Compound, pharmaceutical composition, and method for inhibiting the activity of the mct4 monocarboxylate transporter

Abstract

Compounds and compositions useful in the treatment of mct4-mediated diseases, such as inflammatory and proliferative diseases, which have the structure of formula i: are disclosed in this document (i) methods for inhibiting mct4 activity in a human or animal subject are also provided.

Description

COMPOUND, PHARMACEUTICAL COMPOSITION, AND METHOD FOR INHIBITING THE ACTIVITY OF THE MCT4 MONOCARBOXYLATE TRANSPORTER

[001] This application claims the benefit of priority under U.S. Provisional Application No. 62 / 433,113, filed December 12, 2016, the contents of which are incorporated by reference as if written herein in their entirety.

[002] New heterocyclic compositions and compounds are disclosed in this document, and their application as pharmaceutical products for the treatment of diseases. Methods for inhibiting MCT4 activity in a human or animal subject for the treatment of diseases such as cancer are also provided.

[003] Lactic acid export from glycolytic cells is typically mediated by the monocarboxylate transporter MCT4. MCT4 exhibits weak affinity for lactate (Km = 28 mM) coupled with a high turnover rate, allowing the rapid export of large amounts of lactic acid. MCT4 expression is normally limited to highly glycolytic tissues such as white muscle fibers, lymphocytes, astrocytes, and Sertoli cells. Although MCT4 is absent in most normal tissues, its expression is highly upregulated and correlates with poor survival in many cancer indications, including colorectal cancer, glioma, head and neck cancer, triple-negative breast cancer, prostate cancer, KRAS mutant lung cancer, liver cancer, and kidney cancer.

[004] The correlation between MCT4 expression and poor cancer outcome appears to be of significant functional consequence in multiple cancer models. A Petition 870220002363, dated 10 / 01 / 2022, page 5 / 422 2 / 412 Stable expression of MCT4 is highly tumorigenic in a Ras-transformed, respiration-deficient fibroblast xenograft model. Conversely, silencing MCT4 slows or eliminates tumor growth in xenograft models of breast cancer, colorectal cancer, and glioma. MCT4 expression is required for angiogenesis mediated by the inflammatory cytokine IL-8 in xenograft models of breast and colon cancer. MCT4 has also been shown to play important roles in cancer cell migration, invasion, and various aspects of the Warburg effect (e.g., glucose proliferation, extracellular acidification, and lactate secretion).

[005] Inhibition of lactic acid export mediated by MCT4 may be an effective strategy to impair the Warburg effect in cancer. Unfortunately, selective and potent MCT4 inhibitors have not been described. Moderate to weak MCT4 inhibitors are known (e.g., phloretin and α-CN-4-OH-cinnamate); however, these compounds promiscuously inhibit several other transporters, including MCT1.

[006] Thus, there is a need for selective and potent MCT4 inhibitors for use in the treatment or prevention of cancer. DETAILED DESCRIPTION

[007] Innovative pharmaceutical compounds and compositions have been revealed, some of which have been shown to inhibit MCT4, along with methods for synthesizing and using the compounds, including methods for treating MCT4-mediated diseases in a patient by administering the compounds. Petition 870220002363, dated 10 / 01 / 2022, page 6 / 422 3 / 412

[008] A compound of structural formula I is provided (I)

[009] or a salt thereof, where:

[010] A1, A2 and A3 are independently chosen from N and C, where at least one of A1, A2 and A3 is N;

[011] L is chosen from a linkage, methylene and ethylene;

[012] W is chosen from is H or zero, or is chosen from alkenylamino, alkyl, aminoalkenyl and aminoalkyl, any of which is optionally substituted by one to three R1 groups;

[014] Y is chosen from alkenyl, alkenylamino, alkyl, aminoalkenyl, aminoalkyl, aryl, arylmethyl, arylamino, aryloxy, cycloalkyl, Petition 870220002363, dated 10 / 01 / 2022, p. 7 / 422 4 / 412 heterocycloalkyl and heteroaryl, any of which is optionally replaced by one to three R2 groups, or

[015] X and Y together with the atom to which they are attached may form an aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring, any of which is optionally substituted by one to three R7 groups; and

[016] Z is chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, any of which is optionally substituted by one to three R3 groups;

[017] each R1 is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, amino, carboxamide, sulfonamide, halo, cyano, hydroxy, cycloalkyl, aryl, heteroaryl;

[018] each R2 is independently chosen from alkyl, alkenyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy, amino, aminoalkyl, carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or

[019] two R2s, together with the intervening atoms, form a 5 to 7 membered cycloalkyl or heterocycloalkyl ring;

[020] each R3 is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, amino, aminoalkyl, carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl and is optionally replaced by one to three R8 groups, or Petition 870220002363, dated 10 / 01 / 2022, p. 8 / 422 5 / 412

[021] two R3, together with the intervening atoms, form a 5 to 7 membered cycloalkyl or heterocycloalkyl ring;

[022] R4 and R5 are independently selected from H and C1-C6 alkyl, wherein R4 and R5 together comprise no more than 6 carbons, or

[023] R4 and R5, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl ring with 3 to 7 members;

[024] R6 is chosen from H and C1-C4 alkyl;

[025] each R7 is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, amino, carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, aryl and heteroaryl; and

[026] each R8 is independently chosen from cyano, halo, hydroxy and oxo.

[027] Certain compounds disclosed herein possess useful MCT4 inhibitory activity and can be used in the treatment or prophylaxis of a disease or condition in which MCT4 plays an active role. Thus, in a broad aspect, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods for producing or using the compounds and compositions. Certain embodiments provide methods for inhibiting MCT4. Other embodiments provide methods for treating an MCT4-mediated disorder in a patient who needs such treatment, comprising administering to said patient a therapeutically effective amount of a compound or composition according to the present embodiment. Petition 870220002363, dated 10 / 01 / 2022, page 9 / 422 6 / 412 invention. The use of certain compounds disclosed herein is also provided for use in the manufacture of a medicament for the treatment of a disease or condition relieved by MCT4 inhibition.

[028] In certain embodiments, X is chosen from alkenylamino, alkyl, aminoalkenyl, aminoalkyl and H; and Y is chosen from alkenyl, alkenylamino, alkyl, aminoalkenyl, aminoalkyl, aryl, cycloalkyl and heteroaryl.

[029] In certain embodiments, X and Y together with the atoms to which they are attached can form an aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring.

[030] In certain modalities, exactly two of A1, A2 and A3 are N.

[031] In certain modalities, exactly one of A1, A2 and A3 is N.

[032] In certain modalities, A1 and A2 are C; and A3 is N.

[033] In certain embodiments, X is hydrogen.

[034] In certain of the O , O , O dvoy^NzS°2CH3 R5R4H .

[035] In certain of the θ and θ . modes, W is chosen OO >^οΧΛνη2 R5 R4 , R5 R4 and modes, W is chosen Petition 870220002363, dated 10 / 01 / 2022, p. 10 / 422 7 / 412 O »°>AoR6

[036] In certain modes, W is R5R4 .

[037] In certain embodiments, Y is chosen from aryl and heteroaryl, either of which is optionally replaced by one to three R2 groups.

[038] In certain embodiments, Y is chosen from phenyl, thienyl, thiazolyl, quinolinyl, isoquinolinyl, cinolinyl, indazolyl and indolyl.

[039] In certain embodiments, Y is chosen from quinolinyl, isoquinolinyl, cinolinyl, indazolyl and indol.

[040] In certain embodiments, Y is chosen from among phenyl, thienyl and thiazolyl.

[041] In certain embodiments, Z is chosen from among phenyl, pyridinyl, quinolinyl, isoquinolinyl, cinolinyl, indazolyl and indol.

[042] In certain embodiments, Z is chosen from phenyl and pyridinyl.

[043] In certain embodiments, each R2 is independently selected from among alkenyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halo, heteroaryl and haloalkyl.

[044] In certain embodiments, each R2 is independently chosen from among alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo and haloalkyl.

[045] In certain embodiments, two R2s, together with the intervening atoms, form a 5 to 7 membered heterocycloalkyl or cycloalkyl ring. Petition 870220002363, dated 10 / 01 / 2022, p. 11 / 422 8 / 412

[046] In certain embodiments, each R3 is independently chosen from among alkenyl, alkoxy, alkyl, aryl, halo, heteroaryl and haloalkyl.

[047] In certain embodiments, each R3 is independently chosen from among alkoxy, alkyl, aryl and heteroaryl.

[048] In certain embodiments, two R3s, together with the intervening atoms, form a 5- to 7-membered heterocycloalkyl or cycloalkyl ring.

[049] In certain embodiments, each R3 is an alkoxy.

[050] In certain embodiments, each R3 is a methoxy.

[051] In certain embodiments, each R3 is a halo.

[052] In certain embodiments, each R3 is independently selected from F, Br, and I.

[053] In certain embodiments, each R3 is F.

[054] In certain embodiments, R4 and R5 are, independently, chosen from among H and C1-C2 alkyl.

[055] In certain embodiments, R4 and R5 are independently chosen from H and methyl.

[056] In certain embodiments, R4 and R5, together with the atoms to which they are attached, form a heterocycloalkyl or cycloalkyl ring with 3 to 7 members.

[057] In certain embodiments, R6 is chosen from H and C1-C2 alkyl.

[058] In certain embodiments, R6 is chosen from H and methyl.

[059] In certain embodiments, each R7 is independently selected from alkyl, alkoxy, haloalkyl, haloalkoxy, amino, carboxamide, halo, cyano, hydroxy, cycloalkyl, aryl and heteroaryl. Petition 870220002363, dated 10 / 01 / 2022, p. 12 / 422 9 / 412

[060] In certain embodiments, each R7 is independently selected from among alkyl and alkoxy.

[061]

[062] In certain embodiments, the compounds have the structural formula Ia: A6 <J,A8 XA7(Ia) N; methylene; following

[063] or

[064] A5

[065] A6

[066] and combinations:

[067] A7

[068] A7

[069] in

[070] L

[071] W A7 is C is N which is a salt or tautomer thereof, where: is chosen from CX and N; is chosen from between CY and N; A8 A8 is A8 are chosen from among the NH, or N; at least one of A5, A6 and A7 is chosen from a link and OH OH or6 RóR4 is chosen from among and RO RO H Petition 870220002363, dated 10 / 01 / 2022, p. 13 / 422 10 / 412

[072] X is H, or is chosen from alkenylamino, alkyl, aminoalkenyl and aminoalkyl, any of which is optionally replaced by one to three R1 groups;

[073] Y is chosen from alkenyl, alkenylamino, alkyl, aminoalkenyl, aminoalkyl, aryl, cycloalkyl and heteroaryl, any of which is optionally substituted by one to three R2 groups, or

[074] X and Y together with the atom to which they are attached may form an aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring, any of which is optionally substituted by one to three R7 groups; and

[075] Z is chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, any of which is optionally replaced by one to three R3 groups;

[076] each R1 is independently chosen from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, amino, carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, aryl, heteroaryl;

[077] each R2 is independently chosen from alkyl, alkenyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, amino, carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, aryl and heteroaryl;

[078] each R3 is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, amino, carboxamide, sulfonamide, halo, cyano, hydroxy, cycloalkyl, aryl and heteroaryl; Petition 870220002363, dated 10 / 01 / 2022, p. 14 / 422 11 / 412

[079] R4 and R5 are independently selected from H and C1-C6 alkyl groups, wherein R4 and R5 together comprise no more than 6 carbons;

[080] R6 is chosen from among H and C1-C4 alkyl; and

[081] each R7 is independently selected from among alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, aminocarboxamido, sulfonamido, halocyano, hydroxycycloalkyl, aryl and heteroaryl.

[082] In certain forms, the compounds have the Structural formula II: (II)

[083] or a salt thereof, where:

[084] chosen from a link and methylene; THE

[086] Y chosen THE among arylamino aryloxy NH2r5r4 is chosen from aryl, arylmethylcycloalkyl, heterocycloalkyl, and heteroaryl, any of which is optionally substituted by one to three groups. R2;

[087] each of which is chosen from aryl and heteroaryl optionally replaced by one to three R3 groups; Petition 870220002363, dated 10 / 01 / 2022, p. 15 / 422 12 / 412

[088] each R2 is independently chosen from alkyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy, amino, aminoalkyl, carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or

[089] two R2s, together with the intervening atoms, form a 5 to 7 membered cycloalkyl or heterocycloalkyl ring;

[090] each R3 is independently chosen from alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, amino, aminoalkyl, carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl and is optionally replaced by one to three R8 groups, or

[091] two R3, together with the intervening atoms, form a 5 to 7 membered cycloalkyl or heterocycloalkyl ring;

[092] R4 and R5 are independently selected from H and C1-C6 alkyl, wherein R4 and R5 together comprise no more than 6 carbons and wherein at least one of R4 and R5 is C1-C6 alkyl, or

[093] R4 and R5, together with the atoms to which they are attached, form a 3 to 7 membered heterocycloalkyl or cycloalkyl ring;

[094] R6 is chosen from H and C1-C4 alkyl; and

[095] each R8 is independently chosen from cyano, halo, hydroxy and oxo.

[096] In certain forms of Structural Formula II,

[097] L is a connection; and Petition 870220002363, dated 10 / 01 / 2022, p. 16 / 422 13 / 412

[098] each R2 is chosen from among alkenyl, C2C6alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halo, heteroaryl and haloalkyl.

[099] In certain forms of Structural Formula II,

[0100] Z is chosen from aryl and heteroaryl, each of which is replaced by one to three R3 groups;

[0101] each R2 is chosen from among alkenyl, C2C6 alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, heteroaryl and haloalkyl; and

[0102] each R3 is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, amino, carboxamide, sulfonamide, cycloalkyl, aryl and heteroaryl.

[0103] In certain forms of Structural Formula II,

[0104] Y is heteroaryl and is replaced by one to three R2 groups; and

[0105] each R2 is chosen from alkenyl, C2C6alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halo, heteroaryl and haloalkyl.

[0106] In certain forms of Structural Formula II,

[0107] Y is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl and oxazolyl, any of which is replaced by one to three R2 groups; and

[0108] each R2 is chosen from among alkenyl, C2C6alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halo, heteroaryl and haloalkyl. Petition 870220002363, dated 10 / 01 / 2022, p. 17 / 422 14 / 412

[0109] In certain embodiments of structural formula II, at least one of R4 and R5 is H.

[0110] In certain embodiments of structural formula II, exactly one of R4 and R5 is H.

[0111] In certain forms, the compounds have the Structural formula III: RQOR6 R R4 R2b N 1l'z (III)

[0112] or a salt thereof, where:

[0113] L is chosen from a linkage and methylene;

[0114] Z is chosen from aryl and heteroaryl groups, each of which is optionally replaced by one or two R3 groups;

[0115] R2a and R2b are independently selected from H, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, halo, cycloalkyl and heterocycloalkyl;

[0116] each R3 is independently chosen from alkyl, alkoxy, haloalkyl, haloalkoxy, amino, aminoalkyl, carboxamide, halo, cyano, hydroxy and cycloalkyl and is optionally replaced by one or two R8 groups;

[0117] R4 and R5 are independently selected from H and C1-C6 alkyl, wherein R4 and R5 together comprise no more than 6 carbons and wherein at least one of R4 and R5 is C1-C6 alkyl, or Petition 870220002363, dated 10 / 01 / 2022, p. 18 / 422 15 / 412

[0118] R4 and R5, together with the atoms to which they are attached, form a 3- to 7-membered heterocycloalkyl or cycloalkyl ring;

[0119] R6 is chosen from H and methyl; and

[0120] each R8 is independently chosen from cyano, halo, hydroxyl and oxo.

[0121] In certain forms of Structural Formula III,

[0122] Z is chosen from quinolinyl, isoquinolinyl, cinolinyl, indazolyl and indolyl, any of which is optionally replaced by one to three R3 groups; and

[0123] each R3 is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, amino, carboxamide, sulfonamide, halo, cyano, hydroxy, cycloalkyl, aryl and heteroaryl.

[0124] In certain embodiments of Structural Formula III, Z is chosen from alkyl, cycloalkyl and heterocycloalkyl, any of which is optionally substituted by one to three R3 groups;

[0125] In certain embodiments of Structural Formula III, R2 is chosen from among alkenyl, C2-C6 alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halo, heteroaryl and haloalkyl.

[0126] In certain embodiments of Structural Formula III, R2 is selected from alkoxy, alkyl, halo, haloalkyl and haloalkoxy.

[0127] In certain embodiments of Structural Formula III, each R3 is independently chosen from Petition 870220002363, dated 10 / 01 / 2022, p. 19 / 422 16 / 412 alkenyl, alkoxy, alkyl, amino, aryl, halo, heteroaryl and haloalkyl; and

[0128] In certain embodiments of Structural Formula III, Z is chosen from alkyl, cycloalkyl and heterocycloalkyl, any of which is optionally substituted by one to three R3 groups;

[0129] In certain forms of Structural Formula III,

[0130] L is a connection;

[0131] Z is chosen from aryl and heteroaryl, each of which is replaced by one to three R3 groups; and

[0132] each R3 is chosen independently among alkenyl, alkoxy, alkyl, amino, fluorine, bromine and iodine.

[0133] In certain embodiments of Structural Formula III,

[0134]

[0135] L is methylene; Z is chosen from aryl and heteroaryl, each of which is replaced by one to three R3 groups; and

[0136] each R3 is independently chosen from among alkenyl, C2-C6 alkoxy, C4-C8 alkyl, aryl and iodo.

[0137] In certain embodiments of Structural Formula III,

[0138] L is a bond; and

[0139] Z is chosen from pyridin-3-yl and pyridin-4-yl and is optionally replaced by one to three R3 groups.

[0140] In certain embodiments of Structural Formula III,

[0141] L ​​is methylene; and Petition 870220002363, dated 10 / 01 / 2022, p. 20 / 422 17 / 412

[0142] Z is pyridyl and is optionally replaced by one to three R3 groups.

[0143] In certain embodiments of Structural Formula III,

[0144] L is methylene; and

[0145] Z is pyridyl and is optionally replaced by two or three R3 groups.

[0146] In certain forms, the compounds have the Structural formula IV: (IV)

[0147] or a salt thereof, where:

[0148] L is chosen from a linkage and methylene;

[0149] W is chosen from chosen and among alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, any of which is optionally replaced by one to three R3 groups;

[0151] each R3 is independently chosen from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, Petition 870220002363, dated 10 / 01 / 2022, p. 21 / 422 18 / 412 amino carboxamido sulfonamido halo cyano hydroxy cycloalkyl, aryl and heteroaryl;

[0152] R4 and R5 are independently chosen from H and C1-C6 alkyl groups, wherein R4 and R5 together comprise no more than 6 carbons;

[0153] R6 is chosen from H and C1-C4 alkyl;

[0154] n is selected from and 3.

[0155] In certain forms, the compounds have Structural formula

[0156] V: (V) or a salt thereof, where:

[0157] chosen from a methylene linkage;

[0158] chosen from phenyl thienyl furyl, thiazolyl oxazolyl any of which is optionally replaced by one or two R2 groups or

[0159] each R2 is independently chosen from among alkoxy alkylthio haloalkoxy cycloalkoxy cycloalkylmethoxy heterocycloalkylmethoxy and halo;

[0160] R3a is chosen from among H alkoxy haloalkoxy, cycloalkoxy amino and halo;

[0161] R4 and R5 are independently chosen from C1-C3 alkyl, or Petition 870220002363, dated 10 / 01 / 2022, p. 22 / 422 19 / 412

[0162] R4 and R5, together with the atoms to which they are attached, form a 3- to 7-membered heterocycloalkyl or cycloalkyl ring; and

[0163] R6 is chosen from H and C1-C4 alkyl.

[0164] In certain embodiments, the compounds have structural formula VI: in which:

[0166] L is chosen from a linkage and methylene;

[0167] R2a is chosen from among alkoxy, alkylthio, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy and halo;

[0168] R3a is chosen from H, alkoxy, haloalkoxy, cycloalkoxy, amino and halo;

[0169] R4 and R5 are independently selected from C1-C3 alkyl, or

[0170] R4 and R5, together with the atoms to which are linked, forming a heterocycloalkyl or cycloalkyl ring with 3 to 7 members; and

[0171] R6 is chosen from H and C1-C4 alkyl.

[0172] In certain embodiments, the compounds have structural formula VII: Petition 870220002363, dated 10 / 01 / 2022, p. 23 / 422 20 / 412 yAQnYN I 'z(VII)

[0173] or a salt thereof, where:

[0174] Y is chosen from aryl, arylmethyl, arylamino, aryloxy, cycloalkyl, heterocycloalkyl and heteroaryl, any of which is optionally substituted by one to three R2 groups, or

[0175] Z is chosen from aryl and heteroaryl, each of which is optionally replaced by one to three R3 groups;

[0176] each R2 is independently chosen from alkyl, alkenyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy, amino, aminoalkyl, carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or

[0177] two R2s, together with the intervening atoms, form a 5 to 7 membered cycloalkyl or heterocycloalkyl ring;

[0178] each R3 is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, amino, aminoalkyl, carboxamide, sulfonamide, halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl and is optionally replaced by one to three R8 groups, or Petition 870220002363, dated 10 / 01 / 2022, p. 24 / 422 21 / 412

[0179] two R3, together with the intervening atoms, form a 5 to 7 membered cycloalkyl or heterocycloalkyl ring;

[0180] R4 and R5 are independently selected from C1-C6 alkyl groups, wherein exactly one of R4 and R5 is methyl;

[0181] R6 is chosen from H and C1-C4 alkyl; and

[0182] each R8 is independently chosen from cyano, halo, hydroxyl and oxo.

[0183] In certain forms, the compounds have the Structural formula VII: (VII)

[0184] or a salt thereof, where:

[0185] L is chosen from a linkage and methylene;

[0186] is chosen from

[0187] Y is chosen from alkenyl, alkenylamino, alkyl, aminoalkenyl, aminoalkyl, aryl, Petition 870220002363, dated 10 / 01 / 2022, p. 25 / 422 22 / 412 arylmethyl, arylamino, aryloxy, cycloalkyl, heterocycloalkyl and heteroaryl, any of which is optionally substituted by one to three R2 groups;

[0188] each R2 is independently chosen from alkyl, alkenyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy, amino, aminoalkyl, carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

[0189] n is 1 or 2 (forming an azetidin-1-yl or pyrrolidin-1-yl);

[0190] R4e R5 are independently selected from C1-C3 alkyl; and

[0191] R6 is chosen from H and C1-C4 alkyl.

[0192] In certain embodiments of Structural Formula VII, Y is chosen from aryl and heteroaryl, each of which is optionally replaced by one to three R2 groups.

[0193] In certain embodiments of Structural Formula VII, each R2 is independently chosen from among alkoxy, cycloalkoxy, haloalkoxy, alkyl, halo, and haloalkyl.

[0194] In certain Formula 1 categories THE Structural VII W is k5k4.

[0195] In certain embodiments of structural Formula VII, n is 1, forming azetidin-1-yl.

[0196] In certain embodiments of Structural Formula VII, L is a link. Petition 870220002363, dated 10 / 01 / 2022, p. 26 / 422 23 / 412

[0197] In certain forms, the compounds have the Structural formula VIII: (VIII)

[0198] or a salt thereof, where:

[0199] L is chosen from a linkage and methylene;

[0200] Y is chosen from phenyl, indazolyl, tienyl, indazolyl and indolyl, any of which is optionally replaced by one or two R2 groups;

[0201] n is 1 or 2 (forming an azetidin-1-yl or pyrrolidin-1-yl);

[0202] each R2 is independently selected from alkyl, alkoxy, alkylthio, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy and halo;

[0203] R4e R5 are independently selected from C1-C3 alkyl; and

[0204] R6 is chosen from H and C1-C4 alkyl.

[0205] In certain embodiments of Structural Formula VIII, Y is chosen from phenyl and indazolyl, each of which is optionally replaced by one or two R2 groups.

[0206] In certain embodiments of Structural Formula VIII, each R2 is independently chosen from among alkoxy, cycloalkoxy, haloalkoxy, alkyl, halo, and haloalkyl. Petition 870220002363, dated 10 / 01 / 2022, p. 27 / 422 24 / 412

[0207] In certain embodiments of structural Formula VIII, n is 1, forming azetidin-1-yl.

[0208] In certain embodiments of structural formula VIII, L is a bond.

[0209] In certain embodiments of Structural Formula VIII, Y is phenyl substituted by one or two R2 groups independently chosen from among alkoxy, cycloalkoxy, haloalkoxy, alkyl, halo and haloalkyl.

[0210] In certain embodiments of Structural Formula VIII, each R2 is independently chosen from C1-C4 alkoxy, cyclopropoxy, cyclobutoxy and C1-C3 alkyl.

[0211] In certain embodiments of structural Formula VIII, Y is indazolyl substituted by an R2 group chosen from methyl, ethyl, and propyl.

[0212] In certain embodiments of structural Formula VIII, Y is chosen from among: 7J 2, / o (DN) > ·

[0213] R2c is chosen from C1-C4alkoxy and C1- C4cycloalkoxy;

[0214] R2d is chosen from null and C1-C4alkoxy; and

[0215] R2e is C1-C4 alkyl.

[0216] In certain embodiments, the compounds have the Structural formula IX: Petition 870220002363, dated 10 / 01 / 2022, p. 28 / 422 25 / 412 methylene; or6 (IX)

[0217] or a salt thereof, where:

[0218] L is chosen from a link and

[0219] chosen from NH2 Y R5 R4

[0220] is chosen from aryl, arylmethyl, arylamino, aryloxy, cycloalkyl, heterocycloalkyl and heteroaryl, any of which is optionally substituted by one to three R2 groups;

[0221] Z is chosen from aryl and heteroaryl, each of which is optionally replaced by one to three R3 groups;

[0222] each R2 is independently chosen from alkyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy, amino, aminoalkyl, carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

[0223] R4e R5são, independente, escolhidos entre C1-C3alkyl; e

[0224] R6 is chosen from H and C1-C4 alkyl. Petition 870220002363, dated 10 / 01 / 2022, p. 29 / 422 26 / 412

[0225] In certain embodiments of Structural Formula IX, Y is chosen from aryl and heteroaryl, each of which is optionally replaced by one to three R2 groups.

[0226] In certain embodiments of Structural Formula IX, each R2 is independently chosen from among alkoxy, cycloalkoxy, haloalkoxy, alkyl, halo, and haloalkyl. structural

[0227] IX, W

[0228] is In certain embodiments of the Formula Structural Formula IX, L

[0229] is a connection. In certain embodiments of the Formula Structural Formula IX, Y is phenyl substituted by one or two R2 groups independently chosen from alkoxy, cycloalkoxy, haloalkoxy, alkyl, halo and haloalkyl.

[0230] In certain embodiments of Structural Formula IX, each R2 is independently chosen from C1-C4 alkoxy, cyclopropoxy, cyclobutoxy and C1-C3 alkyl.

[0231] Structural formula R2e 1 N. ...

[0232] In certain embodiments, the compounds have X: WN 1 Z (X) or a salt thereof, where: Petition 870220002363, dated 10 / 01 / 2022, p. 30 / 422 27 / 412

[0233] W is chosen from OH

[0234] R2eé C1-C4 alkyl;

[0235] L is chosen from a linkage and methylene;

[0236] Z is chosen from aryl and heteroaryl groups, each of which is optionally replaced by one to three R3 groups;

[0237] each R3 is independently chosen from alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, amino, aminoalkyl, carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl and is optionally replaced by one to three R8 groups, or

[0238] two R3s, together with the intervening atoms, form a 5 to 7 membered cycloalkyl or heterocycloalkyl ring;

[0239] R4e R5são, independente, escolhidos entre C1-C3alkyla;

[0240] R6 is chosen from H and C1-C4 alkyl; and

[0241] each R8 is independently chosen from cyano, halo, hydroxyl and oxo. Petition 870220002363, dated 10 / 01 / 2022, p. 31 / 422 28 / 412

[0242] In certain Formula 1 categories Ο ^°X^OR6structural X, W is R5R4

[0243] In certain embodiments of the structural formula X, L is a bond.

[0244] In certain embodiments of structural formula X, Z is chosen from phenyl and indazolyl, each of which is optionally replaced by one to three R3 groups.

[0245] In certain embodiments of the structural formula X, Z is chosen from:

[0246] n is 1 or 2 (forming an azetidin-1-yl or pyrrolidin-1-yl);

[0247] R4e R5são, independente, escolhidos entre C1-C3alkyla;

[0248] R6 is chosen from H and C1-C4 alkyl; and

[0249] R9 is chosen from halo, amino and C1C4alkoxy.

[0250] In certain embodiments of structural formula X, R9 is chosen from among chlorine, dimethylamino and ethoxy.

[0251] In certain embodiments of structural formula X, R9 is chosen from chlorine and ethoxy.

[0252] In certain embodiments of the structural formula X, n is 1, forming azetidin-1-yl. Petition 870220002363, dated 10 / 01 / 2022, p. 32 / 422 29 / 412

[0253] In certain forms, the compounds have the Structural formula XI: in which: «Ã 'Λ / / 0H

[0255] W is chosen from OH, “—J ,SO2CH3

[0256] n is 1, 2 or 3 (forming a cyclopropyl, cyclobutyl or cyclopentyl);

[0257] L is chosen from a linkage and methylene;

[0258] Z is chosen from aryl and heteroaryl, each of which is optionally replaced by one to three R3 groups;

[0259] each R3 is independently selected from alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, amino, aminoalkyl, carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl and is optionally replaced by one to three R8 groups, or

[0260] two R3s, together with the intervening atoms, form a 5 to 7 membered cycloalkyl or heterocycloalkyl ring; Petition 870220002363, dated 10 / 01 / 2022, p. 33 / 422 30 / 412

[0261] R4e R5são, independente, escolhidos entre C1-C3alkyla;

[0262] R6 is chosen from H and C1-C4 alkyl; and

[0263] from cyano, halo, each R8 is hydroxy and oxo. independently chosen

[0264] structural XI, W is In certain embodiments of the Formula

[0265] structural XI, L is In certain embodiments of the Formula Structurally, XI, Z is chosen from phenyl and indazolyl, each of which is optionally substituted by one to three R3 groups.

[0267] In certain embodiments of the structural formula XI, Z is chosen from:

[0268]

[0269] pirrolidin-1-ila);

[0270] R4e R5são, independente, escolhidos entre C1-C3alkyla;

[0271] R6 is chosen from H and C1-C4 alkyl; and

[0272] R9 is chosen from halo, amino and C1C4alkoxy.

[0273] In certain embodiments of structural formula XI, R9 is chosen from among chlorine, dimethylamino and ethoxy. Petition 870220002363, dated 10 / 01 / 2022, p. 34 / 422 31 / 412

[0274] In certain modalities of Structural formula XI, R9 chosen from chlorine and ethoxy.

[0275] In certain modalities of Structural formula XI, n 1, forming azetidin-1-yl.

[0276] In certain forms, the compounds have the Structural formula II: methylene; OH (II)

[0277]

[0278]

[0279] OH or a salt thereof, where: is chosen from among is chosen from OR6 RüR4 NH2 bond and OH SO2CH3 chosen from: and

[0280] Y Z is chosen from among:

[0282] Petition 870220002363, dated 10 / 01 / 2022, p. 35 / 422 32 / 412

[0283] n is 1 or 2 (forming an azetidin-1-yl or pyrrolidin-1-yl);

[0284] R4e R5 are independently selected from C1-C3 alkyl;

[0285] R6 is chosen from H and C1-C4 alkyl; and

[0286] R9 is chosen from halo and C1-C4 alkoxy.

[0287] In certain embodiments of the Formula THE Rk R4 In structural Formula II, W is r5 r4.

[0288] In certain embodiments of Structural Formula II, R9 is chosen from chlorine and ethoxy.

[0289] In certain embodiments of Structural Formula II, L is a bond.

[0290] In certain embodiments of Structural Formula II Structural II: II 1

[0291] Y is R2d ;

[0292] R2c is chosen from C1-C4alkoxy and C1-C4cycloalkoxy; and

[0293] R2d is chosen from null and C1-C4alkoxy.

[0294] In certain embodiments of Structural Formula II:

[0295] R2c is chosen from methoxy, methylpropoxy, cyclopropoxy, and cyclobutoxy; and

[0296] R2 is chosen from null and methoxy.

[0297] In certain forms of Structural Formula II: Petition 870220002363, dated 10 / 01 / 2022, p. 36 / 422 33 / 412

[0298] R2® ú JY é ; and

[0299] R2e is C1-C4 alkyl.

[0300] In certain embodiments of Structural Formula II, R2e is chosen from ethyl and propyl.

[0301] In certain embodiments of Formula -Vu structural II, Z is \ / Π .

[0302] In certain Formula 1 categories structural II, n is 1, forming azetidin-1-yl.

[0303] In certain embodiments of the structural Formula II, Z is II / 7.

[0304] In certain embodiments of the structural Formula II, Z is R9D.

[0305] In certain embodiments of the Formula Structural II, R9 is chosen from among chlorine and ethoxy.

[0306] There are also options provided in which any of the above options can be combined with any one or more of these options, provided that the combination is not mutually exclusive.

[0307] As used in this document, two modalities are mutually exclusive when one is defined as having something that is different from the other. For example, a modality in which two groups combine to form a Petition 870220002363, dated 10 / 01 / 2022, p. 37 / 422 34 / 412 cycloalkyl is mutually exclusive with respect to an embodiment in which one group is ethyl and the other group is hydrogen. Similarly, an embodiment in which one group is CH2 is mutually exclusive with respect to an embodiment in which the same group is NH.

[0308] A compound chosen from among the Examples disclosed in this document is also provided.

[0309] The present invention also relates to a method for inhibiting at least one function of MCT4 comprising the step of bringing MCT4 into contact with a compound, as described herein. Cell phenotype, cell proliferation, MCT4 activity, alteration in biochemical outcome produced by active MCT4, MCT4 expression or MCT4 binding to a natural binding partner can be monitored. Such methods may be disease treatment modes, biological assays, cell assays, biochemical assays or the like.

[0310] Also provided herein is a method of treating an MCT4-mediated disease comprising administering a therapeutically effective amount of a compound as disclosed herein, or a salt thereof, to a patient in need thereof.

[0311] In certain modalities, the disease is chosen from among proliferative inflammatory diseases.

[0312] In certain modalities, the disease is a metabolic disease.

[0313] In certain modalities, the said metabolic disease is chosen from among metabolic syndrome, diabetes, dyslipidemia, fatty liver disease, non-alcoholic steatohepatitis, obesity and insulin resistance. Petition 870220002363, dated 10 / 01 / 2022, p. 38 / 422 35 / 412

[0314] In certain forms, what is called diabetes is type II diabetes.

[0315] In certain conditions, the so-called dyslipidemia is hyperlipidemia.

[0316] A method is further provided for achieving an effect in a patient comprising administering a therapeutically effective amount of a compound, as disclosed above, to a patient, wherein the effect is selected from the group consisting of triglyceride reduction, cholesterol reduction and hemoglobin A1c reduction.

[0317] It is additionally provided the method, as disclosed above, in which said cholesterol is chosen from among LDL and VLDL cholesterol.

[0318] The method is further provided, as disclosed above, in which said triglycerides are selected from plasma triglycerides and liver triglycerides.

[0319] A compound as disclosed herein is also provided for use as a medicament.

[0320] A compound as disclosed herein is also provided herein for use as a medicament for the treatment of an MCT4-mediated disease.

[0321] The use of a compound as disclosed herein as a medicine is also provided.

[0322] The use of a compound as disclosed herein as a medicament for the treatment of an MCT4-mediated disease is also provided. Petition 870220002363, dated 10 / 01 / 2022, page 39 / 422 36 / 412

[0323] A compound as disclosed herein is also provided for use in the manufacture of a medicament for the treatment of an MCT4-mediated disease.

[0324] The use of a compound as disclosed herein for the treatment of an MCT4-mediated disease is also provided.

[0325] Also provided herein is a method for inhibiting MCT4 comprising contacting MCT4 with a compound as disclosed herein or a salt thereof.

[0326] Also provided herein is a method for achieving an effect in a patient comprising administering a therapeutically effective amount of a compound as disclosed herein, or a salt thereof, to a patient, wherein the effect is chosen from enhanced cognition.

[0327] In certain modalities, MCT4-mediated disease is chosen from among proliferative inflammatory diseases.

[0328] A method is also provided for modulating an MCT4-mediated function in an individual comprising administering a therapeutically effective amount of a compound as disclosed herein.

[0329] A pharmaceutical composition comprising a compound as disclosed herein, together with a pharmaceutically acceptable carrier, is also provided.

[0330] In certain embodiments, the pharmaceutical composition is formulated for oral administration. Petition 870220002363, dated 10 / 01 / 2022, p. 40 / 422 37 / 412

[0331] In certain embodiments, the oral pharmaceutical composition is chosen from between a tablet and a capsule. Abbreviations and Definitions

[0332] To facilitate understanding of the revelation, several terms and abbreviations, as used herein, are defined below as set forth below:

[0333] By introducing elements of the present disclosure or of the preferred embodiment (or embodiments) thereof, the articles a / an, a / an, the / the referred / referred to are intended to mean that there is one or more of the elements. The terms comprise, include and have are intended to be inclusive and mean that there may be additional elements beyond the elements mentioned.

[0334] The term and / or, when used in a list of two or more items, means that any one of the listed items may be used alone or in combination with any one or more of the listed items. For example, the expression A and / or B is intended to mean either or both of A and B, that is, A alone, B alone, or A and B in combination. The expression A, B and / or C is intended to mean A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination, or A, B and C in combination.

[0335] When ranges of values ​​are revealed, and the notation n1...to n2 or between n1...and n2 is used, where n1 and n2 are the numbers, then, unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the terminal values. Petition 870220002363, dated 10 / 01 / 2022, p. 41 / 422 38 / 412 For example, the range of 2 to 6 carbons is intended to include two, three, four, five, and six carbons, since carbons are presented in whole units. By way of example, the range of 1 to 3 μM (micromolar), which is intended to include 1 μM, 3 μM, and everything in between, is compared to any number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0336] The term about, as used in this document, is intended to qualify the numerical values ​​that it modifies, denoting such value as a variable within a margin of error. When no particular margin of error, such as a standard deviation from a given mean value in a graph or data table, is quoted, the term about should be understood as meaning the range that would encompass the quoted value and the range that would be included by rounding up or down to that figure as well, taking into account significant figures.

[0337] The term acyl, as used in this document, alone or in combination, refers to a carbonyl group bonded to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other chemical moiety in which the atom bonded to the carbonyl group is carbon. An acetyl group refers to a -C(O)CH3 group. An alkylcarbonyl or alkanoyl group refers to an alkyl group bonded to the original molecular chemical moiety via a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aroyl.

[0338] The term alkenyl, as used in this document, alone or in combination, refers to a Petition 870220002363, dated 10 / 01 / 2022, p. 42 / 422 39 / 412 straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In some embodiments, said alkenyl group will comprise from 2 to 6 carbon atoms. The term alkenylene refers to a carbon-carbon double bond system linked in two or more positions, such as ethenylene [(-CH=CH), (-C::C-)]. Examples of suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwise specified, the term alkenyl may include alkenylene groups.

[0339] The term alkoxy, as used in this document, alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

[0340] The term alkyl, as used herein, alone or in combination, refers to a straight-chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, said alkyl will comprise from 1 to 10 carbon atoms. In other embodiments, said alkyl will comprise from 1 to 8 carbon atoms. Alkyl groups may be optionally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, nonyl and the like. The term alkylene, as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight-chain or branched-chain hydrocarbon linked in Petition 870220002363, dated 10 / 01 / 2022, pp. 43 / 422 40 / 412 two or more positions, such as methylene (-CH2-) and ethylene (CH2CH2-). Unless otherwise specified, the term alkyl may include alkylene groups.

[0341] The term alkylamino, as used herein, alone or in combination, refers to an alkyl group linked to the original molecular chemical portion via an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,Netylmethylamino and the like.

[0342] The term alkylidene, as used herein, alone or in combination, refers to an alkenyl group in which a carbon atom of the carbon-carbon double bond belongs to the chemical moiety to which the alkenyl group is attached.

[0343] The term alkylthio, as used herein, alone or in combination, refers to an alkyl thioether radical (RS-) wherein the term alkyl is as defined above and wherein the sulfur may be single or doubly oxidized. Examples of suitable alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfynyl and the like.

[0344] The term alkynyl, as used in this document, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term Petition 870220002363, dated 10 / 01 / 2022, pp. 44 / 422 41 / 412 Alkynylene refers to a carbon-carbon triple bond linked in two positions, such as ethynylene (-C:::C-, -C=C-). Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term alkynyl may include alkynylene groups.

[0345] The terms “amido”, “carboxamido” and “carbamoyl”, as used herein, alone or in combination, refer to an amino group as described below linked to the original molecular chemical portion via a carbonyl group or vice versa. The term C-amido, as used herein, alone or in combination, refers to a -C(O)N(RR') group with R and R' as defined herein or as defined by specifically numbered R groups. The term N-amido, as used herein, alone or in combination, refers to an RC(O)N(R')- group with R and R' as defined herein or as defined by specifically numbered R groups. The term acylamino, as used herein, alone or in combination, encompasses an acyl group linked to the original chemical portion via an amino group. An example of an acylamino group is acetylamino (CH3C(O)NH-).

[0346] The term amino, as used herein, alone or in combination, refers to NRR', wherein R and R' are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Additionally, Petition 870220002363, dated 10 / 01 / 2022, p. 45 / 422 42 / 412 R and R' can combine to form heterocycloalkyl groups, either of which can be optionally substituted.

[0347] The term aryl, as used in this document, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings, in which such polycyclic ring systems are fused together. The term aryl encompasses aromatic groups such as phenyl, naphthyl, anthracenyl and phenantryl.

[0348] The term arylalkenyl or aralkenyl, as used in this document, alone or in combination, refers to an aryl group attached to the original molecular chemical portion via an alkenyl group.

[0349] The term arylalkoxy or aralkoxy, as used in this document, alone or in combination, refers to an aryl group attached to the original molecular chemical portion via an alkoxy group.

[0350] The term arylalkyl or aralkyl, as used herein, alone or in combination, refers to an aryl group linked to the original molecular chemical moiety via an alkyl group.

[0351] The term aryl alkynyl or aralkinyl as used in this document, alone or in combination, refers to an aryl group attached to the original molecular chemical portion via an alkynyl group.

