Triazole compounds as GIP-r antagonists

Abstract

The present application provides compounds that may be used as a gastric inhibitory polypeptide receptors (GIP-R) antagonist, or pharmaceutically acceptable salts thereof. Also provided are pharmaceutical compositions containing such compounds, or pharmaceutically acceptable salts thereof. Methods of preparing these compounds and compositions, and methods of using these compounds and compositions to treat or prevent a disease or a condition mediated by GIP-R, are also provided.

Description

Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834TRIAZOLE COMPOUNDS AS GIP-R ANTAGONISTS CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 669,527, filed on July 10, 2024, which is incorporated by reference herein in its entirety for all purposes. BACKGROUND

[0002] Gastric inhibitory polypeptide (GIP) is a 42 amino acid long incretin hormone secreted by the K cells in the intestine in response to ingestion of food and plays a crucial role in energy metabolism. Both GIP and glucagon-like peptide-1 (GLP-1) receptors are present in the brain, influencing appetite regulation.

[0003] Gastric inhibitory polypeptide receptor (GIP-R) antagonism with antibody or peptide modalities has shown promise but efforts to generate small molecule GIP-R antagonists have been largely unsuccessful. Therefore, developing small molecule GIP-R antagonists for an easily-administered treatment for cardiometabolic associated diseases including obesity remains an unmet clinical need. SUMMARY

[0004] Disclosed are compounds that can be used as GIP receptor (GIP-R) antagonists, compositions containing these compounds and methods for treating diseases and / or conditions mediated by GIP-R.

[0005] In some embodiments, the present disclosure provides compounds of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein:Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834R1is H, OH, or C1-6alkyl; R5is H or C1-6alkyl; X1is CH or N; X2is CR2or N; R2is H, C1-6 alkyl, or C1-6 alkoxyl; X3is CH or N; X6is CH or N; R3is H, C1-6 alkyl, or C1-6 alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10 cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10 cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6alkyl, or C1-6alkoxyl, wherein the C1-6alkyl or C1-6alkoxyl is optionally further substituted by one or more halogen, or C1-6haloalkyl.

[0006] In some embodiments, the compound is of Formula (I ):Formula (I )or a pharmaceutically acceptable salt thereof, wherein:Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834R3is H, C1-6 alkyl, or C1-6 alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10 cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6alkyl, or C1-6alkoxyl, wherein the C1-6alkyl or C1-6alkoxyl is optionally further substituted by one or more halogen, or C1-6haloalkyl.

[0007] In some embodiments, the compound is of Formula (I-A):Formula (I-A) or a pharmaceutically acceptable salt thereof, wherein:m is 1, 2, or 3; ois 1, 2, or 3;X4is C(RX4)(RX4’), NRXN4, or O; X5is CH or N; X6is CH or N; RX4is H, C1-6alkyl, C1-6haloalkyl, halogen, C1-6alkoxyl, or C1-6haloalkoxyl; RX4’is H or halogen; RNX4is H, C1-6alkyl, or C1-6haloalkyl; each R7independently is halogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy, wherein the C1-6 alkoxy is optionally further substituted by one or more halogen; p is 0, 1, 2, or 3. R1is H, OH, or C1-6 alkyl; R5is H or C1-6 alkyl; R2is H, C1-6 alkyl, or C1-6 alkoxyl; andDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834R3is H, C1-6 alkyl, or C1-6 alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl.

[0008] In some embodiments, the compound is of Formula (I -A):Formula (I -A)or a pharmaceutically acceptable salt thereof, wherein: R1is H, OH, or C1-6alkyl; R5is H or C1-6alkyl; X1is CH or N; X2is CR2or N; R2is H, C1-6 alkyl, or C1-6 alkoxyl; X3is CH or N; X6is CH or N; R3is H, C1-6 alkyl, or C1-6 alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10 cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10 cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6 alkyl, or C1-6 alkoxyl, wherein the C1-6 alkyl or C1-6 alkoxyl is optionally further substituted by one or more halogen, or C1-6 haloalkyl.

[0009] In some embodiments, the compound is of Formula:or a pharmaceutically acceptable salt thereof, wherein:Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834R1is H, OH, or C1-6 alkyl; R5is H or C1-6 alkyl; X1is CH or N; X2is CR2or N; R2is H, C1-6alkyl, or C1-6alkoxyl; X3is CH or N; X6is CH or N; R3is H, C1-6alkyl, or C1-6alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10 cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6 alkyl, or C1-6 alkoxyl, wherein the C1-6 alkyl or C1-6 alkoxyl is optionally further substituted by one or more halogen, or C1-6 haloalkyl.

[0010] In some embodiments, the compound is of Formula (I -C):Formula (I -C)or a pharmaceutically acceptable salt thereof, wherein: R1is H, OH, or C1-6alkyl; R5is H or C1-6alkyl; X1is CH or N; X2is CR2or N; R2is H, C1-6alkyl, or C1-6alkoxyl; X3is CH or N; X6is CH or N; R3is H, C1-6 alkyl, or C1-6 alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10 cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10 cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6 alkyl, or C1-6 alkoxyl, wherein the C1-6 alkyl or C1-6 alkoxyl isDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834optionally further substituted by one or more halogen, or C1-6 haloalkyl.

[0011] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the compounds in Table 1.

[0012] In some embodiments, the present disclosure provides a pharmaceutical composition comprising the compound of any one of the previous claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0013] In some embodiments, the present disclosure provides a method of treating a disease mediated by gastric inhibitory polypeptide receptor (GIP-1 receptor) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0014] In some embodiments, the disease is a liver disease. In some embodiments, the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or oti-antitrypsin deficiency.

[0015] In some embodiments, the disease is diabetes.

[0016] In some embodiments, the disease is a cardiometabolic disease.

[0017] In some embodiments, the disease is obesity.

[0018] In some embodiments, the present disclosure provides a method of decreasing food intake in an individual in need thereof, comprising administering to the individual a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0019] In some embodiments, the present disclosure provides a method of increasing glucose tolerance in an individual in need thereof, comprising administering to the individual a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0020] In some embodiments, the present disclosure provides a method of increasing glucose tolerance in an individual in need thereof, comprising administering to the individual a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0021] In some embodiments, the present disclosure provides the use a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0022] In some embodiments, the present disclosure provides a pharmaceutical composition comprising the compound of any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0023] In some embodiments, the present disclosure provides a method of treating a disease mediated by gastric inhibitory polypeptide receptor (GIP-R) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, or any pharmaceutical composition disclosed herein.

[0024] In some embodiments, the disease is a liver disease. In some embodiments, the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or oti-antitrypsin deficiency.

[0025] In some embodiments, the disease is diabetes.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0026] In some embodiments, the disease is cardiometabolic disease.

[0027] In some embodiments, the disease is obesity.

[0028] In some embodiments, the present disclosure provides the use any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease mediated by GIP-R.

[0029] In some embodiments, the present disclosure provides a method of decreasing food intake in an individual in need thereof, comprising administering to the individual any one of the compounds disclosed herein, or pharmaceutically acceptable salt thereof, or any pharmaceutical composition herein.

[0030] In some embodiments, the present disclosure provides a method of increasing glucose tolerance in an individual in need thereof, comprising administering to the individual any one of the compounds disclosed herein, or pharmaceutically acceptable salt thereof, or any pharmaceutical composition herein.

[0031] In some embodiments, the present disclosure provides the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, in the preparation of a medicament for the treatment of a disease mediated by gastric inhibitory polypeptide receptor (GIP-1 receptor).

[0032] In some embodiments, the disease is a liver disease. In some embodiments, the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or oti-antitrypsin deficiency.

[0033] In some embodiments, the disease is diabetes.

[0034] In some embodiments, the disease is cardiometabolic disease.

[0035] In some embodiments, the disease is obesity.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0036] In some embodiments, the present disclosure provides the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in the manufacture of a medicament for decreasing food intake.

[0037] In some embodiments, the present disclosure provides the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in the manufacture of a medicament for increasing glucose tolerance.

[0038] In some embodiments, the present disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in treating a disease mediated by gastric inhibitory polypeptide receptor (GIP-R).

[0039] In some embodiments, the disease is a liver disease. In some embodiments, the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or oti-antitrypsin deficiency.

[0040] In some embodiments, the disease is diabetes.

[0041] In some embodiments, the disease is cardiometabolic disease.

[0042] In some embodiments, the disease is obesity.

[0043] In some embodiments, the present disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in decreasing food intake.

[0044] In some embodiments, the present disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in increasing glucose tolerance.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0045] In some embodiments, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Examples A1 to A22.

[0046] In some embodiments, the present disclosure provides a method of modulating GIP-R activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0048] In some embodiments, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0049] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating GIP-R activity (e.g., in vitro or in vivo).

[0050] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0051] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.

[0052] In some embodiments, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating GIP-R activity (e.g., in vitro or in vivo).Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0053] In some embodiments, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0054] In some embodiments, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0055] In some embodiments, the present disclosure provides a method of preparing a compound of the present disclosure.

[0056] In some embodiments, the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0058] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION

[0059] The present disclosure relates to compounds, prodrugs, and pharmaceutically acceptable salts thereof, which may modulate GIP-R activity and are accordingly useful in methods of treatment of the human or animal body, e.g., in the treatment of a disease mediated by GIP-R. The present disclosure also relates to processes for the preparation of theseDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834compounds, to pharmaceutical compositions comprising them and to their use in the treatment of disorders in which GIP-R is implicated, such as diabetes, non-alcoholic fatty liver disease (NASH), obesity, hyperglycemia, and / or insulinoma. Definitions

[0060] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0061] Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options.

[0062] As used herein, “alkyl”, “C1, C2, C3, C4, C5or C6alkyl” or “C1-C6alkyl” is intended to include C1, C2, C3, C4, C5or C6straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6alkyl is intends to include C1, C2, C3, C4, C5and C6alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms. A divalent alkyl group is referred to herein as “alkylene.”

[0063] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino,Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0064] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms. A divalent alkenyl group is referred to herein as “alkenylene.”

[0065] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0066] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6for straight chain, C3-C6for branched chain).Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3- C6” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6alkenylene linker” or “C2-C6alkynylene linker” is intended to include C2, C3, C4, C5or C6chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2- C6alkenylene linker is intended to include C2, C3, C4, C5 and C6 alkenylene linker groups. A divalent alkynyl group is referred to herein as “alkynylene.”

[0067] As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or Heteroaromatic moiety.

[0068] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocyclyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl- piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0069] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non- aromatic. A divalent cycloalkyl group is referred to herein as “cycloalkylene.”

[0070] As used herein, the term “heterocyclyl” refers to a saturated or partially unsaturated 3- 8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1- oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4- c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6- tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7- tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2- azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa- azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H- cyclopenta[b]thiophenyl, and the like. In the case of multicyclic heterocyclyl, only one of the rings in the heterocyclyl needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl, benzo[d][1,3]dioxole, 2,3-dihydrobenzo[b][1,4]dioxine, and the like). A divalent heterocyclyl group is referred to herein as “heterocyclylene.”

[0071] It is understood that when a variable has two attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the variable, as allowed by valency. For example, when a variable (e.g., variable X) is cycloalkyl orDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834heterocyclyl, and has two attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the cycloalkyl or heterocyclyl.

[0072] As used herein, the term “aryl” refers to groups monocyclic or multicyclic systems with one or more aromatic rings that do not contain any heteroatom in the ring structure(s). The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. For example, an aryl is phenyl. A divalent aryl group is referred to herein as “arylene.”

[0073] As used herein, the term “heteroaryl” refers to a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1- 6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogenand sulfur heteroatoms may optionally be oxidised (i.e., N O and S(O)p, where p = 1 or 2).It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, purine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl, 2,3-dihydro-1H-pyrrolopyridine, 1,2,3,4- tetrahydronaphthyridine, 2,3-dihydro-pyridooxazine, 2,3-dihydro-1H-pyrrolopyridine, 2,3- dihydrooxazolopyridine, and the like). A divalent heteroaryl group is referred to herein as “heteroarylene.”

[0074] Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, respectively, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0075] The cycloalkyl, heterocyclyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituentsDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl).

[0076] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N).

[0077] “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0078] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0079] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0080] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O-.

[0081] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0082] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0083] The term “heteroalkyl” refers to an alkyl group, as defined herein, wherein at least one carbon atom has been replaced by a heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur. The nitrogen atom may be substituted or unsubstituted (e.g., NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionallybe oxidised (i.e., N O and S(O)p, where p = 1 or 2). A divalent heteroalkyl is referred toherein as “heteroalkylene.”

[0084] As used herein, the term “optionally substituted haloalkyl” refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0085] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

[0086] As used herein, the term “heteroalkoxy” or “heteroalkoxyl” includes substituted and unsubstituted heteroalkyl, heteroalkenyl and heteroalkynyl groups covalently linked to an oxygen atom.

[0087] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and / or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

[0088] It is to be understood that the present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0089] It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0090] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0091] It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognised reference textbooks of organic synthesis known to those in the artDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0092] One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognise that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999.

[0093] It is to be understood that, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to provide such treatment or prevention as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to prepare a medicament to treat or prevent such condition. The treatment or prevention includes treatment or prevention of human or non-human animals including rodents and other disease models.

[0094] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment includes use of the compounds to prepare a medicament to treat such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

[0095] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human.

[0096] As used herein, the term “subject in need thereof” refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorderDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy.

[0097] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0098] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0099] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0100] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18thedition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

[0101] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0102] As used herein, the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In oneDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0103] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0104] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

[0105] It is to be understood that a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0106] It is to be understood that a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. TheDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

[0107] As used herein, the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by experimentation that is within the skill and judgment of the clinician.

[0108] It is to be understood that, for any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50 % of the population) and LD50(the dose lethal to 50 % of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50 / ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0109] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administeredDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0110] The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilising processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

[0111] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration,suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (BASF,Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), cyclodextrins and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0112] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0113] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, capsules or sachets. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavoring.

[0114] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebuliser.

[0115] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays,Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834powders or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0116] The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

[0117] It may be advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0118] In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression. As used herein,Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.

[0119] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0120] It is to be understood that, for the compounds of the present disclosure being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure.

[0121] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral organic acid salts of basic residues such as amines, alkali organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0122] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0123] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid,Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0124] It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0125] The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognise the advantages of certain routes of administration.

[0126] The dosage regimen utilising the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.

[0127] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19thedition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0128] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0129] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.

[0130] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

[0131] As use herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein, both generically and specifically.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Compounds of the Present Disclosure

[0132] In some embodiments, the present disclosure provides compounds of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein:R5is H or C1-6 alkyl; X1is CH or N; X2is CR2or N; R2is H, C1-6 alkyl, or C1-6 alkoxyl; X3is CH or N; X6is CH or N; R3is H, C1-6alkyl, or C1-6alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6alkyl, or C1-6alkoxyl, wherein the C1-6alkyl or C1-6alkoxyl is optionally further substituted by one or more halogen, or C1-6 haloalkyl.

[0133] In some embodiments, the compound is of Formula (I ):Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834or a pharmaceutically acceptable salt thereof, wherein:R1is H, OH, or C1-6 alkyl; R5is H or C1-6 alkyl; R2is H, C1-6 alkyl, or C1-6 alkoxyl; R3is H, C1-6 alkyl, or C1-6 alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10 cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10 cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6 alkyl, or C1-6 alkoxyl, wherein the C1-6 alkyl or C1-6 alkoxyl is optionally further substituted by one or more halogen, or C1-6 haloalkyl.

[0134] In some embodiments, the compound is of Formula (I-A):Formula (I-A) or a pharmaceutically acceptable salt thereof, wherein:m is 1, 2, or 3; o is 1, 2, or 3; X4is C(RX4)(RX4’), NRXN4, or O; X5is CH or N; X6is CH or N;Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834RX4is H, C1-6 alkyl, C1-6 haloalkyl, halogen, C1-6 alkoxyl, or C1-6 haloalkoxyl; RX4’is H or halogen; RNX4is H, C1-6 alkyl, or C1-6 haloalkyl; each R7independently is halogen, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy, wherein the C1-6alkoxy is optionally further substituted by one or more halogen; p is 0, 1, 2, or 3. R1is H, OH, or C1-6alkyl; R5is H or C1-6alkyl; R2is H, C1-6alkyl, or C1-6alkoxyl; and R3is H, C1-6alkyl, or C1-6alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl.

[0135] In some embodiments, the compound is of Formula:Formula (I -A)or a pharmaceutically acceptable salt thereof, wherein: R1is H, OH, or C1-6 alkyl; R5is H or C1-6 alkyl; X1is CH or N; X2is CR2or N; R2is H, C1-6alkyl, or C1-6alkoxyl; X3is CH or N; X6is CH or N; R3is H, C1-6alkyl, or C1-6alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6 alkyl, or C1-6 alkoxyl, wherein the C1-6 alkyl or C1-6 alkoxyl is optionally further substituted by one or more halogen, or C1-6 haloalkyl.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0136] In some embodiments, the compound is of Formula (I -B):or a pharmaceutically acceptable salt thereof, wherein: R1is H, OH, or C1-6alkyl; R5is H or C1-6alkyl; X1is CH or N; X2is CR2or N; R2is H, C1-6alkyl, or C1-6alkoxyl; X3is CH or N; X6is CH or N; R3is H, C1-6 alkyl, or C1-6 alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10 cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10 cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6 alkyl, or C1-6 alkoxyl, wherein the C1-6 alkyl or C1-6 alkoxyl is optionally further substituted by one or more halogen or C1-6 haloalkyl.

[0137] In some embodiments, the compound is of Formula (I -C):Formula (I -C)or a pharmaceutically acceptable salt thereof, wherein: R1is H, OH, or C1-6 alkyl; R5is H or C1-6 alkyl; X1is CH or N;Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834X2is CR2or N; R2is H, C1-6 alkyl, or C1-6 alkoxyl; X3is CH or N; X6is CH or N; R3is H, C1-6alkyl, or C1-6alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6alkyl, or C1-6alkoxyl, wherein the C1-6alkyl or C1-6alkoxyl is optionally further substituted by one or more halogen or C1-6haloalkyl. Embodiments Related to Ring A

[0138] In some embodiments, Ring

[0139] In some embodiments, Ring

[0140] In some embodiments, Ring

[0141] In some embodiments, RingDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0142] In some embodiments, Ring.

[0143] In some embodiments, Ring A is .

[0144] In some embodiments, Ring.

[0145] In some embodiments, Ring.

[0146] In some embodiments, Ring A is.

[0147] In some embodiments, Ring A is

[0148] In some embodiments, Ring

[0149] In some embodiments, Ring A is.

[0150] In some embodiments, Ring A is

[0151] In some embodiments, Ring A isDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0152] In some embodiments, Ring A is. Embodiments Related to R1and R5

[0153] In some embodiments, R1is H.

[0154] In some embodiments, R1is OH.

[0155] In some embodiments, R1is C1-6 alkyl.

[0156] In some embodiments, R1is C1alkyl.

[0157] In some embodiments, R1is C2alkyl.

[0158] In some embodiments, R1is C3 alkyl.

[0159] In some embodiments, R1is C4 alkyl.

[0160] In some embodiments, R1is C5alkyl.

[0161] In some embodiments, R1is C6alkyl.

[0162] In some embodiments, R5is H.

[0163] In some embodiments, R5is C1-6 alkyl.

[0164] In some embodiments, R5is C1alkyl.

[0165] In some embodiments, R5is C2alkyl.

[0166] In some embodiments, R5is C3alkyl.

[0167] In some embodiments, R5is C4 alkyl.

[0168] In some embodiments, R5is C5 alkyl.

[0169] In some embodiments, R5is C6alkyl. Embodiments Related to X1, X2, R2, X3, X5, X6, and R3

[0170] In some embodiments, X1is CH.

[0171] In some embodiments, X1is N.

[0172] In some embodiments, X2is CR2.

[0173] In some embodiments, X2is N.

[0174] In some embodiments, R2is H.

[0175] In some embodiments, R2is C1-6 alkyl.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0176] In some embodiments, R2is C1 alkyl.

[0177] In some embodiments, R2is C2alkyl.

[0178] In some embodiments, R2is C3alkyl.

[0179] In some embodiments, R2is C4 alkyl.

[0180] In some embodiments, R2is C5 alkyl.

[0181] In some embodiments, R2is C6 alkyl.

[0182] In some embodiments, R2is C1-6alkoxyl.

[0183] In some embodiments, R2is C1alkoxyl.

[0184] In some embodiments, R2is C2 alkoxyl.

[0185] In some embodiments, R2is C3 alkoxyl.

[0186] In some embodiments, R2isalkoxyl.

[0187] In some embodiments, R2is C5alkoxyl.

[0188] In some embodiments, R2is C6 alkoxyl.

[0189] In some embodiments, X3is CH.

[0190] In some embodiments, X3is N.

[0191] In some embodiments, X5is CH.

[0192] In some embodiments, X5is N.

[0193] In some embodiments, X6is CH.

[0194] In some embodiments, X6is N.

[0195] In some embodiments, R3is H.

[0196] In some embodiments, R3is C1-6alkyl.

[0197] In some embodiments, R3is C1 alkyl.

[0198] In some embodiments, R3is C2 alkyl.

[0199] In some embodiments, R3is C3alkyl.

[0200] In some embodiments, R3is C4alkyl.

[0201] In some embodiments, R3is C5 alkyl.

[0202] In some embodiments, R3is C6 alkyl.

[0203] In some embodiments, R3is C1-6 alkoxyl.

[0204] In some embodiments, R3is C1alkoxyl.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0205] In some embodiments, R3is C2 alkoxyl.

[0206] In some embodiments, R3is C3alkoxyl.

[0207] In some embodiments, R3is C4alkoxyl.

[0208] In some embodiments, R3is C5 alkoxyl.

[0209] In some embodiments, R3is C6 alkoxyl.

[0210] In some embodiments, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl.

[0211] In some embodiments, R2and R3, together with the atoms to which they are attached, combine to form a 5-membered cycloalkyl.

[0212] In some embodiments, R2and R3, together with the atoms to which they are attached, combine to form a 6-membered cycloalkyl. Embodiments Related to R4, R4a, o, m, p, R7, X4, RXN4, RX4, and RX4’

[0213] In some embodiments, R4is a ring.

[0214] In some embodiments, R4is a non-aromatic ring.

[0215] In some embodiments, R4is a monocyclic, non-aromatic ring.

[0216] In some embodiments, R4is 4-10 membered heterocyclyl or C3-10cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10cycloalkyl is optionally substituted with one or more R4a; R4ais halogen, C1-6 alkyl, or C1-6 alkoxyl, wherein the C1-6 alkyl or C1-6 alkoxyl is optionally further substituted by one or more halogen or C1-6 haloalkyl.

[0217] In some embodiments, R4is a 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl is optionally substituted by one or more R4a.

[0218] In some embodiments, R4is azetidinyl optionally substituted with one or more C1-6 alkoxyl optionally further substituted by one or more R4a.

[0219] In some embodiments, R4is azetidinyl optionally substituted with one ore more C1 alxoyl optionally further substituted by one or more R4a.

[0220] In some embodiments, R4is azetidinyl optionally substituted by one or more R4a.

[0221] In some embodiments, R4is azetidinyl substituted by one or more R4a.

[0222] In some embodiments, R4is piperidinyl optionally substituted by one or more R4a.

[0223] In some embodiments, R4is piperidinyl substituted by one or more R4a.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0224] In some embodiments,.

[0225] In some embodiments,

[0226] In some embodiments,.

[0227] In some embodiments,.

[0228] In some embodiments,

[0229] In some embodiments,

[0230] In some embodiments, R4is.In some embodiments, R4is morpholino optionally substituted by one or more R4a.

[0231] In some embodiments, R4is morpholino substituted by one or more R4a.

[0232] In some embodiments,.

[0233] In some embodiments,.

