Vasopressin receptor 2 modulators and methods of use thereof

Abstract

The disclosure provides compounds, e.g., compounds of Formula I, and their use in treating medical diseases or disorders, for example, kidney disorders. The compounds are contemplated to be modulators of vasopressin receptor 2 (V2R). (I)

Description

Attorney Docket No. RTX-003WOVASOPRESSIN RECEPTOR 2 MODULATORS AND METHODS OF USE THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, International (PCT) Application No. PCT / CN2024 / 110085, filed on August 6, 2024; and U.S. Provisional Patent Application No. 63 / 687,902, filed on August 28, 2024; the content of each of which is hereby incorporated by reference herein in its entirety.BACKGROUND

[0002] Vasopressin receptor 2 (V2R), or arginine vasopressin receptor 2 (AVPR2), is a protein in the subfamily of G-protein-coupled receptor and acts as receptor for vasopressin. Vasopressin itself, also known as antidiuretic hormone (ADH), is a peptide hormone that, in part, regulates osmotic pressure gradient of body fluids. Under hypertonic conditions, vasopressin causes the kidneys to reabsorb solute-free water and return it to the circulation from the tubules of the nephron, thus returning the tonicity of the body fluids toward normal.

[0003] Predominantly expressed in the kidney, V2R’s primary function is to respond to vasopressin by stimulating mechanisms that concentrate the urine and maintain water homeostasis in the organism. Loss of function of V2R is one cause of nephrogenic diabetes insipidus (NDI).

[0004] Vasopressin receptor 2 antagonists, for example, promote an increase in urine production, which reduces the associated symptoms of water retention and edema.Vasopressin antagonists selective for the V2 receptor have been used for the treatment of autosomal dominant polycystic kidney disease (ADPKD) and hyponatremia. In animal models, V2R antagonists show promising efficacy for autosomal recessive polycystic kidney disease (ARPKD).

[0005] Antagonism or inhibition of V2R may also provide an alternative decongestive strategy in patients with acute and chronic heart failure, characterized by congestion and fluid overload. While loop diuretics are the main treatment for patients with acute HF, they are often associated with neurohormonal activation and worsening renal function, and do not improve long-term outcomes. Therefore, management of severe congestion in the higherIPTS / 200087585.1Attorney Docket No. RTX-003WO risk group with kidney function impairment, while offering renal protection, remains a target in the treatment of HF.

[0006] Thus, an unmet need exists to develop new vasopressin receptor 2 modulators (for example, antagonists or inhibitors) that show safety and efficacy profiles necessary for treating kidney diseases (e.g., ADPKD and ARPKD), electrolyte imbalance (e.g., hyponatremia), cardiovascular disorders (e.g., congestive heart failure) and other conditions that are affected by, associated with, or would benefit from modulation (e.g., antagonism or inhibition) of vasopressin receptor 2.SUMMARY

[0007] The disclosure is directed, in part, to compounds that act Fas modulators (for example, antagonists or inhibitors) of vasopressin receptor 2 (V2R). Also disclosed herein are pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier.

[0008] For example, disclosed herein is a compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting of halogen, hydroxyl, -N(RD)(RE), cyano, - NO2, Ci-ealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-ealkoxy, Cs-Cecycloalkyl, -C(=O)NRDRE, - NRD(C=O)RE, -O(C=O)NRDRE, -NRD(C=O)ORE, -NRD(C=O)NRDRE, -(C=O)Ci-C6alkyl, - (C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, S(O)2NRDRE, and - NRDS(O)2 Ci-Cealkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, Ci-Cealkyl, and Ci- Cealkoxy;L1is Ci-3alkylene, wherein Ci-3alkylene may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, -CH3, and -CF3; or L1is absent;IPTS / 200087585.1Attorney Docket No. RTX-003WO Ring A is an 8-9 membered fused bicyclic heterocyclyl having at least two ring nitrogens, wherein if the heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may be optionally substituted with RA, and wherein if the heterocyclyl contains a substitutable ring sulfur atom, that ring sulfur atom may be optionally substituted with two O atoms or one O atom and one NH group; Ring B is selected from the group consisting of phenyl, 3-6 membered carbocyclyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl; R2is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, oxo, cyano, C1-6alkyl, C1-6alkoxy, -C(O)C1-6alkyl, -COOH, - C(O)N(RB)(RC), -S(O)2N(RD)(RE), -N(RB)(RC), -C(O)NHC(O)SO2C1-6alkyl, C(O)NHC(O)SO2-phenyl, -NH-SO2-C1-6alkyl, -PH(O)C1-6alkyl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl; wherein C1-6alkyl and C1-6alkoxy may be optionally substituted with one or more substituents independently selected from halogen, hydroxyl, and C1-3alkoxy; or two geminal R2groups, together with the carbon atom to which they are attached, may be joined together to form a 5-6 membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, C1-3alkyl, and C1-3alkoxy; R3is selected from the group consisting of halogen, hydroxyl, -N(RD)(RE), cyano, - NO2, C1-6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-6alkoxy, C3-C6cycloalkyl, -C(=O)NRDRE, - NRD(C=O)RE, -O(C=O)NRDRE, -NRD(C=O)ORE, -NRD(C=O)NRDRE, -(C=O)C1-C6alkyl, - (C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, S(O)2NRDRE, and - NRDS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1- C6alkoxy; RAis selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, -C(O)C1-6alkyl, - C(O)OC1-6alkyl, -C(O)N(RD)(RE), -CH2C(O)N(RD)(RE), -N(RD)(RE), -S(O)2N(RD)(RE), and - S(O)2C1-6alkyl, wherein the -C(O)C1-6alkyl, C3-6cycloalkyl, -C(O)C1-6alkyl, -C(O)OC1-6alkyl, and -S(O)2C1-6alkyl may be optionally substituted with one or more substituents independently selected from halogen and hydroxyl; IPTS / 200087585.1 3Attorney Docket No. RTX-003WORBis independently selected for each occurrence from the group consisting of hydrogen and Ci-ealkyl;Rcis independently selected for each occurrence from the group consisting of hydrogen, Ci-ealkyl, and -C(O)Ci-ealkyl;RDis selected from the group consisting of hydrogen and Ci-ealkyl;REis selected from the group consisting of hydrogen and Ci-ealkyl; m is 0, 1, 2, 3, or 4; and n is 1, 2, or 3.

[0009] Also disclosed herein is a compound represented by Formula II:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is independently selected for each occurrence from the group consisting of chloro, fluoro, -CH3, and -CF3;L1is selected from the group consisting of -CH2-,-CH(CH3)-, -C(CH3)2-, and -CF2-; or L1is absent;Ring B is selected from the group consisting of cyclohexenyl, cyclopentenyl, phenyl, pyridyl, pyridonyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydropyranyl, and tetrahydrothiopyranyl; wherein if ring B contains a substitutable ring nitrogen atom, that ring nitrogen atom may be optionally substituted with RF;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, oxo, cyano, Ci-ealkyl, Ci-ealkoxy, -C(O)Ci-ealkyl, -COOH, - C(O)N(RB)(RC), -S(O)2N(RD)(RE), -N(RB)(RC), -C(O)NHC(O)SO2Ci-6alkyl, C(O)NHC(O)SO2-phenyl, -NH-SCh-Ci-ealkyl, -PH(O)Ci -ealkyl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl; wherein Ci-ealkyl and Ci-ealkoxy may be optionally substituted with one or more substituents independently selected from halogen, hydroxyl, and Ci-3alkoxy;IPTS / 200087585.1Attorney Docket No. RTX-003WORFis selected from the group consisting of Ci-3alkyl, cyclopropyl, -C(O)Ci-3alkyl, - C(O)OCi-3alkyl, -C(O)N(RD)(RE), -CH2C(O)N(RD)(RE), -S(O)2N(RD)(RE), and -S(O)2Ci- salkyl; wherein -C(O)Ci-ealkyl, C3-6cycloalkyl, -C(O)Ci-ealkyl, and -C(O)OCi-ealkyl may be optionally substituted with one or more substituents each independently selected from halogen and hydroxyl;RGand RHare each independently selected for each occurrence from the group consisting of hydrogen and Ci-ealkyl;R1and RJare each independently selected from the group consisting of hydrogen and Ci-ealkyl; m is 0, 1, 2, 3, or 4; and n is 1, 2, or 3.

[0010] In addition, disclosed herein are pharmaceutical compositions comprising at least one compound of the disclosure and at least one pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions comprise at least one additional therapeutic agent.

[0011] Also disclosed herein are methods of treating a patient suffering from a condition, disease, or disorder that is affected by, associated with, or would benefit from modulation (e.g., antagonism or inhibition) of V2R, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0012] For example, disclosed herein are methods of treating a V2R protein-related disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the present disclosure provides a method of treating a disease or disorder responsive to V2R modulation (e.g., antagonism or inhibition). In some embodiments, the disease or disorder is, for example, hyponatremia. On other embodiments, the disease or disorder is, for example, acute or chronic congestive heart failure. In further embodiments, the disease or disorder is, for example, the disease or disorder is, for example, autosomal recessive polycystic kidney disease (ARPKD).IPTS / 200087585.1Attorney Docket No. RTX-003WODETAILED DESCRIPTION

[0013] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.Definitions

[0014] The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.

[0015] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as Ci-ealkyl, Ci-4alkyl, and Ci-3alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -butyl, 3-methyl-2-butyl, 2-methyl-l-pentyl, 3-methyl-l- pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- dimethyl-1 -butyl, 3, 3 -dimethyl- 1 -butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0016] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as Ci-Csalkenyl, C2-Cealkenyl, and C3-C4alkenyl, respectively.Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

[0017] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C2-ealkynyl, and C3-6alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

[0018] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to,IPTS / 200087585.1Attorney Docket No. RTX-003WO alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as Ci-Csalkoxy, Ci-Cealkoxy, and C2-Cealkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.

[0019] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g, bicyclic or tricyclic) 4n+2 aromatic ring system (e.g, having 6, 10, or 14 p electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Cuaryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Examples of representative substituted aryls include the followingwherein one of R56and R57may be hydrogen and at least one of R56and R57is each independently selected from Ci-Cs alkyl, Ci-Cs haloalkyl, 4-10 membered heterocyclyl, alkanoyl, Ci-Cs alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59, SO2NR58R59, S-alkyl, SOalkyl, SChalkyl, Saryl, SOaryl, SCharyl; or R56and R57may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R60and R61are each independently hydrogen, Ci-Cs alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Ce-Cio aryl, substituted Ce-Cio aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.IPTS / 200087585.1Attorney Docket No. RTX-003WO

[0020] The term “carbonyl” as used herein refers to the radical -C(O)-.

[0021] The term “cyano” as used herein refers to the radical -CN.

[0022] The terms “cycloalkyl” or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as Cs-Ciocycloalkyl, Cs-ecycloalkyl or C4-6cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.

[0023] The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

[0024] The terms “haloalkyl” as used herein refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (i.e., CF3), difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like. Exemplary haloalkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms substituted with a halogen (i.e., Cl, F, Br and I), referred to herein as Ci-ehaloalkyl, Ci-4 haloalkyl, and Ci-3haloalkyl, respectively.

[0025] The term “hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0026] The terms “heteroaryl” or “heteroaromatic group” as used herein refers to an aromatic 5-10 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. The term may also be used to refer to a 5-7 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, pyrrolopyridine, indole, thiazole, oxazole, isothiazole, isoxazole, imidazole, benzoimidazole, imidazopyridine, pyrazole, triazole, pyridine or pyrimidine, etc.

[0027] The terms “heterocyclyl,” “heterocycle,” or “heterocyclic group” are art- recognized and refer to saturated or partially unsaturated 3-12 membered ring structures, for example, 4-10 membered ring structures, for example, 4-8 membered ring structures, whoseIPTS / 200087585.1Attorney Docket No. RTX-003WO ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur, wherein the sulfur atom may be oxidized to SO or SO2.. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. The term may also be used to refer to 4-10 membered saturated or partially unsaturated ring structures that are bridged, fused or spirocyclic ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc. Further examples include Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyi, piperidonyl, 4-piperidinonyl, quinudidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro- 1 H,3H,5H- oxazolo[3,4-c]oxazolyl, tetrahydro- 1 'H,3'H- spiro [cyclopropane- 1 ,2'-pyrrolizine] , hexahy dro- 1 H-pyrroliziny 1, hexahy dro- 1 H-pyrrolo [2,1- c][l]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(lH)-oxide, tetrahydro- 2H-thiopyranyI 1 -oxide and tetrahydro-2H- thiopyranyl 1,1 -dioxide. In some embodiments, the heterocycle is a spiro heterocycle (e.g., 2,8-diazaspiro[4.5]decane). In some embodiments, the heterocycle is a bridged heterocycle (e.g., octahydro-lH-4,7-methanoisoindole). "Spiro heterocyclyl," or “spiro heterocycle” refers to a polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O)m(wherein m is an integer of 0 to 2) as ring atoms.

[0028] The terms “hydroxy” and “hydroxyl” as used herein refers to the radical -OH.

[0029] The term “oxo” as used herein refers to the radical =0.

[0030] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.IPTS / 200087585.1Attorney Docket No. RTX-003WO

[0031] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0032] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0033] “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). “Modulation” includes antagonism (e.g., inhibition), inverse agonism, agonism, biased agonism, biased signal transduction, functionally selective agonism, partial antagonism and / or partial agonism.

[0034] In the present specification, the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and / or prophylactic effect.

[0035] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions.Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide,IPTS / 200087585.1Attorney Docket No. RTX-003WO nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

[0036] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

[0037] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol — denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carboncarbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.IPTS / 200087585.1Attorney Docket No. RTX-003WO

[0038] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans,” where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans .”

[0039] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0040] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a singleIPTS / 200087585.1Attorney Docket No. RTX-003WO polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0041] The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,170,31P,32P,35S,18F, and36C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0042] Certain isotopically labeled disclosed compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (z.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (z.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0043] The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound of the disclosure or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-s)alkyl, (C2- i2)alkylcarbonyloxymethyl, l-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-l-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxy carbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxy carbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1 -(alkoxy carbonyloxy)ethyl having from 5 to 8IPTS / 200087585.1Attorney Docket No. RTX-003WO carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3 -phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-2)alkylamino(C2-3)alkyl (such as P- dimethylaminoethyl), carbamoyl-(Ci-2)alkyl, N,N-di(Ci-2)alkylcarbamoyl-(Ci-2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-3)alkyl.

[0044] Similarly, if a compound of the disclosure contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-6)alkylcarbonyloxym ethyl, l-((Ci-6)alkylcarbonyloxy)ethyl, 1 -methyl- l-((Ci-6)alkylcarbonyloxy)ethyl (Ci-6)alkoxycarbonyloxymethyl, N-(Ci- 6)alkoxycarbonylaminomethyl, succinoyl, (Ci-e)alkylcarbonyl, a-amino(Ci-4)alkylcarbonyl, arylalkylcarbonyl and a-aminoalkylcarbonyl, or a-aminoalkylcarbonyl-a- aminoalkylcarbonyl, where each a -aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(Ci-e)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0045] If a compound of the disclosure incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N- alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplicio, et al., Molecules 2008, 13, 519 and references therein.I. Compounds

[0046] The disclosure is directed, in part, to compounds that act as modulators (for example, antagonists or inhibitors) of vasopressin receptor 2 (V2R). Also disclosed herein are pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier.

[0047] For example, disclosed herein is a compound represented by Formula I:IPTS / 200087585.1Attorney Docket No. RTX-003WOor a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting of halogen, hydroxyl, -N(RD)(RE), cyano, - NO2, Ci-ealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-ealkoxy, Cs-Cecycloalkyl, -C(=O)NRDRE, - NRD(C=O)RE, -O(C=O)NRDRE, -NRD(C=O)ORE, -NRD(C=O)NRDRE, -(C=O)Ci-C6alkyl, - (C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, S(O)2NRDRE, and - NRDS(0)2 Ci-Cealkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, Ci-Cealkyl, and Ci- Cealkoxy;L1is Ci-3alkylene, wherein Ci-3alkylene may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, -CH3, and -CF3; or L1is absent;Ring A is an 8-9 membered fused bicyclic heterocyclyl having at least two ring nitrogens, wherein if the heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may be optionally substituted with RA, and wherein if the heterocyclyl contains a substitutable ring sulfur atom, that ring sulfur atom may be optionally substituted with two O atoms or one O atom and one NH group;Ring B is selected from the group consisting of phenyl, 3-6 membered carbocyclyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl;R2is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, oxo, cyano, Ci-ealkyl, Ci-ealkoxy, -C(O)Ci-ealkyl, -COOH, - C(O)N(RB)(RC), -S(O)2N(RD)(RE), -N(RB)(RC), -C(O)NHC(O)SO2Ci-6alkyl, C(O)NHC(O)SO2-phenyl, -NH-SCh-Ci-ealkyl, -PH(O)Ci -ealkyl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl; wherein Ci-ealkyl and Ci-ealkoxy may be optionally substituted with one or more substituents independently selected from halogen, hydroxyl, and Ci-3alkoxy; orIPTS / 200087585.1Attorney Docket No. RTX-003WO two geminal R2groups, together with the carbon atom to which they are attached, may be joined together to form a 5-6 membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, Ci-3alkyl, and Ci-3alkoxy;R3is selected from the group consisting of halogen, hydroxyl, -N(RD)(RE), cyano, - NO2, Ci-ealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-ealkoxy, Cs-Cecycloalkyl, -C(=O)NRDRE, - NRD(C=O)RE, -O(C=O)NRDRE, -NRD(C=O)ORE, -NRD(C=O)NRDRE, -(C=O)Ci-C6alkyl, - (C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, S(O)2NRDRE, and - NRDS(0)2 Ci-Cealkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, Ci-Cealkyl, and Ci- Cealkoxy;RAis selected from the group consisting of Ci-ealkyl, C3-6cycloalkyl, -C(O)Ci-ealkyl, - C(O)OCi-6alkyl, -C(O)N(RD)(RE), -CH2C(O)N(RD)(RE), -N(RD)(RE), -S(O)2N(RD)(RE), and - S(O)2Ci-ealkyl, wherein the -C(O)Ci-ealkyl, C3-6cycloalkyl, -C(O)Ci-ealkyl, -C(O)OCi-ealkyl, and -S(O)2Ci-ealkyl may be optionally substituted with one or more substituents independently selected from halogen and hydroxyl;RBis independently selected for each occurrence from the group consisting of hydrogen and Ci-ealkyl;Rcis independently selected for each occurrence from the group consisting of hydrogen, Ci-ealkyl, and -C(O)Ci-ealkyl;RDis selected from the group consisting of hydrogen and Ci-ealkyl;REis selected from the group consisting of hydrogen and Ci-ealkyl; m is 0, 1, 2, 3, or 4; and n is 1, 2, or 3.

[0048] In some embodiments, for example, R1is independently selected for each occurrence from the group consisting of chloro, fluoro, -CH3, and -CF3. In other embodiments, L1is selected from the group consisting of, for example, -CH2-,-CH(CH3)-, - C(CH3)2-, and -CF2-. In still other embodiments, L1is absent. In further embodiments, ring B is selected from the group consisting of, for example, phenyl, pyridyl oxazolyl, thiazolyl,IPTS / 200087585.1Attorney Docket No. RTX-003WO cyclopropyl, cyclohexyl, and tetrahydropyranyl. For example, in certain embodiments ring B is phenyl.

[0049] In some embodiments, ring A is selected from the group consisting of, forwherein * denotes the point of attachment to L1.

[0050] In other embodiments, m is 0. In certain embodiments, for example, ring A is selected from the group consisting ofwherein * denotes the point of attachment to L1.

[0051] In some embodiments, RAis selected from the group consisting of, for example, Ci-3alkyl, cyclopropyl, -C(O)Ci-3alkyl, -C(O)OCi-3alkyl, -C(O)N(RD)(RE), - CH2C(O)N(RD)(RE), -S(O)2N(RD)(RE), and -S(O)2Ci-3alkyl, wherein the -C(O)Ci-3alkyl may be optionally substituted with hydroxyl. In further embodiments, RAis selected from the group consisting of, for example, -CH3, -C(H)(CH3)2, cyclopropyl, -C(O)CH3, - C(O)CH2OH, -C(O)OCH3, -CH2C(O)N(RD)(RE), -C(O)N(RD)(RE), -S(O)2CH3, and -IPTS / 200087585.1Attorney Docket No. RTX-003WOSO2NH2. In other embodiments, RDis hydrogen. In still other embodiments, REis, for example, hydrogen or CH3.

[0052] In some embodiments, wherein m is 1. For example, in some embodiments ringA is selected from the group consisting ofwherein * denotes the point of attachment to L1.

[0053] In other embodiments, R2is selected from the group consisting of, for example, hydroxyl, oxo, cyano, Ci-3alkyl, Ci-3alkoxy, -C(O)Ci-ealkyl, -COOH, -C(O)N(RB)(Rc), - S(O)2N(RD)(RE), -C(O)NHC(O)SO2Ci-6alkyl, -C(O)NHC(O)SO2-phenyl, -NH-SO2-C1- ealkyl, -PH(O)Ci -ealkyl, 5-6 membered heteroaryl, and -N(RB)(RC), wherein the Ci-3alkyl may be optionally substituted with one or more substituents independently selected from halogen and hydroxyl. For example, in certain embodiments R2is selected from the group consisting of hydroxyl, oxo, -CF3, -OCH3, -C(O)CH3, -COOH, -SO2NH2, -C(O)N(RB)(Rc), - C(O)NHC(O)SO2CH3-C(O)NHC(O)SO2-phenyl, -NH-SO2-CH3, -PH(O)CH2CH3, tetrazolyl, and -N(RB)(RC). In some embodiments, RBis hydrogen or -CH3. In other embodiments, Rcis, for example, hydrogen or -CH3.

[0054] In some embodiments, m is 2. In certain embodiments, for example, ring A is selected from the group consisting ofIPTS / 200087585.1Attorney Docket No. RTX-003WOwherein * denotes the point of attachment to L1.

[0055] In other embodiments, R2is independently selected for each occurrence from the group consisting of, for example, hydroxyl, halogen, -CH3, -CH2OH, -C(CH3)2OH, -OCH3, - CH2OCH3, -C(0)NH2, -COOH, and oxetanyl.

[0056] In some embodiments, m is 3. In certain embodiments, for example, ring A is. In other embodiments, R2is independently selected for each occurrence from the group consisting of, for example, hydroxyl, -CH3, and oxo.

[0057] In some embodiments, m is 4. For example, in certain embodiments, ring A is selected from the group consisting ofwherein * denotes the point of attachment to L1.

[0058] In further embodiments, R2is independently selected for each occurrence from the group consisting of, for example, hydroxyl, -CH3, and -COOH. In other embodiments, R3is chloro.

[0059] Also disclosed herein is a compound represented by Formula II:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:IPTS / 200087585.1Attorney Docket No. RTX-003WOR1is independently selected for each occurrence from the group consisting of chloro, fluoro, -CH3, and -CF3;L1is selected from the group consisting of -CH2-,-CH(CH3)-, -C(CH3)2-, and -CF2-; or L1is absent;Ring B is selected from the group consisting of cyclohexenyl, cyclopentenyl, phenyl, pyridyl, pyridonyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydropyranyl, and tetrahydrothiopyranyl; wherein if ring B contains a substitutable ring nitrogen atom, that ring nitrogen atom may be optionally substituted with RF;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, oxo, cyano, Ci-ealkyl, Ci-ealkoxy, -C(O)Ci-ealkyl, -COOH, - C(O)N(RB)(RC), -S(O)2N(RD)(RE), -N(RB)(RC), -C(O)NHC(O)SO2Ci-6alkyl, C(O)NHC(O)SO2-phenyl, -NH-SCh-Ci-ealkyl, -PH(O)Ci -ealkyl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl; wherein Ci-ealkyl and Ci-ealkoxy may be optionally substituted with one or more substituents independently selected from halogen, hydroxyl, and Ci-3alkoxy;RFis selected from the group consisting of Ci-3alkyl, cyclopropyl, -C(O)Ci-3alkyl, - C(O)OCi-3alkyl, -C(O)N(RD)(RE), -CH2C(O)N(RD)(RE), -S(O)2N(RD)(RE), and -S(O)2Ci- salkyl; wherein -C(O)Ci-ealkyl, C3-6cycloalkyl, -C(O)Ci-ealkyl, and -C(O)OCi-ealkyl may be optionally substituted with one or more substituents each independently selected from halogen and hydroxyl;RGand RHare each independently selected for each occurrence from the group consisting of hydrogen and Ci-ealkyl;R1and RJare each independently selected from the group consisting of hydrogen and Ci-ealkyl; m is 0, 1, 2, 3, or 4; and n is 1, 2, or 3.

[0060] For example, in some embodiments L1is -CH2- or -CH(CH3)-. In other embodiments, L1is absent. In still other embodiments, ring B is selected from the group consisting of, for example:IPTS / 200087585.1Attorney Docket No. RTX-003WO

[0061] In some embodiments, m is 0. In certain embodiments, for example, ring B is selected from the group consisting of

[0062] In other embodiments, RFis selected from the group consisting of, for example, - CH3, -C(H)(CH3)2, cyclopropyl, -C(O)CH3, -C(O)CH2OH, -C(O)OCH3, -C(O)NH2, - C(O)NH(CH3), -S(O)2CH3, and -SO2NH2.

[0063] In further embodiments, m is 1. For example, in some embodiments ring B is selected from the group consisting of

[0064] In some embodiments, R2is selected from the group consisting of, for example, hydroxyl, oxo, -CF3, -OCH3, -C(O)CH3, -COOH, -SO2NH2, -C(O)NH2, -C(O)NH(CH3), -IPTS / 200087585.1Attorney Docket No. RTX-003WOC(O)N(CH3)2, -C(O)NHC(O)SO2CH3 -C(0)NHC(0)S02-phenyl, -NH-SO2-CH3, - PH(O)CH2CH3, tetrazolyl, NH2, -NHCH3, and -N(CH3)2.

[0065] In certain embodiments, m is 2. For example, in some embodiments ring B is selected from the group consisting of

[0066] In other embodiments, R2is independently selected for each occurrence from the group consisting of, for example, hydroxyl, halogen, -CH3, -CH2OH, -C(CH3)2OH, -OCH3, - CH2OCH3, -C(O)NH2, -COOH, and oxetanyl.

[0067] In still other embodiments, m is 3. For example, in some embodiments ring B is

[0068] In further embodiments, R2is independently selected for each occurrence from the group consisting of, for example, hydroxyl, -CH3, and oxo.

[0069] In some embodiments, m is 4. For example, in some embodiments ring B is selected from the group consisting of

[0070] In other embodiments, R2is independently selected for each occurrence from the group consisting of, for example, hydroxyl, -CH3, and -COOH.

[0071] In some embodiments, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof.Table 1. Exemplary compounds.IPTS / 200087585.1Attorney Docket No. RTX-003WOIPTS / 200087585.1Attorney Docket No. RTX-003WOIPTS / 200087585.1Attorney Docket No. RTX-003WOIPTS / 200087585.1Attorney Docket No. RTX-003WOIPTS / 200087585.1Attorney Docket No. RTX-003WOIPTS / 200087585.1Attorney Docket No. RTX-003WOIPTS / 200087585.1Attorney Docket No. RTX-003WOIPTS / 200087585.1Attorney Docket No. RTX-003WOIPTS / 200087585.1Attorney Docket No. RTX-003WOIPTS / 200087585.1Attorney Docket No. RTX-003WOIPTS / 200087585.1Attorney Docket No. RTX-003WO

[0072] In some embodiments, a compound of the present disclosure is selected from the group consisting of:or a pharmaceutically acceptable salt and / or a stereoisomer thereof.

[0073] Procedures for making compounds described herein are provided in the examples below. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxyl, amino, thio or carboxyl groups) to avoid their unwanted participation in the reactions. The incorporation of such groups, and the methods required to introduce and remove them are known to those skilled in the art (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). The deprotection step may be the final step in the synthesis such that the removal of protecting groups affords compounds as disclosed herein. Starting materials used in the following scheme can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known by those skilled in the art. The order in which the steps are performed can vary depending on the groups introduced and the reagents used, but would be apparent to those skilled in the art.

[0074] Compounds disclosed herein, or any of the intermediates described in the schemes above, can be further derivatized by using one or more standard synthetic methods known to those skilled in the art. Such methods can involve substitution, oxidation orIPTS / 200087585.1Attorney Docket No. RTX-003WO reduction reactions. These methods can also be used to obtain or modify disclosed compounds or any preceding intermediates by modifying, introducing or removing appropriate functional groups.

[0075] Where it is desired to obtain a particular enantiomer of a disclosed compound, this may be produced from a corresponding mixture of enantiomers by employing any suitable conventional procedure for resolving enantiomers known to those skilled in the art. For example, diastereomeric derivatives (such as salts) can be produced by reaction of a mixture of enantiomers of a disclosed compound (such a racemate) and an appropriate chiral compound (such as a chiral base). The diastereomers can then be separated by any conventional means such as crystallization or chromatography, and the desired enantiomer recovered (such as by treatment with an acid in the instance where the diastereomer is a salt). Alternatively, a racemic mixture of esters can be resolved by kinetic hydrolysis using a variety of biocatalysts (for example, see Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).

[0076] In another resolution process a racemate of disclosed compounds can be separated using chiral High Performance Liquid Chromatography. Alternatively, a particular enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described above. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the disclosure.

[0077] In an alternative embodiment, disclosed compounds may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,13C or14C; oxygen may be, for example,18O; nitrogen may be, for example,15N, and the like. In other embodiments, a particular isotope (e.g.,3H,13C,14C,18O, or15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.II. Methods

[0078] Also disclosed herein are methods of treating a patient suffering from a condition, disease, or disorder that is affected by, associated with, or would benefit fromIPTS / 200087585.1Attorney Docket No. RTX-003WO antagonism of V2R, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0079] For example, disclosed herein are methods of treating a V2R protein-related disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0080] In some embodiments, the present disclosure provides a method of treating a disease or disorder responsive to V2R antagonism. In some embodiment, the disease or disorder is, for example, hyponatremia. On other embodiments, the disease or disorder is, for example, acute or chronic congestive heart failure.

[0081] For example, provided herein is a method of treating a kidney disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein. Also provide herein is a method of treating a kidney disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0082] In some embodiments, the kidney disease or disorder is, for example, autosomal dominant polycystic kidney disease (ADPKD). For example, provided herein is a method of treating autosomal dominant polycystic kidney disease (ADPKD) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein. Also provide herein is a method of treating autosomal dominant polycystic kidney disease (ADPKD) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0083] In some embodiments, the kidney disease or disorder is, for example, autosomal recessive polycystic kidney disease (ARPKD). For example, provided herein is a method of treating autosomal recessive polycystic kidney disease (ARPKD) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein. Also provide herein is a method of treating autosomal recessive polycystic kidney disease (ARPKD) in a patient in need thereof, comprising administeringIPTS / 200087585.1Attorney Docket No. RTX-003WO to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0084] Also provided herein is a method of treating an electrolyte disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein. Also provide herein is a method of treating an electrolyte disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0085] In some embodiments, the electrolyte disorder is, for example, hyponatremia. For example, provided herein is a method of treating hyponatremia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein. Also provide herein is a method of treating hyponatremia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0086] In some embodiments, the patient being treating for hyponatremia is also suffering from one or more of, for example, cirrhosis of the liver, congestive heart failure, and / or syndrome of inappropriate antidiuretic hormone (SIADH). Provided herein is a method of treating a kidney disease or disorder in a patient suffering from one or more of: cirrhosis of the liver, congestive heart failure, and / or syndrome of inappropriate antidiuretic hormone (SIADH), and in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein. Also disclosed herein is a method of treating a kidney disease or disorder in a patient suffering from one or more of: cirrhosis of the liver, congestive heart failure, and / or syndrome of inappropriate antidiuretic hormone (SIADH), and in need of such treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0087] Provided herein is a method of treating hyponatremia in a patient suffering from one or more of: cirrhosis of the liver, congestive heart failure, and / or syndrome of inappropriate antidiuretic hormone (SIADH), and in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein. Also disclosed herein is a method of treating a kidney disease or disorder in a patientIPTS / 200087585.1Attorney Docket No. RTX-003WO suffering from one or more of: cirrhosis of the liver, congestive heart failure, and / or syndrome of inappropriate antidiuretic hormone (SIADH), and in need of such treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0088] Also provided herein is a method of treating a cardiovascular disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein. Also provide herein is a method of treating a cardiovascular disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0089] In some embodiments, the cardiovascular disease or disorder is, for example, congestive heart failure. In some embodiments, the congestive heart failure is acute. In other embodiments, the congestive heart failure is chronic. For example, provided herein is a method of treating acute or chronic congestive heart failure in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein. Also provide herein is a method of treating acute or chronic congestive heart failure in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0090] Also disclosed herein are methods of antagonizing vasopressin receptor 2 in a target cell or tissue, comprising contacting the cell or tissue with a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. Further disclosed herein are methods of antagonizing vasopressin receptor 2 in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0091] In particular, in certain embodiments, the disclosure provides a method of treating the medical indications contemplated herein comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein.

[0092] In certain embodiments, a compound described herein is administered as a pure chemical. In some embodiments, the compound described herein is combined with aIPTS / 200087585.1Attorney Docket No. RTX-003WO pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration (e.g., oral administration) and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0093] In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0094] Compounds and pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity). Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0095] For example, in some embodiments a disclosed compound or composition may be administered once daily to the patient. In other embodiments, a disclosed compound or composition may be administered twice daily to the patient.

[0096] In some embodiments, a disclosed compound or pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, a suspension, a dispersion, a solution, or an emulsion. In some embodiments, the pharmaceutical composition is formulated as a tablet, for example, a tablet formulated for oral administration.

[0097] Suitable doses and dosage regimens are determined by conventional rangefinding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compoundIPTS / 200087585.1Attorney Docket No. RTX-003WO disclosed herein. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In some embodiments, the present method involves the administration of about 0.1 pg to about 50 mg of at least one compound described herein per kg body weight of the subject. For a 70 kg patient, dosages of from about 10 pg to about 200 mg of the compound disclosed herein would be more commonly used, depending on a subject’s physiological response.

[0098] By way of example only, the dose of the compound described herein for methods of treating a disease as described herein is about 0.001 to about 1 mg / kg body weight of the subject per day, for example, about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg / kg body weight per day. In some embodiments, the dose of compound described herein for the described methods is about 1 to about 1000 mg / kg body weight of the subject being treated per day, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.

[0099] Further, by way of example only, the dose of the compound for methods of treating a disease as described herein may be a fixed dose, e.g., a fixed dose of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg.

[0100] In some embodiments, a compound described herein is administered in combination with one or more additional therapeutic agents. In certain instances, a compound described herein is administered in combination with a second therapeutic agent. In some embodiments, the benefit experienced by a patient is increased by administering a compound described herein with a second therapeutic agent that also has therapeutic benefit. In one specific embodiment, a compound described herein is co-administered with a second therapeutic agent wherein the compound described herein and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone. The overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit.IPTS / 200087585.1Attorney Docket No. RTX-003WO

[0101] For example, in some embodiments, the one or more additional therapeutic agents may be selected from the group consisting of PKD channel (e.g., the poly cystin channel) correctors and PKD channel potentiators.

[0102] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors (e.g., the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.

[0103] The compounds describe herein are administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds and compositions described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.

[0104] The compounds described herein can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein. For clarity, contemplated herein are both a fixed composition comprising a disclosed compound and another therapeutic agent such as disclosed herein, and methods of administering, separately a disclosed compound and a disclosed therapeutic. For example, provided in the present disclosure is a pharmaceutical composition comprising a compound described herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a disclosed compound and one additional therapeutic agent is administered. In some embodiments, a disclosed compound as defined herein and two additional therapeutic agents are administered. In some embodiments, a disclosed compound as defined herein and three additional therapeutic agents are administered. Combination therapy can beIPTS / 200087585.1Attorney Docket No. RTX-003WO achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a disclosed compound and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a disclosed compound as one therapeutic agent and one or more additional therapeutic agents. For example, a disclosed compound and an additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases, even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.

[0105] The methods described herein include administering to the patient a therapeutically effective amount of at least one compound as described herein, which is optionally formulated in a pharmaceutical composition. In various embodiments, a therapeutically effective amount of at least one compound described herein present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition.III. Pharmaceutical Compositions and Kits

[0106] Another aspect of the disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, intranasal, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. ForIPTS / 200087585.1Attorney Docket No. RTX-003WO example, disclosed compositions may be formulated as a unit dose, and / or may be formulated for oral or subcutaneous administration.

[0107] Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compounds of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0108] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0109] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions mayIPTS / 200087585.1Attorney Docket No. RTX-003WO also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0110] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent.Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

[0111] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0112] Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0113] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.IPTS / 200087585.1Attorney Docket No. RTX-003WO

[0114] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0115] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0116] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0117] Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.Aerosols generally are prepared from isotonic solutions.

[0118] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers,IPTS / 200087585.1Attorney Docket No. RTX-003WO bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0119] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0120] In another aspect, the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenumjejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g. , Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials isIPTS / 200087585.1Attorney Docket No. RTX-003WO either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present disclosure.

