Pharmaceutical combinations including substituted thiophene condensed cyclohexanone derivatives and cyclooxygenase (COX) inhibitors, and their use for the treatment of pain.

Abstract

A combination of pharmaceuticals is provided comprising a cyclooxygenase (COX) inhibitor and a compound having formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the COX inhibitor may include a nonsteroidal anti-inflammatory drug (NSAID). The combination of pharmaceuticals may be used in the treatment of pain in subjects requiring it, such as inflammatory pain. Also provided is a kit comprising a first single-dosage form of a cyclooxygenase (COX) inhibitor, a second single-dosage form of a compound having formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and instructions for use. (I) [Case 1] JPEG2026529607000353.jpg19170

Description

[Technical Field]

[0001] (Priority application) This application claims priority to U.S. Provisional Patent Application No. 63 / 519,108, filed on 11 August 2023, which is incorporated herein by reference.

[0002] (Field of invention) This technical field generally relates to drug combinations and their use in the treatment of pain. These drug combinations include thiophene-condensed cyclohexanone derivatives and cyclooxygenase (COX) inhibitors. In particular, thiophene-condensed cyclohexanone derivatives are acid-sensitive ion channel (ASIC) inhibitors. [Background technology]

[0003] Since the discovery of acid-sensitive ion channels (ASICs) in 1997, the importance of neurons and other non-neuronal cells in health has become extremely important. ASICs play a crucial role in mediating pain, and their activity contributes to diseases such as stroke, inflammation, arthritis, cancer, and migraines.

[0004] ASICs are permeable to Na+ ions (and other cations), are activated by low extracellular pH, and are widely expressed in the central nervous system (CNS) and peripheral nervous system (PNS). ASICs are formed from homotrimeric and heterotrimeric assemblies of subunits including ASIC1a, ASIC1b, ASIC2a, ASIC2b, and ASIC3. ASIC1a is expressed in both the PNS and CNS, while ASIC1b is expressed in the PNS.

[0005] Tissue damage and inflammation can lead to acidosis, and acidification is considered a significant contributing factor to associated pain. The literature shows that ASIC inhibitors can alleviate pain in a variety of clinical conditions. Furthermore, because they have different mechanisms of action, ASIC antagonists may offer a new treatment option for patients who do not benefit from or cannot tolerate the adverse side effects of certain current analgesics.

[0006] Therefore, developing novel drug combinations that include small molecule inhibitors specific to ASICs is important to provide alternative treatments for ASIC-related diseases or conditions such as pain. [Overview of the project]

[0007] This application relates to a pharmaceutical combination comprising a cyclooxygenase (COX) inhibitor and a compound that is a thiophene-condensed cyclohexanone derivative of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The pharmaceutical combination may be useful for the treatment of pain.

[0008] According to one aspect, this application relates to a combination of pharmaceuticals, and the combination of pharmaceuticals is (a) Cyclooxygenase (COX) inhibitors, and (b) Compounds having formula (I),

[0009] [ka] or comprising a pharmaceutically acceptable salt, solvate, or prodrug thereof, During the ceremony, R a -NH2, -NH-OH, -OH, -NHR b , or -NHR c R d And, R bis C1-C6 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C1-C6 alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -OC1-C3 alkyl, -COOH, or cyclopropyl optionally substituted with -OH, wherein C3-C6 cycloalkyl is optionally substituted with -CN, R c and R d , together with the nitrogen to which they are bonded, form a 4-membered heterocycloalkyl, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C1-C3 alkyl,

[0010] [Chemical Formula] represents one of the following residues from residue A0 to residue A 12 ,

[0011] [Chemical Formula] wherein, R is H, C1-C6 alkyl or phenyl, R 1 and R 2 are each independently -CN, C6-C 10 aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHR 5 , -C(O)R 6 , or -C(O)OR 5 , wherein each C1-C6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C6-C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, provided that R a is -OH,