[0234] In some embodiments,.

[0235] In some embodiments,.

[0236] In some embodiments, R4is C3-10cycloalkyl optionally substituted by one or more R4a.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0237] In some embodiments, R4is C3-10 cycloalkyl substituted by one or more R4a.

[0238] In some embodiments, R4is azetidinyl optionally substituted with one or more C1-6alkoxyl optionally further substituted by one or more halogen.

[0239] In some embodiments, R4is azetidinyl optionally substituted with one ore more C1 alxoyl optionally further substituted by one or more halogen.

[0240] In some embodiments, R4is azetidinyl optionally substituted with -OCF3.

[0241] In some embodiments, R4is azetidinyl substituted with -OCF3.

[0242] In some embodiments, R4is azetidinyl optionally substituted with one or more C1-6haloalkyl.

[0243] In some embodiments, R4is azetidinyl optionally substituted with one or more C1 haloalkyl.

[0244] In some embodiments, R4is azetidinyl optionally substituted with one or more -CF3.

[0245] In some embodiments, R4is azetidinyl substituted with -CF3.

[0246] In some embodiments, R4is piperidinyl optionally substituted with one or more C1-6 alkoxy optionally further substituted by one or more halogen.

[0247] In some embodiments, R4is piperidinyl substituted with -OCF3.

[0248] In some embodiments, R4is piperidinyl, optionally substituted with one or more C1-6 haloalkyl.

[0249] In some embodiments, R4is piperidinyl substituted with -CF3.

[0250] In some embodiments, R4is piperazinyl optionally substituted with one ore more C1-6haloalkyl.

[0251] In some embodiments, R4is piperazinyl substituted with C3 haloalkyl.

[0252] In some embodiments, R4is piperazinyl substituted with trifluoropropyl.

[0253] In some embodiments, R4is piperazinyl substituted with -CH2CH2CF3.

[0254] In some embodiments, R4is piperazinyl substituted with -CHCH3CF3.

[0255] In some embodiments, R4is piperazinyl substituted with trifluoropropyl and methyl.

[0256] In some embodiments, R4is piperazinyl substituted with (R)-3-methyl-1-(3,3,3- trifluoropropyl)piperazinyl.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0257] In some embodiments, R4is piperazinyl substituted with (S)-3-methyl-1-(3,3,3- trifluoropropyl)piperazinyl.

[0258] In some embodiments, R4is piperazinyl substituted with a methyl and a 3,3,3- trifluoropropyl.

[0259] In some embodiments,.

[0260] In some embodiments,.

[0261] In some embodiments, R4is morpholino optionally substituted with one or more C1-C6 alkyl.

[0262] In some embodiments, R4is morpholino optionally substituted with one or more C1alkyl.

[0263] In some embodiments, R4is morpholino optionally substituted with one or more C1-6 haloalkyl.

[0264] In some embodiments, R4is morpholino optionally substituted with C1haloalkyl.

[0265] In some embodiments, R4is morpholino optionally substituted with -CF3.

[0266] In some embodiments, R4is C3-10 cycloalkyl, wherein the C3-10 cycloalkyl is optionally substituted with one or more (i) halogen, (ii) C1-6 alkyl, (iii) C1-6 alkoxy optionally further substituted by one or more halogen, or (iv) C1-6haloalkyl.

[0267] In some embodiments, R4is C3-10cycloalkyl, wherein the C3-10cycloalkyl is optionally substituted with one or more halogen.

[0268] In some embodiments, R4is C6 cycloalkyl substituted with one or more halogen.

[0269] In some embodiments, R4is C6cycloalkyl substituted with one or more fluoro.

[0270] In some embodiments, R4is cyclohexyl substituted with one or more fluoro.

[0271] In some embodiments, R4ais halogen.

[0272] In some embodiments, R4ais fluoro.

[0273] In some embodiments, R4ais C1-6 alkoxyl optionally further substituted by one or more halogen.

[0274] In some embodiments, R4ais -OCF3.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0275] In some embodiments, R4ais C1-6 alkyl optionally further substituted by one or more C1-6haloalkyl.

[0276] In some embodiments, R4ais -CH2CH2CF3.

[0277] In some embodiments, R4ais -CHCH3CF3.

[0278] In some embodiments, R4ais C1-6 alkyl optionally further substituted by one or more halogen.

[0279] In some embodiments, R4ais -CF3.

[0280] In some embodiments, R4ais C1-6alkyl.

[0281] In some embodiments, R4ais C1 alkyl.

[0282] In some embodiments, o is 1.

[0283] In some embodiments, o is 2.

[0284] In some embodiments, o is 3.

[0285] In some embodiments, o is 1 or 2.

[0286] In some embodiments, m is 1.

[0287] In some embodiments, m is 2.

[0288] In some embodiments, m is 3.

[0289] In some embodiments, m is 1 or 2.

[0290] In some embodiments, p is 0.

[0291] In some embodiments, p is 1.

[0292] In some embodiments, p is 2.

[0293] In some embodiments, p is 3.

[0294] In some embodiments, each R7independently is halogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy optionally further substituted by one or more halogen.

[0295] In some embodiments, R7is C1-6alkyl.

[0296] In some embodiments, R7is C1alkyl.

[0297] In some embodiments, R7is C1-6 haloalkyl.

[0298] In some embodiments, R7is C1 haloalkyl.

[0299] In some embodiments, R7is -CF3.

[0300] In some embodiments, X4is C(RX4)(RX4’), NRXN4, or O.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0301] In some embodiments, X4is C(RX4)(RX4’).

[0302] In some embodiments, X4is NRXN4.

[0303] In some embodiments, X4is O.

[0304] In some embodiments, RX4is H, C1-6 alkyl, C1-6 haloalkyl, halogen, C1-6 alkoxyl, or C1- 6 haloalkoxy.

[0305] In some embodiments, RX4is H.

[0306] In some embodiments, RX4is C1-6alkyl.

[0307] In some embodiments, RX4is C1-6haloalkyl.

[0308] In some embodiments, RX4is C1-5 haloalkyl.

[0309] In some embodiments, RX4is C1 haloalkyl.

[0310] In some embodiments, RX4is -CF3.

[0311] In some embodiments, RX4is C2haloalkyl.

[0312] In some embodiments, RX4is C3 haloalkyl.

[0313] In some embodiments, RX4is trifluoropropyl.

[0314] In some embodiments, RX4is -CH2CH2CF3.

[0315] In some embodiments, RX4is halogen.

[0316] In some embodiments, RX4is fluoro.

[0317] In some embodiments, RX4is C1-6 alkoxyl.

[0318] In some embodiments, RX4is C1 alkoxyl.

[0319] In some embodiments, RX4is trifluoromethoxyl.

[0320] In some embodiments, RX4is -OCF3.

[0321] In some embodiments, RX4’is H or halogen.

[0322] In some embodiments, RX4’is H.

[0323] In some embodiments, RX4’is halogen.

[0324] In some embodiments, RX4’is fluoro.

[0325] In some embodiments, RXN4is H, C1-6 alkyl, or C1-6 haloalkyl.

[0326] In some embodiments, RXN4is H.

[0327] In some embodiments, RXN4is C1-6 alkyl.

[0328] In some embodiments, RXN4is C1-6haloalkyl.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0329] In some embodiments, RXN4is C1 haloalkyl.

[0330] In some embodiments, RXN4is C2haloalkyl.

[0331] In some embodiments, RXN4is C3haloalkyl.

[0332] In some embodiments, RXN4is trifluoropropyl.

[0333] In some embodiments, RXN4is -CH2CH2CF3.

[0334] In some embodiments, RXN4is -CHCH3CF3.

[0335] In some embodiments, the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0336] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0337] In some embodiments, the compound is selected from the prodrugs of compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0338] In some embodiments, the compound is selected from the compounds described in Table 1. TABLE 1Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0339] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1.

[0340] In some embodiments, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.

[0341] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0342] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0343] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0344] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0345] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognised techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0346] In some embodiments, the isotopic derivative is a deuterium labeled compound.

[0347] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.

[0348] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula (I), (I ), (I-A), (I -A), (I -B), or (I -C) is isotopicallyDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834enriched with regard to, or labelled with, one or more isotopes as compared to thecorresponding compound of Formula (I), (I ), (I-A), (I -A),or (I -C). In someembodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from2H,13C,14C,15N,18O,29Si,31P, and34S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with2H with regard to one or more atoms thereof). In some embodiments, the compound is a18F labeled compound. In some embodiments, the compound is a123I labeled compound, a124I labeled compound, a125I labeled compound, a129I labeled compound, a131I labeled compound, a135I labeled compound, or any combination thereof. In some embodiments, the compound is a33S labeled compound, a34S labeled compound, a35S labeled compound, a36S labeled compound, or any combination thereof.

[0349] It is understood that the18F,123I,124I,125I,129I,131I,135I,32S,34S,35S, and / or36S labeled compound, can be prepared using any of a variety of art-recognised techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a18F,123I,124I,125I,129I,131I,135I,3S,34S,35S, and / or36S labeled reagent for a non-isotope labeled reagent.

[0350] A compound of the invention or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned18F,123I,124I,125I,129I,131I,135I,32S,34S,35S, and36S atom(s) is within the scope of the invention. Further, substitution with isotope (e.g,,18F,123I,124I,125I,129I,131I,135I,3S,34S,35S, and / or36S) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0351] For the avoidance of doubt it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[0352] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methaneDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0353] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds.

[0354] It will be understood that while compounds disclosed herein may be presented in one particular configuration. Such particular configuration is not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers. In some embodiments, the presentation of a compound herein in a particular configuration intends to encompass, and to refer to, each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof; while the presentation further intends to refer to the specific configuration of the compound.

[0355] It will be understood that while compounds disclosed herein may be presented without specified configuration (e.g., without specified stereochemistry). Such presentation intends to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, the presentation of a compound herein without specified configuration intends to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof.

[0356] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of eachDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0357] As used herein, the term “chiral centre” refers to a carbon atom bonded to four nonidentical substituents.

[0358] As used herein, the term “chiral isomer” means a compound with at least one chiral centre. Compounds with more than one chiral centre may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral centre is present, a stereoisomer may be characterised by the absolute configuration (R or S) of that chiral centre. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral centre. The substituents attached to the chiral centre under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ.1964, 41, 116).

[0359] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0360] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.

[0361] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0362] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[0363] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[0364] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0365] An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0366] The compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess GIP-R antagonist activity.

[0367] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.

[0368] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0369] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0370] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or asDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0371] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0372] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure origin to the reference compound.

[0373] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0374] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev.96, 3147-3176, 1996.

[0375] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate,Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess GIP-R antagonist activity.

[0376] Compounds of any one of the Formulae disclosed herein may exist in a number ofdifferent tautomeric forms and references to compounds of Formula (I), (I ), (I-A), (I -A), (I -B), or (I -C) include all such forms. For the avoidance of doubt, where a compound can existin one of several tautomeric forms, and only one is specifically described or shown, all othersare nevertheless embraced by Formula (I), (I ), (I-A),or (I -C). Examples oftautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.keto enol enolate

[0377] Compounds of any one of the Formulae disclosed herein containing an amine functionmay also form N-oxides. A reference herein to a compound of Formula (I), (I ), (I-A), (I -A),or (I -C) that contains an amine function also includes the N-oxide. Where a compoundcontains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm.1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0378] The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed whenDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834the compound of the disclosure contains a suitable group or substituent to which a property- modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein.

[0379] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically-produced compound or a metabolically-produced compound.

[0380] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol.42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard- Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p.113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0381] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceuticallyDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4- (C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0382] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-C4alkoxy-C2-C4alkylamine such as 2-methoxyethylamine, a phenyl-C1- C4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0383] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1- ylmethyl.

[0384] The in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As statedDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug). Pharmaceutical Compositions

[0385] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0386] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0387] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in- fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0388] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity / suspending agent, buffer, and pH modifying agent, and a mixture thereof.

[0389] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting ofhydroxypropyl- -cyclodextrin, methyl- -cyclodextrin, randomly methylated- -cyclodextrin,ethylated- -cyclodextrin, triacetyl- -cyclodextrin, peracetylated- -cyclodextrin,Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834carboxymethyl- -cyclodextrin, hydroxyethyl- -cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl- -cyclodextrin, glucosyl- -cyclodextrin, sulfated -cyclodextrin(S- -CD), maltosyl- -cyclodextrin, -cyclodextrin sulfobutyl ether, branched- -cyclodextrin,hydroxypropyl- -cyclodextrin, randomly methylated- -cyclodextrin, and trimethyl- -cyclodextrin, and mixtures thereof.

[0390] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0391] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0392] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.

[0393] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0394] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0395] The aqueous vehicle may also contain a buffering agent to stabilise the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and -aminocaproic acid, and mixtures thereof.

[0396] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0397] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, orDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavouring agent such as peppermint, methyl salicylate, orange flavoring.

[0398] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0399] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0400] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0401] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a GIP-R related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0402] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a GIP-R related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0403] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula(I), (I ), (I-A), (I -A), (I -B), or (I -C) will naturally vary according to the nature and severityDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine. Methods of Use

[0404] In some embodiments, the present disclosure provides a method of modulating GIP-R activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0405] In some embodiments, the present disclosure provides a method of modulating GIP-R activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0406] In some embodiments, the present disclosure provides a method of modulating GIP-R activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0407] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0408] In some embodiments, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0409] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0410] In some embodiments, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0411] In some embodiments, the disease or disorder is associated with an implicated GIP-R activity. In some embodiments, the disease or disorder is a disease or disorder in which GIP-R activity is implicated.

[0412] In some embodiments, the disease or disorder is diabetes, NASH, insulinoma, obesity, and / or hyperglycemia.

[0413] In some embodiments, the present disclosure provides a method of treating or preventing diabetes, NASH, insulinoma, obesity, and / or hyperglycemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0414] In some embodiments, the present disclosure provides a method of treating diabetes, NASH, insulinoma, obesity, and / or hyperglycemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0415] In some embodiments, the present disclosure provides a method of treating or preventing diabetes, NASH, insulinoma, obesity, and / or hyperglycemia in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0416] In some embodiments, the present disclosure provides a method of treating diabetes, NASH, insulinoma, obesity, and / or hyperglycemia in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0417] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating GIP-R activity (e.g., in vitro or in vivo).Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0418] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating GIP-R activity (e.g., in vitro or in vivo).

[0419] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0420] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.

[0421] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing diabetes, NASH, insulinoma, obesity, and / or hyperglycemia in a subject in need thereof.

[0422] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating diabetes, NASH, insulinoma, obesity, and / or hyperglycemia in a subject in need thereof.

[0423] In some embodiments, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating GIP-R activity (e.g., in vitro or in vivo).

[0424] In some embodiments, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0425] In some embodiments, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0426] In some embodiments, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing diabetes, NASH, insulinoma, obesity, and / or hyperglycemia in a subject in need thereof.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0427] In some embodiments, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject in need thereof.

[0428] The present disclosure provides compounds that function as modulators of GIP-R activity.

[0429] In some embodiments, the compounds of the present disclosure are antagonists of the GIP-1 receptor.

[0430] In some embodiments, the modulation of the GIP-R receptor is activation of the GIP-R receptor.

[0431] Effectiveness of compounds of the disclosure can be determined by industry-accepted assays / disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.

[0432] The present disclosure also provides a method of treating a disease or disorder in which GIP-R activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0433] In accordance with the present application, a disease or condition to be treated and / or prevented is selected from the group consisting of cardiometabolic and associated diseases including diabetes (type 1 diabetes (T1 D) and / or type 2 diabetes mellitus (T2DM), including pre-diabetes), idiopathic T1 D (Type 1 b), latent autoimmune diabetes in adults (LADA), early- onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea, obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain from use of other agents (e.g., from use of steroids andDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834antipsychotics), excessive sugar craving, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol (low-density lipoprotein cholesterol), and low HDL cholesterol (high-density lipoprotein cholesterol)), hyperinsulinemia, liver diseases such as NAFLD, steatosis, NASH, fibrosis, cirrhosis, and hepatocellular carcinoma, cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson’s Disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, Polycystic Ovary Syndrome and addiction (e.g., alcohol and / or drug abuse), prevention or treatment of Polycystic Ovary Syndrome and treatment of addiction (e.g., alcohol and / or drug abuse).

[0434] In some embodiments, provided herein is a method of treating a cardiometabolic disease in a subject (e.g., a human patient) in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0435] In some embodiments, provided herein is a method of treating diabetes in a subject (e.g., a human patient) in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. Exemplary diabetes include, but are not limited to, T1 D, T2DM, pre-Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834diabetes, idiopathic T1 D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, and gestational diabetes.

[0436] In some embodiments, provided herein is a method of treating a liver disorder in a subject (e.g., a human patient) in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. Exemplary liver disorders include, without limitation, liver inflammation, fibrosis, and steatohepatitis. In some embodiments, the liver disorder is selected from the list consisting of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren’s syndrome, sarcoidosis, Wilson’s disease, Gaucher’s disease, hemochromatosis, and oti-antitrypsin deficiency. In some embodiments, the liver disorder is selected from the list consisting of liver inflammation, liver fibrosis, alcohol induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). In some embodiments, the liver disorder is selected from the group consisting of liver fibrosis, alcohol induced fibrosis, steatosis, alcoholic steatosis, NAFLD, and NASH. In one embodiment, the liver disorder is NASH. In another embodiment, the liver disorder is liver inflammation. In another embodiment, the liver disorder is liver fibrosis. In another embodiment, the liver disorder is alcohol induced fibrosis. In another embodiment, the liver disorder is steatosis. In another embodiment, the liver disorder is alcoholic steatosis. In another embodiment, the liver disorder is NAFLD. In one embodiment, the treatment methods provided herein impedes or slows the progression of NAFLD to NASH. In one embodiment, the treatment methods provided herein impedes or slows the progression of NASH. NASH can progress, e.g., to one or more of liver cirrhosis, hepatic cancer, etc. In some embodiments, the liver disorder is NASH. In some embodiments, the patient has had a liverDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834biopsy. In some embodiments, the method further comprising obtaining the results of a liver biopsy.

[0437] In accordance with the present application, a compound described herein, or a pharmaceutically acceptable salt thereof, can be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. In some embodiments, it is a compound of any embodiment of Formula(I), (I ), (I-A), (I -A), (I -B), or (I -C) or a sub-formula thereof, or selected from the compoundsof Table 1, or a pharmaceutically acceptable salt thereof. The compounds and / or compositions described herein may be administered orally, rectally, vaginally, parenterally, or topically.

[0438] In some embodiments, the compounds and / or compositions may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

[0439] In some embodiments, the compounds and / or compositions may be administered directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

[0440] In some embodiments, the compounds and / or compositions may be administered topically to the skin or mucosa, that is, dermally or transdermally. In some embodiments, the compounds and / or compositions may be administered intranasally or by inhalation. In some embodiments, the compounds and / or compositions may be administered rectally or vaginally. In some embodiments, the compounds and / or compositions may be administered directly to the eye or ear.

[0441] The compounds and / or compositions described herein can be used alone, or in combination with other therapeutic agents. The administration of two or more agents “in combination” means that all of the agents are administered closely enough in time that each may generate a biological effect in the same time frame. The presence of one agent may alterDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834the biological effects of the other agent(s). The two or more agents may be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the agents prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration.

[0442] In some embodiments, the one or more other therapeutic agent is an anti-diabetic agent including but not limited to a biguanide (e.g., metformin), a sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide.glyclopyramide, glimepiride, or glipizide), a thiazolidinedione (e.g., pioglitazone, rosiglitazone, or lobeglitazone), a glitazar (e.g., saroglitazar, aleglitazar, muraglitazar or tesaglitazar), a meglitinide (e.g., nateglinide, repaglinide), a dipeptidyl peptidase 4 (DPP-4) inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, dutogliptin, or omarigliptin), a glitazone (e.g., pioglitazone, rosiglitazone, balaglitazone, rivoglitazone, or lobeglitazone), a sodium-glucose linked transporter 2 (SGLT2) inhibitor (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, Ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), an SGLT1 (sodium-glucose linked transporter 1) inhibitor, a G Protein Coupled Receptor 40 (GPR40) agonist (free fatty acid receptor 1 (FFAR1 also known as FFA1) agonist, e.g. fasiglifam), glucose-dependent insulinotropic peptide (GIP) and analogues thereof, an alpha glucosidase inhibitor (e.g. voglibose, acarbose, or miglitol), or an insulin or an insulin analogue, including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.

[0443] In some embodiments, the one or more other therapeutic agent is an antiobesity agent including but not limited to a glucagon-like peptide-1 receptor (GLP-1R) agonist, peptide YY or an analogue thereof, a neuropeptide Y receptor type 2 (NPYR2) agonist, a neuropeptide Y receptor type 1 (NPYR1) or neuropeptide Y receptor type 5 (NPYR5) antagonist, a cannabinoid receptor type 1 (CB1 R) antagonist, a lipase inhibitor (e.g., orlistat), a human proislet peptide (HIP), a melanocortin receptor 4 agonist (e.g., setmelanotide), a melanin concentrating hormone receptor 1 antagonist, a farnesoid X receptor (FXR) agonist (e.g. obeticholic acid),Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834zonisamide, phentermine (alone or in combination with topiramate), a norepinephrine / dopamine reuptake inhibitor (e.g., buproprion), an opioid receptor antagonist (e.g., naltrexone), a combination of norepinephrine / dopamine reuptake inhibitor and opioid receptor antagonist (e.g., a combination of bupropion and naltrexone), a growth differentiating factor 15 (GDF-15) analog, sibutramine, a cholecystokinin agonist, amylin and analogues therof (e.g., pramlintide), leptin and analogues thereof (e.g., metroleptin), a serotonergic agent (e.g., lorcaserin), a methionine aminopeptidase 2 (MetAP2) inhibitor (e.g., beloranib or ZGN- 1061), phendimetrazine, diethylpropion, benzphetamine, an SGLT2 inhibitor (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, Ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), an SGLT1 inhibitor, a dual SGLT2 / SGLT1 inhibitor, a fibroblast growth factor receptor (FGFR) modulator, an AMP- activated protein kinase (AMPK) activator, biotin, a MAS receptor modulator, or a glucagon receptor agonist (alone or in combination with another GLP-1R agonist, e.g., liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, or semaglutide), including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.In some embodiments, the one or more other therapeutic agent is an agent to treat NASH including but not limited to PF-05221304, an Farnesoid X receptor (FXR) agonist (e.g., obeticholic acid), a peroxisome proliferator-activated receptor ( / agonist (e.g., elafibranor), a synthetic fatty acid-bile acid conjugate(e.g., aramchol), a caspase inhibitor (e.g., emricasan), an anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody (e.g., simtuzumab), a galectin 3 inhibitor (e.g., GR-MD-02), a mitogen-activated protein kinase 5(MAPK5) inhibitor (e.g., GS- 4997), a dual antagonist of chemokine receptor 2 (CCR2) and C-C chemokine receptor type 5 (CCR5) (e.g., cenicriviroc), a fibroblast growth factor21 (FGF21) agonist (e.g., BMS-986036), a leukotriene D4 (LTD4) receptor antagonist (e.g., tipelukast), a niacin analogue (e.g., ARI 3037MO), an apical sodium- dependent bile acid transporter (ASBT) inhibitor (e.g., volixibat), an acetyl-CoA carboxylase (ACC) inhibitor (e.g., NDI 010976), a ketohexokinase (KHK) inhibitor, a diacylglyceryl acyltransferase 2 (DGAT2) inhibitor, a CB1 receptor antagonist, an anti-cannabinoid receptor type 1 (anti-CB1 R) antibody, or an apoptosis signal-regulating kinase 1 (ASK1) inhibitor,Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts. Articles of Manufacture and Kits

[0444] The present disclosure further provides articles of manufacture comprising a compound, or a pharmaceutically acceptable salt thereof in accordance with the present application, a composition described herein, or one or more unit dosages described herein in suitable packaging. In certain embodiments, the article of manufacture is for use in any of the methods described herein. Suitable packaging (e.g., containers) is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and / or sealed.