[0121] The disclosure also provides kits for use by a e.g., a consumer in need of treatment of a disease or disorder described herein. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[0122] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . “ etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.IPTS / 200087585.1Attorney Docket No. RTX-003WOEXAMPLES

[0123] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.Synthesis of (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Intermediate 1):Step 1 : ethyl (2-(4-chlorobenzoyl)hydrazine-l-carbonyl)glycinate

[0124] A suspension of 4-chlorobenzohydrazide (100.00 g 586.2 mmol, 1.0 eq) in dry THF (IL) was initially charged at 20 °C, and a solution of ethyl 2-isocyanatoacetate (98.40 g, 762.1 mmol, 1.3 eq) in dry THF (IL) was added dropwise. Initially, a solution was obtained, and then a precipitate formed. The mixture was stirred at 20 °C for a further 2 hrs. The crystals were isolated by filtration, washed with a little diethyl ether and dried under high vacuum to give the product (175.0 g, 99% yield) as a white solid. LC-MS (m / z): 300.1 [M+H]+.IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 2: 2-(3-(4-chlorophenyl)-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl) acetic acid

[0125] A mixture of ethyl (2-(4-chlorobenzoyl)hydrazine-l-carbonyl)glycinate (175.00 g 583.9 mmol, 1.0 eq) and 5% NaOH aqueous solution (2L) was stirred under reflux for 16 hrs. The reaction mixture was cooled to RT, adjusted to pH=l~2 with 12N HC1 slowly. The precipitated solid was isolated by filtration, washed with water and dried at 60 °C under reduced pressure to give the product (140 g, 94% yield). LC-MS (m / z): 254.0 [M+H]+.JH NMR (400 MHz, DMSO_d6) 5 =13.25 (br d, J = 7.2Hz, 1H), 12.09 (s, 1H), 7.65-7.56 (m, 4H), 4.45 (s, 2H).Step 3: 5-(4-chlorophenyl)-4-( 3, 3, 3 -trifluor o-2, 2 -dihydroxypropyl) -2, 4-dihydro-3H-l, 2, 4- triazol-3-one & 5-( 4-chlorophenyl)-4-( 3, 3, 3-trifluoro-2-oxopropyl)-2, 4-dihydro-3H-l, 2, 4- triazol-3-one

[0126] To a mixture of 2-(3-(4-chlorophenyl)-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl) acetic acid (20.00 g 78.8 mmol, 1.0 eq) in pyridine (1 L) was added TFAA (66.30 g, 315.6 mmol, 315.6 mmol). During the addition, the temperature increased to about 40 °C. After stirred at 40 °C for 1 hr, the mixture was concentrated to remove pyridine. The residue was added IN HC1 (500 mL). This mixture was stirred at 70 °C for 1 hr. The reaction mixture was treated with EtOAc and water, the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness to give the crude product (20.00 g) which was used in the next step without purification. LC-MS (m / z): 324.0&306.0 [M+H]+.Step 4: (S)-5-(4-chlorophenyl)-4-(3,3,3-trijluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4- triazol-3-one

[0127] To a mixture of 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2,2-dihydroxypropyl)-2,4- dihydro-3H-l,2,4-triazol-3-one & 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-oxopropyl)-2,4- dihydro-3H-l,2,4-triazol-3-one (30.00 g, 98.1 mmol, 1.0 eq) in DMAc(300 ml) was added (S,S)-N-(p-Toluenesulfonyl)-l,2-diphenylethanediamine(chloro)(p-cymene) ruthenium(II) (3.00 g, 4.9 mmol, 0.05 eq), formic acid (22.60 g, 491.0 mmol, 5.0 eq) and TEA (600 mg, 5.9 mmol, 0.06 eq) under N2. The reaction mixture was stirred at 20 °C for 3 hrs. The mixture was added 0.1 N HC1 (300 ml) and extracted with EtOAc. The combined organic phases were washed with saturated Na2COs solution, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel to give the target compound (20.00 g, 70% yield) as a yellow solid. LC-MS (m / z):IPTS / 200087585.1Attorney Docket No. RTX-003WO308.0 [M+H]+. 'HNMR (400 MHz, DMSO-de ) 5 12.11 (s, 1H), 7.82-7.70 (m, 2H), 7.68- 7.57 (m, 2H), 6.86 (d, J = 6.4 Hz, 1H), 4.37-4.24 (m, 1H), 3.93 (dd, J = 14.7, 3.4 Hz, 1H), 3.84-3.70 (m, 1H), 2.95 (s, 1H), 2.79 (s, 1H), 1.99 (s, 1H). The enantiomeric excess (ee) was determined chromatographically as 95%: S enantiomer RT, = 6.34 min, R enantiomer RT, = 7.91 min.Example 1: Synthesis of (S)-5-(4-chlorophenyl)-2-((l-(3-chlorophenyl)-4, 5,6,7- tetrahydro-lH-pyrazolo [3,4-c]pyridin-3-yl)methyl)-4-(3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 101)Step 1: 6-(tert-butyl) 3-ethyl l-(3-chlorophenyl)-l,4,5, 7-tetrahydro-6H-pyrazolo[3,4-c] pyridine-3, 6-dicarboxylate

[0128] A mixture of 6-(tert-butyl) 3-ethyl l,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridine-3, 6-dicarboxylate (600 mg, 2.0 mmol, 1.0 eq), 3-Chlorophenylboronic acid (476 mg, 3.0 mmol, 1.5 eq), Cu(OAc)2 (738 mg, 4.1 mmol, 2.0 eq) were suspended in DCM (20 mL) and pyridine (5 mL). Pumped and refilled with oxygen three times. The resulting mixture was heated to 25 °C to react for 14 hrs under oxygen atmosphere. The reaction solution was concentrated. The residue was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with brine, dried over MgSO4, and concentrated to dryness. The crude product was purified through column chromatography to obtain a colorless oil compound (200 mg, 24% yield). LC-MS(m / z): 406.2 [M+H]+. 'H NMR (400 MHz, CHLOROFORM-d) 5 7.59 (s, 1H), 7.50-7.35 (m, 3H), 4.66 (br s, 2H), 4.50-4.40 (m, 2H), 3.71 (br t, J= 5.5 Hz, 2H), 2.94 (br t, J= 5.6 Hz, 2H), 1.49 (s, 9H), 1.43 (t, J= 7.1 Hz, 3H).IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 2: tert-butyl l-(3-chlorophenyl)-3-(hydroxymethyl)-l,4,5, 7-tetrahydro-6H- pyrazolo[3, 4-c] pyridine-6-carboxylate

[0129] 6-(tert-butyl) 3-ethyl l-(3-chlorophenyl)-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-c] pyridine-3,6-dicarboxylate (200 mg, 493 pmol, 1.0 eq) was dissolved in THF (4 mL), then LAH (28 mg, 738 pmol, 1.5 eq) was added at 0 °C. The reaction mixture was stirred 1 hr at 0 °C. The reaction mixture was added H2O (28 mg), 15% NaOH (28 mg), H2O (84 mg) at 0 °C, dried over MgSCh and evaporated to dryness to afford the crude product (150 mg) as a light yellow oil, which was used directly in the next step without further purification. LC- MS (m / z): 364.1 [M+H]+.Step 3: tert-butyl 3-(chloromethyl)-l-(3-chlorophenyl)-l,4,5, 7-tetrahydro-6H-pyrazolo [3,4- c] pyridine-6-carboxylate

[0130] tert-butyl l-(3-chlorophenyl)-3-(hydroxymethyl)-l,4,5,7-tetrahydro-6H-pyrazolo [3, 4-c] pyridine-6-carboxylate (150 mg, 412 pmol, 1.0 eq), TEA (83 mg, 820 pmol, 2.0 eq) were dissolved in DCM (5 mL), then EsCl (58 mg, 451 pmol, 1.1 eq) was added at 0 °C. The reaction mixture was stirred 16 hrs at 15 °C. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a light yellow oil crude product (70 mg, 44% yield). LC- MS (m / z): 382.2 [M+H]+.Step 4: tert-butyl (S)-l-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-l, 4, 5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0131] A mixture of tert-butyl 3-(chloromethyl)-l-(3-chlorophenyl)-l,4,5,7-tetrahydro- 6H-pyrazolo[3,4-c] pyridine-6-carboxylate (70 mg, 183 pmol, 1.0 eq), (S)-5-(4-chloro phenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (61 mg, 198 pmol, 1.1 eq), K2CO3 (76 mg, 550 pmol, 3.0 eq) were suspended in MeCN (5 mL). Pumped and refilled with nitrogen three times. The resulting mixture was heated to 80 °C to react for 16 hrs under a nitrogen atmosphere. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSO4, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (100 mg, 84% yield). LC-MS (m / z): 653.2 [M+H]+.IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 5: (S)-5-(4-chlorophenyl)-2-((l-(3-chlorophenyl)-4,5,6, 7-tetrahydro-lH-pyrazolo[3,4- c ]pyridin-3-yl)methyl)-4-(3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4-triazol-3- one

[0132] tert-butyl (S)- 1 -(3 -chlorophenyl)-3-((3 -(4-chlorophenyl)-5-oxo-4-(3 ,3 ,3 -trifluoro -2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl) methyl)- 1,4, 5, 7-tetrahydro-6H- pyrazolo[3,4-c] pyridine-6-carboxylate (100 mg, 153 pmol,1.0 eq) was dissolved in 1,4- dioxane (1 mL), then HCl / dioxane (4 M, 2 mL, 52.0 eq) was added. The reaction mixture was stirred 16 hrs at 15 °C. The reaction solution was concentrated then added water. The mixture was adjusted to pH=8-9 with saturated NaHCCh solution. The reaction mixture was treated with water and DCM, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (20 mg, 24% yield). LC-MS (m / z): 553.2 [M-H] 'H NMR (400 MHz, DMSO-de) 57.75 (brd, J=8.6Hz,2H), 7.66-7.57 (m,3H), 7.56-7.50 (m, 1H), 7.497.45 (m,lH),7.42 (brd, J=7.8Hz, 1H),6.9O (brd,J=6.4Hz, 1H), 4.98 (s, 2H),4.42-4.23(m, lH),4.17-3.88(m,4H),3.87- 3.79(m,lH),2.88(brt,J=5.4Hz,2H),2.45-2.35(m, 2H).Example 2: Synthesis of (S)-2-((l-(2-chlorobenzyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4- c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Compound 102)Step 1: 6-(tert-butyl) 3-ethyl l-(2-chlorobenzyl)-l,4,5, 7-tetrahydro-6H-pyrazolo[3,4- c]pyridine-3, 6-dicarboxylateIPTS / 200087585.1Attorney Docket No. RTX-003WO

[0133] A mixture of 6-(tert-butyl) 3-ethyl l,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridine-3,6-dicarboxylate (360 mg, 1.2 mmol, 1.0 eq), 2-Chlorobenzyl bromide (275 mg, 1.3 mmol, 1.1 eq), CS2CO3 (1.19 g, 3.6 mmol, 3.0 eq) were suspended in MeCN (12 mL). Pumped and refilled with nitrogen three times. The resulting mixture was heated to 80 °C to react for Ihr under a nitrogen atmosphere. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a light yellow oil product (350 mg, 68% yield). LC-MS (m / z): 420.2 [M+H]+. 'HNMR (400 MHz, CHLOROFORM-d) 5 7.41 (br d, J = 7.8 Hz, 1H), 7.33- 7.13 (m, 2H), 7.09-6.70 (m, 1H), 5.46 (s, 2H), 4.54-4.25 (m, 4H), 3.61 (br t, J = 5.4 Hz, 2H), 2.88 (t, J = 5.6 Hz, 2H), 2.06 (s, 1H), 1.59-1.36 (m, 12H).Step 2: tert-butyl l-(2-chlorobenzyl)-3-(hydroxymethyl)-l,4,5, 7-tetrahydro-6H-pyrazolo[3,4- c ]pyridine-6-carboxylate

[0134] 6-(tert-butyl) 3-ethyl l-(2-chlorobenzyl)-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-c] pyridine-3,6-dicarboxylate (300 mg, 714 pmol, 1.0 eq) was dissolved in THF (5 mL), then LAH (41 mg, 1.1 mmol, 1.5 eq) was added at 0 °C. The reaction mixture was added H2O (41 mg), 15% NaOH (41 mg), H2O (41 mg) at 0 °C, dried over MgSCh and evaporated to dryness to afford the crude product (240 mg) as a light yellow oil, which was used directly in the next step without further purification. LC-MS (m / z): 378.2 [M+H]+.Step 3: tert-butyl l-(2-chlorobenzyl)-3-(chloromethyl)-l,4,5, 7-tetrahydro-6H-pyrazolo[3,4- c] pyridine-6-carboxylate

[0135] tert-butyl l-(2-chlorobenzyl)-3-(hydroxymethyl)-l,4,5,7-tetrahydro-6H-pyrazolo [3,4-c]pyridine-6-carboxylate (240 mg, 6359 pmol, 1.0 eq), TEA (128 mg, 1.3 mmol, 2.0 eq) were dissolved in DCM (8 mL), then EsCl (89 mg, 692 pmol, 1.1 eq) was added at 0 °C. The reaction mixture was stirred 3 hrs at 20 °C. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSO4, and concentrated to dryness. The crude product was purified through column chromatography to obtain a light yellow oil product (100 mg, 40% yield). LC-MS (m / z): 396.0 [M+H]+.Step 4: tert-butyl (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-l, 4, 5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylateIPTS / 200087585.1Attorney Docket No. RTX-003WO

[0136] A mixture of tert-butyl l-(2-chlorobenzyl)-3-(chloromethyl)-l,4,5,7-tetrahydro- 6H-pyrazolo[3,4-c] pyridine-6-carboxylate (100 mg, 252 pmol, 1.0 eq), 5-(4-Chloro- phenyl)-4-(3,3,3-trifluoro-2-hydroxy-propyl)-2,4-dihydro-[l,2,4]triazol-3-one(85 mg, 276 pmol, 1.1 eq) , K2CO3 (105 mg, 760 pmol, 3.0 eq) were suspended in MeCN (5 mL).Pumped and refilled with nitrogen three times. The resulting mixture was heated to 80 °C to react for 16 hr under a nitrogen atmosphere. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (100 mg, 59% yield). LC-MS (m / z): 668.8 [M+H]+.Step 5:(S)-2-((l-(2-chlorobenzyl)-4,5, 6, 7-tetrahydro-lH-pyrazolo[3,4-c]pyridin-3- yl)methyl)-5-( 4-chlorophenyl)-4-( 3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4- triazol-3-one

[0137] tert-butyl (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro- 2-hydroxypropyl)-4, 5 -dihydro- 1H- 1 ,2,4-triazol- l-yl)m ethyl)- 1 ,4,5,7-tetrahydro-6H- pyrazolo[3,4-c]pyridine-6-carboxylate (100 mg, 150 pmol, 1.0 eq) was dissolved in 1,4- di oxane (2 mL), then HCl / dioxane(4 M, 2 mL, 53.0 eq) was added in the reaction mixture. The reaction mixture was stirred 16 hrs at 15 °C. The reaction solution was concentrated then added water. The mixture was adjusted to pH=8-9 with saturated NaHCCh solution.The reaction mixture was treated with water and DCM, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (27 mg, 32% yield). LC-MS (m / z):566.8[M+H]+.1HNMR(400MHZ,DMSO_d6): 7.73(d,lH),7.62(d,lH), 7.48-7.49 (m, 1H), 7.28-7.33(m,2H),6.87- 6.89(m,2H),5.23(s,2H),4.87(s,2H), 4.28-4.30 (m, 1H), 3.95-4.00 (m,lH),3.75-3.85(m, lH),3.67(s, 2H),2.76-2.79(m, 2H),2.33-2.35(m, 2H).Example 3: Synthesis of (S)-5-(4-chlorophenyl)-2-((l-(3-chlorophenyl)-4, 5,6,7- tetrahydro-lH-indazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one (Compound 103)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: ethyl l-(3-chlorophenyl)-4,5,6, 7-tetrahydro-lH-indazole-3-carboxylate

[0138] To a mixture of ethyl 4,5,6,7-tetrahydro-lH-indazole-3-carboxylate (600 mg, 3.1 mmol, 1.0 eq) and Cu(OAc)2 (1.12 g, 6.2 mmol, 2.0 eq) in DCM (20 mL) and pyridine (5 mL) was added (3-chlorophenyl)boronic acid (724 mg, 4.6 mmol, 1.5 eq). The mixture was degassed and backfilled with O2 three times. The reaction mixture was stirred at 25 °C under O2 atmosphere (15 psi) for 14 hrs. The reaction mixture was diluted with DCM (30 mL), which was filtered through a pad of Celite and the filter cake was washed with DCM (10 mL). The combined filtrate was concentrated to remove the solvent to give the crude product, which was diluted with EtOAc. The mixture was washed with water and brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (280 mg, 30% yield) as a colorless oil. LC-MS (m / z): 305.1 [M+H]+. 'H NMR (400 MHz, CDCh) 5 7.64-7.58 (m, 1H), 7.46-7.34 (m, 3H), 5.63 (s, 1H), 4.49-4.40 (m, 2H), 2.93-2.81 (m, 2H), 2.78-2.68 (m, 2H), 1.90-1.78 (m, 4H), 1.43 (t, J= 7.1 Hz, 3H).Step 2: (l-(3-chlorophenyl)-4,5,6, 7-tetrahydro-lH-indazol-3-yl) methanol

[0139] To a stirred solution of ethyl 1 ethyl l-(3-chlorophenyl)-4,5,6,7-tetrahydro-lH- indazole-3 -carboxylate (280 mg, 919 pmol, 1.0 eq) in THF (5 mL) was added LAH (52 mg, 1.4 mmol, 1.5 eq) at 0 °C under N2 atmosphere, then the reaction mixture was stirred at 25 °C for Ihr. The reaction was quenched by addition of H2O (0.1 mL) and 15% aqueous NaOH (0.1 mL) at 0°C and the mixture was diluted with THF (50 mL), then anhydrous MgSCh (2.00 g) was added. The suspension was filtered through a pad ofIPTS / 200087585.1Attorney Docket No. RTX-003WOCelite and the filter cake was washed with THF (20 mL). The combined filtrate was concentrated to dryness to give the crude product. The crude product was purified by silica gel chromatography to give the title compound (75 mg, 31% yield) as a colorless oil. LC-MS (m / z): 263.1 [M+H]+.Step 3: 3-(chloromethyl)-l-(3-chlorophenyl)-4,5,6, 7 -tetrahydro- IH-indazole

[0140] To a stirred solution of (l-(3-chlorophenyl)-4,5,6,7-tetrahydro-lH-indazol-3-yl) methanol (75 mg, 285 pmol, 1.0 eq) in DCM (3 mL) was added SOCh (51 mg, 428 pmol, 1.5 eq) at 0 °C under N2 atmosphere, then the reaction mixture was stirred at 0 °C for Ihr. The reaction mixture was concentrated in vacuo to dryness to give the title compound (10 mg, 12% yield) as a light yellow oil. LC-MS (m / z): 325.1 [M+ H]+.Step 4: (S)-5-(4-chlorophenyl)-2-((l-(3-chlorophenyl)-4,5,6, 7-tetrahydro-lH-indazol-3- yl)methyl)-4-( 3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4-triazol-3-one

[0141] To a solution of 3-(chloromethyl)-l-(3-chlorophenyl)-4,5,6,7-tetrahydro-lH- indazole (10 mg, 36 pmol, 1.0 eq) and (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (12 mg, 39 pmol, 1.1 eq) in MeCN (3 mL) was added K2CO3 (10 mg, 72 pmol, 2.0 eq). Then the mixture was stirred at 80 °C for 6 hrs. The reaction mixture was cooled to rt, which was diluted with EtOAc (30 mL). The mixture was washed with water (10 mL) and brine (10 mL), dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (5 mg, 25% yield) as a white solid. LC-MS (m / z): 552.1 [M+H]+. 'H NMR (400 MHz, DMSO-de) 5 (ppm) = 7.77 - 7.72 (m, 2H), 7.65 - 7.59 (m, 3H), 7.55 - 7.50 (m, 2H), 7.46 - 7.39 (m, 1H), 6.88 (d, J= 6.4 Hz, 1H), 4.96 (s, 2H), 4.34 - 4.24 (m, 1H), 4.02 - 3.96 (m, 1H), 3.89 - 3.78 (m, 1H), 2.83 - 2.72 (m, 2H), 2.47 - 2.40 (m, 2H), 1.77 - 1.65 (m, 4H).Example 4: Synthesis of (S)-2-((l-(2-chlorobenzyl)-4,5,6,7-tetrahydro-lH-indazol-3- yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Compound 104)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: ethyl l-(2-chlorobenzyl)-4,5,6, 7-tetrahydro-lH-indazole-3-carboxylate

[0142] A mixture of ethyl 4,5,6,7-tetrahydro-lH-indazole-3-carboxylate (450 mg, 2.3 mmol, 1.0 eq), 2-Chlorobenzyl bromide (523 mg, 2.5 mmol, 1.1 eq), Cs2CO3 (2.26 g, 6.9 mmol, 3.0 eq) was suspended in MeCN (12 mL). Pumped and refilled with nitrogen three times. The resulting mixture was heated to 80 °C to react for Ihr under a nitrogen atmosphere. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a light yellow oil product (450 mg, 61% yield). LC-MS (m / z): 319.2 [M+H]+.JH NMR (400 MHz, CHLOROFORM-d) 5 7.42-7.34 (m, 1H), 7.26-7.13 (m, 2H), 6.70-6.52 (m, 1H), 5.45 (s, 2H), 4.49-4.36 (m, 2H), 2.80 (t, J = 5.8 Hz, 2H), 2.44 (t, J = 5.9 Hz, 2H), 1.88- 1.71 (m, 4H), 1.42 (t, J = 7.1 Hz, 3H).Step 2: (l-(2-chlorobenzyl)-4,5,6, 7-tetrahydro-lH-indazol-3-yl) methanol

[0143] Ethyl l-(2-chlorobenzyl)-4,5,6,7-tetrahydro-lH-indazole-3-carboxylate (250 mg, 784 pmol, 1.0 eq) was dissolved in THF (5 mL), then LAH (45 mg, 1.2 mmol, 1.5 eq) was added at 0 °C. The reaction mixture was stirred 1 hr at 20 °C. The reaction mixture was added H2O (45 mg), 15% NaOH (45 mg), H2O (45 mg) at 0 °C, dried over MgSCh and evaporated to dryness. The crude product was purified through column chromatography to obtain a white solid product (160 mg, 74% yield). LC-MS (m / z): 277.1 [M+H]+.Step 3: l-(2-chlorobenzyl)-3-(chloromethyl)-4,5,6, 7-tetrahydro-lH-indazole

[0144] (l-(2-chlorobenzyl)-4,5,6,7-tetrahydro-lH-indazol-3-yl) methanol (160 mg, 578 pmol, 1 eq), TEA (87 mg, 860 pmol, 1.5 eq) were dissolved in DCM (5 mL), then EsCl (81IPTS / 200087585.1Attorney Docket No. RTX-003WO mg, 630 pmol, 1.1 eq) was added at 0 °C. The reaction mixture was stirred 2 hrs at 20 °C. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a light yellow oil product (70 mg, 41% yield). LC-MS (m / z): 296.2 [M+H]+.Step 4: (S)-2-((l-(2-chlorobenzyl)-4,5,6, 7-tetrahydro-lH-indazol-3-yl)methyl)-5-(4- chlorophenyl)-4-( 3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4-triazol-3-one

[0145] A mixture of l-(2-chlorobenzyl)-3-(chloromethyl)-4,5,6,7-tetrahydro-lH- indazole (70 mg, 237 pmol, 1.0 eq), (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (7 7mg, 250 pmol, 1.1 eq), K2CO3 (98 mg, 709 pmol, 3.0 eq) were suspended in MeCN (5 mL). Pumped and refilled with nitrogen three times. The resulting mixture was heated to 80 °C to react for 16 hrs under a nitrogen atmosphere. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSO4, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (60 mg, 45% yield). LC-MS (m / z):565.8[M+H]+.1HNMR(400MHZ,DMSO_d6):7.71-7.73(m,lH),7.62(d,lH), 7.47-7.49 (m,lH),7.27-7.33(m,2H), 6.88(d, 1H), 6.76(d, lH),5.28(s,2H),4.85(m,2H),4.21-4.28(m, 1H), 3.96-4.00 (m, lH),3.81-3.85(m, lH),2.47-2.49(m, 2H),2.37-2.40(m, 2H).Example 5: Synthesis of (S)-2-((l-(2-chlorobenzyl)-6-methyl-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 105)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: 6-(tert-butyl) 3-ethyl l-(2-chlorobenzyl)-l,4,5, 7-tetrahydro-6H-pyrazolo[3,4- c]pyridine-3, 6-dicarboxylate

[0146] A mixture of 6-(tert-butyl) 3-ethyl l,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridine-3,6-dicarboxylate(2.00 g, 6.8 mmol, 1.0 eq), 2-Chlorobenzyl bromide (1.53 g, 7.4 mmol, 1.1 eq), CS2CO3 (6.62 g, 20.3 mmol, 3.0 eq) were suspended in MeCN (30 mL). Pumped and refilled with nitrogen three times. The resulting mixture was heated to 80 °C to react for 1 hr under a nitrogen atmosphere. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a light yellow oil product (1.80 g, 63% yield). LC-MS (m / z):420.2 [M+H]+ 1H NMR (400 MHz, CHLOROFORM-d) 5 7.41 (br d, J = 7.8 Hz, 1H), 7.33- 7.13 (m, 2H), 7.09-6.70 (m, 1H), 5.46 (s, 2H), 4.54-4.25 (m, 4H), 3.61 (br t, J = 5.4 Hz, 2H), 2.88 (t, J = 5.6 Hz, 2H), 2.06 (s, 1H), 1.59-1.36 (m, 12H).Step 2: tert-butyl l-(2-chlorobenzyl)-3-(hydroxymethyl)-l,4,5, 7-tetrahydro-6H-pyrazolo[3,4- c ]pyridine-6-carboxylate

[0147] 6-(tert-butyl) 3-ethyl l-(2-chlorobenzyl)-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-c] pyridine-3, 6-dicarboxylate (1.80 g, 4.3 mmol, 1.0 eq) was dissolved in THF (20 mL), then LAH (245 mg, 6.5 mmol, 1.5 eq) was added at 0 °C. The reaction mixture was stirred 0.5 hrIPTS / 200087585.1Attorney Docket No. RTX-003WO at 0 °C. The reaction mixture was quenched by addition of H2O (245mg), 15% aqueous NaOH (245 mg) and H2O (245 mg), dried over MgSCh and evaporated to dryness. The crude product was purified through column chromatography to obtain a white solid product (1.45 g, 89% yield).LC-MS (m / z): 378.2 [M+H]+.Step 3: tert-butyl l-(2-chlorobenzyl)-3-(chloromethyl)-l,4,5, 7-tetrahydro-6H-pyrazolo [3,4- c ]pyridine-6-carboxylate

[0148] tert-butyl l-(2-chlorobenzyl)-3-(hydroxymethyl)-l,4,5,7-tetrahydro-6H-pyrazolo [3,4-c]pyridine-6-carboxylate (1.20 g, 3.2 mmol, 1.0 eq),TEA(642 mg, 6.3 mmol, 2.0 eq) were dissolved in DCM (15 mL), then EsCl (613 mg, 4.8 mmol, 1.5 eq) was added at 0 °C. The reaction mixture was stirred 2 hrs at 15 °C. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a light yellow oil product (750 mg, 60% yield). LC-MS (m / z): 396.0 [M+H]+.Step 4: tert-butyl (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-l, 4, 5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0149] A mixture of tert-butyl l-(2-chlorobenzyl)-3-(chloromethyl)-l,4,5,7-tetrahydro- 6H-pyrazolo[3,4-c]pyridine-6-carboxylate (750 mg, 1.9 mmol, 1.0 eq), (S)-5-(4- chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (700 mg, 2.3 mmol, 1.2 eq), K2CO3 (785 mg, 5.7 mmol, 3.0 eq) were suspended in MeCN (15 mL). Pumped and refilled with nitrogen three times. The resulting mixture was heated to 80 °C to react for 16 hrs under a nitrogen atmosphere. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSO4, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (850 mg, 67% yield). LC- MS (m / z): 668.8 [M+H]+.Step 5: (S)-2-((l-(2-chlorobenzyl)-4,5,6, 7 -tetrahydro- IH-pyrazolo [3, 4-c]pyridin-3- yl)methyl)-5-( 4-chlorophenyl)-4-( 3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4- triazol-3-one

[0150] tert-butyl (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro -2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl) methyl)- 1,4,5, 7-tetrahydro-6H-IPTS / 200087585.1Attorney Docket No. RTX-003WO pyrazolo[3,4-c] pyridine-6-carboxylate (850 mg, 1.3 mmol, 1.0 eq) was dissolved in HCl / Dioxane (4 M, 10 mL, 31.4 eq). The reaction mixture was stirred 3 hrs at 15 °C. The reaction solution was concentrated then added water. The mixture was adjusted to pH=8-9 with saturated NaHCCh solution. The reaction mixture was treated with water and DCM, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness to afford the white solid product (720 mg, 99% yield). LC-MS (m / z): 566.8 [M+H]+.1HNMR(400MHZ,DMSO_d6): 7.73(d, lH),7.62(d, 1H),7.48- 7.49(m, lH),7.28-7.33(m, 2H),6.87-6.89(m, 2H), 5.23(s, 2H), 4.87(s,2H),4.28- 4.30(m,lH),3.95-4.00(m,lH), 3.75-3.85(m, lH),3.67(s, 2H),2.76-2.79(m, 2H),2.33-2.35(m, 2H).Step 6: (S)-2-((l-(2-chlorobenzyl)-6-methyl-4,5,6, 7 -tetrahydro- IH-pyrazolo [3, 4-c]pyridin- 3-yl)methyl)-5-( 4-chlorophenyl)-4-( 3, 3, 3-trifhioro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4- triazol-3-one

[0151] (S)-2-((l-(2-chlorobenzyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridin-3-yl) methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4 - triazol-3-one (100 mg, 176 pmol, 1.0 eq) was dissolved in MeOH (3 mL), then methanal (29 mg, 357 pmol, 37% purity, 2.0 eq), CH3COOH (11 mg, 183 pmol, 1.0 eq)were added in mixture. 0.5hr later, NaBH(OAc)3 (112 mg, 528 pmol, 3.0 eq) was added in mixture. The reaction mixture was stirred 16 hrs at 15 °C. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (41 mg, 40 % yield). LC-MS (m / z): 582.8 [M+H]+.1HNMR(400MHz,DMSO-d6) 57.73(brd, J=8.1Hz, 2H),7.63(brd, J=8.3Hz, 2H), 7.49 (brd, J=7.8Hz, 1H), 7.38-7.25 (m, 2H), 6.90 (brd, J=6.1Hz, 1H),6.79 (brd, J=7.1Hz, 1H), 5.25(s, 2H), 4.87(s, 2H), 4.29 (brd, J=5.1Hz, 1H), 4.05-3.93(m, 1H),3.88- 3.77(m, 1H), 3.35 (brd, J= 10.5Hz, 4H), 2.45(brd, J=4.2Hz, 2H),2.31(s, 3H).Example 6: Synthesis of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-l,4,5,7- tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide (Compound 106)IPTS / 200087585.1Attorney Docket No. RTX-003WO

[0152] A mixture of (S)-2-((l-(2-chlorobenzyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4- c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one (100 mg, 176 pmol, 1.0 eq), hydrochloric acid (1 M, 0.4 mL, 2.3 eq), potassium cyanate (43 mg, 530 pmol, 3.0 eq)were suspended in H2O (5mL). The reaction mixture was stirred 16 hrs at 60 °C. The mixture was adjusted to pH=8-9 with saturated NaHCCh solution. The reaction mixture was treated with water and DCM, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (61 mg, 57% yield). LC-MS (m / z):610.2[M+H]+.1HNMR(400MHz,DMSO-d6) 57.78-7.69(m,2H),7.68-7.58(m, 2H),7.56-7.43(m,lH), 7.40- 7.24(m,2H),6.90(d,J=6.4Hz,lH),6.85-6.78(m,lH), 6.12(s, 2H),5.27(s,2H),4.95-4.8 l(m,2H), 4.4 l(s,2H), 4.34-4.2 l(m, 1H), 4.00-3.94(m,lH), 3.87-3.74(m,lH), 3.48(brt, J=5.6Hz, 2H),2.45(brt, J=5.4Hz,2H).Example 7: Synthesis of (S)-2-((l-(2-chlorobenzyl)-7-methoxy-lH-pyrazolo[3,4- c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Compound 107)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: 7-methoxy-lH-pyrazolo[3,4-c]pyridine

[0153] To a CH3OH (10 mL) solution of 7-chloro-lH-pyrazolo[3,4-c]pyridine (500 mg, 3.3 mmol, 1.0 eq) was added CH3OK (1.14 g, 16.3 mmol, 5.0 eq). The reaction mixture was heated at 90 °C for 12 hrs under a nitrogen atmosphere. The reaction solution was concentrated then the residue was treated with water and EtOAc, and the organic phase was isolated, then concentrated to dryness to obtain the title compound as white solid (410 mg, 84% yield), which was used directly for the next step. LC-MS ( m z y. 150.1 [M+H]+.Step 2: 3-bromo-7 -methoxy- IH-pyrazolo [3, 4-c]pyridine

[0154] To a DMF (5 mL) solution of 7-methoxy-lH-pyrazolo[3,4-c]pyridine (410 mg, 2.7 mmol, 1.0 eq) was added NBS (513 mg, 2.9 mmol, 1.1 eq) in several portions. The reaction mixture was stirred for 16 hrs at ambient temperature. The reaction mixture was treated with water and EtOAc, the separated organic layer was washed with water, dried over MgSO4 and evaporated to dryness to afford the title compound (620 mg, 99% yield). LC-MS (m / z):229.9 [M+H]+.Step 3: 3-bromo-l-(2-chlorobenzyl)-7-methoxy-lH-pyrazolo[3, 4-c]pyridine

[0155] To a DMF (10 mL) solution of 3-bromo-7-methoxy-lH-pyrazolo[3,4-c]pyridine (620 mg, 2.7 mmol, 1.0 eq) was added K2CO3 (1.13 g, 8.2 mmol, 3.0 eq) and 1- (bromomethyl)-2-chloro-benzene (671 mg, 3.3 mmol, 1.2 eq). The reaction mixture wasIPTS / 200087585.1Attorney Docket No. RTX-003WO heated at 80 °C for 2 hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid (710 mg, 74% yield). LC-MS (m / z):351.8 [M+H]+.Step 4: methyl l-(2-chlorobenzyl)-7-methoxy-lH-pyrazolo[3,4-c]pyridine-3- carboxylate

[0156] A mixture of 3-bromo-l-(2-chlorobenzyl)-7-methoxy-lH-pyrazolo[3,4-c] pyridine (650 mg, 1.8 mmol, 1.0 eq), Pd(dppf)C12 (135 mg, 185 pmol, 0.1 eq), TEA (560 mg, 5.5 mmol, 3.0 eq) was suspended in CH3OH (50 mL). Pumped and refilled with CO three times. The resulting mixture was heated to 90 °C to react for 16 hrs under a 3 Mpa CO atmosphere. The reaction solution was concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid (402 mg, 66% yield). LC- MS m / zy. 331.9 [M+H]+.Step 5: (l-( 2-chlorobenzyl)-7-methoxy-lH-pyrazolo[ 3, 4-c ]pyridin-3-yl)methanol

[0157] To an anhydrous THF (8 mL) solution of methyl l-(2-chlorobenzyl)-7-methoxy- lH-pyrazolo[3,4-c] pyridine-3 -carboxylate (400 mg, 1.2 mmol, 1.0 eq) was cooled in icewater bath, then added LiAlEL (68 mg, 1.8 mmol, 1.5 eq) in portions. The resulting mixture was stirred at 0~4 °C for 2 hrs. The reaction solution was quenched by addition of 68 mg of H2O, followed by 68 mg of 15% aqueous NaOH and H2O (68 mg). After being stirred at room temperature for 0.5 hr, the solid was removed by filtration. The filtrate was concentrated to dryness to give crude targeted product (300 mg) as pale yellow solid. LC- MS m / zy 304.0 [M+H]+. 'H NMR (400 MHz, DMSO-t / e) 5 7.74 (d, J= 6.0 Hz, 1H), 7.51- 7.49 (m, 1H), 7.42 (d, J= 5.6 Hz, 1H), 7.32-7.23 (m, 2H), 6.74-6.71 (m, 1H), 5.88 (s, 2H), 5.39 (t, J= 6.0 Hz, 1H), 4.76 (d, J= 6.0 Hz, 2H), 3.99 (s, 3H).Step 6: l-(2-chlorobenzyl)-3-(chloromethyl)-7-methoxy-lH-pyrazolo[3,4-c]pyridine

[0158] To a anhydrous DCM (5 mL) solution of (l-(2-chlorobenzyl)-7-methoxy-lH- pyrazolo[3,4-c]pyri din-3 -yl)methanol (300 mg, 988 pmol, 1.0 eq) and TEA (200 mg, 2.0 mmol, 2.0 eq) was cooled in ice-water bath, then added EsCl (190 mg, 1.5 mmol, 1.5 eq) in dropwise. The resulting mixture was stirred at ambient temperature for 4 hr. The reaction solution was treated with water and EtOAc, then the organic phase was isolated, and concentrated to dryness. The crude product was purified through column chromatography to obtain a colorless oil (150 mg, 47% yield). LC-MS m / zy 323.9 [M+H]+.IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 7: (S)-2-((l-(2-chlorobenzyl)-7-methoxy-lH-pyrazolo[3,4-c]pyridin-3-yl)methyl) -5-(4- chlorophenyl)-4-( 3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4-triazol-3-one

[0159] l-(2-chlorobenzyl)-3-(chloromethyl)-7-methoxy-lH-pyrazolo[3,4-c]pyridine (150 mg, 466 pmol, 1.0 eq), (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxy propyl)- 2,4-dihydro-3H-l,2,4-triazol-3-one (143 mg, 465 pmol, 1.0 eq), K2CO3 (193 mg, 1.4 mmol, 3.0 eq) was suspended in CH3CN (5 mL). The resulting mixture was heated to 70 °C to react for 5 hrs. The reaction solution was treated with water and EtOAc, and the organic phase was isolated, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid (170 mg, 62% yield). LC-MS (m / z): 592.9 [M+H]+. 'HNMR (400 MHz, DMSO ) 5 7.76 (d, J= 5.6 Hz, 1H), 7.72-7.69 (m, 2H), 7.63-7.60 (m, 2H), 7.50 (d, J= 1.2 Hz, 1H), 7.35-7.34 (m, 2H), 7.21-7.19 (m, 1H), 6.88 (d, J= 6.4 Hz, 1H), 6.74 (d, J= 6.0 Hz, 1H), 5.91 (s, 2H), 5.35-5.26 (m, 2H), 4.31-4.29 (m, 1H), 4.03-3.98 (m, 4H), 3.87-3.81 (m, 1H).Example 8: Synthesis of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-l,6-dihydro-7H- pyrazolo[3,4-c]pyridin-7-one (Compound 108)