[0012] [ka] This represents A0, and R 1 but

[0013] [ka] If so, R in residue A0 2 teeth,

[0014] [ka] Unlike, Each R 5 These are independently C1-C6 alkyl groups, where each C1-C6 alkyl group has 1-3 R groups. 9 Substituents are optionally replaced, Each R 6 These are independently C3-C6 cycloalkyl, 4-6 member heterocycloalkyl, or C6-C 10 It is Ariel, Each R 7 These are independently -OH and -C(O)R 11 , C3~C6 cycloalkyl, -CN, C6~C 10 Aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6 alkyl), -N(C1-C4 alkyl)(C(O)OC1-C6 alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6 alkyl), -OR 20 -SC1~C6 alkyl, -NH2, -NH(C1~C4 alkyl), or -N(C1~C4 alkyl)2, where each C3~C6 cycloalkyl has 1 to 3 R 12 Substituents are optionally substituted, and each 5- to 10-membered heteroaryl has 1 to 3 R 13 Substituents are optionally substituted, and each 4- to 6-membered heterocycloalkyl group is optionally substituted with a C1- to C4 alkyl group or an oxo group. Each R8 These are independently halogens, C1-C6 alkyls, -OC1-C6 alkyls, C3-C6 cycloalkyls, or 5-membered-to-10-membered heteroaryls, where each -OC1-C6 alkyl is optionally substituted with a -OC1-C4 alkyl, and each 5-membered-to-10-membered heteroaryl is optionally substituted with a C1-C4 alkyl. Each R 22 These are independently C1-C6 alkyl groups that are optionally substituted with phenyl. Each R 9 These are independently -OH and -C(O)R 15 , C3~C6 cycloalkyl, -CN, C6~C 10 These are aryl, halogen, -C(O)OH, 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6 alkyl), -OC1-C6 alkyl, -SC1-C6 alkyl, -NH2, -NH(C1-C4 alkyl), or -N(C1-C4 alkyl)2, where each 4- to 6-membered heterocycloalkyl is optionally substituted with a C1-C4 alkyl, and each -OC1-C6 alkyl is optionally substituted with a -OC1-C4 alkyl. Each R 11 These are independently -NH2, -NH(C1~C4 alkyl), -N(C1~C4 alkyl)2, or 4-membered to 6-membered heterocycloalkyl groups. Each R 20 These are independently C1-C6 alkyl or 5- to 10-membered heteroaryl groups, where each C1-C6 alkyl group has 1-3 R groups. 14 The substituents are optionally substituted, and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH (cyclopropyl). Each R 12 These are independently C1-C4 alkyl, -SC1-C4 alkyl, -Ph, -OC1-C4 alkyl, or -SPh, where each C1-C4 alkyl is optionally substituted with -OH. Each R 13These are independently halogen, C1-C4 alkyl, C3-C6 cycloalkyl, -OH, -OC1-C6 alkyl, -SC1-C6 alkyl, -S(O)2C1-C6 alkyl, -NH2, -NH(C1-C4 alkyl), or -N(C1-C4 alkyl)2, where each of -OC1-C6 alkyl, -SC1-C6 alkyl, -S(O)2C1-C6 alkyl, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2 contains 1-3 R 9 Substituents are optionally replaced, Each R 14 These are independently halogens, -OC1~C4 alkyls, or C3~C6 cycloalkyls. Each R 15 These are independently -NH2, -NH(C1~C4 alkyl), -N(C1~C4 alkyl)2, or 4-membered to 6-membered heterocycloalkyl groups. R 4 These are C1-C6 alkyl, C3-C8 cycloalkyl, and C6-C 10 The aryl group is a 7- to 10-membered partially unsaturated heterocyclic group, or a 5- to 10-membered heteroaryl group, where C1-C6 alkyl and C3-C8 cycloalkyl groups have 1-3 R groups. 9 Substituents are optionally substituted, C6~C 10 Aryls and 5- to 10-membered heteroaryls have 1 to 3 R 10 Substituents are optionally replaced, however (i)R a is -OH, -NH2, or

[0015] [ka] And,

[0016] [ka] If represents A2, then the R in residue A2 4 Unlike -CH3, (ii)R a is -NH2,