[0445] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub- unit doses. For example, kits may be provided that contain sufficient dosages of a compound, or a pharmaceutically acceptable salt thereof in accordance with the present application, a composition described herein, and / or one or more other therapeutic agent useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds / compositions described herein and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies

[0446] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure. The instructions included with the kit generally include information as to the components and their administration to an individual. Routes of Administration

[0447] Compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered alone as a sole therapy or can be administered in addition with one or moreDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834other substances and / or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.

[0448] For example, therapeutic effectiveness may be enhanced by administration of an adjuvant (i.e. by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by an individualmay be increased by administering the compound of Formula (I), (I ), (I-A),or(I -C) with another therapeutic agent (which also includes a therapeutic regimen) that also hastherapeutic benefit.

[0449] In the instances where the compound of the present disclosure is administered in combination with other therapeutic agents, the compound of the disclosure need not be administered via the same route as other therapeutic agents, and may, because of different physical and chemical characteristics, be administered by a different route. For example, the compound of the disclosure may be administered orally to generate and maintain good blood levels thereof, while the other therapeutic agent may be administered intravenously. The initial administration may be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[0450] The particular choice of other therapeutic agent will depend upon the diagnosis of the attending physicians and their judgment of the condition of the individual and the appropriate treatment protocol. According to this aspect of the disclosure there is provided a combination for use in the treatment of a disease in which GIP-R activity is implicated comprising a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and another suitable agent.

[0451] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with a suitable, in association with a pharmaceutically acceptable diluent or carrier.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0452] In addition to its use in therapeutic medicine, compounds of Formula (I), (I ), (I-A), (I -A), or (I -C) and pharmaceutically acceptable salts thereof are also useful aspharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of modulators of GIP-R activity in laboratory animals such as dogs, rabbits, monkeys, mini-pigs, rats and mice, as part of the search for new therapeutic agents.

[0453] In any of the above-mentioned pharmaceutical composition, process, method, use, medicament, and manufacturing features of the instant disclosure, any of the alternate embodiments of macromolecules of the present disclosure described herein also apply.

[0454] The compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0455] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray or powder); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. Methods of Synthesis

[0456] In some embodiments, the present disclosure provides a method of preparing a compound of the present disclosure.

[0457] In some embodiments, the present disclosure provides a method of a compound, comprising one or more steps as described herein.

[0458] In some embodiments, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0459] In some embodiments, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein.

[0460] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0461] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0462] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.

[0463] It will be appreciated that during the synthesis of the compounds of the disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0464] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for exampleDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0465] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0466] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0467] Once a compound of Formula (I), (I ), (I-A), (I -A),or (I -C) has beensynthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) convertingthe compound Formula (I), (I ), (I-A), (I -A), (I -B), or (I -C) into another compound ofDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Formula (I), (I ), (I-A), (I -A),or (I -C); (iii) forming a pharmaceutically acceptablesalt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0468] The resultant compounds of Formula (I), (I ), (I-A), (I -A),or (I -C) can beisolated and purified using techniques well known in the art.

[0469] In some embodiments, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water.

[0470] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used.

[0471] Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours.

[0472] Moreover, by utilising the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0473] As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognise which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance – wherever necessary or useful – in order to obtain the compounds of the present disclosure. Furthermore, some of the compounds of the present disclosure can readily be synthesised by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled person will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well- known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons).

[0474] Compounds herein may be named differently according to various systems of nomenclature; however, a person of ordinary skill in the art will recognize the identify of the compound by the name and / or chemical structure as used herein.

[0475] General routes for the preparation of a compound of the application are described in Schemes herein. Numbered Embodiments

[0476] Embodiment 1. A compound of Formula (I):Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834or a pharmaceutically acceptable salt thereof, wherein:R1is H, OH, or C1-6alkyl; R5is H or C1-6 alkyl; X1is CH or N; X2is CR2or N; R2is H, C1-6 alkyl, or C1-6 alkoxyl; X3is CH or N; X6is CH or N; R3is H, C1-6 alkyl, or C1-6 alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10 cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6alkyl, or C1-6alkoxyl, wherein the C1-6alkyl or C1-6alkoxyl is optionally further substituted by one or more halogen, or C1-6haloalkyl.

[0477] Embodiment 2. The compound of embodiment 1, wherein the compound ofFormula (I) is of Formula (I ):Formula (I )or a pharmaceutically acceptable salt thereof, wherein:Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834R1is H, OH, or C1-6 alkyl; R5is H or C1-6 alkyl; R2is H, C1-6 alkyl, or C1-6 alkoxyl; R3is H, C1-6alkyl, or C1-6alkoxyl; alternatively R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6alkyl, or C1-6alkoxyl, wherein the C1-6alkyl or C1-6alkoxyl is optionally further substituted by one or more halogen, or C1-6haloalkyl.

[0478] Embodiment 3. The compound of any one of the preceding embodiments, wherein the compound of Formula (I) is of Formula (I-A):Formula (I-A) or a pharmaceutically acceptable salt thereof, wherein:m is 1, 2, or 3; o is 1, 2, or 3; X4is C(RX4)(RX4’), NRXN4, or O; X5is CH or N; X6is CH or N; RX4is H, C1-6 alkyl, C1-6 haloalkyl, halogen, C1-6 alkoxyl, or C1-6 haloalkoxyl; RX4’is H or halogen; RNX4is H, C1-6 alkyl, or C1-6 haloalkyl; each R7independently is halogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy, wherein the C1-6 alkoxy is optionally further substituted by one or more halogen;Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834p is 0, 1, 2, or 3. R1is H, OH, or C1-6 alkyl; R5is H or C1-6 alkyl; R2is H, C1-6alkyl, or C1-6alkoxyl; and R3is H, C1-6alkyl, or C1-6alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl.

[0479] Embodiment 4. The compound of any one of the preceding embodiments,wherein the compound of Formula (I) is of Formula (I -A):Formula (I -A)or a pharmaceutically acceptable salt thereof, wherein: R1is H, OH, or C1-6 alkyl; R5is H or C1-6 alkyl; X1is CH or N; X2is CR2or N; R2is H, C1-6 alkyl, or C1-6 alkoxyl; X3is CH or N; X6is CH or N; R3is H, C1-6alkyl, or C1-6alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6alkyl, or C1-6alkoxyl, wherein the C1-6alkyl or C1-6alkoxyl is optionally further substituted by one or more halogen, or C1-6 haloalkyl.

[0480] Embodiment 5. The compound of any one of the preceding embodiments,wherein the compound of Formula (I) is of Formula (I -B):Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834or a pharmaceutically acceptable salt thereof, wherein: R1is H, OH, or C1-6 alkyl; R5is H or C1-6alkyl; X1is CH or N; X2is CR2or N; R2is H, C1-6alkyl, or C1-6alkoxyl; X3is CH or N; X6is CH or N; R3is H, C1-6alkyl, or C1-6alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10 cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10 cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6 alkyl, or C1-6 alkoxyl, wherein the C1-6 alkyl or C1-6 alkoxyl is optionally further substituted by one or more halogen, or C1-6 haloalkyl.

[0481] Embodiment 6. The compound of any one of the preceding embodiments,wherein the compound of Formula (I) is of Formula (I -C):Formula (I -C)or a pharmaceutically acceptable salt thereof, wherein: R1is H, OH, or C1-6 alkyl; R5is H or C1-6 alkyl; X1is CH or N;Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834X2is CR2or N; R2is H, C1-6 alkyl, or C1-6 alkoxyl; X3is CH or N; X6is CH or N; R3is H, C1-6alkyl, or C1-6alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6alkyl, or C1-6alkoxyl, wherein the C1-6alkyl or C1-6alkoxyl is optionally further substituted by one or more halogen, or C1-6haloalkyl.

[0482] Embodiment 7. The compound of any one of the preceding embodiments, wherein X1is CH.

[0483] Embodiment 8. The compound of any one of the preceding embodiments wherein X2is CR2and R2is H.

[0484] Embodiment 9. The compound of any one of the preceding embodiments, wherein X2is CR2and R2is methyl.

[0485] Embodiment 10. The compound of any one of the preceding embodiments, wherein X3is CH.

[0486] Embodiment 11. The compound of any one of the preceding embodiments, wherein Ring.

[0487] Embodiment 12. The compound of any one of the preceding embodiments, wherein Ring.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0488] Embodiment 13. The compound of any one of the preceding embodiments, wherein Ring

[0489] Embodiment 14.of any one of the preceding embodiments, wherein Ring.

[0490] Embodiment 15. The compound of any one of the preceding embodiments,wherein Ring A isH .

[0491] Embodiment 16. The compound of any one of the preceding embodiments, wherein Ring.

[0492] Embodiment 17. The compound of any one of the preceding embodiments, wherein Ring.

[0493] Embodiment 18. The compound of any one of the preceding embodiments, wherein Ring.

[0494] Embodiment 19. The compound of any one of the preceding embodiments, wherein Ring.

[0495] Embodiment 20. The compound of any one of the preceding embodiments, wherein RingDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0496] Embodiment 21. The compound of any one of the preceding embodiments, wherein R1is H, OH, or methyl.

[0497] Embodiment 22. The compound of any one of the preceding embodiments, wherein R1is H.

[0498] Embodiment 23. The compound of any one of the preceding embodiments, wherein R1is OH.

[0499] Embodiment 24. The compound of any one of the preceding embodiments, wherein R1is methyl.

[0500] Embodiment 25. The compound of any one of the preceding embodiments, wherein R5is H or methyl.

[0501] Embodiment 26. The compound of any one of the preceding embodiments, wherein R5is H.

[0502] Embodiment 27. The compound of any one of the preceding embodiments, wherein R5is methyl.

[0503] Embodiment 28. The compound of any one of the preceding embodiments, wherein X5is CH.

[0504] Embodiment 29. The compound of any one of the preceding embodiments, wherein X5is N.

[0505] Embodiment 30. The compound of any one of the preceding embodiments, wherein X6is CH.

[0506] Embodiment 31. The compound of any one of the preceding embodiments, wherein X6is N.

[0507] Embodiment 32. The compound of any one of the preceding embodiments, wherein R3is H, methyl, methoxyl, or ethoxyl.

[0508] Embodiment 33. The compound of any one of the preceding embodiments, wherein R3is H.

[0509] Embodiment 34. The compound of any one of the preceding embodiments, wherein R3is methyl.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0510] Embodiment 35. The compound of any one of the preceding embodiments, wherein R3is methoxyl.

[0511] Embodiment 36. The compound of any one of the preceding embodiments, wherein R3is ethoxyl.

[0512] Embodiment 37. The compound of any one of the preceding embodiments, wherein R2and R3, together with the atoms to which they are attached, combine to form a 5- membered cycloalkyl.

[0513] Embodiment 38. The compound of any one of the preceding embodiments, wherein R4is is azetidinyl substituted with -OCF3.

[0514] Embodiment 39. The compound of any one of the preceding embodiments, wherein R4is is azetidinyl substituted with -CF3.

[0515] Embodiment 40. The compound of any one of the preceding embodiments, wherein R4is piperidinyl substituted with -OCF3.

[0516] Embodiment 41. The compound of any one of the preceding embodiments, wherein R4is piperidinyl substituted with -CF3.

[0517] Embodiment 42. The compound of any one of the preceding embodiments, wherein R4is piperazinyl substituted with -CH2CH2CF3.

[0518] Embodiment 43. The compound of any one of the preceding embodiments, wherein R4is piperazinyl substituted with -CHCH3CF3.

[0519] Embodiment 44. The compound of any one of the preceding embodiments, wherein.

[0520] Embodiment 45. The compound of any one of the preceding embodiments, wherein.

[0521] Embodiment 46. The compound of any one of the preceding embodiments, wherein R4is cyclohexyl substituted with one or more fluoro.

[0522] Embodiment 47. The compound of any one of the preceding embodiments, wherein R4is morpholino substituted with one or more methyl.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0523] Embodiment 48. The compound of any one of the preceding embodiments, wherein R4is morpholino substituted with -CF3.

[0524] Embodiment 49. The compound of any one of the preceding embodiments, wherein R4ais -OCF3.

[0525] Embodiment 50. The compound of any one of the preceding embodiments, wherein R4ais -CH2CH2CF3.

[0526] Embodiment 51. The compound of any one of the preceding embodiments, wherein R4ais -CHCH3CF3.

[0527] Embodiment 52. The compound of any one of the preceding embodiments, wherein R4ais -CF3.

[0528] Embodiment 53. The compound of any one of the preceding embodiments, wherein R4ais -CH3.

[0529] Embodiment 54. The compound of any one of the preceding embodiments, wherein o is 1 or 2.

[0530] Embodiment 55. The compoundany one of the preceding embodiments, wherein o is 1.

[0531] Embodiment 56.compoundany one of the preceding embodiments, wherein o is 2.

[0532] Embodiment 57. The compound of any one of the preceding embodiments, wherein m is 1.

[0533] Embodiment 58. The compound of any one of the preceding embodiments, wherein m is 2.

[0534] Embodiment 59. The compound of any one of the preceding embodiments, wherein p is 0 or 1.

[0535] Embodiment 60. The compound of any one of the preceding embodiments, wherein p is 0.

[0536] Embodiment 61.compound of any one of the preceding embodiments, wherein p is 1.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0537] Embodiment 62. The compound of any one of the preceding embodiments, wherein R7is methyl or -CF3.

[0538] Embodiment 63. The compound of any one of the preceding embodiments, wherein X4is C(RX4)(RX4’).

[0539] Embodiment 64. The compound of any one of the preceding embodiments,

[0540] Embodiment 65. The compound of any one of the preceding embodiments, wherein X4is O.

[0541] Embodiment 66. The compound of any one of the preceding embodiments, wherein RX4is H.

[0542] Embodiment 67. The compound of any one of the preceding embodiments, wherein RX4is -CF3.

[0543] Embodiment 68. The compound of any one of the preceding embodiments, wherein RX4is -CH2CH2CF3.

[0544] Embodiment 69. The compound of any one of the preceding embodiments, wherein RX4is fluoro.

[0545] Embodiment 70. The compound of any one of the preceding embodiments, wherein RX4is -OCF3.

[0546] Embodiment 71. The compound of any one of the preceding embodiments, wherein RX4’is H.

[0547] Embodiment 72. The compound of any one of the preceding embodiments, wherein RX4’is fluoro.

[0548] EmbodimentThe compound of any one of the preceding embodiments, wherein RXN4is C1-6haloalkyl.

[0549] Embodiment 74. The compound of any one of the preceding embodiments, wherein RXN4is -CH2CH2CF3.

[0550] Embodiment 75. The compound of any one of the preceding embodiments, wherein RXN4is -CHCH3CF3.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0551] Embodiment 76. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the compounds in Table 1.

[0552] Embodiment 77. The compound of embodiment 76, wherein the compound is:, or a pharmaceutically acceptable salt thereof.

[0553] Embodiment 78. A pharmaceutical composition comprising the compound of any one of the previous embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0554] Embodiment 79. A method of treating a disease mediated by gastric inhibitory polypeptide receptor (GIP-1 receptor) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the compound of any one of embodiments 1-77, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 78.

[0555] Embodiment 80. The method of embodiment 79, wherein the disease is a liver disease.

[0556] Embodiment 81. The method of embodiment 80, wherein the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or oti-antitrypsin deficiency.

[0557] Embodiment 82. The method of embodiment 79, wherein the disease is diabetes.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0558] Embodiment 83. The method of embodiment 79, wherein the disease is a cardiometabolic disease.

[0559] Embodiment 84. The method of embodiment 79, wherein the disease is obesity.

[0560] Embodiment 85. A method of decreasing food intake in an individual in need thereof, comprising administering to the individual a compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1-77 or the pharmaceutical composition of embodiment 78.

[0561] Embodiment 86. A method of increasing glucose tolerance in an individual in need thereof, comprising administering to the individual a compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1-77 or the pharmaceutical composition of embodiment 78.

[0562] Embodiment 87. Use of the compound of any one of embodiments 1-77, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 78, in the preparation of a medicament for the treatment of a disease mediated by gastric inhibitory polypeptide receptor (GIP-1 receptor).

[0563] Embodiment 88. The use of embodiment 87, wherein the disease is a liver disease.

[0564] Embodiment 89. The use of embodiment 88, wherein the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or oti- antitrypsin deficiency.

[0565] Embodiment 90. The use of embodiment 87, wherein the disease is diabetes.

[0566] Embodiment 91. The use of embodiment 87, wherein the disease is a cardiometabolic disease.

[0567] Embodiment 92. The use of embodiment 87, wherein the disease is obesity.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0568] Embodiment 93. Use of the compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1-77 or the pharmaceutical composition of embodiment 78 for use in the manufacture of a medicament for decreasing food intake.

[0569] Embodiment 94. Use of the compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1-77 or the pharmaceutical composition of embodiment 78 for use in the manufacture of a medicament for increasing glucose tolerance.

[0570] Embodiment 95. The compound of any one of embodiments 1-77, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 78, for use in treating a disease mediated by gastric inhibitory polypeptide receptor (GIP-R).

[0571] Embodiment 96. The compound, or salt thereof, or pharmaceutical composition, for use according to embodiment 95, wherein the disease is a liver disease.

[0572] Embodiment 97. The compound, or salt thereof, or pharmaceutical composition, for use according to embodiment 96, wherein the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or oti-antitrypsin deficiency.

[0573] Embodiment 98. The compound, or salt thereof, or pharmaceutical composition, for use according to embodiment 95, wherein the disease is diabetes.

[0574] Embodiment 99. The compound, or salt thereof, or pharmaceutical composition, for use according to embodiment 95, wherein the disease is a cardiometabolic disease.

[0575] Embodiment 100. The compound, or salt thereof, or pharmaceutical composition, for use according to embodiment 95, wherein the disease is obesity.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0576] Embodiment 101. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1-77 or the pharmaceutical composition of embodiment 78 for use in decreasing food intake.

[0577] Embodiment 102. The compound, or pharmaceutically acceptable salt thereof, of any one of embodiments 1-77 or the pharmaceutical composition of embodiment 78 for use in increasing glucose tolerance. EXAMPLES Example A: Synthetic Protocols Example A1: Synthesis of Compound 1:

[0578] Preparation of Intermediate 2: tert-butyl 4-(trifluoromethoxy)piperidine-1-carboxylate

[0579] To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (10 g, 49.69 mmol, 1 eq), AgOTf (38.30 g, 149.06 mmol, 3 eq), KF (11.55 g, 198.75 mmol, 4 eq) and 2- fluoropyridine (14.47 g, 149.06 mmol, 12.81 mL, 3 eq) in EtOAc (100 mL) was added trifluoromethyltrimethylsilane (TMSCF3) (21.20 g, 149.06 mmol, 3 eq) and Select F (31.68 g, 89.44 mmol, 1.8 eq) under N2 atmosphere. The mixture was degassed and purged with N23 times, and then the mixture was stirred at 25 °C for 16 h under N2. The reactionDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834mixture was filtered, the filter cake was washed by EtOAc (30 ml*2). The filtrate was then concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~15% Ethyl acetate / Petroleum ethergradient at 80 mL / min) to provide tert-butyl 4- (trifluoromethoxy)piperidine-1-carboxylate (4g, 14.86 mmol, 29.90% yield) as a white solid.

[0580] Proton nuclear magnetic resonance (1H NMR) (400 MHz, CHLOROFORM-d) = 4.41 (tt, J = 3.7, 7.6 Hz, 1H), 3.76 - 3.64 (m, 2H), 3.36 - 3.21 (m, 2H), 1.93 - 1.85 (m, 2H), 1.79 - 1.70 (m, 2H), 1.47 (s, 9H)

[0581] Preparation of Intermediate 3: 4-(trifluoromethoxy)piperidine

[0582] Tert-butyl 4-(trifluoromethoxy)piperidine-1-carboxylate (4 g, 14.86 mmol, 1 eq) was taken up in HCl / EtOAc (2 M, 40 mL, 5.39 eq) and the mixture was stirred at 20 °C for 2 h then concentrated under reduced pressure to give 4-(trifluoromethoxy)piperidine (3 g, 14.59 mmol, 98.22% yield, HCl) as a white solid that was used in the next reaction without further purification.

[0583] 1H NMR (400 MHz, CHLOROFORM-d) = 9.78 (br s, 1H), 4.75 - 4.50 (m, 1H), 3.32 (br d, J = 2.5 Hz, 4H), 2.33 (td, J = 7.1, 14.2 Hz, 2H), 2.15 (br dd, J = 4.1, 14.8 Hz, 2H)

[0584] Preparation of Intermediate 5: 3-methyl-5-[4-(trifluoromethoxy)-1- piperidyl]benzaldehydeDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0585] A mixture of 3-bromo-5-methyl-benzaldehyde (1 g, 5.02 mmol, 1 eq) , 4- (trifluoromethoxy)piperidine (1.03 g, 5.02 mmol, 1 eq, HCl), SPhos Pd G3 (78.40 mg, 100.48 mol, 0.02 eq) and Cs2CO3(4.91 g, 15.07 mmol, 3 eq) in dioxane (10 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 90 °C for 12 h under N2. The reaction mixture was cooled to r.t. and diluted with water (20 mL) then extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 24g SepaFlash® Silica Flash Column, Eluent of 0~7% Ethyl acetate / Petroleum ethergradient at 45mL / min) to give 3-methyl-5-[4- (trifluoromethoxy)-1-piperidyl]benzaldehyde (290 mg, 1.01 mmol, 20.09% yield) as a yellow oil.

[0586] 1H NMR (400 MHz, CHLOROFORM-d) = 9.93 (s, 1H), 7.19 (br s, 2H), 7.12 - 6.94 (m, 1H), 4.53 - 4.40 (m, 1H), 3.55 (ddd, J = 4.1, 7.3, 11.9 Hz, 2H), 3.17 (br d, J = 8.1 Hz, 2H), 2.41 (s, 3H), 2.18 - 2.04 (m, 2H), 2.03 - 1.93 (m, 2H)

[0587] Preparation of Intermediate 6: 1H-triazole-4-carbohydrazide

[0588] To a solution of methyl 1H-triazole-4-carboxylate (1 g, 7.87 mmol, 1 eq) in EtOH (10 mL) was added NH2NH2. H2O (2.17 g, 43.35 mmol, 2.10 mL, 5.51 eq). The mixture was then stirred at 90 °C for 16 hr. The reaction mixture was filtered to give a crude product that was triturated with EtOH (5 mL) at 60°C for 15 min and then filtered, the filter cake was dried under vacuum to give 1H-triazole-4-carbohydrazide (0.9 g, 7.08 mmol, 90.00% yield) as a white solid.

[0589] Preparation of Compound 1: (E)-N'-(3-methyl-5-(4-(trifluoromethoxy)piperidin-1- yl)benzylidene)-1H-1,2,3-triazole-4-carbohydrazideDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Compound 1

[0590] To a solution of 3-methyl-5-[4-(trifluoromethoxy)-1-piperidyl]benzaldehyde (30 mg, 104.43 mol, 1 eq) in MeOH (1 mL) was added AcOH (627.11 g, 10.44 mol, 5.98e-1 L, 0.1 eq) and 1H-triazole-4-carbohydrazide (13.27 mg, 104.43 mol, 1 eq) and the mixture was stirred at 20 °C for 1 h. The mixture was then concentrated under reduced pressure to give a residue that was purified by prep-High-performance liquid chromatography (HPLC) (column: Waters xbridge 150*25mm 10um;mobile phase: [water( NH4HCO3)-ACN];gradient:30%-50% B over 8 min) followed by lyophilization to give (E)-N'-(3-methyl-5-(4- (trifluoromethoxy)piperidin-1-yl)benzylidene)-1H-1,2,3-triazole-4-carbohydrazide (8.09 mg, 20.21 mol, 19.35% yield, 99% purity) as a yellow solid.