[0160] (S)-2-((l-(2-chlorobenzyl)-7-methoxy-lH-pyrazolo[3,4-c]pyridin-3-yl)methyl)- 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (120 mg, 202 pmol, 1.0 eq) was added HCl / dioxane (4 M, 10 mL). The reaction mixture was stirred for 18 hrs at ambient temperature, then the reaction solution was basified with aqueous NaHCCh till pH=7~8 and extracted with EtOAc. The collected organic phase was then dried over MgSO4, and concentrated to afford the crude product, which was purified through Prep-TLC to obtain a white solid (33 mg, 28% yield). LC-MS (m / z) 578.9 [M+H]+.1H NMR (400 MHz, DMSO ) 5 11.42 (d, J= 5.2 Hz, 1H ), 7.72-7.70 (m, 2H), 7.63-7.61 (m, 2H), 7.50 (d, J= 1.2 Hz, 1H), 7.48-7.47 (m, 1H), 7.22-7.20 (m, 1H), 6.88 (d, J= 6.4 Hz, 1H), 6.74 (d, J= 6.0 Hz, 1H), 6.59 (d, J= 6.8 Hz, 1H), 5.98 (s, 2H), 5.23-5.14 (m, 2H), 4.30-4.28 (m, 1H), 4.02- 3.97 (m, 1H), 3.86-3.80 (m, 1H).IPTS / 200087585.1Attorney Docket No. RTX-003WOExample 9: Synthesis of (S)-2-((6-acetyl-l-(2-chlorobenzyl)-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 109)

[0161] (S)-2-((l-(2-chlorobenzyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridin-3-yl) methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4 - triazol-3-one (50 mg, 88 pmol, 1.0 eq) was dissolved in DCM (2 mL), then Acetic anhydride (14 mg, 137 pmol, 1.6 eq) was added at 0 °C. The reaction mixture was stirred 16 hrs at 15 °C. The reaction mixture was treated with water and DCM, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (27 mg, 50% yield). LC-MS (m / z): 609.2 [M+H]+.1HNMR(400MHz,DMSO- d6) 8(ppm) 7.78-7.69(m,2H), 7.63(d, J=8.3Hz, 2H), 7.50(brd, J=7.8Hz,lH), 7.39- 7.23(m,2H), 6.92-6.82(m,2H), 5.39-5.25 (m, 2H), 4.88(s,2H), 4.61-4.48(m,2H), 4.37- 4.22(m,lH), 4.02-3.91(m,lH), 3.87-3.75 (m, 1H), 3.70-3.53(m, 2H), 2.50-2.36(m,2H), 2.11- 2.00(m,3H).Example 10: Synthesis of (S)-2-((l-(2-chlorobenzyl)-6-(2-hydroxyacetyl)-4, 5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3- trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 110)

[0162] A mixture of (S)-2-((l-(2-chlorobenzyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4- c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one(40 mg, 70 pmol, 1.0 eq), Glycolic acid (8 mg, 105 pmol, 1.5 eq), DIPEA (18 mg, 139 pmol, 2.0 eq) and HATU (40 mg, 105 pmol, 1.5 eq) were suspended inIPTS / 200087585.1Attorney Docket No. RTX-003WODCM (4 mL). Pumped and refilled with nitrogen three times. The resulting mixture was heated to 15 °C to react for 2 hrs under a nitrogen atmosphere. The reaction mixture was treated with water and DCM, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (36 mg, 82% yield). LC-MS (m / z): 625.2 tM+H]+ 1HNMR(400MHz,DMSO-d6) 5(ppm)7.73(brd, J=8.3Hz, 2H), 7.62(brd, J=8.6Hz, 2H), 7.50(brd, J=7.8Hz, 1H), 7.41-7.20(m, 2H), 6.98- 6.80(m, 2H), 5.32 (brs, 2H), 4.89(s, 2H), 4.76-4.62(m, 1H), 4.61-4.43(m, 2H), 4.29(brd, J=3.4Hz, 1H), 4.22-4.05(m,2H), 4.01-3.92 (m, 1H), 3.87-3.76(m, 1H), 3.68 (brs, 1H), 3.51(brs, 1H), 2.50-2.41 (m, 2H).Example 11: Synthesis of 5-(4-chlorophenyl)-2-((l-(l-(2-chlorophenyl)ethyl)-4, 5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridin-3-yl)methyl)-4-((S)-3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 111)Step 1: l-chloro-2-(l-chloroethyl)benzene

[0163] To an anhydrous DCE (5 mL) solution of l-(2-chlorophenyl)ethan-l-ol (150 mg, 958 pmol, 1.0 eq) and TEA (291 mg, 2.9 mmol, 3.0 eq) was cooled in ice-water bath, then added EsCl (370 mg, 2.9 mmol, 3.0 eq) in dropwise. The resulting mixture was stirred at 60 °C for 4 hrs. The reaction solution was treated with water and EtOAc, then the organic phaseIPTS / 200087585.1Attorney Docket No. RTX-003WO was isolated, and concentrated to afford the crude product (160 mg, 95% yield), which was used directly in the next step without further purification.Step 2: 6-(tert-butyl) 3-methyl l-(l-(2-chlorophenyl)ethyl)-l,4,5, 7-tetrahydro-6H - pyrazolo[ 3, 4-c ]pyridine-3, 6-dicarboxylate

[0164] To a DMF (5 mL) solution of 6-(tert-butyl) 3-methyl l,4,5,7-tetrahydro-6H- pyrazolo[3,4-c]pyridine-3, 6-dicarboxylate (170 mg, 604 pmol, 1.0 eq) was added K2CO3 (250 mg, 1.8 mmol, 3.0 eq) and l-chloro-2-(l-chloroethyl)benzene (160 mg, 904 pmol, 1.5 eq). The resulting mixture was heated at 100 °C for 30 hrs. The reaction solution was treated with water and EtOAc and the organic phase was isolated. The organic phase was washed with water, dried over MgSO4, and concentrated to dryness. The crude product was purified through column chromatography to obtain a colorless oil (67 mg, 26% yield). LC-MS (m / z): 420.0 [M+H]+.Step 3: tert-butyl l-(l-(2-chlorophenyl)ethyl)-3-(hydroxymethyl)-l,4,5, 7-tetrahydro -6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0165] To an anhydrous THF (5 mL) solution of 6-(tert-butyl) 3-methyl l-(l-(2- chlorophenyl)ethyl)-l,4,5,7-tetrahydro-6H -pyrazolo[3,4-c]pyridine-3, 6-dicarboxylate (130 mg, 310 pmol, 1.0 eq) was cooled in ice-water bath, then added LiAlEL (17 mg, 448 pmol, 1.4 eq) in portions. The resulting mixture was stirred at 0~4 °C for 2 hrs. The reaction solution was quenched by addition of 17 mg of H2O, followed by 17 mg of 15% aqueous NaOH. After being stirred at room temperature for 0.5 hr, the solid was removed by filtration. The filtrate was concentrated to dryness to give crude targeted product (104 mg, 86% yield) as colorless oil. LC-MS (m / z): 392.0 [M+H]+.Step 4: tert-butyl 3-(chloromethyl)-l-(l-(2-chlorophenyl)ethyl)-l,4,5, 7-tetrahydro-6H - pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0166] To an anhydrous DCM (3 mL) solution of tert-butyl l-(l-(2- chlorophenyl) ethyl) -3-(hydroxymethyl)-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (104 mg, 265 pmol, 1.0 eq) and TEA (53 mg, 524 pmol, 2.0 eq) was cooled in ice-water bath, then added EsCl (51 mg, 397 pmol, 1.5 eq) in dropwise. The resulting mixture was stirred at ambient temperature for 3 hrs. The reaction solution was treated with water and EtOAc, and the organic phase was isolated, and concentrated to dryness. The crude product was purified through column chromatography to obtain a colorless oil (24 mg, 22% yield). LC-MS m / z) 409.9 [M+H]+.IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 5: tert-butyl 3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3-trifluoro-2- hydroxypropyl)-4,5- dihydro-lH-1, 2, 4-triazol-l-yl)methyl)-l-( I -(2 -chlorophenyl) ethyl)- 1, 4, 5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0167] tert-butyl 3-(chloromethyl)-l-(l-(2-chlorophenyl)ethyl)-l,4,5,7-tetrahydro-6H - pyrazolo[3,4-c]pyridine-6-carboxylate (24 mg, 58 pmol, 1.0 eq), (S)-5-(4-chloro phenyl)-4- (3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (21 mg, 68 pmol, 1.2 eq), K2CO3 (24 mg, 174 pmol, 3.0 eq) was suspended in CH3CN (3 mL). The resulting mixture was heated to 70 °C to react for 12 hrs. The reaction solution was treated with water and EtOAc, then the organic phase was isolated, and concentrated to dryness to afford the crude product (35 mg, 88% yield), which was used directly in the next step without further purification. LC-MS (m / z)'. 680.9 [M+H]+.Step 6: 5-(4-chlorophenyl)-2-((l-(l-(2-chlorophenyl)ethyl)-4,5,6, 7 -tetrahydro- 1H- pyrazolo[ 3, 4-c ]pyridin-3-yl)methyl)-4-( (S)-3, 3, 3-trifhioro-2-hydroxypropyl)-2, 4-dihydro- 3H-1, 2, 4-triazol-3-one

[0168] tert-butyl 3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3-trifluoro-2-hydroxypropyl) - 4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-l-(l-(2-chlorophenyl)ethyl)-l,4,5,7-tetrahydro- 6H-pyrazolo[3,4-c]pyridine-6-carboxylate (35 mg, 51 pmol, 1.0 eq) was added HCl / Dioxane (4 M, 3 mL). The resulting mixture was stirred for 1 hr at ambient temperature, then the reaction solution was basified with aqueous NaHCCh till pH=7~8 and extracted with organic solvent. The collected organic phase was then dried over MgSCh, and concentrated to afford the crude product, which was purified through Prep-TLC to obtain a white solid (19 mg, 64% yield). LC-MS (m / z): 414.1 [M+H]+. 'HNMR (400 MHz, DMSO-t / e) 5 7.74 (d, J= 8.0 Hz, 2H), 7.63 (d, J= 7.6 Hz, 2H), 7.46-7.45 (m, 1H), 7.30-7.28 (m, 2H),7.20-7.18 (m, 1H), 6.90-6.89 (m, 1H), 5.67 (q, J= 6.4 Hz, 1H), 4.93 (s, 2H), 4.31-4.29 (m, 1H), 4.01-3.97 (m, 1H), 3.90-3.86 (m, 2H), 3.40 (s, 2H), 2.79 - 2.71 (m, 2H), 2.51 (s, 2H), 1.74 (d, J= 6.8 Hz, 3H).Example 12: Synthesis of (S)-2-((l-(2-chlorobenzyl)-6-(methylsulfonyl)-4, 5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3- trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 112)IPTS / 200087585.1Attorney Docket No. RTX-003WO

[0169] A mixture of (S)-2-((l-(2-chlorobenzyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4- c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one (45 mg, 79pmol, 1.0 eq), TEA(9 mg, 89 pmol, 1.1 eq), Methanesulfonic anhydride (21 mg, 121 pmol, 1.5 eq) were suspended in DCM (4 mL). Pumped and refilled with nitrogen three times. The resulting mixture was heated to 15 °C to react for 48 hrs under a nitrogen atmosphere. The reaction mixture was treated with water and DCM, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (28 mg, 55% yield). LC-MS (m / z): 645.2 [M+H]+ 1HNMR(400MHz,DMSO-d6) 57.76-7.68(m, 2H), 7.67-7.59(m, 2H),7.54- 7.44(m, lH),7.41-7.25(m, 2H),6.956.77(m, 2H),5.32(s, 2H), 4.90(s, 2H),4.39-4.23(m, 3H), 4.02-3.93(m, lH),3.87-3.75(m, lH),3.39(brt, J=5.6Hz, 2H), 2.92 (s, 3H), 2.56(brs, 2H).Example 13: Synthesis of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-l,4,5,7- tetrahydro-6H-indazol-6-one (Compound 113)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: ethyl l,4,5, 7-tetrahydrospiro[indazole-6,2'-[l,3]dioxolane]-3-carboxylate

[0170] To a stirred solution of l,4-dioxaspiro[4.5]decan-7-one (1.00 g, 6.4 mmol, 1.0 eq) and diethyl oxalate (936 mg, 6.4 mmol, 1.0 eq) in THF (10 mL) and EtOH (1 mL) was added potassium tert-butoxide (1 M, 8 mL, 1.2 eq) dropwise at 0 °C under N2 atmosphere, then the reaction mixture was stirred at 20 °C for 1.5 hrs. Then Hydrazine dihydrochloride (526 mg, 7.7 mmol, 1.2 eq) in H2O (3 mL) was added to the mixture at 0 °C, the reaction mixture was stirred at 20 °C for 12.5 hrs. The solvent was removed under reduce pressure to give a yellow oil, which was added water. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (1.15 g, 71% yield) as a light-yellow solid. LC-MS (m / z): 253.1 [M+H]+. 'HNMR (400 MHz, CDCh) 5 (ppm) 10.97 (br s, 1H), 4.43 - 4.33 (m, 2H), 4.08 - 4.02 (m, 4H), 3.01 - 2.89 (m, 4H), 1.97 (t, J= 6.7 Hz, 2H), 1.39 (t, J= 7.2 Hz, 3H).Step 2: ethyl l-(2-chlorobenzyl)-l,4,5, 7-tetrahydrospiro[indazole-6,2'-[l,3] dioxolane]-3- carboxylate

[0171] To a mixture of ethyl l,4,5,7-tetrahydrospiro[indazole-6,2'-[l,3]dioxolane]-3- carboxylate (1.10 g, 4.4 mmol, 1.0 eq) and K2CO3 (1.81 g, 13.1 mmol, 3.0 eq) in MeCN (30 mL) was added l-(bromomethyl)-2-chloro-benzene (1.00 g, 4.9 mmol, 1.1 eq) . Then theIPTS / 200087585.1Attorney Docket No. RTX-003WO mixture was stirred at 80 °C for 6 hrs. The reaction mixture was diluted with water, which was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a colorless oil. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (1.05 g, 64% yield) as a light-yellow solid. LC-MS (m / z): 377.1 [M + H]+. ‘H NMR (400 MHz, CDC13) 5 7.42-7.35 (m, 1H), 7.27-7.15 (m, 2H), 6.72-6.65 (m, 1H), 5.43 (s, 2H), 4.46-4.37 (m, 2H), 4.04-3.92 (m, 4H), 2.97 (t, J= 6.5 Hz, 2H), 2.67 (s, 2H), 1.92 (t, J= 6.6 Hz, 2H), 1.41 (t, J= 7.1 Hz, 3H).Step 3: (l-(2-chlorobenzyl)-l,4,5, 7-tetrahydrospiro[indazole-6,2'-[l,3]dioxolan]-3- yl)methanol

[0172] To a stirred solution of ethyl l-(2-chlorobenzyl)-l, 4,5,7- tetrahydrospiro[indazole-6,2'-[l,3] dioxolane]-3-carboxylate (1.00 g, 2.7 mmol, 1.0 eq) in THF (20 mL) was added LAH (151 mg, 4.0 mmol, 1.5 eq) at 0 °C under N2 atmosphere, then the reaction mixture was stirred at 25 °C for 1 hr. The reaction was quenched by addition of H2O (0.2 mL) and 15% aqueous NaOH (0.2 mL) at 0 °C and the mixture was diluted with THF, then anhydrous MgSCh (2.00 g) was added. The suspension was filtered through a pad of Celite and the filter cake was washed with THF (20 mL). The combined filtrate was concentrated to dryness to give the crude product. The crude product was purified by silica gel chromatography to give the title compound (810 mg, 91% yield) as a white solid. LC-MS (m / z): 335.1 [M + H]+.Step 4: l-(2-chlorobenzyl)-3-(chloromethyl)-l,4,5, 7 -tetrahydrospiro [indazole-6,2'-[1.3 ] dioxolane ]

[0173] To a stirred solution of (l-(2-chlorobenzyl)-l,4,5,7-tetrahydrospiro[indazole-6,2'-[1.3]dioxolan]-3-yl)methanol (700 mg, 2.1 mmol, 1.0 eq) in DCM (10 mL) was added SOCI2 (325 mg, 2.7 mmol, 1.3 eq), at 0 °C under N2 atmosphere, then the reaction mixture was stirred at 0 °C for 1 hr. The reaction mixture was concentrated in vacuo to dryness to give the title compound (730 mg, 99% yield) as a colorless oil. LC-MS (m / z): 353.1 [M + H]+.Step 5: (S)-2-((l-(2-chlorobenzyl)-l,4,5, 7 -tetrahydrospiro [indazole-6,2'-[ 1 , 3]dioxolan] -3- yl)methyl)-5-( 4-chlorophenyl)-4-( 3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4- triazol-3-oneIPTS / 200087585.1Attorney Docket No. RTX-003WO

[0174] To a solution of l-(2-chlorobenzyl)-3-(chloromethyl)-l,4,5,7-tetrahydrospiro [indazole-6,2'-[l,3]dioxolane] (830 mg, 2.4 mmol, 1.0 eq) and 3-(4-chlorophenyl)-4-[(2S)- 3,3,3-trifluoro-2-hydroxy-propyl]-lH-l,2,4-triazol-5-one (750 mg, 2.4 mmol, 1.0 eq) in MeCN (15 mL) was added K2CO3 (975 mg, 7.1 mmol, 3.0 eq). Then the mixture was stirred at 80 °C for 16 hrs. The reaction mixture was cooled to rt, which was added water. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (1.05 g, 72% yield) as an off-white solid. LC- MS (m / z) (ESI): 624.1 [M + H]+.Step 6: (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-l, 4, 5, 7-tetrahydro-6H-indazol-6- one

[0175] A solution of (S)-2-((l-(2-chlorobenzyl)-l,4,5,7-tetrahydrospiro[indazole-6,2'- [l,3]dioxolan]-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4- dihydro-3H-l,2,4-triazol-3-one (300 mg, 480 pmol, 1.0 eq) in TFA (5 mL) was stirred at 70 °C for 4 hrs. The solvent was removed under reduce pressure to give a yellow oil, which was diluted with EtOAc. The mixture was washed with saturated NaHCOs aqueous and brine, dried over with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (1.15 g, 71% yield) as a white solid. LC-MS (m / z) (ESI): 580.1 [M + H]+. *HNMR (400 MHz, DMSO-de) 5 2.55 (t, 2H), 2.69-2.81 (m, 2H), 3.50 (s, 2H), 3.76-3.87 (m, 1H), 3.92-4.03 (m, 1H), 4.22-4.37 (m, 1H), 4.91 (s, 2H), 5.27 (s, 2H), 6.86-6.95 (m, 2H), 7.25-7.38 (m, 2H), 7.46-7.52 (m, 1H), 7.59-7.67 (m, 2H), 7.69-7.76 (m, 2H).Example 14: Synthesis of 2-((l-(2-chlorobenzyl)-6-hydroxy-4,5,6,7-tetrahydro-lH- indazol-3-yl)methyl)-5-(4-chlorophenyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Compound 114)IPTS / 200087585.1Attorney Docket No. RTX-003WO

[0176] A solution of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4, 5 -dihydro- 1H- 1 ,2,4-triazol- 1 -yl)methyl)- 1 ,4,5,7-tetrahydro- 6H-indazol-6-one (50 mg, 86 pmol, 1.0 eq) in MeOH (3 mL) was added NaBH4 (10 mg, 264 pmol, 3.1 eq). The mixture was stirred at 20 °C for 30 min. The reaction was quenched by addition of water at 0 °C, which was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (35 mg, 70% yield) as a white solid.LC- MS (m / z): 582.1 [M + H]+. 'HNMR (400 MHz, DMSO-de) 5 1.52-1.66 (m, 1H), 1.70-1.82 (m, 1H), 2.24-2.41 (m, 2H), 2.46-2.50 (m, 1H), 2.52-2.56 (m, 1H), 2.72-2.85 (m, 1H), 3.75-3.87 (m, 1H), 3.88-4.06 (m, 2H), 4.29 (br s, 1H), 4.76-4.93 (m, 2H), 5.25 (d, 2H), 6.79 (d, 1H), 6.89 (br s, 1H), 7.17-7.39 (m, 2H), 7.43-7.53 (m, 1H), 7.56-7.67 (m, 2H), 7.73 (d, 2H).Example 15: Synthesis of 2-((6-amino-l-(2-chlorobenzyl)-4,5,6,7-tetrahydro-lH- indazol-3-yl)methyl)-5-(4-chlorophenyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Compound 115)

[0177] A mixture of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4, 5 -dihydro- 1H- 1 ,2,4-triazol- 1 -yl)methyl)- 1 ,4,5,7-tetrahydro- 6H-indazol-6-one (200 mg, 345 pmol, 1.0 eq) and Ammonium acetate (266 mg, 3.5 mmol, 10 eq) in MeOH (10 mL) was attired at 20 °C for 5 min. Then Sodium cyanoborohydride (65 mg, 1.0 mmol, 3.0 eq) was added. The mixture was stirred at 70 °C for 3 hrs. The reaction was quenched by addition of water at 0 °C, which was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (180 mg, 90% yield) as a white solid. LC-MS (m / z): 581.1 [M + H]+. 'H NMR (400 MHz, DMSO-de) 5 (ppm) 7.77 - 7.69 (m, 2H), 7.68 - 7.60 (m, 2H), 7.52 - 7.46 (m, 1H), 7.37 - 7.24 (m, 2H), 6.96 - 6.85 (m, 1H), 6.83 - 6.74 (m, 1H), 5.26 (s, 2H), 4.93 - 4.78 (m, 2H), 4.29 (br s, 1H),IPTS / 200087585.1Attorney Docket No. RTX-003WO4.03 - 3.94 (m, 1H), 3.87 - 3.79 (m, 1H), 3.38 - 3.25 (m, 2H), 3.24 - 3.14 (m, 1H), 2.89 -2.80 (m, 1H), 2.60 - 2.53 (m, 1H), 2.43 - 2.22 (m, 2H), 1.96 - 1.81 (m, 1H), 1.58 - 1.43 (m, 1H).Example 16: Synthesis of (S)-2-((l-(2-chlorobenzyl)-6-isopropyl-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 116)

[0178] A mixture of (S)-2-((l-(2-chlorobenzyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4- c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one (50 mg, 88 pmol, 1.0 eq), 2-iodopropane (18 mg, 106 pmol, 1.2 eq), NaHCChQ l mg, 131 pmol, 1.5 eq) were suspended in MeCN (4 mL). Pumped and refilled with nitrogen three times. The resulting mixture was heated to 15 °C to react for 48 hrs under a nitrogen atmosphere. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (44 mg, 82% yield). LC-MS (m / z): 609.3 [M+H]+ 1HNMR(400MHz,DMSO-d6)5 7.77-7.70(m,2H), 7.65-7.61(m,2H),7.51- 7.46(m,lH),7.37-7.25(m,2H),6.89(d,J=6.4Hz,lH), 6.84-6.79 (m, lH),5.26(s,2H),4.86(s,2H),4.37-4.21(m,lH), 4.02-3.93(m,lH), 3.88-3.74(m,lH), 3.48 (s, 2H),2.93-2.79(m,lH),2.60(brt,J=5.5Hz,2H),2.39(brt,J=5.1Hz,2H),0.99(d,J=6.6Hz,6H).Example 17: Synthesis of methyl(S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4- (3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-l,4,5,7- tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (Compound 117)IPTS / 200087585.1Attorney Docket No. RTX-003WO

[0179] A mixture of (S)-2-((l-(2-chlorobenzyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4- c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one (100 mg, 176 pmol, 1.0 eq)was suspended in DCM (3 mL). then DMC (26 mg, 194 pmol, 1.1 eq) was added at 0 °C. The reaction mixture was stirred 16 hrs at 15 °C. The reaction mixture was treated with water and DCM, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (22 mg, 20% yield). LC-MS (m / z): 625.2 [M+H]+ 1HNMR(400MHz,DMSO- d6) 5 7.77-7 ,69(m,2H),7.69-7 ,56(m,2H), 7.55 -7.44(m, lH),7.40-7.25(m, 2H), 6.96-6.82(m, 2H),5.31(s, 2H),4.88(s, 2H),4.49(s, 2H), 4.34-4.21(m,lH),4.01-3.94(m,lH),3.86- 3.77(m,lH),3.61(s,3H),3.56(brt, J=5.8Hz, 2H), 2.46(brt, J=5.1Hz, 2H).Example 18: Synthesis of l-(2-Chloro-benzyl)-3-[3-(4-chloro-phenyl)-5-oxo-4-[(2S)- (3,3,3-trifluoro-2-hydroxy-propyl)]-4,5-dihydro-[l,2,4]triazol-l-ylmethyl]-lH-indazole- 6-carboxylic acid amide (Compound 118)Step 1: (6-Bromo-lH-indazol-3-yl)-methanol

[0180] To a solution of 6-Bromo-lH-indazole-3-carboxylic acid methyl ester (2.00 g,7.8 mmol, 1.0 eq) in THF (30 mL) was added LAH (298 mg, 7.8 mmol, 1.0 eq) at 0 °C. The mixture was stirred at 20 °C for 16 hours. The reaction mixture was cooled to 0 °C, quenched by addition of H2O (0.3 mL),15% aqueous NaOH (0.3 mL) and H2O (0.3 mL),IPTS / 200087585.1Attorney Docket No. RTX-003WO dried over MgSCh and evaporated to dryness. The crude product was triturated with EtOAc / n-heptane and filtered to afford a white solid (1.30 g,73% yield). LC-MS (m / z): 226.9 [M+H]+.Step 2: 3-Hydroxymethyl-lH-indazole-6-carboxylic acid methyl ester

[0181] To a solution of (6-Bromo-lH-indazol-3-yl)-methanol (270 mg, 1.2 mmol, 1.0 eq) in MeOH (12 mL) and DMF (4 mL) was added Pd(dppf)C12 (87 mg, 119 pmol,0.1 eq) and TEA (361 mg, 3.6 mmol, 3.0 eq). The suspension was degassed under vacuum and purged with CO three times, then heated to 80 °C and stirred under CO for 40 hours. The reaction mixture was concentrated, treated with water and EtOAc, the organic layers were washed with water and brine, dried over MgSO4 and evaporated to dryness to give crude product (210 mg, 86%yield) as a light yellow solid. LC-MS (m / z): 205.1 [M-H]'.Step 3: l-(2-Chloro-benzyl)-3-hydroxymethyl-lH-indazole-6-carboxylic acid methyl ester

[0182] To a mixture of 3-Hydroxymethyl-lH-indazole-6-carboxylic acid methyl ester (270 mg, 1.3 mmol, 1.0 eq) in MeCN (6 mL) was added l-Bromomethyl-2-chloro-benzene (295 mg, 1.4 mmol, 1.1 eq) and K2COs(542 mg, 3.9 mmol, 3.0 eq). The mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the product (180 mg, 42% yield) as a white solid. 'H NMR (400 MHz, DMSO-de) 5 8.33 (s, 1H), 8.08 - 7.97 (m, 1H), 7.74 (dd, J = 8.4, 1.3 Hz, 1H), 7.51 (dd, J = 7.9, 1.1 Hz, 1H), 7.33 (td, J = 7.7, 1.7 Hz, 1H), 7.26 (td, J = 7.5, 1.2 Hz, 1H), 6.86 (dd, J = 7.6, 1.5 Hz, 1H), 5.80 (s, 2H), 5.40 (t, J = 5.7 Hz, 1H), 4.81 (d, J = 5.6 Hz, 2H), 3.89 (s, 3H).Step 4: l-(2-Chloro-benzyl)-3-chloromethyl-lH-indazole-6-carboxylic acid methyl ester

[0183] To a solution of l-(2-Chloro-benzyl)-3-hydroxymethyl-lH-indazole-6-carboxylic acid methyl ester (50 mg, 15 pmol, 1.0 eq) in DCM (2 mL) was added SOCh (26 mg, 219 pmol, 1.4 eq) at 0 °C. The mixture was stirred at 20 °C for Ihr. The reaction mixture was concentrated to dryness to give crude product (52 mg) as a white solid, which was used directly for the next step without purification. LC-MS (m / z): 349.1 [M+H]+.Step 5: l-(2-Chloro-benzyl)-3-[ 3-( 4-chloro-phenyl)-5-oxo-4-[ (2S)-( 3, 3, 3 -trifluor o-2- hydroxy-propyl) ]-4, 5-dihydro-[ 1, 2, 4 ] triazol- 1-ylmethyl ]-lH-indazole-6-carboxylic acid methyl esterIPTS / 200087585.1Attorney Docket No. RTX-003WO

[0184] To a mixture of l-(2-Chloro-benzyl)-3-chloromethyl-lH-indazole-6-carboxylic acid methyl ester (50 mg, 143 pmol, 1.0 eq) in MeCN (3 mL) was added 3-(4-chlorophenyl)- 4-[(2S)-3,3,3-trifluoro-2-hydroxy-propyl]-lH-l,2,4-triazol-5-one(46 mg, 149 pmol, 1.0 eq) and K2CO3 (59 mg, 427 pmol, 3.0 eq). The mixture was stirred at 80 °C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the product (80 mg, 90% yield) as a white solid. LC-MS (m / z): 620.1 [M+H]+.Step 6: l-(2-Chloro-benzyl)-3-[ 3-( 4-chloro-phenyl)-5-oxo-4-[ (2S)-( 3, 3, 3-trtfluoro-2- hydroxy-propyl) ]-4, 5-dihydro-[ 1, 2, 4 ] triazol- 1-ylmethyl ]-lH-indazole-6-carboxylic acid amide

[0185] A solution of l-(2-Chloro-benzyl)-3-[3-(4-chloro-phenyl)-5-oxo-4-[(2S)-(3,3,3- tri fluoro-2-hydroxy-propyl)]-4,5-dihydro-[l, 2, 4]tri azol- 1-ylmethyl]- lH-indazole-6- carboxylic acid methyl ester (80 mg, 129 pmol,l .0 eq) in 7M NHVMeOH (3 mL) was stirred at 80 °C for 48 hours. The reaction mixture was concentrated. The residue was purified by column chromatography to give the product (22 mg, 28% yield) as a white solid. LC-MS (m / z): 605.2 [M+H]+. 'HNMR (400 MHz, DMSO-de) 5 8.24 (s, 1H), 8.04 (br s, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.66-7.74 (m, 3H), 7.61 (d, J=8.6 Hz, 2H), 7.45-7.54 (m, 2H), 7.31-7.38 (m, 1H), 7.18-7.27 (m, 1H), 6.89 (d, J=6.4 Hz, 1H), 6.70-6.83 (m, 1H), 5.77 (s, 2H), 5.25-5.39 (m, 2H), 4.23-4.37 (m, 1H), 3.95-4.08 (m, 1H), 3.75-3.91 (m, 1H).Example 19: Synthesis of 2-[l-(2-Chloro-benzyl)-4,5,6,7-tetrahydro-lH-pyrazolo[4,3- c]pyridin-3-ylmethyl]-5-(4-chloro-phenyl)-4-[(2S)-(3,3,3-ti'ifluoro-2-hydroxy-propyl)]- 2,4-dihydro-[l,2,4]triazol-3-one (Compound 119)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: l-(2-Chloro-benzyl)-l,4,6, 7-tetrahydro-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-tert-butyl ester 3-ethyl ester

[0186] To a mixture of l,4,6,7-Tetrahydro-pyrazolo[4,3-c] pyridine-3,5-dicarboxylic acid 5-tert-butyl ester 3-ethyl ester (2.00 g, 6.8 mmol,l eq) in MeCN (30 mL) was added 1- Bromomethyl-2-chloro-benzene (1.53 g,7.4 mmol, 1.1 eq) and K2COs (2.80 g, 20.3 mmol, 3.0 eq). The mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the product (2.10 g, 74% yield) as a colourless oil. 'H NMR (400 MHz, DMSO-de) 5 7.40 (dd, J = 7.8, 1.2 Hz, 1H), 7.28 -7.16 (m, 2H), 6.77 (dd, J = 7.7, 1.3 Hz, 1H), 5.47 (s, 2H), 4.66 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.68 (br s, 2H), 2.56 (br s, 2H), 1.49 (s, 9H).Step 2: l-(2-Chloro-benzyl)-3-hydr oxymethyl- 1,4, 6, 7-tetrahydro-pyrazolo [4, 3-c]pyridine-5- carboxylic acid tert-butyl ester

[0187] To a solution of l-(2-Chloro-benzyl)-l,4,6,7-tetrahydro-pyrazolo[4,3-c] pyridine- 3,5-dicarboxylic acid 5-tert-butyl ester 3-ethyl ester (2.10 g, 5.0 mmol, 1.0 eq) in THF (30 mL) was added LAH (189 mg, 5.0 mmol, 1.0 eq) at 0 °C. The mixture was stirred at 20 °C for 1 hr. The reaction mixture was cooled to 0 °C, quenched by addition of H2O (0.19 mL), 15% aqueous NaOH (0.19 mL) and H2O (0.19 mL), dried over MgSCh and evaporated to dryness to afford a yellow solid (1.70 g, 90% yield). LC-MS (m / z): 378.2 [M+H]+.Step 3: l-(2-Chloro-benzyl)-3-chloromethyl-l,4,6, 7-tetrahydro-pyrazolo [4, 3-c]pyridine-5- carboxylic acid tert-butyl ester

[0188] To a solution of l-(2-Chloro-benzyl)-3-hydroxymethyl-l,4,6,7-tetrahydro- pyrazolo[4,3-c] pyridine-5-carboxylic acid tert-butyl ester (250 mg, 662 pmol,1.0 eq) in DCM (3 mL) was added SOCh(l 18 mg, 992 pmol,1.5 eq) at 0°C. The mixture was stirred at 20°C for Ihr. The reaction mixture was adjusted to pH=8~9 with saturated NaHCCh solution, extracted with DCM, the organic layer was separated, wash with saturated NaCl solution, dried over MgSCh and evaporated to dryness to give crude product (260 mg) as a light yellow oil. LC-MS (m / z): 396.1 [M+H]+.Step 4: l-(2-Chloro-benzyl)-3-[ 3-( 4-chloro-phenyl)-5-oxo-4-[ (2S)-( 3, 3, 3 -trifluor o-2- hydroxy-propyl) ]-4, 5-dihydro-[ 1, 2, 4 ] triazol- 1-ylmethyl ]-l, 4, 6, 7-tetrahydro-pyrazolo [ 4, 3- c]pyridine-5-carboxylic acid tert-butyl ester

[0189] To a mixture of l-(2-Chloro-benzyl)-3 -chloromethyl- 1, 4, 6, 7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester (310 mg, 782 pmol,1.0 eq) in MeCN (5IPTS / 200087585.1Attorney Docket No. RTX-003WO mL) was added 3-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxy-propyl]-lH-l,2,4- triazol-5-one (324 mg, 2.3 mmol, 3.0 eq) and K2CO3 (252 mg, 819 pmol, 1.0 eq). The mixture was stirred at 80°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the product (380 mg, 73% yield) as a white solid. LC-MS (m / z): 667.2 [M+H]+.Step 5: 2-[l-(2-Chloro-benzyl)-4,5,6, 7-tetrahydro-lH-pyrazolo [4, 3-c]pyridin-3-ylmethyl] -5- ( 4-chloro-phenyl)-4-[(2S)-( 3, 3, 3-trifluoro-2-hydroxy-propyl) ]-2, 4-dihydro-[ 1, 2, 4 ]triazol-3- one

[0190] A mixture of l-(2-Chloro-benzyl)-3-[3-(4-chloro-phenyl)-5-oxo-4-[(2S)-(3,3,3- trifluoro-2-hydroxy-propyl)]-4,5-dihydro-[l,2,4]triazol-l-ylmethyl]-l,4,6,7-tetrahydro - pyrazolo [4,3-c]pyridine-5-carboxylic acid tert-butyl ester (380 mg, 569 pmol, 1.0 eq) and HCl / dioxane(4 M,6 mL,42.0 eq) was stirred at 20°C for Ihr. The reaction mixture was concentrated. The residue was adjusted to pH=8~9 with saturated NaHCCh solution, extracted with EtOAc, the organic layer was separated, wash with saturated NaCl solution, dried over MgSCh and evaporated to dryness. The crude product was purified by column chromatography to give the target compound (200 mg, 62% yield) as a white solid. LC-MS (m / z):567.2 [M+H]+.1H NMR(400 MHz, DMSO_d6) 5 (ppm) 7.71-7.80 (m, 2H), 7.57-7.68 (m, 2H), 7.45-7.52 (m, 1H), 7.24-7.39 (m, 2H), 6.92 (d, J=6.3 Hz, 1H), 6.78-6.86 (m, 1H), 5.27 (s, 2H), 4.77-4.95 (m, 2H), 4.30 (br d, J=6.5 Hz, 1H), 3.92-4.01 (m, 1H), 3.75-3.87 (m, 1H), 3.58 (s, 2H), 2.86 (br t, J=5.6 Hz, 2H), 2.45-2.49 (m, 2H).Example 20: Synthesis of N-(l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-((S)- 3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-4,5,6,7- tetrahydro-lH-indazol-6-yl)acetamide (Compound 120)