[0017] [ka] If this represents A3, then the R in residue A3 4 Unlike -C(CH3)3, Each R 10 These are independently C1-C4 alkyl, halogen, -OC1-C6 alkyl, -NH2, -NH(C1-C4 alkyl), or -N(C1-C4 alkyl)2, where each C1-C4 alkyl is optionally substituted with 1-3 halogens. R 2a These are C1-C6 alkyl, C3-C8 cycloalkyl, or C6-C 10 It is an aryl group, where C1-C6 alkyl and C3-C8 cycloalkyl groups have 1-3 R 9 Substituents are optionally substituted, C6~C 10 A aryl has 1 to 3 R 10 Substituting with substituents, R 1a and R 2b These are independently -CN, C6~C 10 Aryl, C1-C6 alkyl, C3-C8 cycloalkyl, -C(O)NH2, -C(O)NHR 5 , or -C(O)OC1~C6 alkyl, where each C1~C6 alkyl has 1~3 R 16 Substituents are optionally substituted, and each C6~C 10 A aryl has 1 to 3 R 17 Substituents are optionally replaced, Each R 16 These are independently -OH, -C(O)NH2, -C(O)NH(C1~C4 alkyl), C3~C6 cycloalkyl, -CN, C6~C 10 These are aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6 alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6 alkyl), or -OC1-C4 alkyl(OC1-C4 alkyl), where each C3-C6 cycloalkyl has 1-3 R 18 Substituents are optionally substituted, and each 5- to 10-membered heteroaryl has 1 to 3 R 21Substituents are optionally substituted, and each 4- to 6-membered heterocycloalkyl group is optionally substituted with C1- to C4 alkyl groups. Each R 17 These are independently halogens, C1-C6 alkyl groups, -OC1-C6 alkyl groups, or 5- to 10-membered heteroaryl groups, where each 5- to 10-membered heteroaryl group is optionally substituted with a C1-C4 alkyl group. Each R 18 These are independently C1-C4 alkyl, -SC1-C4 alkyl, -Ph, or -OC1-C4 alkyl. Each R 21 These are independently halogens or C1-C4 alkyls. R 4a The C1-C6 alkyl or C3-C8 cycloalkyl group is a C1-C6 alkyl or C3-C8 cycloalkyl group, where each C1-C6 alkyl and C3-C8 cycloalkyl group has 1-3 R groups. 19 Substituents are optionally replaced, Each R 19 These are independently halogen, -OH, -OC1~C4 alkyl, -SC1~C4 alkyl, -NH2, -NH(C1~C4 alkyl), or -N(C1~C4 alkyl)2. R 1b and R 2c These, together with the carbon atoms to which they are bonded, form C3-C8 cycloalkyl groups, 4- to 14-membered heterocycloalkyl groups, 8- to 14-membered partially unsaturated heterocyclic groups, or 8- to 14-membered partially unsaturated carbocyclic groups, where the C3-C8 cycloalkyl group has 1-3 R 9 The substituents are optionally substituted, and the 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group are optionally substituted with 1 to 3 substituents independently selected from oxo (=O), oxime (=N-OH), C1-C3 alkoxyoxime (=N-OC1-C3 alkyl), or -OH and -CF3. R 2d and R 4bThese, together with the carbon atoms to which they are bonded, form C3-C8 cycloalkyl or 4-membered-14-membered heterocycloalkyl groups, where the C3-C8 cycloalkyl group has 1-3 R atoms. 19 Substituents are optionally replaced, R 1c and R 3 These, together with the carbon atoms to which they are bonded, form C3-C8 cycloalkyl or 4-membered-14-membered heterocycloalkyl groups, where the C3-C8 cycloalkyl group has 1-3 R atoms. 19 Substitutions are optionally replaced.

[0018] In some embodiments, the pharmaceutical combination may include a compound of formula (I) which is a compound of formula (Ia), formula (Ia'), formula (Ib), formula (Ib'), formula (Ic), formula (Ic'), formula (Id), formula (Id'), formula (Ie), formula (Ie'), formula (If), formula (If'), or formula (Ig) as described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0019] In some embodiments, the pharmaceutical combination may include a compound of formula (I) which is a compound of Table 1 herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0020] In some embodiments, the drug combination may include a nonsteroidal anti-inflammatory drug (NSAID) as the COX inhibitor. In some embodiments, the drug combination may be acetaminophen as the COX inhibitor.

[0021] In some embodiments, the drug combination may be a synergistic drug combination.

[0022] Another aspect relates to a combination of pharmaceuticals as defined herein for use in treating pain in a subject that requires it. Similarly, this aspect relates to the use of a combination of pharmaceuticals as defined herein for treating pain in a subject that requires it. Furthermore, this aspect relates to a method for treating pain, comprising administering a combination of pharmaceuticals as defined herein to a subject that requires it. In some embodiments, the pain is inflammatory pain, neuropathic pain, or cancer pain. In some embodiments, the pain is inflammatory pain. In another embodiment, the pain is neuropathic pain. In yet another embodiment, the pain is cancer pain. In some embodiments, the treatment is oral treatment.

[0023] Another embodiment relates to a method for treating pain, comprising administering a cyclooxygenase (COX) inhibitor and a compound having formula (I) as defined herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to a subject in need. In some embodiments, the COX inhibitor may include a nonsteroidal anti-inflammatory drug (NSAID). In some embodiments, the COX inhibitor is acetaminophen. In some embodiments, the pain is inflammatory pain, neuropathic pain, or cancer pain. In some embodiments, the pain is inflammatory pain. In another embodiment, the pain is neuropathic pain. In yet another embodiment, the pain is cancer pain. In some embodiments, the COX inhibitor and the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered orally.