[0352] The term arylalkaneyl or aralkaneyl or aroyl, as used in this document, alone or in combination, refers to an acyl radical derived from an aryl-substituted alkanecarboxylic acid, such as benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl Petition 870220002363, dated 10 / 01 / 2022, p. 46 / 422 43 / 412 (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl and similar compounds.

[0353] The term aryloxy, as used in this document, alone or in combination, refers to an aryl group attached to the original molecular chemical portion via an oxy.

[0354] The terms benzo and benz, as used herein, alone or in combination, refer to the divalent radical C6H4= derived from benzene. Examples include benzothiophene and benzimidazole.

[0355] The term carbamate, as used herein, alone or in combination, refers to a carbamic acid ester (-NHCOO-) that may be attached to the original molecular chemical portion of the nitrogen or acid end and may optionally be substituted as defined herein.

[0356] The term O-carbamyl, as used in this document, alone or in combination, refers to an -OC(O)NRR' group, with R and R' as defined in this document.

[0357] The term N-carbamyl, as used in this document, alone or in combination, refers to a ROC(O)NR'- group, with R and R' as defined in this document.

[0358] The term carbonyl, as used in this document, when alone, includes formyl [-C(O)H] and, in combination, is a -C(O)- group.

[0359] The term carboxyl or carboxy, as used herein, refers to -C(O)OH or the corresponding carboxylate anion, as it is in an acid salt. Petition 870220002363, dated 10 / 01 / 2022, p. 47 / 422 44 / 412 carboxylic. An O-carboxy group refers to an RC(O)O group, where R is as defined in this document. A C-carboxy group refers to a -C(O)OR group, where R is as defined in this document.

[0360] The term cyan, as used in this document, alone or in combination, refers to -CN.

[0361] The term cycloalkyl or, alternatively, carbocyclo, as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group in which each cyclic chemical moiety contains from 3 to 12 carbon atom ring members and which may optionally be a fused benzo ring system that is optionally substituted as defined herein. In some embodiments, the so-called cycloalkyl will comprise from 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1-hindenyl, adamantyl and the like.It is intended that bicyclic and tricyclic, as used herein, include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene, as well as the saturated or partially unsaturated multicyclic type (with multiple centers). The latter type of isomer is generally exemplified by bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

[0362] The term ester, as used in this document, alone or in combination, refers to a Petition 870220002363, dated 10 / 01 / 2022, pp. 48 / 422 45 / 412 carboxy group that bridges two chemical moieties bonded to carbon atoms.

[0363] The term ether, as used in this document, alone or in combination, refers to an oxy group bridging two chemical moieties bonded at carbon atoms.

[0364] The term halo or halogen, as used in this document, alone or in combination, refers to fluorine, chlorine, bromine or iodine.

[0365] The term haloalkoxy, as used herein, alone or in combination, refers to a haloalkyl group attached to the original molecular chemical moiety via an oxygen atom.

[0366] The term haloalkyl, as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined above in which one or more hydrogens are replaced by a halogen. Mono-haloalkyl, di-haloalkyl and poly-haloalkyl radicals are specifically covered. A mono-haloalkyl radical, for example, may have an iodine, bromine, chlorine or fluorine atom within the radical. Di-halo and poly-haloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. Haloalkylene refers to a haloalkyl group attached at two or more positions. Examples Petition 870220002363, dated 10 / 01 / 2022, pp. 49 / 422 46 / 412 include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-) and similar substances.

[0367] The term heteroalkyl, as used herein, alone or in combination, refers to a straight or branched chain or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of a determined number of carbon atoms and one to three heteroatoms chosen from N, O and S, wherein the N and S atoms may optionally be oxidized and the N heteroatom may optionally be quaternized. The heteroatom (or heteroatoms) may be placed in any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3.

[0368] The term heteroaryl, as used herein, alone or in combination, refers to an unsaturated heteromonocyclic ring with 3 to 15 members or a fused monocyclic, bicyclic or tricyclic ring system, wherein at least one of the fused rings is aromatic, which contains at least one atom chosen from O, S and N. In certain embodiments, said heteroaryl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said heteroaryl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said heteroaryl will comprise from 5 to 7 atoms. The term also encompasses fused polycyclic groups, in which heterocyclic rings are fused to aryl rings, in which heteroaryl rings are fused to other heteroaryl rings, in which heteroaryl rings are fused to heterocycloalkyl rings, or in which heteroaryl rings are fused to cycloalkyl rings. Examples of heteroaryl groups include pyrrolyl, Petition 870220002363, dated 10 / 01 / 2022, p. 50 / 4 47 / 412 pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetra-hydroquinolinyl, tetrazolopyridazinyl, tetra-hydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Examples of tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0369] The terms heterocycloalkyl and, interchangeably, heterocycle, as used herein, alone or in combination, each refer to a saturated, partially unsaturated or completely unsaturated (but not aromatic) monocyclic, bicyclic or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently selected from the group consisting of nitrogen, oxygen and sulfur. In certain embodiments, said heterocycloaryl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said heterocycloaryl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said heterocycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, said Petition 870220002363, dated 10 / 01 / 2022, page 51 / 422 48 / 412 heterocycloalkyl will comprise from 3 to 7 ring members in each ring. In other embodiments, said heterocycloalkyl will comprise from 5 to 6 ring members in each ring. Heterocycloalkyl and heterocycle are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members and carbocyclic and benzo fused ring systems; additionally, both terms also include systems in which a heterocyclic ring is fused to an aryl group, as defined herein, or an additional heterocyclic group. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl and the like.Heterocyclic groups may be optionally substituted unless specifically prohibited.

[0370] The term hydrazinyl, as used in this document, alone or in combination, refers to two amino groups joined by a single bond, i.e., -NN-.

[0371] The term hydroxy, as used in this document, alone or in combination, refers to -OH.

[0372] The term hydroxyalkyl, as used herein, alone or in combination, refers to a hydroxy group linked to the original molecular chemical portion via an alkyl group. Petition 870220002363, dated 10 / 01 / 2022, p. 52 / 422 49 / 412

[0373] The term imino, as used herein, alone or in combination, refers to =N

[0374] The term imino-hydroxy, as used herein, alone or in combination, refers to =N(OH) and =NO-.

[0375] The phrase in the main chain refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group for compounds of any of the formulas disclosed in this document.

[0376] The term isocyanate refers to an -NCO group.

[0377] The term isothiocyanate refers to an -NCS group.

[0378] The phrase linear chain of atoms refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen, and sulfur.

[0379] The term lower, as used in this document, alone or in combination, unless otherwise specifically defined, means that it contains 1 ae including 6 carbon atoms (i.e., C1-C6 alkyl).

[0380] The term lower aryl, as used in this document, alone or in combination, means phenyl or naphthyl, either of which may be optionally substituted as supplied.

[0381] The term lower heteroaryl, as used in this document, alone or in combination, means either 1) monocyclic heteroaryl comprising five or six ring members, of which between one and four are said Petition 870220002363, dated 10 / 01 / 2022, p. 53 / 422 50 / 412 members may be heteroatoms chosen from N, O, and S or 2) bicyclic heteroaryl, wherein each of the fused rings comprises five or six ring members comprising one to four heteroatoms chosen from N, O, and S.

[0382] Lower cycloalkyl, as used herein, alone or in combination, means a monocyclic cycloalkyl having between three and six ring members (i.e., C3-C6 cycloalkyl). Lower cycloalkyls may be unsaturated. Examples of lower cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0383] The term lower heterocycloalkyl, as used herein, alone or in combination, means a monocyclic heterocycloalkyl having between three and six ring members, of which between one and four may be heteroatoms chosen from N, O and S (i.e., C3-C6 heterocycloalkyl). Examples of heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl and morpholinyl. Lower heterocycloalkyls may be unsaturated.

[0384] The term lower amino, as used herein, alone or in combination, refers to -NRR', wherein R and R' are independently chosen from hydrogen and lower alkyl, each of which may be optionally substituted.

[0385] The term mercaptile, as used herein, alone or in combination, refers to an RS- group—, where R is as defined herein.

[0386] The term nitro, as used here, alone or in combination, refers to -NO2. Petition 870220002363, dated 10 / 01 / 2022, page 54 / 422 51 / 412

[0387] The terms oxy or oxa, as used in this document, alone or in combination, refer to -O-.

[0388] The term oxo, as used in this document, alone or in combination, refers to =O.

[0389] The term per-haloalkoxy refers to an alkoxy group in which all hydrogen atoms are replaced by halogen atoms.

[0390] The term per-haloalkyl, as used herein, alone or in combination, refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms.

[0391] The terms sulfonate, sulfonic acid and sulfonic, as used herein, alone or in combination, refer to the -SO3H group, and its anion when sulfonic acid is used in salt formation.

[0392] The term sulfanil, as used herein, alone or in combination, refers to -S

[0393] The term sulfinil, as used herein, alone or in combination, refers to S(O)-.

[0394] The term sulfonyl, as used in this document, alone or in combination, refers to S(O)2-.

[0395] The term N-sulfonamido refers to an RS(O)2NR'- group with R and R' as defined herein.

[0396] The term S-sulfonamido refers to a -S(O)2NRR' group, with R and R' as defined herein. Petition 870220002363, dated 10 / 01 / 2022, page 55 / 422 52 / 412

[0397] The term sulfonamide encompasses both N-sulfonamide and S-sulfonamide groups.

[0398] The terms tia and thio, as used herein, alone or in combination, refer to an -S- group or an ether in which oxygen is replaced by sulfur. The oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of tia and thio.

[0399] The term thiol, as used in this document, alone or in combination, refers to an -SH group.

[0400] The term thiocarbonyl, as used in this document, when alone, includes thioformyl -C(S)H and, in combination, is a -C(S)- group.

[0401] The term N-thiocarbamyl refers to a ROC(S)NR'- group, with R and R' as defined herein.

[0402] The term O-thiocarbamyl refers to an -OC(S)NRR' group, with R and R' as defined in this document.

[0403] The term thiocyanate refers to a -CNS group.

[0404] The term trihalomethanesulfonamide refers to an X3CS(O)2NR- group with X being a halogen and R as defined herein.

[0405] The term trihalomethanesulfonyl refers to an X3CS(O)2- group where X is a halogen.

[0406] The term tri-halomethoxy refers to an X3CO- group where X is a halogen.

[0407] The term trisubstituted silyl, as used in this document, alone or in combination, refers to a silicon group substituted in its three valences. Petition 870220002363, dated 10 / 01 / 2022, page 56 / 422 53 / 412 free amino acids with groups as listed in this document under the definition of substituted amino acids. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, and the like.

[0408] Any definition in this document may be used in combination with any other definition to describe a compound structural group. By convention, the last element of any such definition is the one that attaches to the original chemical moiety. For example, the compound group alkylamido would represent an alkyl group attached to the original molecule via an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the original molecule via an alkyl group.

[0409] When a group is defined as being null, it is understood that the said group is absent.

[0410] The term optionally substituted means that the preceding group may be substituted or unsubstituted. When substituted, the substituents of an optionally substituted group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: short-chain alkyl, short-chain alkenyl, short-chain alkynyl, short-chain alkanoyl, short-chain heteroalkyl, short-chain heterocycloalkyl, short-chain haloalkyl, short-chain haloalkenyl, short-chain haloalkynyl, short-chain per-haloalkyl, short-chain per-haloalkoxy, short-chain cycloalkyl, phenyl, aryl, aryloxy, short-chain alkoxy, short-chain haloalkoxy, oxo, short-chain acyloxy, carbonyl, carboxyl, short-chain alkylcarbonyl, Petition 870220002363, dated 10 / 01 / 2022, p. 57 / 422 54 / 412 short-chain carboxyester, short-chain carboxamide, cyano, hydrogen, halogen, hydroxy, amino, short-chain alkylamino, arylamino, amido, nitro, thiol, short-chain alkylthio, short-chain haloalkylthio, short-chain per-haloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, short-chain carbamate, and short-chain urea. When structurally feasible, two substituents may be linked together to form a fused carbocyclic or heterocyclic ring with five, six, or seven members consisting of zero to three heteroatoms, for example, forming methylenedioxy or ethylenedioxy. An optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CF3).When substituents are cited without qualification as to substitution, both substituted and unsubstituted forms are covered. When a substituent is qualified as substituted, the substituted form is specifically desired. Additionally, different sets of optional substitutions to a particular chemical moiety may be defined as needed; in such cases, the optional substitution will be as defined, often immediately following the optionally substituted phrase.

[0411] The term R or the term R', appearing alone and without a numerical designation, unless otherwise defined, refers to a chemical moiety chosen from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and Petition 870220002363, dated 10 / 01 / 2022, p. 58 / 422 55 / 412 heterocycloalkyl, any of which may be optionally substituted. Such R and R' groups should be understood as being optionally substituted as defined herein. Whether or not an R group has a numerical designation, each R group, including R, R' and Rn where n = (1, 2, 3, ... n), each substituent and each term should be understood as being independent of each other in terms of group selection. If any variable, substituent or term (e.g., aryl, heterocycle, R, etc.) occurs more than once in a generic formula or structure, its definition in each occurrence is independent of the definition in each other occurrence. Those skilled in the art will further recognize that certain groups may be attached to an original molecule or may occupy a position in a chain of elements from either end as written.For example, an asymmetric group, such as -C(O)N(R)-, can be attached to the original chemical portion on either the carbon or the nitrogen.

[0412] There are asymmetric centers in the compounds disclosed in this document. These centers are designated by the symbols R or S, depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1-isomers and mixtures thereof. The individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing chiral centers or by preparing mixtures of enantiomeric products followed by separation, such as conversion of Petition 870220002363, dated 10 / 01 / 2022, p. 59 / 422 56 / 412 a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other suitable method known in the art. The starting compounds of particular stereochemistry are either commercially available or can be made and solved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusamen (Z) isomers as well as appropriate mixtures thereof. Additionally, the compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Furthermore, the compounds disclosed herein may exist in non-solvated forms as well as solvated with pharmaceutically acceptable solvents such as water, ethanol, and the like.In general, solvated forms are considered equivalent to non-solvated forms.

[0413] The term bond refers to a covalent bond between two atoms or two chemical moieties when the atoms joined by the bond are considered part of the larger substructure. A bond can be single, double, or triple, unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.

[0414] The term disease as used in this document is intended to be generally synonymous with, and is used interchangeably with, the terms disorder, syndrome and condition (as in medical condition), wherein all Petition 870220002363, dated 10 / 01 / 2022, p. 60 / 422 57 / 412 reflect an abnormal condition of the human or animal body or one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced lifespan or quality of life.

[0415] The term combination therapy means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes the co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple separate capsules for each active ingredient. In addition, this administration also includes the use of each type of therapeutic agent in a sequential manner. In both cases, the treatment regimen will provide the beneficial effects of the drug combination in the treatment of the conditions or disorders described herein.

[0416] The term MCT4 inhibitor is used in this document to refer to a compound that exhibits an IC50 with respect to MCT4 activity of not more than about 100 μM and, more typically, not more than about 50 μM, as measured in the MCT4 enzyme assay described herein in general. IC50 is the concentration of inhibitor that reduces the activity of an enzyme (e.g., MCT4) to half the maximum level. Certain compounds disclosed in this document have been found to exhibit inhibition against MCT4. In certain embodiments, the compounds will exhibit an IC50 with respect to MCT4 of not more than about 10 μM; in further embodiments, the compounds will exhibit an IC50 with respect to MCT4 Petition 870220002363, dated 10 / 01 / 2022, page 61 / 422 58 / 412 of no more than about 5 μM; in still other embodiments, the compounds will exhibit an IC50 with respect to MCT4 of no more than about 1 μM; in yet other embodiments, the compounds will exhibit an IC50 with respect to MCT4 of no more than about 200 nM, as measured in the MCT4 binding assay described herein.

[0417] The phrase therapeutically effective is intended to qualify the quantity of active ingredients used in the treatment of a disease or disorder or in the effect of a clinical endpoint.

[0418] The term therapeutically acceptable refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) that are suitable for use in contact with patient tissues without undue toxicity, irritation and allergic response, are proportionate to a reasonable risk / benefit ratio and are effective for their intended use.

[0419] As used in this document, reference to the treatment of a patient is intended to include prophylaxis. Treatment may also be preemptive in nature, that is, it may include the prevention of disease. Prevention of a disease may involve complete protection against the disease, for example, as in the case of preventing infection with a pathogen, or it may involve preventing the progression of the disease. For example, prevention of a disease may not mean the total exclusion of any disease-related effect at any level, but instead may mean preventing the symptoms of a disease at a clinically significant or detectable level. Prevention of Petition 870220002363, dated 10 / 01 / 2022, p. 62 / 422 59 / 412 diseases can also mean preventing the progression of a disease to a later stage.

[0420] The term patient is generally synonymous with the term subject and includes all mammals, including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs and rabbits, and pets such as dogs, cats, rabbits and horses. Preferably, the patient is a human being.

[0421] The term prodrug refers to a compound that is made more active in vivo. Certain compounds disclosed herein may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). The prodrugs of the compounds disclosed herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions in order to provide the compound. Furthermore, prodrugs can be converted into the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted into a compound when placed in a transdermal adhesive reservoir with a suitable enzyme or chemical reagent.Prodrugs are often useful because, in some situations, they can be easier to administer than the original compound or drug. For example, they may be bioavailable for oral administration while the original drug is not. The prodrug may also have improved solubility in pharmaceutical compositions compared to the original drug. A wide variety of prodrug derivatives exist. Petition 870220002363, dated 10 / 01 / 2022, p. 63 / 422 60 / 412 known in the art, such as those that depend on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound that is administered as an ester (the prodrug) but is then metabolically hydrolyzed into the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.

[0422] The compounds disclosed in this document may exist as therapeutically acceptable salts. The present invention includes the above-listed compounds in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be useful in the preparation and purification of the compound in question. Base addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0423] The term therapeutically acceptable salt, as used herein, represents salts or zwitterionic forms of the compounds disclosed herein that are soluble in water or oil or dispersible and therapeutically acceptable as defined herein. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts Petition 870220002363, dated 10 / 01 / 2022, page 64 / 422 61 / 412 incluem acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenosulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hipurate, hydrochloride, hydrobromide, iodihydrate, 2-hidroxiethanesulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenosulfonate, methanosulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartarate, L-tartarate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (ptosilate), and undecanoate.Furthermore, the basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids that can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric acids, and organic acids such as oxalic, maleic, succinic, and citric acids. Salts can also be formed by coordinating the compounds with an alkali or alkaline earth metal ion. Therefore, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein and similar compounds.

[0424] Base addition salts can be prepared during the final isolation and purification of Petition 870220002363, dated 10 / 01 / 2022, page 65 / 422 62 / 412 compounds formed by reacting a carboxy group with a suitable base, such as the hydroxide, carbonate or bicarbonate of a metallic cation, or with ammonia or a primary, secondary or tertiary organic amine. Therapeutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0425] Although it may be possible for the compounds of the present invention to be administered as the crude chemical product, it is also possible to present them as a pharmaceutical formulation. Consequently, pharmaceutical formulations comprising one or more of the compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and, optionally, one or more other therapeutic ingredients, are provided herein. The vehicle (or vehicles) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. The appropriate formulation is dependent on the chosen route of administration. Any one Petition 870220002363, dated 10 / 01 / 2022, p. 66 / 422 63 / 412 among well-known techniques, carriers and excipients may be used as appropriate and as understood in the art. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, for example, by conventional processes of mixing, dissolution, granulation, production of dragees, levigation, emulsification, encapsulation, capture or compression.

[0426] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intra-articular and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of combining a compound of the present invention or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof (active ingredient) with the carrier which constitutes one or more accessory ingredients.In general, formulations are prepared by uniformly and intimately combining the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0427] The formulations of the compounds disclosed herein suitable for oral administration may be presented as distinct units, such as capsules, wafers or tablets, each containing a quantity Petition 870220002363, dated 10 / 01 / 2022, page 67 / 422 64 / 412 predetermined form of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as a liquid oil-in-water emulsion or a liquid water-in-oil emulsion. The active ingredient may also be presented as a bolus, electrum, or paste.

[0428] Pharmaceutical preparations that can be used orally include tablets, hard capsules made from gelatin, as well as sealed soft capsules made from gelatin and a plasticizer, such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Pressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binding agents, inert diluents, or lubricants, surface-active agents or dispersants. Molded tablets can be made by molding, in a suitable machine, a mixture of the powder compound moistened with an inert liquid diluent. Tablets can optionally be coated and scored and can be formulated to provide low or controlled release of the active ingredient.All formulations for oral administration must be in dosages suitable for such administration. Hard capsules may contain the active ingredients mixed by addition with the filler, such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils. Petition 870220002363, dated 10 / 01 / 2022, p. 68 / 422 65 / 412 liquid paraffin or liquid polyethylene glycols. Additionally, stabilizers may be added. The dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for identification or to distinguish different combinations of doses of the active compound.

[0429] Compounds may be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injection formulations may be presented in unit dose form, for example, in ampoules or in multi-dose containers, with an added preservative. Compositions may take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulation agents such as suspending agents, stabilizers and / or dispersants. Formulations may be presented in unit dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, sterile saline or pyrogen-free water, immediately before use.Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, or tablets of the type previously described. Petition 870220002363, dated 10 / 01 / 2022, page 69 / 422 66 / 412

[0430] Formulations for parenteral administration include sterile aqueous and non-aqueous (oily) solutions for injection of the active compounds, which may contain antioxidants, buffers, bacteriostatics, and solutes that make the formulation isotonic with the intended recipient's blood; and sterile aqueous and non-aqueous suspensions, which may include suspending agents and thickening agents. Suitable lipophilic vehicles or solvents include fatty oils such as sesame oil or esters of synthetic fatty acids such as ethyl oleate or triglycerides or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow the preparation of highly concentrated solutions.

[0431] In addition to the formulations described above, compounds may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion-exchange resins or as moderately soluble derivatives, e.g., as a moderately soluble salt.

[0432] For oral or sublingual administration, the compositions may take the form of conventionally formulated tablets, lozenges, pastilles or gels. Such Petition 870220002363, dated 10 / 01 / 2022, page 70 / 422 67 / 412 compositions may comprise the active ingredient in a flavored base, such as sucrose and acacia or tragacanth.

[0433] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter, polyethylene glycol or other glycerides.

[0434] Certain compounds disclosed herein may be administered topically, i.e., by non-systemic administration. This includes applying a compound disclosed herein externally to the epidermis or oral cavity and instilling such a compound into the ear, eye, and nose, so that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0435] Suitable formulations for topical administration include liquid and semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, and eye drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient comprises as much as 10% w / w. In other embodiments, it may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise from 2% w / w to 5% w / w. In other embodiments, it may comprise from 0.1% to 1% w / w of the formulation. Petition 870220002363, dated 10 / 01 / 2022, page 71 / 422 68 / 412

[0436] For administration by inhalation, the compounds can be conveniently administered from an insufflator, pressurized nebulizer canisters, or other convenient means of delivering an aerosol spray. Pressurized canisters may comprise a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a measured quantity. Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example, a powder mixture of the compound and a suitable powder base, such as lactose or starch.The powder composition may be presented in unit dosage form, for example, capsules, cartridges, gelatin or blister packs from which the powder can be administered with the aid of an inhaler or insufflator.

[0437] Preferred unit dosage formulations are those that contain an effective dose, as mentioned below in this document, or an appropriate fraction thereof, of the active ingredient.

[0438] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations described above may include other conventional agents in the art, considering the type of formulation in question; for example, those for oral administration may include flavoring agents.

[0439] The compounds can be administered orally or by injection at a dose of 0.1 to 500 mg / kg Petition 870220002363, dated 10 / 01 / 2022, page 72 / 422 69 / 412 per day. The dosage range for adult humans is generally 5 mg to 2 g / day. Tablets or other forms of presentation supplied in separate units may conveniently contain an amount of one or more compounds that is effective at such dosage or as a plurality thereof, for example, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.

[0440] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host being treated and the particular mode of administration.

[0441] Compounds can be administered in various ways, for example, orally, topically, or by injection. The precise amount of compound administered to a patient will be the responsibility of the attending physician. The specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound used, age, body weight, general health, sex, diet, timing of administration, route of administration, excretion rate, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. The route of administration may vary depending on the condition and its severity.

[0442] In certain cases, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension, Petition 870220002363, dated 10 / 01 / 2022, page 73 / 422 70 / 412 Therefore, it may be appropriate to administer an antihypertensive agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be increased by administering an adjuvant (i.e., by itself the adjuvant may have only minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is increased). Or, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. By way of example only, in a treatment for diabetes involving the administration of one of the compounds described herein, increased therapeutic benefit may result from also providing the patient with another therapeutic agent for diabetes.In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may simply be additive from the two therapeutic agents, or the patient may experience a synergistic benefit.

[0443] In another aspect, certain modalities provide methods for treating MCT4-mediated disorders in a human or animal individual who needs such treatment, comprising administering to said individual an amount of a compound disclosed herein effective in reducing or preventing said disorder in the individual, in combination with at least one additional agent for the treatment of said disorder that is known in the art. In a related aspect, certain modalities Petition 870220002363, dated 10 / 01 / 2022, p. 74 / 422 71 / 412 provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of MCT4-mediated disorders.

[0444] Also provided herein is a method for treating a disorder mediated by the MCT4 monocarboxylate transporter in a subject in need thereof comprising the co-administration or sequential administration of a compound, as disclosed herein, or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

[0445] In certain modalities, the therapeutic agent is a protein kinase inhibitor.

[0446] In certain embodiments, the protein kinase inhibitor is chosen from among Aurora B, EGFR, PLK-1, CDK inhibitors.

[0447] In certain embodiments, the therapeutic agent is chosen from among an antimetabolite, bcr-abl inhibitor, DNA damage agent, EGFR inhibitor, microtubule stabilizing inhibitor, mitotic capture inhibitor, S-phase inhibitor, and a taxane.

[0448] In certain embodiments, the therapeutic agent is a DNA-damaging agent chosen from among an alkylating agent, anthracycline, antimetabolite agent, crosslinking agent, DNA replication inhibitor, intercalator, microtubule disruptor, PARP inhibitor, radiomimetic agent, radiosensitizer, strand-breaking agent, and topoisomerase II inhibitor.

[0449] In certain modalities, the therapeutic agent is chosen from aminoglutethimide, ansacrine, Petition 870220002363, dated 10 / 01 / 2022, page 75 / 422 72 / 412 anastrozol, asparaginase, barasertibe, bcg, bicalutamida, bleomicina, buserelina, busulfano, campotecina, capecitabina, carboplatina, carmustina, clorambucil, cloroquina, cisplatina, cladribina, clodronato, colchicina, ciclofosfamida, ciproterona, citarabina, dacarbazina, dactinomicina, daunorubicina, demetoxiviridina, dicloroacetato, dienestrol, dietilstilbestrol, docetaxel, doxorubicina, epirubicina, estradiol, estramustina, etoposida, everolimus, exemestano, filgrastim, fludarabina, fludrocortisona, fluorouracil, fluoximesterona, flutamida, gencitabina, genisteina, goserelina, hidroxiureia, idarubicina, ifosfamida, imatinibe, interferon, irinotecano, ironotecano, letrozol, leucovorina, leuprolida, levamisol, lomustina, lonidamina, mecloretamina, medroxiprogesterona, megestrol, melfalano, mercaptopurina, mesna, metformina, metotrexato, mitomicina, mitotano, mitoxantrona, nilutamida, nocodazol, olaparibe, octreotida, oxaliplatina, paclitaxel, pamidronato, pentostatina,perifosine, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, sorafenib, streptozocin, sunitinib, suramin, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine and vinorelbine.

[0450] For use in cancer and neoplastic diseases, an MCT4 inhibitor may ideally be used in conjunction with one or more of the following non-limiting examples of anticancer agents: (1) alkylating agents, including but not limited to cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN) and cyclophosphamide (ENDOXAN); (2) antimetabolites, Petition 870220002363, dated 10 / 01 / 2022, page 76 / 422 73 / 412 including, but not limited to, mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (ARAC), gemcitabine (GEMZAR), fluorouracil (CARAC), leucovorin (FUSILEV) and methotrexate (RHEUMATREX); (3) plant alkaloids and terpenoids, including, but not limited to, vincristine (ONCOVIN), vinblastine and paclitaxel (TAXOL); (4) topoisomerase inhibitors, including, but not limited to, irinotecan (CAMPTOSAR), topotecan (HYCAMTIN) and etoposide (EPOSIN); (5) cytotoxic antibiotics, including, but not limited to, actinomycin D (COSMEGEN), doxorubicin (ADRIAMYCIN), bleomycin (BLENOXANE) and mitomycin (MITOSOL); (6) angiogenesis inhibitors, including, but not limited to, sunitinib (SUTENT) and bevacizumab (AVASTIN); and (7) tyrosine kinase inhibitors, including, but not limited to, imatinib (GLEEVEC), erlotinib (TARCEVA), lapatitinib (TYKERB) and axitinib (INLYTA).

[0451] In which a subject is suffering from or at risk of suffering from an inflammatory condition, an MCT4 inhibitor compound described herein is optionally used in conjunction with one or more agents or methods to treat an inflammatory condition in any combination. Therapeutic agents / treatments to treat an autoimmune and / or inflammatory condition include, but are not limited to, any of the following examples: (1) corticosteroids, including, but not limited to, cortisone, dexamethasone, and methylprednisolone; (2) nonsteroidal anti-inflammatory drugs (NSAIDs), including, but not limited to, ibuprofen, naproxen, acetaminophen, aspirin, fenoprofen (NALFON), flurbiprofen (ANSAID), ketoprofen, oxaprozin (DAYPRO), diclofenac sodium (VOLTAREN), diclofenac potassium (CATAFLAM), etodolac Petition 870220002363, dated 10 / 01 / 2022, page 77 / 422 74 / 412 (LODINE), indomethacin (INDOCIN), ketorolac (TORADOL), sulindac (CLINORIL), tolmetin (TOLECTIN), meclofenamate (MECLOMEN), mefenamic acid (PONSTEL), nabumetone (RELAFEN) and piroxicam (FELDENE); (3) immunosuppressants, including but not limited to methotrexate (RHEUMATREX), leflunomide (ARAVA), azathioprine (IMURAN), cyclosporine (NEORAL, SANDIMMUNE), tacrolimus and cyclophosphamide (CYTOXAN); (4) CD20 blockers, including but not limited to rituximab (RITUXAN); (5) Tumor Necrosis Factor (TNF) blockers, including but not limited to etanercept (ENBREL), infliximab (REMICADE) and adalimumab (HUMIRA); (6) Interleukin-1 receptor antagonists, including but not limited to anakinra (KINERET); (7) Interleukin-6 inhibitors, including but not limited to tocilizumab (ACTEMRA); (8) Interleukin-17 inhibitors, including but not limited to AIN457; (9) Janus kinase inhibitors, including but not limited to tasocititinib;and (10) syk inhibitors, including, but not limited to, fostamatinib.;

[0452] In certain modalities, the method additionally includes administering non-chemical methods of cancer treatment.

[0453] In certain modalities, the method additionally involves administering radiotherapy.

[0454] In certain modalities, the method additionally comprises administering surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or any combination thereof.

[0455] In any case, multiple therapeutic agents (at least one of which is a compound disclosed herein) may be administered in any Petition 870220002363, dated 10 / 01 / 2022, page 78 / 422 75 / 412 order or even simultaneously. If administered simultaneously, the multiple therapeutic agents may be provided in a single, unified form or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be provided in multiple doses, or both may be provided as multiple doses. If not simultaneous, the timing between multiple doses may be any duration of time in the range of a few minutes to four weeks.

[0456] In another aspect, certain embodiments provide methods for treating MCT4-mediated disorders in a human or animal individual requiring such treatment, comprising administering to said individual an amount of a compound disclosed herein effective in reducing or preventing said disorder in the individual, in combination with at least one additional agent for the treatment of said disorder that is known in the art. In a related aspect, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of MCT4-mediated disorders.

[0457] The present disclosure provides pharmaceutical compounds and compositions that inhibit glutaminase activity, particularly MCT4 activity, and are thus useful in the treatment or prevention of MCT4-associated disorders. The pharmaceutical compounds and compositions of the present disclosure selectively modulate MCT4 and are thus useful in the treatment or prevention of a range of associated disorders. Petition 870220002363, dated 10 / 01 / 2022, page 79 / 422 76 / 412 and MCT4 include, but are not limited to, inflammatory and proliferative diseases.

[0458] Consequently, a method for inhibiting the activity of the monocarboxylate transporter MCT4, or a mutant thereof, in a biological sample is provided herein, characterized by comprising the step of bringing said biological sample into contact with a compound, as disclosed herein, or a salt thereof.

[0459] Also provided herein is a method for inhibiting the activity of the monocarboxylate transporter MCT4, or a mutant thereof, in a patient, comprising the step of administering to the patient a compound as disclosed herein, or a salt thereof.

[0460] Also provided herein is a method for selectively inhibiting the activity of the monocarboxylate transporter MCT4, or a mutant thereof, with respect to the monocarboxylate transporter MCT1, or a mutant thereof, in a patient, comprising the step of administering to the patient a compound, as disclosed herein, or a salt thereof.

[0461] In certain modalities, inhibition is at least 100 times selective for MCT4 compared to MCT1.

[0462] In certain embodiments, the pharmaceutical compounds and compositions of the present disclosure may be useful in the treatment or prevention of cancer.

[0463] In certain embodiments, the compounds of the present disclosure may be used to prevent or treat cancer, wherein the cancer is a variant of Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, or AIDS-related cancers. Petition 870220002363, dated 10 / 01 / 2022, page 80 / 422 77 / 412 (Lymphoma and Kaposi's Sarcoma), Anal Cancer, Appendix Cancer, Atypical Teratoid / Rhabdoid Tumor, Basal Cell Carcinoma, Bile Duct Cancer (including Extrahepatic), Bladder Cancer, Bone Cancer (including Osteosarcoma and Malignant Fibrous Histiocytoma), Brain Tumor (such as Astrocytomas, Brain and Spinal Cord Tumors, Brainstem Glioma, Atypical Teratoid / Rhabdoid Tumor of the Central Nervous System, Embryonic Tumors of the Central Nervous System, Craniopharyngioma, Ependymoblastoma, Ependymoma, Medulloblastoma, Medulloepithelioma, Intermediate Differentiation Pineal Parenchymal Tumors, Supratentorial Primitive Neuroectodermal Tumors and Pineoblastoma), Breast Cancer, Bronchial Tumors, Burkitt's Lymphoma, Carcinoid Tumor, Primary Central Nervous System Carcinoma of Unknown Type (such as Atypical Teratoid / Rhabdoid Tumor, Embryonal Tumors and Lymphoma), Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia (CLL),Chronic Myeloid Leukemia (CML), Chronic Myeloproliferative Disorders, Colon Cancer, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma (Mycosis Fungoides and Sézary Syndrome), Bile Duct (Extrahepatic), Ductal Carcinoma In Situ (DCIS), Embryonic Tumors (Central Nervous System), Endometrial Cancer, Ependymoblastoma, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing's Sarcoma Family of Tumors, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer (such as Intraocular Melanoma, Retinoblastoma), Fibrous Histiocytoma of Bone (including Malignant and Osteosarcoma), Gallbladder Cancer, Cancer, Petition 870220002363, dated 10 / 01 / 2022, page 81 / 422 78 / 412 Gastric (Stomach), Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors (GIST), Germ Cell Tumor (Extracranial, Extragonadal, Ovarian), Gestational Trophoblastic Tumor, Glioma, Hair Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular Cancer (Liver), Histiocytosis, Langerhans Cell Histiocytosis, Hodgkin's Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors (Endocrine, Pancreas), Kaposi's Sarcoma, Kidney (including Renal Cell), Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia (including Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL)), Chronic Myeloid Lymphoma (CML), Hair-Cell Lymphoma), Oral Cavity and Lip Cancer, Liver Cancer (Primary), Lobular Carcinoma In Situ (LCIS), Lung Cancer (Non-Small Cell and Small Cell), Lymphoma (AIDS-related, Burkitt's, Cutaneous T-cell (Mycosis Fungoides and Sézary Syndrome), Hodgkin's, Non-Hodgkin'sPrimary Central Nervous System (CNS) Cancer, Macroglobulinemia, Waldenstrom's Syndrome, Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Medulloblastoma, Medulloepithelioma, Melanoma (including Intraocular (Eyes)), Merkel Cell Carcinoma, Mesothelioma (Malignant), Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma involving the NUT Gene, Oral Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma / Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic / Myeloproliferative Neoplasms, Myeloid Leukemia, Chronic Myeloid Leukemia (CML), Acute Myeloid Leukemia (AML), Myeloma and Multiple Myeloma. Myeloproliferative Disorders (Chronic), Cancer of, Petition 870220002363, dated 10 / 01 / 2022, page 82 / 422 79 / 412 Paranasal Sinus and Nasal Cavity Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Oropharyngeal and Lip Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer (such as Epithelial, Germ Cell Tumor and Low-Level Malignant Tumor), Pancreatic Cancer (including Islet Cell Tumors), Papillomatosis, Paraganglioma, Nasal Cavity and Paranasal Sinus Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Intermediate Differentiation Pineal Parenchymal Tumors, Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors, Pituitary Tumor, Plasma Cell Neoplasm / Myeloma Multiple Lymphoma, Pleuropulmonary Blastoma, Breast Cancer and Pregnancy, Central Nervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer, Renal Cell (Kidney) Cancer, Transitional Cell Cancer of the Ureter and Renal Pelvis, Retinoblastoma,Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma (such as Ewing's Family of Tumors, Kaposi's Family, Soft Tissue, Uterine), Sézary Syndrome, Skin Cancer (such as Melanoma, Merkel Cell Carcinoma, Non-melanoma), Small Cell Lung Cancer, Small Bowel Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, Metastatic Stomach Cancer (Gastric), Supratentorial Primary Neuroectodermal Tumors, T-Cell Lymphoma (Cutaneous, Mycosis Fungoides and Sézary Syndrome), Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Trophoblastic Tumor (Gestational), Primary Unknown, Cancers, Petition 870220002363, dated 10 / 01 / 2022, page 83 / 422 80 / 412 uncommon childhood cancers, Transitional Cell Cancer of the Renal Pelvis and Ureter, Urethral Cancer, Uterine Cancer, Endometrial Cancer, Uterine Sarcoma, Waldenstrom's Macroglobulinemia or Wilms' Tumor.

[0464] In certain modalities, the cancer to be treated is a specific T-cell cancer, such as T-cell lymphoma and lymphoblastic T-cell leukemia.

[0465] In certain embodiments, the methods described in this document are used to treat a disease condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the condition is cancer that has developed resistance to chemotherapeutic drugs and / or ionizing radiation.

[0466] In certain embodiments, the pharmaceutical compounds and compositions of the present disclosure may be useful in the treatment or prevention of an inflammatory disease.

[0467] In certain embodiments, the compounds of the present disclosure may be used to prevent or treat inflammatory disease, wherein the inflammatory disease is one or a variant of acid-induced lung injury, acne (PAP), acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, aging, AIDS, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, angina pectoris, angioedema, anhidrotic ectodermal dysplasia (e.g. with immune deficiency), Petition 870220002363, dated 10 / 01 / 2022, page 84 / 422 81 / 412 ankylosing spondylitis, anterior segment inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, Behcet's disease, Bell's palsy, berylliosis, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysm, chemical irritant-induced inflammation, chorioretinitis, chronic heart failure, chronic lung disease of prematurity, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue disease, corneal ulcer, Crohn's disease, cryopyrin-associated periodic syndromes, cryptococcosis, cystic fibrosis, interleukin-1 receptor antagonist deficiency, dermatitis, endotoxemia of dermatitis, dermatomyositis, endometriosis, endotoxemia, epicondylitis, erythroblastopenia,Familial amyloidotic polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerular nephritis, gout, gouty arthritis, graft-versus-host disease, intestinal diseases, head injury, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Scholein purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster and simplex, HIV-1, Huntington's disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia D with recurrent fever, hypoplastic anemia and other anemias, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, incontinence pigmenti, infectious mononucleosis, disease, Petition 870220002363, dated 10 / 01 / 2022, page 85 / 422 82 / 412 inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, iritis, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney injury caused by parasitic infections, kidney transplant rejection prophylaxis, leptospirosis, Loeffler's syndrome, lung injury, lupus, lupus nephritis, meningitis, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria, deafness, amyloidosis), multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungoides, myelodysplastic syndrome, myositis, nasal sinusitis, necrotizing enterocolitis, neonatal-onset multisystem inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological diseases, non-allergen-induced asthma, obesity, ocular allergy, optic neuritis, organ transplant, osteoarthritis, otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease.Pemphigus, pericarditis, periodic fever, periodontitis, whooping cough, perineal or peritoneal endometriosis, pharyngitis and adenitis (PFAPA syndrome), plant irritant-induced inflammation, pneumocystosis infection, pneumonia, pneumonitis, poison ivy / urushiol oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psychosocial stress disorder, lung disease, pulmonary fibrosis, pulmonary hypertension, pyoderma gangrenosum, pyogenic sterile arthritis, kidney disease, retinal disease, rheumatic disease, rheumatoid arthritis, rheumatic carditis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell anemia, silica-induced diseases, Sjögren's syndrome, skin diseases, sleep apnea, spinal cord injury, Petition 870220002363, dated 10 / 01 / 2022, page 86 / 422 83 / 412 Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, systemic sclerosis (scleroderma), temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplantation, TNF receptor-associated periodic syndrome (TRAPS), toxoplasmosis, transplantation, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticaria, uveitis, Wegener's granulomatosis, and weight loss.

[0468] Thus, in another aspect, certain modalities provide methods for treating a disorder mediated by the MCT4 monocarboxylate transporter in a subject who needs it, characterized by comprising the step of administering to said patient a compound, as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0469] In certain modalities, the subject is a human being.

[0470] In certain modalities, the disorder mediated by the monocarboxylate transporter MCT4 is chosen from among an inflammatory disorder and a proliferative disorder.

[0471] In certain forms, the disorder mediated by the monocarboxylate transporter MCT4 is a proliferative disorder.

[0472] In certain forms, the proliferative disorder is cancer.