[0191] A solution of 2-((6-amino-l-(2-chlorobenzyl)-4,5,6,7-tetrahydro-lH-indazol-3- yl) methyl)-5-(4-chlorophenyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H- l,2,4-triazol-3-one (100 mg, 172 pmol, 1.0 eq) in DCM (4 mL) was stirred at 0°C. Then acetic anhydride (40 mg, 392 pmol, 2.3 eq) in DCM (1 mL) was added. The mixture wasIPTS / 200087585.1Attorney Docket No. RTX-003WO stirred at 20°C for 30min. The solvent was removed under reduced pressure to give colorless oil, which was purified by silica gel chromatography to give the title compound (65 mg, 61% yield) as a white solid. LC-MS (m / z): 623.2 [M + H]+. 'H NMR (400 MHz, DMSO-de) 5 (ppm) 7.93 (d, J= 7.6 Hz, 1H), 7.77 - 7.71 (m, 2H), 7.67 - 7.59 (m, 2H), 7.51 - 7.46 (m, 1H), 7.38 - 7.23 (m, 2H), 6.93 - 6.87 (m, 1H), 6.79 - 6.72 (m, 1H), 5.34 - 5.16 (m, 2H), 4.96 - 4.75 (m, 2H), 4.39 - 4.23 (m, 1H), 4.02 - 3.88 (m, 2H), 3.88 - 3.77 (m, 1H), 2.91 - 2.80 (m, 1H), 2.61 - 2.53 (m, 1H), 2.42 - 2.24 (m, 2H), 1.91 - 1.80 (m, 1H), 1.78 (s, 3H), 1.64 - 1.46 (m, 1H).Example 21: Synthesis of (S)-2-((l-(2-chlorobenzyl)-6,6-dioxido-l, 4,5,7- tetrahydrothiopyrano[3,4-c]pyrazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro- 2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 121)Step 1: ethyl 2-diazo-2-(4-hydroxy-l,l-dioxidotetrahydro-2H-thiopyran-4-yl) acetate

[0192] To an anhydrous THF (40 mL) solution of 2,6-diisopropylaniline (1.86 g, 18.4 mmol, 1.7 eq) was cooled to -78°C, then added n-BuLi (2.5 M, 6.5 mL, 1.5 eq) in dropwise. The reaction mixture was stirred at -78 °C for 20 min. Then the reaction solution was added to an anhydrous THF (30 mL) solution of l,l-dioxothian-4-one (1.60 g, 10.8 mmol, 1.0 eq) and ethyl 2-diazoacetate (1.97 g, 17.3 mmol, 1.6 eq) at -78°C, the resulting mixture was stirred at -78 °C for 2 hrs. Then saturated NH4C1 solution was added, the collected organic phase was then dried over MgSCh, and concentrated to afford the crude product, which wasIPTS / 200087585.1Attorney Docket No. RTX-003WO purified through column chromatography to obtain a pale yellow solid (1.70 g, 60% yield). LC-MS (m / z): 263.0 [M+H]+.Step 2: ethyl 2-diazo-2-(l , l-dioxido-3,6-dihydro-2H-thiopyran-4-yl) acetate

[0193] To an anhydrous pyridine (30 mL) solution of ethyl 2-diazo-2-(4-hydroxy-l,l- dioxidotetrahydro-2H-thiopyran-4-yl) acetate (1.70 g, 6.5 mmol, 1.0 eq) was added POCh (4.33 g, 28.2 mmol, 4.4 eq) dropwise, and the resulting mixture was stirred at ambient temperature for 12 hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated, and concentrated to dryness to obtain the title compound as brown oil (1.10 g, 69% yield), which was used directly for the next step. LC-MS (m / z): 245.1 [M+H]+.Step 3: ethyl l,4,5, 7-tetrahydrothiopyrano[3,4-c] pyrazole-3-carboxylate 6,6-dioxide

[0194] Ethyl 2-diazo-2-(l,l-dioxido-3,6-dihydro-2H-thiopyran-4-yl) acetate (1.10 g, 4.5 mmol, 1.0 eq) was added n-octane (10 mL). The resulting mixture was stirred for 2 hrs at 110°C. The reaction solution was concentrated then purified by column chromatography to obtain a white solid (700 mg, 64% yield). LC-MS (m / z): 245.1 [M+H]+. ’H NMR (400 MHz, DMSO-tA) 5 14.03 (s, 1H), 4.46 (s, 2H), 4.33 -4.29 (m, 2H), 3.42 -3.40 (m, 2H), 3.17- 3.14 (m, 2H), 1.33 -1.30 (s, 3H).Step 4: ethyl l-(2-chlorobenzyl)-l,4,5, 7-tetrahydrothiopyrano[3,4-c] pyrazole-3- carboxylate 6, 6-dioxide

[0195] To a DMF (10 mL) solution of ethyl l,4,5,7-tetrahydrothiopyrano[3,4-c] pyrazole-3 -carboxylate 6,6-dioxide (600 mg, 2.5 mmol, 1.0 eq) was added K2CO3 (1.02 g, 7.4 mmol, 3.0 eq) and l-(bromomethyl)-2-chloro-benzene (606 mg, 2.9 mmol, 1.2 eq). The resulting mixture was heated at 80 °C for 3hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSO4, and concentrated to dryness. The crude product was purified through column chromatography) to obtain a white solid (680 mg, 75% yield). LC-MS (m / z):368.9 [M+H]+. 'HNMR (400 MHz, CDCI3) 5 7.44 (d, J= 8.0 Hz, 1H), 7.43 -7.25 (m, 2H), 6.88 - 6.87 (m, 1H), 5.47 (s, 2H), 4.45 (q, J= 7.2 Hz, 2H), 4.06 (s, 2H), 3.50 -3.47 (m, 2H), 3.25 - 3.22 (m, 2H), 1.44 (t, J= 7.2 Hz, 3H).Step 5: l-(2-chlorobenzyl)-3-(hydr oxymethyl)- 1,4, 5, 7-tetrahydrothiopyrano[3,4-c] pyrazole 6, 6-dioxideIPTS / 200087585.1Attorney Docket No. RTX-003WO

[0196] To an anhydrous THF (5 mL) solution of ethyl l-(2-chlorobenzyl)-l,4,5,7- tetrahydrothiopyrano[3,4-c] pyrazole-3- carboxylate 6,6-dioxide (200 mg, 542 pmol, 1.0 eq) was cooled in ice-water bath, then added Li AIH4 (31 mg, 817 pmol, 1.5 eq) in portions. The resulting mixture was stirred at 0 - 4°C for 1 hr. The reaction solution was quenched by addition of 31 mg of H2O, followed by 31 mg of 15% aqueous NaOH. After being stirred at room temperature for 0.5 hr, the solid was removed by filtration, the filtrate was dried under vacuum to produce targeted compound (170 mg, 96% yield) as yellow oil, which was used directly for the next step. LC-MS m / zy 326.9 [M+H]+.Step 6: l-(2-chlorobenzyl)-3-(chloromethyl)-l,4,5, 7-tetrahydrothiopyrano[3,4-c] pyrazole 6, 6-dioxide

[0197] To an anhydrous DCM (3 mL) solution of l-(2-chlorobenzyl)-3- (hydroxymethyl)- l,4,5,7-tetrahydrothiopyrano[3,4-c] pyrazole 6,6-dioxide (170 mg, 520 pmol, 1.0 eq) was cooled in ice-water bath, then added SOCh (93 mg, 782 pmol, 1.5 eq) in dropwise. The resulting mixture was stirred at ambient temperature for 2 hrs. The reaction solution was concentrated to dryness to obtain the title compound as yellow oil (120 mg, 67% yield), which was used directly for the next step. LC-MS (m / zy. 346.8 [M+H]+.Step 7: (S)-2-((l-(2-chlorobenzyl)-6,6-dioxido-l,4,5, 7-tetrahydrothiopyrano[3,4-c] pyrazol- 3-yl) methyl)-5-( 4-chlorophenyl)-4-( 3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4- triazol-3-one

[0198] l-(2-chlorobenzyl)-3-(chloromethyl)-l,4,5,7-tetrahydrothiopyrano[3,4-c] pyrazole 6,6-dioxide (120 mg, 348 pmol, 2.1 eq), (S)-5-(4-chlorophenyl)-4-(3,3,3- trifluoro- 2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (50 mg, 163 pmol, 1.0 eq), K2CO3 (67 mg, 485 pmol, 3.0 eq) was suspended in CH3CN (3 mL). The resulting mixture was heated to 80 °C to react for 12 hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated, and concentrated to dryness. The crude product was purified through Prep-TLC to obtain a white solid (27 mg, 27% yield). LC-MS m / zy. 615.8 [M+H]+. 'HNMR (400 MHz, DMSO ) 5 7.74 -7.72 (m, 2H), 7.64 -7.62 (m, 2H), 7.50 -7.48 (m, 1H), 7.31 -7.29 (m, 2H), 6.89 (d, J= 6.4 Hz, 1H), 5.31 (s, 2H), 4.91 -4.90 (m, 2H), 4.55 (s, 2H), 4.31 -4.28 (m, 1H), 3.99 -3.95 (m, 1H), 3.84-3.82 (m, 1H), 3.41 -3.38 (m, 2H), 2.98 - 2.95 (m, 2H).IPTS / 200087585.1Attorney Docket No. RTX-003WOExample 22: Synthesis of 2-((l-(2-chlorobenzyl)-6-(trifluoromethyl)-4, 5,6,7- tetrahydro-lH-indazol-3-yl)methyl)-5-(4-chlorophenyl)-4-((S)-3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 122)Step 1: ethyl 6-(trifluoromethyl)-4,5,6, 7-tetrahydro-lH-indazole-3-carboxylate

[0199] To an anhydrous DMSO (10 mL) solution of 4-(trifluoromethyl)cyclohexanone (1.00 g, 6.0 mmol, 2.0 eq) and pyrrolidine (43 mg, 605 pmol, 0.2 eq) was added 4A molecular sieve. The reaction mixture was stirred at ambient temperature for 20 min, then added ethyl 2-diazoacetate (343 mg, 3.0 mmol, 1.0 eq), The resulting mixture was heated to 50 °C to react for 48 hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated, and concentrated to dryness. The crude product was purified through column chromatography to obtain a pale solid (290 mg, 37% yield). LC-MS (m / z . 263.3 [M+H]+.Step 2: ethyl l-(2-chlorobenzyl)-6-(trifluoromethyl)-4,5,6, 7-tetrahydro-lH-indazole-3 - carboxylate

[0200] To a DMF (5 mL) solution of ethyl 6-(trifluoromethyl)-4,5,6,7-tetrahydro-lH- indazole-3 -carboxylate (290 mg, 1.1 mmol, 1.0 eq) was added K2CO3 (459 mg, 3.3 mmol, 3.0 eq) and l-(bromomethyl)-2-chloro-benzene (273 mg, 1.3 mmol, 1.2 eq). The resulting mixture was heated at 60 °C for 2 hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSO4, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid (260 mg, 61% yield). LC-MS (m / z):386.9 [M+H]+.1H NMR (400 MHz, CDCh) 5 7.39 (d, J= 8.8 Hz, 1H), 7.21 - 7.15 (m, 2H), 6.53 - 6.50 (m,IPTS / 200087585.1Attorney Docket No. RTX-003WO1H), 5.85 (s, 2H), 4.29 (q, J= 7.2 Hz, 2H), 3.14 - 3.06 (m, 2H), 2.78 - 2.71 (m, 2H), 2.54 - 2.50 (m, 1H), 2.25 - 2.24 (m, 1H), 1.75 - 1.70 (m, 1H),1.3O (t, J= 7.2 Hz, 3H).Step 3: (l-(2-chlorobenzyl)-6-(trifluoromethyl)-4,5,6, 7-ielrahydro- 1 H-indazol-3-yl) methanol

[0201] To an anhydrous THF (5 mL) solution of ethyl l-(2-chlorobenzyl)-6- (trifluoromethyl)-4,5,6,7-tetrahydro-lH-indazole-3 -carboxylate (230 mg, 595 pmol, 1.0 eq) was cooled in ice-water bath, then added LiAlH4 (34 mg, 896 pmol, 1.5 eq) in portions. The resulting mixture was stirred at 0~4 °C for 2 hrs. The reaction solution was quenched by addition of 34 mg of H2O, followed by 34 mg of 15% aqueous NaOH. After being stirred at room temperature for 0.5 hr, the solid was removed by filtration, the filtrate was dried under vacuum to produce targeted compound (200 mg, 98% yield) as yellow oil, which was used directly for the next step. LC-MS m / zy 344.9 [M+H]+.Step 4: l-(2-chlorobenzyl)-3-(chloromethyl)-6-(trifluoromethyl)-4,5,6, 7-tetrahydro -1H- indazole

[0202] To an anhydrous DCM (5 mL) solution of (l-(2-chlorobenzyl)-6- (trifluoromethyl)-4,5,6,7-tetrahydro-lH-indazol-3-yl) methanol (200 mg, 580 pmol, 1.0 eq) was cooled in ice-water bath, then added SOCI2 (90 mg, 756 pmol, 1.3 eq) in dropwise. The resulting mixture was stirred at ambient temperature for 1 hr. The reaction solution was concentrated to dryness to obtain the title compound as yellow oil (200 mg, 95% yield), which was used directly for the next step. LC-MS (m / z): 363.1 [M+H]+.Step 5: 2-((l-(2-chlorobenzyl)-6-(trifluoromethyl)-4,5,6, 7 -tetrahydro- lH-indazol-3-yl) methyl)-5-( 4-chlorophenyl)-4-((S)-3, 3, 3-trifhioro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4- triazol-3-one

[0203] l-(2-chlorobenzyl)-3-(chloromethyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydro -1H- indazole (120 mg, 348 pmol, 2.1 eq), (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro -2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (50 mg, 163 pmol, 1.0 eq), K2CO3 (67 mg, 485 pmol, 3.0 eq) was suspended in CH3CN (3 mL). The resulting mixture was heated to 80 °C to react for 12 hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid (27 mg, 19% yield). LC-MS m / z)'. 634.0 [M+H]+. 'HNMR (400 MHz, DMSO-t / e) 5 7.75 - 7.72 (m, 2H), 7.64 - 7.62 (m, 2H), 7.48 (d, J= 1.2 Hz, 1H), 7.28 - 7.25 (m, 2H), 6.90 - 6.82 (m, 2H), 5.36 - 5.31 (m, 2H), 4.93 -IPTS / 200087585.1Attorney Docket No. RTX-003WO4.82 (m, 2H), 4.30 (s, 1H), 4.00 - 3.96 (m, 1H), 3.85 - 3.79 (m, 1H), 2.97- 2.92 (m, 1H), 2.65 - 2.55 (m, 2H), 2.45 - 2.40 (m, 2H),2.09 - 2.05 (m, 1H),1.54 - 1.50 (m, 1H) .Example 23: Synthesis of (S)-2-((l-(2-chlorobenzyl)-6,6-difluoro-4,5,6,7-tetrahydro- lH-indazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Compound 123)

[0204] Stepl: ethyl l-(2-chlorobenzyl)-6-oxo-4,5,6, 7-tetrahydro-lH-indazole-3- carboxylate

[0205] Ethyl l-(2-chlorobenzyl)- 1,4,5, 7-tetrahydrospiro[indazole-6,2'-[l, 3]dioxolane]-3- carboxylate (1.60 g, 4.2 mmol, 1.0 eq.) was dissolved in TFA (20 mL). The reaction mixture was stirred at 70 °C for 3 hrs. The reaction was mixture poured into saturated NaHCCh solution, extracted with EA, and the organic phase was isolated, and concentrated to dryness. The crude product was purified through column chromatography to obtain an off-white solid (1.30 g, 92% yield). LC-MS (m / z): 333.0 [M+H]+.Step 2: ethyl l-(2-chlorobenzyl)-6,6-difluoro-4,5,6, 7-tetrahydro-lH-indazole-3-carboxylate

[0206] To a stirred solution of ethyl l-(2-chlorobenzyl)-6-oxo-4,5,6,7-tetrahydro-lH- indazole-3 -carboxylate (300 mg, 902 umol, 1.0 eq) in DCM (5 mL) was added DAST (363 mg, 2.2 mmol, 2.5 eq) at 0 °C, stirred for 0.5 hr. The reaction mixture was stirred at 25 °C for 3 hrs. The reaction mixture was poured into saturated Na2COs solution, extracted with EA, and the organic phase was isolated, and concentrated to dryness. The crude product was purified through column chromatography to obtain a colourless oil (150 mg, 47% yield). LC-MS (m / z): 355.0 [M+H]+.IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 3: (l-(2-chlorobenzyl)-6,6-difluoro-4,5,6, 7-tetrahydro-lH-indazol-3-yl) methanol

[0207] To a stirred solution of ethyl l-(2-chlorobenzyl)-6,6-difluoro-4,5,6,7-tetrahydro- lH-indazole-3-carboxylate (150 mg, 423 umol, 1.0 eq) in THF (5 mL) was added LAH (24 mg, 632 umol, 1.5 eq) in several portions. The reaction mixture was stirred at 25 °C for 1 hr. The reaction mixture was treated with 0.1 mL H2O, O. lmL 15% NaOH solution, 0.3 mL H2O. The reaction mixture was filtered and washed with EA, and the filtrate was concentrated to remove the volatiles. The crude product was purified through column chromatography to obtain a colourless oil (100 mg, 76% yield).Step 4: l-(2-chlorobenzyl)-3-(chloromethyl)-6,6-difluoro-4,5,6, 7-tetrahydro-lH-indazole

[0208] To a stirred solution of (l-(2-chlorobenzyl)-6,6-difluoro-4,5,6,7-tetrahydro-lH- indazol-3-yl) methanol (100 mg, 320 umol, 1.0 eq) in DCM (5 mL) was added SOCI2 (76 mg, 639 umol, 2.0 eq). The reaction mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated to remove the volatiles to obtain a colourless oil (105 mg, 99% yield).Step 5: (S)-2-((l-(2-chlorobenzyl)-6,6-difluoro-4,5,6, 7-tetrahydro-lH-indazol-3-yl) methyl)- 5-( 4-chlorophenyl)-4-( 3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4-triazol-3-one

[0209] To a stirred solution of l-(2-chlorobenzyl)-3-(chloromethyl)-6,6-difluoro-4, 5,6,7- tetrahydro-lH-indazole (105 mg, 317.0 umol, 1.0 eq) in MeCN (5 mL) was added (S)-5-(4- chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (98 mg, 317 mmol, 1.0 eq) and K2CO3 (131 mg, 951 mmol, 3.0 eq). The reaction mixture was stirred at 80 °C for 16 hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated, and concentrated to dryness. The crude product was purified through column chromatography followed by prep. HPLC purification, the eluent was concentrated. The residual aqueous solution was lyophilized to give a white solid (15 mg, 16% yield). LC-MS (m / z): 601.80[M+H]+. 'HNMR (400 MHz, DMSO-t / e) 5 7.71-7.73 (m, 2H), 7.61-7.63 (m, 2H), 7.48-7.50 (m, 1H), 7.27-7.36 (m, 2H), 6.86-6.88 (m, 2H), 5.29 (s, 2H), 4.88 (s, 2H), 4.29 (m, 1H), 3.95-4.00 (m, 1H), 3.78-3.84 (m, 1H), 3.19-3.26 (m, 2H), 2.51-2.60 (m, 2H), 2.14-2.22 (m, 2H).Example 24: Synthesis of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-N-methyl-l,4,5,7- tetrahydro-6H-pyrazolo [3,4-c] pyridine-6-carboxamide (Compound 124)IPTS / 200087585.1Attorney Docket No. RTX-003WO

[0210] A mixture of (S)-2-((l-(2-chlorobenzyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4- c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one (100 mg, 176 pmol, 1.0 eq), N-methyl-lH-imidazole-l-carboxamide (24 mg, 192 pmol, 1.1 eq), TEA(20 mg, 198 pmol, 1.1 eq) were suspended in DCM (5 mL). Pumped and refilled with nitrogen three times. The resulting mixture was heated to 15 °C to react for 16 hrs under a nitrogen atmosphere. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (58 mg, 53%, 1 eq). LC-MS (m / z): 623.9 [M+H]+ 1HNMR(400MHz,DMSO-d6) 8 7.79-7.71(m, 2H),7.67-7.61(m, 2H),7.55- 7.47(m, lH),7.40-7.26(m, 2H),6.91(d, J=5.7Hz, lH),6.87-6.78(m, 1H), 6.66-6.50(m, lH),5.29(s, 2H),4.89(d, J=2.7Hz, 2H), 4.42(s, 2H), 4.34-4.23(m, 1H), 4.03-3.92(m, 1H), 3.90-3.74(m, 1H), 3.49(brt, J=5.6Hz, 2H), 2.58(d, J=4.2Hz, 3H), 2.46(brt, J=5.2Hz, 2H).Example 25: Synthesis of (S)-l-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-l,4,5,7- tetrahydro-6H-pyrazolo [3,4-c] pyridine-6-carboxamide (Compound 125)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: 6-(tert-butyl) 3-ethyl l-(3-chlorophenyl)-l,4,5, 7-tetrahydro-6H-pyrazolo[3,4-c] pyridine-3, 6-dicarboxylate

[0211] A mixture of 6-(tert-butyl) 3-ethyl l,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridine-3,6-dicarboxylate(800 mg, 2.7 mmol, 1.0 eq), 3-Chlorophenylboronic acid (635 mg, 4.1mmol,1.5 eq), Cu(OAc)2 (984 mg, 5.4 mmol, 2.0 eq) was suspended in DCM (20 mL) and pyridine (5 mL). Pumped and refilled with oxygen three times. The resulting mixture was heated to 15°C to react for 48 hrs under oxygen atmosphere. The reaction solution was concentrated. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with brine, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a colorless oil compound (220 mg, 20% yield).LC-MS (m / z) (ESI): 406.2 [M + H]+ 1H NMR (400 MHz, CHLOROFORM-d) 5 7.59 (s, 1H), 7.50 - 7.35 (m, 3H), 4.66 (br s, 2H), 4.50 - 4.40 (m, 2H), 3.71 (br t, J= 5.5 Hz, 2H), 2.94 (br t, J= 5.6 Hz, 2H), 1.49 (s, 9H), 1.43 (t, J= 7.1 Hz, 3H).Step 2: tert-butyl l-(3-chlorophenyl)-3-(hydroxymethyl)-l,4,5, 7-tetrahydro-6H- pyrazolo[3, 4-c] pyridine-6-carboxylateIPTS / 200087585.1Attorney Docket No. RTX-003WO

[0212] 6-(tert-butyl) 3-ethyl l-(3-chlorophenyl)-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-c] pyridine-3,6-dicarboxylate (200 mg, 493 pmol,1.0 eq) was dissolved in THF (4 mL), then LAH (28 mg, 738 pmol,1.5 eq) was added at 0 °C. The reaction mixture was stirred 1 hr at 0 °C. The reaction mixture was added H2O (28mg), 15%NaOH (28mg), H2O (84mg) under 0 °C, dried over MgSCh. The mixture was filtered, the filtrate was concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (160 mg, 81% yield). LC-MS (m / z): 364.2 [M+H]+.Step 3: tert-butyl 3-(chloromethyl)-l-(3-chlorophenyl)-l,4,5, 7-tetrahydro-6H-pyrazolo[3,4- c] pyridine-6-carboxylate

[0213] tert-butyl l-(3-chlorophenyl)-3-(hydroxymethyl)-l,4,5,7-tetrahydro-6H-pyrazolo [3,4-c] pyridine-6-carboxylate (160 mg, 440 pmol,1.0 eq) was dissolved in DCM(3mL), then SOCh(78 mg, 656 pmol,1.5 eq) was added at 0 °C. The reaction mixture was stirred 1 hr at 15 °C. The reaction solution was concentrated and obtained the light yellow oil crude product (168 mg). LC-MS (m / z): 382.2 [M+H]+.Step 4: l-(3-Chloro-phenyl)-3-[3-(4-chloro-phenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxy- propyl)-4, 5-dihydro-[ 1,2,4] triazol- 1-ylmethyl ]-l, 4, 5, 7-tetrahydro-pyrazolo [ 3, 4-c ]pyridine- 6-carboxylic acid tert-butyl ester

[0214] A mixture of tert-butyl 3-(chloromethyl)-l-(3-chlorophenyl)-l,4,5,7-tetrahydro- 6H-pyrazolo[3,4-c] pyridine-6-carboxylate (168 mg, 439 pmol,1.0 eq), (S)-5-(4- chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (148 mg, 481 pmol,l. l eq), K2CO3(182 mg, 1.3 mmol, 3.0 eq) were suspended in MeCN (5 mL). Pumped and refilled with nitrogen three times. The resulting mixture was heated to 80 °C to react for 16 hrs under a nitrogen atmosphere. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (160 mg, 56% yield).LC-MS (m / z): 653.2 [M+H]+.Step 5: (S)-5-(4-chlorophenyl)-2-((l-(3-chlorophenyl)-4,5,6, 7-tetrahydro-lH-pyrazolo[3,4- c] pyridin-3-yl) methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro -3H-l,2,4-triazol- 3-one

[0215] 1 -(3 -Chloro-phenyl)-3 - [3 -(4-chloro-phenyl)-5 -oxo-4-(3 , 3 ,3 -trifluoro-2-hy droxy- propyl)-4,5-dihydro-[l,2,4] triazol-l-ylmethyl]-l,4,5,7-tetrahydro-pyrazolo[3,4-c] pyridine-IPTS / 200087585.1Attorney Docket No. RTX-003WO6-carboxylic acid tert-butyl ester (160 mg, 245 pmol,1.0 eq) was dissolved in HCl / dioxane(4 M,6 mL,98.0 eq). The reaction mixture was stirred 1 hr at 15°C.The reaction solution was concentrated then added water. The mixture was adjusted to pH=8~9 with saturated NaHCCh solution. The reaction mixture was treated with water and DCM, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness to afford a white solid product(120 mg, 89% yield).LC-MS (m / z): 553.2 [M+H]+ 1HNMR(400MHz,DMSO-d6) 8 7.75(brd, J=8.6Hz, 2H),7.66-7.57(m, 3H),7.56-7.50(m, lH),7.49-7.45(m,lH),7.42 (brd,J=7.8Hz,lH),6.90(brd,J=6.4Hz,lH),4.98(s,2H),4.42-4.23(m,lH), 4.17-3.88(m, 4H), 3.87-3.79(m,lH),2.88(brt, J=5.4Hz,2H),2.45-2.35(m,2H).Step 6: (S)-l-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl) methyl)-!, 4, 5, 7-tetrahydro-6H- pyrazolo[3, 4-c] pyridine-6-carboxamide

[0216] A mixture of (S)-5-(4-chlorophenyl)-2-((l-(3-chlorophenyl)-4,5,6,7-tetrahydro- lH-pyrazolo[3,4-c] pyridin-3-yl) methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one (100 mg, 181 pmol,1.0 eq), hydrochloric acid (0.5 M, 0.5 mL,1.4 eq), KCNO (44 mg, 542 pmol,3.0 eq) were suspended in H2O(5mL). The reaction mixture was stirred 16 hrs at 60°C.The mixture was adjusted to pH=8~9 with saturated NaHCCh solution. The reaction mixture was treated with water and DCM, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain the white solid product (49 mg, 46% yield). LC-MS (m / z): 596.1[M+H]+.1HNMR(400MHz, DMSO-de) 5 7.76(d, J=8.5Hz, 2H),7.64(d, J=8.4Hz, 3H),7.61-7.45(m, 3H),6.91(brd, J=4.3Hz, lH),6.21(s, 2H),5.00(s, 2H),4.67(s, 2H), 4.38-4.29(m,lH),4.06-3.94(m, lH),3.90-3.75(m,lH),3.56(brt, J=5.6Hz, 2H), 2.56-2.53 (m, 2H).Example 26: Synthesis of (S)-2-((l-(2-chlorobenzyl)-6-cyclopropyl-4,5,6,7-tetrahydro- lH-pyrazolo[3,4-c] pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 126)IPTS / 200087585.1Attorney Docket No. RTX-003WO

[0217] A mixture of (S)-2-((l-(2-chlorobenzyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c] pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one (100 mg, 176 pmol, 1.0 eq), cyclopropylboronic acid (46 mg, 536 pmol,3.0 eq), Cu(OAc)2 (36 mg, 180 pmol, 1.0 eq) ,2,2'-Bipyridine(28 mg, 179 pmol, 1.0 eq) and Na2COs (94 mg, 887pmol,5.0 eq) were suspended in DCE (5 mL). Pumped and refilled with oxygen three times. The resulting mixture was heated to 80°C to react for 16 hrs under oxygen atmosphere. The reaction solution was concentrated. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with brine, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (28 mg, 26% yield). LC-MS (m / z): 606.9 [M+H]+.1HNMR(400MHz,DMSO-d6)57.78-7.71(m,2H),7.66- 7.60(m,2H),7.54-7.48(m,lH),7.40-7.27(m,2H),6.90(d,J=6.3Hz,lH),6.86- 6.79(m,lH),5.28(s,2H), 4.87(s, 2H),4.38-4.22(m,lH),4.10-3.93(m,lH),3.91- 3.76(m,lH),3.59(s,2H),2.77(t,J=5.6Hz, 2H), 2.43(brt, J=5.4Hz,2H), 1.90-1.79(m,lH), 0.53- 0.43 (m, 2H),0.37-0.26(m,2H).Example 27: Synthesis of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl) methyl)-!, 4, 5, 7- tetrahydro-6H-pyrazolo[3,4-c] pyridine-6-sulfonamide (Compound 127)

[0218] A mixture of 2-[l-(2-Chloro-benzyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c] pyridin-3-ylmethyl]-5-(4-chloro-phenyl)-4-(3,3,3-trifluoro-2-hydroxy-propyl)-2,4-dihydro- [l,2,4]triazol-3-one (100 mg, 176 pmol, 1.0 eq), sulfamide (20 mg, 208 pmol, 1.2 eq) wereIPTS / 200087585.1Attorney Docket No. RTX-003WO suspended in 1,4-di oxane (6 mL). Pumped and refilled with nitrogen three times. The resulting mixture was heated to 80 °C to react for 24 hrs under a nitrogen atmosphere. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (35 mg, 31% yield). LC-MS (m / z): 646.2[M+H]+.1HNMR(400MHz,DMSO-d6)5(ppm)7.79- 7.69(m,2H),7.67-7.57(m, 2H), 7.55-7 ,46(m,lH),7.42-7.22(m,2H),6.99-6.87(m,3H),6.85- 6.71(m,lH),5.30(s,2H), 4.90 (s, 2H),4.30(brs,lH),4.13(s,2H),4.02-3.94(m,lH),3.88- 3.75(m,lH),3.20(brt, J=5.6 Hz, 2H), 2.56(brt, J=5.4Hz,2H).Example 28: Synthesis of l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3- trifluoro-2-hydroxy propyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-4,5,6,7- tetrahydro-lH-indazole-6-carbonitrile (Compound 128)Step 1: ethyl l-(2-chlorobenzyl)-6-oxo-4,5,6, 7-tetrahydro-lH-indazole-3-carboxylate

[0219] A solution of ethyl l-(2-chlorobenzyl)-l,4,5,7-tetrahydrospiro[indazole-6,2'-[l,3] dioxolane]-3-carboxylate (1.00 g, 2.7 mmol, 1.0 eq) in TFA (20 mL) was stirred at 75°C for 3hrs. The solvent was removed under reduce pressure to give a yellow oil, which was diluted with EtOAc. The mixture was washed with saturated NaHCOs aqueous and brine, dried over with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuoIPTS / 200087585.1Attorney Docket No. RTX-003WO to give the title compound (850 mg, 96% yield) as a light-yellow solid, which was used for next step directly without further purification. LC-MS (m / z): 333.1 [M + H]+.Step 2: ethyl l-(2-chlorobenzyl)-6-(((trifluoromethyl)sulfonyl) oxy)-4,5-dihydro-lH- indazole-3-carboxylate

[0220] To a stirred solution of ethyl l-(2-chlorobenzyl)-6-oxo-4,5,6,7-tetrahydro-lH- indazole-3 -carboxylate (850 mg, 2.6 mmol, 1.0 eq) in THF (15 mL) was added potassium tert-butoxide (1 M in THF, 4 mL, 1.6 eq) dropwise at 0 °C. Then 1,1,1-trifluoro-N-phenyl- N-(trifhioromethylsulfonyl) methanesulfonamide (1.10 g, 3.1 mmol, 1.2 eq) in THF (5 mL) was added dropwise. The mixture was stirred at 20 °C for Ihr. The reaction was quenched by addition of water, which was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (560 mg, 47% yield) as a white solid. LC-MS (m / z): 465.0 [M + H]+.Step 3: ethyl l-(2-chlorobenzyl)-6-cyano-4,5-dihydro-lH-indazole-3-carboxylate

[0221] To a stirred solution of ethyl l-(2-chlorobenzyl)-6-(((trifluoromethyl)sulfonyl) oxy)-4,5-dihydro-lH-indazole-3-carboxylate (560 mg, 1.2 mmol, 1.0 eq) in DMF (6 mL) was added Tetrakis(triphenylphosphine)palladium (140 mg, 121 pmol, 0.1 eq) and Zn(CN)2 (212 mg, 1.8 mmol, 1.5 eq). The mixture was degassed and backfilled with N2 for three times. Then the reaction mixture was stirred at 60°C for 3hrs. The reaction was diluted with water, which was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (205 mg, 50% yield) as a white solid. LC-MS (m / z): 342.1 [M + H]+.Step 4: l-(2-chlorobenzyl)-3-(hydroxymethyl)-4,5,6, 7 -tetrahydro- lH-indazole-6-carbonitrile

[0222] To a solution of ethyl l-(2-chlorobenzyl)-6-cyano-4,5-dihydro-lH-indazole-3- carboxylate (205 mg, 600 pmol, 1.0 eq) in EtOH (10 mL) was added NaBH4 (227 mg, 6.0 mmol, 10 eq). Then the mixture was stirred at 75°C for 14 hrs. The reaction was diluted with water, which was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuoIPTS / 200087585.1Attorney Docket No. RTX-003WO to give the title compound (50 mg, 28% yield) as a white solid, which was used for next step directly without further purification. LC-MS (m / z): 302.1 [M + H]+.Step 5: l-(2-chlorobenzyl)-3-(chloromethyl)-4,5,6, 7-tetrahydro-lH-indazole-6-carbonitrile

[0223] To a stirred solution of l-(2-chlorobenzyl)-3-(hydroxymethyl)-4, 5,6,7- tetrahydro-lH-indazole-6-carbonitrile (50 mg, 166 pmol, 1.0 eq) in DCM (3 mL) was added SOCh (40 mg, 336 pmol, 2.0 eq) at 0°C under N2 atmosphere, then the reaction mixture was stirred at 0 °C for Ihr. The reaction mixture was concentrated in vacuo to dryness to give the title compound (30 mg, 57% yield) as a white solid. LC-MS (m / z) : 320.1 [M + H]+.Step 6: l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl) methyl)-4, 5, 6, 7 -tetrahydro- IH-indazole- 6-carbonitrile

[0224] To a solution of l-(2-chlorobenzyl)-3-(chloromethyl)-4,5,6,7-tetrahydro-lH- indazole-6-carbonitrile (30 mg, 94 pmol, 1.0 eq) and (S)-5-(4-chlorophenyl)-4-(3,3,3- trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (30 mg, 98 pmol, 1.0 eq) in MeCN (3 mL) was added K2CO3 (30 mg, 217 pmol, 2.3 eq). Then the mixture was stirred at 80°C for 14 hrs. The reaction mixture was cooled to rt, which was added water. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (30 mg, 54% yield) as a white solid. LC-MS (m / z) (ESI): 591.1 [M + H]+. 'HNMR (400 MHz, DMSO-de) 5 7.73 (d, J= 8.3 Hz, 2H), 7.62 (d, J= 8.6 Hz, 2H), 7.52 - 7.47 (m, 1H), 7.38 - 7.31 (m, 1H), 7.31 - 7.24 (m, 1H), 6.92 - 6.86 (m, 1H), 6.82 (d, J= 7.6 Hz, 1H), 5.29 (s, 2H), 4.95 - 4.76 (m, 2H), 4.39 - 4.20 (m, 1H), 4.02 - 3.91 (m, 1H), 3.87 - 3.75 (m, 1H), 3.33 - 3.27 (m, 1H), 3.04 - 2.92 (m, 1H), 2.90 - 2.81 (m, 1H), 2.58 - 2.52 (m, 2H), 2.01 - 1.87 (m, 2H).Example 29: Synthesis of (S)-2-((6-amino-l-(2-chlorobenzyl)-lH-indazol-3-yl)methyl)- 5-phenyl-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 129)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: (6-bromo-l-(2-chlorobenzyl)-lH-indazol-3-yl)methanol

[0225] To a mixture of (6-bromo-lH-indazol-3-yl) methanol (600 mg, 2.6 mmol, 1.0 eq) in MeCN (10 mL) was added l-Bromomethyl-2-chloro-benzene (596 mg, 2.9 mmol, 1.1 eq) and K2CO3 (1.09 g,7.9 mmol, 3.0 eq). The mixture was stirred at 80°C for 4 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the product (430 mg, 46% yield) as a white solid. LC-MS (m / z): 352.9 [M+H]+.‘HNMR (400 MHz, DMSO-de) 5 8.03 (d, J = 1.0 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.50 (dd, J = 7.9, 1.1 Hz, 1H), 7.36-7.22 (m, 3H), 6.83 (dd, J = 7.6, 1.5 Hz, 1H), 5.68 (s, 2H), 5.37 (t, J = 5.7 Hz, 1H), 4.76 (d, J = 5.9 Hz, 2H).Step 2: 6-bromo-l-(2-chlorobenzyl)-3-(chloromethyl)-lH-indazole

[0226] To a solution of (6-bromo-l-(2-chlorobenzyl)-lH-indazol-3-yl) methanol (381 mg, 1.1 mmol, 1.0 eq) in DCM (10 mL) was added SOCh (155 mg, 1.3 mmol, 1.2 eq) at 0°C. The mixture was stirred at 20°C for 2hrs. The reaction mixture was evaporated to dryness to give crude product (400 mg) as a white solid. LC-MS (m / z): 370.9 [M+H]+.Step 3: (S)-2-((6-bromo-l-(2-chlorobenzyl)-lH-indazol-3-yl) methyl)-5-(4-chloro phenyl)-4- ( 3, 3, 3 -trifluor o-2 -hydroxypropyl) -2, 4-dihydro-3H-l, 2, 4-triazol-3-one