[0024] Another embodiment relates to a kit comprising a first monodose form of a cyclooxygenase (COX) inhibitor and a second monodose form of a compound having formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as well as instructions for use. In some embodiments, the kit may include a COX inhibitor that is a nonsteroidal anti-inflammatory drug (NSAID). In some embodiments, the COX inhibitor may be acetaminophen. In some embodiments, the kit is for use in the treatment of pain. In some embodiments, the pain is inflammatory pain, neuropathic pain, or cancer pain. In some embodiments, the pain is inflammatory pain. In another embodiment, the pain is neuropathic pain. In yet another embodiment, the pain is cancer pain. In some embodiments, the treatment is oral treatment. [Brief explanation of the drawing]

[0025] [Figure 1] The following is shown: (A) Dose-response curves of compound 61, naproxen, and the compound 61:naproxen combination in a carrageenan-induced inflammation model. Analysis of carrageenan-treated rats using linear regression analysis revealed that the combination produced an ED50 of 1.4 mg / kg, with 95% confidence intervals (CL) of 1.0 and 2.0 mg / kg, compared to compound 61 or naproxen alone, which produced ED50s of 6.7 and 8.1 mg / kg, respectively. All compounds were administered orally and tested 30 minutes later. The dose ratio of the combination was 1:0.83 (naproxen:compound 61). Nonlinear regression analysis using a variable gradient sigmoid model. Anti-algesic hypersensitivity % = (PWL (dose) - PWL (vehicle)) / (PWL (untreated) - PWL (vehicle)) × 100. The dotted line represents 95% CL. (B) Isobologram of compound 61 relative to naproxen. Isobologram analysis was performed using normalized data. The data points representing the ED50 values ​​of the combination therapy are located below the additive line (the line connecting the ED50 values ​​of compound 61 and naproxen), and their 95% CL never intersects the dotted line. [Figure 2]The following is shown: (A) Dose-response curves of compound 61, naproxen, and the compound 61:naproxen combination in a carrageenan-induced inflammation model. Analysis of carrageenan-treated rats using linear regression analysis revealed that the combination produced an ED50 of 1.8 mg / kg, with 95% confidence intervals (CL) of 1.4 and 2.3 mg / kg, compared to compound 61 or naproxen alone, which produced ED50s of 6.7 and 8.1 mg / kg, respectively. All compounds were administered orally and tested 30 minutes later. The dose ratio of the combination was 1:0.83 (naproxen:compound 61). Nonlinear regression analysis using a variable gradient sigmoid model. Anti-algesic hypersensitivity % = (PWL (dose) - PWL (vehicle)) / (PWL (untreated) - PWL (vehicle)) × 100. The dotted line represents 95% CL. (B) Isobologram of compound 61 relative to naproxen. Isobologram analysis was performed using normalized data. The data points representing the ED50 values ​​of the combination therapy are located below the additive line (the line connecting the ED50 values ​​of compound 61 and naproxen), and their 95% CL never intersects the dotted line. [Figure 3] The following is shown: (A) Dose-response curves of compound 61, celecoxib, and compound 61:celecoxib combination in a carrageenan-induced inflammation model. Analysis of carrageenan-treated rats using linear regression analysis revealed that the combination produced an ED50 of 2.3 mg / kg, with 95% confidence intervals (CL) of 1.5 and 2.9 mg / kg, compared to compound 61 or celecoxib alone, which produced ED50s of 6.7 and 12.9 mg / kg, respectively. All compounds were administered orally and tested 30 minutes later. The dose ratio of the combination was 1:0.52 (celecoxib:compound 61). Nonlinear regression analysis was performed using a variable gradient sigmoid model. Anti-algesic hypersensitivity % = (PWL (dose) - PWL (vehicle)) / (PWL (untreated) - PWL (vehicle)) × 100. The dotted line represents 95% CL. (B) Isobologram of compound 61 against celecoxib. Isobologram analysis was performed using normalized data. The data points representing the ED50 values ​​of the combination therapy are located below the additive line (the line connecting the ED50 values ​​of compound 61 and celecoxib), and their 95% CL never intersects the dotted line. [Figure 4]The following is shown: (A) Dose-response curves of compound 61, ibuprofen, and the compound 61:ibuprofen combination in a carrageenan-induced inflammation model. Analysis of carrageenan-treated rats using linear regression analysis revealed that the combination produced an ED50 of 2.1 mg / kg, with 95% confidence intervals (CL) of 1.1 and 4.6 mg / kg, compared to compound 61 or ibuprofen alone, which produced ED50s of 6.7 and 12.6 mg / kg, respectively. All compounds were administered orally and tested 30 minutes later. The dose ratio of the combination was 1:0.53 (ibuprofen:compound 61). Nonlinear regression analysis using a variable gradient sigmoid model. Anti-algesic hypersensitivity % = (PWL (dose) - PWL (vehicle)) / (PWL (untreated) - PWL (vehicle)) × 100. The dotted line represents 95% CL. (B) Isobologram of compound 61 relative to ibuprofen. Isobologram analysis was performed using normalized data. The data points representing the ED50 values ​​of the combination therapy are located below the additive line (the line connecting the ED50 values ​​of compound 61 and ibuprofen), and their 95% CL never intersects the dotted line. [Figure 5] The following is shown: (A) Dose-response curves of compound 61, diclofenac, and the compound 61:diclofenac combination in a carrageenan-induced inflammation model. Analysis of carrageenan-treated rats using linear regression analysis revealed that the combination produced an ED50 of 1.6 mg / kg, with 95% confidence intervals (CL) of 0.9 and 2.8 mg / kg, compared to compound 61 or diclofenac alone, which produced ED50s of 6.7 and 11.7 mg / kg, respectively. All compounds were administered orally and tested 30 minutes later. The dose ratio of the combination was 1:0.57 (diclofenac:compound 61). Nonlinear regression analysis was performed using a variable gradient sigmoid model. Anti-algesic hypersensitivity % = (PWL (dose) - PWL (vehicle)) / (PWL (untreated) - PWL (vehicle)) × 100. The dotted line represents 95% CL. (B) Isobologram of compound 61 against diclofenac. Isobologram analysis was performed using normalized data. The data points representing the ED50 values ​​of the combination therapy are located below the additive line (the line connecting the ED50 values ​​of compound 61 and diclofenac), and their 95% CL never intersects the dotted line. [Figure 6] The following is shown: (A) Dose-response curves of compound 63, naproxen, and the compound 63:naproxen combination in a carrageenan-induced inflammation model. Analysis of carrageenan-treated rats using linear regression analysis revealed that the combination produced an ED50 of 0.87 mg / kg, with 95% confidence intervals (CL) of 0.4 and 2.0 mg / kg, compared to compound 63 or naproxen alone, which produced ED50s of 1.4 and 8.1 mg / kg, respectively. All compounds were administered orally and tested 30 minutes later. The dose ratio of the combination was 1:0.178 (naproxen:compound 63). Nonlinear regression analysis using a variable gradient sigmoid model. Anti-algesic hypersensitivity % = (PWL (dose) - PWL (vehicle)) / (PWL (untreated) - PWL (vehicle)) × 100. The dotted line represents 95% CL. (B) Isobologram of compound 63 relative to naproxen. Isobologram analysis was performed using normalized data. The data points representing the ED50 values ​​of the combination therapy are located below the additive line (the line connecting the ED50 values ​​of compound 63 and naproxen), and their 95% CL never intersects the dotted line. [Modes for carrying out the invention]

