] Synthesis of 2-(difluoromethoxy)-N-(thiazolo [4,5-c]quinolin-2- ylmethyl)benzamide (Compound 40):

[0227] Step 1: Synthesis of 2-aminonaphthalen-1-ol.

[0228] To a stirred solution of 2-nitronaphthalen-1-ol (2g, 10.52mmol) in methanol (20mL) at room temperature was added 10% Pd / C (1g). Then the reaction mixture was stirred at 50psi under hydrogen atmosphere for 12h at room temperature. The reaction mixture was then filtered through a celite bed and washed with methanol (25mL). The combined filtrates were concentrated to obtain 2-aminonaphthalen-1-ol (1.5g, 89.0 %) as off-white solid.1H NMR (400 MHz, DMSO) δ 11.51 (bs, 1H), 8.12 (d, J = 8.0Hz, 2H), 8.57 (s, 1H), 7.49 (d, J = 3.6Hz, 2H), 7.21-7.17 (m, 1H), 4.42 (s, 2H). LC-MS m / z (M+H): 161.1.

[0229] Step 2: Synthesis of tert-butyl (2-((4-hydroxyquinolin-3-yl) amino)-2- oxoethyl) carbamate.

[0230] To a stirred solution of 2-aminonaphthalen-1-ol (2g, 12.49mmol) and HATU (7.12g, 18.73mmol) in DCM (250mL) were added (tert-butoxycarbonyl) glycine (12.49g, 2.19g) and DIPEA (4.83g, 37.47mmol) at room temperature. The resultant mixture was stirred at room temperature for 1h, then diluted with EtOAc and filtered. The organic layer was dried over Na2SO4and concentrated to obtain the crude product. It was then purified by flash column chromatography (eluent: 2% MeOH + DCM) to obtain tert-butyl (2-((4- hydroxyquinolin-3-yl) amino)-2-oxoethyl) carbamate (2g, 50.4 %) as off-white solid.1H NMR (400 MHz, DMSO) δ 11.91 (s, 1H), 9.18 (d, J = 4.4Hz, 1H), 9.00 (t, J = 5.6Hz, 1H), 8.18 (t, J = 5.2Hz, 1H), 7.69-7.58 (m, 2H), 7.42-7.31 (m, 2H), 3.77 (d, J = 5.2Hz, 2H), 1.43 (s, 9H); LC-MS m / z (M-H): 316.0. 50ME149145978v.1Docket No.: 119992-22820

[0231] Step 3: Synthesis of tert-butyl (thiazolo [4, 5-c] quinolin-2-ylmethyl) carbamate.

[0232] A mixture of tert-butyl (2-((4-hydroxyquinolin-3-yl) amino)-2-oxoethyl) carbamate (0.3g, 1.0mmol) and Lawesson reagent (0.32g, 0.8mmol) in THF (20mL) was stirred at 80oC for 2.5h. The reaction was quenched by the addition of aqueous NaHCO3 solution (20mL) and the mixture was extracted with EtOAc (2 x 150mL). The combined organic layer was dried over Na2SO4and concentrated to obtain the crude product. It was then purified by flash column chromatography (eluent: 60% EtOAc + petroleum ether) to obtain tert-butyl (2-((4-hydroxyquinolin-3-yl) amino)-2-oxoethyl) carbamate (280mg, 90.0%) as off-white solid.1H NMR (400 MHz, DMSO) δ 9.42 (d, J = 6.4Hz, 1H), 8.25-8.19 (m, 2H), 8.03 (d, J = 5.6Hz, 1H), 7.86-7.72 (m, 2H), 4.64 (d, J = 6.0Hz, 2H), 1.44 (s, 9H); LC- MS m / z (M+H): 316.0.

[0233] Step 4: Synthesis of thiazolo [4, 5-c] quinolin-2-ylmethanamine hydrochloride.

[0234] To a stirred solution of tert-butyl (2-((4-hydroxyquinolin-3-yl) amino)-2-oxoethyl) carbamate (0.28g, 0.89mmol) in DCM (5mL) at 0oC was added 4.0M HCl in dioxane (5mL). Then the reaction mixture was stirred at room temperature for 3h. It was concentrated and the crude compound was washed with diethyl ether and dried to obtain thiazolo [4,5- c]quinolin-2-ylmethanamine hydrochloride (210mg, 90.0 %) as yellow solid.1H NMR (400 MHz, DMSO) δ 9.61 (d, J = 4.8Hz, 1H), 8.94 (bs, 3H), 8.34-8.28 (m, 2H), 7.94-7.81 (m, 2H), 4.77 (d, J = 9.6Hz, 2H); LC-MS m / z (M+H): 216.1.