[0227] To a mixture of 6-bromo-l-(2-chlorobenzyl)-3-(chloromethyl)-lH-indazole (400 mg, 1.1 mmol, 1.0 eq) in MeCN (10 mL) was added (S)-5-(4-chlorophenyl)-4-(3,3,3-IPTS / 200087585.1Attorney Docket No. RTX-003WO trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (349 mg, 1.1 mmol, 1.1 eq) and K2CO3 (448 mg, 3.2 mmol, 3.0 eq). The mixture was stirred at 80°C for 2hrs. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the product (430 mg, 62% yield) as a white solid. LC-MS (m / z): 642.0 [M+H]+.Step 4: tert-butyl (S)-(l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl) methyl)-lH-indazol-6-yl)carbamate

[0228] To a mixture of (S)-2-((6-bromo-l-(2-chlorobenzyl)-lH-indazol-3-yl)methyl)-5- (4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3- one(380 mg, 593 pmol, 1.0 eq) and tert-butyl carbamate (76 mg, 649 pmol, 1.1 eq) in dioxane (10 mL) was added Cs2CO3(578 mg, 1.8 mmol, 3.0 eq), PD2(DBA)3 (30 mg, 33 pmol, 0.06 eq) and XantPhos (38 mg, 66 pmol, 0.1 eq). The suspension was degassed under vacuum and purged with N2 three times, then heated to 90°C and stirred under N2 for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the product (230 mg, 57% yield) as a white solid. LC-MS (m / z): 677.2 [M+H]+.Step 5: (S)-2-((6-amino-l-(2-chlorobenzyl)-lH-indazol-3-yl) methyl)-5-phenyl-4-(3,3,3- trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4-triazol-3-one

[0229] A mixture of tert-butyl (S)-(l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4- (3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro- 1H- 1 ,2,4-triazol- 1 -yl) methyl)- IH-indazol -6- yl) carbamate (230 mg, 339 pmol, 1.0 eq) and HCl / dioxane (4 M,5 mL,58.9 eq) was stirred at 20°C for 2hrs. The reaction mixture was concentrated. The residue was adjusted to pH=8~9 with saturated NaHCCh solution, extracted with EtOAc, the organic layer was separated, wash with saturated NaCl solution, dried over MgSCh and evaporated to dryness. The crude product was purified by column chromatography to give the target compound (150 mg, 77%yelid) as a white solid. LC-MS (m / z):577.2 [M+H]+.1HNMR(400 MHz, DMSO_d6) 5 (ppm) 7.75-7.69 (m, 2H), 7.66-7.58 (m, 2H), 7.55-7.40 (m, 2H), 7.36-7.27 (m, 1H), 7.27- 7.14 (m, 1H), 6.90 (d, J = 6.4 Hz, 1H), 6.75-6.67 (m, 1H), 6.56-6.49 (m, 1H), 6.40 (d, J = 1.2 Hz, 1H), 5.52-5.47 (m, 1H), 5.47 (s, 1H), 5.51-5.44 (m, 1H), 5.40 (s, 2H), 5.22-5.10 (m, 2H), 4.38-4.21 (m, 1H), 4.06-3.96 (m, 1H), 3.91-3.77 (m, 1H).IPTS / 200087585.1Attorney Docket No. RTX-003WOExample 30: Synthesis of (S)-N-(l-(2-chlorobenzyl)-3-((5-oxo-3-phenyl-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-lH-indazol-6- yl)acetamide (Compound 130)

[0230] To a mixture of (S)-2-((6-amino-l-(2-chlorobenzyl)-lH-indazol-3-yl) methyl)-5- phenyl-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one(80 mg, 139 pmol, 1.0 eq) in DCM (3 mL) was added Ac2O(16 mg, 158 pmol,l.leq). The mixture was stirred at 20°C for 16hrs. The reaction mixture was concentrated. The crude product was purified by column chromatography to give the target compound (58 mg, 68% yield) as a white solid. LC-MS (m / z): 619.2 [M+H]+.1HNMR(400 MHz, DMSO de ) 5 (ppm) 10.13 (s, 1H), 8.05 (s, 1H), 7.76- 7.68 (m, 3H), 7.65- 7.58 (m, 2H), 7.54- 7.48 (m, 1H), 7.37- 7.30 (m, 1H), 7.26- 7.15 (m, 2H), 6.89 (d, J = 6.4 Hz, 1H), 6.87- 6.79 (m, 1H), 5.61 (s, 2H), 5.33- 5.20 (m, 2H), 4.36- 4.24 (m, 1H), 4.07- 3.96 (m, 1H), 3.90- 3.79 (m, 1H), 2.05 (s, 3H).Example 31: Synthesis of l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-4,5,6,7- tetrahydro-lH-indazole-6-carboxamide (Compound 131)

[0231] To a mixture of l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3- trifluoro-2-hydroxypropyl)-4, 5 -dihydro- 1H- 1,2, 4-tri azol- l-yl)methyl)-4, 5,6, 7-tetrahydro- lH-indazole-6-carbonitrile (30 mg, 51 pmol, 1.0 eq) and K2CO3 (10 mg, 72 pmol, 1.4 eq) in DMSO (3 mL) was added H2O2 (30 mg, 265 pmol, 30% purity, 5.2 eq) dropwise. The mixture was stirred at 20°C for 2 hrs. The reaction mixture was diluted with water. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuoIPTS / 200087585.1Attorney Docket No. RTX-003WO to give the crude product as a white solid. The crude product was purified by Prep-HPLC to give the title compound (25 mg, 81% yield) as a white solid. LC-MS (m / z): 609.1 [M + H]+. 'HNMR (400 MHz, DMSO-de) 5 = 7.78-7.69 (m, 2H), 7.68-7.59 (m, 2H), 7.53-7.46 (m, 1H), 7.40-7.25 (m, 3H), 6.92-6.84 (m, 2H), 6.75 (d, J= 7.6 Hz, 1H), 5.40-5.19 (m, 2H), 4.94-4.78 (m, 2H), 4.38-4.23 (m, 1H), 4.02-3.94 (m, 1H), 3.88-3.75 (m, 1H), 2.74-2.66 (m, 1H), 2.60-2.53 (m, 2H), 2.49-2.42 (m, 1H), 2.39-2.26 (m, 1H), 1.95 (br d, J= 12.5 Hz, 1H), 1.63-1.47 (m, 1H).Example 32: Synthesis of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-N-methyl-lH- indazole-6-carboxamide (Compound 132)Step 1: (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl) methyl) -lH-indazole-6-carboxylic acid

[0232] To a solution of methyl (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4- (3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-lH-indazole-6- carboxylate (420 mg, 677 pmol, 1.0 eq) in MeOH (4 mL) was added H2O (4 mL) and NaOH(54 mg, 1.4 mmol, 2.0 eq). The mixture was stirred at 50°C for 2hrs. The reaction mixture was concentrated. The residue was adjusted to pH=l~2 with 3N HC1. The mixture was filtered and the filter cake were washed with water, dried in vacuum to give the target compound (380 mg, 93%yelid) as a white solid. LC-MS (m / z):604.1 [M-H]'.Step 2: (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl) methyl) -N-methy l-l H-indazole-6- carboxamide

[0233] To a mixture of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4, 5 -dihydro- 1H- 1 ,2,4-triazol- 1 -yl)methyl)- lH-indazole-6- carboxylic acid (60 mg, 99 pmol, 1.0 eq) in DCM (5 mL) was added Methylamine hydrochloride (14 mg, 207 pmol, 2.1 eq) , HATU(46 mg, 121 pmol, 1.2 eq) and DIPEA(39 mg, 302 pmol, 3.1 eq). The mixture was stirred at 20°C for 16hrs. The reaction mixture wasIPTS / 200087585.1Attorney Docket No. RTX-003WO treated with water and DCM, the organic layers were washed with water and brine, dried over MgSCh and evaporated to dryness. The residue was purified by column chromatography to give the target compound (16 mg, 26 % yield) as a white solid. LC-MS (m / z):619.2 [M+H]+.JHNMR(400 MHz, DMSO_d6) 5 (ppm) 8.52 (br s, 1H), 8.18 (br s, 1H), 7.96- 7.48 (m, 7H), 7.42- 7.16 (m, 2H), 7.06- 6.72 (m, 2H), 5.77 (br s, 2H), 5.52- 5.18 (m, 2H), 4.40- 4.19 (m, 1H), 4.12- 3.96 (m, 1H), 3.94- 3.72 (m, 1H), 2.81 (br s, 3H).Example 33: Synthesis of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-N,N-dimethyl- lH-indazole-6-carboxamide (Compound 133)

[0234] To a mixture of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4, 5 -dihydro- 1H- 1 ,2,4-triazol- 1 -yl)methyl)- lH-indazole-6- carboxylic acid (80 mg, 132 pmol, 1.0 eq) in DCM(5 mL) was added Dimethylamine hydrochloride (22 mg, 270 pmol,2.0 eq), HATU(60 mg, 158 pmol, 1.2 eq) and DIPEA(52 mg, 402 pmol, 3.0 eq) . The mixture was stirred at 20°C for 16hrs. The reaction mixture was treated with water and DCM, the organic layers were washed with water and brine, dried over MgSCh and evaporated to dryness. The residue was purified by column chromatography to give the target compound (20 mg, 24%yelid) as a white solid. LC-MS (m / z):633.2 [M+H]+.1H NMR(400 MHz, DMSO_d6) 5 (ppm) 7.96 - 7.85 (m, 1H), 7.82 - 7.67 (m, 3H), 7.66 - 7.58 (m, 2H), 7.55 - 7.47 (m, 1H), 7.41 - 7.29 (m, 1H), 7.29 - 7.15 (m, 2H), 7.00 - 6.78 (m, 2H), 5.91 - 5.66 (m, 2H), 5.49 - 5.19 (m, 2H), 4.30 (br d, J = 1.7 Hz, 1H), 4.08 - 3.96 (m, 1H), 3.91 - 3.77 (m, 1H), 3.09 - 2.95 (m, 3H), 2.95 - 2.76 (m, 3H).Example 34: Synthesis of (S)-2-((l-(2-chlorobenzyl)-l,4,5,7-tetrahydrothiopyrano[3,4- c]pyrazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Compound 134)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: ethyl l,4,5, 7-tetrahydrothiopyrano[3,4-c] pyrazole-3-carboxylate

[0235] To an anhydrous DMSO (15 mL) solution of tetrahydrothiopyran-4-one (3.05 g, 26.3 mmol, 2.0 eq) and pyrrolidine (280 mg, 3.9 mmol, 0.3 eq) was added 4A molecular sieve. The reaction mixture was stirred at ambient temperature for 20 min, then added ethyl 2-diazoacetate (1.50 g, 13.1 mmol, 1.0 eq), The resulting mixture was heated to 50 °C to react for 24 hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated, and concentrated to dryness. The crude product was purified through column chromatography to obtain a pale solid (1.83 g, 66% yield). LC-MS (m / z): 213.1 [M+H]+.Step 2: ethyl l-(2-chlorobenzyl)-l,4,5, 7-tetrahydrothiopyrano[3,4-c] pyrazole-3- carboxylate

[0236] To a DMF (15 mL) solution of ethyl l,4,5,7-tetrahydrothiopyrano[3,4-c] pyrazole-3 -carboxylate (1.83 g, 8.6 mmol, 1.0 eq) was added K2CO3 (3.57 g, 25.8 mmol, 3.0 eq) and l-(bromomethyl)-2-chloro-benzene (2.13 g, 10.4 mmol, 1.2 eq). The resulting mixture was heated at 60 °C for 3hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSO4, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid (1.45 g, 50% yield). LC-MS (m / z):337.2 [M+H]+.JH NMR (400 MHz, CDCh) 5 7.42 -7.40 (m, 1H), 7.28-7.20 (m, 2H), 6.70 -6.70 (m, 1H), 5.50 (s, 2H), 4.43 (q, J = 7.2 Hz, 2H), 3.51 (s, 2H), 3.17 -3.14 (m, 2H), 2.86 -2.83 (m, 2H), 1.43 (t, J = 7.2 Hz, 3H).Step 3: (l-(2-chlorobenzyl)-l,4,5, 7-tetrahydrothiopyrano[3,4-c]pyrazol-3-yl) methanolIPTS / 200087585.1Attorney Docket No. RTX-003WO

[0237] To an anhydrous THF (5 mL) solution of ethyl l-(2-chlorobenzyl)-l,4,5,7 - tetrahydrothiopyrano[3,4-c] pyrazole-3- carboxylate (400 mg, 1.2 mmol, 1.0 eq) was cooled in ice-water bath, then added LiAIT (67 mg, 1.8 mmol, 1.5 eq) in portions. The resulting mixture was stirred at 0~4°C for 2 hrs. The reaction solution was quenched by addition of 67 mg of H2O, followed by 67 mg of 15% aqueous NaOH. After being stirred at room temperature for 0.5 hr, the solid was removed by filtration, the filtrate was dried under vacuum to produce targeted compound (350 mg, 100 % yield) as yellow oil, which was used directly for the next step. LC-MS (m / z): 295.6 [M+H]+.Step 4: l-(2-chlorobenzyl)-3-(chloromethyl)-l,4,5, 7-tetrahydrothiopyrano[3,4-c] pyrazole

[0238] To an anhydrous DCM (5 mL) solution of (l-(2-chlorobenzyl)-l, 4,5,7- tetrahydrothiopyrano[3,4-c] pyrazol-3-yl) methanol (300 mg, 1.0 mmol, 1.0 eq) was cooled in ice-water bath, then added SOCh (157 mg, 1.3 mmol, 1.3 eq) in dropwise. The resulting mixture was stirred at ambient temperature for 1 hr. The reaction solution was concentrated to dryness to obtain the title compound as yellow oil (300 mg, 94% yield), which was used directly for the next step. LC-MS (m / z): 315.6 [M+H]+.Step 5: (S)-2-((l-(2-chlorobenzyl)-l,4,5, 7-tetrahydrothiopyrano[3,4-c] pyrazol-3-yl) methyl)-5-( 4-chlorophenyl)-4-(3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4- triazol-3-one

[0239] l-(2-chlorobenzyl)-3-(chloromethyl)-l,4,5,7-tetrahydrothiopyrano[3,4-c] pyrazole (120 mg, 348 pmol, 2.1 eq), 3-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2- hydroxypropyl]- 1H- 1,2, 4-triazol-5-one (50 mg, 163 pmol, 1.0 eq), K2CO3 (67 mg, 485 pmol, 3.0 eq) was suspended in CH3CN (3 mL). The resulting mixture was heated to 80 °C to react for 12 hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid (60 mg, 32% yield). LC-MS (m / z): 583.4 [M+H]+. 'HNMR (400 MHz, DMSO-de) 5 7.73 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.50 - 7.48 (m, 1H), 7.34 -7.27 (m, 2H), 6.89 (d, J = 6.4 Hz, 1H), 6.77 (d, J = 6.4 Hz, 1H), 5.32 (s, 2H), 4.87 (s, 2H), 4.30 -4.28 (m, 1H), 4.00 -3.96 (m, 1H), 3.85-3.79 (m, 1H), 3.69 (s, 2H), 2.81 -2.78 (m, 2H), 2.71 -2.69 (m, 2H).Example 35: Synthesis of 2-((l-(2-chlorobenzyl)-6-(methylamino)-4,5,6,7-tetrahydro- lH-indazol-3-yl)methyl)-5-(4-chlorophenyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)- 2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 135)IPTS / 200087585.1Attorney Docket No. RTX-003WO

[0240] A mixture of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4, 5 -dihydro- 1H- 1 ,2,4-triazol- 1 -yl)methyl)- 1 ,4,5,7-tetrahydro- 6H-indazol-6-one (50 mg, 86 pmol, 1.0 eq), methanamine hydrochloride (58 mg, 859 pmol, 10.0 eq) and Potassium Acetate (85 mg, 866 pmol, 10.0 eq) in MeOH (3 mL) was attired at 20°C for 5min. Then Sodium cyanoborohydride (27 mg, 430 pmol, 5.0 eq) was added. The mixture was stirred at 70°C for 2hrs. The reaction was quenched by addition of water at 0°C, which was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a white solid. The crude product was purified by Prep-HPLC to give the title compound (30 mg, 58% yield) as a white solid. LC-MS (m / z): 595.2 [M + H]+.1H NMR (400 MHz, DMSO-de) 5 8.81 - 8.57 (m, 2H), 7.78 - 7.70 (m, 2H), 7.66 - 7.58 (m, 2H), 7.50 (d, J= 7.8 Hz, 1H), 7.40 - 7.22 (m, 2H), 6.96 - 6.84 (m, 1H), 6.81 (br d, J= 7.3 Hz, 1H), 5.30 (s, 2H), 4.97 - 4.78 (m, 2H), 4.36 - 4.25 (m, 1H), 4.01 - 3.95 (m, 2H), 3.86 - 3.81 (m, 1H), 3.49 - 3.30 (m, 1H), 3.19 - 3.05 (m, 1H), 2.66 - 2.57 (m, 4H), 2.45 - 2.34 (m, 1H), 2.21 - 2.04 (m, 1H), 1.74 - 1.61 (m, 1H)Example 36: Synthesis of 2-((l-(2-chlorobenzyl)-6-(dimethylamino)-4,5,6,7-tetrahydro- lH-indazol-3-yl)methyl)-5-(4-chlorophenyl)-4-((S)-3,3,3-ti'ifluoro-2-hydroxypropyl)- 2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 136)

[0241] A mixture of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4, 5 -dihydro- 1H- 1 ,2,4-triazol- 1 -yl)methyl)- 1 ,4,5,7-tetrahydro- 6H-indazol-6-one(100 mg, 172 pmol, 1.0 eq), dimethylamine hydrochloride (140 mg, 1.7 mmol, 10.0 eq) and potassium acetate (169 mg, 1.7 mmol, 10.0 eq) in MeOH (5 mL) was attired at 20°C for 5min. Then sodium cyanoborohydride (54 mg, 859 pmol, 5.0 eq) wasIPTS / 200087585.1Attorney Docket No. RTX-003WO added. The mixture was stirred at 70°C for 2hrs. The reaction was quenched by addition of water at 0°C, which was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a white solid. The crude product was purified by Prep- HPLC to give the title compound (50 mg, 48% yield) as a white solid. LC-MS (m / z):609.2 [M + H]+. 'HNMR (400 MHz, DMSO-de) 5 9.81 (br s, 1H), 7.77- 7.68 (m, 2H), 7.66- 7.59 (m, 2H), 7.51 (d, J= 7.8 Hz, 1H), 7.39- 7.24 (m, 2H), 6.97- 6.86 (m, 1H), 6.81 (br d, J= 7.6 Hz, 1H), 5.30 (s, 2H), 4.98- 4.73 (m, 2H), 4.39- 4.21 (m, 1H), 4.02- 3.96 (m, 1H), 3.86- 3.81 (m, 2H), 3.63- 3.57 (m, 1H), 3.17- 3.01 (m, 1H), 2.84- 2.77 (m, 6H), 2.75- 2.61 (m, 1H), 2.46- 2.29 (m, 1H), 2.23- 2.08 (m, 1H), 1.82- 1.62 (m, 1H).Example 37: Synthesis of 2-((l-(2-chlorobenzyl)-6-hydroxy-6-methyl-4, 5,6,7- tetrahydro-lH-indazol-3-yl)methyl)-5-(4-chlorophenyl)-4-((S)-3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 137)

[0242] To a stirred solution of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4- (3,3,3-trifhioro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-l,4,5,7- tetrahydro-6H-indazol-6-one(70 mg, 121 pmol, 1.0 eq) in THF (3 mL) was added methylmagnesium chloride (3 M, 0.2 mL, 5.0 eq) dropwise at 0°C under N2 atmosphere, then the reaction mixture was stirred at 20 °C for 2 hrs. The reaction was quenched by addition of saturated NH4Q aqueous (5 mL) and H2O (10 mL) at 0°C, which was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by Prep-HPLC to give the title compound (10 mg, 14% yield) as a white solid. LC-MS (m / z): 596.1 [M + H]+. 'HNMR (400 MHz, DMSO-de) 5 (ppm) 7.77-7.70 (m, 2H), 7.65-7.60 (m, 2H), 7.52-7.43 (m, 1H), 7.37-7.23 (m, 2H), 6.92-6.85 (m, 1H), 6.76-6.70 (m, 1H), 5.22 (s, 2H), 4.96-4.75 (m, 2H), 4.33-4.23 (m, 1H), 4.08-3.91 (m, 1H), 3.88-3.75 (m, 1H), 2.48 (s, 4H), 2.42-2.29 (m, 1H), 1.74-1.62 (m, 1H), 1.57-1.45 (m, 1H), 1.17 (s, 3H).IPTS / 200087585.1Attorney Docket No. RTX-003WOExample 38: Synthesis of 2-((l-(2-chlorobenzyl)-7-methyl-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-((S)-3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 138)Step 1 :6-(tert-butyl) 3-ethyl 7-methyl-l,4,5, 7-tetrahydro-6H-pyrazolo[3,4-c] pyridine-3,6- dicarboxylate

[0243] A mixture of 2-Methyl-3 -oxo-piperidine- 1 -carboxylic acid tert-butyl ester (660 mg, 3.1 mmol, 1.0 eq), Diethyl oxalate (453 mg, 3.1 mmol, 1.0 eq) were suspended in THF (8 mL) and EtOH (0.8 mL). Then t-BuOK(l M, 3.8 mL, 1.2 eq, dissolved in tetrahydrofuran) was added at 0 °C. The reaction mixture was stirred 2 hrs at 15 °C. Then EtOH (8 mL) was added in the reaction mixture and Hydrazine monohydrochloride (255 mg, 3.7 mmol, 1.2 eq, dissolved in H2O (2.5 mL)) was added in the reaction mixture. The reaction mixture was stirred 14 hrs at 15 °C. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with brine, dried over MgSO4, and concentrated to dryness. The crude product was purified through column chromatography to obtain the white solid compound (830 mg, 87%, 1 eq). LC-MS (m / z): 209.3 [M+H]+. *H NMR (400 MHz, CHLOROFORM-d) 5 11.22- 9.92 (m, 1H), 5.62- 4.99 (m, 1H), 4.53- 4.24 (m, 3H), 3.05- 2.84 (m, 2H), 2.81- 2.66 (m, 1H), 1.51 (s, 9H), 1.47 (d, J = 6.8 Hz, 3H), 1.40 (t, J = 7.1 Hz, 3H)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 2: 6-(tert-butyl) 3-ethyl l-(2-chlorobenzyl)-7-methyl-l,4,5, 7-tetrahydro-6H- pyrazolo[3, 4-c] pyridine-3, 6-dicarboxylate

[0244] A mixture of 6-(tert-butyl) 3-ethyl 7-methyl-l,4,5,7-tetrahydro-6H-pyrazolo[3,4- c] pyridine-3, 6-dicarboxylate (640 mg, 2.1mmol,l eq), 2-Chlorobenzyl bromide (510 mg, 2.5 mmol, 1.2 eq), Cs2CO3(2.02 g,6.2 mmol, 3.0 eq) were suspended in MeCN (12 mL).Pumped and refilled with nitrogen three times. The resulting mixture was heated to 80 °C to react for 2hr under a nitrogen atmosphere. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain the colourless oil product (550 mg, 61% yield). LC-MS (m / z): 433.6 [M+H]+ 1H NMR (400 MHz, CHLOROFORM-d) 5 7.40 (br d, J = 7.3 Hz, 1H), 7.28- 7.13 (m, 2H), 6.89- 6.53 (m, 1H), 5.61- 5.41 (m, 2H), 5.39- 4.94 (m, 1H), 4.56- 4.39 (m, 2H), 4.39- 4.19 (m, 1H), 3.15- 2.98 (m, 1H), 2.98- 2.87 (m, 1H), 2.86- 2.73 (m, 1H), 1.55- 1.37 (m, 12H), 1.32- 1.28 (m, 3H).Step 3: tert-butyl l-(2-chlorobenzyl)-3-(hydroxymethyl)-7-methyl-l,4,5, 7-tetrahydro-6H- pyrazolo[3, 4-c] pyridine-6-carboxylate

[0245] 6-(tert-butyl) 3-ethyl l-(2-chlorobenzyl)-7-methyl-l,4,5,7-tetrahydro-6H- pyrazolo[3,4-c] pyridine-3, 6-dicarboxylate (550 mg, 1.3 mmol, 1.0 eq) was dissolved in THF (10 mL), then LAH (72 mg, 1.9 mmol, 1.5 eq) was added at 0 °C. The reaction mixture was stirred 0.5 hr at 0 °C. The mixture was added H2O (78 mg), 15% NaOH solution (78 mg), H2O (234 mg) at 0 °C, dried over MgSCh and filtered. The filtrate was concentrated to dryness. The crude product was purified through column chromatography to obtain a light yellow oil product (440 mg, 89%yield). LC-MS (m / z): 391.5 [M+H]+.Step 4: tert-butyl l-(2-chlorobenzyl)-3-(chloromethyl)-7-methyl-l,4,5, 7-tetrahydro-6H- pyrazolo[3, 4-c] pyridine-6-carboxylate

[0246] tert-butyl l-(2-chlorobenzyl)-3-(hydroxymethyl)-7-methyl-l,4,5,7-tetrahydro- 6H-pyrazolo[3,4-c] pyridine-6-carboxylate (200 mg, 510 pmol,1.0 eq) was dissolved in DCM(5mL), then SOC12(91 mg, 765 pmol,1.5 eq) was added at 0 °C. The reaction mixture was stirred 1 hr at 15 °C. The reaction solution was concentrated and obtained a white solid crude product (200 mg).LC-MS (m / z): 411.7 [M+H]+.IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 5: tert-butyl l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3-trifluoro-2- hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl) me thy I) -7 -me thy I- 1,4, 5, 7-tetrahydro-6H- pyrazolo[3, 4-c] pyridine-6-carboxylate

[0247] A mixture of tert-butyl l-(2-chlorobenzyl)-3-(chloromethyl)-7-methyl-l, 4,5,7- tetrahydro-6H-pyrazolo[3,4-c] pyridine-6-carboxylate (200 mg, 487 pmol,1.0 eq), (S)-5-(4- chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (180 mg, 585 pmol,1.2 eq), K2COs(202 mg, 1.5 mmol, 3.0 eq) were suspended in MeCN (6 mL). Pumped and refilled with nitrogen three times. The resulting mixture was heated to 80 °C to react for 16 hrs under a nitrogen atmosphere. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (220 mg, 66% yield).LC-MS (m / z): 681.5 [M+H]+.Step 6: 2-((l-(2-chlorobenzyl)-7-methyl-4,5,6, 7 -tetrahydro- IH-pyrazolo [3, 4-c] pyridin-3-yl) methyl)-5-( 4-chlorophenyl)-4-((S)-3, 3, 3-trifhioro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4- triazol-3-one

[0248] tert-butyl l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3-trifluoro -2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl) methyl)-7-methyl- 1,4,5, 7-tetrahydro- 6H-pyrazolo[3,4-c] pyridine-6-carboxylate (220 mg, 323 pmol,1.0 eq) was dissolved in HCl / l,4-di oxane (4 M,6 mL,74.3 eq). The reaction mixture was stirred 1 hr at 15°C.The reaction solution was concentrated then added water. The mixture was adjusted to pH=8~9 with saturated NaHCCh solution. The reaction mixture was treated with water and DCM, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (130 mg, 69% yield). LC-MS (m / z): 581.4 [M+H]+.1HNMR(400MHz,DMSO-d6)5(ppm) 7.81-7.70(m, 2H),7.68-7.59(m, 2H),7.52- 7.43(m, lH),7.36-7.29(m, lH),7.28-7.23(m, 1H), 6.90(brd, J=5.6Hz, lH),6.72-6.61(m, lH),5.29(d, J=1.5Hz, 2H),4.96-4.79(m, 2H),4.35-4.25(m, lH),4.03-3.91(m, 2H),3.88- 3.77(m, lH),2.93-2.69(m, 2H),2.40-2.23(m, 3H), 1.1 l(d, J=5.9Hz,3H).Example 39: Synthesis of 2-((l-(2-chlorobenzyl)-6-imino-6-oxido-4,5,6,7-tetrahydro- lH-thiopyrano[3,4-c]pyrazol-3-yl)methyl)-5-(4-chlorophenyl)-4-((S)-3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 139)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: l-(2-chlorobenzyl)-3-(chloromethyl)-l,4,5, 7-tetrahydrothiopyrano[3,4-c] pyrazole 6-oxide

[0249] To a DCM (3 mL) solution of l-(2-chlorobenzyl)-3 -(chloromethyl)- 1, 4,5,7- tetrahydrothiopyrano[3,4-c] pyrazole (200 mg, 638 pmol, 1.0 eq) was cooled in ice-water bath, then added m-CPBA (141 mg, 695 pmol, 1.1 eq) in portions. The reaction mixture was stirred at 0~4 for 2 hrs. Then saturated NaHCCh solution was added, the collected organic phase was then dried over MgSCh and concentrated to afford the crude product (210 mg), which was used directly in the next step without further purification. LC-MS (m / z) 330.5 [M+H]+.Step 2: tert-butyl (l-(2-chlorobenzyl)-3-(chloromethyl)-6-oxido-l,4,5, 7-tetrahydro- thiopyrano[3,4-c] pyrazol-6-ylidene) carbamate

[0250] l-(2-chlorobenzyl)-3-(chloromethyl)-l,4,5,7-tetrahydrothiopyrano[3,4-c] pyrazol 6-oxide (280 mg, 850 pmol, 1.0 eq), BOC-NH2 (300 mg, 2.6 mmol, 3.0 eq), MgO (137 mg, 3.4 mmol, 4.0 eq), RI12 (OAc)4 (32 mg, 72 pmol, 0.1 eq), lodosobenzene diacetate (410 mg, 1.3 mmol, 1.5 eq) was suspended in DCM (15 mL). The reaction mixture was stirred for 20 hrs at ambient temperature. Filter to remove the solid, the filtrate was dried under vacuum and purified through column chromatography to produce targeted compound (130 mg, 34% yield) as white solid. LC-MS (m / z): 441.5 [M-H]'.Step 3: tert-butyl (l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3 -trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-6-oxido-l, 4, 5, 7-tetrahydro- thiopyrano[ 3, 4-c ]pyrazol-6-ylidene) carbamate

[0251] tert-butyl (1 -(2-chlorobenzyl)-3-(chloromethyl)-6-oxido- 1,4,5, 7-tetrahydro- thiopyrano[3,4-c] pyrazol-6-ylidene) carbamate (120 mg, 270 pmol, 1.0 eq), (S)-5-(4-IPTS / 200087585.1Attorney Docket No. RTX-003WO chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (90 mg, 293 pmol, 1.1 eq), K2CO3 (112 mg, 810 pmol, 3.0 eq) was suspended in CH3CN (3 mL). The resulting mixture was heated to 70 °C to react for 2 hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated, and concentrated to afford the crude product (150 mg, 78% yield), which was used directly in the next step without further purification. LC-MS (m / z)'. 712.2 [M-H]'.Step 4: 2-((l-(2-chlorobenzyl)-6-imino-6-oxido-4,5,6, 7 -tetrahydro- IH-thiopyr ano [3,4- c ]pyrazol-3-yl)methyl)-5-( 4-chlorophenyl)-4-( (S)-3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4- dihydro-3H-l, 2, 4-triazol-3-one

[0252] tert-butyl (l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3 - tri fluoro-2-hydroxypropyl)-4, 5 -dihydro- 1H- 1,2, 4-tri azol- l-yl)methyl)-6-oxido- 1,4, 5,7- tetrahydro-thiopyrano[3,4-c]pyrazol-6-ylidene)carbamate (150 mg, 210 pmol, 1.0 eq) was added HCl / dioxane (1 M, 5 mL). The reaction mixture was stirred for 2 hrs at ambient temperature, then saturated NaHCCh solution was added, the collected organic phase was then dried over MgSCh, and concentrated to afford the crude product, which was purified through Prep-TLC to obtain a white solid (75 mg, 58% yield). LC-MS m / zy 615.0 [M+H]+. 'HNMR (400 MHz, DMSO ) 5 7.73 (d, J= 8.4 Hz, 2H), 7.62 (d, J= 8.4 Hz, 2H), 7.50 - 7.48 (m, 1H), 7.35 -7.28 (m, 2H),6.90 -6.87 (m, 1H), 5.29 (s, 2H), 4.90 -4.89 (m, 2H), 4.35 - 4.31 (m, 3H), 4.04 (s, 1H), 4.00 -3.95 (m, 1H), 3.84 -3.81 (m, 1H), 3.24-3.22 (m, 2H), 2.91 - 2.88 (m, 2H).Example 40: Synthesis of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-6-methyl-l,6- dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (Compound 140)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: l-(2-chlorobenzyl)-3-(chloromethyl)-l,6-dihydro-7H-pyrazolo[3, 4-c] pyridin- 7-one

[0253] l-(2-chlorobenzyl)-3-(chloromethyl)-7-methoxy-lH-pyrazolo[3,4-c] pyridine (200 mg, 621 pmol, 1.0 eq) was added HCl / dioxane (4 M, 8 mL). The reaction mixture was stirred for 14 hrs at ambient temperature, then saturated NaHCCh solution was added, the collected organic phase was then dried over MgSCh, and concentrated to afford the crude product, which was used directly in the next step without further purification. (160 mg, 84% yield). LC-MS (m / z): 309.5 [M+H]+.Step 2: l-(2-chlorobenzyl)-3-(chloromethyl)-6-methyl-l,6-dihydro-7H-pyrazolo[3,4 - c ] pyridin- 7 -one

[0254] To a DMF (5 mL) solution of l-(2-chlorobenzyl)-3 -(chi orom ethyl)- 1,6-dihydro- 7H-pyrazolo[3,4-c] pyridin-7-one (150 mg, 487 pmol, 1.0 eq) and CS2CO3 (475 mg, 1.5 mmol, 3.0 eq) was added CH3I (138 mg, 972 pmol, 2.0 eq). The reaction mixture was stirred for 3 hr at ambient temperature. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid (120 mg, 77% yield). LC- MS (m / z): 322.0 [M+H]+. 'H NMR (400 MHz, CDCI3) 5 7.83 (d, J= 6.0 Hz, 1H), 7.43- 7.11 (m, 4H), 6.64- 6.62 (m, 1H), 5.96 (s, 2H), 4.95 (s, 2H), 4.06 (s, 3H).Step 3: l-[(2-chlorophenyl)methyl]-3-[[3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3- trifluoro-2- hydroxy-propyl -l, 2, 4-triazol-l-yl methyl ]-6-methyl-pyrazolo[ 3, 4-c ] pyridine- 7 -one

[0255] l-(2-chlorobenzyl)-3-(chloromethyl)-6-methyl-l,6-dihydro-7H-pyrazolo [3, 4-c] pyridin-7-one (40 mg, 124 pmol, 1.0 eq), (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro- 2-IPTS / 200087585.1Attorney Docket No. RTX-003WO hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (42 mg, 137 pmol , 1.1 eq), K2CO3 (51 mg, 369 pmol, 3.0 eq) was suspended in CH3CN (3 mL). The resulting mixture was heated to 70 °C to react for 2 hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated, and concentrated to dryness to afford the crude product, which was purified through Prep-TLC to obtain a white solid (30 mg, 41% yield). LC-MS (m / z): 593.2(400 MHz, DMSO-t / e) 5 7.71 (d, J= 8.8 Hz, 2H), 7.62 (d, J= 8.8Hz, 2H), 7.50- 7.48 (m, 1H), 7.31- 7.29 (m, 2H), 7.21- 7.19 (m, 1H), 6.89 (d, J= 6.4 Hz, 1H), 6.69 (d, J= 7.2 Hz, 1H), 6.61 (d, J= 7.2 Hz, 1H), 6.00 (s, 2H), 5.24- 5.15 (m, 2H), 4.30- 4.28 (m, 1H), 4.04- 3.80 (m, 2H), 3.49 (s, 3H).Example 41: Synthesis of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-6-cyclopropyl- l,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (Compound 141)

[0256] (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydroxypropyl)-4, 5 -dihydro- 1H- 1 ,2,4-triazol- 1 -yl) methyl)- 1 ,6-dihydro-7H-pyrazolo[3 ,4-c] pyridin-7-one (100 mg, 173 pmol, 1.0 eq), cyclopropylboronic acid (74 mg, 861 pmmol, 5.0 eq), CU(OAC)2 (47 mg, 259 pmol, 1.5 eq), TEA (35 mg, 346 pmol, 2.0 eq) was suspended in DCE (4 mL). Pumped and refilled with oxygen three times. The resulting mixture was heated to 60 °C to react for 20 hrs under an oxygen atmosphere. Filter to remove the solid, the filtrate was dried under vacuum which was purified through Prep-TLC to obtain a white solid (37 mg, 35% yield). LC-MS (m / z): 618.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 7.72 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.51-7.49 (m, 1H), 7.22-7.19 (m, 2H), 6.88 (d, J = 6.0 Hz, 1H), 6.71 (d, J = 6.0 Hz, 1H), 6.58 (d, J = 6.0 Hz, 1H), 6.00 (s, 2H), 5.22- 5.13 (m, 1H), 4.30- 4.28 (m, 1H), 4.01- 3.80 (m, 2H), 3.31-3.27 (m, 1H), 1.03- 0.99 (m, 2H), 0.86-0.83 (m, 2H).Example 42: Synthesis of (S)-2-((7-amino-l-(2-chlorobenzyl)-lH-pyrazolo[3,4- c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-triflnoro-2-hydroxypropyl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Compound 142)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: 3-bromo-7-chloro-lH-pyrazolo[3,4-c]pyridine

[0257] To a mixture of 7-chloro-lH-pyrazolo[3,4-c] pyridine (1.00 g,6.5 mmol, 1.0 eq) in DMF (10 mL) was added NBS (1.16 g,6.5 mmol, 1.0 eq). The mixture was stirred at 20°C for 16hrs. The reaction mixture was poured into water, filtered and the filter cake were washed with water, dried in vacuum to give the target compound (1.20 g, 79% yield) as a yellow solid. LC-MS (m / z):233.9 [M+H]+.Step 2: 3-bromo-7-chloro-l-(2-chlorobenzyl)-lH-pyrazolo[3, 4-c]pyridine