[0591] LCMS (ESI) : m / z [M + H] calcd for C17H20F3N6O2: 397.15; found: 397.3

[0592] 1H NMR (400 MHz, DMSO-d6) = 11.95 (s, 1H), 8.51 (s, 1H), 8.41 (s, 1H), 7.05 (s, 1H), 6.96 (s, 1H), 6.88 (s, 1H), 4.64 (td, J = 4.4, 8.5 Hz, 1H), 3.56 - 3.48 (m, 2H), 3.11 - 3.02 (m, 2H), 2.30 (s, 3H), 2.05 (br d, J = 9.9 Hz, 2H), 1.86 - 1.73 (m, 2H) Example A2: Synthesis of Compound 2:

[0593] Preparation of Compound(E)-N'-(3-methoxy-4-methyl-5-(4- (trifluoromethoxy)piperidin-1-yl)benzylidene)-1H-1,2,3-triazole-4-carbohydrazideDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0594] To a solution of 3-methoxy-4-methyl-5-[4-(trifluoromethoxy)-1-piperidyl] benzaldehyde (50 mg, 157.58 mol, 1 eq) and 1H-triazole-4-carbohydrazide (40.06 mg, 315.16 mol, 2 eq) in MeOH (1 mL) was added AcOH (946.29 g, 15.76 mol, 9.02e-1 L, 0.1 eq). The mixture was stirred at 20 °C for 0.5 h then was concentrated under reduced pressure to give a crude product that was purified by prep-HPLC (column: Waters xbridge 150*25mm 10um; mobile phase: [water (NH4HCO3)-ACN]; gradient:33%-53% B over 8 min) followed by lyophilization. (E)-N'-(3-methoxy-4-methyl-5-(4- (trifluoromethoxy)piperidin-1-yl)benzylidene)-1H-1,2,3-triazole-4-carbohydrazide (25.96 mg, 60.88 mol, 38.64% yield, 100% purity) was obtained as white solid.

[0595] LCMS (ESI): m / z [M + H] calcd for C18H22F3N6O3: 427.16; found: 427.2

[0596] 1H NMR (400 MHz, DMSO-d6) = 11.96 (s, 1H), 8.50 (br s, 1H), 8.45 (s, 1H), 7.02 (s, 1H), 7.01 (s, 1H), 4.62 (td, J = 4.2, 8.3 Hz, 1H), 3.84 (s, 3H), 3.06 - 2.99 (m, 2H), 2.83 (br t, J = 9.3 Hz, 2H), 2.11 (s, 3H), 2.08 (br d, J = 4.5 Hz, 2H), 1.92 - 1.83 (m, 2H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834:3dnuopmoCfosisehtnyS:3AelpmaxEDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0597] Preparation of Intermediate 3: 7-(4,4-difluorocyclohexen-1-yl)indane-5-carboxylic acid

[0598] A mixture of 7-bromoindane-5-carboxylic acid (500 mg, 2.07 mmol, 1 eq) , 2-(4,4- difluorocyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (658.10 mg, 2.70 mmol, 1.3 eq) , Pd(dppf)Cl2(151.75 mg, 207.40 mol, 0.1 eq) , K2CO3(859.91 mg, 6.22 mmol, 3 eq) and H2O (2.00 g, 111.02 mmol, 2 mL, 53.53 eq) in dioxane (10 mL) was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was cooled and acidified with 1N HCl to pH=5 then diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL*3).The combined organic layers were washed with sat.NaCl (20 mL), dried over Na2SO4and filtered. The filtrate was concentrated in vacuo to give a residue that was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~35% Ethylacetate / Petroleum ethergradient at 35 mL / min) to provide 7-(4,4-difluorocyclohexen-1-yl)indane-5-carboxylic acid (320 mg, 1.15 mmol, 55.44% yield) as a yellow solid.

[0599] 1H NMR (400 MHz, CHLOROFORM-d) = 7.89 (s, 1H), 7.79 (s, 1H), 5.64 (br s, 1H), 3.03 - 2.92 (m, 4H), 2.73 (br t, J = 14.8 Hz, 2H), 2.68 - 2.61 (m, 2H), 2.27 - 2.16 (m, 2H), 2.15- 2.08 (m, 2H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0600] Preparation of Intermediate 4: 7-(4,4-difluorocyclohexyl)indane-5-carboxylic acid

[0601] To a solution of 7-(4,4-difluorocyclohexen-1-yl)indane-5-carboxylic acid (320 mg, 1.15 mmol, 1 eq) in THF (2 mL) was added Pd / C (100 mg, 10% purity) under N2atmosphere. The suspension was degassed and purged with H2 3 times then stirred under H2 (15 Psi) at 50 °C for 16 h. The reaction mixture was filtered and then the filtrate was concentrated under reduced pressure to give 7-(4,4-difluorocyclohexyl)indane-5-carboxylic acid (300 mg, 1.07 mmol, 93.08% yield) as a white solid that was used in the next step without purification.

[0602] 1H NMR (400 MHz, DMSO-d6) = 13.15 - 12.46 (m, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 2.98 (q, J = 7.6 Hz, 4H), 2.88 (br s, 1H), 2.23 - 1.99 (m, 6H), 1.91 (br d, J = 13.2 Hz, 2H), 1.77- 1.65 (m, 2H)

[0603] Preparation of Intermediate 5: [7-(4,4-difluorocyclohexyl)indan-5-yl]methanol

[0604] To a solution of 7-(4,4-difluorocyclohexyl)indane-5-carboxylic acid (300 mg, 1.07 mmol, 1 eq) in THF (5 mL) was added BH3.THF (1 M, 3.21 mL, 3 eq) at 0 °C under N2. The mixture was stirred at 25 °C for 2 h then quenched by the addition of MeOH (3 ml). The resulting mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL*4). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentratedDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834in vacuo to give [7-(4,4-difluorocyclohexyl)indan-5-yl]methanol (270 mg, crude) as a colorless oil that was used without additional purification.

[0605] 1H NMR (400 MHz, DMSO-d6) = 7.01 (s, 1H), 6.96 (s, 1H), 4.43 (d, J = 5.6 Hz, 2H), 2.84 (br t, J = 7.2 Hz, 4H), 2.79 - 2.68 (m, 1H), 2.18 - 2.07 (m, 2H), 2.05 - 1.92 (m, 4H), 1.84- 1.77 (m, 2H), 1.71 - 1.61 (m, 2H)

[0606] Preparation of Intermediate 6: 7-(4,4-difluorocyclohexyl)indane-5-carbaldehyde

[0607] To a solution of [7-(4,4-difluorocyclohexyl)indan-5-yl]methanol (250 mg, 938.70 mol, 1 eq) in dichloromethane (DCM) (3 mL) was added Dess-Martin periodinane (597.21 mg, 1.41 mmol, 436.24 L, 1.5 eq) at 0 °C .The mixture was stirred at 25 °C for 1 h then filtered and the filtrate was concentrated under reduced pressure to give a residue that was purified by prep-thin layer chromatography (TLC) (SiO2, Petroleum ether: Ethyl acetate = 5:1) to provide 7-(4,4-difluorocyclohexyl)indane-5-carbaldehyde (240 mg, 908.03 mol, 96.73% yield) as a white solid.

[0608] 1H NMR (400 MHz, CHLOROFORM-d) = 9.97 (s, 1H), 7.61 (d, J = 16.0 Hz, 2H), 3.00 (td, J = 7.6, 14.8 Hz, 4H), 2.83 - 2.66 (m, 1H), 2.32 - 2.22 (m, 2H), 2.17 (quin, J = 7.6 Hz, 2H), 2.00 - 1.79 (m, 6H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0609] Preparation of Compound 3: (E)-N'-((7-(4,4-difluorocyclohexyl)-2,3-dihydro-1H- inden-5-yl)methylene)-1H-1,2,3-triazole-4-carbohydrazide

[0610] To a mixture of 7-(4,4-difluorocyclohexyl)indane-5-carbaldehyde (20 mg, 75.67 mol, 1 eq) and 1H-triazole-4-carbohydrazide (9.62 mg, 75.67 mol, 1 eq) in MeOH (1 mL) was added AcOH (20.98 mg, 349.37 mol, 0.02 mL, 4.62 eq).The mixture was stirred at 25 °C for 1 h then concentrated under reduced pressure to give a residue that was purified by prep-HPLC (column:Waters xbridge 150*25mm 10um; mobile phase: [water(NH4HCO3)- ACN];gradient:35%-55% B over 8 min) followed by lyophilization. (E)-N'-((7-(4,4- difluorocyclohexyl)-2,3-dihydro-1H-inden-5-yl)methylene)-1H-1,2,3-triazole-4- carbohydrazide (17.58 mg, 46.14 mol, 60.98% yield, 98% purity) was isolated as a white solid.

[0611] LCMS (ESI) : m / z [M + H] calcd for C19H22N5OF2: 374.17; found: 374.20

[0612] 1H NMR (400 MHz, DMSO-d6) = 11.91 (s, 1H), 8.58 - 8.40 (m, 2H), 7.43 (s, 1H), 7.34 (s, 1H), 2.96 - 2.87 (m, 4H), 2.81 (br s, 1H), 2.19 - 1.94 (m, 6H), 1.86 (br d, J = 12.0 Hz, 2H), 1.76 - 1.63 (m, 2H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834:4dnuopmoCfosisehtnyS:4AelpmaxEDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0613] Preparation of Intermediate 3: methyl 4-methyl-3-[4-(trifluoromethoxy)-1- piperidyl]benzoate

[0614] A mixture of methyl 3-iodo-4-methyl-benzoate (1 g, 3.62 mmol, 1 eq) , 4- (trifluoromethoxy)piperidine;hydrochloride (819.23 mg, 3.98 mmol, 1.1 eq) , Pd(dba)2 (208.28 mg, 362.23 mol, 0.1 eq) , Cs2CO3 (2.36 g, 7.24 mmol, 2 eq) and XPhos (172.68 mg, 362.23 mol, 0.1 eq) in dioxane (10 mL) was degassed and purged with N23 times, then stirred at 110 °C for 16 h under N2. The reaction mixture was cooled and diluted with water (15 mL) then extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue that was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: [water(FA)-ACN];gradient:62%-92% B over 10 min) followed by lyophilization to give methyl 4-methyl-3-[4-(trifluoromethoxy)-1- piperidyl]benzoate (380 mg, 1.20 mmol, 33.06% yield) as a white solid.

[0615] Preparation of Intermediate 4: [4-methyl-3-[4-(trifluoromethoxy)-1- piperidyl]phenyl]methanolDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0616] To a solution of methyl 4-methyl-3-[4-(trifluoromethoxy)-1-piperidyl]benzoate (380 mg, 1.20 mmol, 1 eq) in tetrahydrofuran (THF) (0.5 mL) was added LiAlH4(54.54 mg, 1.44 mmol, 1.2 eq) at 0 °C .The mixture was stirred at 0 °C for 1 h under N2. The reaction mixture was quenched by addition of Na2SO4•10 H2O (0.4 g) and then filtered. The filtrate was concentrated in vacuo to give [4-methyl-3-[4-(trifluoromethoxy)-1-piperidyl]phenyl]methanol (330 mg, 1.14 mmol, 95.25% yield) as a yellow oil that was used without further purification.

[0617] Preparation of Intermediate 5: 4-methyl-3-[4-(trifluoromethoxy)-1- piperidyl]benzaldehyde

[0618] To a solution of [4-methyl-3-[4-(trifluoromethoxy)-1-piperidyl]phenyl]methanol (330 mg, 1.14 mmol, 1 eq) in DCM (3 mL) was added Dess–Martin periodinane (DMP) (725.74 mg, 1.71 mmol, 530.12 L, 1.5 eq) at 0 °C and the mixture stirred at 20 °C for 2 h. The mixture was then treated with sat. NaHCO3 to pH=7, then the resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~9% Ethyl acetate / Petroleum ethergradient at 40 mL / min) to give 4-methyl-3-[4- (trifluoromethoxy)-1-piperidyl]benzaldehyde (210 mg, 731.00 mol, 64.08% yield) as a yellow oil .

[0619] 1H NMR (400 MHz, CHLOROFORM-d) = 9.94 (s, 1H), 7.55 (s, 1H), 7.50 (dd, J = 1.3, 7.6 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 4.44 (tt, J = 3.9, 7.9 Hz, 1H), 3.20 - 3.11 (m, 2H), 2.85 (ddd, J = 3.1, 8.7, 11.9 Hz, 2H), 2.39 (s, 3H), 2.17 - 2.08 (m, 2H), 2.05 - 1.96 (m, 2H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0620] Preparation of Compound 4: (E)-N'-(4-methyl-3-(4-(trifluoromethoxy)piperidin-1- yl)benzylidene)-1H-1,2,3-triazole-4-carbohydrazide

[0621] To a solution of 1H-triazole-4-carbohydrazide (13.27 mg, 104.43 mol, 2 eq) in MeOH (0.5 mL) was added AcOH (313.56 g, 5.22 mol, 0.1 eq) and 4-methyl-3-[4- (trifluoromethoxy)-1-piperidyl]benzaldehyde (15 mg, 52.21 mol, 1 eq). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue that was purified by prep-HPLC (column: Waters xbridge 150*25mm 10um;mobile phase: [water( NH4HCO3)-ACN];gradient:36%-56% B over 8 min) followed by lyophilization to give (E)-N'-(4-methyl-3-(4-(trifluoromethoxy)piperidin-1-yl)benzylidene)-1H-1,2,3- triazole-4-carbohydrazide (19.54 mg, 49.30 mol, 94.41% yield, 100% purity) as a white solid.

[0622] Liquid chromatography-mass spectrometry (LCMS) (ESI): m / z [M + H] calcd for C17H20F3N6O2: 397.15; found: 397.2

[0623] 1H NMR (400 MHz, DMSO-d6) = 11.95 (s, 1H), 8.51 (s, 1H), 8.46 (s, 1H), 7.39 (s, 1H), 7.30 - 7.23 (m, 2H), 4.67 - 4.59 (m, 1H), 3.09 - 3.02 (m, 2H), 2.85 (br t, J = 9.2 Hz, 2H), 2.28 (s, 3H), 2.13 - 2.06 (m, 2H), 1.92 - 1.82 (m, 2H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Example A5: Synthesis of Compound 5:

[0624] Preparation of Intermediate 2: methyl 3-amino-4, 5-dimethyl-benzoate

[0625] To a mixture of methyl 3-amino-5-bromo-4-methyl-benzoate (500 mg, 2.05 mmol, 1 eq) and MeB(OH)2(367.86 mg, 6.15 mmol, 3 eq) in dioxane (5 mL) was added Pd(dppf)Cl2(149.89 mg, 204.85 mol, 0.1 eq) and CsF (933.49 mg, 6.15 mmol, 3 eq) under N2. The mixture was stirred at 80 °C for 16 h then cooled and filtered and the filtrate was concentrated in vacuum to provide a residue that was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 10 / 1, 3 / 1. TLC (Petroleum ether: Ethyl acetate = 3: 1; Rf = 0.47)) to give methyl 3-amino-4, 5-dimethyl-benzoate (350 mg, 1.95 mmol, 95.34% yield) as a colorless oil.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0626] Preparation of Intermediate 3: methyl 3-bromo-4, 5-dimethyl-benzoate

[0627] To a solution of methyl 3-amino-4, 5-dimethyl-benzoate (350 mg, 1.95 mmol, 1 eq) in Acetonitrile (ACN) (5 mL) was added t-BuONO (422.92 mg, 4.10 mmol, 487.79 L, 2.1 eq) and CuBr2(420.23 mg, 2.93 mmol, 89.22 L, 1.5 eq) under 0 °C and the mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with H2O (20 mL) and the whole was extracted with ethyl acetate (30 mL*3). The combined organic phases were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue that was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 5 / 1, 3 / 1. TLC (Petroleum ether: Ethyl acetate = 3: 1; Rf = 0.66)) to give methyl 3- bromo-4, 5-dimethyl-benzoate (200 mg, 822.72 mol, 42.13% yield) as colorless oil.

[0628] 1H NMR (400 MHz, DMSO-d6) = 7.90 (s, 1H), 7.73 (s, 1H), 3.84 (s, 3H), 2.36 (s, 6H)

[0629] Preparation of Intermediate 4: (3-bromo-4, 5-dimethyl-phenyl) methanol

[0630] To a solution of methyl 3-bromo-4, 5-dimethyl-benzoate (200 mg, 822.72 mol, 1 eq) in THF (2 mL) was added LiAlH4 (2.5 M, 493.63 L, 1.5 eq) under 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with Ethyl acetate (10 mL) and quenched by addition of Na2SO4•10H2O (2 g). The resulting mixture was filtered and theDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834filtrate was concentrated in vacuo to give (3-bromo-4, 5-dimethyl-phenyl) methanol (180 mg, crude) as a colorless oil that was used in the next step without further purification.

[0631] 1H NMR (400 MHz, DMSO-d6) = 7.35 (s, 1H), 7.09 (s, 1H), 5.21 (t, J = 5.8 Hz, 1H), 4.41 (d, J = 5.8 Hz, 2H), 2.28 (d, J = 2.9 Hz, 6H)

[0632] Preparation of Intermediate 5: 3-bromo-4, 5-dimethyl-benzaldehyde

[0633] To a solution of (3-bromo-4, 5-dimethyl-phenyl) methanol (180 mg, 836.87 mol, 1 eq) in DCM (3 mL) was added DMP (532.43 mg, 1.26 mmol, 388.92 L, 1.5 eq) under 0 °C. The mixture was stirred at 20 °C for 1 h then concentrated in vacuum to give a residue that was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 5 / 1, 3 / 1. TLC (Petroleum ether: Ethyl acetate = 3: 1; Rf = 0.65)) to give 3-bromo-4, 5- dimethyl-benzaldehyde (160 mg, 750.92 mol, 89.73% yield) as a colorless oil.

[0634] 1H NMR (400 MHz, DMSO-d6) = 9.89 (s, 1H), 7.95 (d, J = 1.3 Hz, 1H), 7.70 (s, 1H), 2.40 (s, 6H)

[0635] Preparation of Intermediate 7: 3, 4-dimethyl-5-[4-(3, 3, 3-trifluoropropyl) piperazin-1- yl] benzaldehyde

[0636] To a mixture of 3-bromo-4, 5-dimethyl-benzaldehyde (160 mg, 750.92 mol, 1 eq) and 1-(3, 3, 3-trifluoropropyl) piperazine (164.19 mg, 750.92 mol, 1 eq, HCl) in dioxane (3 mL) was added SPhos Pd G3(58.59 mg, 75.09 mol, 0.1 eq) and Cs2CO3(734.00 mg, 2.25 mmol, 3 eq) under N2and the mixture was then stirred at 80 °C for 16 h. The reaction mixture was then cooled and concentrated in vacuum to give a residue that was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 10 / 1, 1 / 1. TLC (Petroleum ether: Ethyl acetate = 1: 1; Rf = 0.33)) to provide 3, 4-dimethyl-5-[4-(3, 3, 3- trifluoropropyl) piperazin-1-yl] benzaldehyde (50 mg, crude) as colorless oil.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0637] Preparation of Compound 5: (E)-N'-(3,4-dimethyl-5-(4-(3,3,3- trifluoropropyl)piperazin-1-yl)benzylidene)-1H-1,2,3-triazole-5-carbohydrazide

[0638] To a mixture of 1H-triazole-5-carbohydrazide (10.11 mg, 79.53 mol, 1 eq) and 3, 4- dimethyl-5-[4-(3, 3, 3-trifluoropropyl) piperazin-1-yl]benzaldehyde (50 mg, 159.06 mol, 2 eq) in MeOH (1 mL) was added AcOH (9.55 mg, 159.06 mol, 9.11 L, 2 eq) and the mixture was stirred at 20 °C for 16 h then concentrated and purified by prep-HPLC (column: Welch Xtimate C18150*25 mm*5um; mobile phase: [water (FA) -ACN]; gradient: 8%-38% B over 10 min) to provide (E)-N'-(3,4-dimethyl-5-(4-(3,3,3-trifluoropropyl)piperazin-1- yl)benzylidene)-1H-1,2,3-triazole-5-carbohydrazide (1.66 mg, 3.92 mol, 4.93% yield) as a white solid.

[0639] LCMS (ESI): m / z [M + H] calcd for C19H25F3N7O: 424.20; found: 424.2

[0640] 1H NMR (400 MHz, DMSO-d6) = 11.88 (s, 1H), 8.50 - 8.45 (m, 1H), 8.42 (s, 1H), 7.21 (s, 2H), 2.85 (br s, 4H), 2.64 - 2.59 (m, 4H), 2.54 (br s, 4H), 2.26 (s, 3H), 2.19 (s, 3H) Example A6: Synthesis of Compound 6:Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0641] Preparation of Intermediate 2: 5 -methyl- 1H-triazole- 4 -carbohydrazide

[0642] To a mixture of methyl 5 -methyl- 1H-triazole- 4 -carboxylate (300 mg, 2.13 mmol, 1 eq) in EtOH (3 mL) was added NH2NH2. H2O (532.07 mg, 10.63 mmol, 515.57 L, 5 eq) at 0 °C under N2. Then the mixture was stirred at 90 °C for 16 h, cooled and filtered and the filter cake was triturated with MeCN (5 mL) at 20 °C for 15 min. Then the mixture was filtered and the filtered cake was dried under vacumm to give 5 -methyl- 1H-triazole- 4 -carbohydrazide (80 mg, crude) as a white solid.

[0643] 1H NMR: (400 MHz, DMSO-d6) = 9.48 (br s, 1H), 4.68 - 4.14 (m, 2H), 2.44 (s, 3H)

[0644] Preparation of Compound 6: (E)-N'-(3-methoxy-4-methyl-5-(4- (trifluoromethoxy)piperidin-1-yl)benzylidene)-5-methyl-1H-1,2,3-triazole-4-carbohydrazide

[0645] A mixture of 5 -methyl- 1H-triazole- 4 -carbohydrazide (6.67 mg, 47.27 mol, 1 eq), 3 -methoxy- 4 -methyl- 5 - [4 - (trifluoromethoxy) - 1 -piperidyl] benzaldehyde (15 mg, 47.27 mol, 1 eq), and AcOH (2.84 mg, 47.27 mol, 2.71 L, 1 eq) in MeOH (0.5 mL) was degassed and purged with N23 times, and then the mixture was stirred at 20 °C for 1 h under N2. The mixture was concentrated under reduced pressure to give a residue that was purified by prep- HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3) -ACN];Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834gradient: 35%- 55% B over 10 min) to give (E)-N'-(3-methoxy-4-methyl-5-(4- (trifluoromethoxy)piperidin-1-yl)benzylidene)-5-methyl-1H-1,2,3-triazole-4-carbohydrazide (14.6 mg, 31.82 mol, 67.32% yield, 96% purity) as a white solid.