[0473] In certain modalities, the cancer is chosen from among adenocarcinoma, adult T-cell leukemia / lymphoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectal cancer, esophageal cancer, cancer Petition 870220002363, dated 10 / 01 / 2022, page 87 / 422 84 / 412 gastrointestinal, glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer, head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, bowel cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, eye cancer, optic nerve tumor, oral cancer, ovarian cancer, pituitary tumor, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, sarcoma, skin cancer, spinal tumor, small bowel cancer, stomach cancer, T-cell lymphoma, testicular cancer, thyroid cancer, throat cancer, urogenital cancer, urothelial carcinoma, uterine cancer, vaginal cancer, and Wilms' tumor.

[0474] In certain modalities, the disorder mediated by the monocarboxylate transporter MCT4 is an inflammatory disorder.

[0475] In certain modalities, the inflammatory disorder is chosen from among Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma).

[0476] Also provided herein is a compound, as disclosed herein, or a pharmaceutically acceptable salt thereof, for use in human therapy.

[0477] Also provided is a compound, as disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder mediated by the monocarboxylate transporter MCT4, by Petition 870220002363, dated 10 / 01 / 2022, page 88 / 422 85 / 412 example, as revealed in any of the modalities and paragraphs above that pertain to treatment methods.

[0478] Also provided herein is the use of a compound, as disclosed herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament to treat a disorder mediated by the MCT4 monocarboxylate transporter, for example, as disclosed in any of the above embodiments and paragraphs pertaining to treatment methods.

[0479] Metabolic syndrome (also known as metabolic syndrome X) is characterized by having at least three of the following symptoms: insulin resistance; abdominal fat – in men this is defined as a waist circumference of 101.6 centimeters (40 inches) or greater, in women 88.9 centimeters (35 inches) or greater; high blood sugar levels – at least 110 milligrams per deciliter (mg / dL) after fasting; high triglycerides – at least 150 mg / dL in the bloodstream; low HDL – less than 40 mg / dL; prothrombotic state (e.g., high levels of plasminogen activator inhibitor or fibrinogen in the blood); or blood pressure of 130 / 85 mmHg or higher. A connection has been found between metabolic syndrome and other conditions such as obesity, high blood pressure, and high LDL cholesterol levels, all of which are risk factors for cardiovascular disease. For example, an increased link has been shown between metabolic syndrome and atherosclerosis.People with metabolic syndrome are also more likely to develop type 2 diabetes, as well as PCOS (polycystic ovary syndrome) in women and prostate cancer in men. Petition 870220002363, dated 10 / 01 / 2022, page 89 / 422 86 / 412

[0480] As described above, insulin resistance can manifest in several ways, including type 2 diabetes. Type 2 diabetes is the condition most obviously linked to insulin resistance. Compensatory hyperinsulinemia helps maintain normal glucose levels, often for decades, before explicit diabetes develops. Eventually, the beta cells of the pancreas are unable to overcome insulin resistance through hypersecretion. Glucose levels rise, and a diagnosis of diabetes can be made. Patients with type 2 diabetes remain hyperinsulinemic until they are in an advanced stage of the disease. As described above, insulin resistance can also correlate with hypertension. Half of patients with essential hypertension are insulin resistant and hyperinsulinemic, and there is evidence that blood pressure is linked to the degree of insulin resistance.Hyperlipidemia is also associated with insulin resistance. The lipid profile of patients with type 2 diabetes includes increased serum levels of triglycerides and very low-density lipoprotein cholesterol, and sometimes a decreased level of low-density lipoprotein cholesterol. Insulin resistance has been found in people with low levels of high-density lipoprotein. Insulin levels have also been linked to the synthesis of very low-density lipoprotein and plasma triglyceride levels.

[0481] Consequently, methods are also revealed for treating insulin resistance in a subject comprising selecting a subject who needs treatment for insulin resistance; and administering to the subject an effective amount of a compound that inhibits MCT4. Petition 870220002363, dated 10 / 01 / 2022, page 90 / 422 87 / 412

[0482] The specific diseases to be treated by the compounds, compositions, and methods disclosed herein are those mediated, at least in part, by MCT4. Consequently, methods are disclosed herein: to reduce glycogen accumulation in a subject; to raise HDL or HDLc, lower LDL or LDLc, shift LDL particle size from small to normal dense LDL, lower VLDL, lower triglycerides, or inhibit cholesterol absorption in a subject; to reduce insulin resistance, enhance glucose utilization, or lower blood pressure in a subject; to reduce visceral fat in a subject; to reduce serum transaminases in a subject; or to treat disease; all of which comprise administering a therapeutic amount of a compound as described herein to a patient in need thereof. In further embodiments, the disease to be treated may be a metabolic disease.In an additional modality, the metabolic disease may be selected from the group consisting of: obesity, diabetes mellitus, especially type 2 diabetes, hyperinsulinemia, glucose intolerance, metabolic syndrome X, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, and hepatic steatosis. In other modalities, the disease to be treated may be selected from the group consisting of: cardiovascular diseases including vascular disease, atherosclerosis, coronary heart disease, cerebrovascular disease, heart failure, and peripheral vascular disease. In preferred modalities, the above methods do not result in the induction or maintenance of a hypoglycemic state.

[0483] In addition to being useful for human treatment, certain compounds and formulations disclosed in Petition 870220002363, dated 10 / 01 / 2022, page 91 / 422 88 / 412 of this document may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents and similar animals. The most preferred animals include horses, dogs and cats.

[0484] List of Abbreviations

[0485] Ac2O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = aqueous; BAST = bis(2-methoxyethyl)aminosulfur trifluoride; BCECF = 2',7'-bis-(carboxyethyl)-5(6)carboxyfluorescein; Bu = butyl; Bu3SnH = tributyltin hydride; CD3OD = deuterated MeOH; CDCl3 = deuterated chloroform; CDI = 1,1'-carbonyldiimidazole; DAST = (diethylamino)sulfur trifluoride; dba = dibenzylideneacetone; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DIAD = diisopropyl azodicarboxylate; DIBAL-H = diisobutylaluminum hydride; DIEA = DIPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = N,N-dimethylformamide; DMSO-d6 = deuterated dimethyl sulfoxide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphorylazide; dppf = 1,1'-bis(diphenylphosphino)ferrocene; EDC^HCl = EDCI*HCl = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et = ethyl; Et2O = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; h = hour; HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium methanaminium hexafluorophosphate; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; i-Pr = isopropyl = 2-propyl; i-PrOH = isopropanol; LAH = lithium aluminum hydride; LDA = lithium diisopropylamide; LiHMDS = lithium bis(trimethylsilyl)amide; MeCN = acetonitrile; MeI = methyl iodide; MeOH = MeOH; MP-carbonate resin = resin. Petition 870220002363, dated 10 / 01 / 2022, p. 92 / 422 89 / 412 of macroporous triethylammonium methylpolystyrene carbonate; MsCl = mesyl chloride; MTBE = tertiary methyl(butyl) ether; n-BuLi = n-butyllithium; NaHMDS = sodium bis(trimethylsilyl)amide; NaOEt = sodium ethoxide; NaOMe = sodium methoxide; NaOtBu = sodium t-butoxide; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NIS = niodosuccinimide; NMP = N-methyl-2-pyrrolidone; Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium(0); Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0); PdCl2(PPh3)2 = bis(triphenylphosphine)palladium(II) dichloride; PG = protecting group; Ph = phenyl; prep-HPLC = preparative high-performance liquid chromatography; PMBCl = para-methoxybenzyl; PMBCl = para-methoxybenzyl chloride; PMBOH = paramethoxybenzyl alcohol; PyBop = (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; Pyr = pyridine; TA = room temperature; RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; sat.= saturated; ss = saturated solution; tBu = t-Bu = tert-butyl = 1,1-dimethylethyl; TBAF = tetrabutylammonium fluoride; TBDPS = t-butyldiphenylsilyl; t-BuOH = tert-butanol; T3P = propylphosphonic anhydride; TEA = Et3N = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; TIPS = triisopropylsilyl; Tol = toluene; TsCl = tosyl chloride; Trt = trityl = (triphenyl)methyl; Xantphos = 4,5Bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. Petition 870220002363, dated 10 / 01 / 2022, p. 93 / 422 90 / 412

[0487] General synthetic methods for preparing compounds

[0488] The following diagrams can be used to practice the present invention. shown in Scheme I. A suitably substituted 2,4-diketobutanoic ester is reacted with a substituted hydrazine to form the pyrazole nucleus. Reduction of the ester generates a hydroxymethyl compound. The side chain can be completed via direct alkylation with a 2-haloester, as shown in route (a). Alternatively, the hydroxymethyl functionality is converted to a halomethyl group, which can undergo displacement with a 2-hydroxyester, as shown in route (b), or be transformed via Wittig chemistry, as shown in route (c) to generate an alkene. Petition 870220002363, dated 10 / 01 / 2022, p. 94 / 422 91 / 412 Scheme II (a) i) BuLi Rioo* _____________________ 201 ü) MeCON(Me)(OMe) MeOOC-COOMe

[0490] Scheme II, shown above, can be used to prepare certain examples revealed in this document. In step (a), the organohalide 201 is converted into an organolithium, followed by condensation with the substituted acetamide to generate acetyl-functionalized compound 202. This compound is reacted in step (b) under Claisen conditions with an oxalate ester to generate 2,4-diketoester 203, which is then reacted with a substituted hydrazine in step (c) to construct the pyrazole core of 204. The ester functionality is reduced in step (d), and in step (e) the resulting alcohol 205 is alkylated with a suitable haloacetate ester, yielding ether 206. Finally, the ester is hydrolyzed in step (f) under basic conditions to yield carboxylic acid 207. In the scheme as represented, R100 to R103 will be understood by a person skilled in the art to be any suitable group.For example, in certain embodiments, R100 and R101 can be independently selected from among aryl, cycloalkyl, heterocycloalkyl, and heteroaryl. Petition 870220002363, dated 10 / 01 / 2022, p. 95 / 422 92 / 412 any of which is optionally substituted. Similarly, in certain embodiments, R102 and R103 may be independently selected from hydrogen, alkyl, and halogen. R100 to R103 may also correspond to the groups defined in Formula I, II, or any other formula disclosed herein. Finally, this scheme may be joined at any point by employing a suitable intermediate shown herein which is available from commercial sources or alternative synthetic methods. Scheme III

[0491] Scheme III, shown above, can be used to synthesize certain exemplary compounds disclosed in this document. Steps (a) to (d) of Scheme I are used to obtain pyrazolmethanol 301, which is then converted to bromomethyl compound 302 in step (e), using one of several techniques available for this transformation. The alkyl halide 302 is then reacted under Williamson ether conditions with a hydroxy ester in step (f) to generate 303. The synthesis is then completed in step (g) by ester hydrolysis to 304. Petition 870220002363, dated 10 / 01 / 2022, page 96 / 422 93 / 412 Scheme IV

[0492] Scheme IV, represented above, can be used for certain exemplary compounds disclosed in this document. Steps (a) to (d) of Scheme I are used to obtain pyrazolmethanol 401, which is alkylated to generate tBu ester 402. The cleavage of the ester is carried out under acidic conditions, to generate acid 403. Scheme V

[0493] Scheme V, shown above, can be used for certain exemplary compounds revealed. Petition 870220002363, dated 10 / 01 / 2022, p. 97 / 422 94 / 412 in this document. Steps (a) to (e) of Scheme III are used to obtain (bromomethyl)pyrazole 501. The reaction with a hydroxy ester under basic conditions generates tBu ester 502. The cleavage of the ester is carried out under acidic conditions, to generate acid 503. Scheme VI Scheme II (d) - (f) or Scheme III (d) - (g)

[0494] Scheme VI, shown above, can be used to prepare certain exemplary compounds disclosed in this document. Phenylacetone is condensed with an oxalate ester to generate the 5-phenylpentanoate ester 601. Condensation with substituted hydrazine forms the pyrazole nucleus of 602. Ester reduction, alcohol alkylation, and ester hydrolysis proceed as before. The synthesis of acid 603 is completed using steps (d) to (f) of Scheme II, or steps (d) to (g) of Scheme III. Petition 870220002363, dated 10 / 01 / 2022, p. 98 / 422 95 / 412 MeOOC-COOMe Scheme II (d) - (f) base R134θ to be or Scheme III (d) - (g)

[0495] used for Scheme VII, represented above, can synthesize certain exemplary compounds disclosed in this document. The acetylated hydroxyaryl compound 701 reacts under ether conditions Williamson with an alkyl halide or similar compound yielding alkoxyaryl compound 702. Condensation with an oxalate ester yields a 2,4-diketoester 703 as in Scheme II. The synthesis is completed using steps (d) to (f) of Scheme II, or steps (d) to (g) of Scheme III. Scheme VIII D íir 801 Petition 870220002363, dated 10 / 01 / 2022, p. 99 / 422 96 / 412

[0496] Scheme VIII, represented above, can be used to synthesize certain exemplary compounds disclosed in this document. Bromoaryl compound 801 is converted to methoxyaryl compound 802 in the presence of a suitable metal catalyst in the presence of a base. The methyl ether is cleaved with a Lewis acid. The resulting hydroxyl compound is reacted under Williamson ether conditions to generate alkoxyaryl compound 803. Alternatively, the bromoaryl compound is reacted directly with an alcohol of interest to produce the desired ether 803 directly. In the scheme as represented, R100 to R106 will be understood by a person skilled in the art to be any suitable group. The synthesis of 804 is completed using steps (c) to (f) of Scheme II, or steps (c) to (g) of Scheme III. Scheme IX Petition 870220002363, dated 10 / 01 / 2022, page 100 / 422 97 / 412

[0497] Scheme IX, shown above, can be used to synthesize certain exemplary compounds disclosed in this document. The bromoaryl compound 901 is converted to (bromomethyl)pyrazole 904. The compound is reacted under Williamson ether conditions with a suitable glycol ester to generate ether 905. Transesterification to methyl ester 905 is followed by displacement of the aryl bromide using a suitable Pd° catalyst. The synthesis is completed by basic hydrolysis of the methyl ester, yielding acid 906. Scheme X

[0498] Scheme X, shown above, can be used to synthesize certain exemplary compounds disclosed in this document. The chloroaryl carboxylic ester 1001 is coupled with an organozinc reagent in the presence of copper(I) iodide to generate 1002. The ester functionality is converted to methyl ketone 1003. Condensation with diethyl oxalate generates the α-diketone compound. The synthesis of 1004 is completed using steps (c) to (f) of Scheme II, or steps (c) to (g) of Scheme III. Petition 870220002363, dated 10 / 01 / 2022, page 101 / 422 98 / 412 Scheme XI

[0499] Scheme XI, shown above, can be used to synthesize certain exemplary compounds disclosed in this document. Pyrazole ester 1101 is obtained through steps (a) to (c) of Scheme II. The compound is coupled under Mitsunobu conditions with a suitable alcohol to generate the alkylated product 1102. The synthesis of acid 1103 is completed using steps (d) to (f) of Scheme II, or steps (d) to (g) of Scheme III. Scheme XII

[0500] Scheme XII, shown above, can be used to synthesize certain exemplary compounds disclosed in this document. Pyrazole ester 1201 is obtained through steps (a) to (c) of Scheme Petition 870220002363, dated 10 / 01 / 2022, page 102 / 422 99 / 412 II. The compound is coupled with an alkyl halide in the presence of a base to generate 12O2. The synthesis of acid 12O3 is completed using steps (d) (f) of Scheme II, or steps (d) to (g) of Scheme III. R 1302 Scheme III (d) - (g) Rio O , □ NN N(CH2R.llc)2 1303 N(CH2RllD)2

[0501] Scheme XIII, shown above, can be used to prepare certain exemplary compounds disclosed in this document. A 2,4-diketoester is condensed with a nitroaromatic compound, such as 4-nitroaniline, to generate pyrazole chemical moiety 1301. Reduction of the nitro group is followed by reductive amination to generate a (dialkyl)amino compound 1302. The synthesis of acid 1303 is completed using steps (d) to (f) of Scheme II, or steps (d) to (g) of Scheme III. Petition 870220002363, dated 10 / 01 / 2022, p. 103 / 422 100 / 412 Scheme XIV nh2nh2 1} Znc 2} R.l1oCHO, NaCNKHa Scheme II (d) - (f) or Scheme III (d) - (g) N(CHsR11c)s N(GH2R11c)2

[0502] Scheme XIV, shown above, can be used to synthesize certain exemplary compounds disclosed in this document. A 2,4-diketoester is condensed with hydrazine to form pyrazole 1401, which is then alkylated with a substituted benzyl bromide to give 1402. Reduction to the amine is followed by reductive alkylation to generate substituted amine 1403. The synthesis of acid 1404 is completed by using steps (d) to (f) of Scheme II, or steps (d) to (g) of Scheme III. Petition 870220002363, dated 10 / 01 / 2022, p. 104 / 422 101 / 412 Scheme XV R 1C2-^-P 103 üHC COüiBu base

[0503] Scheme XV, shown above, can be used to synthesize certain exemplary compounds disclosed in this document. (Bromomethyl)pyrazole 1501, obtained via steps (a) to (e) of Scheme II, is converted to phosphonium salt 1502. Treatment with a base forms phosphorane ylide 1503; Wittig reaction with an aldehyde generates alkene 1504. The alkene can optionally be hydrogenated to generate alkane 1506. The synthesis is completed by ester hydrolysis which generates alkene 1505 or alkane 1507, respectively. Petition 870220002363, dated 10 / 01 / 2022, p. 105 / 422 102 / 412 Scheme XVI MeOOC-COOMe t-BuOK NC CH3CN OK An THE i) H 1601 R101NHNH2 H2N N 1602 R101 R-112X R101 Boc2O Pd(0); base 1603 DMAP Rl -| 2 N Goat R-101 1604 1)[H] R103O RlO2^M 2) XC(R102)(Rio3)-COOCH3 OH 3) OH Rl -| 2 N1IBoCR101 1605 H Rl03,O Rl02 R-ιοί 1606 ser

[0504] Scheme XVI shown above can be used to prepare certain exemplary compounds disclosed in this document. Acetonitrile is condensed with an oxalate ester to generate a ketoester product, which can be isolated as its salt 1601. Neutralization of the salt is followed by condensation with a substituted hydrazine to generate a 5-aminopyrazole compound 1602. The amino functionality is then replaced by reaction with an organohalide in a palladium (0)-mediated reaction, yielding 1603, and then protected as its Boc carbamate 1604. Ester reduction, alcohol alkylation, and ester hydrolysis proceed as before to generate acid 1605. The Boc protecting group is removed under acidic conditions, yielding 1606. Petition 870220002363, dated 10 / 01 / 2022, p. 106 / 422 103 / 412 Scheme XVII Scheme II (d) - (f) or Scheme III (d) - (g)

[0505] Scheme XVII, shown above, can be used to prepare certain exemplary compounds disclosed in this document. The 2-ketosuccinate ester is condensed with a substituted hydrazine to generate the 5-hydroxypyrazole compound 1701, shown here as its keto tautomer. The hydroxy group is alkylated with an electrophilic arene, such as 2-fluoronitrobenzene, generating ether 1702. The nitro functionality is removed by stepwise reduction with zinc (0) to amine 1703, followed by deamination with alkyl nitrite, yielding 1704. The synthesis of acid 1705 is completed using steps (d) to (f) of Scheme II, or steps (d) to (g) of Scheme III. Petition 870220002363, dated 10 / 01 / 2022, page 107 / 422 104 / 412 Scheme XVIII

[0506] Scheme XVIII, shown above, can be used to prepare certain exemplary compounds disclosed in this document. Nitro acetophenone 1801 is reacted under Claisen conditions with an oxalate ester to generate 2,4-diketoester 1802, which is then reacted with a substituted hydrazine in step (c) to construct the pyrazole core of 1803, which is alkylated to give 1804. The ester functionality is reduced to the alcohol (not shown) and alkylated to generate ester 1805. At this point, the nitro group is reduced with zinc to generate amine. Petition 870220002363, dated 10 / 01 / 2022, p. 108 / 422 105 / 412 1806, and acylated using standard coupling reagents to generate amide 1807. The synthesis is completed with basic hydrolysis of the ester, yielding carboxylic acid 1808.

[0507] Scheme XIX, shown above, can be used to prepare certain compounds. Petition 870220002363, dated 10 / 01 / 2022, page 109 / 422 106 / 412 exemplary methods disclosed in this document. In route (a), amine 1806, prepared using the Scheme XVIII method, is treated with an organonitrile in the presence of a disulfide to provide a thioether, which is oxidized to sulfone 1901. In route (b), amine 1806 is reacted with a sulfonyl chloride to generate sulfonamide 1903. In route (c), amine 1806 is treated with an aldehyde under reductive amination conditions to generate amine 1905. In routes (a), (b), and (c), the synthesis is completed with basic hydrolysis of the ester, providing carboxylic acids 1902, 1904, and 1906, respectively. Scheme XX used to prepare certain exemplary compounds disclosed in this document. Benzyl ether 206 is prepared using steps (a) to (e) of Scheme II. Treatment with acid cleaves both the ether and ester groups. Petition 870220002363, dated 10 / 01 / 2022, p. 110 / 422 107 / 412 methyl to generate acid 2001. If desired, the synthesis can be continued by Fischer esterification to 2002, alkylation of the phenol under basic conditions, and hydrolysis of the methyl ester to generate acid 2003. Scheme XXI

[0509] Scheme XXI, shown above, can be used to prepare certain exemplary compounds disclosed in this document. Carboxylic acid 207 is prepared using steps (a) to (f) of Scheme II. Treatment of the acid with an alkylsulfonamide yielded ester 2101. Scheme XXII THE

[0510] Scheme XXII, represented above, can be used to prepare certain exemplary compounds disclosed in this document. Aryl-lithium 2201, prepared by lithification, halogen-metal exchange, or other methods available in the art, is reacted with N-methyl-N-methoxyacetamide, which provides the acetyl compound 2202, which can be transformed into the desired product via any of the preceding schemes. Petition 870220002363, dated 10 / 01 / 2022, p. 111 / 422 108 / 412 Scheme XXIII 0 Ar^OH H2NCH3(OCH3) j? i) CH3Li j? _________> Ar''Ή' 3 ________ Ar^CH3 0CH3 ii) H+ / H2O 2301 2302 2303

[0511] Scheme XXIII, shown above, can be used to prepare certain exemplary compounds disclosed in this document. The carboxylic acid 2301 is converted to the corresponding alkoxyamide 2302 using standard amide-forming procedures. The alkoxyamide is then reacted with an appropriate organolithium reagent, which provides the ketone compound 2303, which can be transformed into the desired product via any of the preceding schemes. Scheme XXIV

[0512] Scheme XXIV, shown above, can be used to prepare certain exemplary compounds disclosed herein. Aryl halide 2401, prepared using any of the methods disclosed herein, is converted into the corresponding arylamine 2402. This transformation can be achieved with a copper-based catalyst, or other techniques known in the art. The synthesis can then be completed using methods disclosed herein. Petition 870220002363, dated 10 / 01 / 2022, p. 112 / 422 109 / 412 Scheme XXV

[0513] Scheme XXV, shown above, can be used to prepare certain exemplary compounds disclosed herein. Aryl halide 2501, prepared using any of the methods disclosed herein, is converted into the corresponding arylamide 2502. This transformation can be achieved with a copper-based catalyst, or other techniques known in the art. The synthesis can then be completed using methods disclosed herein. Examples disclosed in this document. Aryl halide 2601, prepared using any of the methods disclosed in this document, is converted into the corresponding arylnitrile 2602. This transformation can be achieved with Petition 870220002363, dated 10 / 01 / 2022, p. 113 / 422 110 / 412 a Pd-based catalyst, or other techniques known in the art. The synthesis can then be completed using methods disclosed in this document. Scheme XXVII

[0515] Scheme XXVII, shown above, can be used to prepare certain exemplary compounds disclosed herein. Carboxylic acid 2701, prepared using any of the methods disclosed herein, is converted into the corresponding carboxylate salt 2702. This transformation can be achieved with a metal hydroxide or metal oxide. The metal can be chosen from alkali metals, alkaline earth metals, or other metals. Rioi-Br 2801 1) t-BuCONHNH2 BrettPhos Pd G3 R101-NHNH2 2) H+ / H2O 2802 R R101 OO THE Scheme XXVIII

[0516] Scheme XXVIII, shown above, can be used to prepare certain exemplary compounds disclosed in this document. An aryl or heteroaryl halide 2801 is converted into hydrazine Petition 870220002363, dated 10 / 01 / 2022, page 114 / 422 111 / 412 corresponding to 2802. The synthesis of the pyrazole nucleus is achieved by condensation with an appropriate carbonyl compound, as disclosed herein. The amine functionality in the aryl or heteroaryl chemical moiety of 2801 can be protected by attachment of a suitable protecting group, such as the SEM protecting group. The protecting group can be removed at a convenient point in synthesis using methods known in the art. Petition 870220002363, dated 10 / 01 / 2022, page 115 / 422 112 / 412 Intermediaries

[0517] The following intermediates were synthesized for use in the preparation of the compounds of this disclosure. Intermediate A-1: ​​1-(1-methyl-1H-indol-6-yl)ethan-1-one

[0518] 6-bromo-1-methyl-1H-indol A mixture of 6-bromo-1H-indol (5 g, 25.50 mmol, 1.00 equiv), K2CO3 (7 g, 50.65 mmol, 2.00 equiv), and CH3I (7.3 g, 51.43 mmol, 2.00 equiv) in acetone (100 mL) was stirred for 16 h at 55 °C, then cooled to rt, diluted with 100 mL of H2O, and extracted with 2x200 mL of EtOAc. The combined organic layers were washed with 100 mL of brine, dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:10) to give 3.4 g (63%) of the title compound as a yellow oil. LC-MS: (ES, m / z): 208.1H NMR (300 MHz, DMSO-d6) δ 7.69 (dt, J = 1.6, 0.7 Hz, 1H), 7.49 (dd, J = 8.4, 0.6 Hz, 1H), 7.34 (d, J = 3.1 Hz, 1H), 7.13 (dd, J = 8.4, 1.8 Hz, 1H), 6.43 (dd, J = 3.1, 0.9 Hz, 1H), 3.77 (s, 3H).

[0519] 1-(1-methyl-1H-indol-6-yl)ethan-1-one A solution of 6-bromo-1-methyl-1H-indol (3.4 g, 16.19 mmol, 1.00 equiv) in THF (100 mL) BuLi (12 mL, 2.00 equiv, 2.5 M) was added dropwise with stirring at -78 °C. The solution was stirred for 1 h, then N-methoxy-N-methylacetamide (4.1 g, 39.76 mmol, 2.50 equiv) was added dropwise with stirring at -78 °C. The solution was stirred for 30 min, then Petition 870220002363, dated 10 / 01 / 2022, p. 116 / 422 113 / 412 heated to rt and stirred for an additional 2 h. The reaction mixture was cooled to 0 °C, then rapidly cooled by the addition of 1 M HCl and extracted with 2 x 200 mL of EtOAc. The combined organic layers were washed with 100 mL of brine, dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:5) to give 1.9 g (68%) of the title compound as a yellow solid. LC-MS: (ES, m / z): 173. 1H NMR: (300 MHz, DMSO-d 6) δ 8.12 (dt, J = 1.5, 0.8 Hz, 1H), 7.70 7.59 (m, 2H), 7.57 (d, J = 3.0 Hz, 1H), 6.51 (dd, J = 3.0, 0.9 Hz, 1H), 3.88 (s, 3H), 2.63 (s, 3H). Intermediate A—2: 1—(1—methyl—1H—indazol—6—yl)ethan—1-one

[0520] 1-(1-methyl-1H-indazol-6-yl)ethan-1-one To a solution of 6-bromo-1-methyl-1H-indazole (2.5 g, 11.85 mmol, 1.00 equiv) in THF (50 mL) under N2 at -78 °C, nBuLi (10 mL, 2.00 equiv) was added dropwise with stirring. The solution was stirred for 60 min at this temperature, then N-methoxy-N-methylacetamide (3 g, 29.09 mmol, 2.50 equiv) was added, and the solution was stirred for a further 60 min at this temperature. The resulting solution was stirred for 1 h at room temperature, cooled to 0 °C, rapidly cooled by the addition of HCl (1M), and extracted with 2 x 100 mL of EtOAc. The combined organic layers were washed with 50 mL of brine, dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:10) to yield 1.5 g (73%) of the title compound as a Petition 870220002363, dated 10 / 01 / 2022, p. 117 / 422 114 / 412 yellow oil. LC-MS: (ES, m / z): 174. 1H NMR: (400 MHz, DMSOd 6) δ 8.36 (q, J = 1.1 Hz, 1H), 8.16 (d, J = 1.0 Hz, 1H), 7.86 (dd, J = 0.5 Hz, 1.69 Hz), (dd, J = 8.5, 1.4 Hz, 1H), 4.16 (s, 3H), 2.70 (s, 3H).

[0521] The following acetyl arenes were obtained from similar routes. Table 1: Synthesis of acetyl arenes from aryl bromides. Aryl bromate Spectral Product 1-bromo-3(propan-2yl)benzene 1-[3-(propan-2yl)phenyl]ethane-1- one A-3 6-bromo-1-ethyl- 1H-indazole 1-(1-ethyl-1Hindazol-6- yl)ethane-1-one A-4-1-MS LC / 189 : LC. (ES, 1-bromo-3-chloro- 5-methoxybenzene 1- (3-chloro-5methoxyphenyl)ethan- 1-one A-5 LC-MS m / z) : 182. (ES, 5-bromo-1-methyl- 1H-indazole 1-(1-methyl-15-Hyndazole) LC-MS m / z) : 174. (ES, 4-bromo-1-methyl- 1H-indazole 1-(1-methyl-1Hindazol-4yl)ethane-1-one A-7 LC-MS m / z) : 1,2,3- benzotriazole-6yl)ethane-1-one A-8 LC-MS m / z) 189. (ES, Petition 870220002363, dated 10 / 01 / 2022, p. 118 / 422 115 / 412

[0522] The following acetyl arene intermediates were prepared using Scheme XXII. Intermediate A—9: 1-(3-cyclobutoxyphenyl)ethan-1—one O

[0523] To a mixture of 1-(3-hydroxyphenyl)ethan1-one (4.5 g, 33.05 mmol, 1.00 equiv) and Cs2CO3 (10.78 g, 33.09 mmol, 1.00 equiv) in DMA (50 mL) bromocyclobutane (9.0 g, 66.67 mmol, 2.00 equiv) was added dropwise with stirring at rt. The resulting mixture was stirred for 16 h at 130 °C, then cooled and diluted with 200 mL of EtOAc. The combined organic layers were washed with 2 x 200 mL of H2O and 2 x 200 mL of brine, then dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:10) to provide 5.0 g (80%) of the title compound as colorless oil. 1H NMR: (300 MHz, DMSO-d 6) δ 7.53 (ddd, J = 7.6, 1.7, 1.1 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.32 (dd, J = 2.6, 1.6 Hz, 1H), 7.10 (ddd, J = 8.1, 2.7, 1.0 Hz, 1H), 4.83 - 4, 67 (m, 1H), 2.55 (s, 3H), 2.47 - 2.31 (m, 2H), 2.14 - 1.94 (m, 2H), 1.88 - 1.72 (m, 1H), 1.72 - 1.56 (m, 1H). Intermediate A—10: 1 — [3—(oxetan—3— ylmethoxy)phenyl]etan—1—one

[0524] A solution of oxetan-3-ylmethanol (3.24 g, 36.77 mmol, 1.00 equiv) in THF (100 mL) and 1-(3-hydroxyphenyl)ethan-1-one (5 g, 36.72 mmol) were combined in a flask under N2. Petition 870220002363, dated 10 / 01 / 2022, p. 119 / 422 116 / 412 1.00 equiv), and PPh3 (14.5 g, 1.50 equiv), followed by the addition of DEAD (8.3 g, 47.66 mmol, 1.30 equiv) by dropwise stirring at 0 °C. The resulting solution was stirred for 12 h at rt, then extracted with EtOAc. The combined organic layers were dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography with EtOAc / petroleum ether (0 to 20%) to give 4.4 g (58%) of the title compound as a light yellow oil. LC-MS: (ES, m / z): 206.90. H-NMR: δ h (300 MHz, DMSO-d 6) 7.56 (1 H, ddd, J =7.6, 1.6, 1.0 Hz), 7.45 (2 H, m), 7.23 (1 H, ddd, J =8.2, 2.7, 1.1 Hz), 4.71 (2 H, dd, J= 7.9, 6.0 Hz), 4.44 (2 H, t, J= 6.0, 6.0 Hz), 4.26 (2 H, d, J= 6.7 Hz),3.39 (1 H, m), 2.57 (3 H, s).

[0525] The following alkylated compounds were obtained from the Williamson synthesis of 3-hydroxyacetophenone. Table 2: Williamson synthesis of alkoxy acetophenones. Alkyl halide Base / solvent Temperature Product Spectral 3-bromo-oxetane Cs2CO3 / DMA 130 °C 1-[3-(oxetan- 3-yloxy)phenyl] tan-1-one A- 11 LC-MS: (ES, m / z): 193. Bromocyclopropane Cs2CO3 / DMA 150 °C 1-(3- cyclopropoxyf A- 12 Petition 870220002363, dated 10 / 01 / 2022, p. 120 / 422 117 / 412 enyl)ethan-1-one 1-bromo-2,2dimethylpropane K2CO3 / DMF 110 °C 1- [3-(2,2dimethylpropoxy)phenyl]ethan1-one A- 13 LC-MS: (ES, m / z): 206.9. (Bromomethyl)cyclobutane K2CO3 / DMF 110 °C 1-[3-(cyclobutylmethoxy)phenyl]ethane-1-one A-14 LC-MS: (ES, m / z): 291.25. (Bromomethyl)cyclopropane K2CO3 / DMF 80 °C 1-[3-(cyclopropylmethoxy)phenyl]ethan-1-one A-15 LC-MS: (ES, m / z): 191. Iodoethane K2CO3 / DMF 90 °C 1-(3-ethoxyphenyl)ethan-1-one A-16 LC-MS: (ES, m / z): 165. Benzyl bromide K2CO3 / DMF 80 °C 1-[3-(benzyloxy)phenyl]ethan-1-one A-17 LC-MS: (ES, m / z): 226.95. 1-bromo-2-methylpropane K3PO4 / DMSO 60 °C 1-[3-(2-methylpropoxy)phenyl]ethan-1-one A-18 Petition 870220002363, dated 10 / 01 / 2022, p. 121 / 422 118 / 412 Intermediate A-19: 1-(3,5-dimethoxyphenyl)ethan-1-one THE °\

[0526] In a flask, 1-(3,5-dihydroxyphenyl)ethan-1-one (2 g, 13.15 mmol, 1.00 equiv), iodomethane (6.5 g, 45.79 mmol, 4.00 equiv), K2CO3 (3.6 g, 25.86 mmol, 2.00 equiv), and acetone (40 mL) were combined. The resulting mixture was stirred for 16 hours at 56 °C, then cooled to room temperature, diluted with 100 mL of water, and extracted with 2 x 50 mL of EtOAc. The combined organic layers were washed with 20 mL of brine, dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:10) to give 2 g (84%) of the title product as colorless oil. LC-MS: (ES, m / z): 181. 1H NMR: (300 MHz, DMSO-d 6) δ 7.07 (d, J = 2.3 Hz, 2H), 6.77 (t, J = 2.3 Hz, 1H), 3.89 — 3.71 (m, 6H), 2.56 (s, 3H). Intermediate A-20: 1-(3,5-diethoxyphenyl)ethan-1-one

[0527] In a flask, 1-(3,5-dihydroxyphenyl)ethan-1-one (5 g, 32.86 mmol, 1.00 equiv), iodoethane (20 g, 128.23 mmol, 4.00 equiv), K2CO3 (18 g, 130.43 mmol, 4.00 equiv), and acetone (100 mL) were combined. The resulting mixture was heated under reflux overnight, then cooled at room temperature and extracted with 3 x 100 mL of EtOAc. The combined organic layers were dried with Na2SO4 and concentrated under vacuum. Petition 870220002363, dated 10 / 01 / 2022, p. 122 / 422 119 / 412 to provide 6 g (88%) of the title compound as a brown solid. LC-MS: (ES, m / z): 208.95. Intermediate A—21: 1—(3—ethoxy—5—methoxyphenyl)ethan— 1—one

[0528] 1-(3-hydroxy-5-methoxyphenyl)ethan-1-one To a mixture of 1-(3,5-dihydroxyphenyl)ethan-1-one (5.0 g, 32.86 mmol, 1.00 equiv), K2CO3 (6.85 g, 49.56 mmol, 1.50 equiv), and acetone (100 mL) was added MeI (4.67 g, 32.89 mmol, 1.00 equiv) by dropwise stirring at room temperature. The resulting solution was heated to reflux for 2 h, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:3) to give 2 g (37%) of the title compound as a white solid. LC-MS: (ES, m / z): 167.

[0529] 1-(3-ethoxy-5-methoxyphenyl)ethan-1-one To a mixture of 1-(3-hydroxy-5-methoxyphenyl)ethan-1-one (2 g, 12.04 mmol, 1.00 equiv), K2CO3 (2.5 g, 18.09 mmol, 1.50 equiv), and DMF (50 mL) was added EtI (2.8 g, 17.95 mmol, 1.00 equiv) by dropwise stirring in the rt. The resulting solution was stirred for 16 hours at 90 °C, diluted with 100 mL of EtOAc, washed with 1 x 100 mL of water and 1 x 100 mL of brine, dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:5) to yield 950 mg (41%) of the title compound as a colorless oil. LC-MS: (ES, m / z): 195. 1H-NMR: (DMSO, ppm): δ: Petition 870220002363, dated 10 / 01 / 2022, p. 123 / 422 120 / 412 7.06 (dq, J = 2.9, 1.4 Hz, (q, J = 7.0 Hz, 2H), 2.56 Intermediate oxazol-5-yl]ethan-1-one

[0530] Acid 2H), 6.75 (t, J = 2.3 Hz, 1H), 4.07 (s, 3H), 1.34 (t, J = 6.9 Hz, 3H). A-22: 1-[2-(propan-2-yloxy)-1,32-hydroxy-1,3-oxazole-5-carboxylic acid] A solution of ethyl 2-chloro-1,3-oxazole-5-carboxylate (3 g, 17.09 mmol, 1.00 equiv) and LiOH (1.7 g, 70.98 mmol, 4.00 equiv) in THF / H2O (60 / 15 mL) was stirred for 16 h at 30 °C. The pH was then adjusted to 4 with 1 M HCl, and the resulting solution was extracted with 4 x 50 mL of EtOAc. The combined organic layers were dried with anhydrous Na2SO4 and concentrated under vacuum to provide 2 g (91%) of the title compound as a yellow solid. LC-MS: (ES, m / z): 129.

[0531] 2-hydroxy-N-methoxy-N-methyl-1,3-oxazole-5-carboxamide A solution of N-methoxy-N-methylamine hydrochloride (1.8 g, 18.45 mmol, 1.20 equiv), HATU (7.6 g, 20.54 mmol, 1.30 equiv), DIEA (6 g, 46.43 mmol, 3.00 equiv), and 2-hydroxy-1,3-oxazole-5-carboxylic acid (2 g, 15.50 mmol, 1.00 equiv) in DMF (60 mL) was stirred for 5 h at room temperature. The resulting mixture was concentrated under vacuum and purified by silica gel chromatography using CH2Cl2 / MeOH (50:1) to give 1.3 g (49%) of the title compound as a yellow solid. LC-MS: (ES, m / z): 173.

[0532] N-methoxy-N-methyl-2-(propan-2-yloxy)-1,3oxazol-5-carboxamide A mixture of 2-hydroxy-N-methoxy-N methyl-1,3-oxazol-5-carboxamide (1.8 g, 10.46 mmol, 1.00 equiv), 2-iodopropane (3.6 g, 2.00 equiv), K2CO3 (2.9 g, 2.00 Petition 870220002363, dated 10 / 01 / 2022, pp. 124 / 422 121 / 412 equiv) and DMF (15 mL) in a sealed 20 mL tube was shaken for 16 hours at 90 °C. The reaction mixture was cooled to room temperature, diluted with 20 mL of H2O, and extracted with 4 x 20 mL of EtOAc. The combined organic layers were dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using CH2Cl2 / MeOH (100:1) to provide 1.5 g (67%) of the title compound as a yellow solid. LCMS: (ES, m / z): 214.

[0533] 1-[2-(propan-2-yloxy)-1,3-oxazol-5-yl]ethan-1-one To a solution of N-methoxy-N-methyl-2-(propan-2-yloxy)-1,3-oxazol-5-carboxamide (1.5 g, 7.00 mmol, 1.00 equiv) in THF (40 mL) under N2 at -78 °C was added in portions MeMgBr (21 mL, 3.00 equiv). The resulting solution was stirred for 2 h at room temperature, cooled to 0 °C, rapidly cooled by the addition of HCl (1M), and extracted with 2 x 50 mL of EtOAc. The combined organic layers were washed with 30 mL of brine, dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:10) to give 670 mg (57%) of the title compound as a yellow solid. LC-MS: (ES, m / z): 169. Intermediary A-23:1-[1,3-dimethyl-1H-thieno[2, 3c]pyrazol-5-yl]ethan-1-one

[0534] N-methoxy-N,1,3-trimethyl-1H-thieno[2,3c]pyrazole-5-carboxamide A solution of 1,3-dimethyl-1Hthieno[2,3-c]pyrazole-5-carboxylic acid (2 g, 10.19 mmol, 1.00 equiv), methoxy(methyl)amine hydrochloride (1.06 g, 10.87 mmol, Petition 870220002363, dated 10 / 01 / 2022, p. 125 / 422 122 / 412 1.10 equiv), DIEA (4 g, 30.95 mmol, 3.00 equiv), and HATU (5.8 g, 15.26 mmol, 1.50 equiv) in DMF (30 mL) was stirred for 2 h at room temperature, diluted with 100 mL of water, and extracted with 2 x 100 mL of EtOAc. The combined organic layers were washed with 100 mL of brine, dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:3) to give 2.2 g (90%) of the title compound as a yellow solid. LC-MS: (ES, m / z): 240.