[0258] To a mixture of 3-bromo-7-chloro-lH-pyrazolo[3,4-c] pyridine(1.20 g,5.2 mmol, 1.0 eq) in MeCN (15 mL) was added l-(bromomethyl)-2-chlorobenzene (1.15 g, 5.6 mmol, 1.1 eq) and K2CO3(2.14 g, 15.5 mmol, 3.0 eq). The mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the product (1.15g, 62% yield) as a white solid. LC-MS (m / z):355.9 [M+H]+.‘HNMR (400 MHz, DMSO-de) 5 8.18 (d, J = 5.4 Hz, 1H), 7.54 (d, J = 5.4 Hz, 1H), 7.45 (dd, J = 7.9, 0.9 Hz, 1H), 7.26 (td, J = 7.7, 1.5 Hz, 1H), 7.18- 7.10 (m, 1H), 6.51 (d, J = 7.6 Hz, 1H), 6.12 (s, 2H).Step 3: 3-bromo-l-(2-chlorobenzyl)-N-(2,4-dimethoxybenzyl)-lH-pyrazolo[3,4-c] pyridin-7- amine

[0259] To a mixture of 3-bromo-7-chloro-l-(2-chlorobenzyl)-lH-pyrazolo[3,4-c] pyridine (1.05 g,2.9 mmol, 1.0 eq) and (2,4-dimethoxyphenyl) methanamine(7.37 g, 44.1mmol, 15.0 eq) was added Na2COs(623 mg, 5.9 mmol, 2.0 eq). The mixture was stirred atIPTS / 200087585.1Attorney Docket No. RTX-003WO130°C for 16 hours. The reaction mixture was poured into water, extracted with EtOAc, the organic layers were washed with water and brine, dried over MgSCh and evaporated to dryness. The residue was purified by column chromatography to give the product (1.20g, 84% yield) as a light yellow oil. LC-MS (m / z):489.0 [M+H]+.Step 4: methyl l-(2-chlorobenzyl)-7-((2,4-dimethoxybenzyl)amino)-lH-pyrazolo[3,4- c ]pyridine-3-carboxylate

[0260] To a mixture of 3-bromo-l-(2-chlorobenzyl)-N-(2,4-dimethoxybenzyl)-lH- pyrazolo[3,4-c]pyridin-7- (1.20 g, 2.5 mmol, 1.0 eq) in MeOH (30 mL) was added Pd(dppf)C12 (180 mg, 246 pmol,0.1 eq) and TEA(748 mg, 7.4 mmol, 3.0 eq). The suspension was degassed under vacuum and purged with CO three times, then heated to 90°C and stirred under CO (3MPa) for 40 hours. The reaction mixture was concentrated, treated with water and EtOAc, the organic layers were washed with water and brine, dried over MgSO4 and evaporated to dryness The residue was purified by column chromatography to give the product (640 mg, 56% yield) as a light yellow solid. LC-MS (m / z): 467.1 [M+H]+.Step 5: (l-( 2-chlorobenzyl)-7-( 2, 4-dimethoxybenzyl)amino)-lH-pyrazolo[ 3, 4-c ]pyridin-3- yl)methanol

[0261] To a solution of methyl l-(2-chlorobenzyl)-7-((2,4-dimethoxybenzyl)amino)-lH- pyrazolo[3,4-c]pyridine-3 -carboxylate (540 mg, 1.2 mmol, 1.0 eq) in THF (10 mL) was added LAH (54 mg, 1.4 mmol, 1.2 eq) at 0°C.The mixture was stirred at 20°C for 2 hours. The reaction mixture was cooled to 0°C, quenched by addition of FLO (54 mg), 15% aqueous NaOH (54 mg) and H2O (54 mg), dried over MgSO4 and evaporated to dryness. The crude product was triturated with EtOAc / n-heptane and filtered to afford a light yellow oil (500 mg, 99% yield). LC-MS (m / z): 436.1 [M+H]+.Step 6: l-(2-chlorobenzyl)-3-(chloromethyl)-N-(2,4-dimethoxybenzyl)-lH-pyrazolo [3, 4-c] pyridin- 7 -amine

[0262] To a solution of (l-(2-chlorobenzyl)-7-((2,4-dimethoxybenzyl)amino)-lH- pyrazolo[3,4-c]pyri din-3 -yl)methanol (500 mg, 1.1 mmol, 1.0 eq) in DCM (10 mL) was added SOCI2 (204 mg,F.7mmol,L5 eq) at 0°C. The mixture was stirred at 20°C for Ihr The reaction mixture was evaporated to dryness to give crude product (520 mg) as a light yellow solid. LC-MS (m / z): 457.1 [M+H]+.IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 7: (S)-2-( 1 -(2-chlorobenzyl)-7-( (2, 4-dimethoxybenzyl)amino)-lH-pyrazolo[ 3, 4- c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3, 3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro- 3H-1, 2, 4-triazol-3-one

[0263] To a mixture of l-(2-chlorobenzyl)-3-(chloromethyl)-N-(2,4-dimethoxybenzyl)- lH-pyrazolo[3,4-c]pyridin-7-amine (614 mg, 1.3 mmol, 1.0 eq) in MeCN (10 mL) was added (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3- one (414 mg, 1.3 mmol, 1.0 eq) and K2CO3 (556 mg, 4.0 mmol, 3.0 eq) . The mixture was stirred at 80°C for 16hrs. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the product (430 mg, 44% yield) as a light yellow solid. LC-MS (m / z): 728.2 [M+H]+.Step 8: (S)-2-((7-amino-l-(2-chlorobenzyl)-lH-pyrazolo[3,4-c]pyridin-3-yl)methyl)-5-(4- chlorophenyl)-4-( 3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4-triazol-3-one

[0264] A mixture of (S)-2-((l-(2-chlorobenzyl)-7-((2,4-dimethoxybenzyl) amino)-lH- pyrazolo[3,4-c] pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one(100 mg, 137 pmol,1.0 eq) and TFA (3 mL) was stirred at 20°C for 16hrs. The reaction mixture was concentrated. The residue was adjusted to pH=8~9 with saturated NaHCCh solution, extracted with EtOAc, the organic layer was separated, wash with saturated NaCl solution, dried over MgSCh and evaporated to dryness. The crude product was purified by prep.TLC to give the target compound (12 mg, 77%yelid) as a white solid. LC-MS (m / z):578.1 [M+H]+.1H NMR(400MHz, DMSO de ) 5 (ppm) 7.74-7.68 (m, 2H), 7.65-7.57 (m, 3H), 7.50 (d, J = 7.8 Hz, 1H), 7.30 (br t, J = 7.3 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 5.9 Hz, 1H), 6.90 (d, J = 6.1 Hz, 1H), 6.40 (br d, J = 7.6 Hz, 1H), 6.27 (br s, 2H), 5.94 (s, 2H), 5.29-5.17 (m, 2H), 4.29 (br d, J = 5.9 Hz, 1H), 4.05-3.95 (m, 1H), 3.84 (br dd, J = 9.5, 14.7 Hz, 1H).Example 43: Synthesis of (S)-2-((5-amino-l-(2-chlorobenzyl)-lH-pyrazolo[3,4- c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Compound 143)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: 3-bromo-5-chloro-l-(2-chlorobenzyl)-lH-pyrazolo[3, 4-c]pyridine

[0265] A mixture of 3-Bromo-5-chloro-lH-pyrazolo[3,4-c] pyridine (1.60 g,6.9 mmol, 1.0 eq), 2-Chlorobenzyl bromide (510 mg, 2.5 mmol, 1.2 eq), K2CO3(2.85 g, 20.6 mmol, 3.0 eq), 2-Chlorobenzyl bromide (1.55 g,7.5 mmol, 1.1 eq) were suspended in MeCN (30 mL). The resulting mixture was heated to 80 °C to react for 3hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain the off-white solid product (1.74 g, 71% yield).LC-MS (m / z): 355.9 [M + H] .'H NMR (400 MHz, DMSO-de ) 5 9.20 (d, J = 1.0 Hz, 1H), 7.80 (d, J = 1.0 Hz, 1H), 7.57 - 7.48 (m, 1H), 7.44 - 7.28 (m, 2H), 7.20 (dd, J = 7.5, 1.8 Hz, 1H), 5.88 (s, 2H).Step 2: methyl 5-chloro-l-(2-chlorobenzyl)-lH-pyrazolo[3,4-c]pyridine-3-carboxylate

[0266] A mixture of 3-bromo-5-chloro-l-(2-chlorobenzyl)-lH-pyrazolo[3,4-c] pyridine (1.40 g, 3.9 mmol, 1.0 eq), Pd(dppf)C12(287 mg, 392 pmol, 0.1 eq), TEA (1.19 g, 11.8 mmol, 3.0 eq) were suspended in MeOH (50 mL) and DMF (10 mL). Pumped and refilled with carbon monoxide three times. The resulting mixture was heated to 80 °C to react for 14hrs under a carbon monoxide(15psi) atmosphere. The reaction solution was concentrated then the reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSO4, and concentrated to dryness.IPTS / 200087585.1Attorney Docket No. RTX-003WOThe crude product was purified through column chromatography to obtain a white solid product (700 mg, 53%yield).LC-MS (m / z) 336.0 [M + H]+.Step 3: methyl 5-((tert-butoxycarbonyl) amino)-l-(2-chlorobenzyl)-lH-pyrazolo[3,4-c] pyridine-3-carboxylate

[0267] A mixture of methyl 5-chloro-l-(2-chlorobenzyl)-lH-pyrazolo[3,4-c]pyridine-3- carboxylate (650 mg, 1.9 mmol, 1.0 eq) ,tert-Butyl carbamate (272 mg, 2.3 mmol, 1.2 eq) ,Pd2(dba)s(177 mg, 193 pmol,0.1 eq), BrettPhos(104 mg, 194 pmol,0.1 eq), CS2CO3 (1.26 g, 3.9 mmol, 2.0 eq) were suspended in 1,4-dioxane (15 mL). Pumped and refilled with nitrogen three times. The resulting mixture was heated to 120 °C to react for 4hrs under a nitrogen atmosphere. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain the light yellow solid product (135 mg, 17% yield). LC-MS (m / z): 417.1 [M + H]+.Step 4: tert-butyl (l-(2-chlorobenzyl)-3-(hydroxymethyl)-lH-pyrazolo[3,4-c]pyridin-5- y I) carbamate

[0268] Methyl 5-((tert-butoxycarbonyl) amino)-l-(2-chlorobenzyl)-lH-pyrazolo[3,4-c] pyridine-3 -carboxylate (110 mg, 264pmol,1.0 eq) was dissolved in THF (3 mL), then LAH (15 mg, 395 pmol, 1.5 eq) was added at 0 °C. The reaction mixture was stirred 0.5 hr at 0 °C. The mixture was added H2O (15mg),15%NaOH (15mg) and H2O (45mg), dried over MgSCh and filtered. The filtrate was concentrated to dryness. The crude product was purified through column chromatography to obtain a colourless oil product (70 mg, 68% yield). LC- MS (m / z): 389.1 [M+H]+.Step 5: tert-butyl (l-(2-chlorobenzyl)-3-(chloromethyl)-lH-pyrazolo[3,4-c] pyridin-5-yl) carbamate

[0269] tert-butyl (l-(2-chlorobenzyl)-3-(hydroxymethyl)-lH-pyrazolo[3,4-c] pyridin-5- yl) carbamate (70 mg, 180 pmol, 1.0 eq) was dissolved in DCM(5mL), then SOCh(24 mg, 202 pmol, 1.1 eq) was added at 0 °C. The reaction mixture was stirred 0.5 hr at 15 °C. The reaction solution was concentrated and obtained a yellow oil crude product (60 mg, 82% yield).IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 6: tert-butyl (S)-(l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl) methyl) -IH-pyrazolo [3, 4-c] pyridin-5- yl) carbamate

[0270] tert-butyl (l-(2-chlorobenzyl)-3-(chloromethyl)-lH-pyrazolo[3,4-c] pyridin-5-yl) carbamate (60 mg, 147 pmol, 1.0 eq), (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (54 mg, 176 pmol, 1.2 eq), K2CO3 (61 mg, 441 pmol, 3.0 eq) were suspended in MeCN (6 mL). Pumped and refilled with nitrogen three times. The resulting mixture was heated to 80 °C to react for 16 hrs under a nitrogen atmosphere. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid product (60 mg, 60% yield).LC-MS (m / z): 678.2 [M+H]+.Step 7: (S)-2-((5-amino-l-(2-chlorobenzyl)-lH-pyrazolo[3,4-c]pyridin-3-yl)methyl)-5-(4- chlorophenyl)-4-( 3, 3, 3-trifhioro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4-triazol-3-one

[0271] tert-butyl (S)-(l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl) methyl)- IH-pyrazolo [3, 4-c] pyridin-5-yl) carbamate (60 mg, 88 pmol, 1.0 eq) was dissolved in HCl / l,4-dioane (4 M, 6 mL,74.3 eq). The reaction mixture was stirred 6 hrs at 15°C. The reaction solution was concentrated then added water. The mixture was adjusted to pH=8~9 with saturated NaHCCh solution. The reaction mixture was treated with water and DCM, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a yellow solid product (7 mg, 14% yield). LC-MS (m / z): 578.1[M+H]+ 1HNMR(400MHz,DMSO-d6) 5(ppm) 8.59(d, J=1.3Hz,lH),7.75-7.69(m, 2H),7.64- 7.59(m, 2H),7.53-7.47(m, 1H), 7.37-7.3 l(m, lH),7.28-7.22(m, 1H), 6.9-6.92 (m, 1H), 6.89(d, J=6.3Hz, lH),6.64(d, J=1.3Hz, 1H), 5.69(s, 2H),5.55(brs, 2H), 5.24-5.12 (m,2H), 4.37- 4.27(m,lH), 4.06-3.93(m,lH), 3.87-3.79(m,lH).Example 44: Synthesis of (S)-l-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-4,6- dihydropyrrolo[3,4-c]pyrazole-5(lH)-carboxamide (Compound 144)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: tert-butyl 3-bromo-l-(3-chlorophenyl)-4,6-dihydropyrrolo[3,4-c] pyrazole-5(lH)- carboxylate

[0272] To a mixture of tert-butyl 3-bromo-4,6-dihydropyrrolo[3,4-c]pyrazole-5(lH)- carboxylate (500 mg, 1.7 mmol, 1.0 eq) in DCM (15 mL) and Py (5 mL) was added (3- chlorophenyl)boronic acid (407 mg, 2.6 mmol, 1.5 eq) and Cu(OAc)2(630 mg, 3.5 mmol, 2.0 eq) . The suspension was degassed under vacuum and purged with O2 three times, then stirred at 20°C under O2 balloon for 16 hours. The reaction mixture was filtered and the filtrate was concentrated, treated with water and EtOAc, the organic layer was washed with water and brine, dried over MgSCh and evaporated to dryness The residue was purified by column chromatography to give the product (600 mg, 87% yield) as a white solid(mixture). LC-MS (m / z): 400.0 [M+H]+.Step 2: 5 -(tert-butyl) 3-methyl l-(3-chlorophenyl)-4,6-dihydropyrrolo[3,4-c] pyrazole- 3, 5(lH)-dicarboxylate

[0273] To a mixture of tert-butyl 3-bromo-l-(3-chlorophenyl)-4,6-dihydropyrrolo[3,4- c]pyrazole-5(lH)-carboxylate (600 mg, 1.5 mmol, 1.0 eq) in MeOH (20 mL) was added Pd(dppf)C12 (110 mg, 150 pmol, 0.1 eq) and TEA(456 mg, 4.5 mmol, 3.0 eq). The suspension was degassed under vacuum and purged with CO three times, then heated to 60 °C and stirred under CO (3MPa) for 16 hours. The reaction mixture was concentrated, treated with water and EtOAc, the organic layers were washed with water and brine, dried over MgSO4 and evaporated to dryness. The residue was purified by columnIPTS / 200087585.1Attorney Docket No. RTX-003WO chromatography to give the product (200 mg, 35% yield) as a white solid. LC-MS (m / z): 378.1 [M+H]+. 'HNMR (400 MHz, DMSO-de) 5 7.79 -7.72 (m, 1H), 7.52 -7.40 (m, 2H), 7.39 -7.33 (m, 1H), 4.90 -4.75 (m, 2H), 4.69 -4.57 (m, 2H), 4.03 -3.94 (m, 3H), 1.58 -1.52 (m, 9H).Step 3: tert-butyl l-(3-chlorophenyl)-3-(hydroxymethyl)-4,6-dihydropyrrolo[3,4-c] pyrazole- 5( I H) -carboxylate

[0274] To a solution of methyl 5 -(tert-butyl) 3-methyl l-(3-chlorophenyl)-4,6- dihydropyrrolo[3,4-c] pyrazole-3,5(lH)-dicarboxylate (180 mg, 476 pmol, 1.0 eq) in THF (5 mL) was added LAH (18 mg, 474 pmol, 1.0 eq) at 0°C.The mixture was stirred at 20°C for Ihr. The reaction mixture was cooled to 0°C, quenched by addition of H2O (18 mg), 15% aqueous NaOH (18 mg) and H2O (18 mg), dried over MgSCh and evaporated to dryness.The crude product was triturated with EtOAc / n-heptane and filtered to afford a yellow oil (140 mg, 84% yield). LC-MS (m / z): 350.1 [M+H]+.Step 4: tert-butyl 3-(chloromethyl)-l-(3-chlorophenyl)-4,6-dihydropyrrolo[3,4-c] pyrazole- 5( I H) -carboxylate

[0275] To a solution of tert-butyl l-(3-chlorophenyl)-3-(hydroxymethyl)-4,6- dihydropyrrolo[3,4-c] pyrazole-5(lH)-carboxylate (140 mg, 400 pmol, 1.0 eq) in DCM (10 mL) was added SOCI2 (48 mg, 403 pmol, 1.0 eq) at 0°C. The mixture was stirred at 20°C for Ihr. The reaction mixture was adjusted to pH=8~9 with saturated NaHCCh solution, extracted with DCM, the organic layer was separated, wash with saturated NaCl solution, dried over MgSCh and evaporated to dryness to give crude product (140 mg, 95% yield) as a light yellow solid. LC-MS (m / z): 368.1 [M+H]+.Step 5: tert-butyl (S)-l-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-4, 6-dihydropyrrolo[ 3, 4-c ] pyrazole-5( lH)-carboxylate

[0276] To a mixture of tert-butyl 3 -(chloromethyl)- 1 -(3 -chi orophenyl)-4, 6- dihydropyrrolo[3,4-c] pyrazole-5(lH)-carboxylate (140 mg, 380 pmol, 1.0 eq) in MeCN (5 mL) was added (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H- l,2,4-triazol-3-one (117 mg, 380 pmol, 1.0 eq) and K2CO3 (158 mg, 1.1 mmol, 3.0 eq). The mixture was stirred at 80°C for 2hrs. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the product (120 mg, 49% yelid) as a light yellow solid. LC-MS (m / z): 639.1 [M+H]+.IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 6: (S)-5-(4-chlorophenyl)-2-( 1 -(3-chlorophenyl)-l , 4, 5, 6-tetrahydropyrrolo[ 3, 4-c ] yv&zo\-3-yl) elhyl)-4-( 3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4-triazol-3-one

[0277] A mixture of tert-butyl (S)-l-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4- (3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl) methyl)-4,6- dihydropyrrolo[3,4-c] pyrazole-5(lH)-carboxylate (120 mg, 188 pmol, 1.0 eq) and HCl / di oxane (4 M,6 mL,42.2 eq) was stirred at 20°C for 16hrs. The reaction mixture was concentrated to give the target compound (108 mg, crude) as a colourless oil. LC-MS (m / z):539.1 [M+H]+.Step 7: (S)-l-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-4, 6-dihydropyrrolo[ 3, 4- c Jpyrazole-5(1H) -carboxamide

[0278] To a mixture of (S)-5-(4-chlorophenyl)-2-((l-(3-chlorophenyl)-l, 4,5,6- tetrahydropyrrolo[3,4-c] pyrazol-3-yl) methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4- dihydro-3H-l,2,4-triazol-3-one (108 mg, 188 pmol, 1.0 eq) and potassium cyanate (46 mg, 567 pmol, 3.0 eq) in H2O (10 mL) was added HC1 (0.5 M, 1 mL, 2.7 eq). The mixture was stirred at 60°C for 5hrs. The residue was adjusted to pH=8~9 with saturated NaHCCh solution, extracted with EtOAc, the organic layer was separated, wash with saturated NaCl solution, dried over MgSCh and evaporated to dryness. The crude product was purified by column chromatography to give the target compound (15 mg, 14% yield) as a white solid. LC-MS (m / z): 582.1[M+H]+.1H NMR(400 MHz, DMSO_d6) 5 (ppm) 7.77 (d, J = 8.8 Hz, 2H), 7.67 -7.60 (m, 3H), 7.58 -7.51 (m, 2H), 7.45 -7.34 (m, 1H), 6.98 (br d, J = 5.8 Hz, 1H), 6.06 (br s, 2H), 5.05 (s, 2H), 4.79 (br s, 2H), 4.41 -4.28 (m, 1H), 4.22 (br s, 2H), 4.04 -3.97 (m, 1H), 3.84 (dd, J = 14.6, 9.6 Hz, 1H).Example 45: Synthesis of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-lH-pyrazolo[4,3- c]pyridine-6-carboxamide (Compound 145)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: methyl 6-chloro-l-(2-chlorobenzyl)-lH-pyrazolo[4,3-c]pyridine-3-carboxylate

[0279] To a mixture of methyl 6-chloro-lH-pyrazolo[4,3-c] pyridine-3 -carboxylate (1.00 g, 4.7 mmol, 1.0 eq) in MeCN (15 mL) was added l-Bromomethyl-2-chloro-benzene (1.02 g, 4.9 mmol, 1.1 eq) and K2CO3 (1.96 g, 14.2 mmol, 3.0 eq). The mixture was stirred at 80°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the product (1.26 g, 74% yield) as a white solid. 'H NMR (400 MHz, DMSO-de) 5 9.32 (d, J = 1.0 Hz, 1H), 7.46 (dd, J = 7.9, 1.1 Hz, 1H), 7.38 (d, J = 1.0 Hz, 1H), 7.33-7.29 (m, 1H), 7.21 (td, J = 7.6, 1.2 Hz, 1H), 6.95 (dd, J = 7.7, 1.3 Hz, 1H), 5.78 (s, 2H), 4.10 (s, 3H).Step 2: (6-chloro-l-(2-chlorobenzyl)-lH-pyrazolo[4,3-c] pyridin-3-yl) methanol

[0280] To a solution of l-(2-Chloro-benzyl)-l,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine- 3,5-dicarboxylic acid 5-tert-butyl ester 3-ethyl ester (620 mg, 1.8 mmol, 1.0 eq) in THF (30 mL) was added LAH (70 mg, 1.8 mmol, 1.0 eq) at 0°C.The mixture was stirred at 20°C for 2hrs. The reaction mixture was cooled to 0°C, quenched by addition of H2O (70 mg), 15% aqueous NaOH (70 mg) and H2O (70 mg), dried over MgSCh and evaporated to dryness to afford a light yellow solid (380 mg, 67% yield). LC-MS (m / z): 308.0 [M+H]+.Step 3: 6-chloro-l-(2-chlorobenzyl)-3-(chloromethyl)-lH-pyrazolo[4,3-c]pyridine

[0281] To a solution of (6-chloro-l-(2-chlorobenzyl)-lH-pyrazolo[4,3-c]pyridin-3- yl)methanol (450 mg, 1.5 mmol, 1.0 eq) in DCM (10 mL) was added SOCI2 (209 mg, 1.8 mmol, 1.2 eq) at 0°C. The mixture was stirred at 20°C for Ihr. The reaction mixture was evaporated to dryness to give crude product (476 mg) as a light yellow solid. LC-MS (m / z): 326.0 [M+H]+.IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 4: (S)-2-( 6-chloro-l-(2-chlorobenzyl)-lH-pyrazolo[ 4, 3-c ]pyridin-3-yl)methyl)-5-( 4- chlorophenyl)-4-( 3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4-triazol-3-one

[0282] To a mixture of 6-chloro-l-(2-chlorobenzyl)-3-(chloromethyl)-lH-pyrazolo[4,3- c] pyridine (426 mg, 1.3 mmol, 1.0 eq) in MeCN (10 mL) was added (S)-5-(4-chlorophenyl) - 4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (401 mg, 1.3 mmol, 1.0 eq) and K2CO3 (540 mg, 3.9 mmol, 3.0 eq). The mixture was stirred at 80°C for 16hrs. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the product (200 mg, 26% yield) as a light yellow solid. LC-MS (m / z): 597.1 [M+H]+.Step 5: methyl (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-lH-pyrazolo[ 4, 3-c ]pyridine-6- carboxylate

[0283] To a mixture of (S)-2-((6-chloro-l-(2-chlorobenzyl)-lH-pyrazolo[4,3-c] pyridin- 3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4- triazol-3-one (50 mg, 84 pmol, 1.0 eq) in MeOH (5 mL) was added Pd(dppf)C12 (8 mg, 10.9 pmol, 0.13 eq) and TEA(30 mg, 296 pmol,3.5 eq). The suspension was degassed under vacuum and purged with CO three times, then heated to 80°C and stirred under CO balloon for 16 hours. The reaction mixture was concentrated, treated with water and EtOAc, the organic layers were washed with water and brine, dried over MgSO4 and evaporated to dryness The residue was purified by column chromatography to give the product (50 mg, 96% yield) as a white solid. LC-MS (m / z): 621.1 [M+H]+.Step 6: (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-lH-pyrazolo[ 4, 3-c ]pyridine-6- carboxamide

[0284] A mixture of methyl (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4- (3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro- 1H- 1 ,2,4-triazol- 1 -yl) methyl)- 1H- pyrazolo[4,3-c]pyridine-6-carboxylate (50 mg, 80 pmol, 1.0 eq) in NH3 / MeOH(7 M,3 mL,260.9 eq) was stirred at 80°C for 16 hours. The crude product was triturated with EtOAc / n-heptane and filtered to afford a white solid (20 mg, 41% yield) as a white solid. LC-MS (m / z): 606.1 [M+H]+.JHNMR(400 MHz, DMSO de ) 5 (ppm) 9.19 (d, J = 0.8 Hz, 1H), 8.40 (d, J = 0.8 Hz, 1H), 8.25 (br d, J = 2.3 Hz, 1H), 7.72 (br d, J = 8.5 Hz, 3H), 7.65- 7.58 (m, 2H), 7.51 (dd, J = 0.9, 7.9 Hz, 1H), 7.37 (dt, J = 1.6, 7.7 Hz, 1H), 7.29 (dt, J = 1.0,IPTS / 200087585.1Attorney Docket No. RTX-003WO7.5 Hz, 1H), 7.05 (dd, J = 1.3, 7.8 Hz, 1H), 6.89 (br d, J = 4.8 Hz, 1H), 5.86 (s, 2H), 5.42 - 5.37(m, 2H), 4.29 (br d, J = 3.8 Hz, 1H), 4.00 (dd, J = 3.4, 14.6 Hz, 1H), 3.83 (dd, J = 9.6, 14.6 Hz, 1H) .Example 46: Synthesis of (S)-l-(4-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-l,4,5,7- tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide (Compound 146)Step 1: 6-(tert-butyl) 3-methyl l-(4-chlorophenyl)-l ,4,5, 7-tetrahydro-6H-pyrazolo [3,4- c]pyridine-3, 6-dicarboxylate

[0285] 6-(tert-butyl) 3-methyl l,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-3,6- dicarboxylate (350 mg, 173 pmol, 1.0 eq), cyclopropylboronic acid (74 mg, 861 pmmol, 5.0 eq), CU(OAC)2 (47 mg, 259 pmol, 1.5 eq), TEA(35 mg, 346 pmol, 2.0 eq) was suspended in DCE (4 mL). Pumped and refilled with oxygen three times. The resulting mixture was heated to 60 °C to react for 20 hrs under an oxygen atmosphere. Filter to remove the solid, the filtrate was dried under vacuum which was purified through Prep-TLC to obtain a white solid (120 mg, 25% yield). LC-MS (m / z): 392.1 [M+H]+. 1H NMR (400 MHz, CDC13) 5 7.47 (s, 4H), 4.63 (s, 2H), 3.97 (s, 3H), 3.72- 3.69 (m, 2H), 2.96- 2.93 (m, 2H), 1.49 (s, 9H).IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 2: tert-butyl l-(4-chlorophenyl)-3-(hydroxymethyl)-l,4,5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0286] To a anhydrous THF (3 mL) solution of 6-(tert-butyl) 3-methyl l-(4- chlorophenyl)-l,4,5,7-tetrahydro-6H-pyrazolo [3,4-c]pyridine-3,6-dicarboxylate (100 mg, 246 pmol, 1.0 eq) was cooled in ice- water bath, then added LiAlLL (12 mg, 316 pmol, 1.3 eq) in portions. The reaction mixture was stirred at 0~4 °C for 0.5 hr. The reaction solution was quenched by addition of 12 mg of H2O, followed by 12 mg of 15% aqueous NaOH. After being stirred at room temperature for 0.5 hr, the solid was removed by filtration. The filtrate was concentrated to dryness to give crude targeted product (85 mg, 95% yield) as colorless oil. LC-MS (m / z): 364.1 [M+H]+.Step 3: tert-butyl 3-(chloromethyl)-l-(4-chlorophenyl)-l,4,5, 7-tetrahydro-6H- pyrazolo [3,4- c] pyridine-6-carboxylate

[0287] To a anhydrous DCM (3 mL) solution of tert-butyl l-(4-chlorophenyl) -3- (hydroxymethyl)-l,4,5,7-tetrahydro-6H- pyrazolo[3,4-c]pyridine-6-carboxylate (85 mg, 234 pmol, 1.0 eq) was cooled in ice-water bath, then added SOCh (33 mg, 277 pmol, 1.2 eq) in dropwise. The reaction mixture was stirred at ambient temperature for 2 hrs. The reaction solution was concentrated to dryness to obtain the title compound as yellow oil (89 mg, 100% yield), which was used directly for the next step. LC-MS (m z) 382.0 [M+H]+.Step 4: tert-butyl (S)-l-(4-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluor o-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-l, 4, 5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0288] tert-butyl 3 -(chloromethyl)- 1 -(4-chlorophenyl)- 1 ,4, 5,7-tetrahydro-6H- pyrazolo[3,4-c]pyridine-6-carboxylate (89 mg, 233 pmol, 1.0 eq), 3-(4-chlorophenyl)-4-[(2S) -3,3,3- trifhioro-2-hydroxy-propyl]-lH-l,2,4-triazol-5-one (78 mg, 254 pmol, 1.1 eq), K2CO3 (96 mg, 695 pmol, 3.0 eq) was suspended in CH3CN (3 mL). The resulting mixture was heated to 70 °C to react for 12 hr. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid (120 mg, 79% yield). LC-MS (m / z): 653.1 [M+H]+.Step 5: (S)-5-(4-chlorophenyl)-2-((l-(4-chlorophenyl)-4,5,6, 7 -tetrahydro- 1H- pyrazolo[3,4- c ]pyridin-3-yl)methyl)-4-(3, 3, 3-tri luoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4-triazol-3- oneIPTS / 200087585.1Attorney Docket No. RTX-003WO

[0289] tert-butyl (S)- 1 -(4-chlorophenyl)-3-((3 -(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4, 5 -dihydro- 1H- 1 ,2,4-triazol- 1 -yl)methyl)- 1 ,4,5,7-tetrahydro- 6H-pyrazolo[3,4-c]pyridine-6-carboxylate (120 mg, 184 pmol, 1.0 eq) was added HCl / Dioxane (4 M, 5 mL). The reaction mixture was stirred for 1 hr at ambient temperature, then saturated NaHCCh solution was added, the collected organic phase was then dried over MgSCh, and concentrated to afford the crude product (100 mg, 98% yield), which was used directly in the next step without further purification.Step 6: (S)-l-(4-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-l, 4, 5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxamide

[0290] To a H2O (10 mL) solution of (S)-5-(4-chlorophenyl)-2-((l-(4-chlorophenyl) - 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridin-3-yl)methyl)-4-(3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (100 mg, 170 pmol, 1.0 eq) was added HC1 (1 M, 2 mL) and KOCN(47 mg, 552 pmol, 3.0 eq). The reaction mixture was heated at 60 °C for 16hrs. Then saturated NaHCCh solution was added, the collected organic phase was then dried over MgSCh, and concentrated to afford the crude product which was purified through Prep-TLC to obtain a white solid (50 mg, 49% yield). LC-MS (m / z): 596.2 [M+H]+. 'HNMR (400 MHz, DMSO ) 5 7.75- 7.73 (m, 2H), 7.64- 7.57 (m, 6H), 6.90 (d, J= 6.4 Hz, 1H), 6.18 (s, 2H), 4.98 (s, 2H),4.62 (s, 2H), 4.31- 4.30 (m, 1H), 4.01- 3.79 (m, 2H), 3.57- 3.54 (m, 2H), 2.53- 2.52 (m, 2H).Example 47: Synthesis of (S)-2-(4-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-2,4,5,7- tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide (Compound 147)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: 6-(tert-butyl) 3-methyl 2-(4-chlorophenyl)-2,4,5, 7-tetrahydro-6H-pyrazolo [3,4-c] pyridine-3, 6-dicarboxylate

[0291] 6-(tert-butyl) 3-methyl 1,4, 5, 7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-3, 6- dicarboxylate (350 mg, 173 pmol, 1.0 eq), cyclopropylboronic acid (74 mg, 861 pmol, 5.0 eq), CU(OAC)2 (47 mg, 259 pmol, 1.5 eq), TEA (35 mg, 346 pmol, 2.0 eq) was suspended in DCE (4 mL). Pumped and refilled with oxygen three times. The resulting mixture was heated to 60 °C to react for 20hrs under an oxygen atmosphere. Filter to remove the solid, the filtrate was dried under vacuum which was purified through Prep-TLC to obtain a white solid (210 mg, 43% yield). LC-MS (m / z): 392.1 [M+H]+. 1H NMR (400 MHz, CDC13) 5 7.44 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 4.66 (s, 2H), 3.82 (s, 3H), 3.72 (s, 2H), 2.94-2.91 (m, 2H), 1.51 (s, 9H).Step 2: tert-butyl 2-(4-chlorophenyl)-3-(hydroxymethyl)-2,4,5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0292] To a anhydrous THF (5 mL) solution of 6-(tert-butyl) 3-methyl 2-(4- chlorophenyl)-2,4,5,7-tetrahydro-6H-pyrazolo [3,4-c] pyridine-3, 6-dicarboxylate (190 mg, 468 pmol, 1.0 eq) was cooled in ice-water bath, then added LiAlH4 (22 mg, 580 pmol, 1.2IPTS / 200087585.1Attorney Docket No. RTX-003WO eq) in portions. The reaction mixture was stirred at 0~4 °C for 1 hr. The reaction solution was quenched by addition of 22 mg of H2O, followed by 22 mg of 15% aqueous NaOH. After being stirred at room temperature for 0.5 hr, the solid was removed by filtration. The filtrate was concentrated to dryness to give crude targeted product (170 mg, 100% yield) as colorless oil. LC-MS (m / z): 364.1 [M+H]+.Step 3: tert-butyl 3-(chloromethyl)-2-(4-chlorophenyl)-2,4,5, 7-tetrahydro-6H- pyrazolo[3,4- c] pyridine-6-carboxylate

[0293] To a anhydrous DCM (3 mL) solution of tert-butyl 2-(4-chlorophenyl)-3- (hydroxymethyl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate(170 mg, 467 pmol, 1.0 eq) was cooled in ice-water bath, then added SOCh (66 mg, 555 pmol, 1.2 eq) in dropwise. The reaction mixture was stirred at ambient temperature for 1 hr. The reaction solution was concentrated to dryness to obtain the title compound as yellow oil (170 mg, 95% yield), which was used directly for the next step. LC-MS (m / z): 382.0 [M+H]+.Step 4: tert-butyl (S)-2-(4-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluor o-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-2, 4, 5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0294] tert-butyl 3-(chloromethyl)-2-(4-chlorophenyl)-2,4,5,7-tetrahydro-6H- pyrazolo[3,4-c]pyridine-6-carboxylate(170 mg, 445 pmol, 1.0 eq), (S)-5-(4- chlorophenyl)- 4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (137 mg, 445 pmol, 1.0 eq), K2CO3 (184 mg, 1.3 mmol, 3.0 eq) was suspended in CH3CN (3 mL). The resulting mixture was heated to 70 °C to react for 12 hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid (190 mg, 65% yield). LC-MS (m / z): 653.1 [M+H]+.Step 5: (S)-5-(4-chlorophenyl)-2-((2-(4-chlorophenyl)-4,5,6, 7-tetrahydro-2H- pyrazolo[3,4- c ]pyridin-3-yl)methyl)-4-(3, 3, 3-tri luoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4-triazol-3- one

[0295] tert-butyl (S)-2-(4-chlorophenyl)-3-((3 -(4-chlorophenyl)-5-oxo-4-(3 ,3 ,3 - trifluoro-2-hydroxypropyl)-4, 5 -dihydro- 1H- 1,2, 4-tri azol- l-yl)methyl)-2, 4,5, 7-tetrahydro- 6H-pyrazolo[3,4-c]pyridine-6-carboxylate (190 mg, 291 pmol, 1.0 eq) was added HCl / Dioxane (4 M, 5 mL). The reaction mixture was stirred for 1 hr at ambient temperature, then saturated NaHCCh solution was added, the collected organic phase was then dried overIPTS / 200087585.1Attorney Docket No. RTX-003WOMgSCh, and concentrated to afford the crude product(150 mg), which was used directly in the next step without further purification.Step 6: (S)-2-(4-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-2, 4, 5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxamide

[0296] To a H2O (5 mL) solution of (S)-5-(4-chlorophenyl)-2-((2-(4- chlorophenyl) - 4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl)methyl)-4-(3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (150 mg, 271 pmol, 1.0 eq) was added HC1 (1 M, 0.5 mL) and KOCN(69 mg, 810 pmol, 3.0 eq). The reaction mixture was heated at 60 °C for 18hrs. Then saturated NaHCCh solution was added, the collected organic phase was then dried over MgSCh, and concentrated to afford the crude product which was purified through Prep-TLC to obtain a white solid (50 mg, 31% yield). LC-MS (m / z): 596.2 [M+H]+. 'HNMR (400 MHz, DMSO ) 5 7.70-7.68 (m, 2H), 7.63-7.57 (m, 6H), 6.90 (d, J = 6.4 Hz, 1H), 6.13 (s, 2H), 5.09-5.00 (m, 2H), 4.47 (s, 2H), 4.28-4.26 (m, 1H), 3.95-3.77 (m, 2H), 3.57-3.54 (m, 2H), 2.55-2.54 (m, 2H).Example 48: Synthesis of (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-4,6- dihydropyrrolo[3,4-c]pyrazole-5(lH)-carboxamide (Compound 148)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: tert-butyl 3-bromo-l-(2-chlorobenzyl)-4,6-dihydropyrrolo[3,4-c]pyrazole- 5(1H)~ carboxylate

[0297] To a DMF (10 mL) solution of tert-butyl 3-bromo-4,6-dihydropyrrolo[3,4-c] pyrazole-5(lH)-carboxylate (1.50 g, 5.2 mmol, 1.0 eq) was added K2CO3 (2.16 g, 15.6 mmol, 3.0 eq) and l-(bromomethyl)-2-chloro-benzene (1.28 g, 6.2 mmol, 1.2 eq). The reaction mixture was heated at 60 °C for 2hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated. The organic phase was washed with water, dried over MgSCh, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid (650 mg, 30% yield). LC-MS (m / z): 412.0 [M+H]+.Step 2: 5 -(tert-butyl) 3 -methyl l-(2-chlorobenzyl)-4,6-dihydropyrrolo[3,4-c] pyrazole- 3, 5(lH)-dicarboxylate

[0298] A mixture of tert-butyl 3-bromo-l-(2-chlorobenzyl)-4,6-dihydropyrrolo [3,4- c]pyrazole- 5(lH)-carboxylate (450 mg, 1.1 mmol, 1.0 eq), Pd(dppf)C12 (79 mg, 108 pmol, 0.1 eq), TEA (330 mg, 3.3 mmol, 3.0 eq) was suspended in CH3OH (50 mL). Pumped and refilled with CO three times. The resulting mixture was heated to 50 °C to react for 18 hrs under a 3Mpa CO atmosphere. The reaction solution was concentrated. The crude product was purified through column chromatography to obtain a white solid (300 mg, 70% yield). LC-MS (m / z) 392.0 [M+H]+. 'HNMR (400 MHz, CDCI3) 5 7.44-7.43 (m, 1H), 7.35- 7.25 (m, 3H), 5.49-5.47 (m, 2H), 4.55-4.49 (m, 2H), 4.15-4.09 (m, 2H), 3.96-3.96 (m, 3H), 1.49- 1.47 (m, 9H).Step 3: tert-butyl l-(2-chlorobenzyl)-3-(hydroxymethyl)-4,6-dihydropyrrolo[3,4-c] pyrazole- 5( I H) -carboxylate

[0299] To an anhydrous THF (10 mL) solution of 5 -(tert-butyl)3 -methyl l-(2- chlorobenzyl)-4,6-dihydropyrrolo[3,4-c] pyrazole-3,5(lH)-dicarboxylate (280 mg, 715 pmol, 1.0 eq) was cooled in ice-water bath, then added LiAlH4 (40 mg, 1.1 mmol, 1.5 eq) in portions. The reaction mixture was stirred at 0~4 for 2 hrs. The reaction mixture was treated with water, 15%NaOH solution and water in sequence, filter to remove the solid, the filtrate was dried under vacuum to produce targeted compound (250 mg, 96% yield) as colorless oil. LC-MS (m / z): 364.1 [M+H]+.Step 4: tert-butyl l-(2-chlorobenzyl)-3-(chloromethyl)-4,6-dihydropyrrolo[3,4-c] pyrazole- 5( I H) -carboxylateIPTS / 200087585.1Attorney Docket No. RTX-003WO

[0300] To an anhydrous DCM (5 mL) solution of tert-butyl l-(2-chlorobenzyl)-3- (hydroxymethyl)-4,6-dihydropyrrolo[3,4-c] pyrazole-5(lH)-carboxylate (240 mg, 660 pmol, 1.0 eq) was cooled in ice-water bath, then added SOCh (94 mg, 790 pmol, 1.2 eq) in dropwise. The reaction mixture was stirred at ambient temperature for 2 hrs. The reaction solution was concentrated to dryness to obtain the title compound as yellow oil (240 mg, 95% yield), which was used directly for the next step.Step 5: tert-butyl (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-4, 6-dihydropyrrolo[ 3, 4- c Jpyrazole-5(1H) -carboxylate

[0301] tert-butyl l-(2-chlorobenzyl)-3-(chloromethyl)-4,6-dihydropyrrolo[3,4-c] pyrazole-5(lH)-carboxylate (240 mg, 628 pmol, 1.0 eq), (S)-5-(4-chlorophenyl)-4- (3,3,3- trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (194 mg, 631 pmol, 1.0 eq), K2CO3 (260 mg, 1.9 mmol, 3.0 eq) was suspended in CH3CN (5 mL). The resulting mixture was heated to 70 °C to react for 2 hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid (250 mg, 61% yield). LC-MS (m / z) 653.1 [M+H]+.Step 6: (S)-2-((l-(2-chlorobenzyl)-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) methyl)-5- ( 4-chlorophenyl)-4-( 3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4-triazol-3-one

[0302] tert-butyl (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifluoro -2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-4,6-dihydropyrrolo[3,4- c]pyrazole-5(lH)-carboxylate (250 mg, 383 pmol, 1.0 eq) was added HCl / dioxane (4 M, 10 mL). The reaction mixture was stirred for 2 hrs at ambient temperature, then saturated NaHCCh solution was added, the collected organic phase was then dried over MgSCh, and concentrated to afford the crude product (220 mg, 97% yield), which was used directly in the next step without further purification. LC-MS (m / z)'. 553.2 [M+H]+.Step 7: (S)-l-(2-chlorobenzyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-4, 6-dihydropyrrolo[ 3, 4- c Jpyrazole-5(1H) -carboxamide

[0303] To a H2O (5 mL) solution of (S)-2-((l-(2-chlorobenzyl)-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro -2 - hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (200 mg, 339 pmol, 1.0 eq) was addedIPTS / 200087585.1Attorney Docket No. RTX-003WOHC1 (1 M, 2 mL) and KOCN (86 mg, 1.0 mmol, 3.0 eq). The reaction mixture was heated at 60 °C for 3hrs. Then saturated NaHCCh solution was added, the collected organic phase was then dried over MgSCh, and concentrated to afford the crude product which was purified through Prep-TLC to obtain a white solid (20 mg, 10% yield). LC-MS (m / z): 596.1 [M+H]+. 'HNMR (400 MHz, DMSO ) 5 7.76 (d, J= 6.8 Hz, 2H),7.74 (d, J= 6.8 Hz, 2H), 7.64- 7.62 (m, 1H), 7.39-7.37 (m, 2H), 7.26-7.25 (m, 1H), 6.96 (d, J= 6.0 Hz, 1H), 5.91 (s, 2H), 5.32 (s, 2H), 4.90 (s, 2H), 4.34-4.32 (m, 1H), 4.22 (s, 2H),4.13 (s, 2H), 4.00-3.79 (m, 2H).Example 49: Synthesis of 5-(4-chlorophenyl)-2-((l-(3-chlorophenyl)-6-hydroxy-6- methyl-4,5,6,7-tetrahydro-lH-indazol-3-yl)methyl)-4-((S)-3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 149)Step 1: ethyl l-(3-chlorophenyl)-l,4,5, 7-tetrahydrospiro[indazole-6,2'-[l,3] dioxolane]-3- carboxylate

[0304] To a mixture of ethyl l,4,5,7-tetrahydrospiro[indazole-6,2'-[l,3]dioxolane]-3- carboxylate (2.00 g, 7.9 mmol, 1.0 eq) and Cu(OAc)2 (2.88 g, 15.9 mmol, 2.0 eq) in DCM (40 mL) and pyridine (10 mL) was added (3-chlorophenyl)boronic acid (1.86 g, 11.9 mmol, 1.5 eq). The mixture was degassed and backfilled with O2 three times. The reaction mixture was stirred at 25°C under O2 atmosphere (15 psi) for 20 hrs. The reaction mixture was diluted with DCM (50 mL), which was filtered through a pad of Celite and the filter cakeIPTS / 200087585.1Attorney Docket No. RTX-003WO was washed with DCM (10 mL). The combined filtrate was concentrated to remove the solvent to give the crude product, which was diluted with EtOAc. The mixture was washed with water and brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (750 mg, 26% yield) as a light-yellow solid. LC-MS (m / z): 363.1 [M + H]+. 'HNMR (400 MHz, CDCh) 5 7.59-7.54 (m, 1H), 7.44-7.35 (m, 3H), 4.44 (q, J= 7.2 Hz, 2H), 4.09-3.97 (m, 4H), 3.02 (t, J= 6.6 Hz, 2H), 2.95 (s, 2H), 2.00 (t, J= 6.6 Hz, 2H), 1.42 (t, J= 7.2 Hz, 3H).Step 2: (l-(3-chlorophenyl)-l,4,5, 7-tetrahydrospiro[indazole-6,2'-[l,3]dioxolan]-3- yl)methanol

[0305] To a stirred solution of ethyl 1 -(3 -chlorophenyl)- 1, 4,5,7- tetrahydrospiro[indazole-6,2'-[l,3] dioxolane]-3-carboxylate (500 mg, 1.4 mmol, 1 eq) in THF (10 mL) was added LAH (55 mg, 1.5 mmol, 1.1 eq) at 0°C under N2 atmosphere, then the reaction mixture was stirred at 20 °C for 1 hr. The reaction was quenched by addition of H2O (0.1 mL) and 15% aqueous NaOH (0.1 mL) at 0°C and the mixture was diluted with THF (50 mL), then anhydrous MgS04 (2.00 g) was added. The suspension was filtered through a pad of Celite and the filter cake was washed with THF (20 mL). The combined filtrate was concentrated to dryness to give the title compound (400 mg, 90% yield) as a light-yellow solid. LC-MS (m / z): 321.1 [M + H]+.Step 3: 3-(chloromethyl)-l-(3-chlorophenyl)-l,4,5, 7-tetrahydrospiro[indazole-6,2'-[l,3] dioxolane]

[0306] To a stirred solution of (l-(3-chlorophenyl)-l,4,5,7-tetrahydrospiro[indazole-6,2'- [l,3]dioxolan]-3-yl)methanol (400 mg, 1.2 mmol, 1.0 eq) in DCM (10 mL) was added SOCI2 (178 mg, 1.5 mmol, 1.2 eq) at 0°C under N2 atmosphere, then the reaction mixture was stirred at 0 °C for 20 min. The reaction mixture was concentrated in vacuo to dryness to give the title compound (400 mg, 95% yield) as a white solid. LC-MS (m / z): 339.1 [M + H]+.Step 4: (S)-5-(4-chlorophenyl)-2-((l-(3-chlorophenyl)-l ,4,5, 7 -tetrahydrospiro [indazole- 6, 2 '-[ 1, 3 ]dioxolan ] -3-yl)methyl)-4-( 3, 3, 3-trifhioro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4- triazol-3-one

[0307] To a solution of 3-(chloromethyl)-l-(3-chlorophenyl)-l,4,5,7-tetrahydrospiro [indazole-6,2'-[l,3] dioxolane] (400 mg, 1.2 mmol, 1.0 eq) and 3-(4-chlorophenyl)-4-[(2S)-IPTS / 200087585.1Attorney Docket No. RTX-003WO3.3.3-trifluoro-2-hydroxy-propyl]-lH-l,2,4-triazol-5-one (363 mg, 1.2 mmol, 1.0 eq) in MeCN (5 mL) was added K2CO3 (326 mg, 2.4 mmol, 2.0 eq). Then the mixture was stirred at 80°C for 16 hrs. The reaction mixture was cooled to rt, which was added water. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (480 mg, 67% yield) as a light-yellow solid. LC- MS (m / z): 610.1 [M + H]+.Step 5: (S)-l-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-l, 4, 5, 7-tetrahydro-6H-indazol-6- one

[0308] A solution of (S)-5-(4-chlorophenyl)-2-((l-(3-chlorophenyl)-l, 4,5,7- tetrahydrospiro [indazole-6,2'-[l,3]dioxolan]-3-yl)methyl)-4-(3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (480 mg, 786 pmol, 1.0 eq) in TFA (10 mL) was stirred at 80°C for 3 hrs. The solvent was removed under reduce pressure to give a yellow oil, which was diluted with EtOAc. The mixture was washed with saturated NaHCOi aqueous and brine, dried over with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (410 mg, 92% yield) as a light-yellow solid. LC-MS (m / z): 566.1 [M + H]+.Step 6: 5-(4-chlorophenyl)-2-((l-(3-chlorophenyl)-6-hydroxy-6-methyl-4,5,6, 7-tetrahydro- lH-indazol-3-yl)methyl)-4-((S)-3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4- triazol-3-one

[0309] To a stirred solution of l-(3-chlorophenyl)-3-[[3-(4-chlorophenyl)-5-oxo-4-[(2S)-3.3.3-trifluoro-2-hydroxy-propyl]-l,2,4-triazol-l-yl]methyl]-5,7-dihydro-4H-indazol-6-one (410 mg, 724 pmol, 1.0 eq) in THF (5 mL) was added methylmagnesium bromide (3 M, 1 mL, 4.1 eq) dropwise at 0°C under N2 atmosphere, then the reaction mixture was stirred at 20 °C for 2hrs. The reaction was quenched by addition of saturated NH4Q aqueous solution and H2O at 0°C, which was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by Prep-HPLC to give the title compound (60 mg, 14% yield) as a white solid. LC-IPTS / 200087585.1Attorney Docket No. RTX-003WOMS (m / z): 582.1 [M + H]+. *H NMR (400 MHz, DMSO-de) 5 1.22 (s, 3H), 1.50-1.63 (m, 1H), 1.68-1.79 (m, 1H), 2.36-2.48 (m, 1H), 2.53-2.59 (m, 1H), 2.61-2.72 (m, 1H), 2.81-2.90 (m, 1H), 3.79-3.87 (m, 1H), 3.98 (br d, J=3.42 Hz, 1H), 4.24-4.36 (m, 2H), 4.89-5.07 (m, 2H), 6.79-7.02 (m, 1H), 7.39-7.46 (m, 1H), 7.47-7.56 (m, 2H), 7.57-7.66 (m, 3H), 7.74 (d, J=8.56 Hz, 2H).Example 50: Synthesis of l-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3- trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-4,5,6,7- tetrahydro-lH-indazole-6-carboxamide (Compound 150)Step 1: ethyl l-(3-chlorophenyl)-6-oxo-4,5,6, 7-tetrahydro-lH-indazole-3-carboxylate

[0310] A solution of ethyl l-(3-chlorophenyl)-l,4,5,7-tetrahydrospiro[indazole-6,2'- [l,3]dioxolane]-3-carboxylate (1.40 g, 3.9 mmol, 1.0 eq) in TFA (20 mL) was stirred at 80°C for 3hrs. The solvent was removed under reduce pressure to give a yellow oil, which was diluted with EtOAc. The mixture was washed with saturated NaHCCh aqueous and brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the title compound (1.15 g, 93% yield) as a light-yellow solid, which was used for next step directly without further purification. LC-MS (m / z) : 319.1 [M + H]+.Step 2: ethyl l-(3-chlorophenyl)-6-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydro-lH- indazole-3-carboxylateIPTS / 200087585.1Attorney Docket No. RTX-003WO

[0311] To a stirred solution of ethyl l-(3-chlorophenyl)-6-oxo-4,5,6,7-tetrahydro-lH- indazole-3 -carboxylate (1.10 g, 3.5 mmol,l eq) in THF (20 mL) was added potassium tert- butoxide(l M in THF, 4.5 mL, 1.3 eq) dropwise at 0°C. Then 1,1,1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl)methanesulfonamide (1.48 g, 4.1 mmol, 1.2 eq) in THF (5 mL) was added dropwise. The mixture was stirred at 20°C for 2 hrs. LCMS showed the starting material was consumed. The reaction was quenched by addition of water, which was extracted with EtOAc. The combined organic layers were washed with brine (30 mL), dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (1.25 g, 80% yield) as a white solid. LC-MS (m / z): 451.0 [M + H]+.Step 3: ethyl l-(3-chlorophenyl)-6-cyano-4,5-dihydro-lH-indazole-3-carboxylate

[0312] To a stirred solution of ethyl l-(3-chlorophenyl)-6-(((trifluoromethyl)sulfonyl) oxy)-4,5-dihydro-lH-indazole-3-carboxylate (1.25 g, 2.8 mmol, 1.0 eq) in DMF (15 mL) was added Tetrakis(triphenylphosphine)palladium (300 mg, 260 pmol, 0.1 eq) and Zn(CN)2 (651 mg, 5.6 mmol, 2.0 eq). The mixture was degassed and backfilled with N2 for three times. Then the reaction mixture was stirred at 60°C for 5 hrs. The reaction was diluted with water, which was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (760 mg, 84% yield) as a white solid. LC-MS (m / z): 328.1 [M + H]+.Step 4: ethyl l-(3-chlorophenyl)-6-cyano-4,5,6, 7-tetrahydro-lH-indazole-3-carboxylate

[0313] A solution of ethyl l-(3-chlorophenyl)-6-cyano-4,5-dihydro-lH-indazole-3- carboxylate (280 mg, 854 pmol, 1.0 eq) in MeOH (30 mL) and EtOAc (10 mL) was added Palladium 10% on Carbon (250 mg, wetted with ca. 55% Water). The reaction mixture was degassed and backfilled with H2 for three times. Then the mixture was stirred under H2 atmosphere (balloon, 15 psi) at 20°C for 4hrs. The mixture was filtered through a pad of Celite and the filter cake was washed with MeOH (10 mL). The solvent was removed under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography to give the title compound (100 mg, 35% yield) as a white solid. LC-MS (m / z): 330.1 [M + H]+.IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 5: l-(3-chlorophenyl)-3-(hydroxymethyl)-4,5,6, 7-tetrahydro-lH-indazole-6-carbonitrile

[0314] To a solution of ethyl l-(3-chlorophenyl)-6-cyano-4,5,6,7-tetrahydro-lH- indazole-3 -carboxylate (140 mg, 425 pmol, 1.0 eq) in THF (5 mL) and EtOH (5 mL) was added LiBH4 (20 mg, 918 pmol, 2.2 eq). Then the mixture was stirred at 55°C for 14 hrs. The reaction was diluted with water, which was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography to give the title compound (55 mg, 45% yield) as a white solid. LC-MS (m / z): 288.1 [M + H]+.Step 6: 3-(chloromethyl)-l-(3-chlorophenyl)-4,5,6, 7 -tetrahydro- lH-indazole-6-carbonitrile

[0315] To a stirred solution of l-(3-chlorophenyl)-3-(hydroxymethyl)-4, 5,6,7- tetrahydro-lH-indazole-6-carbonitrile (55 mg, 191 pmol, 1.0 eq) in DCM (3 mL) was added SOCh (34 mg, 286 pmol, 1.5 eq) at 0°C under N2 atmosphere, then the reaction mixture was stirred at 0 °C for 1 hr. The reaction mixture was concentrated in vacuo to dryness to give the title compound (58 mg, 99% yield) as a white solid. LC-MS (m / z) : 306.1 [M + H]+.Step 7: l-( 3 -chlorophenyl)- 3 -( ( 3-( 4-chlorophenyl)-5-oxo-4-( (S)-3, 3, 3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-4, 5, 6, 7 -tetrahydro- IH-indazole- 6-carbonitrile

[0316] To a solution of 3-(chloromethyl)-l-(3-chlorophenyl)-4,5,6,7-tetrahydro-lH- indazole-6-carbonitrile (58 mg, 189 pmol, 1.0 eq) and 3-(4-chlorophenyl)-4-[(2S)-3,3,3- trifluoro-2-hydroxy-propyl]-lH-l,2,4-triazol-5-one (60 mg, 195 pmol, 1.0 eq) in MeCN (3 mL) was added K2CO3 (79 mg, 572 pmol, 3.0 eq) Then the mixture was stirred at 80°C for 14 hrs. The reaction mixture was cooled to rt, which was added water. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (80 mg, 73% yield) as a white solid. LC-MS (m / z) (ESI): 577.1 [M + H]+.Step 8: l-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-4, 5, 6, 7 -tetrahydro- IH-indazole- 6-carboxamideIPTS / 200087585.1Attorney Docket No. RTX-003WO

[0317] To a mixture of l-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3- trifluoro-2-hydroxypropyl)-4, 5 -dihydro- 1H- 1,2, 4-tri azol- l-yl)methyl)-4, 5,6, 7-tetrahydro- lH-indazole-6-carbonitrile (80 mg, 139 pmol, 1.0 eq) and K2CO3 (30 mg, 217 pmol, 1.6 eq) in DMSO (2 mL) was added H2O2 (100 mg, 882 pmol, 30% purity, 6.4 eq) dropwise. The mixture was stirred at 20°C for 1 hr. The reaction mixture was diluted with water. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a white solid. The crude product was purified by silica gel chromatography to give the title compound (55 mg, 67% yield) as a white solid. LC-MS (m / z): 595.1 [M + H]+.XH NMR (400 MHz, DMSO -d6) 5 1.59-1.70 (m, 1H), 1.95-2.04 (m, 1H), 2.32-2.48 (m, 2H), 2.57-2.68 (m, 1H), 2.73-2.85 (m, 1H), 2.90-3.01 (m, 1H), 3.77-3.91 (m, 1H), 3.94-4.04 (m, 1H), 4.23-4.36 (m, 1H), 4.87-5.02 (m, 2H), 6.85-6.97 (m, 2H), 7.33- 7.40 (m, 1H), 7.41-7.47 (m, 1H), 7.50-7.57 (m, 2H), 7.60-7.67 (m, 3H), 7.71-7.79 (m, 2H).Example 51: Synthesis of (S)-l-(3-chloro-4-fluorophenyl)-3-((3-(4-chlorophenyl)-5-oxo- 4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-l,4,5,7- tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide (Compound 151)Step 1: 6-(tert-butyl) 3-methyl l-(3-chloro-4-fluorophenyl)-l,4,5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-3, 6-dicarboxylateIPTS / 200087585.1Attorney Docket No. RTX-003WO

[0318] To a mixture of 6-(tert-butyl) 3-methyl l,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridine-3,6-dicarboxylate (500 mg, 1.8 mmol, 1.0 eq) in DCM (15 mL) and Py (5 mL) was added (3-chloro-4-fluorophenyl)boronic acid (310 mg, 1.8 mmol, 1.0 eq) and CU(OAC)2(645 mg, 3.6 mmol, 2.0 eq) . The suspension was degassed under vacuum and purged with O2 three times, then stirred at 20°C under O2 balloon for 16 hours. The reaction mixture was filtered and the filtrate was concentrated, treated with water and EtOAc, the organic layers were washed with water and brine, dried over MgSCh and evaporated to dryness. The residue was purified by column chromatography to give the product (80 mg, 11% yield) as a light yellow solid. LC-MS (m / z): 410.0 [M+H]+.JH NMR (400 MHz, DMSO-d6) 5 7.64 (dd, J = 6.0, 2.1 Hz, 1H), 7.39 (dt, J = 8.3, 3.3 Hz, 1H), 7.28 - 7.22 (m, 1H), 4.62 (br s, 2H), 3.96 (s, 3H), 3.69 (br t, J = 4.9 Hz, 2H), 2.93 (br t, J = 5.5 Hz, 2H), 1.50 -1.44 (m, 9H).Step 2: tert-butyl l-(3-chloro-4-fluorophenyl)-3-(hydr oxymethyl)- 1,4, 5, 7-tetrahydr 0-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0319] To a solution of 6-(tert-butyl) 3-methyl l-(3-chloro-4-fluorophenyl)-l,4,5,7- tetrahydro-6H-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate(80 mg, 195 pmol, 1.0 eq) in THF (5 mL) was added LAH(8 mg, 211 pmol, 1.1 eq) at 0°C.The mixture was stirred at 20°C for Ihr. The reaction mixture was cooled to 0°C, quenched by addition of H2O (8 mg), 15% aqueous NaOH (8 mg) and H2O (8 mg), dried over MgSCh and evaporated to dryness to afford a yellow oil (70 mg, 94% yield). LC-MS (m / z): 382.1 [M+H]+.Step 3: tert-butyl 1 -(3-chlor o-4-fhiorophenyl)-3-(chlor omethyl)- 1,4, 5, 7-tetrahydr 0-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0320] To a solution of tert-butyl l-(3-chloro-4-fluorophenyl)-3-(hydroxymethyl)- 1,4, 5, 7 -tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (70 mg, 183 pmol, 1.0 eq) in DCM (5 mL) was added SOCI2 (32 mg, 269 pmol, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 2hrs. The reaction mixture was adjusted to pH=8~9 with saturated NaHCCh solution, extracted with DCM, the organic layer was separated, wash with saturated NaCl solution, dried over MgSCh and evaporated to dryness to give crude product (70 mg, 95% yield) as a light yellow solid. LC-MS (m / z): 400.1 [M+H]+.Step 4: tert-butyl (S)-l-(3-chloro-4-fhiorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- trifhioro-2-hydroxypropyl)-4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-l, 4, 5, 7-tetrahydro- 6H-pyrazolo[ 3, 4-c ]pyridine-6-carboxylateIPTS / 200087585.1Attorney Docket No. RTX-003WO

[0321] To a mixture of tert-butyl 1 -(3 -chi oro-4-fluorophenyl)-3 -(chloromethyl)- 1, 4,5,7- tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (70 mg, 175 pmol, 1.0 eq) in MeCN (5 mL) was added (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H- l,2,4-triazol-3-one (53 mg, 172 pmol, 1.0 eq) and K2COs(72 mg, 521 pmol,3.0 eq) . The mixture was stirred at 80°C forl6hrs. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the product (50 mg, 43% yield) as a light yellow solid. LC-MS (m / z): 671.2 [M+H]+.Step 5: (S)-2-((l-(3-chloro-4-fluorophenyl)-4,5,6, 7-tetrahydro-lH-pyrazolo[3,4-c]pyridin-3- yl)methyl)-5-( 4-chlorophenyl)-4-( 3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4- triazol-3-one

[0322] A mixture of tert-butyl tert-butyl (S)-l-(3-chloro-4-fluorophenyl)-3-((3-(4- chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l- yl)methyl)-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate(50 mg, 74 pmol, 1.0 eq) and HCl / dioxane(4 M,3 mL, 161.1 eq)was stirred at 20°C for Ihr. The reaction mixture was concentrated to give the target compound (45mg, crude) as a colourless oil. LC-MS (m / z): 571.1 [M+H]+.Step 6: (S)-l-(3-chloro-4-fluorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydr oxypropyl) -4, 5-dihydro-lH-l, 2, 4-triazol-l-yl)methyl)-l, 4, 5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxamide

[0323] To a mixture of (S)-2-((l-(3-chloro-4-fluorophenyl)-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridin-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2- hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (45 mg, 74 pmol, 1.0 eq) and Potassium cyanate(18 mg, 222 pmol, 3.0 eq) in H2O (3 mL) was added HCl(0.5 M,0.4 mL,2.7 eq). The mixture was stirred at 60°C for 16hrs. The residue was adjusted to pH=8~9 with saturated NaHCCh solution, extracted with EtOAc, the organic layer was separated, wash with saturated NaCl solution, dried over MgSCh and evaporated to dryness. The crude product was purified by column chromatography to give the target compound (15 mg, 33% yield) as a white solid. LC-MS (m / z): KlfM+^.'HNMR (400 MHz, DMSO_d6) 5 (ppm) 7.78- 7.73 (m, 3H), 7.64-7.56 (m, 4H), 6.91 (d, J = 6.4 Hz, 1H), 6.19 (s, 2H), 4.98 (s, 2H), 4.62 (s, 2H), 4.31-4.29 (m, 1H), 4.04 - 3.97 (m, 1H), 3.85 - 3.82 (m, 1H), 3.54 - 3.53 (m, 2H), 3.39 - 3.17 (m, 2H).IPTS / 200087585.1Attorney Docket No. RTX-003WOExample 52: Synthesis of (S)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-l-(2-chloropyridin-4-yl)- l,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide (Compound 152)Step 1: 6-(tert-butyl) 3-methyl l-(2-chloropyridin-4-yl)-l,4,5, 7-tetrahydro-6H-pyrazolo[3,4- c]pyridine-3, 6-dicarboxylate

[0324] To a mixture of 6-(tert-butyl) 3-methyl l,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridine-3, 6-dicarboxylate (500 mg, 1.8 mmol, 1.0 eq) in NMP (8 mL) was added 2- chloro-4-fluoropyridine (280 mg,2.1mmol,1.5 eq) and K2COs(589 mg, 4.3 mmol, 3.0 eq). The mixture was poured into water, extracted with EtOAc, the organic layers were washed with water and brine, dried over MgSCh and evaporated to dryness. The residue was purified by column chromatography to give the product (250 mg, 45% yelid) as a light yellow solid. LC- MS (m / z): 393.1[M+H]+. ‘H NMR (400 MHz, DMSO-de) 5 8.50 (br d, J = 4.9 Hz, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.47 (br d, J = 4.4 Hz, 1H), 4.81 (br s, 2H), 3.98 (s, 3H), 3.76-3.64 (m, 2H), 2.94 (br t, J = 5.6 Hz, 2H), 1.53-1.48 (m, 9H).Step 2: tert-butyl l-(2-chloropyridin-4-yl)-3-(hydroxymethyl)-l,4,5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0325] To a solution of 6-(tert-butyl) 3-methyl l-(2-chloropyridin-4-yl)-l,4,5,7- tetrahydro-6H-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate(80mg, 195pmol, 1.0 eq) in THFIPTS / 200087585.1Attorney Docket No. RTX-003WO(10 mL) was added LAH(26 mg, 685 pmol, 1.1 eq) at 0 °C. The mixture was stirred at 20°C for Ihr. The reaction mixture was cooled to 0 °C, quenched by addition of H2O (26 mg), 15% aqueous NaOH (26 mg) and H2O (26 mg), dried over MgSCh and evaporated to dryness to afford a yellow solid (230 mg, 99% yield). LC-MS (m / z): 365.1 [M+H]+.Step 3: tert-butyl 3-(chloromethyl)-l-(2-chloropyridin-4-yl)-l,4,5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0326] To a solution of tert-butyl l-(2-chloropyridin-4-yl)-3-(hydroxymethyl)-l, 4,5,7- tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (230 mg, 630 pmol, 1.0 eq) in DCM (10 mL) was added SOCI2 (150 mg, 1.3 mmol, 2.0 eq) at 0°C. The mixture was stirred at 20°C for Ihr. The reaction mixture was adjusted to pH=8~9 with saturated NaHCCh solution, extracted with DCM, the organic layer was separated, wash with saturated NaCl solution, dried over MgSCh and evaporated to dryness to give crude product (140 mg, 58% yield) as a light yellow solid. LC-MS (m / z): 383.1 [M+H]+.Step 4: tert-butyl (S)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trijluoro-2-hydroxypropyl)-4,5- dihydro-lH-1, 2, 4-triazol-l-yl)methyl)-l-(2-chloropyridin-4-yl)-l, 4, 5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0327] To a mixture of tert-butyl 3 -(chloromethyl)- l-(2-chloropyridin-4-yl)-l, 4,5,7- tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylat (140 mg, 365 pmol, 1.0 eq) in MeCN (6 mL) was added (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one (112 mg, 364 pmol, 1.0 eq) and K2CO3 (151 mg, 1.1 mmol, 3.0 eq) . The mixture was stirred at 80°C forl6hrs. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the product (100 mg, 42% yield) as a light yellow solid. LC-MS (m / z): 654.2 [M+H]+.Step 5: (S)-5-(4-chlorophenyl)-2-((l-(2-chloropyridin-4-yl)-4,5,6, 7 -tetrahydro- 1H- pyrazolo[ 3, 4-c ]pyridin-3-yl)methyl)-4-( 3, 3, 3 -trifluor o-2 -hydroxypropyl) -2, 4-dihydro-3H- 1, 2, 4-triazol-3-one

[0328] A mixture of tert-butyl (S)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hy droxypropyl)-4,5-dihydro-lH- 1,2, 4-tri azol- l-yl)methyl)-l -(2-chloropyridin-4-yl)- 1,4, 5,7- tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (100 mg, 153 pmol, 1.0 eq) and HCl / dioxane(4 M,6 mL,157.1eq) was stirred at 20°C for Ihr. The reaction mixture was concentrated to give the target compound (84 mg, crude) as a light yellow solid. LC-MS (m / z):554.1 [M+H]+.IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 6: (S)-3-( 3-(4-chlorophenyl)-5-oxo-4-( 3, 3, 3-trifluoro-2-hydroxypropyl)-4, 5-dihydro- 1H-1, 2, 4-triazol-l-yl)methyl)-l-(2-chloropyridin-4-yl)-l, 4, 5, 7-tetrahydro-6H-pyrazolo[ 3, 4- c ]pyridine-6-carboxamide

[0329] To a mixture of (S)-5-(4-chlorophenyl)-2-((l-(2-chloropyridin-4-yl)-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridin-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4- dihydro-3H-l,2,4-triazol-3-one (60 mg, 108 pmol, 1.0 eq) and TEA(35 mg, 346 pmol, 3.2eq) in DCM (5 mL) was added trimethyl silyl isocyanate (18 mg, 156 pmol, 1.4 eq). The mixture was stirred at 20°C for 4hrs. The mixture was poured into NaHCCh solution, extracted with EtOAc, the organic layer was separated, wash with saturated NaCl solution, dried over MgSCh and evaporated to dryness. The crude product was purified by column chromatography to give the target compound (12 mg, 19% yield) as a white solid. LC-MS (m / z):597.1[M+H]+.1HNMR(400 MHz, DMSO de ) 5 (ppm) 8.51 (d, J = 5.6 Hz, 1H), 7.79-7.70 (m, 2H), 7.66-7.62 (m, 4H), 6.92 (br d, J = 6.1 Hz, 1H), 6.26 (br s, 2H), 5.02 (s, 2H), 4.79 (s, 2H), 4.30-4.28 (m, 1H), 4.01-3.98 (m, 1H), 3.86-3.79(m, 1H), 3.55-3.53 (m, 2H) .Example 53: Synthesis of (S)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-l-(m-tolyl)-l,4,5,7- tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide (Compound 153)IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 1: 6-(tert-butyl) 3-methyl l-(m-tolyl)-l,4,5, 7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 3, 6-dicarboxylate

[0330] To a mixture of 6-(tert-butyl) 3-methyl l,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridine-3, 6-dicarboxylate (1.00 g,3.6 mmol, 1.0 eq) in DCM (15 mL) and Py (5 mL) was added m-tolylboronic acid (500 mg, 3.6 mmol, 1.000 eq) and Cu(OAc)2 (1.29 g,7.1 mmol, 2.0 eq). The suspension was degassed under vacuum and purged with O2 three times , then stirred at 20°C under O2 balloon for 16 hours. The reaction mixture was filtered and the filtrate was concentrated, treated with water and EtOAc, the organic layers were washed with water and brine, dried over MgSCh and evaporated to dryness. The residue was purified by column chromatography to give the product (450 mg, 34% yield) as a light yellow solid. LC-MS (m / z): 372.2 [M+H]+. 'HNMR (400 MHz, DMSO-de) 5 7.40-7.29 (m, 2H), 7.28- 7.16 (m, 2H), 4.62 (br s, 2H), 3.94 (s, 3H), 3.80-3.71 (m, 2H), 3.71-3.62 (m, 2H), 2.93 (br t, J = 5.6 Hz, 2H), 2.41 (s, 3H), 1.85 (dt, J = 6.5, 3.2 Hz, 2H), 1.53-1.40 (m, 9H).Step 2: tert-butyl 3-(hydroxymethyl)-l-(m-tolyl)-l,4,5, 7-tetrahydro-6H-pyrazolo[3,4- c ]pyridine-6-carboxylate

[0331] To a solution of 6-(tert-butyl) 3-methyl l-(m-tolyl)-l,4,5,7-tetrahydro-6H- pyrazolo[3,4-c]pyridine-3, 6-dicarboxylate (450 mg, 1.2 mmol, 1.0 eq) in THF (10 mL) was added LAH (49 mg, 1.3 mmol, 1.1 eq) at 0°C. The mixture was stirred at 20°C for Ihr. The reaction mixture was cooled to 0°C, quenched by addition of H2O (49 mg), 15% aqueous NaOH (49 mg) and H2O (49 mg), dried over MgSCh and evaporated to dryness to afford a yellow solid (380 mg, 91% yield). LC-MS (m / z): 344.2 [M+H]+.Step 3: tert-butyl 3-(chloromethyl)-l-(m-tolyl)-l,4,5, 7-tetrahydro-6H-pyrazolo[3,4- c ]pyridine-6-carboxylate

[0332] To a solution of tert-butyl 3-(hydroxymethyl)-l-(m-tolyl)-l,4,5,7-tetrahydro-6H- pyrazolo[3,4-c]pyridine-6-carboxylate (150 mg, 437 pmol,1.0 eq) in DCM (5mL) was added SOCI2 (62 mg, 521 pmol, 1.2 eq) at 0 °C. The mixture was stirred at 20 °C for Ihr. The reaction mixture was adjusted to pH=8~9 with saturated NaHCCh solution, extracted with DCM, the organic layer was separated, wash with saturated NaCl solution, dried over MgSCh and evaporated to dryness to give crude product (150 mg, 95% yield) as a light yellow solid. LC-MS (m / z): 363.2 [M+H]+.IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 4: tert-butyl (S)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5- dihydro-lH-1, 2, 4-triazol-l-yl)methyl)-l-(m-tolyl)-l, 4, 5, 7-tetrahydro-6H-pyrazolo[ 3, 4- c ]pyridine-6-carboxylate