[0646] LCMS (ESI): m / z [M + H] calcd for C19H24F3N6O3: 441.3; found: 441.3

[0647] 1H NMR: (400 MHz, DMSO-d6) = 11.89 (s, 1H), 8.44 (s, 1H), 7.00 (d, J = 9.3 Hz, 2H), 4.67 - 4.57 (m, 1H), 3.83 (s, 3H), 3.08 - 2.96 (m, 2H), 2.82 (br t, J = 9.1 Hz, 2H), 2.49 - 2.48 (m, 3H), 2.14 - 2.04 (m, 5H), 1.93 - 1.81 (m, 2H) Example A7: Synthesis of Compound 7:

[0648] Preparation of Intermediate 2: 1-hydroxy-1H-1,2,3-triazole-4-carbohydrazide

[0649] To a solution of ethyl 1-hydroxytriazole-4-carboxylate (500 mg, 3.18 mmol, 1 eq) in EtOH (5 mL) was added NH2NH2. H2O (796.49 mg, 15.91 mmol, 771.79 L, 5 eq) at 0 °C under N2 then the mixture stirred at 90 °C for 16 h then cooled and filtered. The filter cake was triturated with MeCN (5 mL) at 20 °C for 15 min then the mixture was filtered and the filter cake was dried over Na2SO4to give 1 -hydroxytriazole- 4 -carbohydrazide (300 mg, crude) as a white solid that was used in the next step without further purification.

[0650] 1H NMR: (400 MHz, DMSO-d6) = 9.39 - 8.70 (m, 1H), 7.48 (s, 1H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0651] Preparation of Compound 7: (E)-1-hydroxy-N'-(3-methoxy-4-methyl-5-(4- (trifluoromethoxy)piperidin-1-yl)benzylidene)-1H-1,2,3-triazole-4-carbohydrazide

[0652] A mixture of 1-hydroxytriazole-4-carbohydrazide (6.77 mg, 47.27 mol, 1 eq), 3- methoxy-4-methyl-5-[4-(trifluoromethoxy)-1-piperidyl] benzaldehyde (15 mg, 47.27 mol, 1 eq), AcOH (2.84 mg, 47.27 mol, 2.71 L, 1 eq) in MeOH (0.5 mL) was degassed and purged with N23 times, and then the mixture was stirred at 20 °C for 2 h under N2. The product was concentrated under reduced pressure to give a residue that was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 22%- 52% B over 10 min) to give (E)-1-hydroxy-N'-(3-methoxy-4-methyl-5-(4- (trifluoromethoxy)piperidin-1-yl)benzylidene)-1H-1,2,3-triazole-4-carbohydrazide (12.93 mg, 29.23 mol, 61.83% yield, 100% purity) as a white solid.

[0653] LCMS (ESI): m / z [M + H] calcd for C18H22F3N6O4: 443.3; found: 443.3

[0654] 1H NMR: (400 MHz, DMSO-d6) = 11.70 (s, 1H), 8.42 (s, 1H), 7.95 (br s, 1H), 7.19 - 7.11 (m, 1H), 6.99 (d, J = 8.4 Hz, 2H), 4.66 - 4.56 (m, 1H), 3.83 (s, 3H), 3.05 - 2.99 (m, 2H), 2.86 - 2.78 (m, 2H), 2.12 - 2.06 (m, 5H), 1.91 - 1.83 (m, 2H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Example A8: Synthesis of Compound 8:

[0655] Preparation of Intermediate 3: methyl 3-methoxy-4-methyl-5-[4-(trifluoromethyl)-1- piperidyl]benzoate

[0656] A mixture of 4-(trifluoromethyl)piperidine (839.76 mg, 5.48 mmol, 1.2 eq) , methyl 3- methoxy-4-methyl-5-(trifluoromethylsulfonyloxy)benzoate (1.5 g, 4.57 mmol, 1 eq) , SPhos Pd G3 (356.54 mg, 456.95 mol, 0.1 eq) and Cs2CO3 (2.98 g, 9.14 mmol, 2 eq) in dioxane (15 mL) was degassed and purged with N23 times. The mixture was stirred at 110 °C for 12 h under N2then cooled, diluted with water (15 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent ofDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-28340~7% Ethyl acetate / Petroleum ethergradient at 60 mL / min) to give methyl 3-methoxy-4- methyl-5-[4-(trifluoromethyl)-1-piperidyl]benzoate (700 mg, 2.11 mmol, 46.23% yield) as a white solid.

[0657] 1H NMR (400 MHz, CHLOROFORM-d) = 7.38 (s, 1H), 7.30 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.20 (br d, J = 12.0 Hz, 2H), 2.68 (br t, J = 11.8 Hz, 2H), 2.21 (s, 3H), 2.15 (dt, J = 4.2, 8.2 Hz, 1H), 1.97 (br d, J = 12.3 Hz, 2H), 1.86 - 1.75 (m, 2H)

[0658] Preparation of Intermediate 4: [3-methoxy-4-methyl-5-[4-(trifluoromethyl)-1- piperidyl]phenyl]methanolmethyl 3-methoxy-4-methyl-5-[4-(trifluoromethyl)-1- piperidyl]benzoate (700 mg, 2.11 mmol, 1 eq) in THF (7 mL) was added LiAlH4(96.21 mg, 2.54 mmol, 1.2 eq) at 0 °C . The mixture was stirred at 0 °C for 1 h under N2 then quenched by the addition of Na2SO4•10 H2O (1 g) and filtered. The filtrate was concentrated in vacuo to give [3-methoxy-4-methyl-5-[4-(trifluoromethyl)-1-piperidyl]phenyl]methanol (610 mg, 2.01 mmol, 95.19% yield) as a white solid that was used in the next step without further purification.

[0660] Preparation of Intermediate 5: 3-methoxy-4-methyl-5-[4-(trifluoromethyl)-1- piperidyl]benzaldehydeDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0661] To a solution of [3-methoxy-4-methyl-5-[4-(trifluoromethyl)-1- piperidyl]phenyl]methanol (610 mg, 2.01 mmol, 1 eq) in DCM (6 mL) was added DMP (1.28 g, 3.02 mmol, 934.60 L, 1.5 eq) at 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was adjusted to pH=7 with sat. NaHCO3, then diluted with water (10 mL) and extracted with EtOAC(10 mL*3).The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~6% Ethyl acetate / Petroleum ethergradient at 40 mL / min) to give 3- methoxy-4-methyl-5-[4-(trifluoromethyl)-1-piperidyl]benzaldehyde (500 mg, 1.66 mmol, 82.52% yield) as a white solid.

[0662] Preparation of Compound 8: (E)-N'-(3-methoxy-4-methyl-5-(4- (trifluoromethyl)piperidin-1-yl)benzylidene)-1H-1,2,3-triazole-4-carbohydrazide

[0663] To a solution of 3-methoxy-4-methyl-5-[4-(trifluoromethyl)-1-piperidyl]benzaldehyde (20 mg, 66.38 mol, 1 eq) in MeOH (0.5 mL) was added AcOH (398.61 g, 6.64 mol, 0.38 L, 0.1 eq) and 1H-triazole-4-carbohydrazide (16.87 mg, 132.76 mol, 2 eq) and the mixture stirred at 20 °C for 1h . The reaction mixture was then concentrated under reduced pressure to give a residue that was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH4HCO3)-ACN];gradient:22%-52% B over 5 min) followed by lyophilization to give (E)-N'-(3-methoxy-4-methyl-5-(4-(trifluoromethyl)piperidin-1- yl)benzylidene)-1H-1,2,3-triazole-4-carbohydrazide (14.51 mg, 35.36 mol, 53.26% yield, 100% purity) as a white solid.

[0664] LCMS (ESI): m / z [M + H] calcd for C18H22F3N6O2: 411.17; found:411.2Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0665] 1H NMR (400 MHz, DMSO-d6) = 11.95 (br s, 1H), 8.63 - 8.29 (m, 2H), 7.02 (br d, J = 2.9 Hz, 2H), 3.84 (s, 3H), 3.13 (br d, J = 11.9 Hz, 2H), 2.70 (br t, J = 11.2 Hz, 2H), 2.45 (br s, 1H), 2.11 (s, 3H), 1.92 (br d, J = 11.9 Hz, 2H), 1.64 (dq, J = 3.5, 12.1 Hz, 2H) Example A9: Synthesis of Compound 9:

[0666] Preparation of Compound 9: (E)-N'-(3-methoxy-4-methyl-5-(3- (trifluoromethoxy)azetidin-1-yl)benzylidene)-1H-1,2,3-triazole-4-carbohydrazide

[0667] To a mixture of 3 -methoxy- 4 -methyl- 5 - [3 - (trifluoromethoxy) azetidin- 1 -yl] benzaldehyde (15 mg, 51.86 mol, 1 eq) and 1H-triazole- 4 -carbohydrazide (6.59 mg, 51.86 mol, 1 eq) in MeOH (1 mL) was added AcOH (3.11 mg, 51.86 mol, 2.97 L, 1 eq) and the resultant mixture stirred at 20 °C for 1h. The reaction mixture was then concentrated in vacuo to give a residue that was purified by prep-HPLC (column : Waters xbridge 150*25 mm 10um;mobile phase : [water (NH4HCO3) -ACN] ;gradient : 30%- 50% B over 8 min) followed by lyophilization. Compound (E)-N'-(3-methoxy-4-methyl-5-(3-(trifluoromethoxy)azetidin-1-Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834yl)benzylidene)-1H-1,2,3-triazole-4-carbohydrazide (8.16 mg, 19.67 mol, 37.92% yield, 96% purity) was obtained as yellow solid.

[0668] LCMS (ESI) : m / z [M + H] calcd for C16H18F3N6O3: 399.13; found: 399.1

[0669] 1H NMR (400 MHz, DMSO-d6) = 11.91 (s, 1H), 8.53 - 8.39 (m, 2H), 6.87 (s, 1H), 6.51 (s, 1H), 5.27 - 5.19 (m, 1H), 4.31 (br t, J = 7.4 Hz, 2H), 3.93 (br dd, J = 4.2, 8.4 Hz, 2H), 3.82 (s, 3H), 2.01 (s, 3H) Example A10: Synthesis of Compound 10:

[0670] Preparation of Intermediate 3: methyl 3-methoxy-4-methyl-5-[3-(trifluoromethyl) azetidin-1-yl]benzoate

[0671] To a solution of 3-(trifluoromethyl) azetidine; hydrochloride (73.82 mg, 456.95 mol, 1 eq) and methyl 3-methoxy-4-methyl-5-(trifluoromethylsulfonyloxy) benzoate (150 mg, 456.95 mol, 1 eq) in dioxane (2 mL) was added SPhos Pd G3 (35.65 mg, 45.70 mol, 0.1 eq) and Cs2CO3 (446.65 mg, 1.37 mmol, 3 eq) under N2. The mixture was stirred at 80 °C for 16 hDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834then cooled and concentrated to give residue that was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 10 / 1, 5 / 1. TLC (Petroleum ether: Ethyl acetate = 3: 1; Rf = 0.74)) to give methyl 3-methoxy-4-methyl-5-[3-(trifluoromethyl) azetidin-1-yl]benzoate (120 mg, 395.68 mol, 86.59% yield) as colorless oil.

[0672] Preparation of Intermediate 4: [3-methoxy-4-methyl-5-[3-(trifluoromethyl) azetidin-1- yl]phenyl]methanol

[0673] To a solution of methyl 3-methoxy-4-methyl-5-[3-(trifluoromethyl) azetidin-1- yl]benzoate (120 mg, 395.68 mol, 1 eq) in THF (2 mL) at 0 °C was added LiAlH4 (2.5 M, 237.41 L, 1.5 eq). The mixture was stirred at 20 °C for 2 h then diluted with THF (10 mL) and quenched by addition of Na2SO4•10H2O (2 g). The resulting mixture was dried over Na2SO4 and filtered, then the filtrate was concentrated in vacuo to give [3-methoxy-4-methyl- 5-[3-(trifluoromethyl) azetidin-1-yl]phenyl]methanol (110 mg, crude) as a colorless oil.

[0674] Preparation of Intermediate 5: 3-methoxy-4-methyl-5-[3-(trifluoromethyl) azetidin-1- yl]benzaldehyde

[0675] To a solution of [3-methoxy-4-methyl-5-[3-(trifluoromethyl) azetidin-1- yl]phenyl]methanol (110 mg, 399.61 mol, 1 eq) in DCM (2 mL) was added DMP (254.24 mg, 599.42 mol, 1.5 eq) under 0 °C and the mixture stirred at 20 °C for 1 h. The reaction mixtureDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834was concentrated in vacuo to give a residue that was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 5 / 1, 3 / 1. TLC (Petroleum ether: Ethyl acetate = 3: 1; Rf = 0.65)) to give 3-methoxy-4-methyl-5-[3-(trifluoromethyl) azetidin-1- yl]benzaldehyde (90 mg, 329.37 mol, 82.42% yield) as a colorless oil.

[0676] Preparation of Compound 10: (E)-N'-(3-methoxy-4-methyl-5-(3- (trifluoromethyl)azetidin-1-yl)benzylidene)-1H-1,2,3-triazole-4-carbohydrazide

[0677] To a mixture of 3-methoxy-4-methyl-5-[3-(trifluoromethyl) azetidin-1- yl]benzaldehyde (30 mg, 109.79 mol, 1 eq) and 1H-triazole-5-carbohydrazide (13.95 mg, 109.79 mol, 1 eq) in MeOH (1 mL) was added AcOH (13.19 mg, 219.58 mol, 12.57 L, 2 eq). The mixture was stirred at 20 °C for 16 h then concentrated and purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 12%-42% B over 5 min) to give (E)-N'-(3-methoxy-4-methyl-5-(3- (trifluoromethyl)azetidin-1-yl)benzylidene)-1H-1,2,3-triazole-4-carbohydrazide (30.86 mg, 80.71 mol, 73.52% yield) as an off-white gum.

[0678] LCMS (ESI): m / z [M + H] calcd for C16H18F3N6O2: 383.14; found: 383.2

[0679] 1H NMR (400 MHz, DMSO-d6) = 11.93 (s, 1H), 8.49 (s, 1H), 8.42 (s, 1H), 6.86 (s, 1H), 6.51 (s, 1H), 4.16 (t, J = 8.3 Hz, 2H), 3.92 (dd, J = 5.9, 7.8 Hz, 2H), 3.82 (s, 3H), 3.68 - 3.60 (m, 1H), 2.02 (s, 3H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Example A11: Synthesis of Compound 11:

[0680] Preparation of Intermediate 2: 1-methyltriazole-4-carbohydrazide

[0681] To a mixture of methyl 1 -methyltriazole- 4 -carboxylate (300 mg, 2.13 mmol, 1 eq) in EtOH (3 mL) was added hydrazine; hydrate (325.76 mg, 6.38 mmol, 315.66 L, 3 eq) under N2 The mixture was degassed and purged with N23 times, and then stirred at 80 °C for 16 h under N2. The mixture was cooled and filtered and the filter cake was triturated with MeOH at 60 °C for 30 min three times. The resulting mixture was filtered and the filter cake was dried under vacumm to afford 1 -methyltriazole- 4 -carbohydrazide (104 mg, 736.90 mol, 34.67% yield) as a white solid that was used in the next step without further purification.

[0682] 1H NMR: (400 MHz, DMSO-d6) = 9.66 (br s, 1H), 8.46 (s, 1H), 4.44 (d, J = 3.9 Hz, 2H), 4.08 (s, 3H).Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0683] Preparation of Compound 11: (E)-N'-(3-methoxy-4-methyl-5-(4- (trifluoromethoxy)piperidin-1-yl)benzylidene)-1-methyl-1H-1,2,3-triazole-4-carbohydrazide

[0684] A mixture of 1 -methyltriazole- 4 -carbohydrazide (10 mg, 70.86 mol, 1 eq), 3 - methoxy- 4 -methyl- 5 - [4 - (trifluoromethoxy) - 1 -piperidyl] benzaldehyde (22.48 mg, 70.86 mol, 1 eq) and AcOH (425.50 g, 7.09 mol, 0.1 eq) in MeOH (1 mL) was stirred at 25 °C for 1 h. The reaction mixture was then concentrated under reduced pressure to give a residue that was purified by prep-HPLC (column: Waters xbridge 150*25 mm 10um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 54%- 74% B over 8 min), followed by lyophilization to afford (E)-N'-(3-methoxy-4-methyl-5-(4-(trifluoromethoxy)piperidin-1-yl)benzylidene)-1- methyl-1H-1,2,3-triazole-4-carbohydrazide (10.44 mg, 23.70 mol, 33.45% yield, 100% purity) as a white solid.

[0685] LCMS (ESI): m / z [M + H] calcd for C19H24F3N6O3: 441.18; found: 441.30

[0686] 1H NMR: (400 MHz, DMSO-d6) = 12.03 (br s, 1H), 8.68 (s, 1H), 8.46 (s, 1H), 7.01 (d, J = 7.3 Hz, 2H), 4.65 - 4.59 (m, 1H), 4.13 (s, 3H), 3.84 (s, 3H), 3.05 - 2.99 (m, 2H), 2.86 - 2.79 (m, 2H), 2.12 - 2.06 (m, 5H), 1.92 - 1.83 (m, 2H). Example A12: Synthesis of Compound 12:Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0687] Preparation of Intermediate 2: 2-methyltriazole-4-carbohydrazide

[0688] To a solution of methyl 2-methyltriazole-4-carboxylate (0.5 g, 3.54 mmol, 1 eq) in EtOH (5 mL) was added NH2NH2. H2O (0.78 g, 15.58 mmol, 755.81 L, 4.40 eq) .The mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered and the filter cake was triturated with MeOH (5 mL) at 60°C for 15 min then filtered and the filter cake was dried under vacuum to give 2-methyltriazole-4-carbohydrazide (200 mg, 1.42 mmol, 40.00% yield) as a white solid that was used in the next step without further purification.

[0689] Preparation of Compound 12: (E)-N'-(3-methoxy-4-methyl-5-(4- (trifluoromethoxy)piperidin-1-yl)benzylidene)-2-methyl-2H-1,2,3-triazole-4-carbohydrazide

[0690] To a solution of 3-methoxy-4-methyl-5-[4-(trifluoromethoxy)-1- piperidyl]benzaldehyde (11.24 mg, 35.43 mol, 1 eq) in MeOH (0.5 mL) was added AcOH (0.21 mg, 3.54 mol, 0.20 L, 0.1 eq) and 2-methyltriazole-4-carbohydrazide (10 mg, 70.86 mol, 2 eq) and the mixture was stirred at 20 °C for 1h. The reaction mixture was then filtered to give (E)-N'-(3-methoxy-4-methyl-5-(4-(trifluoromethoxy)piperidin-1-yl)benzylidene)-2- methyl-2H-1,2,3-triazole-4-carbohydrazide (5.37 mg, 12.19 mol, 34.42% yield, 100% purity) as a white solid.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0691] LCMS (ESI): m / z [M + H] calcd for C19H24F3N6O3: 441.18; found: 441.2

[0692] 1H NMR (400 MHz, DMSO-d6) = 11.96 (br s, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 7.02 (d, J = 7.0 Hz, 2H), 4.65 - 4.59 (m, 1H), 4.27 (s, 3H), 3.84 (s, 3H), 3.06 - 2.99 (m, 2H), 2.86 - 2.79 (m, 2H), 2.12 (s, 3H), 2.07 (br s, 2H), 1.92 - 1.83 (m, 2H) Example A13: Synthesis of Compound 13:

[0693] Preparation of Intermediate 2: 3-methyltriazole-4-carbohydrazide

[0694] To a solution of methyl 3-methyltriazole-4-carboxylate (500 mg, 3.54 mmol, 1 eq) in EtOH (5 mL) was added hydrazine hydrate (886.79 mg, 17.71 mmol, 859.29 L, 5 eq). The mixture was stirred at 90 °C for 16 h then cooled and filtered. The filter cake was dried undervacuum to give a residue that was triturated with EtOH (5 mL) at 90 for 30 min then cooledand re-filtered. The filter cake was dried under vacuum to afford 3-methyltriazole-4- carbohydrazide (170 mg, 1.20 mmol, 34.00% yield) as a white solid that was used in the next step without further purification.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0695] Preparation of Compound 13: (E)-N'-(3-methoxy-4-methyl-5-(4- (trifluoromethoxy)piperidin-1-yl)benzylidene)-1-methyl-1H-1,2,3-triazole-5-carbohydrazide

[0696] To a solution of 3-methyltriazole-4-carbohydrazide (8.90 mg, 63.03 mol, 1 eq) in MeOH (1 mL) was added AcOH (3.79 mg, 63.03 mol, 3.61 L, 1 eq) and 3-methoxy-4- methyl-5-[4- (trifluoromethoxy)-1-piperidyl] benzaldehyde (20 mg, 63.03 mol, 1 eq). The mixture was stirred at 20 °C for 1 h then concentrated under vacuum to give a residue that was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 40%-70% B over 5 min) followed by lyophilization to afford (E)-N'-(3-methoxy-4-methyl-5-(4-(trifluoromethoxy)piperidin-1-yl)benzylidene)-1-methyl- 1H-1,2,3-triazole-5-carbohydrazide (15.61 mg, 33.67 mol, 53.42% yield, 95% purity) as a white solid.

[0697] LCMS (ESI): m / z [M + H] calcd for C19H24O3N6F3: 465.16; found: 465.20

[0698] 1H NMR (400 MHz, DMSO-d6) = 12.31 - 11.80 (m, 1H), 8.36 - 8.31 (m, 1H), 8.30 - 8.25 (m, 1H), 7.07 (d, J = 3.6 Hz, 1H), 4.68 - 4.57 (m, 1H), 4.25 (s, 3H), 3.89 - 3.79 (m, 3H), 3.09 - 2.96 (m, 2H), 2.82 (br t, J = 8.9 Hz, 2H), 2.14 - 2.05 (m, 5H), 1.94 - 1.81 (m, 2H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834:41dnuopmoCfosisehtnyS:41AelpmaxEDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0699] Preparation of Intermediate(2,2,2-trifluoro-1-methyl-ethyl) trifluoromethanesulfonate

[0700] To a solution of 1,1,1-trifluoropropan-2-ol (3 g, 26.30 mmol, 2.38 mL, 1 eq) and pyridine (4.16 g, 52.60 mmol, 4.25 mL, 2 eq) in DCM (30 mL) was added trifluoromethylsulfonyl trifluoromethanesulfonate (7.42 g, 26.30 mmol, 4.34 mL, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h and the reaction mixture used directly in the next step [i.e. crude (2,2,2-trifluoro-1-methyl-ethyl) trifluoromethanesulfonate (~2.5 g) in DCM (20 mL) as a yellow liquid].

[0701] Preparation of Intermediate 4: benzyl 4-(2,2,2-trifluoro-1-methyl-ethyl)piperazine-1- carboxylate

[0702] To a solution of benzyl piperazine-1-carboxylate (2 g, 9.08 mmol, 1.75 mL, 1 eq) and TEA (2.76 g, 27.24 mmol, 3.79 mL, 3 eq) in DMF (20 mL) was added (2,2,2- trifluoro-1-methyl-ethyl) trifluoromethanesulfonate (2.23 g, 9.08 mmol, 1 eq) and the mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with H2O (40 mL) and then extracted with ethyl acetate (40 mL*3). The combined organic layers were washed with sat. NaCl (50mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue that was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column,Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Eluent of 0~40% Ethyl acetate / Petroleum ethergradient at 35 mL / min) to give benzyl 4-(2,2,2- trifluoro-1-methyl-ethyl)piperazine-1-carboxylate (350 mg, 1.11 mmol, 12.19% yield) as a colorless oil.

[0703] 1H NMR (400 MHz, CHLOROFORM-d) = 7.42 - 7.31 (m, 5H), 5.14 (s, 2H), 3.50 (br t, J = 5.2 Hz, 4H), 3.18 (td, J = 7.6, 15.3 Hz, 1H), 2.82 - 2.56 (m, 4H), 1.24 (d, J = 7.2 Hz, 3H)

[0704] Preparation of Intermediate 5: 1-(2,2,2-trifluoro-1-methyl-ethyl)piperazine

[0705] To a solution of benzyl 4-(2,2,2-trifluoro-1-methyl-ethyl)piperazine-1-carboxylate (350 mg, 1.11 mmol, 1 eq) in MeOH (3 mL) was added Pd(OH)2 (100 mg, 20% purity) under N2. The suspension was degassed and purged with H23 times then stirred under H2(15 Psi) at 25 °C for 2 h. The product mixture was filtered and the filtrate was concentrated under reduced pressure to give 1-(2,2,2-trifluoro-1-methyl-ethyl)piperazine (110 mg, 603.78 mol, 54.57% yield) as a colorless oil that was used in the next step without purification.