[0026] general definition All technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art in which this technology pertains. For convenience, the meanings of specific terms and phrases used herein are provided below.

[0027] To the extent that definitions of terms in publications, patents, and patent applications incorporated herein by reference conflict with the definitions set forth herein, the definitions herein shall prevail. Section headings used herein are for structural purposes only and should not be construed as limiting the subject matter disclosed.

[0028] The terms used herein are intended solely to describe and not to limit specific embodiments. Note that the singular forms “a,” “an,” and “the” also include the plural form unless the context clearly indicates otherwise. Thus, for example, a reference to a composition containing a “compound” also intends to include a mixture of two or more compounds. Also note that the term “or” is generally used to include “and / or” unless the context clearly indicates otherwise. Furthermore, the terms “including,” “includes,” “having,” “has,” “with,” or variations thereof, are intended to be as comprehensive as the term “comprising,” insofar as they are used in either the detailed description and / or the claims.

[0029] The term "approximately" means that a particular value is within an acceptable margin of error, as determined by those skilled in the art, and this depends in part on how the value is measured or determined, i.e., on the limits of the measuring system. For example, "approximately" may mean a standard deviation of 1 or more than 1, depending on the practice in the art. Alternatively, "approximately" may mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Or, particularly with respect to biological systems or processes, the term may mean within one order of magnitude of a value, preferably up to five times, and more preferably up to two times. Where a particular value is described in this application and claims, unless otherwise specified, the term "approximately" should be assumed to mean within an acceptable margin of error for that particular value.