[0333] To a mixture of tert-butyl 3-(chloromethyl)-l-(m-tolyl)-l,4,5,7-tetrahydro-6H- pyrazolo[3,4-c]pyridine-6-carboxylate(150 mg, 415 pmol, 1.0 eq) in MeCN (6 mL) was added (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4- triazol-3-one (127 mg, 413 pmol, 1.0 eq) and K2CO3 (172 mg, 1.2 mmol, 3.0 eq). The mixture was stirred at 80°C forl6hrs. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the product (150 mg, 57% yield) as a light yellow solid. LC-MS (m / z): 633.2 [M+H]+.Step 5: (S)-5-(4-chlorophenyl)-2-((l-(m-tolyl)-4,5,6, 7-tetrahydro-lH-pyrazolo[3,4- c ]pyridin-3-yl)methyl)-4-(3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4-triazol-3- one

[0334] A mixture of tert-butyl tert-butyl (S)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3- tri fhioro-2-hydroxypropyl)-4, 5 -dihydro- 1H- 1,2, 4-tri azol- l-yl)methyl)-l -(m-tolyl)- 1,4, 5,7- tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (150 mg, 237 pmol, 1.0 eq) and HCl / dioxane(4 M,6 mL, 157.1 eq) was stirred at 20°C for 2hrs. The reaction mixture was concentrated to give the target compound (134 mg, crude) as a light yellow solid. LC-MS (m / z):533.2 [M+H]+.Step 6: (S)-3-( f 3-(4-chlorophenyl)-5-oxo-4-( 3, 3, 3-trifluoro-2-hydroxypropyl)-4, 5-dihydro- 1H-1, 2, 4-triazol-l-yl)methyl)-l-(m-tolyl)-l, 4, 5, 7-tetrahydro-6H-pyrazolo[ 3, 4-c ]pyridine-6- carboxamide

[0335] To a mixture of (S)-5-(4-chlorophenyl)-2-((l-(m-tolyl)-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridin-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H- l,2,4-triazol-3-one (134 mg, 235 pmol, 1.0 eq) and TEA(72 mg, 712 pmol, 3.0 eq) in DCM (5 mL) was added trimethyl silyl isocyanate (41 mg, 356 pmol, 1.5 eq). The mixture was stirred at 20°C for 16hrs.The mixture was poured into NaHCCh solution, extracted with EtOAc, the organic layer was separated, wash with saturated NaCl solution, dried over MgSCh and evaporated to dryness. The crude product was purified by column chromatography to give the target compound (12 mg, 19% yield) as a white solid. LC-MS (m / z):576.1 [M+H]+ 1H NMR(400 MHz, DMSO_d6) 5 (ppm) 7.76 - 7.74 (m, 2H), 7.63 (d, J = 8.6 Hz, 2H), 7.41 - 7.38 (m, 1H), 7.35 (s, 1H), 7.30 (br d, J = 8.1 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.92 (d, J =IPTS / 200087585.1Attorney Docket No. RTX-003WO6.4 Hz, 1H), 6.18 (s, 2H), 4.98 (s, 2H), 4.61 (s, 2H), 4.31 - 4.29 (m, 1H), 4.00- 3.96 (m, 1H), 3.85-3.79 (m, 1H), 3.55 (br t, J = 5.6 Hz, 2H), 3.34-3.30 (m, 2H), 2.34 (s, 3H).Example 54: Synthesis of 5-(4-chlorophenyl)-2-((6-hydroxy-6-methyl-l-(m-tolyl)- 4,5,6,7-tetrahydro-lH-indazol-3-yl)methyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Compound 154)Step 1: ethyl l-(m-tolyl)-l,4,5, 7-tetrahydrospiro[indazole-6,2'-[l,3]dioxolane]-3- carboxylate

[0336] To a mixture of ethyl l,4,5,7-tetrahydrospiro[indazole-6,2'-[l,3]dioxolane]-3- carboxylate (2.00 g, 7.9 mmol, 1.0 eq) and Cu(OAc)2 (2.88 g, 15.9 mmol, 2.0 eq) in DCM (40 mL) and pyridine (10 mL) was added m-tolylboronic acid (1.40 g, 10.3 mmol, 1.3 eq). The mixture was degassed and backfilled with O2 three times. The reaction mixture was stirred at 25°C under O2 atmosphere (15 psi) for 20 hrs. The reaction mixture was diluted with DCM (50 mL), which was filtered through a pad of Celite and the filter cake was washed with DCM (10 mL). The combined filtrate was concentrated to remove the solvent to give the crude product, which was diluted with EtOAc. The mixture was washed with water and brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product wasIPTS / 200087585.1Attorney Docket No. RTX-003WO purified by silica gel chromatography to give the title compound (1.50 g, 55% yield) as a colorless oil. LC-MS (m / z): 343.2 [M + H]+. 'HNMR (400 MHz, CDCh) 5 7.39-7.31 (m, 2H), 7.28-7.23 (m, 1H), 7.21 (d, J= 7.6 Hz, 1H), 4.43 (q, J= 7.1 Hz, 2H), 4.05-3.94 (m, 4H), 3.02 (t, J= 6.5 Hz, 2H), 2.94 (s, 2H), 2.42 (s, 3H), 2.00 (t, J= 6.5 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H).Step 2: (l-(m-tolyl)-l,4,5, 7-tetrahydrospiro[indazole-6,2'-[l,3]dioxolan]-3-yl)methanol

[0337] To a stirred solution of ethyl l-(m-tolyl)-l,4,5,7-tetrahydrospiro[indazole-6,2'-[1.3]dioxolane]-3-carboxylate (500 mg, 1.5 mmol, 1.0 eq) in THF (10 mL) was added LAH (56 mg, 1.5 mmol, 1.0 eq) at 0°C under N2 atmosphere, then the reaction mixture was stirred at 20 °C for 1 hr. The reaction was quenched by addition of H2O (0.1 mL) and 15% aqueous NaOH (0.1 mL) at 0°C and the mixture was diluted with THF (50 mL), then anhydrous MgSCh (2.00 g) was added. The suspension was filtered through a pad of Celite and the filter cake was washed with THF (20 mL). The combined filtrate was concentrated to dryness to give the title compound (430 mg, 98% yield) as a white solid.LC- MS (m / z): 301.2 [M + H]+.Step 3: 3-(chloromethyl)-l-(m-tolyl)-l,4,5, 7 -tetrahydrospiro [indazole-6,2'-[ 1 , 3] dioxolane]

[0338] To a stirred solution of (l-(m-tolyl)-l,4,5,7-tetrahydrospiro[indazole-6,2'-[1.3]dioxolan]-3-yl)methanol (430 mg, 1.4 mmol, 1.0 eq) in DCM (10 mL) was added SOCI2 (200 mg, 1.7 mmol, 1.2 eq) at 0°C under N2 atmosphere, then the reaction mixture was stirred at 0 °C for 20 min. The reaction mixture was concentrated in vacuo to dryness to give the title compound (450 mg, 99% yield) as a white solid. LC-MS (m / z):319.1 [M + H]+.Step 4: (S)-5-(4-chlorophenyl)-2-((l-(m-tolyl)-l,4,5, 7 -tetrahydrospiro [indazole-6,2'-[1.3 ]dioxolan ]-3-yl)methyl)-4-(3, 3, 3-trifhioro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4- triazol-3-one

[0339] To a solution of 3-(chloromethyl)-l-(m-tolyl)-l,4,5,7-tetrahydrospiro[indazole- 6,2'-[l,3]dioxolane] (450 mg, 1.4 mmol, 1.0 eq) and (S)-5-(4-chlorophenyl)-4-(3,3,3- trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (450 mg, 1.5 mmol, 1.0 eq) in MeCN (15 mL) was added K2CO3 (585 mg, 4.2 mmol, 3.0 eq). Then the mixture was stirred at 80°C for 16 hrs. The reaction mixture was cooled to rt, which was added water. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuoIPTS / 200087585.1Attorney Docket No. RTX-003WO to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (550 mg, 66% yield) as a light-yellow solid. LC- MS (m / z): 590.2 [M + H]+.Step 5: (S)-3-( f 3-(4-chlorophenyl)-5-oxo-4-( 3, 3, 3-trifluoro-2-hydroxypropyl)-4, 5-dihydro- 1H-1,2, 4-triazol-l-yl)methyl)-l-(m-tolyl)-l, 4,5, 7-tetrahydro-6H-indazol-6-one

[0340] A solution of (S)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl) methyl)- 1 -(m -tolyl)- 1, 4,5, 7-tetrahydro- 6H-indazol-6-one (550 mg, 932 pmol, 1.0 eq) in TFA (6 mL) was stirred at 80 °C for 3 hrs. LCMS showed the starting material was consumed completely. The solvent was removed under reduce pressure to give a yellow oil, which was diluted with EtOAc. The mixture was washed with saturated NaHCCh aqueous and brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (450 mg, 88% yield) as a white solid. LC-MS (m / z): 546.2 [M + H]+.Step 6: 5-(4-chlorophenyl)-2-((6-hydroxy-6-methyl-l-(m-tolyl)-4,5,6, 7 -tetrahydro- 1H- indazol-3-yl)methyl)-4-((S)-3, 3, 3-trifluoro-2-hydroxypropyl)-2, 4-dihydro-3H-l, 2, 4-triazol-3- one

[0341] To a stirred solution of 3-[[3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2- hydroxy-propyl]-l,2,4-triazol-l-yl]methyl]-l-(m-tolyl)-5,7-dihydro-4H-indazol-6-one (450 mg, 824 pmol, 1.0 eq) in THF (8 mL) was added methylmagnesium bromide (3 M, 1.5 mL, 5.5 eq) dropwise at 0 °C under N2 atmosphere, then the reaction mixture was stirred at 20 °C for 1 hr. The reaction was quenched by addition of saturated NH4Q aqueous and H2O at 0°C, which was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (130 mg, 28% yield) as a white solid. LC-MS (m / z): 562.2 [M + H]+. 'H NMR (400 MHz, DMSO-de) 5 7.81-7.70 (m, 2H), 7.67-7.60 (m, 2H), 7.42-7.30 (m, 2H), 7.29-7.23 (m, 1H), 7.19-7.13 (m, 1H), 6.94-6.86 (m, 1H), 4.95 (s, 2H), 4.48 (s, 1H), 4.37-4.23 (m, 1H), 4.05-3.95 (m, 1H), 3.83 (dd, J= 14.4, 9.5 Hz, 1H), 2.82-2.73 (m, 1H), 2.66-2.59 (m, 1H), 2.58-2.52 (m, 1H), 2.48-2.42 (m, 1H), 2.38 (s, 3H), 1.78-1.67 (m, 1H), 1.64-1.51 (m, 1H), 1.21 (s, 3H)IPTS / 200087585.1Attorney Docket No. RTX-003WOExample 55: Synthesis of 3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3-trifluoro-2- hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-l-(m-tolyl)-4,5,6,7- tetrahydro-lH-indazole-6-carboxamide (Compound 155)Step 1: ethyl 6-oxo-l-(m-tolyl)-4,5,6, 7-tetrahydro-lH-indazole-3-carboxylate

[0342] A solution of ethyl l-(m-tolyl)-l,4,5,7-tetrahydrospiro[indazole-6,2'-[l,3] dioxolane]-3-carboxylate (750 mg, 2.2 mmol, 1.0 eq) in TFA (10 mL) was stirred at 80°C for 3 hrs. The solvent was removed under reduce pressure to give a yellow oil, which was diluted with EtOAc. The mixture was washed with saturated NaHCCh aqueous and brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography to give the title compound (630 mg, 96% yield) as a light-yellow solid. LC-MS (m / z):299.1 [M + H]+.Step 2: ethyl l-(m-tolyl)-6-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydro-lH-indazole-3- carboxylate

[0343] To a stirred solution of ethyl 6-oxo-l-(m-tolyl)-4,5,6,7-tetrahydro-lH-indazole- 3-carboxylate (630 mg, 2.1 mmol, 1.0 eq) in THF (10 mL) was added potassium tert- butoxide (1 M in THF, 2.5 mL, 1.2 eq) dropwise at 0°C. Then 1,1,1-trifhioro-N-phenyl-N-IPTS / 200087585.1Attorney Docket No. RTX-003WO(trifluoromethylsulfonyl)methanesulfonamide (905 mg, 2.5 mmol, 1.2 eq) in THF (2 mL) was added dropwise. The mixture was stirred at 20°C for 2 hrs. The reaction was quenched by addition of water, which was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (650 mg, 72% yield) as a colorless oil.LC-MS(ESI): 431.1 [M + H]+.Step 3: ethyl 6-cyano-l-(m-tolyl)-4,5-dihydro-lH-indazole-3-carboxylate

[0344] To a stirred solution of ethyl l-(m-tolyl)-6-(((trifhioromethyl)sulfonyl)oxy)-4,5- dihydro-lH-indazole-3-carboxylate (650 mg, 1.5 mmol, 1.0 eq) in DMF (10 mL) was added Tetrakis(triphenylphosphine)palladium (175 mg, 151 pmol, 0.1 eq) and Zn(CN)2 (355 mg, 3.0 mmol, 2.0 eq). The mixture was degassed and backfilled with N2 for three times. Then the reaction mixture was stirred at 60°C for 4 hrs. The reaction was diluted with water, which was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (300 mg, 65% yield) as a white solid. LC-MS (m / z): 308.1 [M + H]+.Step 4: ethyl 6-cyano-l-(m-tolyl)-4,5,6, 7-tetrahydro-lH-indazole-3-carboxylate

[0345] A solution of ethyl 6-cyano-l-(m-tolyl)-4,5-dihydro-lH-indazole-3-carboxylate (300 mg, 976 pmol, 1.0 eq) in MeOH (8 mL) and THF (8 mL) was added Palladium 10% on Carbon (60 mg, wetted with ca. 55% Water). The reaction mixture was degassed and backfilled with H2 for three times. Then the mixture was stirred under H2 atmosphere (balloon, 15 psi) at 20°C for 6 hrs. The mixture was filtered through a pad of Celite and the filter cake was washed with MeOH (10 mL). The solvent was removed under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography to give the title compound (110 mg, 36% yield) as a colorless oil. LC-MS (m / z): 310.2 [M + H]+.Step 5: 3-(hydroxymethyl)-l-(m-tolyl)-4,5,6, 7 -tetrahydro- lH-indazole-6-carbonitrile

[0346] To a solution of ethyl 6-cyano-l-(m-tolyl)-4,5,6,7-tetrahydro-lH-indazole-3- carboxylate (110 mg, 356 pmol, 1.0 eq) in THF (8 mL) and EtOH (8 mL) was added LiBH4 (80 mg, 3.7 mmol, 10.3 eq). Then the mixture was stirred at 50°C for 1 hr. The reaction wasIPTS / 200087585.1Attorney Docket No. RTX-003WO diluted with water, which was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSCh and filtered. The filtrate was concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography to give the title compound (75 mg, 79% yield) as a white solid. LC- MS (m / z): 268.3 [M + H]+.Step 6: 3-(chloromethyl)-l-(m-tolyl)-4,5,6, 7 -tetrahydro- lH-indazole-6-carbonitrile

[0347] To a stirred solution of 3-(hydroxymethyl)-l-(m-tolyl)-4,5,6,7-tetrahydro-lH- indazole-6-carbonitrile (75 mg, 281 pmol, 1.0 eq) in DCM (3 mL) was added SOCh (70 mg, 588 pmol, 2.1 eq) at 0°C under N2 atmosphere, then the reaction mixture was stirred at 0 °C for 1 hr. The reaction mixture was concentrated in vacuo to dryness to give the title compound (80 mg, 100% yield) as a white solid. LC-MS (m / z): 286.1 [M + H]+.Step 7: 3-((3-( 4-chlorophenyl)-5-oxo-4-((S)-3, 3, 3-trifhioro-2-hydroxypropyl)-4, 5-dihydro- 1H-1, 2, 4-triazol-l-yl)methyl)-l-(m-tolyl)-4, 5, 6, 7 -tetrahydro- lH-indazole-6-carbonitrile

[0348] To a solution of 3-(chloromethyl)-l-(m-tolyl)-4,5,6,7-tetrahydro-lH-indazole-6- carbonitrile(80 mg, 279.945 pmol,l eq) and 3-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2- hydroxy-propyl]-lH-l,2,4-triazol-5-one (90 mg, 293 pmol, 1.5 eq) in MeCN (5 mL) was added K2CO3 (116 mg, 839 pmol, 3.0 eq). Then the mixture was stirred at 80°C for 14 hrs. The reaction mixture was cooled to rt, which was added water. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel chromatography to give the title compound (105 mg, 67% yield) as a white solid. LC-MS (m / z): 557.2 [M + H]+.Step 8: 3-( 3-(4-chlorophenyl)-5-oxo-4-( (S)-3, 3, 3-trifluoro-2-hydroxypropyl)-4, 5-dihydro- 1H-1, 2, 4-triazol-l-yl)methyl)-l-(m-tolyl)-4, 5, 6, 7 -tetrahydro- lH-indazole-6-carboxamide

[0349] To a mixture of 3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3-trifluoro-2- hydroxypropyl) -4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-l-(m-tolyl)-4,5,6,7-tetrahydro- lH-indazole-6-carbonitrile (105 mg, 189 pmol, 1.0 eq) and K2COs (39 mg, 282 pmol, 1.5 eq) in DMSO (3 mL) was added H2O2 (171 mg, 1.5 mmol, 30% purity, 8.0 eq) dropwise. The mixture was stirred at 20°C for 1 hr. The reaction mixture was diluted with water. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuoIPTS / 200087585.1Attorney Docket No. RTX-003WO to give the crude product as a white solid. The crude product was purified by silica gel chromatography to give the title compound (80 mg, 74% yield) as a white solid. LC-MS (m / z) (ESI): 575.2 [M + H]+. 'HNMR (400 MHz, DMSO-de) 5 7.79-7.70 (m, 2H), 7.66-7.58 (m, 2H), 7.42-7.27 (m, 4H), 7.18 (d, J= 7.6 Hz, 1H), 6.95-6.86 (m, 2H), 5.02-4.87 (m, 2H), 4.41-4.24 (m, 1H), 4.04-3.94 (m, 1H), 3.90-3.72 (m, 1H), 2.96-2.84 (m, 1H), 2.77-2.57 (m, 2H), 2.49-2.32 (m, 5H), 2.03-1.95 (m, 1H), 1.78-1.56 (m, 1H).Example 56: Synthesis of (S)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2- hydroxypropyl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)methyl)-l-(2,3-dichlorophenyl)- l,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide (Compound 156)Step 1: tert-butyl 4-(2-ethoxy-2-oxoacetyl)-3-oxopiperidine-l-carboxylate

[0350] To a stirred solution of tert-butyl 3 -oxopiperidine- 1 -carboxylate in THF (10 mL) was added LiHMDS (1 M, 10 mL,1.0 eq) at -70°C under N2 atmosphere, the reaction mixture was stirred at -70 °C for 30 min. Then diethyl oxalate (1.47 g, 10.1 mmol, 1.0 eq) was added to the reaction mixture at -70°C, the mixture was stirred at 20°C for 16hr. The reaction mixture was quenched by saturated NH4Q, then the solution was adjusted to pH=4~5 and with HC1, extracted with organic solvent. The collected organic phase was then dried over MgSCh and concentrated to dryness. The crude product was purified through column chromatography to obtain an orange oil (1.70 g, 57% yield). LC-MS (m / z . 298.1IPTS / 200087585.1Attorney Docket No. RTX-003WO[M-H]-. ‘H NMR (400 MHz, DMSO-t / e) 5 4.21 (q, J= 7.2 Hz, 2H), 4.07 (s, 2H), 3.43-3.36 (m, 3H), 2.22 (s, 2H), 1.42 (s, 9H), 1.24 (t, J= 7.2 Hz, 3H).Step 2: 6-(tert-butyl) 3-methyl l-(2,3-dichlorophenyl)-l,4,5, 7-tetrahydro-6H- pyrazolo[3,4- c] pyridine-3, 6-dicarboxylate

[0351] To a stirred soultion of tert-butyl 4-(2-ethoxy-2-oxoacetyl)-3-oxopiperidine-l - carboxylate(500 mg, 1.7 mmol, 1.0 eq) in EtOH (10 mL) was added (2,3- dichlorophenyl)hydrazine;hydrochloride (535 mg, 2.5 mmol, 1.5 eq) at 20 °C, then the reaction mixture was stirred at 80 °C for 2 hrs. The reaction solution was concentrated to dryness. The crude product was purified through column chromatography to obtain a yellow oil (300 mg, 41% yield). LC-MS (m / z): 440.1 [M+H]+. 'HNMR (400 MHz, CDCh) 5 7.65- 7.63 (m, 1H), 7.41-7.36 (m, 2H), 4.44 (q, J= 7.2 Hz, 2H), 4.37 (s, 2H), 3.71 (s, 2H), 2.97- 2.94 (m, 2H), 1.48 (s, 9H), 1.42 (t, J= 7.2 Hz, 3H).Step 3: tert-butyl l-(2,3-dichlorophenyl)-3-(hydroxymethyl)-l,4,5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0352] To a anhydrous THF (5 mL) solution of 6-(tert-butyl) 3-methyl 1 -(2,3- dichlorophenyl)-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-3,6- dicarboxylate (280 mg, 636 pmol, 1.0 eq) was cooled in ice-water bath, then added LiAlH4 (25 mg, 659 pmol, 1.0 eq) in portions. The reaction mixture was stirred at 0 - 4 °C for 1 hr. The reaction solution was quenched by addition of 25 mg of H2O, followed by 25 mg of 15% aqueous NaOH. After being stirred at room temperature for 0.5 hr, the solid was removed by filtration. The filtrate was concentrated to dryness to give crude targeted product (220 mg, 87% yield) as colorless oil. LC-MS (m / z): 400.2 [M+H]+.Step 4: tert-butyl 3-(chloromethyl)-l-(2,3-dichlorophenyl)-l,4,5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0353] To a anhydrous DCM (10 mL) solution of tert-butyl 1 -(2,3- dichlorophenyl)-3- (hydroxymethyl)-l,4,5,7-tetrahydro-6H- pyrazolo[3,4-c]pyridine -6 -carboxylate (220 mg, 552 pmol, 1.0 eq) was cooled in ice- water bath, then added SOCh (72 mg, 605 pmol, 1.1 eq) in dropwise. The reaction mixture was stirred at ambient temperature for 1 hr. The reaction solution was concentrated to dryness to obtain the title compound as yellow oil (220 mg, 96% yield), which was used directly for the next step. LC-MS (m / z): 416.0 [M+H]+.IPTS / 200087585.1Attorney Docket No. RTX-003WOStep 5: tert-butyl (S)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trijluoro-2 -hydroxypropyl)-4,5- dihydro-lH-1, 2, 4-triazol-l-yl)methyl)-l-(2, 3 -dichlorophenyl)-!, 4, 5, 7-tetrahydro-6H- pyrazolo[ 3, 4-c ]pyridine-6-carboxylate

[0354] Tert-butyl 3-(chl oromethyl)-l-(2, 3-di chlorophenyl)- 1,4,5, 7-tetrahydro-6H- pyrazolo[3,4-c]pyridine-6-carboxylate (200 mg, 480 pmol, 1.0 eq), (S)-5-(4- chlorophenyl)- 4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (148 mg, 481 pmol, 1.0 eq), K2CO3 (199 mg, 1.4 mmol, 3.0 eq) was suspended in CH3CN (5 mL). The resulting mixture was heated to 80 °C to react for 12 hrs. The reaction mixture was treated with water and EtOAc, and the organic phase was isolated, and concentrated to dryness. The crude product was purified through column chromatography to obtain a white solid (250 mg, 76% yield). LC-MS (m / z): 687.1 [M+H]+.Step 6: (S)-5-(4-chlorophenyl)-2-((l-(2,3-dichlorophenyl)-4,5,6, 7 -tetrahydro- 1H- pyrazolo[ 3, 4-c ]pyridin-3-yl)methyl)-4-( 3, 3, 3 -trifluor o-2 -hydroxypropyl) -2, 4-dihydro-3H- 1, 2, 4-triazol-3-one

[0355] Tert-butyl (S)-3-((3-(4-chloroph...

Claims

Attorney Docket No. RTX-003WOCLAIMSWhat is claimed is:

1. A compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting of halogen, hydroxyl, -N(RD)(RE), cyano, - NO2, Ci-ealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-ealkoxy, Cs-Cecycloalkyl, -C(=O)NRDRE, - NRD(C=O)RE, -O(C=O)NRDRE, -NRD(C=O)ORE, -NRD(C=O)NRDRE, -(C=O)Ci-C6alkyl, - (C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, S(O)2NRDRE, and - NRDS(0)2 Ci-Cealkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, Ci-Cealkyl, and Ci- Cealkoxy;L1is Ci-3alkylene, wherein Ci-3alkylene may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, -CH3, and -CF3; or L1is absent;Ring A is an 8-9 membered fused bicyclic heterocyclyl having at least two ring nitrogens, wherein if the heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may be optionally substituted with RA, and wherein if the heterocyclyl contains a substitutable ring sulfur atom, that ring sulfur atom may be optionally substituted with two O atoms or one O atom and one NH group;Ring B is selected from the group consisting of phenyl, 3-6 membered carbocyclyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl;R2is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, oxo, cyano, Ci-ealkyl, Ci-ealkoxy, -C(O)Ci-ealkyl, -COOH, - C(O)N(RB)(RC), -S(O)2N(RD)(RE), -N(RB)(RC), -C(O)NHC(O)SO2Ci-6alkyl, C(O)NHC(O)SO2-phenyl, -NH-SCh-Ci-ealkyl, -PH(O)Ci -ealkyl, 5-6 membered heteroaryl,IPTS / 200087585.1Attorney Docket No. RTX-003WO and 4-6 membered heterocyclyl; wherein Ci-ealkyl and Ci-ealkoxy may be optionally substituted with one or more substituents independently selected from halogen, hydroxyl, and Ci-3alkoxy; or two geminal R2groups, together with the carbon atom to which they are attached, may be joined together to form a 5-6 membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, Ci-3alkyl, and Ci-3alkoxy;R3is selected from the group consisting of halogen, hydroxyl, -N(RD)(RE), cyano, - NO2, Ci-ealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-ealkoxy, Cs-Cecycloalkyl, -C(=O)NRDRE, - NRD(C=O)RE, -O(C=O)NRDRE, -NRD(C=O)ORE, -NRD(C=O)NRDRE, -(C=O)Ci-C6alkyl, - (C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, S(O)2NRDRE, and - NRDS(0)2 Ci-Cealkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, Ci-Cealkyl, and Ci- Cealkoxy;RAis selected from the group consisting of Ci-ealkyl, C3-6cycloalkyl, -C(O)Ci-ealkyl, - C(O)OCi-6alkyl, -C(O)N(RD)(RE), -CH2C(O)N(RD)(RE), -N(RD)(RE), -S(O)2N(RD)(RE), and - S(O)2Ci-ealkyl, wherein the -C(O)Ci-ealkyl, C3-6cycloalkyl, -C(O)Ci-ealkyl, -C(O)OCi-ealkyl, and -S(O)2Ci-ealkyl may be optionally substituted with one or more substituents independently selected from halogen and hydroxyl;RBis independently selected for each occurrence from the group consisting of hydrogen and Ci-ealkyl;Rcis independently selected for each occurrence from the group consisting of hydrogen, Ci-ealkyl, and -C(O)Ci-ealkyl;RDis selected from the group consisting of hydrogen and Ci-ealkyl;REis selected from the group consisting of hydrogen and Ci-ealkyl; m is 0, 1, 2, 3, or 4; and n is 1, 2, or 3.

2. The compound of claim 1, wherein R1is independently selected for each occurrence from the group consisting of chloro, fluoro, -CH3, and -CF3.IPTS / 200087585.1Attorney Docket No. RTX-003WO3. The compound of claim 1 or 2, wherein L1is selected from the group consisting of -CH2-,- CH(CH3)-, -C(CH3)2-, and -CF2-.

4. The compound of claim 1 or 2, wherein L1is absent.

5. The compound of any one of claims 1-5, wherein ring B is selected from the group consisting of phenyl, pyridyl, oxazolyl, thiazolyl, cyclopropyl, cyclohexyl, and tetrahydropyranyl .

6. The compound of any one of claims 1-5, wherein ring B is phenyl.

7. The compound of claims 1-6, wherein ring A is selected from the group consisting ofwherein * denotes the point of attachment to L1.

8. The compound of any one of claims 1-7, wherein m is 0.

9. The compound of any one of claims 1-8, wherein ring A is selected from the group consisting ofwherein * denotes the point of attachment to L1.IPTS / 200087585.1Attorney Docket No. RTX-003WO10. The compound of any one of claims 1-9, wherein RAis selected from the group consisting of Ci-3alkyl, cyclopropyl, -C(O)Ci-3alkyl, -C(O)OCi-3alkyl, -C(O)N(RD)(RE), - CH2C(O)N(RD)(RE), -S(O)2N(RD)(RE), and -S(O)2Ci-3alkyl, wherein the -C(O)Ci-3alkyl may be optionally substituted with hydroxyl.

11. The compound of any one of claims 1-10, wherein RAis selected from the group consisting of-CHs, -C(H)(CH3)2, cyclopropyl, -C(O)CH3, -C(O)CH2OH, -C(O)OCH3, - CH2C(O)N(RD)(RE), -C(O)N(RD)(RE), -S(O)2CH3, and -SO2NH2.

12. The compound of any one of claims 1-11, wherein RDis hydrogen.

13. The compound of any one of claims 1-12, wherein REis hydrogen or CH3.

14. The compound of any one of claims 1-7, wherein m is 1.

15. The compound of claim 14, wherein ring A is selected from the group consisting ofwherein * denotes the point of attachment to L1.

16. The compound of claim 15, wherein R2is selected from the group consisting of hydroxyl, oxo, cyano, Ci-3alkyl, Ci-3alkoxy, -C(O)Ci-ealkyl, -COOH, -C(O)N(RB)(Rc), - S(O)2N(RD)(RE), -C(O)NHC(O)SO2Ci-6alkyl, -C(O)NHC(O)SO2-phenyl, -NH-SO2-Ci-6alkyl, -PH(O)Ci-ealkyl, 5-6 membered heteroaryl, and -N(RB)(RC), wherein the Ci-3alkyl may be optionally substituted with one or more substituents independently selected from halogen and hydroxyl.

17. The compound of claim 15 or 16, wherein R2is selected from the group consisting of hydroxyl, oxo, -CF3, -OCH3, -C(O)CH3, -COOH, -SO2NH2, -C(O)N(RB)(Rc), - C(O)NHC(O)SO2CH3-C(O)NHC(O)SO2-phenyl, -NH-SO2-CH3, -PH(O)CH2CH3, tetrazolyl, and -N(RB)(RC).

18. The compound of any one of claims 15-17, wherein RBis hydrogen or -CH3.IPTS / 200087585.1Attorney Docket No. RTX-003WO19. The compound of any one of claims 15-18, wherein Rcis hydrogen or -CH3.

20. The compound of any one of claims 1-7, wherein m is 2.

21. The compound of claim 20, wherein ring A is selected from the group consisting ofwherein * denotes the point of attachment to L1.

22. The compound of claim 21, wherein R2is independently selected for each occurrence from the group consisting of hydroxyl, halogen, -CH3, -CH2OH, -C(CH3)2OH, -OCH3, - CH2OCH3, -C(O)NH2, -COOH, -C(O)NH2, and oxetanyl.

23. The compound of any one of claims 1-7, wherein m is 3.

24. The compound of claim 23, wherein ring A is 1wherein * denotes the point of attachment to L .

25. The compound of claim 23 or 24, wherein R2is independently selected for each occurrence from the group consisting of hydroxyl, -CH3, and oxo.

26. The compound of any one of claims 1-7, wherein m is 4.

27. The compound of claim 26, wherein ring A is selected from the group consisting ofwherein * denotes the point of attachment to L1.IPTS / 200087585.1Attorney Docket No. RTX-003WO28. The compound of claim 26 or 27, wherein R2is independently selected for each occurrence from the group consisting of hydroxyl, -CH3, and -COOH.

29. The compound of any one of claims 1-28, wherein R3is chloro.

30. A compound represented by Formula II:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is independently selected for each occurrence from the group consisting of chloro, fluoro, -CH3, and -CF3;L1is selected from the group consisting of -CH2-,-CH(CH3)-, -C(CH3)2-, and -CF2-; or L1is absent;Ring B is selected from the group consisting of cyclohexenyl, cyclopentenyl, phenyl, pyridyl, pyridonyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydropyranyl, and tetrahydrothiopyranyl; wherein if ring B contains a substitutable ring nitrogen atom, that ring nitrogen atom may be optionally substituted with RF;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, oxo, cyano, Ci-ealkyl, Ci-ealkoxy, -C(O)Ci-ealkyl, -COOH, - C(O)N(RB)(RC), -S(O)2N(RD)(RE), -N(RB)(RC), -C(O)NHC(O)SO2Ci-6alkyl, C(O)NHC(O)SO2-phenyl, -NH-SO2-Ci-ealkyl, -PH(O)Ci -ealkyl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl; wherein Ci-ealkyl and Ci-ealkoxy may be optionally substituted with one or more substituents independently selected from halogen, hydroxyl, and Ci-3alkoxy;RFis selected from the group consisting of Ci-3alkyl, cyclopropyl, -C(O)Ci-3alkyl, - C(O)OCi-3alkyl, -C(O)N(RD)(RE), -CH2C(O)N(RD)(RE), -S(O)2N(RD)(RE), and -S(O)2Ci- salkyl; wherein -C(O)Ci-ealkyl, C3-6cycloalkyl, -C(O)Ci-ealkyl, and -C(O)OCi-ealkyl may be optionally substituted with one or more substituents each independently selected from halogen and hydroxyl;IPTS / 200087585.1Attorney Docket No. RTX-003WORGand RHare each independently selected for each occurrence from the group consisting of hydrogen and Ci-ealkyl;R1and RJare each independently selected from the group consisting of hydrogen and Ci-ealkyl; m is 0, 1, 2, 3, or 4; and n is 1, 2, or 3.

31. The compound of claim 30, wherein L1is -CH2- or -CH(CH3)-.

32. The compound of claim 30 or 31, wherein L1is absent.

33. The compound of any one of claims 30-32, wherein ring B is selected from the group consisting of34. The compound of any one of claims 30-33, wherein m is 0.

35. The compound of any one of claims 30-34, wherein ring B is selected from the group consisting of36. The compound of any one of claims 30-34, wherein RFis selected from the group consisting of-CHs, -C(H)(CH3)2, cyclopropyl, -C(O)CH3, -C(O)CH2OH, -C(O)OCH3, - C(O)NH2, -C(O)NH(CH3), -S(O)2CH3, and -SO2NH2.

37. The compound of any one of claims 30-33, wherein m is 1.IPTS / 200087585.1Attorney Docket No. RTX-003WO38. The compound of claim 37, wherein ring B is selected from the group consisting of39. The compound of claim 37 or 38, wherein R2is selected from the group consisting of hydroxyl, oxo, -CF3, -OCH3, -C(O)CH3, -COOH, -SO2NH2, -C(O)NH2, -C(O)NH(CH3), - C(O)N(CH3)2, -C(O)NHC(O)SO2CH3-C(O)NHC(O)SO2-phenyl, -NH-SO2-CH3, - PH(O)CH2CH3, tetrazolyl, NH2, -NHCH3, and -N(CH3)2.

40. The compound of any one of claims 30-33, wherein m is 2.

41. The compound of claim 40, wherein ring B is selected from the group consisting of42. The compound of claim 40 or 42, wherein R2is independently selected for each occurrence from the group consisting of hydroxyl, halogen, -CH3, -CH2OH, -C(CH3)2OH, - OCH3, -CH2OCH3, -C(O)NH2, -COOH, and oxetanyl.

43. The compound of any one of claims 30-33, wherein m is 3.

44. The compound of claim 43, wherein ring B is45. The compound of claim 43 or 44, wherein R2is independently selected for each occurrence from the group consisting of hydroxyl, -CH3, and oxo.

46. The compound of any one of claims 30-33, wherein m is 4.

47. The compound of claim 46, wherein ring B is selected from the group consisting ofIPTS / 200087585.1Attorney Docket No. RTX-003WO48. The compound of claim 46 or 47, wherein R2is independently selected for each occurrence from the group consisting of hydroxyl, -CH3, and -COOH.

49. A compound selected from the group consisting of:IPTS / 200087585.1Attorney Docket No. RTX-003WOIPTS / 200087585.1Attorney Docket No. RTX-003WOIPTS / 200087585.1Attorney Docket No. RTX-003WOIPTS / 200087585.1Attorney Docket No. RTX-003WOIPTS / 200087585.1Attorney Docket No. RTX-003WOIPTS / 200087585.1Attorney Docket NoRTX-003WOIPTS / 200087585.IAttorney Docket No. RTX-003WOor a pharmaceutically acceptable salt and / or a stereoisomer thereof.

50. A compound selected from the group consisting of:IPTS / 200087585.1Attorney Docket No. RTX-003WOor a pharmaceutically acceptable salt and / or a stereoisomer thereof.

51. A pharmaceutical composition comprising a compound of any one of claims 1-50, or a pharmaceutically acceptable salt and / or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

52. A method of treating a condition, disease, or disorder responsive to antagonism of vasopressin receptor 2, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-50, or the pharmaceutical composition of claim 51.

53. A method of treating a kidney disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-50, or the pharmaceutical composition of claim 51.

54. The method of claim 53, wherein the kidney disease or disorder is selected from the group consisting of autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

55. A method of treating autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-50, or the pharmaceutical composition of claim 51.

56. A method of treating hyponatremia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-50, or the pharmaceutical composition of claim 51.

57. The method of claim 56, wherein the patient suffering from one or more of: cirrhosis of the liver, congestive heart failure, and / or syndrome of inappropriate antidiuretic hormone (SIADH).IPTS / 200087585.1Attorney Docket No. RTX-003WO58. A method of treating a cardiovascular disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-50, or the pharmaceutical composition of claim 51.

59. A method of treating congestive heart failure in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-50, or the pharmaceutical composition of claim 51.

60. The method of claim 59, wherein the patient is also suffering from a kidney disease or disorder.IPTS / 200087585.1

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