[0706] 1H NMR (400 MHz, CHLOROFORM-d) = 3.19 - 3.04 (m, 1H), 2.90 (t, J = 4.8 Hz, 3H), 2.79 - 2.72 (m, 2H), 2.71 - 2.63 (m, 3H), 1.24 (d, J = 7.2 Hz, 3H)

[0707] Preparation of Intermediate 7: methyl 3-methoxy-4-methyl-5-[4-(2,2,2-trifluoro-1- methyl-ethyl)piperazin-1-yl]benzoateDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0708] A mixture of 1-(2,2,2-trifluoro-1-methyl-ethyl)piperazine (110 mg, 603.78 mol, 1 eq) , methyl 3-methoxy-4-methyl-5-(trifluoromethylsulfonyloxy)benzoate (208.63 mg, 603.78 mol, 1 eq) , Cs2CO3(590.17 mg, 1.81 mmol, 3 eq) and SPhos Pd G3 (47.11 mg, 60.38 mol, 0.1 eq) in dioxane (3 mL) was stirred at 90 °C for 16 h under N2. The reaction mixture was cooled and filtered and the filtrate was concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethylacetate / Petroleum ethergradient at 35 mL / min) to give methyl 3-methoxy-4-methyl-5-[4-(2,2,2-trifluoro-1-methyl-ethyl)piperazin-1- yl]benzoate (80 mg, 221.99 mol, 36.77% yield) as a yellow oil.

[0709] Preparation of Intermediate 8: [3-methoxy-4-methyl-5-[4-(2,2,2-trifluoro-1-methyl- ethyl)piperazin-1-yl]phenyl]methanol

[0710] To a solution of methyl 3-methoxy-4-methyl-5-[4-(2,2,2-trifluoro-1-methyl- ethyl)piperazin-1-yl]benzoate (80 mg, 221.99 mol, 1 eq) in THF (2 mL) was added LiAlH4 (2.5 M, 133.20 L, 1.5 eq) at 0 °C under N2 atmosphere. The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by Na2SO410H2O (500 mg) and then filtered. The filtrate was concentrated under reduced pressure to give a [3-methoxy-4-methyl-5-[4-(2,2,2- trifluoro-1-methyl-ethyl)piperazin-1-yl]phenyl]methanol (70 mg, crude) as a brown solid that was used in the next step without further purification.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0711] Preparation of Intermediate 9: 3-methoxy-4-methyl-5-[4-(2,2,2-trifluoro-1-methyl- ethyl)piperazin-1-yl]benzaldehyde

[0712] To a solution of [3-methoxy-4-methyl-5-[4-(2,2,2-trifluoro-1-methyl-ethyl)piperazin- 1-yl]phenyl]methanol (70 mg, 210.61 mol, 1 eq) in DCM (2 mL) was added DMP (134.00 mg, 315.92 mol, 1.5 eq) at 0 °C and the mixture stirred at 25 °C for 1 h. The product mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethylacetate / Petroleum ethergradient at 30 mL / min) to give 3-methoxy-4- methyl-5-[4-(2,2,2-trifluoro-1-methyl-ethyl)piperazin-1-yl]benzaldehyde (50 mg, 151.36 mol, 71.86% yield) as a yellow oil.

[0713] 1H NMR (400 MHz, CHLOROFORM-d) = 9.91 (s, 1H), 7.21 (s, 1H), 7.14 (s, 1H), 3.90 (s, 3H), 3.31 - 3.20 (m, 1H), 3.01 - 2.92 (m, 6H), 2.91 - 2.84 (m, 2H), 2.24 (s, 3H), 1.31 (br d, J = 6.8 Hz, 3H)

[0714] Preparation of Compound 14: (E)-N'-(3-methoxy-4-methyl-5-(4-(1,1,1- trifluoropropan-2-yl)piperazin-1-yl)benzylidene)-1H-1,2,3-triazole-5-carbohydrazideDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0715] To a mixture of 3-methoxy-4-methyl-5-[4-(2,2,2-trifluoro-1-methyl-ethyl)piperazin-1- yl]benzaldehyde (25 mg, 75.68 mol, 1 eq) and 1H-triazole-5-carbohydrazide (9.62 mg, 75.68 mol, 1 eq) in MeOH (2 mL) was added AcOH (20.98 mg, 349.37 mol, 0.02 mL, 4.62 eq) and the mixture stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give a residue that was purified by prep-HPLC(column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH4HCO3)-ACN];gradient:25%-55% B over 5 min) followed by lyophilization. (E)-N'-(3-methoxy-4-methyl-5-(4-(1,1,1-trifluoropropan-2- yl)piperazin-1-yl)benzylidene)-1H-1,2,3-triazole-5-carbohydrazide (22.13 mg, 50.36 mol, 66.54% yield, 100% purity) was obtained as a white solid.

[0716] LCMS (ESI) : m / z [M + H] calcd for C19H25N7O2F3: 440.19; found: 440.2

[0717] 1H NMR (400 MHz, DMSO-d6) = 11.94 (s, 1H), 8.47 (br d, J = 15.6 Hz, 2H), 7.04 (s, 1H), 6.97 (s, 1H), 3.84 (s, 3H), 3.54 (br s, 1H), 2.91 - 2.76 (m, 8H), 2.11 (s, 3H), 1.22 (d, J = 7.2 Hz, 3H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-283461dnuopmoC&51dnuopmoCfosisehtnyS:51AelpmaxEDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0718] Preparation of Intermediate 3: tert-butyl (2R)-2-methyl-4-(3,3,3- trifluoropropyl)piperazine-1-carboxylate

[0719] To a mixture of 1,1,1-trifluoro-3-iodo-propane (1.12 g, 4.99 mmol, 585.17 L, 1 eq) and tert-butyl (2R)-2-methylpiperazine-1-carboxylate (1.00 g, 4.99 mmol, 1 eq) in MeCN (10 mL) was added K2CO3(1.73 g, 12.48 mmol, 2.5 eq) and the mixture stirred at 80 °C for 16 h then cooled and filtered. The filtrate was concentrated and purified by prep- HPLC(column: Waters xbridge 150*25mm 10um;mobile phase: [water( NH4HCO3)- ACN];gradient:48%-78% B over 10 min) followed by lyophilization to give tert-butyl (2R)-2- methyl-4-(3,3,3-trifluoropropyl)piperazine-1-carboxylate (700 mg, 2.36 mmol, 47.31% yield) as a yellow oil.

[0720] 1H NMR (400 MHz, CHLOROFORM-d) = 4.23 (br d, J = 3.6 Hz, 1H), 4.01 - 3.77 (m, 1H), 3.20 - 2.99 (m, 1H), 2.75 (br d, J = 10.4 Hz, 1H), 2.69 - 2.45 (m, 3H), 2.40 - 2.16 (m, 3H), 2.07 - 1.97 (m, 1H), 1.59 - 1.44 (m, 9H), 1.30 - 1.21 (m, 3H)

[0721] Preparation of Intermediate 4: (3R)-3-methyl-1-(3,3,3-trifluoropropyl)piperazine

[0722] Tert-butyl (2R)-2-methyl-4-(3,3,3-trifluoropropyl)piperazine-1-carboxylate (700 mg, 2.36 mmol, 1 eq) was treated with HCl / dioxane (2 M, 15 mL, 12.70 eq) and the mixture stirred at 25 °C for 16 h then concentrated under reduced pressure to give (3R)-3-methyl-1-(3,3,3-Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834trifluoropropyl)piperazine (600 mg, crude, HCl) as a white solid that was used in the next step without further purification.

[0723] Preparation of Intermediate 5: methyl 3,4-dimethyl-5-[(2R)-2-methyl-4-(3,3,3- trifluoropropyl)piperazin-1-yl]benzoate

[0724] To a mixture of (3R)-3-methyl-1-(3,3,3-trifluoropropyl)piperazine (95.71 mg, 411.36 mol, HCl salt) and methyl 3-bromo-4,5-dimethyl-benzoate (100 mg, 411.36 mol, 1 eq) in 2- methylbutan-2-ol (2 mL) was added 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H- imidazol-1-ium-2-ide;3-chloropyridine;dichloropalladium (40.02 mg, 41.14 mol, 0.1 eq) and Cs2CO3 (536.11 mg, 1.65 mmol, 4 eq). The mixture was stirred at 90 °C for 16 h under N2 then cooled and filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethylacetate / Petroleum ethergradient at 35 mL / min) to provide methyl 3,4-dimethyl-5-[(2R)-2-methyl-4-(3,3,3-trifluoropropyl)piperazin-1- yl]benzoate (60 mg, 167.41 mol, 40.70% yield) as a white solid.

[0725] 1H NMR (400 MHz, CHLOROFORM-d) = 7.72 (s, 1H), 7.65 (s, 1H), 3.91 (s, 3H), 3.32 - 3.18 (m, 1H), 2.95 - 2.74 (m, 4H), 2.73 - 2.63 (m, 2H), 2.50 - 2.35 (m, 3H), 2.33 (s, 3H), 2.30 (s, 3H), 2.16 - 2.08 (m, 1H), 0.82 (d, J = 6.0 Hz, 3H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0726] Preparation of Intermediate 6: [3,4-dimethyl-5-[(2R)-2-methyl-4-(3,3,3- trifluoropropyl)piperazin-1-yl]phenyl]methanol

[0727] To a solution of methyl 3,4-dimethyl-5-[(2R)-2-methyl-4-(3,3,3- trifluoropropyl)piperazin-1-yl]benzoate (60 mg, 167.41 mol, 1 eq) in THF (2 mL) was added LiAlH4 (2.5 M, 100.45 L, 1.5 eq) at 0 °C under N2. The mixture was then stirred at 25 °C for 1 h, quenched by addition of Na2SO410H2O (500 mg) and then filtered. The filtrate was concentrated under reduced pressure to give [3,4-dimethyl-5-[(2R)-2-methyl-4-(3,3,3- trifluoropropyl)piperazin-1-yl]phenyl]methanol (50 mg, 151.34 mol, 90.40% yield) as a yellow solid that was used in the next step without further purification.

[0728] Preparation of Intermediate 7: 3,4-dimethyl-5-[(2R)-2-methyl-4-(3,3,3- trifluoropropyl)piperazin-1-yl]benzaldehyde

[0729] To a solution of [3,4-dimethyl-5-[(2R)-2-methyl-4-(3,3,3-trifluoropropyl)piperazin-1- yl]phenyl]methanol (50 mg, 151.34 mol, 1 eq) in DCM (2 mL) was added DMP (96.28 mg, 227.01 mol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h then filtered and the filtrate was concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent ofDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-28340~30% Ethylacetate / Petroleum ethergradient at 30 mL / min) to give 3,4-dimethyl-5-[(2R)-2- methyl-4-(3,3,3-trifluoropropyl)piperazin-1-yl]benzaldehyde (45 mg, 137.04 mol, 90.55% yield) as a white solid.

[0730] 1H NMR (400 MHz, CHLOROFORM-d) = 9.91 (s, 1H), 7.53 (s, 1H), 7.46 (s, 1H), 3.39 - 3.17 (m, 1H), 2.98 - 2.61 (m, 6H), 2.51 - 2.36 (m, 3H), 2.34 (d, J = 14.8 Hz, 6H), 2.21 - 2.12 (m, 1H), 0.82 (d, J = 6.0 Hz, 3H)

[0731] Preparation of Compound 15: (R,E)-N'-(3,4-dimethyl-5-(2-methyl-4-(3,3,3- trifluoropropyl)piperazin-1-yl)benzylidene)-1H-1,2,3-triazole-5-carbohydrazide

[0732] To a mixture of 1H-triazole-5-carbohydrazide (9.68 mg, 76.13 mol, 1 eq) and 3,4- dimethyl-5-[(2R)-2-methyl-4-(3,3,3-trifluoropropyl)piperazin-1-yl]benzaldehyde (25 mg, 76.13 mol, 1 eq) in MeOH (2 mL) was added AcOH (20.98 mg, 349.37 mol, 0.02 mL, 4.59 eq). The mixture was stirred at 25 °C for 1 h then concentrated under reduced pressure to give a residue that was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water(NH4HCO3)-ACN];gradient:24%-54% B over 10 min) followed by lyophilization. (R,E)-N'-(3,4-dimethyl-5-(2-methyl-4-(3,3,3-trifluoropropyl)piperazin-1- yl)benzylidene)-1H-1,2,3-triazole-5-carbohydrazide (15.72 mg, 35.22 mol, 46.26% yield, 98% purity) was obtained as a white solid.

[0733] LCMS (ESI) : m / z [M + H] calcd for C20H27N7OF3: 438.22; found: 438.20

[0734] 1H NMR (400 MHz, DMSO-d6) = 11.91 (s, 1H), 8.51 (s, 1H), 8.42 (s, 1H), 7.32 (s, 1H), 7.28 (s, 1H), 3.17 (br d, J = 5.6 Hz, 1H), 2.92 - 2.83 (m, 2H), 2.78 - 2.71 (m, 1H), 2.69 - 2.55 (m, 5H), 2.38 - 2.32 (m, 1H), 2.28 (s, 3H), 2.22 (s, 3H), 2.09 - 1.95 (m, 1H), 0.77 (br d, J = 6.0 Hz, 3H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0735] Preparation of Compound 16: (S,E)-N'-(3,4-dimethyl-5-(2-methyl-4-(3,3,3- trifluoropropyl)piperazin-1-yl)benzylidene)-1H-1,2,3-triazole-5-carbohydrazide

[0736] Compound 16 was synthesized via a procedure similar to Compound 15.

[0737] LCMS (ESI) : m / z [M + H] calcd for C20H27N7OF3: 438.22; found: 438.20

[0738] 1H NMR (400 MHz, DMSO-d6) = 11.92 (s, 1H), 8.51 (br s, 1H), 8.43 (s, 1H), 7.34 - 7.31 (m, 1H), 7.29 (s, 1H), 3.17 (br d, J = 5.6 Hz, 1H), 2.90 - 2.82 (m, 2H), 2.79 - 2.73 (m, 1H), 2.69 - 2.55 (m, 5H), 2.38 - 2.32 (m, 1H), 2.28 (s, 3H), 2.23 (s, 3H), 2.11 - 2.00 (m, 1H), 0.77 (br d, J = 6.0 Hz, 3H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-283471dnuopmoCfosisehtnyS:61AelpmaxEDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0739] Preparation of Intermediate 3: Methyl 3-(2,2-dimethylmorpholin-4-yl)-5-methoxy-4- methyl-benzoate

[0740] To a mixture of methyl 3-methoxy-4-methyl-5- (trifluoromethylsulfonyloxy) benzoate (84 mg, 255.89 mol, 1 eq) and 2, 2-dimethylmorpholine (29.47 mg, 255.89 mol, 1 eq) in dioxane (2 mL) was added SPhos Pd G3 (19.97 mg, 25.59 mol, 0.1 eq) and Cs2CO3(250.13 mg, 767.68 mol, 3 eq). The mixture was stirred at 80 °C for 16 h under N2atmosphere then cooled and poured into H2O (3 mL). The resulting mixture was extracted with ethyl acetate (3 mL*3) and the combined organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under vacuum to give a residue that was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 3 / 1) to afford methyl 3-(2,2-dimethylmorpholin-4-yl)-5-methoxy-4-methyl-benzoate (60 mg, 204.53 mol, 79.93% yield) as a brown solid.

[0741] Preparation of Intermediate 4: [3-(2,2-dimethylmorpholin-4-yl)-5-methoxy-4-methyl- phenyl]methanolDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0742] To a solution of methyl 3-(2,2-dimethylmorpholin-4-yl)-5-methoxy-4-methyl-benzoate (60 mg, 204.53 mol, 1 eq) in THF (1 mL) was added LiAlH4(2.5 M, 81.81 L, 1 eq) at 0 °C. The mixture was stirred at 20 °C for 1 h, quenched by addition of Na2SO4.10H2O (500 mg), and the resulting mixture was filtered. The filtrate was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (5 mL*3) and the combined organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum to give [3- (2,2-dimethylmorpholin-4-yl)-5-methoxy-4-methyl-phenyl]methanol (50 mg, 188.43 mol, 92.13% yield) as brown oil that was used in the next step without further purification.

[0743] Preparation of Intermediate 5: 3-(2,2-dimethylmorpholin-4-yl)-5-methoxy-4-methyl- benzaldehyde

[0744] To a solution of [3-(2, 2-dimethylmorpholin-4-yl)-5-methoxy-4-methyl- phenyl]methanol (50 mg, 188.43 mol, 1 eq) in DCM (1 mL) was added DMP (119.88 mg, 282.65 mol, 87.57 L, 1.5 eq) at 0 °C and the mixture stirred at 20 °C for 1 h. The product mixture was basified to pH 8 with sat. NaHCO3 aqueous, then the resulting mixture was extracted with ethyl acetate (3 mL*3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under vacuum to give a residue that was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 5: 1) to afford 3-(2,2-dimethylmorpholin-4-yl)-5-methoxy-4-methyl-benzaldehyde (30 mg, 113.92 mol, 60.46% yield) as a brown solid.

[0745] 1H NMR (400 MHz, CHLOROFORM-d) = 9.92 (s, 1H), 7.18 (d, J = 18.0 Hz, 2H), 3.95 - 3.89 (m, 5H), 2.97 - 2.86 (m, 2H), 2.75 (s, 2H), 2.28 (s, 3H), 1.55 (s, 6H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0746] Preparation of Compound 17: (E)-N'-(3-(2,2-dimethylmorpholino)-5-methoxy-4- methylbenzylidene)-1H-1,2,3-triazole-5-carbohydrazide

[0747] To a mixture of 1H-triazole-4-carbohydrazide (7.24 mg, 56.96 mol, 1 eq) and 3-(2,2- dimethylmorpholin-4-yl)-5-methoxy-4-methyl-benzaldehyde (15 mg, 56.96 mol, 1 eq) in MeOH (1 mL) was added AcOH (3.42 mg, 56.96 mol, 3.26 L, 1 eq). The mixture was stirred at 20 °C for 1 h then concentrated under vacuum to give a residue that was purified by prep- HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 13%-43% B over 10 min) followed by lyophilization to afford (E)-N'-(3-(2,2- dimethylmorpholino)-5-methoxy-4-methylbenzylidene)-1H-1,2,3-triazole-5-carbohydrazide (3.73 mg, 10.02 mol, 17.58% yield, 100% purity) as a white solid.

[0748] LCMS (ESI): m / z [M + H] calcd for C18H25N6O3: 273.19; found: 273.20

[0749] 1H NMR (400 MHz, DMSO-d6) = 12.01 - 11.86 (s, 1H), 8.51 - 8.43 (m, 2H), 7.06 - 7.01 (m, 1H), 6.97 (s, 1H), 3.84 (s, 3H), 3.81 - 3.74 (m, 2H), 2.86 - 2.69 (m, 2H), 2.69 - 2.64 (m, 2H), 2.18 - 2.13 (m, 3H), 1.28 (s, 6H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Example A17: Synthesis of Compound 18:

[0750] Preparation of Intermediate 3: methyl 3-methoxy-4-methyl-5-(2-methylmorpholin-4- yl) benzoate

[0751] To a mixture of 2-methylmorpholine (46.22 mg, 456.95 mol, 1 eq) and methyl 3- methoxy-4-methyl-5-(trifluoromethylsulfonyloxy) benzoate (150 mg, 456.95 mol, 1 eq) in dioxane (2 mL) was added SPhos Pd G3 (35.65 mg, 45.70 mol, 0.1 eq) and Cs2CO3 (446.65 mg, 1.37 mmol, 3 eq) under N2and the mixture stirred at 80 °C for 16 h then concentrated in vacuum to give a residue that was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 10 / 1, 5 / 1. TLC (Petroleum ether: Ethyl acetate = 3: 1; Rf = 0.74)) to provide methyl 3-methoxy-4-methyl-5-(2-methylmorpholin-4-yl) benzoate (100 mg, 358.00 mol, 78.34% yield) as a colorless oil.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0752] Preparation of Intermediate 4: [3-methoxy-4-methyl-5-(2-methylmorpholin-4-yl) phenyl]methanol

[0753] To a solution of methyl 3-methoxy-4-methyl-5-(2-methylmorpholin-4-yl) benzoate (100 mg, 358.00 mol, 1 eq) in THF (2 mL) at 0 °C under N2was added LiAlH4(2.5 M, 214.80 L, 1.5 eq) and the mixture was stirred at 20 °C for 2 h. The product was diluted with THF (10 mL) and quenched by addition of Na2SO4•10H2O (2 g). The resulting mixture was dried over Na2SO4 and filtered, then the filtrate concentrated in vacuo to give [3-methoxy-4-methyl-5-(2- methylmorpholin-4-yl) phenyl]methanol (90 mg, crude) as a colorless oil that was used without further purification.

[0754] Preparation of Intermediate 5: 3-methoxy-4-methyl-5-(2-methylmorpholin-4-yl) benzaldehyde

[0755] To a solution of [3-methoxy-4-methyl-5-(2-methylmorpholin-4-yl) phenyl]methanol (90 mg, 358.11 mol, 1 eq) in DCM (2 mL) was added DMP (227.83 mg, 537.16 mol, 166.42 L, 1.5 eq) under 0 °C and the mixture stirred at 20 °C for 1 h. The product mixture was then concentrated in vacuum to give residue that was purified by silica gel chromatography (100- 200 mesh silica gel, Petroleum ether / Ethyl acetate = 5 / 1, 3 / 1. TLC (Petroleum ether: EthylDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834acetate = 3: 1; Rf = 0.65)) to give 3-methoxy-4-methyl-5-(2-methylmorpholin-4-yl) benzaldehyde (75 mg, 300.84 mol, 84.01% yield) as a colorless oil.

[0756] Preparation of Compound 18: (E)-N'-(3-methoxy-4-methyl-5-(2- methylmorpholino)benzylidene)-1H-1,2,3-triazole-5-carbohydrazide

[0757] To a mixture of 1H-triazole-5-carbohydrazide (10.20 mg, 80.22 mol, 1 eq) and 3- methoxy-4-methyl-5-(2-methylmorpholin-4-yl) benzaldehyde (20 mg, 80.22 mol, 1 eq) in MeOH (0.5 mL) was added AcOH (9.63 mg, 160.45 mol, 9.18 L, 2 eq) and the mixture stirred at 20 °C for 1 h. The reaction mixture was concentrated and purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 12%-42% B over 10 min) to give (E)-N'-(3-methoxy-4-methyl-5-(2- methylmorpholino)benzylidene)-1H-1,2,3-triazole-5-carbohydrazide (18.68 mg, 52.12 mol, 64.97% yield) as a white solid.