[0535] 1-[1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5yl]ethan-1-one To a solution of the product from the previous step (2.2 g, 9.19 mmol, 1.00 equiv) in THF (50 mL) at -78 °C under N2, methylmagnesium bromide (1.0 M in THF, 29 mL, 3.00 equiv) was added dropwise with stirring. The resulting solution was stirred for 2 h at room temperature, then cooled to 0 °C and then rapidly cooled by the addition of aqueous HCl. The resulting solution was diluted with 100 mL of H2O and extracted with 2 x 200 mL of EtOAc. The combined organic layers were washed with 50 mL of brine, dried with Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography using EtOAc / petroleum ether (1:3) to give 1.4 g (78%) of the title compound as a white solid.

[0536] LC-MS: (ES, m / z): 195.1H NMR (300 MHz, DMSO-d 6) δ 8.04 (s, 1H), 3.86 (s, 3H), 2.52 (s, 4H), 2.39 (s, 3H). Intermediate A—24: 1—(5—methoxythien—2—yl)etan—1—one O Petition 870220002363, dated 10 / 01 / 2022, page 126 / 422 123 / 412

[0537] A mixture of 1-(5-chlorothien-2-yl)-1-ethanone (11 g, 96.35 mmol, 1.00 equiv), CS2CO3 (22 g, 1.20 equiv), and Brettphos Pd G3 (550 mg) in MeOH (60 mL) was heated in a sealed tube for 1 h at 100 °C with microwave radiation. The resulting mixture was concentrated under vacuum, then extracted with 3 x 100 mL of EtOAc. The combined organic layers were dried with MgSO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1 / 50) to provide 5 g (33%) of the title product as a yellow solid. Intermediate A—25: 1 — [2—(2—methylpropoxy)—1,3— thiazol—5—yl]ethan—1—one

[0538] To a solution of 1-(2-bromo-1,3-thiazol-5-yl)ethan-1-one (2 g, 9.71 mmol, 1.00 equiv) in 2-methylpropan-1-ol (15 mL) in a sealed 40 mL tube under N2, Cs2CO3 (6.4 g, 19.64 mmol, 2.00 equiv) and Brettphos Pd G3 (440 mg, 0.49 mmol, 0.05 equiv) were sequentially added. The resulting solution was stirred for 1 hour at 90 °C. The solution was cooled, diluted with 50 mL of H2O, and extracted with 2 x 100 mL of EtOAc. The combined organic layers were washed with 50 mL of aqueous NaCl, dried with anhydrous Na2SO4, concentrated under vacuum, and purified using a silica gel column with EtOAc / petroleum ether (1:10) to provide 550 mg (28%) of the title compound as a yellow oil. Petition 870220002363, dated 10 / 01 / 2022, p. 127 / 422 124 / 412 Intermediate A-26: 1-[5-(2-methylpropoxy)thien-2-yl]ethan-1-one

[0539] 1-(5-hydroxythien-2-yl)ethan-1-one To a solution of 1-(5-methoxythien-2-yl)ethan-1-one, BBr3 (180 mL) was added dropwise with stirring at room temperature. The resulting solution was stirred for 2 days at 35 °C. The reaction mixture was cooled with an ice-water bath. The reaction was then rapidly cooled by the addition of 500 mL of ice-water. The resulting solution was diluted with 500 mL of CH2Cl2. The pH of the solution was adjusted to 7 to 8 with (sat) NaHCO3 (aq) (500 mol / L). The mixture was dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:10). This resulted in the compound being listed as a red oil (5.0 g, 61%).

[0540] 1-[5-(2-methylpropoxy)thien-2-yl]ethan-1-one To a solution of the product from the previous step (800 mg, 5.63 mmol, 1.00 equiv) in DMF (20 mL) was added Cs2CO3 (3.67 g, 11.26 mmol, 2.00 equiv), followed by the addition of 1-iodo-2-methylpropane (2.07 g, 11.25 mmol, 2.00 equiv) by dropwise stirring. The resulting solution was stirred for 16 hours at 90 °C. The resulting solution was diluted with 100 mL of EtOAc, then washed with 2 x 100 mL of water and 2 x 100 mL of brine. The mixture was dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:10). This resulted in the title compound being a yellow oil (600 mg, 54%). Petition 870220002363, dated 10 / 01 / 2022, p. 128 / 422 125 / 412 Intermediate A-27: 1-(4-methoxythien-2-yl)etan-1-one THE MeO

[0541] To a solution of 1-(4-bromothien-2-yl)ethan-1-one (3.0 g, 14.63 mmol, 1.00 equiv) in MeOH (25 mL) was added NaOMe (5.4 mL, 2.00 equiv, 5.4 M) at room temperature, followed by CuBr (627 mg, 4.38 mmol, 0.30 equiv) at room temperature. The resulting solution was stirred for 16 h at 100°C, then diluted with 100 mL of EtOAc, washed with 2 x 100 mL of brine, dried with anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography using EtOAc / petroleum ether (1:20) to provide 700 mg (31%) of the title product as a yellow oil. Intermediate A-28: 1-[2-(2-methylpropyl)-1,3-oxazol-5-yl]ethan-1-one THE

[0542] Ethyl 2-(2-methylpropyl)-1,3-oxazol-5-carboxylate To a solution of ethyl 2-chloro-1,3-oxazol-5-carboxylate (3 g, 17.09 mmol, 1.00 equiv) in THF (45 mL) under N2, copper(I) iodide (1.5 g, 7.88 mmol, 0.50 equiv) was added. This was followed by the addition of bromo(2-methylpropyl)zinc (15 mL, 2.00 equiv) at -5°C. The resulting solution was stirred for 3 h at room temperature. The reaction was then rapidly cooled by the addition of 1 M aq HCl. Petition 870220002363, dated 10 / 01 / 2022, page 129 / 422 126 / 412 The resulting solution was extracted with 2 x 100 mL of EtOAc, and the organic layers were combined and dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:5). This resulted in the title compound as a red oil (1.3 g, 39%).

[0543] 2-(2-methylpropyl)-1,3-oxazol-5-carboxylic acid To a solution of the product from the previous step (1.3 g, 6.59 mmol, 1.00 equiv) in THF / H2O (20 / 5 mL) LiOH (600 mg, 25.05 mmol, 4.00 equiv) was added. The resulting solution was stirred for 3 h at room temperature. The reaction mixture was cooled with an ice-water bath. The pH of the solution was adjusted to 1 with 1 M aq HCl. The resulting solution was extracted with 2 x 50 mL of EtOAc, and the organic layers were combined and dried with anhydrous Na2SO4 and concentrated under vacuum. This resulted in the title compound as a red solid (1 g, 90%).

[0544] 1-[2-(2-methylpropyl)-1,3-oxazol-5-yl]ethan-1-one To a solution of the product from the previous step (1 g, 5.91 mmol, 1.00 equiv) in Et2O (30 mL), under N2, MeLi (7.4 mL, 2.00 equiv) was added. The resulting solution was stirred for 3 hours at 0 °C in an ice-water bath. The reaction was then rapidly cooled by the addition of aq HCl (1M). The resulting solution was extracted with 2 x 50 mL of EtOAc, and the organic layers were combined and dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:5). This resulted in the title compound as a red oil (800 mg, 81%). Petition 870220002363, dated 10 / 01 / 2022, page 130 / 422 127 / 412 Intermediate A-29: 1-(1-methyl-1H-1,3-benzodiazol-6-yl)ethan-1-one [054 5] N-methoxy-N, 1-dimethyl-1H-1,3-benzodiazole-6-carboxamide To a solution of 1-methyl-1H-1,3-benzodiazole-6-carboxylic acid (5.0 g, 28.38 mmol, 1.00 equiv) in CH2Cl2 (100 mL) was added methoxy(methyl)amine hydrochloride (2.78 g, 28.50 mmol, 1.00 equiv), EDC (6.54 g, 42.13 mmol, 1.20 equiv), followed by the addition of DMAP (3.46 g, 28.32 mmol, 1.00 equiv), in portions at the rt. The resulting solution was stirred for 16 h, concentrated under vacuum, and purified by silica gel chromatography using CH2Cl2 / MeOH (100:1) to yield 4.0 g (64%) of the title compound as a yellow solid. LC-MS: (ES, m / z): [M+1] = 220.

[0546] 1-(1-methyl-1H-1,3-benzodiazol-6-yl)ethan1-one To a solution of the product from the previous step (2.0 g, 9.12 mmol, 1.00 equiv) in THF (60 mL) under N2, MeMgBr (9.1 mL, 3.00 equiv) was added dropwise with stirring at 60 °C. The resulting mixture was stirred at this temperature for 30 min, allowed to warm to rt, then stirred for 2 h at rt. The reaction was then rapidly cooled by the addition of water / ice. The resulting solution was extracted with 100 mL of EtOAc, dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using CH2Cl2 / MeOH (50:1) to provide 1.3 g (82%) of the title compound as a yellow solid. Petition 870220002363, dated 10 / 01 / 2022, p. 131 / 422 128 / 412 Intermediate A—30: 3—acetyl—N—(propan—2—yl)benzamide

[0547] To a suspension of 3-acetylbenzoic acid (10 g, 60.92 mmol), HATU (20 g, 52.60 mmol), and propan-2-amine (4 g, 67.67 mmol) in DMF (180 mL) at -5 °C, DIEA was added dropwise. The resulting mixture was stirred at room temperature for 2 h under N2, then poured into 100 mL of H2O, and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with 300 mL of brine, dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. This resulted in 11 g (88%) of the title product as a yellow solid.

[0548] The following 2,4-dioxobutanoate esters were synthesized for use in the preparation of the compounds of this disclosure, including, but not limited to, use in Scheme I. Intermediate B—1: 4—(2—methoxyphenyl)—2,4—methyl dioxobutanoate MeO OO

[0549] To a solution of 1-(2-methoxyphenyl)ethan-1-one (1 g, 6.66 mmol, 1.00 equiv) in MeOH (20 mL) was sequentially added dimethyl oxalate (2.36 g, 19.99 mmol, 3.00 equiv), then MeONa (3.7 mL, 3.00 equiv, 5.4 M). The resulting solution was stirred overnight at 30 °C, then rapidly cooled by the addition of water / ice. The pH of the solution was adjusted to 5 with 1 M HCl aq. The resulting solution Petition 870220002363, dated 10 / 01 / 2022, p. 132 / 422 129 / 412 was extracted with 3 x 50 mL of EtOAc, and the organic layers were combined and dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was applied to a silica gel column with EtOAc / hexane (1 / 4). This resulted in the title compound as a yellow solid (1.2 g, 76%). Intermediate B—2: 4—(3—methoxyphenyl)—2,4—methyl dioxobutanoate OO

[0550] To a solution of 1-(3-methoxyphenyl)ethan-1-one (10 g, 66.59 mmol, 1.00 equiv) in MeOH (200 mL) was sequentially added NaOMe (30 mL) and dimethyl oxalate (10.2 g, 86.38 mmol, 1.3 equiv). The resulting solution was stirred for 8 h at room temperature. The reaction mixture was cooled to 0 °C with an ice-water bath. The resulting solution was diluted with 200 mL of EtOAc. The pH of the solution was adjusted to 3 with aqueous HCl (3 mol / L). The resulting solution was extracted with 2 x 300 mL of EtOAc, and the organic layers were combined and dried with anhydrous Na2SO4 and concentrated under vacuum. This resulted in the title compound as a yellow solid (11 g, 70%). Intermediate B—3:4—[3—(oxetan—3—ylmethoxy)phenyl]—2, 4—methyl dioxobutanoate00

[0551] In a 100 mL bottle, a solution of 1-[3-(oxetan-3-ylmethoxy)phenyl]ethan-1-one (Int. A-10, 3 g, 14.55 mmol, 1.00 equiv) in MeOH (40 mL), sodium oxalate Petition 870220002363, dated 10 / 01 / 2022, p. 133 / 422 130 / 412 dimethyl (3.42 g, 28.96 mmol, 2.00 equiv), and a solution of MeONa (2.36 g, 43.70 mmol, 3.00 equiv) in MeOH (8 mL). The resulting solution was stirred for 12 h at room temperature, then poured over ice / water. The pH was adjusted to 3 with HCl. The solids that were formed were collected by filtration, yielding 3.2 g (75%) of the title compound as a light yellow solid. LC-MS:(ES, m / z): 293.0. 7.9, 6.0 Hz), 4.45 (2 H, t, J 6.0, 6.0 Hz), 4.30 (2 H, d, J =6.7 Hz), 3.86 (3 H, s), 3.40 (1H, tt, J= 8.0, 8.0, 6.3, 6.3 Hz).

[0552] The following substituted 4-aryl-2,4-dioxobutanoate esters were obtained from Claisen condensation of a 1-arylethanone with an oxalic ester. αΛ Λ».RB0Na'RB°H. ArÂ^ORB +orto Table 3: Claisen synthesis of 4-aryl2, 4-dioxobutanoate esters. RbOh / time / temperature Aryl ethanone Spectral ester product 4-aryl-2,4- dioxobutanoate MeOH / 12 h / rt 1- (3-nitrophenyl)eta n-1-one 4-(3-nitrophenyl)- 2,4-dioxobutanoate methyl B-12 h / rt / rt 1-(pyridin-2yl)ethane-1-one 2,4-dioxo-4(pyridin-2- B-5 LC-MS: (ES, Petition 870220002363, dated 10 / 01 / 2022, p. 134 / 422 131 / 412 yl)methyl butanoate m / z) : 291.25. MeOH / 12 h / 30 °C 1-(2,3-dihydro-1,4benzodioxin-6yl)ethane-1-one 4-(2,3-di-hydro-1, 4- benzodioxin-6-yl)2,4-dioxobutanoate de methyl B-6 LC-MS: (ES, m / z) : MeOH / 265 h / rt 1-(2H-1,3benzodioxol-5yl)ethane-1-one 4-(2H-1,3- benzodioxol-5-yl)- 2,4-dioxobutanoate de methyl B-7 LC-MS: (ES, m / z) : 251. MeOH / 16 h / 40 °C 1- (1-methyl-1Hpyrazol-4yl)ethan-1-one 4-(1-methyl-1Hpyrazol-4-yl)-2,4dioxobutanoate de methyl B-8 LC-MS: (ES, m / z): 211 EtOH / 5 h / rt yl)-2,4- ethyl dioxobutanoate B-9 LC-MS: (ES, m / z): 277 MeOH / 2 h / 60 °C 1-(4- bromothien-2yl)ethanone 4-(4-bromothien-2- yl)-2,4- dioxobutanoate B-10 / 16 h / 16 h 4-(1-methyl-1H-indol- 6-yl)-2,4- ethyl dioxobutanoate B-11 LC-MS: (ES, m / z) : 273. EtOH / 16 h / rt A-2 4-(1-methyl-1H- indazol-6-yl)-2, B-14-1 (ES, LC-MS: ES, m / z) Petition 870220002363, dated 10 / 01 / 2022, p. 135 / 422 132 / 412 ethyl dioxobutanoate m / z) : 274 . MeOH / 16 h / rt A-3 4-[3-(propan-2- yl)phenyl]2,4- dioxobutanoate de methyl B-13 MeOH / 16 h / rt A-4 4-(1-ethyl-1H- indazol-6-yl)-2, 4dioxobutanoate de methyl B-14 (ES: LC-14) m / s 275. EtOH / 16 h / rt A-4 4-(1-ethyl-1H- indazol-6-yl)-2, 4dioxobutanoate of ethyl B-15 LC-MS: (ES, m / z) : 288 . MeOH / 16 h / rt A-5 4-(3-chloro-5methoxyphenyl)-2,4dioxobutanoate of methyl B-16 LC-MS: (ES, m / z): 271 EtOH / 16 h / rt A-6 4-(1-methyl-1Hindazol-5-yl) LC-MS: (ES, m / z) : 274 . EtOH / 16 h / rt A-7 4-(1-methyl-1Hindazol-4-yl)-2, 4dioxobutanoate ethyl B-18 LC-MS: (ES, m / z) : 274 . MeOH / 16 h / rt A-8 4-(1-ethyl-1H-1,2,3- benzotriazol-6-yl)- B-19 LC-MS: (ES, m / z): 275 Petition 870220002363, dated 10 / 01 / 2022, p. 136 / 422 133 / 412 2,4-dioxobutanoate methyl EtOH / 16 h / rt A-9 4-(3-cyclobutoxyphenyl)2,4-dioxobutanoate ethyl B-20 LC-MS: (ES, m / z) : 291. EtOH / 12 h / rt A-11 4-[3-(oxetan-3-yloxy)phenyl]-2,4-dioxobutanoate ethyl B-21 LC-MS: (ES, m / z) : 293. MeOH / 12 h / rt A-12 4-(3-cyclopropoxyphenyl)-2,4-dioxobutanoate methyl B-22 LC-MS: (ES, m / z) : 262.85. MeOH / 12 h / rt A-13 4-[3-(2,2-dimethylpropoxy)phenyl]-2,4-dioxobutanoate methyl B-23 LC-MS: (ES, m / z) : 292.95. MeOH / 12 h / rt A-14 4-[3-(cyclobutylmethoxy)phenyl]-2,4-dioxobutanoate methyl B-24 LC-MS: (ES, m / z) : 290.95. MeOH / 16 h / rt A-15 4-[3-(cyclopropylmethoxy)phenyl]-2,4-dioxobutanoate methyl B-25 LC-MS: (ES, m / z) : 276. Petition 870220002363, dated 10 / 01 / 2022, p. 137 / 422 134 / 412 EtOH / 16 h / rt A-16 Ethyl 4-(3-ethoxyphenyl)2,4-dioxobutanoate B-2 6 LC-MS: (ES, m / z) : 264 . MeOH / 12 h / rt A-17 Methyl 4-[3-(benzyloxy)phenyl]-2,4-dioxobutanoate B-27 LC-MS: (ES, m / z) : 313.1. MeOH / 16 h / rt A-18 4-[3-(2-methylpropoxy)phenyl]2,4-dioxobutanoate methyl B-28 LC-MS: (ES, m / z) : 279. MeOH / 16 h / rt A-19 4-(3,5-dimethoxyphenyl)-2,4-dioxobutanoate methyl B-29 LC-MS: (ES, m / z) : 267 . MeOH / 12 h / rt A-20 4-(3,5-dietoxyphenyl)-2,4-dioxobutanoate methyl B-30 LC-MS: (ES, m / z) : 295.2. MeOH / 16 h / rt A-21 Methyl 4-(3-ethoxy-5-methoxyphenyl)-2,4dioxobutanoate B-32 LC-MS: (ES, m / z): 270 Petition 870220002363, dated 10 / 01 / 2022, p. 138 / 422 135 / 412 MeOH / 16 h / rt A-23 4-[1,3-dimethyl-1Hthieno[2,3-c]pyrazol5-yl]-2,4dioxobutanoate de methyl B-33 LC-MS: (ES, m / z) : 281 MeOH / 16 h / rt A-24 4-(5-2-me methyl dioxobutanoate B-34 MeOH / 16 h / rt A-2 6 4-(5-(2- methylpropoxy)thien-2- yl)-2,4- methyl dioxobutanoate B-35 EtOH / 5 h / rt A-28 4-[2-(2- methylpropyl)-1,3oxazol-5-yl]-2,4dioxobutanoate B-36 MeOH / 16 h / rt A-2 9 4-(1-methyl-1H-1, 3- benzodiazol-6-yl)2,4-dioxobutanoate of methyl B-37 LC-MS: (m / m / m) = MeOH / MeOH / 21 16 h / rt A-30 4-[3-[(propan-2- yl)carbamoyl]phenyl]- 2,4-butanedioate methyl B-38 Petition 870220002363, dated 10 / 01 / 2022, p. 139 / 422 136 / 412 Intermediate B-39: 4-[2-(2-methylpropoxy)-1,3thiazol-5-yl]-2,4-dioxobutanoate of ethyl

[0553] To a solution of Int. A-25 (500 mg, 2.51 mmol, 1.00 equiv) in THF (10 mL) was sequentially added diethyl oxalate (1100 mg, 7.53 mmol, 2.00 equiv) and t-BuOK (850 mg, 7.58 mmol, 3.00 equiv). The resulting solution was stirred for 4 h at room temperature followed by dilution with 20 mL of H2O, extraction with 2 x 30 mL of EtOAc, and the organic layers were combined and dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:4). This resulted in the title compound as a yellow solid (400 mg, 53%). Intermediate B-40: ethyl 2,4-dioxo-5-phenylpentanoate

[0554] To a solution of 1-phenyl-2-propanone (1 g, 8.32 mmol, 1.00 equiv) in THF (25 mL) was added NaH (269 mg, 11.21 mmol, 1.50 equiv) in portions at 0 °C over 30 min, followed by the addition of diethyl oxalate (1.64 g, 11.22 mmol, 1.50 equiv). The resulting solution was stirred for 1 h at room temperature, then cooled to 0 °C. The reaction was then rapidly cooled by the addition of 20 mL of water. The resulting solution was extracted with 3 x 50 mL of EtOAc, and the combined organic layers were dried with anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:40) to Petition 870220002363, dated 10 / 01 / 2022, p. 140 / 422 137 / 412 provide 700 mg (36%) of the title product as a yellow liquid.

[0555] The following substituted ketoesters have also been used in the synthesis of pyrazoles. Intermediate B-41: methyl 2,4-dioxo-4-(1-propyl-1H-indazol-6-yl)butanoate Intermediate B-42: methyl 4-(3-cyclobutoxyphenyl)-2,4-dioxobutanoate

[0556] The following aryl-hydrazine intermediates were synthesized for use in the preparation of the compounds of this disclosure, including, but not limited to, use in Scheme I. C-1 Intermediate: 2-(difluoromethoxy)phenylhydrazine trifluoroacetate CF3COOH

[0557] 2-(difluoromethoxy)phenyl]hydrazine protected by Boc A solution of 1-bromo-2 (difluoromethoxy)benzene (8.0 g, 35.87 mmol, 1.00 equiv), (tert-butoxy)carbohydrazide (5.68 g, 42.98 mmol, 1.20 equiv), and BrettPhos Pd G3 (1.74 g, 1.92 mmol, 0.05 equiv) in dioxane (60 mL) under N2 was added Cs2CO3 (11.70 g, 35.91 mmol, 1.00 equiv), in portions at room temperature. The resulting solution was stirred for 16 hours at 100 °C, then cooled, diluted with 200 mL of EtOAc, washed with 200 mL of brine, dried with Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel chromatography using EtOAc / petroleum ether (1:5) to yield 8.0 g (81%) of the compound. Petition 870220002363, dated 10 / 01 / 2022, p. 141 / 422 138 / 412 title as an orange solid. LC-MS: (ES, m / z): 275. 1H NMR (400 MHz, DMSO-d 6) δ 8.83 (s, 1H), 7.29 - 7.22 (m, 1H), 7.07 (q, J = 7.7 Hz, 2H), 6.80 - 6.68 (m, 2H), 1.42 (s, 9H).

[0558] 2-(difluoromethoxy)phenylhydrazine trifluoroacetate A solution of the product from the previous step (2.0 g, 7.29 mmol, 1.00 equiv) and TFA (10 mL) in CH2Cl2 (20 mL) was stirred for 2 h at room temperature, then concentrated under vacuum to provide 1.0 g (48%) of the title compound as a brown oil. LC-MS: (ES, m / z): 175.

[0559] The following aryl-hydrazines were synthesized from the corresponding aryl halides using similar procedures. Table 4: Synthesis of aryl hydrazines from aryl bromides.

[0560] The compounds were isolated as trifluoroacetate salts. Aryl bromide Spectral Product 1-bromo-2-ethoxybenzene (2-ethoxyphenyl)hydrazine C-2 LC-MS: (ES, m / z) : 152. 7-bromo-1-methyl-1H-indazole 7-hydrazinyl-1-methyl-1H-indazole C-3 LC-MS: (ES, m / z) : 163. 4-bromo-1-methyl-1H-indazole 4-hydrazinyl-1-methyl-1H-indazole C-4 LC-MS: (ES, m / z) : 162. Petition 870220002363, dated 10 / 01 / 2022, page 142 / 422 139 / 412 7-bromo-1-ethyl-1H-indazole 1-ethyl-7-hydrazinyl-1H-indazole C-5 LC-MS: (ES, m / z) : 277.

[0561] The free amino groups of the following reagents were protected, firstly, with SEM groups (NaH; SEMCl). Treatment of the coupling product with TFA to remove the Boc groups also achieved the removal of the SEM protecting groups. Table 5: Synthesis of aryl hydrazines from aryl bromides. Aryl bromide Spectral Product 4-bromo-1H-indazole 4-hydrazinyl-1H-indazole C-7 LC-MS: (ES, m / z): 148.9. 7-Bromo-1Hindazole 7-hydrazinyl-1H-indazole C-8 LC-MS: (ES, m / z): 379. 4-Bromo-3methyl-1Hindazole 4-hydrazinyl-3-methyl-1Hindazole C-9 LC-MS: (ES, m / z): 163.2. Petition 870220002363, dated 10 / 01 / 2022, page 143 / 422 140 / 412 7-bromo-1metil-1H-1,3benzodiazol trifluoroacetato de 7- hidrazinil-1-metil-1H- 1,3-benzodiazol C-10 7-bromo-1, 3dimetil-1Hindazol 7-hidrazinil-1,3-dimetil- 1H-indazol C-11 LC-MS: (ES, m / z): 177,1. Intermediário C-12: Trifluoroacetato de 7hidrazinil—1—metil—1H—1,2,3—benzotriazol CF3COOH

[0562] 2-bromo-N-metil-6-nitroanilina A mixture of 1-bromo-2-fluoro-3-nitrobenzene (7 g, 31.82 mmol, 1.00 equiv), K2CO3 (8.8 g, 63.21 mmol, 2.00 equiv), and CH3NH2 (10 mL, 33%) in CH2Cl2 (50 mL) was stirred for 16 h at room temperature, then diluted with 100 mL of water. The resulting solution was extracted with 2 x 200 mL of CH2Cl2. The combined organic layers were washed with 50 mL of brine, dried with Na2SO4, and concentrated under vacuum to give 7 g (95%) of the title compound as a red oil. LC-MS: (ES, m / z): 230. 1H NMR (400 MHz, DMSO-d 6) δ 7.77 (ddd, J = 9.8, 8.0, 1.6 Hz, 2H), 6.70 (t, J = 8.0 Hz, 1H), 6.43 — 6.19 (m, 1H), 2.71 (d, J = 5.3 Hz, 3H).

[0563] 6-bromo-1-N-methylbenzene-1,2-diamine A mixture of the product from the previous step (8 g, 34.62 mmol, 1.00 equiv) and Zn (4 g, 62.50 mmol, 2.00 equiv) in AcOH (120 mL) was stirred for 16 h at room temperature. The solids were removed. Petition 870220002363, dated 10 / 01 / 2022, p. 144 / 422 141 / 412 by filtration, and the filtrate was concentrated under vacuum. The residue was dissolved in 300 mL of CH2Cl2, washed with 100 mL of NaHCO3, dried with Na2SO4, and concentrated under vacuum to provide 4 g (57%) of the title compound as a black oil. LC-MS: (ES, m / z): 201.

[0564] 7-bromo-1-methyl-1H-1,2,3-benzotriazole To a solution of the product from the previous step (4 g, 19.89 mmol, 1.00 equiv) in HBr / H2O (60 mL) at 5 °C, a solution of NaNO2 (2.07 g, 1.50 equiv) in H2O (10 mL) was added dropwise with stirring. The solution was stirred for 4 hours at 15 to 20 °C. The pH was adjusted to 8 with NaHCO3 (3 mol / L). The resulting solution was extracted with 2 x 200 mL of EtOAc. The combined organic layers were washed with 100 mL of brine, dried with anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:5) to provide 4 g (95%) of the title compound as a black solid. LC-MS: (ES, m / z): 212. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (dd, J = 8.3, 0.8 Hz, 1H), 7.84 - 7.73 (m, 1H), 7.31 (dd, J = 8.4, 7.5 Hz, 1H), 4.51 (s, 3H).

[0565] 7-Hydrazinyl-1-methyl-1H-1,2,3-benzotriazole trifluoroacetate was prepared from the previous compound using the C-1 procedure. LC-MS: (ES, m / z) : 163. C-13 Intermediate: [(2-chlorophenyl)methyl]hydrazine dihydrochloride Petition 870220002363, dated 10 / 01 / 2022, page 145 / 422 142 / 412

[0566] To a solution of hydrazine hydrate (85%) (31 g, 8.50 equiv) in EtOH (100 mL) was added dropwise a solution of 1-chloro-2-(chloromethyl)benzene (10 g, 62.10 mmol, 1.00 equiv) in EtOH (50 mL) for 1 h at 70 °C. The resulting solution was stirred for 1 h at 70 °C, concentrated under vacuum, diluted with water, and extracted with EtOAc three times. The combined organic layers were cooled to 0 °C, then a 4N HCl solution in dioxane was added. The solids that were formed were collected by filtration, yielding 6.1 g (63%) of the title product as a white solid. D-1 Intermediate: 5-[[(tert-butoxy)carbonyl](phenyl)amino]-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-carboxylate ethyl

[0567] Ethyl 3-cyano-2-(potassiooxy)prop-2-enoate To a solution of diethyl oxalate (5.06 g, 34.62 mmol, 1.00 equiv) in CH3CN (20 mL) was added t-BuOK (3.90 g, 34.76 mmol, 1.12 equiv), in portions at rt. The resulting solution was stirred for 1.5 h at rt. The solids that were formed were collected by filtration. This resulted in 5.09 g (82%) of the title product as a yellow solid.

[0568] Ethyl 5-amino-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-carboxylate A solution of the product from the previous step (2.0 g, 11.16 mmol, 1.00 equiv) in 1,4-dioxane Petition 870220002363, dated 10 / 01 / 2022, p. 146 / 422 143 / 412 (20 mL) was added TFA (2 mL) dropwise with stirring at room temperature. The resulting mixture was stirred at room temperature for 30 min. To the same, Int. C-13 (2.0 g, 12.77 mmol, 1.15 equiv) was added in portions at room temperature. The resulting solution was stirred overnight at room temperature, then diluted with 200 mL of EtOAc, washed with 2 x 200 mL of brine, dried with anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:3) to provide 1.8 g (58%) of the title compound as a yellow oil.

[0569] Ethyl 1-[(2-chlorophenyl)methyl]-5-(phenylamino)1H-pyrazol-3-carboxylate A solution of the product from the previous step (1.0 g, 3.57 mmol, 1.00 equiv), iodobenzene (768 mg, 3.76 mmol, 1.05 equiv), Brettphos Pd G3 precatalyst (326 mg, 0.36 mmol, 0.10 equiv), and Cs2CO3 (1.4 g, 4.30 mmol, 1.20 equiv) in 1,4-dioxane (20 mL). The resulting solution was stirred in a sealed tube under N2 at 90 °C for 3 h. The resulting solution was diluted with 200 mL of EtOAc, washed with 2 x 200 mL of brine, dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using petroleum ether: EtOAc:DCM (3:1:0.1) to provide 1.3 g (102%) of the title product as a yellow solid.

[0570] 5-[[(tert-butoxy)carbonyl](phenyl)amino]1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-carboxylate ethyl 5-[[(tert-butoxy)carbonyl](phenyl)amino]-1H-pyrazol-3-carboxylate To a solution of the product from the previous step (800 mg, 2.25 mmol, 1.00 equiv) and DMAP (548 mg, 4.49 mmol, 2.00 equiv) in toluene (20 mL) was added di-tert-butyl bicarbonate (980 mg, 4.49 mmol, 2.00 equiv), in portions at the right temperature. The resulting solution was heated under reflux overnight. The resulting solution was diluted with 200 mL of EtOAc, washed with 2x100 Petition 870220002363, dated 10 / 01 / 2022, p. 147 / 422 144 / 412 mL of brine, dried with anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:3) to give 1.0 g (101%) of the title product as a colorless oil. Intermediate D—2: 5—(3—cyclopropoxyphenyl)—1H—pyrazole—3—methyl carboxylate THE V YM. ,N / / / N H

[0571] A solution of Int. B-22 (2 g, 7.63 mmol, 1.00 equiv) and hydrazine hydrate (540 mg, 10.00 mmol, 1.30 equiv) in AcOH (20 mL) was stirred for 2 h at 100 °C, then cooled. The pH was adjusted to 7 with saturated NaHCO3, and the resulting solution was extracted with 3 x 100 mL of EtOAc. The combined organic layers were dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / hexane (1 / 1) to give 1.5 g (76%) of the title compound as a light yellow solid. LC-MS: (ES, m / z): 259. 1H NMR (300 MHz, MeOD) δ 7.35 (m, 3H), 7.13 (d, J = 21.3 Hz, 2H), 3.92 (s, 3H), 3.84 (dp, J = 6.4, 3.0, 3.0, 2.9, 2.9 Hz, 1H), 0.82 (m, 2H), 0.72 (m, 2H).

[0572] The following substituted 3-pyrazolecarboxylic esters were obtained from the condensation of methyl 4-(aryl)-2,4-dioxobutanoate with hydrazine: Petition 870220002363, dated 10 / 01 / 2022, p. 148 / 422 145 / 412 Table 6: Summary of pyrazol with hydrazine. Dicetona Produto Espectral B-2 5-(3-metoxifenil)-1H-pirazol-3carboxylate de methyl D-3 B-4 5-(3-nitrofenil)-1H-pirazol-3carboxylate de methyl D-4 B-6 5-(2,3-di-hidro-1,4-benzodioxin-6il)-1H-pirazol-3-carboxylate de methyl D-5 LC-MS: (ES, m / z) : 261. B-7 5-(2H-1,3-benzodioxol-5-il)-1Hpirazol-3-carboxylate de methyl D-6 LC-MS: (ES, m / z) : 247 . B-8 5-(1-methyl-1H-pyrazol-4-yl)-1Hpyrazol-3-carboxylate de methyl D-7 LC-MS: (ES, m / z) : 207 . B-9 5-(1-benzothiophen-2-yl)-1H-pyrazol- 3-carboxylate de ethyl D-8 LC-MS: (ES, m / z) : 272 . B-11 5-(1-methyl-1H-indol-6-yl)-1H-pyrazol-3-carboxylate de ethyl D-9 LC-MS: (ES, m / z) : 269. B-12 5-(1-methyl-1H-indazol-6-yl)-1Hpyrazol-3-carboxylate de ethyl D-10 LC-MS: (ES, Petition 870220002363, 10 / 01 / 2022, pág. 149 / 422 146 / 412 m / z) : 271. B-14 5-(1-Ethyl-1H-indazol-6-yl)-1H-pyrazol-3-carboxylate de methyl D-11 LC-MS: (ES, m / z) : 271. B-16 5-(3-Chloro-5-methoxyphenyl)-1Hpyrazol-3-carboxylate de methyl D-12 LC-MS: (ES, m / z) : 252 . B-17 5-(1-Methyl-1H-indazol-5-yl)-1Hpyrazol-3-carboxylate de ethyl D-13 LC-MS: (ES, m / z) : 270 . B-18 5-(1-methyl-1H-indazol-4-yl)-1Hpyrazol-3-carboxylate de ethyla D-14 LC-MS: (ES, m / z) : 270 . B-19 5-(1-ethyl-1H-1,2,3-benzotriazol-6yl)-1H-pyrazol-3-ethyl carboxylate D-15 LC-MS: (ES, m / z): 271. B-20 5-(3-cyclobutoxyphenyl)-1H-pyrazol- 3-ethyl carboxylate D-16 LC-MS: (ES, m / z) : 286. B-23 5-[3-(2,2-dimethylpropoxy)phenyl]-1Hpyrazol-3-carboxylate de methyl D-17 LC-MS: (ES, Petition 870220002363, 10 / 01 / 2022, pág. 150 / 422 147 / 412 m / z): 289.1. B-2 6 5-(3-ethoxyphenyl)-1H-pyrazol-3carboxylate de ethyla D-18 LC-MS: (ES, m / z): 260 . B-27 5-[3-(benziloxy)phenyl]-1H-pyrazol- 3-carboxylate de methyl D-19 LC-MS: (ES, m / z) : 309.1. B-28 5-[3-(2-methylpropoxy)phenyl]-1Hpyrazol-3-carboxylate de methyl D-20 B-2 9 5-(3,5-dimethoxyphenyl)-1H-pyrazol-3carboxylate de methyl D-21 LC-MS: (ES, m / z) : 263. B-30 5- (3,5-dietoxiphenyl)-1H-pyrazol-3carboxylate de methyla D-22 LC-MS: (ES, m / z) : 290, 95. B-31 5- (3-ethoxi-5-methoxiphenyl)-1Hpirazol-3-carboxylate de methyla D-23 LC-MS: (ES, m / z) : 277 . B-32 5-[2-(propan-2-yloxy)-1,3-oxazol-5yl]-1H-pyrazol-3-carboxylate ethyl D-24 LC-MS: (ES, m / z) : 266. Petition 870220002363, 10 / 01 / 2022, pág. 151 / 422 148 / 412 B-33 5-[1,3-dimethyl-1H-thieno[2,3c]pyrazol-5-yl]-1H-pyrazol-3carboxylate de methyl D-25 LC-MS: (ES, m / z): 277 . B-38 5-[3-[(propan-2- yl)carbamoyl]phenyl]-1H-pyrazol-3carboxylate de methyl D-2 6 Intermediate D—27: 1 — [(2—chlorophenyl)methyl]—5—(3— (propan—2—yl)phenyl)—1H—pyrazole—3—methyl carboxylate

[0573] A solution of Int. B-13 (1.0 g, 4.03 mmol, 1.00 equiv) and Int. C-13 (1.38 g, 6.01 mmol, 1.50 equiv) in AcOH (20 mL) was stirred for 2 h at 100 °C, then concentrated under vacuum, diluted with 200 mL of EtOAc, washed with 2 x 100 mL of saturated NaHCO3, dried with anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel chromatography using EtOAc / petroleum ether (1:5) to provide 1.05 g (71%) of the title product as a yellow solid. Petition 870220002363, dated 10 / 01 / 2022, page 152 / 422 149 / 412 D-28 Intermediate: 1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazole-3-methylcarboxylate

[0574] To a solution of Int. B-2 (3.8 g, 16.09 mmol, 1.00 equiv) in MeOH (80 mL) was added Int. C-13 (4.8 g, 20.91 mmol, 1.30 equiv). The resulting solution was stirred for 3 h at 65 °C, then concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:2), to give the title compound as a white solid (5.5 g, 96%).