[0235] Step 5: Synthesis of 2-(difluoromethoxy)-N-(thiazolo [4,5-c]quinolin-2- ylmethyl)benzamide:

[0236] To a stirred solution of thiazolo [4, 5-c] quinolin-2-ylmethanamine hydrochloride (0.05g, 0.02mmol), 2-(trifluoromethoxy) benzoic acid (0.037g, 0.02mmol), EDC.HCl (0.056g, 0.03mmol), and HOBt (0.040g, 0.03mmol) in DCM (25mL) at room temperature, was added DIPEA (0.076g, 0.60mmol). Then the reaction mixture was stirred at room temperature for 12h and then concentrated. The residue was diluted with H2O (20mL) and the aqueous phase was extracted with EtOAc (2 x 25mL). The combined EtOAc layer was concentrated and the crude product obtained was purified by flash column chromatography (eluent: 2% MeOH + DCM) to obtain 2-(difluoromethoxy)-N-(thiazolo [4,5-c]quinolin-2- ylmethyl)benzamide (35mg, 45.7%) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.45 (d, J = 5.2Hz, 2H), 8.23-8.17 (m, 2H), 7.86-7.74 (m, 2H), 7.69-7.66 (m, 1H), 7.62-7.56 (m, 1H), 7.46-7.26 (m, 3H), 4.97 (t, J = 5.6Hz, 2H); LC-MS m / z (M+H): 386.0. 51ME149145978v.1Docket No.: 119992-22820

[0237] The following compound was synthesized similarly to the protocol described above:

[0238] Synthesis of 2-(difluoromethoxy)-N-(oxazolo [4, 5-c] quinolin-2- ylmethyl)benzamide (Compound 42):

[0239] Step 1: Synthesis of tert-butyl (oxazolo[4,5-c]quinolin-2-ylmethyl)carbamate.

[0240] A mixture of tert-butyl (2-((4-hydroxyquinolin-3-yl) amino)-2-oxoethyl) carbamate (0.5g, 1.65mmol), hexachloroethane (0.58g, 2.47mmol), trimethylamine (0.66g, 6.60mmol) and triphenyl phosphine (0.65g, 2.47mmol) in DCM (20mL) was stirred at room temperature for 1h. The reaction was quenched with water (15mL) and extracted with DCM (2 x 25mL). The combined organic layer was dried over Na2SO4 and concentrated to obtain the crude product. It was purified by flash column chromatography (eluent: 60% EtOAc + petroleum ether) to afford tert-butyl (oxazolo[4,5-c]quinolin-2-ylmethyl)carbamate (240mg, 50.0%) as off-white solid.1H NMR (400 MHz, DMSO) δ 9.33 (d, J = 1.2Hz, 1H), 8.24-8.21 (m, 2H), 7.88-7.75 (m, 3H), 4.59 (t, J = 5.6Hz, 2H), 1.43 (s, 9H); LC-MS m / z (M+H): 300.0.

[0241] Step 2: Synthesis of oxazolo [4, 5-c] quinolin-2-ylmethanamine hydrochloride. 52ME149145978v.1Docket No.: 119992-22820

[0242] To a stirred solution of tert-butyl (oxazolo [4, 5-c] quinolin-2-ylmethyl) carbamate (0.24g, 0.80mmol) in DCM (5mL) at 0oC was added 4.0M HCl in dioxane (5mL). Then the reaction mixture was stirred at room temperature for 3h and concentrated. The crude product thus obtained was washed with diethyl ether (15mL) and dried to obtain oxazolo [4, 5-c] quinolin-2-ylmethanamine hydrochloride (150mg, 79.3 %) as yellow solid. LC-MS m / z (M+H): 200.0.

[0243] Step-3: Synthesis of 2-(difluoromethoxy)-N-(oxazolo [4, 5-c] quinolin-2- ylmethyl)benzamide.

[0244] To a stirred solution of oxazolo [4,5-c]quinolin-2-ylmethanamine hydrochloride (47mg, 0.02mmol), 2-(trifluoromethoxy)benzoic acid (37mg, 0.02mmol), EDC.HCl (56mg, 0.03mmol), and HOBt (40mg, 0.03mmol) in DCM (25mL), was added DIPEA (76mg, 0.60mmol). Then the reaction mixture was stirred at room temperature for 12h and concentrated. The residue was diluted with H2O (15mL) and extracted with EtOAc (2 x 25mL). The combined organic layer was dried over Na2SO4 and concentrated. The resultant crude product was purified by flash column chromatography (eluent: 2% MeOH + DCM) to obtain 2-(difluoromethoxy)-N-(oxazolo [4, 5-c] quinolin-2-ylmethyl) benzamide (35mg, 45.7%) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 9.23 (t, J = 6.0Hz, 1H), 8.26-8.22 (m, 2H), 7.87-7.79 (m, 2H), 7.66-7.55 (m, 2H), 7.39-7.01 (m, 3H), 4.91(d, J = 5.6Hz, 2H); LC-MS m / z (M+H): 370.0.