[0758] LCMS (ESI) : m / z [M + H] calcd for C17H23N6O3: 359.18; found: 359.2

[0759] 1H NMR (400 MHz, DMSO-d6) = 11.94 (s, 1H), 8.50 (s, 1H), 8.46 (s, 1H), 7.03 (s, 1H), 6.98 (s, 1H), 3.88 (br s, 1H), 3.84 (s, 3H), 3.75 - 3.65 (m, 2H), 3.00 - 2.86 (m, 2H), 2.72 - 2.66 (m, 1H), 2.44 (s, 1H), 2.13 (s, 3H), 1.13 (d, J = 6.4 Hz, 3H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Example A18: Synthesis of Compound 19:

[0760] Preparation of Intermediate 3: methyl 3-methoxy-4-methyl-5-[2- (trifluoromethyl)morpholin-4-yl]benzoate

[0761] To a mixture of methyl 3-methoxy-4-methyl-5-(trifluoromethylsulfonyloxy) benzoate (300 mg, 913.91 mol, 1 eq) and 2-(trifluoromethyl) morpholine hydrochloride (175.09 mg, 913.91 mol, 1 eq) in dioxane (5 mL) was added SPhos Pd G3 (71.31 mg, 91.39 mol, 0.1 eq) and Cs2CO3 (893.30 mg, 2.74 mmol, 3 eq). The reaction solution was degassed and purged with N2 three times, then stirred at 100 °C for 16 h under N2. The product mixture was cooled and diluted with water (10 mL) and the resulting mixture extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0~11% Ethylacetate / Petroleum ethergradient at 40 mL / min) to give methyl 3-methoxy-4-methyl-5-[2 -(trifluoromethyl) morpholin-4-yl] benzoate (230 mg, 690.06 mol, 75.51% yield) as a white solid.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0762] 1H NMR (400 MHz, CHLOROFORM-d) = 7.40 (s, 1H), 7.35 (s, 1H), 4.17 - 4.09 (m, 2H), 3.93 (s, 3H), 3.91 (br s, 1H), 3.90 (s, 3H), 3.15 (br d, J = 11.0 Hz, 1H), 2.98 - 2.93 (m, 2H), 2.93 - 2.89 (m, 1H), 2.23 (s, 3H)

[0763] Preparation of Intermediate 4: [3-methoxy-4-methyl-5-[2-(trifluoromethyl)morpholin- 4-yl]phenyl]methanol

[0764] To a solution of methyl 3-methoxy-4-methyl-5-[2-(trifluoromethyl)morpholin-4-yl] benzoate (230 mg, 690.06 mol, 1 eq) in THF (2 mL) at 0 °C under N2 was added LiAlH4 (2.5 M, 331.23 L, 1.2 eq). The mixture was stirred at 20 °C for 1 h then quenched by addition of Na2SO4.10H2O (50 mg) and the resulting mixture filtered. The filtrate was poured into water (5 mL) and the aqueous phase extracted with ethyl acetate (5 mL*3). The combined organic portions were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give [3 -methoxy- 4 -methyl- 5 - [2 - (trifluoromethyl) morpholin- 4 -yl] phenyl] methanol (200 mg, 655.11 mol, 94.93% yield) as yellow oil that was used without further purification.

[0765] Preparation of Intermediate 5: 3-methoxy-4-methyl-5-[2-(trifluoromethyl)morpholin- 4-yl]benzaldehyde

[0766] To a solution of [3 -methoxy- 4 -methyl- 5 - [2 - (trifluoromethyl) morpholin- 4 -yl] phenyl] methanol (200 mg, 655.11 mol, 1 eq) in DCM (3 mL) at 0 °C was added DMP (416.79Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834mg, 982.67 mol, 304.45 L, 1.5 eq). The mixture was stirred at 20 °C for 1 h then diluted with sat. NaHCO3(aq.) (5 mL) and the resulting mixture was extracted with ethyl acetate (5 mL*3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0~15% Ethylacetate / Petroleum ethergradient at 30 mL / min) to provide 3 -methoxy- 4 -methyl- 5 - [2 - (trifluoromethyl) morpholin- 4 -yl] benzaldehyde (165 mg, 544.06 mol, 83.05% yield) as a red oil.

[0767] 1H NMR (400 MHz, CHLOROFORM-d) = 9.93 (s, 1H), 7.22 (s, 1H), 7.19 (s, 1H), 4.21 - 4.11 (m, 2H), 3.97 - 3.88 (m, 4H), 3.18 (dd, J = 1.9, 11.6 Hz, 1H), 2.98 (d, J = 2.6 Hz, 1H), 2.97 - 2.91 (m, 2H), 2.26 (s, 3H)

[0768] Preparation of Compound 19: (E)-N'-(3-methoxy-4-methyl-5-(2- (trifluoromethyl)morpholino)benzylidene)-1H-1,2,3-triazole-5-carbohydrazide

[0769] To a mixture of 3-methoxy-4-methyl-5-[2-(trifluoromethyl)morpholin-4-yl] benzaldehyde (20 mg, 65.95 mol, 1 eq) and 1H-triazole- 5 -carbohydrazide (8.38 mg, 65.95 mol, 1 eq) in MeOH (1 mL) was added AcOH (3.96 mg, 65.95 mol, 3.78 L, 1 eq) and the reaction mixture was stirred at 20 °C for 1h. The reaction mixture was concentrated in vacuo to give a residue that was purified by prep-HPLC (column : Waters xbridge 150*25 mm 10um;mobile phase : [water (NH4HCO3) -ACN] ;gradient : 32%- 52% B over 8 min) followed by lyophilization. (E)-N'-(3-methoxy-4-methyl-5-(2- (trifluoromethyl)morpholino)benzylidene)-1H-1,2,3-triazole-5-carbohydrazide (10 mg, 23.28 mol, 35.30% yield, 96% purity) was obtained as a white solid.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0770] LCMS (ESI) : m / z [M + H] calcd for C17H20F3N6O3: 413.15; found: 413.1

[0771] 1H NMR (400 MHz, DMSO-d6) = 11.97 (br s, 1H), 8.50 (s, 1H), 8.47 (s, 1H), 7.10 (s, 1H), 7.04 (s, 1H), 4.45 - 4.34 (m, 1H), 4.05 (br d, J = 11.4 Hz, 1H), 3.85 (s, 4H), 3.14 (br d, J = 10.8 Hz, 1H), 2.97 (br d, J = 12.6 Hz, 1H), 2.89 - 2.81 (m, 2H), 2.15 (s, 3H) Example A19: Synthesis of Compound 20:

[0772] Preparation of Intermediate 3: methyl 3, 4-dimethyl-5-(2-methylmorpholin-4-yl) benzoate

[0773] To a mixture of 2-methylmorpholine (41.61 mg, 411.36 mol, 1 eq) and methyl 3- bromo-4, 5-dimethyl-benzoate (100 mg, 411.36 mol, 1 eq) in dioxane (2 mL) under N2was added SPhos Pd G3(32.10 mg, 41.14 mol, 0.1 eq) and Cs2CO3(402.09 mg, 1.23 mmol, 3 eq). The mixture was stirred at 90 °C for 16 h then cooled and concentrated in vacuum to give a residue that was purified by silica gel chromatography (100-200 mesh silica gel, PetroleumDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834ether / Ethyl acetate = 10 / 1, 5 / 1. TLC (Petroleum ether: Ethyl acetate = 3: 1; Rf = 0.74)) to provide methyl 3, 4-dimethyl-5-(2-methylmorpholin-4-yl) benzoate (75 mg, 284.81 mol, 69.24% yield) as a colorless oil.

[0774] Preparation of Intermediate 4: [3, 4-dimethyl-5-(2-methylmorpholin-4-yl) phenyl]methanol

[0775] To a solution of methyl 3, 4-dimethyl-5-(2-methylmorpholin-4-yl) benzoate (75 mg, 284.81 mol, 1 eq) in THF (2 mL) at 0 °C was added LiAlH4(2.5 M, 170.89 L, 1.5 eq). The mixture was stirred at 20 °C for 1 h then diluted with THF (10 mL) and quenched by addition of Na2SO4•10H2O (2 g). The resulting mixture was dried over Na2SO4 and filtered, then the filtrate concentrated in vacuo to give [3, 4-dimethyl-5-(2-methylmorpholin-4-yl) phenyl]methanol (70 mg, crude) as a colorless oil that was used without further purification.

[0776] Preparation of Intermediate 5: 3, 4-dimethyl-5-(2-methylmorpholin-4-yl) benzaldehyde

[0777] To a solution of [3, 4-dimethyl-5-(2-methylmorpholin-4-yl) phenyl]methanol (70 mg, 297.47 mol, 1 eq) in DCM (2 mL) was added DMP (189.25 mg, 446.20 mol, 138.24 L, 1.5 eq) under 0 °C and the mixture stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuo to give a residue that was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 5 / 1, 3 / 1. TLC (Petroleum ether: Ethyl acetate = 3: 1; Rf =Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-28340.65)) to provide 3, 4-dimethyl-5-(2-methylmorpholin-4-yl) benzaldehyde (60 mg, 257.17 mol, 86.45% yield) as a colorless oil.

[0778] Preparation of Compound 20: (E)-N'-(3,4-dimethyl-5-(2- methylmorpholino)benzylidene)-1H-1,2,3-triazole-5-carbohydrazide

[0779] To a mixture of 3, 4-dimethyl-5-(2-methylmorpholin-4-yl) benzaldehyde (20 mg, 85.72 mol, 1 eq) and 1H-triazole-5-carbohydrazide (10.90 mg, 85.72 mol, 1 eq) in MeOH (0.5 mL) was added AcOH (10.30 mg, 171.45 mol, 9.81 L, 2 eq) and the mixture stirred at 20 °C for 1 h. The product mixture was concentrated to give a residue that was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 12%-42% B over 10 min) to provide (E)-N'-(3,4-dimethyl-5-(2- methylmorpholino)benzylidene)-1H-1,2,3-triazole-5-carbohydrazide (13.51 mg, 39.46 mol, 46.03% yield) as a white solid.

[0780] LCMS (ESI) : m / z [M + H] calcd for C17H23N6O2: 343.18; found: 343.2

[0781] 1H NMR (400 MHz, DMSO-d6) = 11.91 (s, 1H), 8.49 (br s, 1H), 8.42 (s, 1H), 7.22 (s, 2H), 3.91 - 3.84 (m, 1H), 3.77 - 3.66 (m, 2H), 2.99 - 2.83 (m, 2H), 2.71 - 2.65 (m, 1H), 2.42 (br d, J = 11.2 Hz, 1H), 2.27 (s, 3H), 2.21 (s, 3H), 1.14 (d, J = 6.4 Hz, 3H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Example A20: Synthesis of Compound 21:

[0782] Preparation of Intermediate 3: methyl 3, 4-dimethyl-5-(3-methylmorpholin-4-yl) benzoate

[0783] To a solution of 3-methylmorpholine (124.82 mg, 1.23 mmol, 1 eq) and methyl 3- bromo-4,5-dimethyl-benzoate (300 mg, 1.23 mmol, 1 eq) in 2-methylbutan-2-ol (6 mL) under N2was added 1, 3-bis[2,6-bis(1-propylbutyl) phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; dichloropalladium (120.05 mg, 123.41 mol, 0.1 eq) and cesium carbonate (1.61 g, 4.94 mmol, 4 eq). The mixture was stirred at 90 °C for 16 h then cooled and concentrated in vacuum to give a residue that was purified by silica gel chromatography (100- 200 mesh silica gel, Petroleum ether / Ethyl acetate = 10 / 1, 5 / 1. TLC (Petroleum ether: Ethyl acetate = 3: 1; Rf = 0.74)) to provide methyl 3,4-dimethyl-5-(3-methylmorpholin-4-yl) benzoate (100 mg, 379.75 mol, 30.77% yield) as colorless oil.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0784] Preparation of Intermediate 4: [3, 4-dimethyl-5-(3-methylmorpholin-4-yl) phenyl]methanol

[0785] To a solution of methyl 3, 4-dimethyl-5-(3-methylmorpholin-4-yl) benzoate (100 mg, 379.75 mol, 1 eq) in THF (2 mL) at 0 °C was added LiAlH4(2.5 M, 227.85 L, 1.5 eq). The mixture was stirred at 20 °C for 1 h then diluted with THF (10 mL) and quenched by addition of Na2SO4•10H2O (2 g). The resulting mixture was dried over Na2SO4 and filtered, then the filtrate was concentrated in vacuo to give [3,4-dimethyl-5-(3-methylmorpholin-4-yl) phenyl]methanol (85 mg, crude) as a colorless oil that was used without further purification.

[0786] Preparation of Intermediate 5: 3, 4-dimethyl-5-(3-methylmorpholin-4-yl) benzaldehyde

[0787] To a solution of [3, 4-dimethyl-5-(3-methylmorpholin-4-yl) phenyl]methanol (85 mg, 361.21 mol, 1 eq) in DCM (2 mL) at 0 °C was added DMP (229.80 mg, 541.81 mol, 167.86 L, 1.5 eq). The mixture was stirred at 20 °C for 1 h then concentrated in vacuo to give a residue that was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 5 / 1, 3 / 1. TLC (Petroleum ether: Ethyl acetate = 3: 1; Rf = 0.65)) to provide 3, 4-dimethyl-5-(3-methylmorpholin-4-yl) benzaldehyde (40 mg, 171.45 mol, 47.47% yield) as a colorless oil.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0788] Preparation of Compound 21: (E)-N'-(3,4-dimethyl-5-(3- methylmorpholino)benzylidene)-1H-1,2,3-triazole-5-carbohydrazide

[0789] To a mixture of 3, 4-dimethyl-5-(3-methylmorpholin-4-yl) benzaldehyde (20.00 mg, 85.72 mol, 1 eq) and 1H-triazole-5-carbohydrazide (10.90 mg, 85.72 mol, 1 eq) in MeOH (0.5 mL) was added AcOH (10.30 mg, 171.45 mol, 9.82 L, 2 eq). The mixture was stirred at 20 °C for 16 h then concentrated and purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 12%-42% B over 10 min) to provide (E)-N'-(3,4-dimethyl-5-(3-methylmorpholino)benzylidene)-1H-1,2,3-triazole- 5-carbohydrazide (5.6 mg, 16.36 mol, 19.08% yield) as a white solid.

[0790] LCMS (ESI): m / z [M + H] calcd for C17H23N6O2: 343.18; found: 343.2

[0791] 1H NMR (400 MHz, DMSO-d6) = 11.90 (s, 1H), 8.49 (br s, 1H), 8.43 (s, 1H), 7.33 (s, 1H), 7.29 (s, 1H), 3.84 (dd, J = 2.6, 10.3 Hz, 1H), 3.81 - 3.74 (m, 1H), 3.73 - 3.64 (m, 1H), 3.27 (br d, J = 2.2 Hz, 1H), 3.19 - 3.13 (m, 1H), 2.83 (br dd, J = 2.3, 4.8 Hz, 1H), 2.64 (br d, J = 10.5 Hz, 1H), 2.28 (s, 3H), 2.24 (s, 3H), 0.71 (d, J = 6.1 Hz, 3H)Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Example A21: Synthesis of Compound 22:

[0792] Preparation of Intermediate 3: 3-ethoxy-4-methyl-5-(3-methylmorpholin-4-yl)benzoic

[0793] To a mixture of methyl 3-ethoxy-4-methyl-5-(trifluoromethylsulfonyloxy)benzoate (300 mg, 876.46 mol, 1 eq) and 3-methylmorpholine (106.38 mg, 1.05 mmol, 1.2 eq) in 2- methylbutan-2-ol (4 mL) were added 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H- imidazol-1-ium-2-ide;3-chloropyridine;dichloropalladium (85.26 mg, 87.65 mol, 0.1 eq) and Cs2CO3 (571.13 mg, 1.75 mmol, 2 eq) and the reaction mixture stirred at 90 °C for 16 h. The reaction mixture was filtered, and the filtrate concentrated in vacuo to give a residue that was purified by prep-HPLC (FA condition). column: Welch Xtimate C18150* 25 mm* 5 um; mobile phase: [water (FA)-ACN]; gradient: 38%-68% B over 10 min to give 3-Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834ethoxy-4-methyl-5-(3-methylmorpholin-4-yl)benzoic acid (35 mg, 125.30 mol, 14.30% yield, 100% purity) as a white solid.

[0794] Preparation of Intermediate 4: [3-ethoxy-4-methyl-5-(3-methylmorpholin-4- yl)phenyl]methanol

[0795] To a solution of 3-ethoxy-4-methyl-5-(3-methylmorpholin-4-yl)benzoic acid (35 mg, 125.30 mol, 1 eq) in THF (1 mL) at 0 °C under N2was added BH3•THF (1 M, 0.5 mL, 3.99 eq). The reaction mixture was stirred at 25 °C for 16 h under N2 then quenched by dropwise addition of H2O (2.0 mL). The whole mixture was extracted with EtOAc (20.0 mL) and the organic phase was washed with brine (20.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue that was purified by prep- TLC (SiO2, Petroleum ether / Ethyl acetate = 2 / 1) to provide [3-ethoxy-4-methyl-5-(3- methylmorpholin-4-yl)phenyl]methanol (30 mg, 113.06 mol, 90.23% yield, 100% purity) as a colorless oil.

[0796] LCMS (ESI): m / z [M + H] calcd for C15H23NO3: 265.17; found: 266.2

[0797] Preparation of Intermediate 5: 3-ethoxy-4-methyl-5-(3-methylmorpholin-4- yl)benzaldehydeDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0798] A mixture of [3-ethoxy-4-methyl-5-(3-methylmorpholin-4-yl)phenyl]methanol (30 mg, 113.06 mol, 1 eq) and MnO2(49.15 mg, 565.30 mol, 5 eq) in dioxane (2 mL) was stirred at 25 °C for 16 h. The reaction mixture was filtered and the filtrate concentrated in vacuo to give 3-ethoxy-4-methyl-5-(3-methylmorpholin-4-yl)benzaldehyde (20 mg, 75.95 mol, 67.18% yield) as a yellow oil that was used without further purification.

[0799] Preparation of Compound 22: (E)-N'-(3-ethoxy-4-methyl-5-(3- methylmorpholino)benzylidene)-1H-1,2,3-triazole-5-carbohydrazide

[0800] To a mixture of 3-ethoxy-4-methyl-5-(3-methylmorpholin-4-yl)benzaldehyde 10 mg,37.98 mol, 1 eq) and 1H-triazole-5-carbohydrazide (5 mg, 39.34 mol, 1 eq) in MeOH (1 mL) was added AcOH (2.36 mg, 39.34 mol, 2.25 L, 1 eq) at 20 °C. The mixture was stirred at 20 °C for 16 h then concentrated in vacuo to give a residue that was purified by prep-HPLC (column: Welch Xtimate C18150* 25 mm* 5 um; mobile phase: [water (FA)-ACN]; gradient: 32%-62% B over 10 min). (E)-N'-(3-ethoxy-4-methyl-5-(3-methylmorpholino)benzylidene)- 1H-1,2,3-triazole-5-carbohydrazide (2.47 mg, 6.63 mol, 16.86% yield, 100% purity) was obtained as a white solid.

[0801] LCMS (ESI): m / z [M + H] calcd for C18H25N6O3: 373.19; found: 373.2(s, 1H), 8.47-8.42 (m, 2H), 7.07 (d, J = 6.8 Hz, 2H), 4.07 (q, J = 6.8 Hz, 2H), 3.85-3.75 (m, 2H), 3.65-3.55 (m, 1H), 3.25-3.10 (m, 2H), 3.85-3.55 (m, 2H), 2.16 (s, 3H), 1.38 (t, J = 6.8 Hz, 3H), 1.38 (d, J = 6.0 Hz, 3H).Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Example A22: Synthesis of Compound 23:

[0803] Preparation of Intermediatemethyl 3-ethoxy-4-methyl-5-[2- (trifluoromethyl)morpholin-4-yl]benzoate

[0804] To a mixture of methyl 3-ethoxy-4-methyl-5-(trifluoromethylsulfonyloxy) benzoate (150 mg, 438.23 mol, 1 eq) and 2-(trifluoromethyl) morpholine hydrochloride (83.96 mg, 438.23 mol, 1 eq) in dioxane (3 mL) was added SPhos Pd G3 (34.19 mg, 43.82 mol, 0.1 eq) and Cs2CO3(428.35 mg, 1.31 mmol, 3 eq), the mixture was degassed and purged under N2three times then stirred at 100 °C for 16 h under N2. The reaction mixture was cooled and diluted with water (10 mL) and the whole extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0~7% Ethylacetate / Petroleum ethergradient at 30 mL / min) to provide methyl 3 -ethoxy- 4 -methyl- 5 - [2 - (trifluoromethyl) morpholin- 4 -yl] benzoate (130 mg, 374.29 mol, 85.41% yield) as a white solid.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0805] 1H NMR (400 MHz, CHLOROFORM-d) = 7.38 (s, 1H), 7.33 (s, 1H), 4.18 - 4.12 (m, 2H), 4.11 - 4.06 (m, 2H), 3.92 (s, 3H), 3.92 - 3.86 (m, 1H), 3.15 (br d, J = 11.2 Hz, 1H), 2.95 (d, J = 4.2 Hz, 1H), 2.95 - 2.90 (m, 2H), 2.23 (s, 3H), 1.45 (t, J = 6.9 Hz, 3H)

[0806] Preparation of Intermediate 4: [3-ethoxy-4-methyl-5-[2-(trifluoromethyl)morpholin-4- yl]phenyl]methanol

[0807] To a solution of methyl 3-ethoxy-4-methyl-5-[2-(trifluoromethyl) morpholin-4-yl] benzoate (130 mg, 374.29 mol, 1 eq) in THF (2 mL) at 0 °C under N2 was added LiAlH4 (2.5 M, 179.66 L, 1.2 eq). The mixture was stirred at 20 °C for 1 h then quenched by addition of Na2SO4.10H2O (50 mg) and the resulting mixture was filtered. The filtrate was poured into water (5 mL) and the aqueous phase extracted with ethyl acetate (5 mL*3). The combined organic phases were dried over anhydrous Na2SO4 and filtered and the filtrate concentrated in vacuo to provide [3-ethoxy-4-methyl-5-[2-(trifluoromethyl) morpholin-4-yl] phenyl] methanol (110 mg, 344.48 mol, 92.04% yield) as a yellow oil that was used without further purification.

[0808] Preparation of Intermediate 5: 3-ethoxy-4-methyl-5-[2-(trifluoromethyl)morpholin-4- yl]benzaldehyde

[0809] To a solution of [3-ethoxy-4-methyl-5-[2-(trifluoromethyl)morpholin-4-yl] phenyl] methanol (110 mg, 344.48 mol, 1 eq) in DCM (2 mL) at 0 °C was added DMP (219.16 mg,Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834516.73 mol, 160.09 L, 1.5 eq). The mixture was stirred at 20 °C for 1 h then diluted with sat. NaHCO3(aq.) (5 mL) and the resulting mixture extracted with ethyl acetate (5 mL*3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0~8% Ethylacetate / Petroleum ethergradient at 30 mL / min) to provide 3 -ethoxy- 4 -methyl- 5 - [2 - (trifluoromethyl) morpholin- 4 -yl] benzaldehyde (85 mg, 267.88 mol, 77.76% yield) as a red oil.

[0810] 1H NMR (400 MHz, CHLOROFORM-d) = 9.92 (s, 1H), 7.20 (s, 1H), 7.17 (s, 1H), 4.22 - 4.14 (m, 2H), 4.14 - 4.08 (m, 2H), 3.92 (td, J = 6.9, 11.3 Hz, 1H), 3.18 (br d, J = 11.7 Hz, 1H), 3.01 - 2.96 (m, 2H), 2.96 - 2.91 (m, 1H), 2.26 (s, 3H), 1.47 (t, J = 7.0 Hz, 3H)

[0811] Preparation of Compound 23: (E)-N'-(3-ethoxy-4-methyl-5-(2- (trifluoromethyl)morpholino)benzylidene)-1H-1,2,3-triazole-5-carbohydrazide

[0812] To a mixture of 3-ethoxy-4-methyl-5-[2- (trifluoromethyl) morpholin- 4 -yl] benzaldehyde (20 mg, 63.03 mol, 1 eq) and 1H-triazole-5-carbohydrazide (8.01 mg, 63.03 mol, 1 eq) in MeOH (1 mL) was added AcOH (3.79 mg, 63.03 mol, 3.61 L, 1 eq), and the mixture stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuo to give a residue that was purified by prep-HPLC (column : Waters xbridge 150*25 mm 10um;mobile phase : [water (NH4HCO3) -ACN] ;gradient : 36%- 56% B over 8 min) followed by lyophilization. (E)-N'-(3-ethoxy-4-methyl-5-(2-(trifluoromethyl)morpholino)benzylidene)- 1H-1,2,3-triazole-5-carbohydrazide (10 mg, 22.51 mol, 35.72% yield, 96% purity) was obtained as a white solid.