[0575] The following substituted 3-pyrazolecarboxylic esters were obtained from the condensation of methyl 4-(aryl)-2,4-dioxobutanoate with various substituted hydrazines: Air-| Table 7: Synthesis of pyrazole with substituted hydrazines. Ar1NHNH2 Dikete na Spectral Product Phenylhydrazine B-28 5- [3-(2- methylpropoxy)phenyl]-1- D — LC-MS: (ES, Petition 870220002363, dated 10 / 01 / 2022, p. 153 / 422 150 / 412 methyl phenyl-1H-pyrazol-3carboxylate 29 m / z): 357. (2-bromophenyl)hydrazide B-14 1-(2-bromophenyl)-5-(1ethyl-1H-indazol-6-yl)-1H-pyrazol-3-methyl carboxylate D - 30 LC-MS: (ES, m / z): 425.1. (2-bromophenyl)hydrazide B-18 1-(2-bromophenyl)-5-(1methyl-1H-indazol-6-yl)-1H-pyrazol-3carboxylate ethyl D - 3 1 LC-MS: (ES, m / z): 425. (2-bromophenyl)hydrazide B-23 Methyl 1-(2-bromophenyl)-5-[3(2,2-dimethylpropoxy)phenyl]1H-pyrazol-3carboxylate D - 3 2 LC-MS: (ES, m / z): 443.1. (2-bromophenyl)hydrazim B-2 9 1-(2-bromophenyl)-5-(3,5-dimethylbutoxyphenyl)-1H-pyrazole-3-carboxylate D - 3 3 LC-MS: (ES, m / z): 417. (2-bromophenyl)hydrazim B-41 1-(2-bromophenyl)-5-(1-propyl-1H-indazol-6-yl)-1H-pyrazole-3-carboxylate D - 3 4 LC-MS: (ES, m / z): 439.1. (2-bromophenyl)hydrazim B-42 1-(2-bromophenyl)-5-(3-cyclobutoxyphenyl)-1H-pyrazole-3-carboxylate D - 3 5 LC-MS: (ES, m / z): 441.2. Petition 870220002363, dated 10 / 01 / 2022, p. 154 / 422 151 / 412 (2-fluorophenyl)hydrazine B-3 1-(2-fluorophenyl)-5[3-(oxetan-3-ylmethoxy)phenyl]-1H-pyrazol-3-carboxylate methyl D - 3 6 LC-MS: (ES, m / z) : 383.1. (2-fluorophenyl)hydrazine B-20 5-(3-cyclobutoxyphenyl)-1-(2-fluorophenyl)-1Hpyrazol-3-carboxylate ethyl yloxy)phenyl]-1H-pyrazol-3-carboxylate D - 3 8 LC-MS: (ES, m / z) : 383. (2-fluorophenyl)hydrazine B-28 1- (2-fluorophenyl)-5- [3-(2-methylpropoxy)phenyl]1H-pyrazol-3- methyl carboxylate D - 3 9 LC-MS: (ES, m / z): 369. (2-methylphenyl)hydrazina B-20 5-(3-cyclobutoxyphenyl)-1(2-methylphenyl)-1Hpyrazol-3-carboxylate ethyl D - 4 0 LC-MS: (ES, m / z) : 376. (2-methylphenyl)hydrazina B-30 5-(3,5-diethoxyphenyl)1-(2-methylphenyl)-1Hpyrazol-3-carboxylate methyl D - 4 1 LC-MS: (ES, m / z) : 381.05. Petition 870220002363, dated 10 / 01 / 2022, p. 155 / 422 152 / 412 (2- nitrophenyl)hidrazi na B-14 5-(1-ethyl-1H-indazol- 6-yl)-1-(2- nitrophenyl)-1H- pyrazol-3-carboxylate de methyl D - 4 2 LC-MS: (ES, m / z): 392.30. Quinolin-8-ylhydrazine B-23 5-[3-(2,2- dimethylpropoxy)phenyl]1-(quinolin-8-yl)-1Hpyrazol-3-carboxylate de methyl D - 4 3 LC-MS: (ES, m / z): [M+1] = 416. C-2 B-2 9 5-(3,5-dimethoxyphenyl)1-(2-ethoxyphenyl)-1Hpyrazol-3-carboxylate de methyl D - 4 4 LC-MS: (ES, m / z): 383. C-3 B-15 5-(1-ethyl-1H-indazol6-yl)-1-(1-methyl-1Hindazol-7-yl)-1H-pyrazol-3-carboxylate de ethyl D - 4 5 LC-MS: (ES, m / z) : 414 . C-3 B-20 5-(3cyclobutoxyphenyl)-1(1-methyl-1H-indazol-7yl)-1H-pyrazol-3carboxylate de methyl D - 4 6 LC-MS: (ES, m / z) : 416. C-3 B-23 5-[3-(2,2-dimethylpropoxy)phenyl]1-(1-methyl-1H-indazol7-yl)-1H-pyrazol-3carboxylate de methyl D - 4 7 LC-MS: (ES, m / z) : 419.10. Petition 870220002363, 10 / 01 / 2022, pág. 156 / 422 153 / 412 C-3 B-24 5- [3-(cyclobutylmethoxy)pheni l]-1-(1-methyl-1Hindazol-7-yl)-1Hpyrazol-3-carboxylate de methyl D - 4 8 LC-MS: (ES, m / z) : 417 . C-3 B-25 5- [3(cyclopropylmethoxy)phenyl]-1-(1-methyl-1Hindazol-7-yl)-1Hpyrazol-3-carboxylate de methyl D - 4 9 LC-MS: (ES, m / z) : 402 . C-3 B-28 1-(1-methyl-1H-indazol-7-yl)-5-[3-(2methylpropoxy)phenyl]- 1H-pyrazol-3carboxylate de methyl D - 5 0 LC-MS: (ES, m / z): 405. C-3 B-2 9 5-(3,5-dimethoxyphenyl)- 1-(1-methyl-1H-indazol- 7-yl)-1H-pyrazol-3carboxylate de methyl D - 5 1 LC-MS: (ES, m / z): 393. C-3 B-30 5-(3,5-diethoxyphenyl)- 1-(1-methyl-1H-indazol- 7-yl)-1H-pyrazol-3carboxylate de methyl D - 5 2 LC-MS: (ES, m / z) : 421.05. C-5 B-23 5-[3-(2,2-dimethylpropoxy)phenyl]1-(1-ethyl-1H-indazol7-yl)-1H-pyrazole-3carboxylate demethyl D - 5 3 LC-MS: (ES, m / z) : 432 . Petition 870220002363, 10 / 01 / 2022, pág. 157 / 422 154 / 412 C-6 B-2 5-(3-methoxyphenyl)-1-[2-(propan-2-yloxy)phenyl]-1Hpyrazol-3-carboxylate de methyl D - 5 4 LC-MS: (ES, m / z): 367 . C-11 B-23 1-(1,3-dimethyl-1Hindazol-7-yl)-5-[3(2,2- dimethylpropoxy)phenyl]1H-pyrazol-3-carboxylate de methyl D - 5 5 LC-MS: (ES, m / z): 433.3. C-12 B-23 5- [3-(2,2dimethylpropoxy)phenyl]1-(1-methyl-1H-1,2,3- benzotriazol-7-yl)-1Hpyrazol-3-carboxylate de methyl D - 5 6 LC-MS: (ES, m / z): 420 . C-13 B-37 1-[(2- chlorophenyl)methyl]-5(1-methyl-1H-1,3- benzodiazol-6-yl)-1Hpyrazol-3-carboxylate de methyl D - 5 7 LC-MS: (ES, m / z): [M+1] = 381. Petition 870220002363, 10 / 01 / 2022, pág. 158 / 422 155 / 412 Ar1NHNH2 Dikete na Product (4nitrophenyl)hydrazine B-28 methyl-5-[3-(2-methylpropoxy)phenyl]1-[(4-nitrophenyl)methyl]-1H-pyrazol3-carboxylate D-58 (pyridin-3yl)hydrazine B-2 5-(3-methoxyphenyl)-1-(pyridin-3-yl) - Methyl 1H-pyrazol-3-carboxylate D-59 C-13 B-1 1-[(2-chlorophenyl)methyl]-5-(2methoxyphenyl)-1H-methyl pyrazol-3carboxylate D-60 C-13 B-10 5-(4-bromothien-2-yl)-1-[(2chlorophenyl)methyl]-1H-pyrazol-3carboxylate methyl D-61 C-13 B-35 Methyl 1-[(2-chlorophenyl)methyl]-5-[5-(2methylpropoxy)thien-2-yl]1H-pyrazol3-carboxylate D-62 C-13 B-36 1-[(2-chlorophenyl)-5-[2-(2methylpropyl)-1,3-oxazol-5-yl]-1Hpyrazol-3-methyl carboxylate D-63 C-13 B-39 Methyl 1-[(2-chlorophenyl)methyl]-5-[2-(2methylpropoxy)-1,3-thiazol-5-yl]-1Hpyrazol-3-carboxylate D-64

[0576] Substituted 3-pyrazolecarboxylic esters were obtained from the condensation of various methyl 4-aryl-2,4-dioxobutanoates with (2-chlorophenyl)hydrazine: Petition 870220002363, dated 10 / 01 / 2022, page 159 / 422 156 / 412 Table 8: Synthesis of pyrazole with 2-chlorophenylhydrazine. Diketone Spectral Product B-2 5-(3-methoxyphenyl)-1-(2-methylphenyl)-1H-pyrazole-3-carboxylate methyl (This product is from the reaction with 2-methylhydrazine) D-65 LC-MS: (ES, m / z) : 322 . B-3 1- (2-chlorophenyl)-5-[3-(oxetan-3-ylmethoxy)phenyl]-1H-pyrazole-3-carboxylate methyl D-66 LC-MS: (ES, m / z) : 399 0 B-5 1-(2-chlorophenyl)-5-(pyridin-2-yl)1H-pyrazole-3-carboxylate methyl D-67 LC-MS: (ES, m / z) : 314.20. B-12 Ethyl 1-(2-chlorophenyl)-5-(1-methyl-1Hindazol-6-yl)-1H-pyrazol-3carboxylate D-68 LC-MS: (ES, m / z): 381. methyl D-69 LC-MS: (ES, Petition 870220002363, dated 10 / 01 / 2022, page 160 / 422 157 / 412 m / z) : 381. B-20 1- (2-chlorophenyl)-5-(3- cyclobutoxyphenyl)-1H-pyrazol-3carboxylate de ethyla D-70 LC-MS: (ES, m / z) : 396. B-21 1- (2-chlorophenyl)-5-[3-(oxetan-3iloxi)phenyl]-1H-pyrazol-3carboxylate de ethyla D-71 LC-MS: (ES, m / z) : 398.95. B-22 1-(2-chlorophenyl)-5-(3cyclopropoxyphenyl)-1H-pyrazol-3carboxylate de methyl D-72 LC-MS: (ES, m / z): 369.25. B-23 1-(2-chlorophenyl)-5-[3-(2,2dimethylpropoxy)phenyl]-1H-pyrazol3-carboxylate de methyl D-73 LC-MS: (ES, m / z): 398.95. B-24 1- (2-chlorophenyl)-5-[3(cyclobutylmethoxy)phenyl]-1Hpyrazol-3-carboxylate de methyl D-74 LC-MS: (ES, m / z): 396.95. B-28 1- (2-chlorophenyl)-5-[3-(2methylpropoxy)phenyl]-1H-pyrazol-3carboxylate de methyl D-75 B-2 9 1- (2-chlorophenyl)-5-(3,5dimethoxyphenyl)-1H-pyrazol-3carboxylate de methyl D-76 LC-MS: (ES, m / z) : 373. Petition 870220002363, 10 / 01 / 2022, pág. 161 / 422 158 / 412 B-30 Methyl 1-(2-chlorophenyl)-5-(3,5diethoxyphenyl)-1H-pyrazol-3carboxylate D-77 LC-MS: (ES, m / z): 401.3. B-40 [ethyl 5-benzyl-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-carboxylate D-78

[0577] The following substituted 3-pyrazolecarboxylic esters obtained from the condensation of Int. B-22 with various substituted hydrazines: ArNHNH2, solvent Spectral Product (2-fluorophenyl)hydrazine hydrochloride, EtOH 5-(3-cyclopropoxyphenyl)-1-(2-fluorophenyl)-1H-pyrazole-3-carboxylate methyl D-79 LC-MS: (ES, m / z) : 353.0. (2-bromophenyl)hydrazine, MeOH 1-(2-bromophenyl)-5-(3-cyclopropoxyphenyl)-1H-pyrazole-3-carboxylate methyl D-80 LC-MS: (ES, m / z) : 413. Petition 870220002363, dated 10 / 01 / 2022, p. 162 / 422 159 / 412 (2-bromo-4-fluorophenyl)hydrazine, MeOH 1-(2-bromo-4-fluorophenyl)-5-(3cyclopropoxyphenyl)-1H-pyrazole-3-carboxylate methyl D-81 LC-MS: (ES, m / z) : 430.90. (2,4dichlorophenyl)hydrazine, MeOH 5-(3-cyclopropoxyphenyl)-1-(2,4dichlorophenyl)-1H-pyrazole-3-carboxylate methyl D-82 LC-MS: (ES, m / z) : 402.95. (2,5- dichlorophenyl)hydrazine, MeOH 5-(3-cyclopropoxyphenyl)-1-(2,5dichlorophenyl)-1H-pyrazole-3-carboxylate methyl D-83 LC-MS: (ES, m / z) : 402.90. [2-(difluoromethoxy)phenyl]hydrazine, CF3COOH / MeOH 5-(3-cyclopropoxyphenyl)-1-[2(difluoromethoxy)phenyl]-1Hpyrazole-3-carboxylate methyl D-84 LC-MS (ES, m / z): 401 (2-ethoxyphenyl)hydrazine, MeOH 5- (3-cyclopropoxyphenyl)-1-(2ethoxyphenyl)-1H-pyrazole-3carboxylate methyl D-85 LC-MS: (ES, m / z) : 378. (2methoxyphenyl)hydrazine 5-(3-cyclopropoxyphenyl)-1-(2methoxyphenyl)-1H-pyrazole-3carboxylate methyl D-86 LC-MS: (ES, m / z) : 364.9.Methyl (2-methylphenyl)hydrazine dihydrochloride, MeOH 5-(3-cyclopropoxyphenyl)-1-(2methylphenyl)-1H-pyrazol-3carboxylate D-87 LC-MS (ES, m / z): 349. Petition 870220002363, dated 10 / 01 / 2022, p. 163 / 422 160 / 412 (2- nitrophenyl)hidrazine, EtOH 5- (3-cyclopropoxyphenyl)-1-(2nitrophenyl)-1H-pyrazol-3methyl carboxylate D-88 LC-MS: (ES, m / z) : 380. (2- (propan-2yl)phenyl)hydrazine, MeOH HCl (3-cyclopropoxyphenyl)-1-[2(propan-2-yl)phenyl]-1H-pyrazole-3carboxylate of methyl D-89 [2- (trifluorometyl)phenyl]hydrazine (HCl) 2, MeOH 5- (3-cyclopropoxyphenyl)-1-[2(trifluoromethyl)phenyl]-1Hpyrazol-3-methyl carboxylate D-90 LC-MS: (ES, m / z) : 403. C-3, MeOH 5-(3-cyclopropoxyphenyl)-1-(1methyl-1H-indazol-7-yl)-1Hpyrazol-3-methyl carboxylate D-91 LC-MS (ES, m / z): 389 C-4, MeOH 5- (3-cyclopropoxyphenyl)-1-(1methyl-1H-indazol-4-yl)-1Hpyrazol-3-methyl carboxylate D-92 LC-MS: (ES, m / z) : 388. C-5, MeOH 5- (3-cyclopropoxyphenyl)-1-(1ethyl-1H-indazol-7-yl)-1H-pyrazol3-methyl carboxylate D-93 LC-MS: (ES, m / z) : 402. C-7, MeOH 5-(3-cyclopropoxyphenyl)-1-(1Hindazol-4-yl)-1H-pyrazol-3methyl carboxylate D-94 LC-MS: (ES, m / z) : 375.1. Petition 870220002363, dated 10 / 01 / 2022, p. 164 / 422 161 / 412 C-8, MeOH methyl 5-(3-cyclopropoxyphenyl)-1-(1-Indazol-7-yl)-1H-pyrazole-3-carboxylate D-95 LC-MS: (ES, m / z) : 375. C-9, MeOH methyl 5-(3-cyclopropoxyphenyl)-1-(3methyl-1H-indazol-4-yl)-1H-pyrazole-3-carboxylate D-96 LC-MS: (ES, m / z) : 388.95. C-10, MeOH methyl 5-(3-cyclopropoxyphenyl)-1-(1methyl-1H-1,3-benzodiazol-7-yl)- 1H-pyrazole-3-carboxylate D-97 LC-MS: (ES, m / z) : 389.0. Intermediate E-1: 1-(bromomethyl)-2-ethoxybenzene Choir

[0578] A solution of (2-ethoxyphenyl)methanol (15.2 g, 99.87 mmol, 1.00 equiv) and CBr4 (50.1 g, 150.00 mmol, 1.50 equiv) in CH2Cl2 (200 mL), PPh3 (39.45 g, 150.41 mmol, 1.50 equiv) was added in portions at 0 °C. The resulting solution was stirred for 16 h at rt, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:10) to provide 14 g (65%) of the title compound as a colorless oil. 1H-NMR: (CDCl3, ppm): δ: 7.51 — 7.25 (m, 1H), 7.06 — 6.86 (m, 1H), 4.65 (s, 1H), 4.16 (q, J = 7.0 Hz, 1H), 1.53 (t, J = 7.0 Hz, 1H). Petition 870220002363, dated 10 / 01 / 2022, p. 165 / 422 162 / 412 Intermediate E-2: 1-(bromomethyl)-2-cyclopropoxybenzene ΓΧΑ

[0579] Methyl 2-cyclopropoxybenzoate To a mixture of methyl 2-hydroxybenzoate (5.0 g, 32.86 mmol, 1.00 equiv) CS2CO3 (32 g, 98.21 mmol, 3.00 equiv) in DMA (100 mL) bromocyclopropane was added dropwise (39.8 g, 328.99 mmol, 10.00 equiv) with stirring at rt. The resulting solution was stirred for 16 h at 130 °C, cooled, diluted with 200 mL of EtOAc, washed with 2x200 mL of water and 2x200 mL of brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography using EtOAc / petroleum ether (1:6) to give 1.6 g (25%) of the title compound as a yellow oil. LC-MS: (ES, m / z) 1H), 7.01 (td, J = 7.5, 7.5, 1.2 Hz, 1H), 3.89 (s, 3H), 3.83 (tt, J = 5.9, 5.9, 3.2, 3.2 Hz, 1H), 0.86 (m, 4H).

[0580] (2-cyclopropoxyphenyl)methanol To a solution of methyl 2-cyclopropoxybenzoate (1.5 g, 7.80 mmol, 1.00 equiv) in THF (100 mL) was added LiAlH4 (594 mg, 15.65 mmol, 2.00 equiv), in portions at 0 °C. The resulting mixture was stirred for 2 h at 0 °C in an ice / salt bath, then rapidly cooled by the addition of Na2SO4 / 10 H2O. Solids were removed by filtration. The resulting solution was concentrated under vacuum and purified by silica gel chromatography using EtOAc / petroleum ether (1:5) to provide 750 mg (59%) of the title compound as a yellow oil. LC-MS: (ES, m / z): 187. 1H NMR: (400 MHz, CDCl3) δ Petition 870220002363, dated 10 / 01 / 2022, page 166 / 422 163 / 412 7.30 (m, 3H), 6.98 (tdd, J = 7.5, 7.5, 3.7, 1.5 Hz, 1H), 4.65 (s, 2H), 3.80 (m, 1H), 0.82 (m, 4H).

[0581] 1-(bromomethyl)-2-cyclopropoxybenzene To a solution of (2-cyclopropoxyphenyl)methanol (750 mg, 4.57 mmol, 1.00 equiv) and CBr4 (3.06 g, 9.16 mmol, 2.00 equiv) in CH2Cl2 (30 mL) was added PPh3 (2.40 g, 9.15 mmol, 2.00 equiv) in portions at 0 °C. The resulting solution was stirred for 2 h at room temperature, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:5) to provide 1.0 g (96%) of the title compound as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.30 (m, 3H), 6.96 (dt, J = 7.6, 1.8, 1.8 Hz, 1H), 4.52 (s, 2H), 3.84 (m, 1H), 0.83 (m, 4H). Intermediate E-3 2—(bromomethyl)—1—ethoxy—3—fluorobenzene F OCBr

[0582] Methyl 2-ethoxy-6-fluorobenzoate A mixture of methyl 2-fluoro-6-hydroxybenzoate (500 mg, 2.94 mmol, 1.00 equiv), K2CO3 (811 mg, 5.87 mmol, 2.00 equiv), EtI (911 mg, 5.84 mmol, 2.00 equiv) in DMF (15 mL) was stirred overnight at 80 °C, cooled to rt, and extracted with 3 x 20 mL of EtOAc. The combined organic layers were dried with Na2SO4 and concentrated under vacuum to provide 500 mg (86%) of the title compound as a light yellow oil.

[0583] LC-MS: (ES, m / z): 199.3. 1H NMR (300 MHz, CDCl3) δ 7.29 (m, 1H), 6.70 (m, 2H), 4.08 (q, J = 7.0, 7.0, 7.0 Hz, 2H), 3.92 (s, 3H), 1.40 (t, J = 7.0, 7.0 Hz, 3H). Petition 870220002363, dated 10 / 01 / 2022, page 167 / 422 164 / 412

[0584] 2-ethoxy-6-fluorobenzoic acid MCT4 (2.6 g, 13.12 mmol, 1.00 equiv) and NaOH (2 g, 50.00 mmol, 4.00 equiv) in MeOH / H2O (20 / 10 mL) were stirred overnight at 40 °C. The pH of the solution was adjusted to 5 with 1 M HCl. The resulting solution was extracted with 3 x 50 mL of EtOAc. The combined organic layers were dried with Na2SO4 and concentrated under vacuum to provide 1.9 g (79%) of the title compound as a colorless oil.

[0585] LC-MS: (ES, m / z): 185.3.

[0586] (2-ethoxy-6-fluorophenyl)methanol To a solution of the product from the previous step (1.9 g, 10.32 mmol, 1.00 equiv) and isobutyl chloroformate (2.1 g, 15.38 mmol, 1.50 equiv) in THF (50 mL) at 0 °C, TEA (4.5 mL, 3.00 equiv) was added. The reaction was stirred for 2 h at 0 °C, then filtered. To the filtrate, NaBH4 (780 mg, 20.62 mmol, 2.00 equiv) at 0 °C was added. The resulting solution was stirred for 3 h at room temperature. The reaction was then rapidly cooled by the addition of 10 mL of water / ice. The resulting solution was extracted with 3 x 50 mL of EtOAc. The combined organic layers were dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (2 / 1) to provide 0.7 g (40%) of the title compound as a light yellow oil.

[0587] 1H NMR (300 MHz, DMSO) δ 7.27 (td, J =8.3, 8.3, 7.0 Hz, 1H), 6.77 (m, 2H), 4.75 (t, J = 5.5, 5.5 Hz, 1H), 4.48 (dd, J = 5.5, 1.9 Hz, 2H), 4.06 (q, J = 7.0, 7.0, 7.0 Hz, 2H), 1.35 (t, J = 6.9, 6.9 Hz,3H).

[0588] 2-(bromomethyl)-1-ethoxy-3-fluorobenzene A solution of the product from the previous step (700 mg, 4.11 mmol, 1.00 equiv), PPh3 (2.16 g, 8.24 mmol, 2.00 equiv), Petition 870220002363, dated 10 / 01 / 2022, p. 168 / 422 165 / 412 and CBr4 (2.7 g, 2.00 equiv) in CH2Cl2 (30 mL) was stirred for 2 h at room temperature. The resulting solution was extracted with 3 x 30 mL of EtOAc. The combined organic layers were dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (5 / 1) to give 0.4 g (42%) of the title compound as a light yellow oil.

[0589] 1H NMR (300 MHz, CDCl3) δ 7.24 (m, 1H), 6.69 (m, 2H), 4.67 (dd, J = 32.8, 1.5 Hz, 2H), 4.13 (qd, J = 7.0, 7.0, 7.0, 2.5 Hz, 2H), 1.48 (td, J = 7.0, 6.9, 3.2 Hz, 3H). Intermediate E—4 1—(bromomethyl)—2—(propan—2—yloxy)benzene ΓT'βγ

[0590] [2-(propan-2-yloxy)phenyl]methanol To a solution of 2-(hydroxymethyl)phenol (2 g, 16.11 mmol, 1.00 equiv) in DMF (10 mL) was sequentially added 2-iodopropane (5.48 g, 32.24 mmol, 2.00 equiv) then Cs2CO3 (10.5 g, 32.23 mmol, 2.00 equiv). The resulting solution was stirred overnight at 85 °C. The reaction mixture was cooled to room temperature. The resulting solution was extracted with 3 x 50 mL of EtOAc, the organic layers were combined and dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was applied to a silica gel column with EtOAc / hexane (1 / 4). This resulted in the title compound being a light yellow oil (2.1 g, 78%).

[0591] 1-(bromomethyl)-2-(propan-2-yloxy)benzene A solution of the product from the previous step (3 g, Petition 870220002363, dated 10 / 01 / 2022, p. 169 / 422 166 / 412 18.05 mmol, 1.00 equiv) in CH2Cl2 (50 mL) were sequentially added to CBr4 (12.84 g, 36.17 mmol, 2.00 equiv) and PPh3 (9.48 g, 36.14 mmol, 2.00 equiv) in an ice bath. The resulting solution was stirred for 5 h at room temperature. The resulting solution was extracted with 3 x 100 mL of CH2Cl2, and the organic layers were combined, dried with anhydrous Na2SO4, and concentrated under vacuum. The residue was applied to a silica gel column with EtOAc / hexane (1 / 4). This resulted in the title compound as a light yellow oil (1.6 g, 39%).

[0592] The following alkylating agents were reacted with pyrazoles as revealed below: Intermediate E-5 1-(chloromethyl)-2-nitrobenzene Intermediate E-6 1-bromo-2-(bromomethyl)-benzene Intermediate E-7 1-(bromomethyl)-2-chlorobenzene Intermediate E-8 2-(bromomethyl)-1-fluoro-3-nitrobenzene Intermediate E-9 (2-bromoethyl)benzene Intermediate E-10 1-(chloromethyl)-2-chlorobenzene Intermediate E-11 2-(bromomethyl)pyridine Intermediate E-12 7-(bromomethyl)-1-methyl-1H-indazole Intermediate E-13 1-bromo-2-methylpropane Intermediate E-14 4-(bromomethyl)tetrahydropyrane Intermediate D-98: 1-[(3-chlorophenyl)methyl]-5- phenyl-1H-pyrazole-3-methylcarboxylate Petition 870220002363, dated 10 / 01 / 2022, page 170 / 422 167 / 412

[0593] To a suspension of methyl 5-phenyl-1H-pyrazole-3-carboxylate (1) (1.0 g, 4.94 mmol) in toluene, NaH (60%) (0.394 g, 9.88 mmol) was added in portions under N2 at room temperature, and stirring was continued for 30 min. To the above mixture, a solution of 3-chlorobenzyl bromide (0.96 mL, 7.42 mmol) in toluene (3 mL) was added dropwise at 60 °C. The reaction mixture was stirred at 110 °C for 16 h. The mixture was cooled to room temperature and then rapidly cooled with aqueous NH4Cl solution. The mixture was partitioned with EtOAc (100 mL) and the organic layer was separated. The EtOAc layer was washed with brine (2 x 25 mL) and dried with Na2SO4, and the solvent was evaporated. The residue was subjected to SiO2 chromatography (ISCO CombiFlash® Rf 200) using a 0 to 50% gradient of EtOAc in hexane to provide the title compound (1.2 g, 75%). 1H NMR (CDCl3, 400 MHz) δ 3.95 (s, 3H), 5.36 (s, 2H), 6.85-6.92 (m, 2H), 6.95-6.99 (m, 1H), 7.17-7.29 (m, 4H).7.35-7.48 (m, 3H). Intermediate D-99: 1—[(2—cyclopropoxyphenyl)methyl]—5—(3—methoxyphenyl)—1H—pyrazole—3—methyl carboxylate

[0594] To a solution of Int. D-3 (793 mg, 3.41 mmol, 1.00 equiv) in toluene (10 mL) was added NaH (164 mg, 6.83 mmol, 2.00 equiv). The resulting solution was stirred at rt for 30 min, then heated to 60 °C. To this, a solution of Int. E-2 (1 g, 4.40 mmol, 1.30 equiv) in toluene (10 mL) was added. The resulting solution was stirred at 60 °C for 1 h, Petition 870220002363, dated 10 / 01 / 2022, p. 171 / 422 168 / 412 then, the solution was heated to 110 °C and stirred for 6 h at this temperature. The reaction mixture was then cooled to rt, rapidly cooled by the addition of 10 mL of water / ice, and extracted with 3 x 100 mL of EtOAc. The combined organic layers were dried with Na2SO4, and concentrated under vacuum, and purified by silica gel column chromatography using EtOAc / hexane (1 / 3) to give 1 g (77%) of the title compound as a yellow oil. LC-MS: (ES, m / z) : 379. Intermediate D—100: 1-[(2-chlorophenyl)methyl]-5(3,5-dimethoxyphenyl)—1H-pyrazole-3-methylcarboxylate

[0595] For a solution of methyl Int. D-21 (1.0 g, 3.81 mmol, 1.00 equiv) in toluene (50 mL), NaH (304 mg, 7.60 mmol, 2.00 equiv) was added in portions at rt. The mixture was stirred at rt for 30 min, then Int. E-7 (1.56 g, 7.59 mmol, 2.00 equiv) was added dropwise with stirring at 60 °C. The resulting solution was stirred for 1 h at 60 °C, then heated to 110 °C and stirred for an additional 3 h. The reaction was then rapidly cooled by the addition of water / ice. The resulting solution was extracted with 200 mL of EtOAc, and the combined organic layers were washed with 2 x 100 mL of brine, dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:3) to yield 800 mg (54%) of the title compound as a colorless oil. LC-MS: (ES, m / z): 387. 1H-NMR: (CDCle, ppm): δ: 7.42 - 7.29 (m, 1H), 7.29 - 7.13 Petition 870220002363, dated 10 / 01 / 2022, p. 172 / 422 169 / 412 (m, 2H), 6.97 (s, 1H), 6.77 - 6.67 (m, 1H), 6.42 (dd, J = 30.5, 2.3 Hz, 3H), 5.55 (s, 2H), 3.97 (d, J = 1.0 Hz, 3H), 3.69 3, 60 (m, 6H).

[0596] The following substituted pyrazoles were obtained from alkylation with an alkyl halide: Table 10: Pyrazole alkylation. Pirazol Haleto de alquila Produto Espectral D-2 E-1 5- (3-ciclopropoxifenil)-1- [(2-etoxifenil)metil]-1H- pirazol-3-carboxylato de methyla D-101 LC-MS: (ES, m / z) : 393. D-2 E-2 5-(3-ciclopropoxifenil)-1- [(2-nitrofenil)metil]-1H- pirazol-3-carboxylato de methyla D-102 LC-MS: (ES, m / z) : 394 . D-2 E-6 1-[(2-bromophenyl)methyl]-5-(3-cyclopropoxyphenyl)-1H-pyrazole-3-carboxylate de methyl D-103 LC-MS: (ES, m / z) : 429.2. D-5 E-7 1-[(2-chlorophenyl)methyl]-5- (2,3-di-hidro-1,4- benzodioxin-6-yl)-1H-pyrazol- 3-carboxylate de methyl D-104 LC-MS: (ES, m / z) : 385. D-6 E-7 5-(2H-1,3-benzodioxol-5-yl)- 1-[(2-chlorophenyl)methyl]-1H- pyrazol-3-carboxylate de methyl D-105 LC-MS: (ES, m / z) : 371. D-7 E-7 1-[(2-chlorophenyl)methyl]-5-(1methyl-1H-pyrazol-4-yl)-1H- D-106 LC-MS: (ES, Petition 870220002363, 10 / 01 / 2022, pág. 173 / 422 170 / 412 pyrazol-3-carboxylate de methyl m / z) : 331. D-8 E-7 5-(1-benzothiophen-2-yl)-1- [(2chlorophenyl)methyl]-1H-pyrazol3-carboxylate de ethyl D-107 LC-MS: (ES, m / z) : 397 . D-9 E-7 1-[(2-chlorophenyl)methyl]-5-(1methyl-1H-indol-6-yl)-1H- pyrazol-3-carboxylate deethyl D-108 LC-MS: (ES, m / z) : 393. D-10 E-1 1-[(2-ethoxyphenyl)methyl]-5-(1methyl-1H-indazol-6-yl)-1Hpyrazol-3-carboxylate de ethyla D-109 LC-MS: (ES, m / z) : 404 . D-10 E-7 1-[(2-chlorophenyl)methyl]-5-(1methyl-1H-indazol-6-yl)-1Hpyrazol-3-carboxylate de ethyla D-110 LC-MS: (ES, m / z) : 394 . D-11 E-7 1-[(2-chlorophenyl)methyl]-5-(1ethyl-1H-indazol-6-yl)-1Hpyrazol-3-carboxylate de methyl D-111 LC-MS: (ES, m / z) : 395. D-11 E-11 5-(1-ethyl-1H-indazol-6-yl)-1- ([pyridin-2-yl]methyl)-1Hpyrazol-3-carboxylate de methyl D-112 LC-MS: (ES, m / z): 362.3. D-12 E-1 5-(3-chloro-5-methoxyphenyl)-1- [(2-ethoxyphenyl)methyl]-1H- pyrazol-3-carboxylate de methyl D-113 LC-MS: (ES, m / z) : 401. Petition 870220002363, 10 / 01 / 2022, pág. 174 / 422 171 / 412D-13 E-7 1-[(2-chlorophenyl)methyl]-5-(1methyl-1H-indazol-5-yl)-1Hpyrazol-3-carboxylate de ethyla D-114 LC-MS: (ES, m / z) : 394 . D-11 E-1 1-[(2-ethoxyphenyl)methyl]-5-(1- ethyl-1H-indazol-6-yl)-1H- pyrazol-3-carboxylate de methyl D-115 LC-MS: (ES, m / z) : 404 . D-14 E-7 1-[(2-chlorophenyl)methyl]-5-(1- methyl-1H-indazol-4-yl)-1H-pyrazol-3-carboxylate ethyl D-116 LC-MS: (ES, m / z) : 381. D-15 E-7 1-[(2-chlorophenyl)methyl]-5-(1ethyl-1H-1,2,3-benzotriazol-6yl)-1H-pyrazol-3-carboxylate methyl D-117 LC-MS: (ES, m / z) : 396. D-16 E-1 5-(3-cyclobutoxyphenyl)-1- [(2etoxyphenyl)methyl]-1H-pyrazol3-carboxylate ethyl D-118 LC-MS: (ES, m / z) : 421. D-16 E-6 1-[(2-bromophenyl)methyl]-5-(3cyclobutoxyphenyl)-1H-pyrazol-3-carboxylate ethyl D-119 LC-MS: (ES, m / z): 454 . D-17 E-12 5-[3-(2,2-dimethylpropoxy)phenyl]-1-[(1-methyl-1H-indazol-7-yl)methyl]- 1H-pyrazol-3-carboxylate methyl D-120 LC-MS: (ES, m / z): 433.3.D-18 E-1 5-(3-ethoxyphenyl)-1-[(2-ethoxyphenyl)methyl]-1H-pyrazol-3-carboxylate methyl D-121 LC-MS: (ES,. Petition 870220002363, dated 10 / 01 / 2022, p. 175 / 422 172 / 412 m / z) : 394 . D-19 E-7 5-[3-(benziloxy)phenyl]-1-[(2chlorophenyl)methyl]-1H-pyrazol3-carboxylate de methyl D-122 LC-MS: (ES, m / z) : 433.05. D-20 E-11 5-[3-(2-methylpropoxy)phenyl]- 1-([pyridin-2-yl]methyl)-1H-pyrazol-3-carboxylate de methyl D-123 LC-MS: (ES, m / z): 366. D-21 E-1 5-(3,5-dimethoxyphenyl)-1-[(2ethoxyphenyl)methyl]-1H-pyrazol-3-carboxylate de methyl D-124 LC-MS: (ES, m / z): 397 D-21 E-9 5-(3,5-dimethoxyphenyl)-1-(2phenylethyl)-1H-pyrazol-3-carboxylate D-125 LC-MS: (ES, m / z): 366. D-21 E-3 5- (3,5-dimethoxyphenyl)-1-[(2ethoxy-6-fluorophenyl)methyl]- 1H-pyrazol-3-carboxylate de methyl D-126 LC-MS: (ES, m / z): 415.10. D-21 E-11 5-(3,5-dimethoxyphenyl)-1- ([pyridin-2-yl]methyl)-1Hpyrazol-3-carboxylate de methyl D-127 LC-MS: (ES, m / z): 354 . D-22 E-1 5-(3,5-diethoxiphenyl)-1- [(2ethoxiphenyl)methyl]-1H-pyrazol3-carboxylate de methyl D-128 LC-MS: (ES, m / z): 425.1. D-22 E-7 1-[(2-chlorophenyl)methyl]-5- (3,5-diethoxyphenyl) -1H- D-129 LC-MS: (ES, Petition 870220002363, 10 / 01 / 2022, pág. 176 / 422 173 / 412 pyrazol-3-carboxylate de methyl m / z): 415.15. D-23 E-1 5-(3-Ethoxy-5-methoxyphenyl)-1-[(2-ethoxyphenyl)methyl]-1H-pyrazol-3-carboxylate de methyl D-130 LC-MS: (ES, m / z) : 411. D-24 E-10 1-[(2-chlorophenyl)methyl]-5-[2(propan-2-yloxy)-1,3-oxazol-5-yl]-1H-pyrazol-3carboxylate de methyl D-131 LC-MS: (ES, m / z) : 389. D-25 E-7 1-[(2-chlorophenyl)methyl]-5[1,3-dimethyl-1H-thieno[2,3c]pyrazol-5-yl]-1H-pyrazol-3carboxylate de methyl D-132 LC-MS: (ES, m / z): 401 Pirazol Haleto de Alquila Produto D-3 E-8 1-[(2-fluoro-6-nitrofenil)metil]-5(3-metoxifenil)-1H-pirazol-3carboxylato de methyla D-133 D-3 E-4 5-(3-metoxifenil)-1-[[2-(propan-2yloxi)fenil]metil]-1H-pirazol-3carboxylato de methyla D-134 D-3 E-13 5-(3-metoxifenil)-1-(2-metilpropil)- 1H-pirazol-3-carboxylato de methyla D-135 D-3 E-14 5-(3-metoxifenil)-1-([oxan-4yl]metil)-1H-pirazol-3-carboxylato de methyla D-136 D-4 E-7 1-[(2-chlorophenyl)methyl]-5-(3nitrophenyl)-1H-pyrazol-3-carboxylate de methyl D-137 Petition 870220002363, dated 10 / 01 / 2022, p. 177 / 422 174 / 412 D-2 6 E-7 1-[(2-chlorophenyl)methyl]-5-[3-[(propan-2-yl)carbamoyl]phenyl]-1H-methyl pyrazol-3-carboxylate D-138 Intermediate D-139: 1-[(2,6-dimethoxyphenyl)methyl]-5-[3-(2-methylpropoxy)phenyl]-1H-pyrazole-3-methylcarboxylate

[0597] To a solution of Int. D-20 (1.37 g, 4.99 mmol, 1.00 equiv) in THF (50 mL) under N2 at 0 °C was added (2,6-dimethoxyphenyl)methanol (1.26 g, 7.49 mmol, 1.50 equiv) followed by PPh3 (1.81 g, 6.90 mmol, 1.30 equiv). Subsequently, DIAD (1.75 g, 8.65 mmol, 1.50 equiv) was added dropwise and the resulting solution was stirred for 16 h at 25 °C. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:19). This resulted in the title compound as a yellow solid (890 mg, 42%). Intermediate D—140: 1—[(3—chloropyridin—2—yl)methyl]—5—(3—methoxyphenyl)—1H—pyrazole—3—methyl carboxylate Petition 870220002363, dated 10 / 01 / 2022, page 178 / 422 175 / 412

[0598] (3-chloropyridin-2-yl)methanol To a solution of 3-chloropyridine-2-carboxylic acid (2.1 g, 13.33 mmol, 1.00 equiv) in THF (40 mL) was added Et3N (2.7 g, 26.68 mmol, 2.00 equiv), followed by the addition of chloro(propan-2-yloxy)methanone (2.45 g, 19.99 mmol, 1.50 equiv) by dropwise stirring at 0 °C. The solution was stirred for 1 h at room temperature. The solid was removed by filtration. NaBH4 (1.53 g, 40.44 mmol, 3.00 equiv) was added to the filtrate. The resulting solution was stirred for 2 h at room temperature, then diluted with 50 mL of H2O and extracted with 2 x 100 mL of EtOAc. The combined organic layers were washed with 50 mL of saturated NaCl, dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:6) to provide 0.9 g (47%) of the title compound as a colorless oil.

[0599] 1-[(3-chloropyridin-2-yl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-carboxylate methyl A solution of the product from the previous step (850 mg, 5.92 mmol, 1.00 equiv) in THF (8.5 mL), under N2, Int. D-3 (1.4 g, 6.03 mmol, 1.00 equiv) and Ph3P (3.1 g, 11.82 mmol, 2.00 equiv), followed by the addition of DIAD (1.8 g, 8.91 mmol, 1.50 equiv) by dropwise stirring at 0 °C. The resulting solution was stirred for 5 h at room temperature, diluted with 30 mL of H2O, and extracted with 2x50 mL of EtOAc. The combined organic layers were washed with 20 mL of saturated NaCl, dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1:10) to provide 1.7 g (80%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d) δ 8.90 (s, 1H), 8.35 (dd, J = 4.7, 1.5 Hz, 1H), 7.99 (dd, J = 8.1, Petition 870220002363, dated 10 / 01 / 2022, p. 179 / 422 176 / 412 1.5 Hz, 1H), 7.51 (s, 1H), 7.45 (dt, J = 7.7, 1.2 Hz, 1H), 7.41 (dd, J = 2.6, 1.5 Hz, 1H), 7.36 — 7.30 (m, 1H), 6.91 (ddd, J = 8.2, 2.7, 1.0 Hz, 1H), 5.99 (s, 2H), 3.80 (s, 3H), 3.77 (s, 3H). Intermediate D-141: 1-[[4-(dimethylamino)phenyl]methyl]-5-[3-(2-methylpropoxy)phenyl]-1H-pyrazol-3-methylcarboxylate

[0600] 1-[(4-aminophenyl)methyl]-5-[3-(2-methylpropoxy)phenyl]-1H-pyrazol-3-carboxylate methyl. To a solution of Int. D-58 (2 g, 4.88 mmol, 1.00 equiv) in AcOH / H2O (100 / 40 mL) Zn (1 g, 15.29 mmol, 3.00 equiv) was added, and the resulting solution was stirred for 5 h at 25 °C. The solids were collected by filtration. The pH of the solution was adjusted to 7 with (sat) NaHCO3 (aq) and the resulting solution was extracted with 200 mL of EtOAc. The combined organic layers were concentrated under vacuum to give 1.5 g (81%) of the title compound as a yellow oil.

[0601] 1-[[4-(dimethylamino)phenyl]methyl]-5-[3-(2-methylpropoxy)phenyl]-1H-pyrazol-3-carboxylate methyl To a solution of the product from the previous step (1.35 g, 3.56 mmol, 1.00 equiv) in MeOH (50 mL) formaldehyde (5 mL, 1.50 equiv) was added over 30 min. To this, NaCNBH3 (800 mg, 12.73 mmol, 3.00 equiv) was added, and the resulting solution was stirred. Petition 870220002363, dated 10 / 01 / 2022, page 180 / 422 177 / 412 for 5 min at 25 °C. The resulting solution was extracted with 200 mL of EtOAc, and the combined organic layers were purified by silica gel chromatography using EtOAc / petroleum ether (1:7) to provide 810 mg (56%) of the title compound as a yellow liquid. Intermediate D-142: 1-[[2-(dimethylamino)-6-fluorophenyl]methyl]-5-(3-methoxyphenyl)-1H-pyrazole-3-carboxylate methyl

[0602] Intermediate D-142 was obtained from Int. D-133 by a zinc reduction / reduction amination sequence similar to that used to prepare Int. D-141. Intermediate D-143: 1-[(2-chlorophenyl)methyl]-5-[3-(oxetan-3-ylmethoxy)phenyl]-1H-pyrazole-3-methylcarboxylate

[0603] Acid A solution of Int. D122 (3.2 g, 7.39 mmol, 1.00 equiv) in AcOH / HCl (15 / 5 mL) was stirred for 2 hours at 90 °C, then cooled, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (2 / 1) to provide 2 g Petition 870220002363, dated 10 / 01 / 2022, p. 181 / 422 178 / 412 (82%) of the compound as a light yellow oil. LC-MS: (ES, m / z): 329, 0. 1H NMR: (300 MHz, DMSO) δ 12.83 (s, 1H), 9.72 (s, 1H), 7.46 (m, 1H), 7.29 (m, 3H), 6.81 (m, 5H), 5.48 (s, 2H).

[0604] 1-[(2-chlorophenyl)methyl]-5-(3-hydroxyphenyl)-1H-pyrazol-3-carboxylate methyl A solution of the product from the previous step (2 g, 6.08 mmol, 1.00 equiv) and H2SO4 (1 mL) in MeOH (20 mL) was stirred for 2 h at 65 °C. The pH was adjusted to 7 with saturated NaHCO3. The resulting solution was extracted with 3 x 30 mL of EtOAc, and the combined organic layers were dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (2 / 1) to provide 1.7 g (82%) of the title compound as a white solid. LC-MS: (ES, m / z): 343.1. 1H NMR: (400 MHz, DMSO) δ 9.74 (s, 1H), 7.46 (m, 1H), 7.31 (m, 3H), 6.93 (s, 1H), 6.83 (m, 4H), 5.50 (s, 2H), 3.82 (s, 3H).