[0030] Thiofen-condensed cyclohexanone derivative ASIC inhibitors This application relates to a pharmaceutical combination comprising a thiophene-condensed cyclohexanone derivative having ASIC inhibitory properties, wherein the compound is of general formula (I).

[0031] [ka] or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in which R a and

[0032] [ka] This is further defined below.

[0033] Accordingly, the compounds described in this application are those represented by the chemical structure of Formula I, with reference to any of the applicable embodiments described below, and exemplary compounds, for example, compounds 4, 8, 9, 14-39, 47-54, 59, 60a, 60b, 61-72, 75, 81-84, 89, 91, 97, 101, 108, 109, and 119 in Table 1. ~136, 138~150, 154, 155, 163, 168~170, 173~175, 178~181, 183, 189~195, 197~202, 211~216, 219, 221, 227~232, 237, 238, 239, 245~251, 253, 254, 255, 257, 258, 263, 264, 271, 272, 273, 2 78~281, 287, 288, 290, 291, 297, 298, 305, 306, 313, 314, 321, 322, 330, 331, 337~349, 352~35 8, 360, 362, 371, 378, 391~393, 394a, 394b, 395a, 395b, 396, 397, 401~403, 406~408, 412~414 This includes 416, 418, 422, 427-431, 433, 434, 445-454, 462-466, 468-476, 478-483, 486, 488, 489, 492, 495-498, 511-515, 520, 523, 524, or 534, and, where applicable, their pharmaceutically acceptable salts, solvates, and prodrugs.

[0034] A compound can be identified by either its chemical structure or its chemical name. In the event of a conflict between the chemical structure and the chemical name, the chemical structure takes precedence.

[0035] Unless otherwise specified, the structure shown herein is also meant to include all isomeric forms of the structure, for example, enantiomeric, diastereomeric, and geometric (or conformational) forms, such as R and S configurations at each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present specification. Unless otherwise specified, all tautomeric forms of the compounds are within the scope of the present specification. In addition, unless otherwise specified, the structure shown herein is also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen with deuterium or tritium, or 13 C or 14 replacement of carbon with C-enriched carbon, compounds having the present structure are within the scope of the present specification. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present specification.

[0036] Definitions of specific functional groups and chemical terms are provided below.

[0037] Chemical structures herein are drawn in accordance with conventional standards well known in the art. Therefore, when a drawn atom, such as a carbon atom, appears to have an unfilled valence, it is assumed that such valence is satisfied by a hydrogen atom, even if the hydrogen atom is not necessarily explicitly drawn. Hydrogen atoms should be inferred to be part of the compound.

[0038] The number of carbon atoms in a hydrocarbyl substituent is indicated by the prefix "C x ~C yThis can be shown by , where x is the minimum number of carbon atoms in the substituent and y is the maximum number. When referring to an "x-member ~ y-member" heterocyclic group (e.g., a heterocycloalkyl, a partially unsaturated heterocyclic group, or a heteroaryl), x and y define the minimum and maximum number of atoms in the cyclic group, including carbon and heteroatoms, respectively.

[0039] As used herein, the term "halogen" refers to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0040] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, more specifically, oxygen, sulfur, or nitrogen.

[0041] As used herein, the term “alkyl” refers to a saturated linear or branched hydrocarbon group. In some embodiments, alkyl groups may contain 1 to 6 carbon atoms, but alkyl groups having more than 6 carbon atoms may also be intended. For example, “C1-C6 alkyl” contains 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, and octyl groups.

[0042] As used herein, the term “alkenyl” refers to a linear or branched hydrocarbon group containing one or more double bonds. In some embodiments, an alkenyl group may contain 2 to 6 carbon atoms, but alkenyl groups having more than 6 carbon atoms may also be intended. For example, “C2-C6 alkenyl” contains 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, 1-methyl-2-buten-1-yl, and hexenyl.

[0043] As used herein, the term "alkynyl" refers to a linear or branched hydrocarbon group containing one or more triple bonds. In some embodiments, the alkynyl group may contain 2 to 6 carbon atoms, but alkynyl groups having more than 6 carbon atoms may also be intended. For example, "C2-C6 alkynyl" contains 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0044] The term “cycloalkyl,” used alone or as part of a larger term, refers to a group containing a saturated carbocyclic ring in a monocyclic or polycyclic ring system having 3 to 15 ring members, including spiro (sharing one atom), condensed (sharing at least one bond), or bridging (sharing two or more bonds) carbocyclic ring systems. In some embodiments, cycloalkyl groups may contain 3 to 8 carbon atoms. For example, “C3-C8 cycloalkyl” contains 3 to 8 carbon atoms in the cyclic ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.2.0]octyl, norbornyl, etc.