[0813] LCMS (ESI) : m / z [M + H] calcd for C18H22F3N6O3: 427.16; found: 427.1Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834

[0814] 1H NMR (400 MHz, DMSO-d6) = 11.97 (br s, 1H), 8.50 (s, 1H), 8.45 (s, 1H), 7.08 (s, 1H), 7.03 (s, 1H), 4.39 (quin, J = 6.8 Hz, 1H), 4.15 - 4.07 (m, 2H), 4.05 (br d, J = 8.6 Hz, 1H), 3.84 (dt, J = 2.3, 11.0 Hz, 1H), 3.14 (br d, J = 10.9 Hz, 1H), 2.97 (br d, J = 12.0 Hz, 1H), 2.89 - 2.79 (m, 2H), 2.15 (s, 3H), 1.38 (t, J = 6.9 Hz, 3H) Example B1: Human GIP-R Assay LANCE cAMP Antagonist Assay (GIP-R)

[0815] cAMP assays were performed using Chinese Hamster Ovary (CHO-K1) cell line stably expressing human GIP-R receptor. Cells were cultured in CHO growth media containing 800 mg / mL G418. Cells were washed with PBS and then dissociated from tissue culture flasks with 0.25% trypsin. Dissociated cells were quenched in full media (F-12K Medium Corning REF#10-025-CV, 10% Avantor Seradigm FB Essence Cat# 10803-034, 1% Penicillin / Streptomycin Cytiva HyClone Cat#SV30010, 800 mg / mL G418 Corning REF# 61- 234-RG) and then collected by centrifugation at 290 x g for 5 min. Cells were resuspended in freezing media (90% FE Essence, 10% DMSO) and dispensed into 1 mL aliquots in cryo- centrifuge tubes. Cells were stored in liquid nitrogen until use.

[0816] On day of assay, frozen cells were quickly thawed in a 37oC water bath and immediately put into a 50 mL centrifuge tube containing 10 mL growth media. Cells were then centrifuged at 290 x g for 5 min and the resulting pellet suspended in assay buffer (0.1% BSA (Roche Ref# 03117057001), 500 mM IBMX (Sigma Ref#15879), in PBS+ / +(Corning REF#20-030-CV)) to a concentration of 3.7x105cells / mL.4 mL / well of cells (1500 cells / well) were dispensed into 384-well Corning plates (REF#3825), in quadruplicate. Cells were incubated at room temperature before compound addition.

[0817] Test compounds were diluted in assay buffer to 3x the final assay concentration.4 mL of test compound was added to the cells for 10 minutes before 4 mL of agonist. The reaction continued for an additional 1 hour at room temperature. 4 mL of cAMP detection reagents (cAMP UltraLANCE Detection Kit Revvity TRF0264) were dispensed onto the cells and plates were incubated for 1 hour at room temperature (cAMP detection reagents were made according to the Revvity kit protocol). Plates were read on an Envision plate reader following Revvity guidelines.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Data Processing

[0818] Raw data for all assays was transmitted directly from plate readers into the database for processing. All assay plates contained both positive and negative control wells to allow for data normalization and scaling. In agonist assays, positive control wells contained assay buffer with no GIP and negative control wells contained 400 pM GIP. All control wells contained DMSO at a final assay concentration that matched the test compound wells.

[0819] In addition to buffer and GIP containing negative and positive control wells, all assay plates contained an 8-point, quadruplicate cAMP standard curve. Counts from the standard curve wells were used to generate a sigmoidal standard curve, which was used to transform the raw counts from each well on the plate (scaling control wells and compound wells) into a pmol / well cAMP value. The pmol / well values for compound wells were scaled to the values in the positive and negative control wells to generate % control values. The negative control wells defined 0% response and the positive control wells defined 100% response. Data from test compound wells was scaled to these controls and are reported as % control values. Reported agonist efficacies represent the % efficacy compared to a maximal positive control response. Percent control data were analyzed by non-linear regression with a sigmoidal dose response algorithm to yield potency and efficacy data.

[0820] The IC50values of exemplary compounds in the human GIP-R assay are shown in Table 2 below, wherein “+” indicates that the IC50is > 5,000 nM, “++” indicates that the IC50is 5,000 nM and > 1,000 nM, “+++” indicates that the IC50 is 1,000 nM and > 100 nM, “++++” indicates that the IC50 is 100 nM and > 10 nM, and “+++++” indicates that the IC50 is 10 nM. Table 2Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Example B2: Mouse GIP-R Assay LANCE cAMP Antagonist Assay (Mouse GIP-R)

[0821] cAMP assays were performed using Chinese Hamster Ovary (CHO-K1) cell lines stabling expressing mouse GIP-R receptor. Cells were cultured in CHO growth media containing 800 g / mL G418. Cells were washed with PBS and then dissociated from tissue culture flasks with 0.25% trypsin. Dissociated cells were quenched in full media (F-12K Medium Corning REF#10-025-CV, 10% Avantor Seradigm FB Essence Cat# 10803-034, 1% Penicillin / Streptomycin Cytiva HyClone Cat#SV30010, 800 g / mL G418 Corning REF# 61- 234-RG) and then collected by centrifugation at 290 x g for 5 min. Cells were resuspended in freezing media (90% FE Essence, 10% DMSO) and dispensed into 1 mL aliquots in cryo- centrifuge tubes. Cells were stored at liquid nitrogen until use.

[0822] On day of assay, frozen cells were quickly thawed in a 37C water bath and immediately put into a 50 mL centrifuge tube containing 10 mL growth media. Cells were then centrifuged at 290 x g for 5 min and the resulting pellet suspended in assay buffer (0.1% BSA (Roche Ref# 03117057001), 500 mM IBMX (Sigma Ref#15879), in PBS+ / +(Corning REF#20-030-CV)) to a concentration of 5x105cells / mL, 4 mL / well of cells (2000 cells / well) were dispensed into 384-well Corning plates (REF#3825), in quadruplicate. Cells were incubated at room temperature before compound addition.

[0823] Test compounds were diluted in assay buffer to 3x the final assay concentration.4 mL of test compound was added to the cells for 10 minutes before 4 mL of agonist. The reaction continued for an additional 1 hour at room temperature. 4 mL of cAMP detection reagents (cAMP UltraLANCE Detection Kit Revvity TRF0264) were dispensed onto the cells and plates were incubated for 1 hour at room temperature (cAMP detection reagents were made accordingDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834to the Revvity kit protocol). Plates were read on an Envision plate reader following Revvity guidelines. Data Processing

[0824] Raw data for all assays was transmitted directly from plate readers into the database for processing. All assay plates contained both positive and negative control wells to allow for data normalization and scaling. In agonist assays, positive control wells contained assay buffer with no GIP and negative control wells contain 2 nM mouse GIP. All control wells contained DMSO at a final assay concentration that matched the test compound wells.

[0825] In addition to buffer and GIP containing negative and positive control wells, all assay plates contained an 8-point, quadruplicate cAMP standard curve. Counts from the standard curve wells were used to generate a sigmoidal standard curve, which was used to transform the raw counts from each well on the plate (scaling control wells and compound wells) into a pmol / well cAMP value. The pmol / well values for compound wells were scaled to the values in the positive and negative control wells to generate % control values. The negative control wells defined 0% response and the positive control wells defined 100% response. Data from test compound wells was scaled to these controls and are reported as % control values. Reported agonist efficacies represent the % efficacy compared to a maximal positive control response.

[0826] Percent control data were analyzed by non-linear regression with a sigmoidal dose response algorithm to yield potency and efficacy data.

[0827] The IC50 values of exemplary compounds in the human GIP-R assay are shown in Table 3 below, wherein “+” indicates that the IC50is > 2,500 nM, “++” indicates that the IC50is 2,500 nM and > 1,000 nM, “+++” indicates that the IC50is 1,000 nM and > 100 nM,indicates that the IC50 is 100 nM and > 10 nM, and “+++++” indicates that the IC50 is 10 nM. Table 3Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834Example B3: Human GCCR Assay LANCE cAMP Antagonist Assay (GIP-R)

[0828] cAMP assays were performed using Chinese Hamster Ovary (CHO-K1) cell line stably expressing human GCGR receptor (glucagon receptor). Cells were cultured in CHO growth media containing 800 mg / mL G418. Cells were washed with PBS and then dissociated from tissue culture flasks with 0.25% trypsin. Dissociated cells were quenched in full media (F-12K Medium Corning REF#10-025-CV, 10% Avantor Seradigm FB Essence Cat# 10803-034, 1% Penicillin / Streptomycin Cytiva HyClone Cat#SV30010, 800 mg / mL G418 Corning REF# 61- 234-RG) and then collected by centrifugation at 290 x g for 5 min. Cells were resuspended in freezing media (90% FE Essence, 10% DMSO) and dispensed into 1 mL aliquots in cryo- centrifuge tubes. Cells were stored in liquid nitrogen until use.

[0829] On day of assay, frozen cells were quickly thawed in a 37oC water bath and immediately put into a 50 mL centrifuge tube containing 10 mL growth media. Cells were then centrifuged at 290 x g for 5 min and the resulting pellet suspended in assay buffer (0.1% BSA (Roche Ref# 03117057001), 500 mM IBMX (Sigma Ref#15879), in PBS+ / +(Corning REF#20-030-CV)) to a concentration of 3.7x105cells / mL.4 mL / well of cells (1500 cells / well) were dispensed into 384-well Corning plates (REF#3825), in quadruplicate. Cells were incubated at room temperature before compound addition.

[0830] Test compounds were diluted in assay buffer to 3x the final assay concentration.4 mL of test compound was added to the cells for 10 minutes before 4 mL of agonist. The reaction continued for an additional 1 hour at room temperature. 4 mL of cAMP detection reagentsDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834(cAMP UltraLANCE Detection Kit Revvity TRF0264) were dispensed onto the cells and plates were incubated for 1 hour at room temperature (cAMP detection reagents were made according to the Revvity kit protocol). Plates were read on an Envision plate reader following Revvity guidelines. Data Processing

[0831] Raw data for all assays was transmitted directly from plate readers into the database for processing. All assay plates contained both positive and negative control wells to allow for data normalization and scaling. In agonist assays, positive control wells contained assay buffer with no GIP and negative control wells contained 80 pM Glucagon. All control wells contained DMSO at a final assay concentration that matched the test compound wells. In addition to buffer and GIP containing negative and positive control wells, all assay plates contained an 8-point, quadruplicate cAMP standard curve. Counts from the standard curve wells were used to generate a sigmoidal standard curve, which was used to transform the raw counts from each well on the plate (scaling control wells and compound wells) into a pmol / well cAMP value. The pmol / well values for compound wells were scaled to the values in the positive and negative control wells to generate % control values. The negative control wells defined 0% response and the positive control wells defined 100% response. Data from test compound wells was scaled to these controls and are reported as % control values. Reported agonist efficacies represent the % efficacy compared to a maximal positive control response.

[0832] Percent control data were analyzed by non-linear regression with a sigmoidal dose response algorithm to yield potency and efficacy data.

[0833] The IC50 values of exemplary compounds in the human GIP-R assay are shown in Table 4 below, wherein “+” indicates that the IC50is > 10,000 nM, “++” indicates that the IC50is 10,000 nM and > 1,000 nM, “+++” indicates that the IC50 is 1,000 nM and > 100 nM, “++++” indicates that the IC50 is 100 nM and > 10 nM, and “+++++” indicates that the IC50 is 10 nM. Table 4Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834EQUIVALENTS

[0834] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference.

[0835] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.

Claims

1. Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834CLAIMS What is claimed is:

1. A compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein:R5is H or C1-6 alkyl; X1is CH or N; X2is CR2or N; R2is H, C1-6alkyl, or C1-6alkoxyl; X3is CH or N; X6is CH or N; R3is H, C1-6alkyl, or C1-6alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10 cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10 cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6 alkyl, or C1-6 alkoxyl, wherein the C1-6 alkyl or C1-6 alkoxyl is optionally further substituted by one or more halogen, or C1-6 haloalkyl.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834The compound of claim 1, wherein the compound of Formula (I) is of Formula (I ):Formula (I )or a pharmaceutically acceptable salt thereof, wherein: RingX6is CH or N; R1is H, OH, or C1-6 alkyl; R5is H or C1-6 alkyl; R2is H, C1-6 alkyl, or C1-6 alkoxyl; R3is H, C1-6 alkyl, or C1-6 alkoxyl; alternatively R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10 cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10 cycloalkyl is optionally substituted with one or more R4a; and R4a is halogen, C1-6alkyl, or C1-6alkoxyl, wherein the C1-6alkyl or C1-6alkoxyl isoptionally further substituted by one or more halogen, or C1-6haloalkyl.

3. The compound of any one of the preceding claims, wherein the compound of Formula (I) is of Formula (I-A):Formula (I-A) or a pharmaceutically acceptable salt thereof, wherein:Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834m is 1, 2, or 3; o is 1, 2, or 3; X4is C(RX4)(RX4’), NRXN4, or O; X5is CH or N; X6is CH or N; RX4is H, C1-6 alkyl, C1-6 haloalkyl, halogen, C1-6 alkoxyl, or C1-6 haloalkoxyl; RX4’is H or halogen; RNX4is H, C1-6 alkyl, or C1-6 haloalkyl; each R7independently is halogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy, wherein the C1-6 alkoxy is optionally further substituted by one or more halogen; p is 0, 1, 2, or 3. R1is H, OH, or C1-6alkyl; R5is H or C1-6alkyl; R2is H, C1-6alkyl, or C1-6alkoxyl; and R3is H, C1-6alkyl, or C1-6alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl.

4. The compound of any one of the preceding claims, wherein the compound of Formula(I) is of Formula (I -A):Formula (I -A)or a pharmaceutically acceptable salt thereof, wherein: R1is H, OH, or C1-6 alkyl; R5is H or C1-6 alkyl;Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834X1is CH or N; X2is CR2or N; R2is H, C1-6 alkyl, or C1-6 alkoxyl; X3is CH or N; X6is CH or N; R3is H, C1-6alkyl, or C1-6alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6alkyl, or C1-6alkoxyl, wherein the C1-6alkyl or C1-6alkoxyl is optionally further substituted by one or more halogen, or C1-6 haloalkyl.

5. The compound of any one of the preceding claims, wherein the compound of Formula(I) is of Formula (I -B):or a pharmaceutically acceptable salt thereof, wherein: R1is H, OH, or C1-6 alkyl; R5is H or C1-6alkyl; X1is CH or N; X2is CR2or N; R2is H, C1-6alkyl, or C1-6alkoxyl; X3is CH or N; X6is CH or N; R3is H, C1-6alkyl, or C1-6alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10 cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10 cycloalkyl is optionally substituted with one or more R4a; andDate of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834R4ais halogen, C1-6 alkyl, or C1-6 alkoxyl, wherein the C1-6 alkyl or C1-6 alkoxyl is optionally further substituted by one or more halogen, or C1-6 haloalkyl.

6. The compound of any one of the preceding claims, wherein the compound of Formula(I) is of Formula (I -C):Formula (I -C)or a pharmaceutically acceptable salt thereof, wherein: R1is H, OH, or C1-6alkyl; R5is H or C1-6alkyl; X1is CH or N; X2is CR2or N; R2is H, C1-6 alkyl, or C1-6 alkoxyl; X3is CH or N; X6is CH or N; R3is H, C1-6 alkyl, or C1-6 alkoxyl; alternatively, R2and R3, together with the atoms to which they are attached, combine to form a 5- or 6-membered cycloalkyl; R4is 4-10 membered heterocyclyl or C3-10 cycloalkyl, wherein the 4-10 membered heterocyclyl or C3-10cycloalkyl is optionally substituted with one or more R4a; and R4ais halogen, C1-6alkyl, or C1-6alkoxyl, wherein the C1-6alkyl or C1-6alkoxyl is optionally further substituted by one or more halogen, or C1-6haloalkyl.

7. The compound of any one of the preceding claims, wherein X1is CH.

8. The compound of any one of the preceding claims wherein X2is CR2and R2is H.

9. The compound of any one of the preceding claims, wherein X2is CR2and R2is methyl.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-283410. The compound of any one of the preceding claims, wherein X3is CH.

11. The compound of any one of the preceding claims, wherein Ring.

12. The compound of any one of the preceding claims, wherein Ring A is R . The compound of any one of the preceding claims, wherein Ring14. The compound of any one of the preceding claims, wherein Ring.

15. The compound of any one of the preceding claims, wherein Ring A is.

16. The compound of any one of the preceding claims, wherein Ring A is. The compound of any one of the preceding claims, wherein Ring.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834The compound of any one of the preceding claims, wherein Ring A is.

19. The compound of any one of the preceding claims, wherein Ring A is. The compound of any one of the preceding claims, wherein Ring A is.

21. The compound of any one of the preceding claims, wherein R1is H, OH, or methyl.

22. The compound of any one of the preceding claims, wherein R1is H.

23. The compound of any one of the preceding claims, wherein R1is OH.

24. The compound of any one of the preceding claims, wherein R1is methyl.

25. The compound of any one of the preceding claims, wherein R5is H or methyl.

26. The compound of any one of the preceding claims, wherein R5is H.

27. The compound of any one of the preceding claims, wherein R5is methyl.

28. The compound of any one of the preceding claims, wherein X5is CH.

29. The compound of any one of the preceding claims, wherein X5is N.

30. The compound of any one of the preceding claims, wherein X6is CH.

31. The compound of any one of the preceding claims, wherein X6is N.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-283432. The compound of any one of the preceding claims, wherein R3is H, methyl, methoxyl, or ethoxyl.

33. The compound of any one of the preceding claims, wherein R3is H.

34. The compound of any one of the preceding claims, wherein R3is methyl.

35. The compound of any one of the preceding claims, wherein R3is methoxyl.

36. The compound of any one of the preceding claims, wherein R3is ethoxyl.

37. The compound of any one of the preceding claims, wherein R2and R3, together with the atoms to which they are attached, combine to form a 5-membered cycloalkyl.

38. The compound of any one of the preceding claims, wherein R4is is azetidinyl substituted with -OCF3.

39. The compound of any one of the preceding claims, wherein R4is is azetidinyl substituted with -CF3.

40. The compound of any one of the preceding claims, wherein R4is piperidinyl substituted with -OCF3.

41. The compound of any one of the preceding claims, wherein R4is piperidinyl substituted with -CF3.

42. The compound of any one of the preceding claims, wherein R4is piperazinyl substituted with -CH2CH2CF3.

43. The compound of any one of the preceding claims, wherein R4is piperazinyl substituted with -CHCH3CF3.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834The compound of any one of the preceding claims, wherein R4is. The compound of any one of the preceding claims, wherein R4is.

46. The compound of any one of the preceding claims, wherein R4is cyclohexyl substituted with one or more fluoro.

47. The compound of any one of the preceding claims, wherein R4is morpholino substituted with one or more methyl.

48. The compound of any one of the preceding claims, wherein R4is morpholino substituted with -CF3.

49. The compound of any one of the preceding claims, wherein R4ais -OCF3.

50. The compound of any one of the preceding claims, wherein R4ais -CH2CH2CF3.

51. The compound of any one of the preceding claims, wherein R4ais -CHCH3CF3.

52. The compound of any one of the preceding claims, wherein R4ais -CF3.

53. The compound of any one of the preceding claims, wherein R4ais -CH3.

54. The compound of any one of the preceding claims, wherein o is 1 or 2.

55. The compound of any one of the preceding claims, wherein o is 1.

56. The compound of any one of the preceding claims, wherein o is 2.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-283457. The compound of any one of the preceding claims, wherein m is 1.

58. The compound of any one of the preceding claims, wherein m is 2.

59. The compound of any one of the preceding claims, wherein p is 0 or 1.

60. The compound of any one of the preceding claims, wherein p is 0.

61. The compound of any one of the preceding claims, wherein p is 1.

62. The compound of any one of the preceding claims, wherein R7is methyl or -CF3.

63. The compound of any one of the preceding claims, wherein X4is C(RX4)(RX4’).

64. The compound of any one of the preceding claims, wherein X4is NRXN4.

65. The compound of any one of the preceding claims, wherein X4is O.

66. The compound of any one of the preceding claims, wherein RX4is H.

67. The compound of any one of the preceding claims, wherein RX4is -CF3.

68. The compound of any one of the preceding claims, wherein RX4is -CH2CH2CF3.

69. The compound of any one of the preceding claims, wherein RX4is fluoro.

70. The compound of any one of the preceding claims, wherein RX4is -OCF3.

71. The compound of any one of the preceding claims, wherein RX4’is H.

72. The compound of any one of the preceding claims, wherein RX4’is fluoro.

73. The compound of any one of the preceding claims, wherein RXN4is C1-6haloalkyl.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-283474. The compound of any one of the preceding claims, wherein RXN4is -CH2CH2CF3.

75. The compound of any one of the preceding claims, wherein RXN4is -CHCH3CF3.

76. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the compounds in Table 1.

77. The compound of claim 76, wherein the compound is:, or a pharmaceutically acceptable salt thereof.

78. A pharmaceutical composition comprising the compound of any one of the previous claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

79. A method of treating a disease mediated by gastric inhibitory polypeptide receptor (GIP-1 receptor) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the compound of any one of claims 1-77, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 78.

80. The method of claim 79, wherein the disease is a liver disease.

81. The method of claim 80, wherein the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome,Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-2834sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or oti-antitrypsin deficiency.

82. The method of claim 79, wherein the disease is diabetes.

83. The method of claim 79, wherein the disease is a cardiometabolic disease.

84. The method of claim 79, wherein the disease is obesity.

85. A method of decreasing food intake in an individual in need thereof, comprising administering to the individual a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-77 or the pharmaceutical composition of claim 78.

86. A method of increasing glucose tolerance in an individual in need thereof, comprising administering to the individual a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-77 or the pharmaceutical composition of claim 78.

87. Use of the compound of any one of claims 1-77, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 78, in the preparation of a medicament for the treatment of a disease mediated by gastric inhibitory polypeptide receptor (GIP-1 receptor).

88. The use of claim 87, wherein the disease is a liver disease.

89. The use of claim 88, wherein the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or oti-antitrypsin deficiency.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-283490. The use of claim 87, wherein the disease is diabetes.

91. The use of claim 87, wherein the disease is a cardiometabolic disease.

92. The use of claim 87, wherein the disease is obesity.

93. Use of the compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-77 or the pharmaceutical composition of claim 78 for use in the manufacture of a medicament for decreasing food intake.

94. Use of the compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-77 or the pharmaceutical composition of claim 78 for use in the manufacture of a medicament for increasing glucose tolerance.

95. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 78, for use in treating a disease mediated by gastric inhibitory polypeptide receptor (GIP-R).

96. The compound, or salt thereof, or pharmaceutical composition, for use according to claim 95, wherein the disease is a liver disease.

97. The compound, or salt thereof, or pharmaceutical composition, for use according to claim 96, wherein the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or oti-antitrypsin deficiency.

98. The compound, or salt thereof, or pharmaceutical composition, for use according to claim 95, wherein the disease is diabetes.Date of Deposit: July 9, 2025 Cooley Docket No.: TRPH-055 / 001WO 346923-283499. The compound, or salt thereof, or pharmaceutical composition, for use according to claim 95, wherein the disease is a cardiometabolic disease.

100. The compound, or salt thereof, or pharmaceutical composition, for use according to claim 95, wherein the disease is obesity.

101. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-77 or the pharmaceutical composition of claim 78 for use in decreasing food intake.

102. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1- 77 or the pharmaceutical composition of claim 78 for use in increasing glucose tolerance.

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