[0605] 1-[(2-chlorophenyl)methyl]-5-[3-(oxetan-3-ylmethoxy)phenyl]-1H-pyrazol-3-carboxylate methyl A solution of the product from the previous step (1.7 g, 4.96 mmol, 1.00 equiv), PPh3 (2.62 g, 9.99 mmol, 2.00 equiv), and (oxetan-3yl)methanol (870 mg, 9.87 mmol, 2.00 equiv) in THF (30 mL) at 10 °C under a N2 atmosphere was added DTAD (1.82 g, 9.01 mmol, 1.80 equiv). The resulting solution was stirred overnight at rt and extracted with 3x30 mL of EtOAc. The combined organic layers were dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1 / 3) to give 1.1 g (54%) of the title compound as a white solid. LC-MS: (ES, m / z): 413.1. Petition 870220002363, dated 10 / 01 / 2022, p. 182 / 422 179 / 412 Intermediate D-144: 5-(3-cyclopropoxyphenyl)-1-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-7-yl)-1H-pyrazol-3-carboxylate

[0606] To a solution of Int. D-95 (600 mg, 1.60 mmol, 1.00 equiv) in CH2Cl2 (15 mL) was added NaH (128 mg, 5.33 mmol, 2.00 equiv). The solution was stirred for 10 min, then SEMCl (664 mg, 2.50 equiv) was added. The resulting solution was stirred for 16 h at room temperature, then rapidly cooled by the addition of water, and extracted with 2 x 100 mL of EtOAc. The combined organic layers were washed with 100 mL of brine, dried with Na2SO4, concentrated under vacuum, and purified by silica gel column using EtOAc / petroleum ether (1:2) to provide 300 mg (37%) of the title compound as a yellow oil. LC-MS: (ES, m / z) : 504. Intermediate D-145: 5—(3—cyclopropoxyphenyl)—1—(1 — [[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-4-yl)-1H-pyrazol-3-carboxylate methyl Petition 870220002363, dated 10 / 01 / 2022, p. 183 / 422 180 / 412

[0607] To a solution of Int. D-94 (460 mg, 1.23 mmol, 1.00 equiv) in CH2Cl2 (10 mL) NaH (57.5 mg, 2.40 mmol, 2.00 equiv) was added at 0 °C. The resulting solution was stirred for 30 min, then SEMCl (253 mg, 0.69 mmol, 1.30 equiv) was added. The resulting solution was stirred for 5 h at rt, then rapidly cooled with H2O and extracted with 3 x 20 mL of EtOAc. The combined organic layers were dried with Na2SO4, concentrated under vacuum, and purified by silica gel chromatography using EtOAc / petroleum ether (1 / 3) to give 300 mg (48%) of the title compound as a colorless oil. LC-MS: (ES, m / z) : 505, 1. Intermediate D—146: 5—(3—cyclopropoxyphenyl)—1—(3—methyl-1-[[2—(trimethylsilyl)ethoxy]methyl]—1H—indazol—4—yl)—1H—pyrazole—3—methyl carboxylate

[0608] To a solution of Int. D-96 (500 mg, A solution of 1.29 mmol, 1.00 equiv) in CH2Cl2 (10 mL) was followed by the addition of NaH (62 mg, 2.58 mmol, 2.00 equiv). The resulting solution was stirred for 30 min at 0 °C, then [2-(chloromethoxy)ethyl]trimethylsilane (278 mg, 1.67 mmol, 1.30 equiv) was added. The resulting solution was stirred for 5 h at room temperature, then rapidly cooled with H2O and extracted with 3 x 20 mL of CH2Cl2. The combined organic layers were dried with Na2SO4, concentrated under vacuum, and purified with prep-TLC using EtOAc / petroleum ether. Petition 870220002363, dated 10 / 01 / 2022, page 184 / 422 181 / 412 (1 / 3) to provide 250 mg (36%) of the title compound as a colorless oil. LC-MS: (ES, m / z): 519.40. Intermediate D-147: 1-[(2-chlorophenyl)methyl]-5-phenoxy-1H-pyrazole-3-ethyl carboxylate

[0609] Ethyl 1-[(2-chlorophenyl)methyl]-5-oxo-4,5-dihydro-1H-pyrazol-3-carboxylate A solution of Int. C13 (4 g, 17.54 mmol, 1.00 equiv) and 1,4-diethyl 2-oxobutanedioate (0 mg, 1.30 equiv) in EtOH (120 mL) was heated to reflux overnight, then concentrated under vacuum. The crude product was purified using silica gel chromatography with EtOAc / petroleum ether (1:20~1:5) to provide 2.8 g (57%) of the title product as a yellow syrup.

[0610] Ethyl 1-[(2-chlorophenyl)methyl]-5-(2-nitrophenoxy)-1H-pyrazol-3-carboxylate A solution of the product from the previous step (2.8 g, 9.97 mmol, 1.00 equiv), 1-fluoro-2-nitrobenzene (2.8 g, 19.84 mmol, 2.00 equiv), and K2CO3 (2.7 g, 19.57 mmol, 2.00 equiv) in DMF (20 mL) was stirred overnight at 90 °C. The resulting solution was diluted with EtOAc, washed with water and brine, dried with anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel chromatography using EtOAc / petroleum ether (1:50 to 1:10) to provide 0.8 g (20%) of the title product as a yellow oil. Petition 870220002363, dated 10 / 01 / 2022, page 185 / 422 182 / 412

[0611] Ethyl 5-(2-aminophenoxy)-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-carboxylate A solution of the product from the previous step (800 mg, 1.99 mmol, 1.00 equiv) in AcOH / H2O (3:1) (8 mL) was stirred with Zn (600 mg, 9.38 mmol, 5.00 equiv) for 3 h at 60 °C. The solids were removed by filtration, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel chromatography using EtOAc / petroleum ether (1:30~1:5) to provide 540 mg (73%) of the title product as a yellow solid.

[0612] Ethyl 1-[(2-chlorophenyl)methyl]-5-phenoxy-1Hpyrazol-3-carboxylate To a solution of the product from the previous step (540 mg, 1.45 mmol, 1.00 equiv) in THF (15 mL) was added tert-butyl nitrite (450 mg, 4.36 mmol, 3.00 equiv). The resulting solution was stirred for 30 min at 60 °C, then concentrated under vacuum. The residue was purified with Prep-TLC (EtOAc:PE=1:3) to provide 220 mg (42%) of the title product as a solid. Intermediate F—1: [1—[(3—chlorophenyl)methyl]—5—phenyl—1H—pyrazol—3—yl]methanol

[0613] A solution of Int. D-98 (0.80 g, 2.45 mmol) in anhydrous THF was cooled to 0 °C. To the above mixture, LiAlH4 (0.14 g, 3.67 mmol) was added in portions, and stirring was continued at 0 °C for 1.5 h. The mixture was then rapidly cooled with water (0.15 mL) and a 30% solution of Petition 870220002363, dated 10 / 01 / 2022, p. 186 / 422 183 / 412 Aqueous NaOH (0.3 mL) at 0°C was added, and stirring was continued for 30 min. The reaction mixture was filtered, the filter cake was washed with THF (2 x 10 mL), and the filtrates were combined and evaporated to dryness. The residue was subjected to chromatography with SiO2 (ISCO CombiFlash® Rf 200) using a 0 to 40% EtOAc gradient in DCM to provide the titer product (0.58 g 79%). 1H NMR (CDCl3, 400 MHz) δ 4.64-4.81 (d, 2H), 5.31 (s, 2H), 6.35 (s, 1H), 6.86-6.94 (m, 1H), 6.98-7.05 (m, 1H), 7.19-7.23 (m, 2H), 7.26-7.35 (m, 2H), 7.39-7.46 (m 3H).

[0614] The following substituted 3-(hydroxymethyl)pyrazoles were obtained from the reduction of LiAlH4 from the corresponding methyl esters: Table 11: L1AIH4 reduction of pyrazole carboxylic esters. Here r Spectral Product D-57 [1-[(2-chlorophenyl)methyl]-5-(1-methyl- 1H-1,3-benzodiazol-6-yl)-1H-pyrazol-3yl]methanol F-2 LC-MS: (ES, m / z): [M+1.] = 593 [5-(3-methoxyphenyl)-1-(pyridine-3-yl)- 1H-pyrazol-3-yl]methanol F-3 D-65 [5-(3-methoxyphenyl)-1-(2-methylphenyl)- 1H-pyrazol-3-yl]methanol F-4 D- 117 [1-[(2-chlorophenyl)methyl]-5-(1-ethyl-1H1,2,3-benzotriazol-6-yl)-1H-pyrazol-3yl]methanol F-5 LC-MS: (ES, m / z): 368. Petition No. 870220002363, dated 10 / 01 / 2022, p. 187 / 422 184 / 412 D- 132 [1-[(2-chlorophenyl)methyl]-5-[1,3- dimethyl-1H-thieno[2,3-c]pyrazol-5-yl]- 1H-pyrazol-3-yl]methanol F-6 LC-MS: (ES, m / z): 373. D- 137 [1-[(2-chlorophenyl)methyl]-5-(3nitrophenyl)-1H-pyrazol-3-yl]methanol F-7 Intermediate F-8: [1 — [(2—chlorophenyl)methyl]—5—(3— methoxyphenyl)—1H—pyrazol—3—yl]methanol

[0615] (iii) A solution of Int. D-28 (5.5 g, A concentration of 15.41 mmol (1.00 equiv) in THF (100 mL) and 20 mL of LiBH4 were added dropwise with stirring at 0 °C over 5 min. The resulting solution was stirred for 16 h at room temperature. The reaction was then rapidly cooled by the addition of 5 mL of water, diluted with 200 mL of H2O, extracted with 2 x 200 mL of EtOAc, and the organic layers were combined. The resulting mixture was washed with 1 x 100 mL of brine, then dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:8). This resulted in the title compound as a white solid (4.3 g, 85%).

[0616] The following substituted 3-(hydroxymethyl)pyrazoles were obtained from the LiBH4 reduction of the corresponding methyl esters: Petition 870220002363, dated 10 / 01 / 2022, p. 188 / 422 185 / 412 Table 12: L1BH4 reduction of pyrazole carboxylic esters. Ester Product Spectral D-2 9 [5-[3-(2-methylpropoxy) phenyl] -1phenyl-1 H-pyrazol-3-yl]methanol F-9 LC-MS: (ES, m / z) : 323. D-30 [1- (2-bromophenyl)-5-(1-ethyl-1H- indazol-6-yl)-1H-pyrazol-3- yl]methanol F-10 LC-MS: (EC, m / z) : 398.9. D-31 [1-(2-bromophenyl)-5-(1-methyl-1H- indazol-6-yl)-1H-pyrazol-3- yl]methanol F-11 LC-MS: (ES, m / z) : 383. D-32 [1-(2-bromophenyl)-5-[3-(2,2dimethylpropoxy)phenyl]-1H-pyrazol-3yl]methanol F-12 LC-MS: (ES, m / z) : 417.00. D-33 [1-(2-bromophenyl) -5-(3,5dimethoxyphenyl)-1H-pyrazol-3yl]methanol F-13 LC-MS: (ES, m / z) : 389. D-34 [1-(2-bromophenyl)-5-(1-propyl-1H- indazol-16-yl-methanol-H-ylrazol)] F-14 LC-MS: (ES, m / z): 413.0. Petition 870220002363, dated 10 / 01 / 2022, p. 189 / 422 186 / 412 D-35 [1-(2-bromophenyl)-5-(3- cyclobutoxyphenyl)-1H-pyrazol-3yl]methanol F-15 LC-MS: (ES, m / z): 399.2. D-36 [1-(2-fluorophenyl)-5-[3-(oxetane-3ylmethoxy)phenyl]-1H-pyrazol-3yl]methanol F-16 LC-MS: (ES, m / z) : 355.2. D-37 [5-(3-cyclobutoxyphenyl)-1-(2fluorophenyl)-1H-pyrazol-3-yl]methanol F-17 LC-MS: (ES, m / z) : 339. D-38 [1-(2-fluorophenyl)-5-[3-(oxetane-3yloxy)-phenylmeth-ol-3-H F-18 LC-MS: (ES, m / z) : 341. D-39 [1-(2-fluorophenyl)-5-[3- (2methylpropoxy)phenyl]-1H-pyrazol-3yl]methanol F-19 LC-MS: (ES, m / z) : 341. D-40 [5-(3-ciclobutoxyphenyl)-1-(2methylphenyl)-1H-pyrazol-3-yl]methanol F-20 LC-MS: (EC, m / z) : 334 . D-41 [5-(3,5-diethoxyphenyl)-1-(2- methylphenyl)-1H-pyrazol-3-yl]methanol F-21 LC-MS: (ES, m / z) : 353, 00 . Petition 870220002363, dated 10 / 01 / 2022, p. 190 / 422 187 / 412 D-42 [5-(1-ethyl-1H-indazol-6-yl)-1-(2- nitrophenyl)-1H-pyrazol-3-yl]methanol F-22 LC-MS: (ES, m / z) : 364.3. D-43 [5-[3-(2,2-dimethylpropoxy)phenyl]-1(quinolin-8-yl)-1H-pyrazol-3yl]methanol F-23 LC-MS: (ES, m / z): [M+1] = 388 . D-44 [5-(3,5-dimethoxyphenyl)-1-(2- ethoxyphenyl)-1H-pyrazol-3-yl]methanol F-24 LC-MS: (ES, m / z) : 355 . D-45 [5-(1-ethyl-1H-indazol-6-yl)-1-(1methyl-1H-indazol-7-yl)-1H-pyrazol-3yl]methanol F-25 LC-MS: (ES, m / z) : 372 . D-46 [5-(3-cyclobuthoxyphenyl)-1-(1-methyl- 1H-indazol-7-yl)-1H-pyrazol-3- il]methanol F-2 6 LC-MS: (ES, m / z) : 375. D-47 [5-[3-(2,2]-dimethylpropo (1-methyl-1H-indazol-7-yl)-1H- pyrazol-3-yl]methanol F-27 LC-MS: (ES, m / z) : 391.10 . D-48 [5-[3-(cyclobutylmethoxy)phenyl]-1-(1methyl-1H-indazol-7-yl)-1H-pyrazol-3yl]methanol F-28 LC-MS: (ES, m / z) : 389. Petition No. 870220002363, dated 10 / 01 / 2022, p. 191 / 422 188 / 412 D-49 [5-[3-(cyclopropylmethoxy)phenyl]-1- (1-methyl-1H-indazol-7-yl)-1H- pyrazol-3-yl]methanol F-2 9 LC-MS: (ES, m / z) : 375. D-50 [1-(1-yl-inda)zol-1H -5-[3(2-methylpropoxy)phenyl]-1H-pyrazol-3yl]methanol F-30 LC-MS: (ES, m / z) : 377 . D-51 [5-(3,5-dimethoxyphenyl)-1-(1-methyl- 1H-indazol-7-yl)-1H-pyrazol-3- il]methanol F-31 LC-MS: (ES, m / z): 365. D-52 [5-(3,5-diethoxyphenyl)-1-(1-methyl-1Hindazol-7-yl)-1H-pyrazol-3- il]methanol F-32 LC-MS: (ES, m / z) : 393.05. D-53 [5-[3-(2,2-dimethylpropoxy)phenyl]-1(1-ethyl-1H-indazol-7-yl)-1H-pyrazol3-yl]methanol F-33 LC-MS: (ES, m / z) : 404 . D-54 [5-(3-methoxyphenyl)-1-[2-(propan-2iloxy)phenyl]-1H-pyrazol-3-yl]methanol F-34 LC-MS: (ES, m / z): 339. D-55 [1-(1, 3-dimethyl-1H-indazol)-5-7-yl [3-(2,2-dimethylpropoxy)phenyl]-1H- pyrazol-3-yl]methanol F-35 LC-MS: (ES, m / z): 405.35. Petition No. 870220002363, dated 10 / 01 / 2022, p. 192 / 422 189 / 412 D-56 [5-[3-(2,2-dimethylpropoxy)phenyl]-1(1-methyl-1H-1,2,3-benzotriazol-7yl)-1H-pyrazol-3-yl]methanol F-36 D-66 [1- (2-chlorophenyl)-5-[3-(oxetane-3ylmethoxy)phenyl]-1H-pyrazol-3yl]methanol F-37 LC-MS: (EC, m / z) : 371.0. D-67 [1- (2-chlorophenyl)-5-(pyridin-2-yl) 1H-pyrazol-3-yl]methanol F-38 LC-MS: (EC, m / z) : 285.85. D-68 [1-(2-chlorophenyl)-5-(1-methyl-1H- indazol-6-yl)-1H-pyrazol-3- yl]methanol F-39 LC-MS: (ES, m / z) : 339. D-69 [1-(2-chlorophenyl)-5-(1-ethyl-1Hindazol-6-yl)-1H-pyrazol-3yl]methanol F-40 LC-MS: (EC, m / z): 353 . D-70 [1-(2-chlorophenyl) - 5-(3- cyclobutoxyphenyl)-1H-pyrazol-3yl]methanol F-41 LC-MS: (EC, m / z) : 355 . D-71 [1- (2-chlorophenyl)-5-[3-(oxetane-3yloxy)phenyl]-1H-pyrazol-3-yl]methanol F-42 LC-MS: (EC, m / z) : 357 . Petition 870220002363, dated 10 / 01 / 2022, p. 193 / 422 190 / 412 D-72 [1-(2-chlorophenyl)-5-(3- cyclopropoxyphenyl)-1H-pyrazol-3yl]methanol F-43 LC-MS: (ES, m / z) : 369.25. D-73 [1-(2-chlorophenyl)-5-[3-(2,2dimethylpropoxy)phenyl]-1H-pyrazol-3yl]methanol F-44 LC-MS: (EC, m / z) : 371, 00 . D-74 [1-(2-chlorophenyl)-5-[3- (cyclobutylmethoxy)phenyl]-1H-pyrazol- 3-yl]methanol F-45 LC-MS: (EC, m / z) : 368.95. D-76 [1-(2-chlorophenyl)-5-(3,5dimethoxyphenyl)-1H-pyrazol-3yl]methanol F-46 LC-MS: (EC, m / z) : 345. D-77 [1-(2-chlorophenyl)-5-(3,5diethoxyphenyl)-1H-pymetrazol-F-47] LC-MS: (ES, m / z) : 373.1. D-79 [5-(3-cyclopropoxyphenyl) -1-(2fluorophenyl)-1H-pyrazol-3-yl]methanol F-48 LC-MS: (ES, m / z) : 325.25. D-80 [1-(2-bromophenyl)-5-(3cyclopropoxyphenyl)-1H-pyrazol-3yl]methanol F-49 LC-MS: (ES, m / z) : 387 . Petition 870220002363, dated 10 / 01 / 2022, p. 194 / 422 191 / 412 D-81 [1-(2-bromo-4-fluorophenyl) -5-(3cyclopropoxyphenyl)-1H-pyrazol-3yl]methanol F-50 LC-MS: (ES, m / z) : 405.0. D-82 [5-(3-cyclopropoxyphenyl)-1-(2,4dichlorophenyl)-1H-pyrazol-3yl]methanol F-51 LC-MS: (ES, m / z) : 375, 00 . D-83 [5-(3-cyclopropoxyphenyl) -1-(2,5dichlorophenyl)-1H-pyrazol-3yl]methanol F-52 LC-MS: (ES, m / z) : 375.05. D-84 [5-(3-cyclopropoxyphenyl) -1-[2(difluoromethoxy)phenyl]-1H-pyrazol-3yl]methanol F-53 LC-MS: (ES, m / z) : 373. D-85 [5-(3-cyclopropoxyphenyl-xylH)-phenylpyrane](2-zol-(3-cycloproxyphenylH)-3-phenylmethol](2-zol F-54 LC-MS: (ES, m / z) : 350 . D-86 [5-(3-cyclopropoxyphenyl) -1-(2methoxyphenyl)-1H-pyrazol-3-yl]methanol F-55 LC-MS: (ES, m / z) : 337 . D-87 [5-(3-cyclopropoxyphenyl)-1-(2methylphenyl)-1H-pyrazol-3-yl]methanol F-56 LC-MS: (ES, m / z) : 321. Petition No. 870220002363, dated 10 / 01 / 2022, p. 195 / 422 192 / 412 D-88 [5-(3-cyclopropoxyphenyl) -1-(2nitrophenyl)-1H-pyrazol-3-yl]methanol F-57 LC-MS: (ES, m / z) : 352 . D-89 [5-(3-cyclopropoxyphenyl)-1-[2(propan-2-yl)phenyl]-1H-pyrazol-3yl]methanol F-58 LC-MS: (ES, m / z) : 349. D-90 [5-(3-cyclopropoxyphenyl) -1-[2(trifluoromethyl)phenyl]-1H-pyrazol-3yl]methanol F-59 LC-MS: (ES, m / z) : 375. D-91 [5-(3-cyclopropoxyphenyl)-1-(1-methyl- 1H-indazol-7-ylzolMS]-tan-3-LCH (ES, m / z) : 361. D-92 [5-(3-cyclopropoxyphenyl)-1-(1-methyl- 1H-indazol-4-yl)-1H-pyrazol-3- il]methanol F-61 LC-MS: (ES, m / z) : 361. D-93 [5- (3-cyclopropoxyphenyl)-1-(1-ethyl1H-indazol-7-yl)-1H-pyrazol-3yl]methanol F-62 LC-MS: (ES, m / z) : 375. D-97 [5-( 3-cyclopropoxyphenyl)-1-(1-methyl1H-1,3-benzodiazol-7-yl)-1H-pyrazol3-yl]methanol F-63 LC-MS: (ES, m / z) : 361.2. Petition No. 870220002363, dated 10 / 01 / 2022, p. 196 / 422 193 / 412 D-99 [1-[(2-cyclopropoxyphenyl)methyl]-5- (3-methoxyphenyl)-1H-pyrazol-3- il]methanol F-64 LC-MS: (ES, m / z) : 351. D- 100 [1-[(2-chlorophenyl)methyl]-5-(3,5dimethoxyphenyl)-1H-pyrazol-3yl]methanol F-65 LC-MS: (ES, m / z) : 359. D- 107 [5-(1-benzothiophen-2-yl)-1-[(3-methyl]pylozorophenyl-1) F-66 LC-MS: (ES, m / z) : 354 . D- 110 [1-[ (2-chlorophenyl)methyl]-5-(1-methyl- 1H-indazol-6-yl)-1H-pyrazol-3- il]methanol F-67 LC-MS: (ES, m / z) : 353. D- 113 [5- (3-chloro-5-methoxyphenyl)-1-[(2ethoxyphenyl)methyl]-1H-pyrazol-3yl]methanol F-68 LC-MS: (ES, m / z): 373. D- 116 [1-[ (2-chlorophenyl)methyl]-5-(1-Hy-indazol)1-14 il]methanol F-69 LC-MS: (ES, m / z) : 353. D- 115 [1-[ (2-ethoxyphenyl)methyl]-5-(1-ethyl- 1H-indazol-6-yl)-1H-pyrazol-3- il]methanol F-70 LC-7: : (ES Petition No. 870220002363, dated 10 / 01 / 2022, p. 197 / 422 194 / 412 D- 121 [5-(3-ethoxyphenyl)-1-[(2ethoxyphenyl)methyl]-1H-pyrazol-3yl]methanol F-71 LC-MS: (ES, m / z) : 352 . D- 130 [5-(3-ethoxy-5-methoxyphenyl) -1-[(2ethoxyphenyl)methyl]-1H-pyrazol-3yl]methanol F-72 LC-MS: (ES, m / z) : 383. D- [5-(3-cyclopropoxyphenyl)-1-[(2ethoxyphenyl)methyl]-1H-pyrazol-3yl]methanol F-73 LC-MS: (EC, m / z) : 364 . D- 102 [5-(3-cyclopropoxyphenyl) -1-[(2nitrophenyl)methyl]-1H-pyrazol-3yl]methanol F-74 LC-MS: (ES, m / z) : 366. D- [1-[(2-bromophenyl)methyl]-5-(3cyclopropoxyphenyl)-1H-pyrazol-3yl]methanol F-75 LC-MS: (ES, m / z) : 399. D- 104 [1-[(2-chlorophenyl)methyl]-5-(2,3-dihydro-1, 4-benzodioxin-6-yl)-1Hpyrazol-3-yl]methanol F-76 LC-MS: (ES, m / z): 357 . D- 105 [5-(2H-1,3-benzodioxol-5-yl) -1-[(2chlorophenyl)methyl]-1H-pyrazol-3yl]methanol F-77 LC-MS: (ES, m / z) : 343. Petition 870220002363, dated 10 / 01 / 2022, p. 198 / 422 195 / 412 D- 106 [1-[(2-chlorophenyl)methyl]-5-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazol-3- il]methanol F-78 LC-MS: (ES, m / z) : 303. D- 108 [1-[-(2-meth]yl-methyl-chloro-chloro- 1H-indol-6-yl)-1H-pyrazol-3- il]methanol F-79 LC-MS: (ES, m / z) : 351. D- 109 [1-[(2-ethoxyphenyl)methyl]-5-(1-methyl- 1H-indazol-6-ylzol]-tanol-1H3-MS (ES, m / z) : 363. D- 128 [5-(3,5-diethoxyphenyl)-1-[(2ethoxyphenyl)methyl]-1H-pyrazol-3yl]methanol F-81 LC-MS: (ES, m / z) : 397.05. D- 111 [1-[ (2-chlorophenyl)methyl]-5-(1-ethyl- 1H-indazol-6-yl)-1H-pyrazol-3- il]methanol F-82 LC-MS: (ES, m / z) : 367 . D- 112 [5-(1-ethyl-1H-indazol-6-yl) -1- ([pyridine-2-yl]methyl)-1H-pyrazol-3yl]methanol F-83 LC-MS: (ES, m / z): 334 . D- 114 [1-[ (2-chlorophenyl)methyl]-5-(1-methyl- 1H-indazol-5-yl)-1H-pyrazol-3- il]methanol F-84 LC-MS: (ES, m / z) : 352 . Petition No. 870220002363, dated 10 / 01 / 2022, p. 199 / 422 196 / 412 D- 118 [5-(3-ciclobutoxyphenyl)-1-[(2ethoxyphenyl)methyl]-1H-pyrazol-3yl]methanol F-85 LC-MS: (ES, m / z) : 379. D- [1-[(2-bromophenyl)methyl]-5-(3cyclobutoxyphenyl)-1H-pyrazol-3yl]methanol F-86 LC-MS: (EC, m / z) : 412 . D- 120 [5-[3-(2,2-dimethylpropoxy)phenyl] -1- [(1-methyl-1H-indazol-7-yl)methyl]-1H- pyrazol-3-yl]methanol F-87 LC-MS: (ES, m / z): 405.3. D- 123 [5-[3-(2-methylpropoxy)phenyl] -1- ([pyridin-2-yl]methyl)-1H-pyrazol-3yl]methanol F-88 LC-MS: (ES, m / z): 338 . D- 124 [5-(3,5-dimethoxyphenyl) -1-[(2ethoxyphenyl)methyl]-1H-pyrazol-3yl]methanol F-89 LC-MS: (ES, m / z) : 369. D- F-90 LC-MS: (ES, m / z) : 339. D- 126 [5-(3,5-dimethoxyphenyl)-1-[(2-ethoxy6-fluorophenyl)methyl]-1H-pyrazol-3yl]methanol F-91 LC-MS: (ES, m / z): 387.1. Petition 870220002363, dated 10 / 01 / 2022, p. 200 / 422 197 / 412 D- 127 [5-(3,5-dimethoxyphenyl)-1-([pyridine2-yl]methyl)-1H-pyrazol-3-yl]methanol F-92 LC-MS: (ES, m / z): 326. D- 129 [1-[ (2-chlorophenyl)methyl]-5-(3,5diethoxyphenyl)-1H-pyrazol-3yl]methanol F-93 LC-MS: (ES, m / z) : 387.00. D- 131 [1-[ (2-chlorophenyl)methyl] -5-[2(propan-2-yloxy)-1,3-oxazol-5-yl]1H-pyrazol-3-yl]methanol F-94 LC-MS: (ES, m / z) : 348 . D- 143 [1-[ (2-chlorophenyl)methyl]-5-[3(oxetan-3-ylmethoxy)phenyl]-1Hpyrazol-3-yl]methanol F-95 LC-MS: (ES, m / z) : 385.1. D- 144 [5-(3-cyclopropoxyphenyl)-1-(1-[[2(trimethylsilyl)ethoxy]methyl]-1Hindazol-7-yl)-1H-pyrazol-3yl]methanol F-96 LC-MS: (ES, m / z) : 477 . D- 145 [5-( 3-cyclopropoxyphenyl)-1-(1-[[2- (trimethylsilyl)ethoxy]methyl]-1H- indazol-4-yl)-1H-pyrazol-3- il]methanol F-97 LC-MS: (ES, m / z) : 477.2. D- 146 [5-(3-cyclopropoxyphenyl)-1-(3-methyl- 1-[ [2- (trimethylsilyl)ethoxy]methyl]- 1H-indazol-4-yl)-1H-pyrazol-3-yl]methanol F-98 LC-MS: (ES, m / z), 4. : 4 Petition No. 870220002363, dated 10 / 01 / 2022, p. 201 / 422 198 / 412 Ester Product D-60 [1-[(2-chlorophenyl)methyl]-5-(2methoxyphenyl)-1H-pyrazol-3-yl]methanol F-99 D-61 [5-(4-bromothien-2-yl)-1-[(2chlorophenyl)methyl]-1H-pyrazol-3-yl]methanol F-100 D-62 [1-[(2-chlorophenyl)methyl]-5-[5-(2methylpropoxy)thien-2-yl]-1H-pyrazol-3-yl]methanol F-101 D-63 1-[(2-chlorophenyl)-5-[2-(2methylpropyl)-1,3-oxazol-5-yl]-1H-pyrazol-3-yl]methanol F-102 D-64 [1-[(2-chlorophenyl)methyl]-5-[2-(2methylpropoxy)-1,3-thiazol-5-yl]-1Hpyrazol-3-yl]methanol F-103 D-75 [1-(2-chlorophenyl)-5-[3-(2-methylpropoxy)phenyl]-1H-pyrazol-3-yl]methanol F-104 D-78 (5-benzyl-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl)-methanol F-105 D-134 (5-(3-methoxyphenyl)-1-[[2-(propan-2-yloxy)phenyl]methyl]-1H-pyrazol-3-yl) methanol F-106 D-135 (5-(3-methoxyphenyl)-1-(2-methylpropyl)- 1H-pyrazol-3-yl)methanol F-107 D-136 (5-(3-methoxyphenyl)-1-([oxan-4- yl]methyl)-1H-pyrazol-3-yl)methanol F-108 D-138 (1-[(2-chlorofenil)metil]-5-[3- [(propan-2-yl)carbamoyl]fenil]-1H- pyrazol-3-yl)-methanol F-109 Petition 870220002363, de 10 / 01 / 2022, pág. 202 / 422 199 / 412 D-139 (1-[(2,6-dimethoxyphenyl)methyl]-5-[3(2-methylpropoxy)phenyl]-1H-pyrazole-3yl)methanol F-110 D-141 (1-[[4-(dimethylamino)phenyl]methyl]-5- [3-(2-methylpropoxy)-H 3-yl)methanol F-111 D-142 (1-[[2-(dimethylamino)-6- fluorophenyl]methyl]-5-(3-methoxyphenyl)- 1H-pyrazol-3-yl)methanol F-112 D-147 (1-[(2-chlorophenyl)methyl)phenoxyol-3-pyrazole-3) F-113 D-1 (5-[[ (terc- butoxy)carbonyl](phenyl)amino]-1-[(2chlorophenyl)methyl]-1H-pyrazol-3yl)methanol F-114 D-140 (1-[(3-chloropyridine-2-yl)methyl]-5-(3methoxy-phenyl-H F-115 Intermediate F-116: [5-(3-cyclopropoxyphenyl)-1[[2-(dimethylemnino)phenyl]methyl]-1H-pyrazol-3-yl]methanol

[0617] [1-[(2-aminophenyl)methyl]-5-(3 cyclopropoxyphenyl)-1H-pyrazol-3-yl]methanol In a 25 mL vial, Int. F-74 [5-(3-cyclopropoxyphenyl)-1[(2-nitrophenyl)methyl]-1H-pyrazol-3-yl]methanol (350 mg, 0.96 mmol, 1.00 equiv), AcOH (7.5 mL), H2O (2.5 mL), and Zn (350 mL, Petition 870220002363, dated 10 / 01 / 2022, p. 203 / 422 200 / 412 5.38 mmol, 5.60 equiv). The resulting mixture was stirred for 3 h at room temperature. The solids were removed. The resulting solution was extracted with 3 x 30 mL of EtOAc. The combined organic layers were dried with Na2SO4 and concentrated under vacuum to give 300 mg (93%) of the title compound as a yellow oil. LC-MS (ES, m / z): 336.

[0618] [5-(3-cyclopropoxyphenyl)-1-[[2(dimethylamino)phenyl]methyl]-1H-pyrazol-3-yl]methanol In a 15 mL flask, the product of the previous step (300 mg, 0.89 mmol, 1.00 equiv) MeOH (5 mL), AcOH (0.25 mL), HCHO (358 mg, 11.92 mmol, 4.00 equiv), and NaCNBH3 (225 mg, 3.57 mmol, 4.00 equiv) were combined. The resulting solution was stirred for 2 hours at 40 °C, rapidly cooled by the addition of 5 mL of water / ice, and extracted with 3 x 30 mL of EtOAc. The combined organic layers were dried with Na2SO4, concentrated under vacuum, and purified by prep-TLC with EtOAc / hexane (1 / 1) to give 300 mg (92%) of the title compound as a yellow oil. LC-MS: (ES, m / z): 365. 1H NMR: (300 MHz, DMSO) δ 7.30 (dd, J = 8.8, 7.6 Hz, 1H), 7.22 (td, J = 7.6, 7.2, 1.6 Hz, 1H), 7.14 (dd, J = 8.1, 1.4 Hz, 1H), 7.00 (m, 2H), 6.88(dd, J = 6.9, 1.5 Hz, 2H), 6.73 (dd, J = 7.7, 1.5 Hz, 1H), 6.42 (s, 1H), 5.35 (s, 2H), 4.46 (s, 2H), 3.67 (dt, J = 5.9, 3.1,3.1 Hz, 1H), 2.55 (s, 6H), 0.62 (ddd, J = 5.9, 3.5, 1.3 Hz,2H), 0.57 (m, 2H).

[0619] The following compounds were obtained via a similar zinc reduction / alkylation sequence. Petition 870220002363, dated 10 / 01 / 2022, pp. 204 / 422 201 / 412 Table 13: Zn reduction / alkylation of (nitroaryl)pyrazoles Cpd of Nitro Spectral Product F-22 [1-[2-(dimethylamino)phenyl]-5-(1-ethyl-1H-indazol-6-yl)1H-pyrazol-3-yl]methanol F-117 LC-MS: (ES, m / z): 362.40. F-57 [5-(3-cyclopropoxyphenyl)-1[2-(dimethylamino)phenyl]-1H-pyrazol-3-yl]methanol F-118 LC-MS: (ES, m / z): 350. Intermediate G-1: 3-(bromomethyl)-1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazole

[0620] To a solution of Int. F-8 (4.3 g, 13.08 mmol, 1.00 equiv) in CH2Cl2 (100 mL) was added CBr4 (6.5 g, 1.50 equiv). This was followed by the addition of a solution of PPh3 (7 g, 26.69 mmol, 2.00 equiv) in CH2Cl2 (10 mL) by dropwise stirring at 0°C over 5 min. The resulting solution was stirred for 4 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:5). This resulted in the title compound as a yellow oil (3.5 g, 68%). Petition 870220002363, dated 10 / 01 / 2022, pp. 205 / 422 202 / 412

[0621] The following substituted 3-(bromomethyl)pyrazoles were obtained from the reaction of the corresponding (hydroxymethyl)pyrazole with PPh3 / CBr4: Table 14: CBr4 bromination of (hydroxymethyl)pyrazoles. Álcool Cpd de bromo Espectral F-6 3-(bromometil)-1-[(2clorofenil)metil]-5-[1,3dimetil-1H-tieno[2,3c]pirazol-5-yl]-1H-pirazol G-2 LC-MS: (ES, m / z) 435. F-9 3-(bromometil)-5-[3-(2metilpropoxi)fenil]-1fenil-1H-pirazol G-3 LC-MS: (ES, m / z): 385. F-10 6-[3-(bromometil)-1-(2bromofenil)-1H-pirazol-5yl]-1-ethyl-1H-indazol G-4 LC-MS: (ES, m / z): 459. F-14 6-[3-(bromomethyl)-1-(2bromophenyl)-1H-pyrazol-5yl]-1-propyl-1H-indazol G-5 LC-MS: (ES, m / z): 475.2 . F-19 3-(bromomethyl)-1-(2fluorophenyl)-5-[3-(2methylpropoxy)phenyl]-1Hpyrazol G-6 LC-MS: (ES, m / z): 403. F-27 7-[3-(bromomethyl)-5-[3(2,2-dimethylpropoxy)phenyl]-1H- G-7 LC-MS: (ES, m / z): 453. Petition 870220002363, 10 / 01 / 2022, pág. 206 / 422 203 / 412 pyrazol-1-yl]-1-methyl-1Hindazol F-30 7-[3-(bromomethyl)-5-[3-(2methylpropoxy)phenyl]-1Hpyrazol-1-yl]-1-methyl-1Hindazol G-8 LC-MS: (ES, m / z): 441.3. F-34 3-(bromomethyl)-5-(3methoxyphenyl)-1-[2-(propan2-yloxy)phenyl]-1H-pyrazol G-9 LC-MS: (ES, m / z): 401. F-43 3-(bromomethyl)-1-(2chlorophenyl)-5-(3cyclopropoxyphenyl)-1Hpyrazol G-10 LC-MS: (SE, m / z): 405.15. F-46 3-(bromomethyl)-1-(2chlorophenyl)-5-(3,5dimethoxyphenyl)-1H-pyrazole G-11 LC-MS: (ES, m / z): 406. 1H-RMN: (300 MHz, DMSOd6) δ 7, 63 (dt, J = 7.5, 2.0 Hz, 2H), 7.59 — 7.41 (m, 2H), 6.87 (s, 1H), 6.44 (t, J = 2.3 Hz, 1H), 6.34 (d, J = 2.3 Hz, 2H), 4.70 (s, 2H), 3, 61 (s, 6H). F-49 3-(bromomethyl)-1-(2bromophenyl)-5-(3cyclopropoxyphenyl)-1Hpyrazol G-12 LC-MS: (ES, m / z): 447. 1H NMR (300 MHz, DMSOd6) δ 7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7.50 (dddd, J = 29.7, 15.0, 7.5, 1.9 Hz, 3H), 7.23 (t, J = 8.0 Hz, 1H), 6.97 - 6.85 (m, 2H), Petition 870220002363, 10 / 01 / 2022, pág. 207 / 422 204 / 412 6, 85 — 6, 75 (m, 2H), 4.78 (s, 1H), 4.68 (s, 1H), 3.55 (tt, J = 6.0, 3.0 Hz, 1H), 0.69 — 0.58 (m, 2H), 0.49 (q, J = 2.7, 2.2 Hz, 2H). F-55 3-(bromomethyl)-5-(3cyclopropoxyphenyl)-1-(2methoxyphenyl)-1H-pyrazol G-13 LC-MS: (ES, m / z): 399 F-60 7-[3-(bromomethyl)-5-(3cyclopropoxyphenyl)-1Hpirazol-1-yl]-1-methyl-1Hindazol G-14 LC-MS: (ES, m / z): 425. F-64 3-(bromomethyl)-1-[(2cyclopropoxyphenyl)methyl]5-(3-methoxyphenyl)-1Hpyrazol G-15 LC-MS: (ES, m / z): 414. F-65 3-(bromomethyl)-1-[(2chlorophenyl)methyl]-5-(3,5dimethoxyphenyl)-1H-pyrazole G-16 LC-MS: (ES, m / z): 423. 1H-RMN: (CDCl3, ppm) : δ: 7.42 - 7.30 (m, 2H), 7.29 - 7.16 (m, 4H), 6.83 - 6.71 (m, 2H), 6, 52 - 6.36 (m, 8H), 5.45 (d, J = 1.0 Hz, 4H), 5.31 (s, 1H), 4.57 (s, 4H), 3.66 (s, 12H) . F-67 6-[3-(bromomethyl)-1-[(2chlorophenyl)methyl]-1Hpyrazol-5-yl]-1-methyl-1Hindazol G-17 LC-MS: (ES, m / z): 417. 1H NMR: (300 MHz, CDCla) δ 8.01 (d, J = 1.0 Hz, 1H), 7.74 (dd, J = 8.3, Petition 870220002363, 10 / 01 / 2022, pág. 208 / 422 205 / 412 0.8 Hz, 1H), 7.42 - 7.33 (m, 1H), 7.28 (s, 1H), 7.26 (dd, J = 3.8, 1, 5 Hz, 2H), 7.10 (dd, J = 8.4, 1.4 Hz, 1H), 6, 95 - 6, 84 (m, 1H), 6.58 (s, 1H), 5.48 (d, J = 0.8 Hz, 2H), 4.61 (s, 2H), 3.99 (s, 3H). F-82 6-[3-(bromomethyl)-1-[(2chlorophenyl)methyl]-1Hpyrazol-5-yl]-1-ethyl-1Hindazol G-18 LC-MS: (ES, m / z): 431. F-89 3-(bromomethyl)-5-(3,5dimethoxyphenyl)-1-[(2ethoxiphenyl)methyl]-1Hpyrazol G-19 LC-MS: (ES, m / z) : 431.0 . F-94 5-[3-(bromomethyl)-1-[(2chlorophenyl)methyl]-1Hpyrazol-5-yl]-2-(propan-2yloxy)-1,3-oxazol G-20 LC-MS: (ES, m / z): 411. F-118 2-[3-(bromomethyl)-5-(3cyclopropoxyphenyl)-1Hpyrazol-1-yl]-N, Ndimethylaniline G-21 LC-MS: (ES, m / z): 413. Álcool Cpd de bromo F-99 3-(bromometil)-1-[(2-clorofenil)metil]-5(2-metoxifenil)-1H-pirazol G-22 Petition 870220002363, 10 / 01 / 2022, pág. 209 / 422 206 / 412 F-100 3-(bromomethyl)-5-(4-bromothien-2-yl)-[1[(2-chlorophenyl)methyl]-1H-pyrazole G-23 F-106 3-(bromomethyl)-(5-(3-methoxyphenyl)-1-[[2(propan-2-yloxy)phenyl]methyl]-1H-pyrazole G-24 F-107 3-(bromomethyl)-(5-(3-methoxyphenyl)-1-(2methylpropyl)-1H-pyrazole G-25 F-108 3-(bromomethyl)-(5-(3-methoxyphenyl)-1- ([oxan-4-yl]methyl)-1H-pyrazole G-2 6 F-116 2-([3-(bromomethyl)-5-(3cyclopropoxyphenyl)-1H-pyrazol-1yl]methyl)-N, N-dimethylaniline G-27 Intermediário H-1: 2—([1—[(3—clorofenil)metil]—5— fenil—1H—pyrazol—3—yl]methoxy)—2—metilpropanoato de methyla

[0622] To a solution of Int. F-1 (0.288 g, 0.964 mmol) DMF, NaH (60%) (0.077 g, 1.93 mmol) was added in portions under N2 at room temperature, and stirring was continued for 30 min. The mixture was cooled to 0 °C and methyl 2-bromo-2-methylpropanoate (0.16 mL, 1.25 mmol) was added dropwise followed by NaI (0.143 g, 0.964 mmol). The reaction mixture was gradually heated to room temperature and stirred overnight. At the end of this period, the aqueous NH4Cl solution was added, and the mixture Petition 870220002363, dated 10 / 01 / 2022, p. 210 / 422 207 / 412 was partitioned with EtOAc (40 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined EtOAc layers were washed with brine and dried with Na2SO4, and the solvent was evaporated. The residue was subjected to chromatography with SiO2 (ISCO CombiFlash® Rf 200) using a 0 to 50% gradient of EtOAc in hexanes to give the title product as an oil (0.068 g, 38%). 1H NMR (CDCle, 400 MHz): δ 1.56 (s, 6H), 3.68 (s, 3H), 4.58 (s, 2H), 5.25 (s, 2H), 6.45 (s, 1H), 6.87-6.93 (m, 1H), 7.00 (s, 1H), 7.16-7.22 (m, 2H), 7.26-7.34 (m, 2H), 7.34-7.42 (m, 3H).