[0045] As used herein, the term “aryl” refers to a monocyclic moiety, or a bicyclic or tricyclic fused ring system, where the ring system is carbocyclic and fully aromatic. In some embodiments, the aryl group may contain 6 to 14 carbon atoms, such as 6 to 10 carbon atoms. For example, “C6~C 10 The "aryl" group contains 6 to 10 carbon atoms in an aromatic system. In certain embodiments, "aryl" refers to aromatic ring systems that include, but are not limited to, phenyl, naphthyl, azlenyl, and anthracyl.

[0046] As used herein, the term “heterocyclic group” refers to a chemically stable saturated, partially unsaturated, or fully aromatic monocyclic or polycyclic ring system containing at least one heteroatom as defined above, including spiro (sharing one atom), condensed (sharing at least one bond), or bridging (sharing two or more bonds) carbocyclic ring systems. A heterocyclic group may be a heterocycloalkyl group, a heteroaryl group, or a partially unsaturated heterocyclic group, as defined herein.

[0047] The term “heterocycloalkyl,” used alone or as part of a larger part, refers to a saturated cyclic group comprising at least one heteroatom as defined herein, which may comprise a monocyclic or two or more rings. In some embodiments, a heterocycloalkyl group may comprise 3 to 14 ring atoms, but heterocycloalkyl groups having more than 14 ring atoms may also be contemplated. In some embodiments, a heterocycloalkyl group may comprise, for example, 4 to 14 ring atoms, or 4 to 6 ring atoms, or 3 to 6 ring atoms. For example, a “3-membered to 14-membered heterocycloalkyl group” contains 3 to 14 atoms in the saturated heterocyclic portion, by counting the total number of carbon atoms and heteroatoms. In some embodiments, a heterocycloalkyl group may comprise 1 to 4 heteroatoms. Heterocycloalkyl groups include oxylanil, azilidinil, oxetanil, tetrahydropyranil (oxanil), tetrahydrofuranil (oxolanil), pyrrolidinil (azolidinil), piperidinil, dioxanil, morpholinil, thietanil, azetidinil, diazetidinil, oxathiolanil, oxepanil, azokanil (octahydroazosinil), thiokanil, azonanil (octahydroazoninil), 1,3-dioxolanil, pyrazolidinil, imidazolidinil, and piperadini. This may include, but is not limited to, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, tetrahydrodithienyl, thiomorpholinyl, thioxanyl, homopiperidinyl, thiepanyl, dithianyl, dithiolanyl, 3-azabicyclo[3,1,0]hexanyl, 3-azabicyclo[4,1,0]heptanyl, quinuclidinyl, decahydroquinolinyl, octahydroindolyl, etc. Heterocycloalkyls may be bonded to their pendant group with any heteroatom or carbon atom that results in a chemically stable structure.

[0048] The term “heteroaryl,” used alone or as part of a larger term, refers to a fully aromatic cyclic group comprising at least one heteroatom as defined herein, which may include a monocyclic or fused ring of two or more rings. In some embodiments, a heteroaryl group may comprise 5 to 10 ring atoms, but heteroaryl groups having more than 10 ring atoms may be intended. In some embodiments, a heteroaryl group may comprise 1 to 4 heteroatoms. Heteroaryl groups may include, but are not limited to, thienyl, furanyl (furyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, benzofuranyl, dibenzofuranyl, benzimidazolyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzoxazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, flupyridinyl, indazolyl, isoindolyl, indolidinyl, purinyl, quinolyl (quinolinyl), isoquinolyl (isoquinolinyl), acridinyl, sinnolinyl, quinazolinyl, naphthilidinyl, carbazolyl, phenantridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and pteridinyl. A heteroaryl group can be bonded to its pendant group with any heteroatom or carbon atom that results in a chemically stable structure.