[0245] The following compound was synthesized similarly to the above protocol.Dissociation Constants (Kd) for Inventive Compounds

[0246] UBE2K Ligand binding to mono-Ub UBE2K and UBE2K was measured by Surface plasma resonance using a Biacore SPR S200 instrument. The proteins and ligands were prepared for experimental measurement as described below. 53ME149145978v.1Docket No.: 119992-22820

[0247] Avi tagged proteins were biotinylated and were immobilized on a Series S / Sensor Chip SA. Proteins were immobilized based on their molar weight as follows - Biotinylated Avi peptide (1000 µM), Biotinylated UBE2K-Ub Complex (12 µM) and Biotinylated UBE2K Wild Type (3 µM). Proteins were immobilized using a buffer comprised of 1X HBS- N Buffer + 0.05% Tween 20 (250mL). Ligands stocks were prepared in affinity buffer comprised of 1% DMSO, 1X PBS-P+ Buffer. Further dilution of stock were prepared in 0% DMSO, 1X PBS-P+ Buffer or 3% DMSO, 1X PBS-P+ Buffer and were used as running buffers. Ligands were prepared as 2 mM or 750 µM stocks in the buffers described above. Titration was performed using the Liquid handler / TECAN EVO (WALL-E) as follows. 1 or 2, 96 deep well plates (1.2mL) were used for performing titrations-Aliquoted 3% DMSO, 1X PBS-P+ buffer. 1:2 dilution was performed by WALL-E (250µL + 250µL) for the rest of titrations till 3.12µM. The titrations of each compound were then transferred to 384 deep well plate in duplicates side- by-side (125µL) each. This plate was then covered with a 384 well S200 compatible foil and used for the affinity method. Solvent Correction buffer with DMSO concentration + and- 0.5% DMSO of running buffer was run in each experimental run.

[0248] Data was collected and processed in accordance with the methodologies described in the Biacore S200 Evaluation Software. Steady state fitting was performed on the data using the software and data represented as sensogram to deconvolute binding and dissociation constants as described in Dahl,G et al., SLAS Discovery, 2017, Vol. 22(2) 203–209. Results are shown in Table 1. Table 154ME149145978v.1Docket No.: 119992-22820 Epoxomicin-induced Cell Toxicity in HD-Fibroblast

[0249] Fibroblast from normal subjects (control fibroblasts) and mHTT containing HD subjects (HD fibroblasts) were treated with epoxomicin, a proteosomal inhibitor leading to decreased UPR / UPS activity, and a combination of epoxomicin with compound 26. As shown by FIG. 1, HD fibroblasts show enhanced sensitivity to treatment with epoxomicin while 25 uM of compound 26 reverses the sensitivity to epoxomicin induced toxicity.

[0250] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art. 55ME149145978v.1

Claims

Docket No.: 119992-22820 1. A compound having the Formula I:or a pharmaceutically acceptable salt thereof, wherein Z1and Z2are each independently N or CH; R1is (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, or –NRcRd, wherein two available hydrogen atoms on said halo(C1-C6)alkyl and halo(C1-C6)alkoxy may be taken together to which the carbon atoms they are attached to form a 3- to 6-membered cycloalkyl optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, halo(C1- C6)alkyl, (C1-C6)alkoxy, and halo(C1-C6)alkoxy; R2is CN, halo, OH, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, or halo(C1- C6)alkoxy; or R1and R2, when on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered oxygen containing heterocyclyl optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, and halo(C1- C6)alkyl; R3is hydrogen, (C1-C6)alkyl, or halo(C1-C6)alkyl; Y is CH2, -CHRa, -CRaRb, S, or SO; p is 0 or 1; Raand Rbare each independently halo, (C1-C6)alkyl, or halo(C1-C6)alkyl; or Raand Rbtogether with the carbon atom they are bound for a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclyl, each of which are optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, (C1- C6)alkylOH, (C1-C6)alkylO(C1-C6)alkyl, and OH; Rcand Rdare each independently hydrogen (C1-C6)alkyl, halo(C1-C6)alkyl, (C1- C6)alkylO(C1-C6)alkyl, halo(C1-C6)alkylO(C1-C6)alkyl, (C1-C6)alkyl-O-halo(C1-C6)alkyl, halo(C1-C6)alkyl-O-halo(C1-C6)alkyl, or (C1-C6)alkylOH; or Rcand Rdtogether with the nitrogen atom they are bound form a 4- to 7-membered heterocyclyl optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, and oxo; 56ME149145978v.1Docket No.: 119992-22820 Z is a tricyclic fused ring having the formula: ; ring A is aromatic; the wavy bond denotes the point of attachment to Y; X, X1, and X2are each, as valency permits, independently selected from -CR7, N, O, and S; the dotted line in ring B represents a single or double bond; R4and R5are each independently selected from hydrogen, (C1-C6)alkyl, halo(C1- C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, -S(C1-C6)alkyl, -SH, OH, (C3-C6)cycloalkyl, (C4-C7)heterocyclyl, and –NReRf, wherein said (C3-C6)cycloalkyl and (C4-C7)heterocyclyl are each optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, halo(C1- C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, and oxo; or R4and R5together at the carbon to which they are attached form =O or =S; R6is hydrogen or (C1-C6)alkyl when the dotted line in ring B is a single bond, or R6is absent when the dotted line in ring B is a double bond; d, d1, d2 and d3 are each independently selected from CR8and N; Reand Rfare each independently hydrogen, (C1-C4)alkyl, (C1-C4)alkylNH(C1- C4)alkyl, (C1-C4)alkylN[(C1-C4)alkyl]2, (C1-C4)alkylO(C1-C4)alkyl; R7is hydrogen or (C1-C6)alkyl; and R8is halogen, hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, CN, or OH.