[0623] Pyrazole carboxylic esters were obtained from the Williamson ether synthesis of the corresponding (hydroxymethyl)pyrazole. Table NaH, THF with BrC(CH3)2COOMe: 15: Synthesis of (hydroxymethyl)pyrazole ether. Alcohol Spectral Product F-10 Methyl 2-([1-(2-bromophenyl)-5(1-ethyl-1H-indazol-6-yl)1H-pyrazol-3-yl]methoxy)2-methylpropanoate H-2 LC-MS: (ES, m / z): 499.1. 1H NMR: (300 MHz, DMSO) δ 8.01 (d, J = 1.0 Hz, 1H), 7.74 (dd, J = 8.0, 1.5 Hz, 1H), 7.66 (dd, Petition 870220002363, dated 10 / 01 / 2022, p. 211 / 422 208 / 412 J = 8.4, 0.8 Hz, 1H), 7.62 (dd, J = 7.8, 1.8 Hz, 1H), 7.53 (td, J = 7.7, 7.6, 1.5 Hz, 1H), 7.48 (dd, J = 1.5, 0.8 Hz, 1H), 7.44 (m, 1H), 6.96 (dd, J = 8.4, 1.4 Hz, 1H), 6.79 (s, 1H), 4.50 (s, 2H), 4.32 (q, J = 7.2, 7.2, 7.2 Hz, 2H), 3.72 (s, 3H), 1.47 (s, 6H), 1.24 (t, J = 7.2, 7.2Hz, 3H) . F-11 2-([1-(2-bromophenyl)-5(1-methyl-1H-indazol-6yl)-1H-pyrazol-3- yl]methoxy)-2-methylpropanoate de methyl H-3 LC-MS: (ES, m / z): 483. 1H NMR: (30 0 MHz, DMSO-d 6) δ 7.99 (d, J = 1.0 Hz, 1H) , 7.73 (dd, J = 7.9, 1.5 Hz, 1H), 7.67 — Petition 870220002363, 10 / 01 / 2022, pág. 212 / 422 209 / 412 7.47 (m, 4H), 7.42 (td, J = 7.6, 1.9 Hz, 1H), 6.86 (dd, J = 8.4, 1.4 Hz, 1H), 6.78 (s, 1H), 4.49 (s, 2H), 3.94 (s, 3H), 3.71 (s, 3H), 1.46 (s, 6H). F-12 2-([1-(2-bromophenyl)-5-[3-(2,2-dimethylpropoxy)phenyl]-1Hpyrazol-3-yl]methoxy)-2methylpropanoate de methyl H-4 LC-MS: (ES, m / z): 517.05. 1H NMR (300 MHz, DMSO) δ 7.76 (dd, J = 7.7, 1.3 Hz, 1H), 7.53 (m, 2H), 7.44 (ddd, J = 7.8, 6.6, 2.6 Hz, 1H), 7.18 (t, J = 8.0, 8.0 Hz, 1H), 6.81 (m, 2H), 6.70 (d, J = 2.4 Hz, 2H), 4.45 (s, 2H), 3.70 (s, 3H), 3.39 (s, 2H), 1.45 (s, Petition 870220002363, 10 / 01 / 2022, pág. 213 / 422 210 / 412 6H), 0.93 (s, 9H) . F-20 2-([5-(3-cyclobutoxyphenyl)-1-(2methylphenyl)-1H-pyrazol-3yl]methoxy)-2-methylpropanoate de methyl H-5 LC-MS: (ES, m / z): 434. 1H NMR: (30 0 MHz, DMSO-d s) δ 12.68 (s, 1H), 7.38 — 7.20 (m, 2H), 7.05 — 6.94 (m, 2H), 6.92 - 6.82 (m, 2H), 6.75 - 6.62 (m, 2H), 6.42 (s, 1H), 5.26 (s, 2H), 4.50 (q, J = 7.1 Hz, 1H), 4.42 (s, 2H), 4.02 (q, J = 6.9 Hz, 2H), 2.30 - 2.15 (m, 2H), 2.03 - 1.86 (m, 2H), 1.79 - 1.65 (m, 1H), 1.63 - 1.47 (m, 1H), 1.40 (s, 6H), 1.24 (t, J = 6, 9 Hz, 3H) . Petition 870220002363, 10 / 01 / 2022, pág. 214 / 422 211 / 412 F-25 2-([5-(1-ethyl-1H-indazol6-yl)-1-(1-methyl-1H- indazol-7-yl)-1H-pyrazol3-yl]methoxy)-2- methylpropanoate de methyl H-6 LC-MS: (ES, m / z): 10 H RMSON: 10 H RMSON. 6) δ 8.18 (s, 1H) , 7.97 (d, J = 0.9 Hz, 1H) , 7.90 (dd, J = 8.1, 1.0 Hz, 1H), 7.59 (dd, J = 8.4, 0.8 Hz, J = 1, 7), 7 7.46 (dd, J = 7.3, 1.0 Hz, 1H), 7.18 (dd, J = 8.1, 7.3 Hz, 1H) , 6.95 (dd, J = 8.4, 1.4 Hz, 1H), 6.91 (s, 1t (H), 4, 4, 2.5 Hz, 2H), 3.72 (s, 3H), 3.48 (s, 3H), 1.48 (s, 6H), 1.17 (t, J = 7.1 Hz, 3H) . Petition No. 870220002363, dated 10 / 01 / 2022, p. 215 / 422 212 / 412 F-2 6 2-( [5-(3- cyclobutoxyphenyl)-1-(1methyl-1H-indazol-7-yl)1H-pyrazol-3-yl]methoxy)2-methylpropanoate de methyl H-7 LC: (ES, m / z): 475. 1H NMR: (30, 60 m / z) DMSO 8.21 (s, 1H) , 7.93 (dd, J = 8.1, 1.0 Hz, 1H), 7.38 (dd, J = 7.3, 1.0 Hz, 1H), 7.28 — 7.09 (m, 2H), 6.94 - 6.86 (m, 1H), 6.75 - 6.66 (m, 1H), 6.45 (dd, J = 2.5, 1.6 Hz, 1H) , 4.50 (s, 2H) , 4.19 - 4.05 (m, 1H), 3.70 (s, 3H), 3.43 (s, 3H), 2H), 1.89 - 1.74 (m, 2H) , 1.67 (dd, J = 11.6, 8.3 Hz, 1H), 1.52 (d, J = 8.3 Hz, 2H), 1.45 (s, 6H) . Petition 870220002363, dated 10 / 01 / 2022, p. 216 / 422 213 / 412 F-27 2- ( [5-[3-(2,2dimethylpropoxy)phenyl]-1(1-methyl-1H-indazol-7yl)-1H-pyrazol-3- yl]methoxy)-2methylpropanoate de methyl H-8 LC-MS: (ES, m / z): 491.3. 1H NMR: (30 0 MHz, DMSO) δ 8.19 (s, 1H), 7.92 (dd, J = 8.1, 1.0 Hz, 1H), 7.39 (dd, J = 7.3, 1.0 Hz, 1H), 7.16 (m, 2H), 6.81 (m, 3H), 6.62 (m, 1H), 4.51 (s, 2H), 3.70 (s, 3H), 3.42 (s, 3H), 3.17 (d, J = 6.6 Hz, 2H), 1.46 (s, 6H), 0.87 (s, 9H) . F-28 2-([5-[3(cyclobutylmethoxy)phenyl]1-(1-methyl-1H-indazol-7yl)-1H-pyrazol-3- yl]methoxy)-2-methylpropanoate de methyl H-9 LC-MS: (ES, m / z): 489. 1H NMR: (30 0 MHz, DMSO-d 6) δ 8.19 (s, 1H), 7.92 (dd, J = 8.1, 1.0 Hz, 1H), 7.39 (dd, J = 7.3, 1.0 Hz, 1H), 7.28 — 7.02 (m, Petition 870220002363, 10 / 01 / 2022, pág. 217 / 422 214 / 412 (2H), 6.94 - 6.71 (m, 3H), 6.65 (dd, J = 2.6, 1.6 Hz, 1H), 4.50 (s, 2H), 3.70 (s, 3H), 3.56 (d, J = 6.8 Hz, 2H), 3.43 (s, 3H), 3.16 (s, 1H), 2.04 - 1.91 (m, 2H), 1.89 - 1.77 (m, 2H), 1.66 (dt, J = 11.0, 7.6 Hz, 2H), 1.45 (s, 6H). δ F-30 8.20 (s, 1H), 7.92 (dd, J = 8.1, 1.0 Hz, 1H), 7.40 (dd, J = 7.4, 1.0 Hz, 1H), 7.26 - 7.08 (m, 2H), 6.91 - 6.74 (m, 3H), 6.64 (dd, Petition: 870220002363, on January 10, 2022, page. 218 / 422 215 / 412 J = 2.5, 1.5 Hz, 1H), 4.52 (s, 2H), 3.71 (s, 3H), 3.44 (s, 3H), 3.35 (d, J = 6.6 Hz, 2H), 1.81 (dh, J = 13, 4, 6, 8 Hz, 1H), 1.47 (s, 6H), 0.85 (d, J = 6.6 Hz, 6H). δ 8.25 (s, 1H), 7.93 (dd, J = 8.1, 1.0 Hz, 1H), 7.33 (dd, J = 7.3, 1.0 Hz, 1H), 7.27 — 7.07 (m, 2H), 6.87 (s, 1H), 6.84 - 6.72 (m, 2H), 6,61 (dd, J = 2.5, 1.6 Hz, 1H), 4.52 (s, 2H), 3.71 (s, 2H), 3.18 (s, Petition: 870220002363, on January 10, 2022, page. 219 / 422 216 / 412 3H), 3.16 (s, 2H), 1.47 (s, 6H), 1.10 (t, J = 7.1 Hz, 3H), 0.87 (s, 9H). F-47 2-([1-(2-chlorophenyl)-5-(3,5-diethoxyphenyl)-1Hpyrazol-3-yl]methoxy)-2methylpropanoate de methyl H-12 LC-MS: (ES, m / z): 473.05. 1H NMR: (30 0 MHz, DMSO) δ 7.57 (m, 4H), 6.70 (s, 1H), 6.38 (t, J = 2.3, 2.3 Hz, 1H), 6.30 (d, J = 2.2 Hz, 2H), 4.45 (s, 2H), 3.85 (q, J = 7.0, 7.0, 7.0 Hz, 4H) , 3.71 (s, 3H), 1.45 (s, 6H) , 1.22 (t, J = 7.0, 7.0 Hz, 6H) . F-48 2-([5-(3-cyclopropoxyphenyl)-1-(2fluorophenyl)-1H-pyrazol3-yl]methoxy]-2-methylpropanoate de methyl H-13 LC-MS: (ES, m / z): 425.2. 1H-NMR: δ h (300 MHz, DMSO-d 6) 7.54 (2 H, m), 7.31 Petition 870220002363, 10 / 01 / 2022, pág. 220 / 422 217 / 412 (3 H, m) , 6, 90 (3 H, m) , 6, 67 (1 H, s), 4.45 (2 H, s), 3.69 (3 H, s) , 3, 61 (1 H, dp, J =6.1, 3.1, 3.1, 3.0, 3.0 Hz), 1.44 (6 H, s), 0.54 (4 H, m) . F-61 2-([5-(3-cyclopropoxyphenyl)-1-(1methyl-1H-indazol-4-yl)1H-pyrazol-3-yl]methoxy)2-methylpropanoate de methyl H-14 LC-MS: (ES, m / z): 461. 1H NMR (300 MHz, DMSO-d 6) δ 7.77 — 7.62 (m, 2H), 7.42 (dd, J = 8.6, 7.3 Hz, 1H) , 7.23 (t, J = 7.9 Hz, 1H) , 7.01 - 6.84 (m, 4H), 6.72 (s, 1H), 4.52 (s, 2H), 4.08 (s, 3H), 3.71 (s, 3H), 3.57 (tt, J = 6.2, 3.0 Hz, 1H), 1.48 (s, 6H), 0.60 - 0.46 Petition 870220002363, 10 / 01 / 2022, pág. 221 / 422 218 / 412 (m, 2H), 0.40 (dq, J = 6.8, 3, 4 Hz, 2H). F-62 2-([5-(3- ciclopropoxifenil)-1-(1etil-1H-indazol-7-il)-1Hpirazol-3-il]metoxi)-2metilpropanoatode metila H-15 LC-MS: (ES, m / z): 475. 1H RMN (300 MHz, DMSO-d s) δ 8.24 (s, 1H), 7.91 (dd, J = 8.0, 1.0 Hz, 1H), 7.30 (dd, J = 7.3, 1.0 Hz, 1H), 7.27 — 7.05 (m, 2H), 6.93 (dt, J = 7.8, 1.2 Hz, 1H), 6.89 — 6.80 (m, 2H), 6.76 (dd, J = 2.5, 1.6 Hz, 1H), 4.51 (s, 2H), 3.70 (s, 3H), 3.35 (d, J = 4.6 Hz, 2H), 3.33 — 3.29 (m, 1H), 1.45 (s, 6H), 1.10 (t, J = 7.1 Hz, 3H), 0.52 - 0.28 (m, 4H). Petition: 870220002363, on January 10, 2022, page. 222 / 422 219 / 412 F-66 2-( [5- (1-benzothiophen-2- yl)-1-[ (2- chlorophenyl)methyl]-1H- pyrazol-3-yl]methoxy)-2- methylpropanoate de methyl H-16 LC-MS: (ES, m / z): 454. 1H NMR: (3 8.04 - 7.96 (m, 1H), 7.90 - 7.82 (m, 1H), 7.59 (d, J = 0.8 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.46 - 7.39 (m, 2H), 2H) , 6.78 - 6.70 (m, 1H), 6.69 (s, 1H), 5.63 (s, 2H), 4.43 (s, 2H), 3.71 (s, 3H), 1.44 (s, 6H) F-69 2-( [1-[ (2- chlorophenyl)methyl]-5-(1methyl-1H-indazol-4-yl)1H-pyrazol-3-yl]methoxy)2-methylpropanoate de methyl H-17 LC-MS: (ES, m / z): 453. 1H NMR (30 M 7.94 (d, J = 1.0 Hz, 1H) , 7.79 - 7.65 (m, 1H), 7.45 (dd, J = 8.5, Petition 870220002363, dated 10 / 01 / 2022, p. 223 / 422 220 / 412 7.1 Hz, 1H), 7.41 — 7.32 (m, 1H), 7.29 - 7.21 (m, 2H), 7.10 (dd, J = 7.1, 0.8 Hz, 1H), 6.85 - 6.73 (m, 1H), 6.58 (s, 1H), 5.40 (s, 2H), 4.45 (s, 2H), 4.09 (s, 3H), 3.69 (s, 3H), 1.44 (s, 6H) . F-70 2-([1-[(2- ethoxyphenyl)methyl]-5-(1- ethyl-1H-indazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate de methyl H-18 LC-MS: (ES, m / z): 477. 1H NMR: (400 MHz, DMSO-d 6) δ 8.09 (d, J = 1.0 Hz, 1H) , 7.80 (dd, J = 8.3, 0.8 Hz, 1H), 7.68 (q, J = 1.0 Hz, 1H), 7.27 - 7.19 (m, 1H), 7.16 (dd, J = 8.4, 1.4 Hz, 1H), 6.95 (dd, J = 8.2, 1.1 Petition 870220002363, 10 / 01 / 2022, pág. 224 / 422 221 / 412 Hz, 1H), 6.86 (td, J = 7.5, 1.1 Hz, 1H) , 6.72 (dd, J = 7.5, 1.7 Hz, 1H), 6.51 (s, 1H), 5.33 (s, 2H), 4.41 (s, 2H), 4.40 — 4.35 (m, 2H) , 3.93 (d, J = 7.0 Hz, 2H), 3.70 (s, 3H), 1.44 (s, 6H), 1.33 (t, J = 7.2 Hz, 3H), 1.12 (t, J = 6.9 Hz, 3H). F-71 2-([5-(3-etoxiphenyl)-1- [(2-etoxiphenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate de methyl H-19 LC-MS: (ES, m / z): 452. 1H NMR (400 MHz, DMSO-d 6) δ 7.33 (t, J = 7.9 Hz, 1H) , 7.24 (ddd, J = 8.2, 7.3, 1.7 Hz, 1H), 7.04 — 6.91 (m, 3H), 6.90 — 6.79 (m, 2H), 6.69 (dd, J = Petition 870220002363, 10 / 01 / 2022, pág. 225 / 422 222 / 412 7.6, 1.7 Hz, 1H), 6.43 (s, 1H), 5.77 (s, 1H), 5.26 (s, 2H), 4.38 (s, 2H), 3.96 (dq, J = 26, 5, 6, 9 Hz, 4H), 3.69 (s, 3H), 1.42 (s, 6H), 1.25 (dt, J = 18.7, 7.0 Hz, 6H). F-75 2-([1-[(2- bromophenyl)methyl]-5-(3cyclopropoxyphenyl)-1Hpyrazol-3-yl]methoxy)-2methylpropanoate de methyl H-20 LC-MS: (ES, m / z): 499.3. 1H NMR: (30 0 MHz, DMSO) δ 7.62 (dd, J = 7.9, 1.3 Hz, 1H), 7.35 (tdd, J = 7.5, 7.5, 2.6, 1.0 Hz, 2H), 7.23 (td, J = 7.6, 7.6, 1.8 Hz, 1H), 7.01 (m, 3H), 6.69 (dd, J = 7.7, 1.7 Hz, 1H), 6.47 (s, 1H), 5.34 (s, 2H), 4.40 (s, 2H), 3.68 Petition 870220002363, 10 / 01 / 2022, pág. 226 / 422 223 / 412 (s, 4H), 1.42 (s, 6H), 0.59 (tt, J = 5.8, 5.8, 2.4, 2.4 Hz, 4H). F-79 2-( [1-[ (2- chlorophenyl)methyl]-5-(1methyl-1H-indol-6-yl)-1Hpirazol-3-yl]methoxy)-2methylpropanoate de methyl H-21 LC-MS: (ES, m / z): 451. 1H NMR (400 MHz, DMSO-d 6) δ 7.59 (d, J = 8.1 Hz, 1H), 7.48 — 7.42 (m, 2H), 7.41 (d, J = 3.1 Hz, 1H), 7.34 — 7.29 (m, 2H), 7.03 (dd, J = 8.2, 1.5 Hz, 1H), 6.84 - 6.76 (m, 1H), 6.49 - 6.42 (m, 2H), 5.44 (s, 2H), 4.42 (s, 2H), 3.74 (s, 3H), 3.70 (s, 3H), 1.44 (s, 6H) . F-80 2-( [1-[ (2- ethoxyphenyl)methyl]-5-(1- methyl-1H-indazol-6-yl)- 1H-pyrazol-3-yl]methoxy)- H-22 LC-MS: (ES, m / z): 463. 1H NMR: (40 0 MHz, DMSO-d 6) δ Petition 870220002363, 10 / 01 / 2022, pág. 227 / 422 224 / 412 2-metal propanoate 8.09 (d, J = 0.9 Hz, 1H), 7.80 (dd, J = 8.3, 0.8 Hz, 1H), 7.69 (q, J = 1.0 Hz, 1H), 7.28 — 7.20 (m, 1H) , 7.16 (dd, J = 8.4, 1.4 Hz, 1H), 6.95 (dd, J = 8.4, 1.1 Hz, 1H), 6.86 (td, J = 7.5, 1.0 Hz, 1H), 6.75 (dd, J = 7.5, 1.7 Hz, 1H), 6.49 (s, 1H), 5.32 (s, 2H), 4,41 (s, 2H), 4.01 (s, 3H), 3.93 (q, J = 7.0 Hz, 2H), 3.70 (s, 3H), 1.43 (s, 6H), 1.12 (t, J = 6.9 Hz, 3H). F-90 2-([5-(3,5- dimetoxifenil)-1-(2feniletil)-1H-pirazol-3- H-23 LC-MS: (ES, m / z): 439. Petition: 870220002363, on January 10, 2022, page. 228 / 422 225 / 412 il]metoxi)-2-methylpropanoato de methyl 1H RMN (400 MHz, DMSO-d 6) δ 7.29 — 7.11 (m, 3H), 7.04 — 6.94 (m, 2H), 6.54 (t, J = 2.3 Hz, 1H), 6.37 (d, J = 2.3 Hz, 2H), 6.26 (s, 1H), 4.39 (s, 2H), 4.25 (dd, J = 8.1, 6.6 Hz, 2H), 3.74 (s, 6H), 3.70 (s, 3H), 3.05 (t, J = 7.3 Hz, 2H), 1.43 (s, 6H). Alcohol l Product Espectral F-13 2-( [1-(2-bromophenyl)-5-(3,5- dimethoxyphenyl)-1H-pyrazol-3-yl]methoxy) -2methylpropanoate de methyl H-24 LC-MS: (ES, m / z) : 489. F-14 2-([1-(2-bromophenyl)-5-(1-propyl-1Hindazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate de methyl H-25 LC-MS: (ES, m / z): 535.1. Petition 870220002363, 10 / 01 / 2022, pág. 229 / 422 226 / 412 F-15 2-( [1-(2-bromophenyl)-5-(3-cyclobutoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-metilpropanoato de metila H-2 6 LC-MS: (ES, m / z): 499.3. F-16 2-( [1-(2-fluorofenil)-5-[3-(oxetan-3ylmethoxy)fenil]-1H-pyrazol-3-yl]methoxy)2-metilpropanoato de methyla H-27 LC-MS: (ES, m / z) : 455.3. F-17 2-( [5-(3-cyclobutoxyphenyl)-1-(2-fluorophenyl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate H-28 LC-MS: (ES, m / z) : 439. F-18 2-( [1-(2-fluorophenyl)-5-[3-(oxetan-3yloxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2methylpropanoate H-2 9 LC-MS: (ES, m / z) : 440 . F-21 2-( [5-(3,5-diethoxyphenyl)-1-(2-methylphenyl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate H-30 LC-MS: (ES, m / z) : 453.25. F-24 2-( [5-(3,5-dimethoxyphenyl)-1-(2ethoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2metilpropanoato de methyla H-31 LC-MS: (ES, m / z) : 455 . F-2 9 2-( [5-[3-(ciclopropylmetoxi)fenil]-1-(1metil-1 H -indazol-7-yl)-1H-pyrazol-3yl]methoxy)-2-metilpropanoato de methyla H-32 LC-MS: (ES, m / z) : 475. Petition 870220002363, dated 10 / 01 / 2022, pp. 230 / 422 227 / 412 F-31 2-([5-(3,5-dimethoxyphenyl)-1-(1-methyl-1Hindazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate of methyl H-33 LC-MS: (ES, m / z): 465 . F-32 2-([5-(3,5-diethoxyphenyl)-1-(1-methyl-1Hindazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate of methyl H-34 LC-MS: (ES, m / z) : 493.15. F-35 2-([1-(1,3-dimethyl-1H-indazol-7-yl)-5- [3(2,2-dimethylpropoxy)phenyl]-1H-pyrazol-3yl]methoxy)-2-methylpropanoate of methyl H-35 LC-MS: (ES, m / z.): 5 F-36 2-([5-[3-(2,2-dimethylpropoxy)phenyl]-1-(1methyl-1H-1,2,3-benzotriazole-7-yl)-1Hpyrazol-3-yl]methoxy)-2-methylpropanoate demethyl H-36 LC2-F-z: (ES 4 4 [1-(2-chlorophenyl)-5-[3-(oxetan-3ylmethoxy)phenyl]-1H-pyrazol-3-yl]methoxy)2-methylpropanoate of methyl H-37 LC-MS: (ES, m / z) : 471.3. F-38 2-([1-(2-chlorophenyl)-5-(pyridin-2-yl)-1Hpyrazol-3-yl]methoxy)-2-methylpropanoate of methyl H-38 LC-MS: (ES, m / z) : 386.00. F-39 2-( [1- (2-chlorophenyl)-5-(1-methyl-1Hindazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate of methyl H-39 LC-MS: (ES, m / z) : 455 . Petition 870220002363, dated 10 / 01 / 2022, pp. 231 / 422 228 / 412 F-40 2-([1-(2-chlorophenyl)-5-(1-ethyl-1Hindazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate de methyl H-40 LC-MS: (ES, m / z) : 453 . F-41 2-([1-(2-chlorophenyl)-5- (3-cyclobutoxyphenyl)-1H-pyrazol-3- yl]methoxy)-2-methylpropanoate de methyl H-41 LC-MS: (ES, m / z) : 455 . F-42 2-([1-(2-chlorophenyl)-5-[3-(oxetan-3iloxi)phenyl]-1H-pyrazol-3-yl]methoxy)-2methylpropanoate de methyl H-42 LC-MS: (ES, m / z) : 457 . F-44 2-([1-(2-chlorophenyl)-5-[3-(2,2dimethylpropoxy)phenyl]-1H-pyrazol-3yl]methoxy)-2-methylpropanoate de methyl H-43 LC-MS: (ES, m / z) : 471.10 . F-45 2-([1-(2-chlorophenyl)-5- [3-(cyclobutylmethoxy)phenyl]-1H-pyrazol-3- yl]methoxy)-2-methylpropanoate de methyl H-44 LC-MS: (ES, m / z) : 469.15. F-46 2-([1-(2-chlorophenyl)-5- (3,5- dimethoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate de methyl H-45 LC-MS: (ES, m / z) : 445. F-49 2-( [1-(2-bromophenyl)-5-(3- cyclopropoxyphenyl)-1H-pyrazol-3- yl]methoxy)-2-methylpropanoate de methyl H-46 LC-MS: (ES, m / z) : 486.95 Petition 870220002363, dated 10 / 01 / 2022, pp. 232 / 422 229 / 412 F-50 2-( [1-(2-bromo-4-fluorophenyl) -5-(3- cyclopropoxyphenyl)-1H-pyrazol-3- il]methoxy)-2-methylpropanoate de methyl H-47 LC-MS: (ES, m / z) : 503.1. F-51 2-( [5-(3-cyclopropoxyphenyl)-1-(2,4dichlorophenyl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate of methyl H-48 LC-MS: (ES, m / z) : 475.05. F-52 2-([5-(3-cyclopropoxyphenyl)-1- (2,5dichlorophenyl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate of methyl H-49 LC-MS: (ES, m / z) : 475.1. F-53 2-([5-(3-cyclopropoxyphenyl)-1-[2(difluoromethoxy)phenyl]-1H-pyrazol-3yl]methoxy)-2-methylpropanoate of methyl H-50 LC-MS: (ES, m / z) : 473 . F-54 2-( [5-(3-cyclopropoxyphenyl)-1-(2ethoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate of methyl H-51 LC-MS: (ES, m / z) : 450 . F-56 2-([5-(3-cyclopropoxyphenyl)-1- (2methylphenyl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate of methyl H-52 LC-MS: (ES, m / z) : 421. F-58 2-([5-(3-cyclopropoxyphenyl)-1-[2-(propan2-yl)phenyl]-1H-pyrazol-3-yl]methoxy)-2methylpropanoate of methyl H-53 LC-MS: (ES, m / z) : 449. Petition 870220002363, dated 10 / 01 / 2022, pp. 233 / 422 230 / 412 F-59 Methyl 2-( [5-(3-cyclopropoxyphenyl) -1-[2(trifluoromethyl)phenyl]-1H-pyrazol-3yl]methoxy)-2-methylpropanoate H-54 LC-MS: (ES, m / z) : 475. F-60 Methyl 2-([5-(3-cyclopropoxyphenyl)-1-(1-methyl- 1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)- 2-methylpropanoate H-55 LC-MS: (ES, m / z) : 461. F-63 Methyl 2-( [5-(3-cyclopropoxyphenyl)-1-(1-methyl1H -1,3-benzodiazol-7-yl)-1H-pyrazol-3yl]methoxy)-2-methylpropanoate H-56 LC-MS: (ES, m / z) : 461.1. F-68 2-( [5-(3-chloro-5-methoxyphenyl)-1-[(2ethoxyphenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate methyl H-57 LC-MS: (ES, m / z): 473 F-72 2-([5-(3-ethoxy-5-methoxyphenyl)-1-[(2ethoxyphenyl)methyl]-1H-pyrazol-3-yl]methoxy) yl]methoxy)-2-methylpropanoate of methyl H-58 LC-MS: (ES, m / z) : 483. F-73 2-( [5-(3-cyclopropoxyphenyl)-1-[(2ethoxyphenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate of methyl H-59 LC-MS: (ES, m / z) : 465 .F-76 2-( [1-[(2-chlorophenyl)methyl]-5-(2,3-di- hydro-1,4-benzodioxin-6-yl)-1H-pyrazol-3yl]methoxy)-2-methylpropanoate de methyl H-60 ​​LC-MS: (ES, m / z) : 457 . Petition 870220002363, 10 / 01 / 2022, pág. 234 / 422 231 / 412 F-77 2-([5-(2H-1,3-benzodioxol-5-yl)-1-[(2chlorophenyl)methyl]-1H-pyrazol-3- il]methoxy)-2-methylpropanoate of methyl H-61 LC-MS: (ES, m / z) : 443 . F-78 2-([1-[(2-chlorophenyl)methyl]-5-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazol-3-yl]methoxy)- 2-methylpropanoate of methyl H-62 LC-MS: (ES, m / z) : F- 403. 2-([5-(3,5-diethoxyphenyl)-1-[(2ethoxyphenyl)methyl]-1H-pyrazol-3- il]methoxy)-2-methylpropanoate of methyl H-63 LC-MS: (ES, m / z) : 497.25. F-82 2-([1-[(2-chlorophenyl)methyl]-5-(1-ethyl-1Hindazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate of methyl H-64 LC-MS: (ES, m / z) : 467 . F-83 2-([5-(1-ethyl-1H-indazol-6-yl)-1- ([pyridin-2-yl]methyl)-1H-pyrazol-3yl]methoxy)-2-methylpropanoate demethyl H-65 LC-MS: (ES, m / z): 434 . F-84 2-([1-[(2-chlorophenyl)methyl]-5-(1-methyl1H-indazol-5-yl)-1H-pyrazol-3-yl]methoxy)2-methylpropanoate of methyl H-66 LC-MS: (ES, m / z) : 452 . F-85 2-([5-(3-cyclobuthoxyphenyl)-1-[(2- ethoxyphenyl)methyl]-1H-pyrazol-3- il]methoxy)-2-methylpropanoate of methyl H-67 LC-MS: (ES, m / z) : 479. Petition 870220002363, dated 10 / 01 / 2022, pp. 235 / 422 232 / 412 F-86 2-([1-[(2-bromofenil)metil]-5-(3-cyclobutoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-metilpropanoato de methyla H-68 LC-MS: (ES, m / z) : 512 . F-87 2-([5-[3-(2,2-dimethylpropoxy)fenil]-1- [(1-metil-1H-indazol-7-yl)metil]-1Hpyrazol-3-yl]methoxy)-2-metilpropanoato de metila H-69 LC-MS: (ES, m / z): 505. F-88 2-metil-2-([5-[3-(2-methylpropoxy)fenil]-1- ( [pyridin-2-yl]methyl)-1H-pyrazol-3yl]methoxy)propanoato de methyla H-70 LC-MS: (ES, m / z): 438 . F-89 2-([5-(3,5-dimethoxyphenyl)-1-[(2-ethoxyphenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate H-71 LC-MS: (ES, m / z) : 469. F-91 2-([5-(3,5-dimethoxyphenyl)-1-[(2-ethoxy-6fluorophenyl)methyl]-1H-pyrazol-3yl]methoxy)-2-methylpropanoate H-72 LC-MS: (ES, m / z): 487.2. F-92 2-([5-(3,5-dimethoxyphenyl)-1-([pyridin-2yl]methyl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate H-73 LC-MS: (ES, m / z): 426. F-93 2-( [1-[(2-chlorophenyl)methyl]-5-(3,5diethoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate H-74 LC-MS: (ES, m / z): 487.2. Petition 870220002363, dated 10 / 01 / 2022, pp. 236 / 422 233 / 412 F-95 2-([1-[(2-chlorofenil)metil]-5-[3-(oxetan-3-ylmethoxy)fenil]-1H-pyrazol-3-yl]methoxy)-2-metilpropanoato de methyla H-75 LC-MS: (ES, m / z) : 485.2. F-96 2-([5-(3-ciclopropoxyphenyl)-1- (1-[ [2(trimetilsilyl)ethoxi]metil]-1H-indazol-7yl)-1H-pyrazol-3-yl]methoxy)-2metilpropanoato de metila H-76 LC-MS: (ES, m / z) : 577 . F-97 2-([5-(3-cyclopropoxyphenyl)-1-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-4yl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate H-77 LC-MS: (ES, m / z) : 577.3. F-98 2-([5-(3-cyclopropoxyphenyl)-1-(3-methyl-1[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-4-yl)-1H-pyrazol-3-yl]methoxy)-2methylpropanoate H-78 LC-MS: (ES, m / z) : 591.3. F-4 2-([5-(3-methoxyphenyl)-1-(2-methylphenyl)1H-pyrazol-3-yl]methoxy)-2-methylpropanoate H-79 LC-MS: (ES, m / z) : 394 . F-2 2-( [1-[(2-chlorophenyl)methyl]-5-(1-methyl1H-1,3-benzodiazol-6-yl)-1H-pyrazol-3yl]methoxy)-2-methylpropanoate H-80 LC-MS: (ES, m / z): 453 .F-5 2-( [1-[ (2-chlorophenyl)methyl]-5-(1-ethyl-1H- 1,2,3-benzotriazol-6-yl)-1H-pyrazol-3yl]methoxy)-2-methylpropanoate of methyl H-81 LC-MS: (ES, m / z.): (ES, m / z.): Petition No. 870220002363, dated 10 / 01 / 2022, p. 237 / 422 234 / 412 F-117 2-([1-[2-(dimethylamino)phenyl]-5-(1-ethyl1H-indazol-6-yl)-1H-pyrazol-3-yl]methoxy)2-methylpropanoate of methyl H-82 LC-MS: (ES, m / z) : 478.3. Alcohol Product F-23 2-([5-[3-(2,2-dimethylpropoxy)phenyl]-1(quinolin-8-yl)-1H-pyrazol-3-yl]methoxy)- 2-methylpropanoate of methyl H-83 F-101 2-([1-[(2-chlorophenyl)methyl]-5-[5-(2- methylpropoxy)thien-2-yl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate of methyl H-84 F-102 2-(1-[ (2-chlorophenyl)-5-[2-(2- methylpropyl)-1,3-oxazol-5-yl]-1H-pyrazol3-yl]methoxy)-2-methylpropanoate of methyl H-85 F-103 2-(1-[(2-chlorophenyl)methyl]-5-[2-(2methylpropoxy)-1,3-thiazol-5-yl]-1Hpyrazol-3-yl]methoxy)-2-methylpropanoate H-86 F-104 2-( [1-(2-chlorophenyl)-5-[3-(2methylpropoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate H-87 F-105 2-([5-benzyl-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate H-88 F-110 2-[1-[(2,6-dimethoxyphenyl)methyl]-5-[3-(2-methylpropoxy)phenyl]-1H-pyrazol-3-yl)methoxy)-2-methylpropanoate H-89 F-111 Methyl 2-[(1-[[4-(dimethylamino)phenyl]methyl]-5[3-(2-methylpropoxy)phenyl]-1H-pyrazol-3yl)methoxy)-2-methylpropanoate H-90 Petition 870220002363, dated 10 / 01 / 2022, pp. 238 / 422 235 / 412 F-112 Methyl 2-(1-[[2-(dimethylamino)-6-fluorophenyl]methyl]-5-(3-methoxyphenyl)-1Hpyrazol-3-yl)methoxy)-2-methyl propanoate H-91 F-113 (1-[(2-chlorophenyl)methyl]-5-phenoxy-1Hpyrazol-3-yl)methoxy)-2-methyl-propanoate H-92 F-114 2- [(5-[[(tert-butoxy)carbonyl](phenyl)amino]-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl)methoxy)-methyl 2-methylpropanoate H-93 F-115 Methyl 2-[(1-[(3-chloropyridin-2-yl)methyl]-5-(3methoxyphenyl)-1H-pyrazol-3-yl)methoxy)-2methylpropanoate H-95

[0624] The following esters of 2-hydroxy-2-methylbutanoic acid were prepared.

[0625] Methyl 2-hydroxy-2-methylbutanoate To a solution of 2-hydroxy-2-methylbutanoic acid (3.0 g, 25.40 mmol, 1.00 equiv) in MeOH (100 mL) was added H2SO4 (3 mL) by dropwise with stirring at 0 °C. The resulting solution was heated to reflux for 16 h, cooled, concentrated under vacuum, diluted with 200 mL of EtOAc, washed with 1 x 100 mL of (sat)NaHCO3(aq), dried with Na2SO4, and concentrated under vacuum to provide 780 mg (23%) of the title compound as a colorless oil.

[0626] (2R)-2-hydroxy-2-methylbutanoate methyl A solution of (2R)-2-hydroxy-2 Petition 870220002363, dated 10 / 01 / 2022, pp. 239 / 422 236 / 412 methylbutanoic acid (1.0 g, 8.47 mmol, 1.00 equiv) in MeOH (50 mL) was added to SOCl2 (2.0 g, 2.00 equiv) by dropwise stirring at 0 °C. The resulting solution was heated to reflux for 16 h, then concentrated under vacuum, diluted with 100 mL of CH2Cl2. The mixture was dried with Na2SO4 and concentrated under vacuum, yielding 700 mg (63%) of the title compound as a colorless oil. 1H-NMR: (300 MHz, CDCl3) δ: 3.79 (s, 3H), 3.04 (s, 1H), 1.89 — 1.61 (m, 2H), 1.41 (s, 3H), 0.88 (t, J = 7.4 Hz, 3H).

[0627] (2S)-2-hydroxy-2-methylbutanoate methyl To a solution of (2S)-2-hydroxy-2-methylbutanoic acid (500 mg, 4.23 mmol, 1.00 equiv) in MeOH (30 mL) was added SOCl2 (1.03 mg, 0.01 mmol, 2.00 equiv) by dropwise stirring at 0 °C. The resulting solution was stirred for 16 h at 60 °C, then concentrated under vacuum, diluted with 200 mL of CH2Cl2, washed with 1 x 100 mL of (sat)NaHCO3(aq), and evaporated under reduced pressure. The solid that formed was dried in an oven under reduced pressure, yielding 400 mg (72%) of the title compound as a colorless oil. LC-MS: (ES, m / z): 132. 1H NMR (DMSO) δ: 5.10 (s, 1H), 3.62 (s, 3H), 1.73 — 1.44 (m, 2H), 1.24 (s, 3H), 0.78 (t, J = 7.4 Hz, 3H).

[0628] The following substituted pyrazole carboxylic esters were obtained from the synthesis of Williamson ether c HO-C(CH3)2COOMe: z-Br O II 1 N Ar io (bromomethyl)pyrazole corresponding with ''^LcOOMe \z ^0 HO OOOMe RO / Tb\ ______YY 'N < / N NaH, THF Ár Petition 870220002363, dated 10 / 01 / 2022, pp. 240 / 422 237 / 412 Table 16: Summary of (bromomethyl) pyrazois ether. Bromine Cpd Espectral Product G-3 2-methyl-2-([5-[3-(2- methylpropoxy)phenyl]-1-phenyl-1Hpyrazol-3-yl]methoxy)propanoate de methyl H-96 LC-MS: (ES, m / z): 423. G-5 (2R )-2-([1-(2-bromophenyl)-5-(1-propyl-1H-indazol-6yl)-1H-pyrazol-3-yl]methoxy)-2-ethyl methylbutanoate (This reaction is made as (2R)-2-hidroxi-2methylbutanoate methyl) H-97 LC-MS: (ES, m / z): 541.1. G-6 2-([1-(2-fluorophenyl)-5-[3-(2methylpropoxy)phenyl]-1H-pyrazol-3yl]methoxy)-2-methylpropanoate de methyl H-98 LC-MS: (ES, m / z): 441. G-9 2-([5-(3-methoxyphenyl)-1-[2-(propan2-yloxy)phenyl]-1H-pyrazol-3- yl]methoxy)-2-methylpropanoate de methyl H-99 LC-MS: (ES, m / z): 439. G-22 2- [3-(bromomethyl)-1-[(2- chlorophenyl)methyl]-5-(2-methoxyphenyl)- 1H-pyrazol-3-yl]methoxy) -2methylpropanoate de methyl H-100 G-10 2-([1-(2-chlorophenyl)-5-(3-cyclopropoxyphenyl)-1H-pyrazol-3yl]methoxy)-2-methylpropanoate de methyl H-101 Petition 870220002363, de 10 / 01 / 2022, pág. 241 / 422 238 / 412 G-12 (2R)-2-([1-(2-bromofenil)-5-(3-cyclopropoxyphenyl)-1H-pyrazol-3yl]methoxy)-2-metilbutanoato de methyla H-102 LC-MS: (ES, m / z): 499.3. G-13 2-([5-(3-cyclopropoxyphenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-metilpropanoato de methyla H-103 LC-MS: (ES, m / z): 437 . G-25 2-([5-(3-methoxyphenyl) -1-(2-methylpropyl)-1H-pyrazol-3yl]methoxy)-2-methylpropanoate H-104 G-2 6 2-([5-(3-methoxyphenyl)-1-([oxan-4-yl] methyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate H-105 G-15 2-( [1-[ (2-cyclopropoxyphenyl)methyl]5-(3-methoxyphenyl)-1H-pyrazol-3yl]methoxy)-2-methylpropanoate H-106 LC-MS: (ES, m / z):451. G-16 2-([1-[(2-clorofenil)metil]-5-(3,5dimethoxyphenyl)-1H-pyrazol-3- yl]methoxy)-2-metilpropanoato de metila H-107 LC-MS: (ES, m / z): 459. G-17 2-([1-[(2-clorofenil)metil]-5-(1metil-1H-indazol-6-yl)-1H-pyrazol-3yl]methoxy)-2-metilpropanoato de metila H-108 LC-MS: (ES, m / z): 453 . Petition 870220002363, 10 / 01 / 2022, pág. 242 / 422 239 / 412 G-20 2-( [1-[(2-chlorophenyl)methyl]-5-[2(propan-2-yloxy)-1,3-oxazol-5-yl]1H-pyrazol-3-yl]methoxy)-2methylpropanoate de methyl H-109 LC-MS: (ES, m / z): 448 . G-2 2-( [1-[(2-chlorophenyl)methyl]-5-[1,3dimethyl-1H-thieno[2,3-c]pyrazol-5yl]-1H-pyrazol-3-yl]methoxy)-2methylpropanoate de methyl H-110 LC-MS: (ES, m / z): 473 . G-27 2-([5-(3-cyclopropoxyphenyl) -1-[[2(dimethylamino)phenyl]methyl]-1Hpirazol-3-yl]methoxy) -2methylpropanoate de methyl H-111 LC-MS: (ES, m / z): 464 . G-21 2-([5-(3-cyclopropoxyphenyl)-1-[2(dimethylamino)phenyl]-1H-pyrazol-3yl]methoxy)-2-methylpropanoate de methyl H-112 LC-MS: (ES, m / z): 450 G-24 2-([5- (3-methoxyphenyl)-1-[[2-(propan2-yloxy)phenyl]methyl]-1H-pyrazol-3yl]-methoxy)-2-methylpropanoate de methyl H-113 Petition 870220002363, 10 / 01 / 2022, pág. 243 / 422 240 / 412 Intermediary H-114: 2-([1-[(2-clorofenil)metil]-5(4-ciclopropoxytien-2-il)-1H-pirazol-3-il]metoxi)-2metilpropanoato de methyla

[0629] 2-([1-[(2-chlorophenyl)methyl]-5-(4-bromothien-2-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate tert-butyl To a solution of 2-hydroxy-2-methylpropanoate tert-butyl (2.14 g, 13.36 mmol, 3.00 equiv) in THF (50 mL) was added NaH (535 mg, 13.38 mmol, 3.00 equiv), in portions at 0 °C. The mixture was stirred at 0 °C for 20 min. To this, Int G-23 (2 g, 4.48 mmol, 1.00 equiv) was added at 0 °C and Bu4NI (1.0 g, 2.72 mmol, 0.50 equiv). The resulting solution was stirred for 16 h at room temperature, then rapidly cooled by the addition of water / ice. The resulting solution was extracted with 500 mL of EtOAc, and the organic layers were combined and dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:2). This resulted in the title compound as a yellow oil (400 mg, 17%).

[0630] 2-([5-(4-bromothien-2-yl)-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate methyl. To a solution of the product from the previous step (400 mg, 0.76 mmol, 1.00 equiv) in MeOH (20 mL) was added HCl aq (1 mL) by dropwise stirring. The resulting solution Petition 870220002363, dated 10 / 01 / 2022, pp. 244 / 422 241 / 412 was stirred for 3 hours at 65 °C, concentrated under vacuum, and diluted with 100 mL of EtOAc. The pH of the solution was adjusted to 7-8 with (sat) NaHCO3 (aq). The mixture was dried with anhydrous Na2SO4 and concentrated under vacuum. This resulted in the title compound as a yellow oil (350 mg, 95%).

[0631] 2-([1-[(2-chlorophenyl)methyl]-5-(4-cyclopropoxythien-2-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate methylpropanoate To a solution of the product from the previous step (350 mg, 0.72 mmol, 1.00 equiv) in dioxane (10 mL) was added in stages Cs2CO3 (473 mg, 1.45 mmol, 2.00 equiv), 2nd Generation XantPhos precatalyst (322 mg, 0.36 mmol, 0.50 equiv), and cyclopropanol (168 mg, 2.89 mmol, 4.00 equiv). The final reaction mixture was irradiated with microwave radiation for 1 h at 85 °C. The resulting solution was diluted with 100 mL of EtOAc. The resulting mixture was washed with 2 x 100 mL of brine. The mixture was dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:2). This resulted in the title compound as a yellow oil (150 mg, 45%). Intermediate H-115: 2-([5-(3-aminophenyl)-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate COOMe Petition 870220002363, dated 10 / 01 / 2022, pp. 245 / 422 242 / 412

[0632] To a solution of Int. H-95 (400 mg, 0.90 mmol, 1.00 equiv) in AcOH / H2O (10 / 1 mL) was added Zn (400 mg, 6.15 mmol), in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature. The solids were removed by filtration. The pH of the solution was adjusted to 7-8 with saturated NaHCO3. The resulting solution was extracted with 100 mL of EtOAc, and the organic layers were combined, washed with 2 x 200 mL of brine, dried with anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by Prep-TLC with DCM / MeOH (30:1), yielding 230 mg (62%) of the title product as a yellow oil. Intermediate H-116: 2-([1-[(2-chlorophenyl)methyl]-5-[3-(2-methylpropanamido)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

[0633] A solution of Int. H-115 (200 mg, 0.48 mmol, 1.00 equiv), HATU (276 mg, 0.73 mmol, 1.50 equiv), 2-methylpropanoic acid (130 mg, 1.48 mmol, 3.00 equiv) and DIEA (187 mg, 1.45 mmol, 3.00 equiv) in DMF (20 mL) was stirred overnight at room temperature, then diluted with 200 mL of EtOAc, washed with 2 x 100 mL of brine, dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Prep-TLC with DCM / MeOH (30:1), to give 155 mg (66%) of the title product as a yellow solid. Petition 870220002363, dated 10 / 01 / 2022, pp. 246 / 422 243 / 412 Intermediate H-117: 2-([1-[(2-chlorophenyl)methyl]-5-[3-(methylsulfanyl)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

[0634] To a solution of Int. H-115 (700 mg, 1.69 mmol, 1.00 equiv) in MeCN (10 mL) was added dimethyl disulfide (319 mg, 3.39 mmol, 2.00 equiv). The resulting mixture was heated at 60 °C for 1 h, then cooled at rt. Tert-butyl nitrite (350 mg, 3.40 mmol, 2.00 equiv) was then added dropwise with stirring, and the resulting solution was stirred for 3 h at 60 °C, then diluted with 200 mL of EtOAc, washed with 2 x 100 mL of brine, dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was applied in Prep-TLC with EtOAc / petroleum ether (1:2). This resulted in 300 mg (40%) of the title product appearing as a yellow oil. Intermediate H-118: 2-([1-[(2-chlorophenyl)methyl]-5(3-methanesulfonylphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate Petition 870220002363, dated 10 / 01 / 2022, pp. 247 / 422 244 / 412

[0635] To a solution of Int. H-117 (300 mg, 0.67 mmol, 1.00 equiv) in MeOH / H2O (10 / 5 mL) was added K2S2O8 (233 mg, 1.53 mmol, 1.00 equiv), in portions at rt. The resulting solution was stirred for 2 h, then diluted with 200 mL of EtOAc, washed with 2 x 100 mL of brine, dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was applied to Prep-TLC with EtOAc / petroleum ether (1:3). This resulted in 180 mg (58%) of the title product as a yellow solid. Intermediate H-119: 2-([1-[(2-chlorophenyl)methyl]-5(3-methanesulfonamidophenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

[0636] A solution of Int. H-115 (200 mg, 0.48 mmol, 1.00 equiv), pyridine (75 mg, 0.95 mmol, 2.00 equiv), and DMAP (6 mg, 0.05 mmol, 0.10 equiv) in DCM (10 mL) was prepared. Methanesulfonyl chloride (83 mg, 0.72 mmol, 1.50 equiv) was added dropwise with stirring at 0 °C. The resulting solution was stirred overnight at rt, then diluted with 100 mL of DCM, washed with 2 x 100 mL of brine, dried with anhydrous Na2SO4, and concentrated under vacuum. The residue was applied to Prep-TLC with EtOAc / petroleum ether (1:4). This resulted in 100 mg (42%) of the title product as a yellow oil. Petition 870220002363, dated 10 / 01 / 2022, pp. 248 / 422 245 / 412 H-120 intermediate: 2-([1-[(2-chlorophenyl)methyl]-5-[3-(methylamino)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate To a solution of Int. H-115 (200 mg, 0.48 mmol, 1.00 equiv) in MeOH (10 mL) was added paraformaldehyde (107 mg, 2.43 mmol, 5.00 equiv), followed by the addition of MeONa (0.45 mL, 5.00 equiv, 5.4 M) by dropwise stirring at room temperature. The resulting solution was stirred for 2 hours at 60 °C, then cooled to 0 °C. NaBH4 (92 mg, 2.43 mmol, 5.00 equiv) was added, and the solution was stirred for 1 hour at 60 °C, then cooled, diluted with 100 mL of EtOAc, washed with 2 x 50 mL of brine, dried with anhydrous Na2SO4, and concentrated under vacuum. The residue was applied in PrepTLC with EtOAc / petroleum ether (1:4). This resulted in 100 mg (48%) of the title product as a yellow oil. Intermediate H-121: 2-([1-[(2-chlorophenyl)methyl]-5(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-ethylbutanoate Petition 870220002363, dated 10 / 01 / 2022, pp. 249 / 422 246 / 412

[0638] Methyl 2-ethyl-2-hydroxybutanoate To a solution of 2-ethyl-2-hydroxybutanoic acid (2.0 g, 15.13 mmol, 1.00 equiv) in MeOH (100 mL) was added H2SO4 (3 mL) by dropwise stirring at rt. The resulting solution was heated to reflux for 16 h, then concentrated under vacuum, diluted with 200 mL of EtOAc, washed with 2 x 100 mL of saturated NaHCO3, dried with anhydrous Na2SO4 and concentrated under vacuum, providing 800 mg (36%) of the title product as a colorless oil.

[0639] 2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-ethylbutanoate Methyl 2-ethylbutanoate (371 mg, 2.54 mmol, 2.00 equiv) in DMF / THF (7 / 7 mL) was added to NaH (100 mg, 4.17 mmol, 2.00 equiv) at 0 °C for 30 min. To this, NaI (140 mg) and Int. G-1 (500 mg, 1.28 mmol, 1.00 equiv) were added. The resulting solution was stirred for 16 h at room temperature. The residue was applied to a Prep-TLC with EtOAc / petroleum ether (1:10). The collected fractions were combined and concentrated under vacuum. This resulted in 210 mg (38%) of the title product as a white liquid. Intermediate H-122: (2R)-2-([5-(3-cyclopropoxyphenyl)-1-(1-methyl-1H-indazol-7-yl)-1H-pyrazol-3yl]methoxy)-2-methylbutanoate Petition 870220002363, dated 10 / 01 / 2022, pp. 250 / 422 247 / 412

[0640] (2R)-2-([5-(3-cyclopropoxyphenyl)-1-(1-methyl-1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate methyl To a solution of (2R)-2-hydroxy-2-methylbutanoate methyl (250 mg, 1.89 mmol, 2.00 equiv) in THF (20 mL) was added NaH (76 mg, 1.90 mmol, 2.00 equiv), in portions at 0 °C. The mixture was stirred at 0 °C for 20 min, then Int. F-10 (400 mg, 0.94 mmol, 1.00 equiv) at 0 °C, Bu4NI (200 mg, 0.54 mmol, 0.50 equiv) was added. The resulting solution was stirred for 16 h at room temperature, then rapidly cooled by the addition of water / ice. The resulting solution was extracted with 100 mL of ethyl acetate, and the combined organic layers were dried with Na2SO4, concentrated under vacuum, and purified with Prep-TLC using EtOAc / petroleum ether (1:1) to provide 160 mg (36%) of the title compound as a yellow solid. LC-MS: (ES, m / z): 475.

[0641] The following substituted pyrazole carboxylic esters were obtained from Williamson ether synthesis of the corresponding (bromomethyl)pyrazole with HO-C(CH3)(Et)COOMe: Petition 870220002363, dated 10 / 01 / 2022, pp. 251 / 422 248 / 412 G-1 (2 S )-2-([1-[(2-chlorophenyl)methyl]-5-(3methoxiphenyl)-1H-pyrazol-3-yl]methoxy)-2methylbutanoate de methyl H-123 LC-MS: (ES, m / z): 443. G-1 (2R)-2-([1-[(2-chlorophenyl)methyl]-5-(3methoxiphenyl)-1H-pyrazol-3-yl]methoxy)-2methylbutanoate de methyl H-124 LC-MS: (ES, m / z): 443. G-4 (2R)-2-([1-(2-bromophenyl)-5-(1-ethyl-1Hindazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2methylbutanoate de ethyla H-125 LC-MS: (ES, m / z): 525. G-7 (2R)-2-([5-[3-(2,2- dimethylpropoxy)phenyl]-1-(1-methyl-1H- indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate methyl H-12 6 LC-MS: (ES, m / z): 505. G-8 (2R)-2-methyl-2-([1-(1-methyl-1H-indazol-7-yl)-5-[3-(2-methylpropoxy)phenyl]-1H-pyrazol-3-yl]methoxy]butanoate ethyl H-127 LC-MS: (ES, m / z): 505.15. G-10 (2R)-2-([1-(2-chlorophenyl) -5-(3- cyclopropoxyphenyl)-1H-pyrazol-3- yl]methoxy)-2-methylbutanoato de ethyla H-128 LC-MS: (ES, m / z): 469.1. G-11 (2R)-2-([1-(2-chlorophenyl)-5-(3,5dimethoxyphenyl)-1H-pyrazol-3-yl]methoxy)2-methylbutanoato de methyla H-12 9 LC-MS: (ES, m / z): 459.G-18 (2R)-2-([1-[(2-chlorophenyl)methyl]-5-(1- ethyl-1H-indazol-6-yl)-1H-pyrazol-3- yl]methoxy)-2-methylbutanoate de methyl H-130 LC-MS: (ES, m / z): 481. G-18 (2 S )-2-([1-[(2-chlorophenyl)methyl]-5-(1- ethyl-1H-indazol-6-yl)-1H-pyrazol-3- yl]methoxy)-2-methylbutanoato de methyla H-131. Petition 870220002363, 10 / 01 / 2022, pág. 252 / 422 249 / 412 G-19 (2R)-2-([5-(3,5-dimethoxyphenyl) -1-[(2- H-132 LC-MS: (ES, ethoxyphenyl)methyl]-1H-pyrazol-3- m / z): il]methoxy)-2-methylbutanoate de ethyla 497.5. Intermediate H-133: 2-([1-[2-(azetidin-1yl)phenyl]-5-(l—ethyl—lH—indazol—6—yl)-1H-pyrazol-3-yl]methoxy)2-methylpropanoate de methyl

[0642] In a 20 mL combined tube 2-([1-(2-bromophenyl)-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3yl]methoxy)-2-methylpropanoate (200 mg, 0.40 mmol, 1.00 equiv), L-proline (46 mg, 0.40 mmol, 1.00 equiv), CuI (38 mg, 0.20 mmol, 0.50 equiv), K2CO3 (166 mg, 1.20 mmol, 3.00 equiv), azetidine (69 mg, 1.21 mmol, 3.00 equiv), and DMSO (10 mL). The resulting solution was stirred overnight at 70 °C. The reaction mixture was cooled to room temperature. The resulting solution was extracted with 3 x 20 mL of EtOAc, and the combined organic layers were dried with Na2SO4 and concentrated under vacuum. The residue was purified by prep-TLC with EtOAc / petroleum ether (1 / 3). This resulted in 50 mg (26%) of the title compound as a light yellow oil. LC-MS: (ES, m / z): 474. 1H NMR: (300 MHz, CDCl3) δ 7.90 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.24 (m, 2H), 7.07 (dd, J = 7.8, 1.5 Hz, 1H), 6.76 (s, 1H), 6.69 (td, J = 7.6, 7.5, 1.3 Hz, 1H), 6.45 (dd, J = 8.2, 1.3 Hz, 1H), 4.63 (s, 2H), 4.25 (q, J Petition 870220002363, dated 10 / 01 / 2022, pp. 253 / 422 250 / 412 = 7.3, 7.3, 7.3 Hz, 2H), 3.79 (s, 3H), 3.58 (dq, J = 24.9, 7.4, 7.3, 7.3 Hz, 4H), 2.10 (p, J = 7.3, 7.3, 7.3, 7.3 Hz, 2H), 1.56 (s, 6H), 1.34 (q, J = 8.2, 8.2, 7.2 Hz, 3H). Intermediate H-134: 2-([1-[2-(azetidin-1-yl)phenyl]-5-[3-(2,2-dimethylpropoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

[0643] In a sealed 30 mL tube, Int. H-4 (200 mg, 0.39 mmol, 1.00 equiv), L-proline (44 mg, 0.38 mmol, 1.00 equiv), CuI (40 mg, 0.21 mmol, 0.50 equiv), K2CO3 (160 mg, 1.16 mmol, 3.00 equiv), azetidine (66 mg, 1.16 mmol, 3.00 equiv), and DMSO (10 mL) were combined. The resulting solution was stirred overnight at 70 °C, cooled, and extracted with 3 x 15 mL of EtOAc. The combined organic layers were dried with Na2SO4, concentrated under vacuum, and purified by prep-TLC using EtOAc / petroleum ether (1 / 3) to provide 70 mg (37%) of the title compound as a light yellow oil. LC-MS: (ES, m / z): 492.30. 1H NMR: (300 MHz, DMSO) δ 7.28 (ddd, J = 8.5, 7.4, 1.6 Hz, 1H), 7.20 (t, J = 7.9, 7.9 Hz, 1H), 6.98 (ddd, J = 9.9, 7.2, 1.5 Hz, 2H), 6.84 (m, 2H), 6.69 (m, 2H), 6.51 (dd, J = 8.3, 1.3 Hz, 1H), 4.44 (s, 2H), 3.71 (s, 3H), 3.50 (m, 2H), 3.42 (m, 2H), 2.07 (m, 2H), 1.45 (s, 6H), 0.94 (s, 9H).

[0644] Amino foram-substituted aryl compounds were obtained through the use of similar copper(I)-mediated coupling procedures. Petition No. 870220002363, dated 10 / 01 / 2022, p. 254 / 422 251 / 412 Table 18: Synthesis of arylamine from (bromoaryl) pyrazois. Halet or de aryl Amine Product Spectrum l H-2 Pyrrolidin 2- ( [5-(1-ethyl-1 Hindazol-6-yl)-1-[2(pyrrolidin-1- il)phenyl]-1H-pyrazol3-yl]methoxy)-2methylpropanoate de methyl, LC H-MSz: 5 488.15. H-3 Pyrrolidine 2-methyl-2-([5-(1methyl-1H-indazol-6yl)-1-[2-(pyrrolidin1-yl)phenyl]-1Hpyrazol-3yl]methoxy]methyl propanoate H13 6 LC-MS: (ES, m / zli.) H- 24 diene [5-(3, 5- dimethoxyphenyl)-1-[2- (pyrrolidin-1-yl)phenyl]-1H-pyrazol- 3-yl]methoxy)-2-methylpropanoate de methyl H13 7 LC-MS: (ES, m / z) : 480. H-21[a-24-Dine Azeti il)phenyl]-5-(3, 5- dimethoxyphenyl)-1H- pyrazol-3-yl]methoxy) - H13 8 LC-MS: (ES, m / z) : 4 66. Petition 870220002363, 10 / 01 / 2022, pág. 255 / 422 252 / 412 2-methylpropanoate de methyl H-25 Azetidine 2-( [1-[2-(azetidin-1yl)phenyl]-5-(1propyl-1H-indazol-6yl)-1H-pyrazol-3yl]methoxy)-2- methylpropanoate de methyl H13 9 LC-MS: (ES, m / z): 488.1. H-25 Pyrrolidine 2-methyl-2-([5-(1propyl-1H-indazol-6yl)-1-[2-(pyrrolidin1-yl)phenyl]-1Hpyrazol-3- yl]methmoxi]propanoate de methyl H14 0 LC-MS: (ES, m / z): 502.2. H-2 6 Azetidine 2-([1-[2-(azetidin-1yl)phenyl]-5-(3cyclobutoxyphenyl) -1Hpirazol-3-yl]methoxy)2-methylpropanoate de methyl H- 14 1 LC-MS: (ES, m / z): 476, 5. H-46 Pyrrolidine 2-([5-(3- cyclopropoxyphenyl)-1[2-(pyrrolidin-1- il)phenyl]-1H-pyrazol3-yl]methoxy)-2methylpropanoate de methyl H- 14 2 LC-MS: (ES, m / z): 476.4. Petition 870220002363, 10 / 01 / 2022, pág. 256 / 422 253 / 412 H-46 Azetidine 2-([1-[2-(azetidin-1yl)phenyl]-5-(3cyclopropoxyphenyl)1H-pyrazol-3yl]methoxy)-2- methylpropanoate of methyl H- 14 3 LC-MS: (ES, m / z) : 462.15 H-46 (3S)-3- hydroxypyrrolidin to 2-([5-(3cyclopropoxyphenyl)-1[2-[ (3S) -3hydroxypyrrolidin-1yl]phenyl]-1H-pyrazol3-yl]methoxy)-2methylpropanoate de methyl : (ES 4 m / z) H-46 Morpholin 2-([5-(3- cyclopropoxyphenyl)-1- [2-(morpholin-4- il)phenyl]-1H-pyrazol- 3-yl]methoxy)-2- methylpropanoate of methyl H- 14 5 LC-MS: (ES, m / z), 49 H-46 2-oxopyrrolidine 2-([5-(3- cyclopropoxyphenyl)-1- [2-(2-oxopyrrolidin- 1-yl)phenyl]-1H- pyrazol-3-yl]methoxy)- 2-methylpropanoate of methyl H14 6, 49 / MS: (LC-1:) Petition No. 870220002363, dated 10 / 01 / 2022, p. 257 / 422 254 / 412 H-46 Pyrazol 2-([5-(3-cyclopropoxyphenyl)-1[2-(1H-pyrazol-1yl)phenyl]-1H-pyrazol3-yl]methoxy)-2methylpropanoate de methyl H- 14 7 LC-MS: (ES, m / z) : 473.25. H-46 (3R)-3-hidroxipyrrolidine 2-([5-(3cyclopropoxyphenyl)-1[2-[ (3R) -3hidroxipyrrolidin-1yl]phenyl]-1H-pyrazol3-yl]methoxy)-2- methylpropanoate de methyl H- 14 8 LC-MS: (ES, m / z) : 492. H-47 Azetidine 2-([1-[2-(azetidin-1yl)-4-fluorophenyl]-5(3-cyclopropoxyphenyl)1H-pyrazol-3yl]methoxy)-2methylpropanoate de methyl H14 9 LC-MS: (ES, m / z) : 480.40. H-20 Pyrrolidine 2-([5-(3-cyclopropoxyphenyl)-1[ [2- (pyrrolidin-1yl)phenyl]methyl]-1Hpyrazol-3-yl]methoxy)2-methylpropanoate de methyl H15 0 LC-MS: (ES, m / z) : 490.15. Petition 870220002363, 10 / 01 / 2022, pág. 258 / 422 255 / 412 H-68 Pyrrolidine 2-([5-(3-cyclobutoxyphenyl)-1[ [2-(pyrrolidin-1yl)phenyl]methyl]-1Hpyrazol-3-yl]methoxy)2-methylpropanoate H- 15 1 LC-MS: (ES, m / z) : 504. H-97 Azetidine (2 R )-2-([1-[2(azetidin-1yl)phenyl]-5-(1propyl-1H-indazol-6yl)-1H-pyrazol-3yl]methoxy)-2methylbutanoate H- 15 2 LC-MS: (ES, m / z): 516.5. H-102 Azetidine (2 R )-2-([1-[2(azetidin-1yl)phenyl]-5-(3cyclopropoxyphenyl)1H-pyrazol-3yl]methoxy)-2methylbutanoate H- 15 3 LC-MS: (ES, m / z): 476.2. H-125 Pyrrolidine (2R)-2-([5-(1-ethyl1H-indazol-6-yl)-1[2- (pyrrolidin-1yl)phenyl]-1H-pyrazol3-yl]methoxy)-2methylbutanoate H- 15 4 LC-MS: (ES, m / z): 516. Petition 870220002363, de 10 / 01 / 2022, pág. 259 / 422 256 / 412 H-125 Azetidina (2 R )-2-([1-[2-(azetidin-1-yl)fenil]-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2-metilbutanoato de etila H- 15 5 LC-MS: (ES, m / z): 502. Intermediate H-156: 2-([1-(2-cyanophenyl)-5-(3-cyclopropoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

[0645] To a solution of Int. H-46 (150 g, 309.04 mmol, 1.00 equiv) and Zn(CN)2 (72 mg, 0.62 mmol, 2.00 equiv) in DMF (15 mL) was added Pd(PPh3)4 (36 mg, 0.03 mmol, 0.10 equiv), in portions at rt. The resulting solution was stirred for 16 h at 100 °C, diluted with 100 mL of EtOAc, washed with 2 x 50 mL of (sat)FeSO4(aq), dried with Na2SO4 and concentrated under vacuum. The residue was applied to a Prep-TLC with EtOAc / petroleum ether (1:2). This resulted in 100 mg of the title compound as a colorless oil. LC-MS: (ES, m / z): 432. Chromatographic Procedures

[0646] All chromatography was performed on a 2#-AnalyseHPLC-SHIMADZU (HPLC-10) instrument, with detection at 254 / 220 nm. Columns used for purification include: Petition 870220002363, dated 10 / 01 / 2022, pp. 260 / 422 257 / 412

[0647] Xselect: Column XSelect CSH Prep C18 OBD, 19*250mm, 5um.

[0648] XBridge:XBridge Prep C18 OBD speaker, 19*150mm 5um. Examples

[0649] The invention is further illustrated by the following examples. Example 1: 2—([1—[(3—chlorophenyl)methyl]—5—phenyl—1H—pyrazol—3—yl]methoxy)—2—methylpropanoic acid.

[0650] To a solution of Int. H-1 (0.068 g, 0.170 mmol) in THF : MeOH : H2O (2:1:1) (8 mL) LiOH * H2O (0.035 g, 0.85 mmol) was added at RT and stirring was continued for a further 3 h. The solvent was then evaporated and to the residue, water (2 mL) was added and acidified with 1 M citric acid. The mixture was extracted with EtOAc (25 mL) and washed with water (10 mL) followed by brine (10 mL). The layer of EtOAc was dried with Na2SO4, and the solvent was removed by evaporation. The crude product was subjected to chromatography with SiO2 (ISCO CombiFlash® Rf 200) using a 0 to 30% MeOH gradient in DCM to provide the titer product as a white solid (0.032 g). 1H NMR(CDCl3): δ 1.56(s, 6H), 4.61 (s, 2H), 5.34 (s, 2H), 6.38(s, 1H), 6.87-6.97(m, 1H), 7.04(s, 1H), 7.18-7.24(m, 2H), 7.26-7.35(m, 2H), 7.35-7.45(m, 3H). Petition 870220002363, dated 10 / 01 / 2022, pp. 261 / 422 258 / 412

[0651] Examples 2 through 50 were prepared in an analogous manner, as described in Example 1. Table 19: Examples 2 to 50. Ex. Structure IUPAC Name Analytical Data 2 / OH O Ã fl I Ί Ácido 2-([5-(4-clorofenil)-1-[(4clorofenil)metil]1H-pirazol-3il]metoxi)-2-metilpropanoico 1H NMR (CD3OD, 400 MHz) δ 1.52(s, 6H), 4.54(s, 2H0, 5.329s, 2H), 6.48(s, 1H), 6.91-7.00(m, 1H), 7.21-7.30-(m, 2H), 7.31-7.38(m, 2H), 7.40-7.48 (m 3H). 3 / OH O o íU^X^On Xj n cr'^-^ 1J cr^'^ 2-([5-(4-chlorophenyl)-1-[(2chlorophenyl)methyl]1H-pyrazol-3yl]methoxy)-2-methylpropanoic acid 1H NMR (CD3OD, 400 MHz) δ 1.50(s, 6H), 4.58(s, 2H), 5.41(s, 2H), 6.56(s, 1H), 6.72-6.80 (m, 1H), 7.20-7.34(m, 2H), 7.34-50 (m, 5H). 4 / OH / ~~° O £ Ji 1J Cl 2-( [1-[ (2-chlorophenyl)methyl]5-(4-fluorophenyl)1H-pyrazol-3yl]methoxy)-2-methylpropanoic acid 1H NMR (CD3OD, 400 MHz) 51.51(s, 6H), 4.58(s, 2H), 5.40(s, 2H), 6.55(s, 1H), 6.70-6.78(m, 1H), 7.14-7.18(m, 2H), 7-20-7.29(m, 2H), 7.32-7.40(m, 3H). Petition 870220002363, 10 / 01 / 2022, pág. 262 / 422 259 / 412 5 / OH O o ^\XJn δ 1.48(s, 6H), 4.58(s, 2H), 5.40(s, 2H), 6.54(s, 1H), 6.73(d, 1H), 7.20-7.38(m, 3H), 7.40-48(m, 3H). 6 OH O o ^\XJn £jn C / '''^'^ (s, 2H), 4, 50 9s, 2H), 5,30 (s, 2H), 6,50 (s, 1H), 6,60-80 (m, 1H), 7,20-70 (m, 6H). 7 / OH / ^° O ^yXn X jT> XX Acid 2-([1-benzil-5-(4-chlorofenil)1H-pirazol-3il]metoxi)-2-methylpropanoico 1H RMN (CD3OD, 400 MHz) δ 1.53(s, 6H), 4.58(s, 2H), 5.38(s, 2H), 6.51(s, 1H), 6.90(d, 2H), 7.18-7.50(m, 7H) . 8 . / OH O 2H), 6.56(s, 1H), 6.75-6.78(m, 1H), 7.20-7.30(m, 4H), 7.32-7.43(m, 4H). Petition: 870220002363, on January 10, 2022, page. 263 / 422 260 / 412 1H RMN (CD3OD, 400 MHz) δ 1.54(s, 6H), 4.589s, 2H), 5.40(s, 2H), 6.55(s, 1H), 6.68-6.74(m, 1H), 7.20-7.42 (m, 8H). 9 \ / ,0H Cl 0 jO Cl'^^ Ácido 2-( [5-(2-chlorofenil)-1-[(2chlorofenil)metil]1H-pirazol-3il]metoxi)-2-metilpropanoico 1H RMN (CD3OD, 400 MHz) δ 1.53(s, 6H), 4.58(s, 2H), 5.28(s, 2H), 6.43(s, 1H), 6.78-7.81(m, 1H), 7.16-34(m, 5H), 7.38-7.42(m, 1H), 7.50-7.56(m, 1H). 10 / OH O o ci . n Xj n CV^ Ácido 2-([5-(3-chlorofenil)-1-[(2chlorofenil)metil]1H-pirazol-3il]metoxi)-2-methylpropanoico 1H RMN (CD3OD, 400 MHz) δ1,32 (S, 6h)4,58(s, 2H), 5,42(s, 2H), 6,57(s, 1H), 6,67-6,80 (m, 1H), 7,22-7,30 (m, 3H), 7,32-42(m, 4H). 11 / OH O XjT\ Ácido 2-([1-[(2-chlorofenil)methyl]5-(m-tolil)1H-pirazol-3il]metoxi)-2-methylpropanoico 1H RMN (CDCl3, 400 MHz) δ 1.58 (s, 6H), 2.35 (s, 3H), 4.61 (s, 2H), 5.42 (s, 2H), 6.39 (s, 1H), 6.75-6.84 (m, 1H), 7.00-7.12 (m, 2H), 7.18-7.29 (4H), 7.29-7.38 (m, 1H). Petition 870220002363, 10 / 01 / 2022, pág. 264 / 422 261 / 412 12 / OH / ^° 0 jO 2-( [1-[(2-chlorophenyl)methyl]5-(3-fluorophenyl)1H-pyrazol-3yl]methoxy)-2-methylpropanoic acid 1H NMR (CDCl3, 400 MHz) δ 1.58(s, 6H), 4.64 (s, 2H), 5.48 (s, 2H), 6,42 (s, 1H), 6, 72-6, 85 (m, 1H), 6,88-7,14 (m, 3H), 7,14-7,40 (m, 4H) . 13 X °X^° / ° / \ Õ 4 / 7 θ 2-([1-[(2-chlorophenyl)methyl]5-[3-(trifluoromethyl)phenyl]1Hpyrazol-3-yl]methoxy)-2methylpropanoic acid 1H NMR (CDCla, 400 MHz) δ 1.58 (s, 6H), 4.62 (s, 2H), 5.41 (s, 2H), 6.46 (s, 1H), 6.80-6.88 (m,1H), 7.17-7.24 (m, 2H), 7.29-7.38 (m, 1H), 7.39-7.47 (m,1H), 7.49-7.54 (m, 2H), 7.59-7.68 (m,1H). 14 / OH 1 OO o^^JTIn (s, 3H), 4.62 (s, 2H), 5.46 (s, 2H),6.42 (s, 1H), 6,746.81 (m,2H), 6, 82 -6, 88 (m, 1H), 6.89-6.94 (m, 1H), 7.15-7023 (m, 2H), 7.26-7.37 (m, 2H) . Petition 870220002363, 10 / 01 / 2022, pág. 265 / 422 262 / 412 15 / OH Z~° 0 6H), 1.57-1.81 (m, 5H), 2.36-2051 (m, 1H), 2,762.91 (m, 1H), 4.56 (s,2H), 5.39 (s, 2H), 6.15 (s, 1H), 6, 54-6, 68 (m, 1H), 7.08-7.25 (m, 2H), 7.31-7.44 (m, 1H) . 16 / OH 0 ξ__J N jO Cl™™™^ 2-( [1-[(2-chlorophenyl)methyl]5-cyclopentyl-1H-pyrazol-3yl]methoxy)-2-methylpropanoic acid 1H RMN (CDCla, 400 MHz) 5 1,22- 1,64(m, 10H), 1.64-1.80(m, 2H), 1.82-2.00(m, 2H), 2.80-2.92(m, 1H), 4.74(s, 2H), 5.40(s, 2H), 6.10(s, 1H), 6, 58-6, 62(m, 1H), 7.10-7.22(m, 2H), 7.38(d, 1H). 17 <1 0H O o ^\ΧΠν Xj n Cl·''™™ ™v™^ 1J Cl·'™™'^ 1-[[5-(4-chlorophenyl)-1-[(2chlorophenyl)methyl]1H-pyrazol-3yl]methoxy]cyclopropanecarboxylic acid 1H NMR (CD3OD, 400 MHz) 51.181.32(m, 3H), 1.64-1.80(m, 1H), 4.61(s, 2H), 5.42(s, 2H), 6.52(s, 1H), 6.60-6.80(m, 1H), 7.20-52(m, 7H) . Petition 870220002363, dated 10 / 01 / 2022, pp. 266 / 422 263 / 412 18 \ z — \ / o / O (9 ΞΕ Ácido 2-( [1-[(2-clorofenil)metil]5-tiazol-2-il-1H-pirazol-3il]metoxi)-2-metilpropanoico 1H RMN (CDCl3, 400 MHz) δ 1,38 (m, 6H), 4,48 (s, 2H), 5,61 (s, 2H), 6, 55-6, 65 (m, 1H), 7,03 (s, 1H), 7,09-7,16 (m, 1H), 7,17-7,23 (m, 1H), 7,27-7,33 (d, 1H), 7,34-7,42 (m, 1H), 7,88-7,96 (d, 1H).19 / OH / ^° 0 JL Ji VX 1J Ácido 2-([5-(4-chlorofenil)-1-[(2fluorofenil)methyl]1H-pirazol-3il]metoxi)-2-methylpropanoico 1H RMN (CD3OD, 400 MHz) δ 1.48 (s, 6H), 4.53(s, 2H) 5.38(s, 2H), 6.50(s, 1H), 6.81-6.92(m 1H), 7.007.13(m, 2H), 7.21-7.31 (m 1H), 7.34-7.48(m 4H) 20<N X / ° / X Y / Z õ> õ Ácido 2-([5-(4-chlorofenil)-1-[(2chlorofenil)methyl]1H-pirazol-3yl]metoxi)-2-methyl-propanamide 1H RMN (CD3OD 4 00 MHz) δ 1.4 6(s, 6H), 4.58(s, 2H), 5.40(s, 2H), 6.52(s, 1H), 6.71-6.76(m, 1H), 7.20-7.58(m, 6H) 21 X °y0 7\ Z / O # \\ x^z \=7 [ 'z~^ õ Ácido 2-([5-(4-chlorofenil)-1- ([piridin-4-il]metil)1H-pirazol-3il]metoxi)-2-methylpropanoico 1H RMN (CD3OD 400 MHz) δ 1.52(s, 6H), 4.58(s, 2H), 5.56(s, 2H), 6.59(s, 1H), 7.21-7.52(m, 6H), 8.50 (sl, 2H). Petition: 870220002363, on January 10, 2022, page. 267 / 422 264 / 412 22 τ °v° Λο ZA õ Ácido 2-([5-(4-chlorofenil)-1- ([piridin-2-il]metil)1H-pirazol-3il]metoxi)-2-metilpropanoico 1H RMN (DMSO-d6, 400 MHz) δ 1.38(s, 6H), 4.40(s, 2H), 5.38(s, 2H), 6.41(s, 1H), 6.90-7.10(m, 1H), 7.20-7.85(m, 6H), 8.51(sl, 1H) 23 T °v° o Acido 2-([5-(4-chlorofenil)-1- ([piridin-3-il]metil)1H-pirazol-3il]metoxi)-2-metilpropanoico 1H RMN (CD3OD 400 MHz) δ 1.52(s, 6H), 4.58(s, 2H), 5.10(s, 2H), 6.55(s, 1H), 7.30-7.41(m, 3H), 7.42-7.51(m, 3H), 8.19(s, 1H), 8.41(d, 1H). 24 / OH / ^° 0 s\-2 / N jO Ácido 2-( [1-[(2-chlorofenil)metil]5-(tien-3-il)1H-pirazol-3il]metoxi)-2-metilpropanoico. 1HRMN(CDCla): 51.37(s, 6H), 4.38(s, 2H), 5.43(s, 2H), 6.48(s, 1H), 6.62-6.64(m, 1H), 7.17-7.31(m, 3H), 7.44-7.46(m, 1H), 7.57-7.64(m, 2H). 25 / OH / ^Oo Q ÍT^ zs^x ,n jO Ácido 2-([1-[(2-chlorofenil)methyl]5-(tien-2-il)1H-pirazol-3il]metoxi)-2-methylpropanoico.1HRMN (CDCl3): δ 1.37(s, 6H), 4.39(s, 2H), 5.47(s, 2H), 6.53(s, 1H), 6.59-6.61(m, 1H), 7.09-7.14(m, 2H), 7.24-7.31(m, 2H), 7.45-7.47(m, 1H), 7.62-7.64(m, 1H). Petition 870220002363, dated 10 / 01 / 2022, pp. 268 / 422 265 / 412 26 / OH X _^°o OyX~ / N XjOi jO F^^ Ácido 2-([1-[(2-fluorofenil)methyl]-5-(3-(2methylpropoxi)fenil)1H-pirazol-3il]metoxi)-2-methylpropanoico 1HRMN(CDCla): δ 0.97 (s, 3H), 0.99(s, 3H), 1.55 (s, 6H), 2.00-2.06 (m, 1H), 3.70(d, 2H), 4.62 (s, 2H), 5.39 (s, 2H), 6.37 (s, 1H), 6.796.80 (m, 1H), 6.87-7.09 (M, 5H), 7.22-7.30(m, 2H) 27 / OH Xj n 1HRMN (CDCl3): δ 0.95(s, 3H)(, 0.96(s, 3H), 1.56(s, 6H), 1.97- 2.03(m, 1H), 3.49(d, 2H), 4.63(s, 2H), 5.43(s, 2H), 6.41(s, 1H), 6, 73-6, 80(m, 2H), 6, 84-6, 92(m, 2H), 7.19-7.28(m,3H), 7.33-7.35(m, 1H) 28 / OH _^°o OyXji XXN 1X cr-^ Ácido 2-( . [1-[(2-chlorofenil)metil]5-(3-etoxifenil)1H-pirazol-3il]metoxi)-2-metilpropanoico. 1HRMN (CDCla): δ 1.34 (t, 3H),, 1.56(s, 6H), 3.86(q, 2H), 4.62(s, 2H), 5.43 (s, 2H), 6.40(s, 1H), 6.76-6.78 (m, 2H), 6.83-6.85(m, 1H), 6.89-6.91(m, 1H), 7.19...

Claims

1. A compound characterized by having the structural formula: and / or a salt thereof.

2. PHARMACEUTICAL COMPOSITION, characterized by comprising a compound as defined in claim 1 and / or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, adjuvant or carrier.

3. METHOD FOR INHIBITING THE ACTIVITY OF THE MONOCARBOXYLATE CARRIER MCT4, in a biological sample, characterized by comprising the step of placing said biological sample in contact with a compound as defined in claim 1, or a salt thereof.