2. The compound of Claim 1, wherein the compound is of the Formula II:or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

4. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Z1and Z2are each CH. 57ME149145978v.1Docket No.: 119992-22820 5. The compound of any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Y is CH2.

6. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein p is 0.

7. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R1is (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, or –NRcRd; and Rcand Rdtogether with the nitrogen atom they are bound form a 5- to 6-membered heterocyclyl optionally substituted with 1 to 3 halo.

8. The compound of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R1is (C1-C3)alkyl, halo(C1-C3)alkyl, (C1-C3)alkoxy, or –NRcRd; and Rcand Rdtogether with the nitrogen atom they are bound form a 5- to 6-membered nitrogen containing heterocyclyl optionally substituted with 1 to 3 halo.

9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R1is OCF3, OCHF2, OCH3, CH3, pyrrolidinyl, or piperidinyl, wherein said pyrrolidinyl, or piperidinyl are optionally substituted with 1 to 3 halo.

10. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein X is N.

11. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein X1is CH or N.

12. The compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein X2is CH, N, S, or O.

13. The compound of any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein X is N, X1is N, and X2is CH; X is N, X1is N, and X2is N; X is N, X1is CH, and X2is S; or X is N, X1is CH, and X2is O. 58ME149145978v.1Docket No.: 119992-22820 14. The compound of any one of Claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein d is N or -CR8.

15. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein d2is N or -CR8.

16. The compound of any one of Claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein d1is -CR8.

17. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein d3is -CR8.

18. The compound of any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Z is selected from19. The compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Z is selected from59ME149145978v.1Docket No.: 119992-22820 20. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R8is hydrogen or halo.

21. The compound of any one of Claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R8is hydrogen.

22. The compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C3- C6)cycloalkyl, halo(C1-C6)alkyl, –NReRf, -SH, -S(C1-C6)alkyl, (C4-C7)heterocyclyl, and (C1- C6)alkylN[(C1-C6)alkyl]2, wherein said (C4-C7)heterocyclyl is optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, and halo(C1- C6)alkoxy.

23. The compound of any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C3- C4)cycloalkyl, halo(C1-C3)alkyl, –NReRf, -SH, -S(C1-C3)alkyl, (C5-C6)heterocyclyl, and (C1- C3)alkylN[(C1-C3)alkyl]2, wherein said (C5-C6)heterocyclyl is optionally substituted with 1 to 3 groups selected from halo, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1- C6)alkoxy.

24. The compound of any one of Claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen, methyl, ethyl, isopropyl, methoxy, cyclopropyl, CF3, NH2, N(CH3)2, NCH3(CH2CH3), -SH, SCH3, morpholino, piperidinyl, pyrrolidinyl, CH3NH(CH2)2N(CH3)2, CH3NH(CH2)2OCH3, and piperazinyl optionally substituted with methyl.

25. The compound of any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen.

26. The compound of any one of Claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R6is selected from hydrogen and (C1-C4)alkyl. 60ME149145978v.1Docket No.: 119992-22820 27. The compound of any one of Claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R6is selected from hydrogen and methyl.

28. The compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, R4and R5together at the carbon to which they are attached form =O or =S.

29. The compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, R4and R5together at the carbon to which they are attached form =S.

30. A pharmaceutical composition comprising a compound of any one of Claims 1 to 29, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

31. A method of treating neurological disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1 to 29, or a pharmaceutically acceptable salt thereof. 61ME149145978v.1

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