[0049] As used herein, the term “partially unsaturated heterocyclic group” refers to a carbocyclic ring system that contains at least one double bond between ring atoms but is not entirely aromatic and contains at least one heteroatom. “Partially unsaturated heterocyclic groups” can be monocyclic, dicyclic, or tricyclic and are intended to encompass ring systems having one or more unsaturated sites. In some embodiments, a partially unsaturated heterocyclic group may include a polycyclic ring system in which at least one ring is aromatic but at least one other ring is not. For example, a partially unsaturated heterocyclic group may include an aryl fused with a heterocycloalkyl, a heteroaryl fused with a cycloalkyl, or a heteroaryl fused with a heterocycloalkyl, each of which may be monocyclic or bicyclic. In some embodiments, a partially unsaturated heterocyclic group may contain 7 to 14 carbon atoms, e.g., 7 to 10 carbon atoms or 8 to 14 carbon atoms. For example, a "7- to 10-membered partially unsaturated heterocyclic group" contains 7 to 10 atoms in the heterocyclic portion, by counting the total number of carbon atoms and heteroatoms. In some embodiments, a partially unsaturated heterocyclic group may contain 1 to 4 heteroatoms. A partially unsaturated heterocyclic group can be bonded to its pendant group with any heteroatom or carbon atom that results in a chemically stable structure. Non-restrictive examples of partially unsaturated heterocyclic groups include pyrazolinyl, imidazolinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, quinolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 1,3-benzodioxolyl, chromanyl, clomenyl, indolinyl, quinolonyl, isoquinolonyl, oxazepinyl, diazepinyl, thiazepinyl, phthalazinyl, quinoxalinyl, pyrido[2,3-b]-l,4-oxazine-3(4H)-one,

[0050] [ka] For example, when used in reference to the ring atoms of a heterocyclic group, the term "nitrogen" includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR0 (as in N-substituted pyrrolidinyl).

[0051] As used herein, the term “partially unsaturated carbocyclic group” refers to a carbocyclic ring system that contains at least one double bond between ring atoms but is not entirely aromatic. “Partially unsaturated carbocyclic group” is intended to encompass ring systems that contain only carbon atoms within the ring, which may be monocyclic, dicyclic, or tricyclic and have one or more unsaturated sites. In some embodiments, a partially unsaturated carbocyclic group may include a polycyclic ring system in which at least one ring is aromatic but at least one other ring is not aromatic. For example, a partially unsaturated heterocyclic group may include an aryl fused with a cycloalkyl, each of which may be monocyclic or bicyclic. In some embodiments, a partially unsaturated carbocyclic group may contain 7 to 14 carbon atoms, such as 7 to 10 carbon atoms or 8 to 14 carbon atoms. For example, an “8- to 14-membered partially unsaturated carbocyclic group” contains 8 to 14 carbon atoms in the cyclic portion. Partially unsaturated carbocyclic groups can have their pendant groups bonded to any carbon atom that results in a chemically stable structure. Non-limiting examples of partially unsaturated carbocyclic groups include:

[0052] [ka] These are some examples.

[0053] As described herein, various chemical groups present in the compounds herein, for example, any of the groups defined above, may be optionally substituted. Generally, the term “substituted” means that one or more hydrogen atoms of a given part are replaced with a suitable substituent. Unless otherwise specified, the chemical group to be substituted may have suitable substituents at each substituted position of the group, and if two or more positions in any given structure can be substituted with two or more substituents selected from a particular group, the substituents may be the same or different at each position. The substituent combinations assumed herein preferably result in the formation of a chemically stable or chemically feasible compound. As used herein, “chemically stable” means a compound that remains substantially unchanged when subjected to conditions that enable their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0054] In some specific embodiments, if any chemical group is substituted, it may be one, two, or three or more hydrogen atoms, halogens (i.e., -F, -Cl, -Br, -I), -OH, -CO2H, alkoxys (such as methoxy, ethoxy, or propyloxy), -OCHF2, -OCH2CHF2, -OCH2CF3, -OCH2CH2OCH3, protected alkoxys, alkyl groups as defined above (such as methyl, ethyl, propyl, or -C(CH3)3), aryl groups as defined above (such as phenyl), cycloalkyl groups as defined above (such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), oxo (=O), thioxo (=S), oxime (=N-OH), C1-C3 alkoxys Xyoxime (=N-OC1~C3 alkyl), -NO2, -CN, -NH2, -NHMe, -NHEt, -N(Me)2, -NHCOMe, -NH(COOtBu), -N(Et)(COOtBu), protected amino, -CH2OH, -COOH, -COOMe, -COOEt, -CONH2, -CONHMe, -CONHEt, -CF3, -CHF2, -CH2F, -Si(Me), -OSi(Me)2(tBu), -SMe, -SO2NH(CH2)3OH, -SO2Me, -SO2Ph, -SPh, pyrazolyl, pyrrolyl, pyridyl, piperidinyl, triazolyl, tetrazolyl, morpholinyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, benzothiazolyl, benzimidazolyl,

[0055] [ka] It can be substituted by independent substitutions, including but not limited to, substituents.

[0056] The term "pharmaceutically acceptable salt" refers to a salt of the compounds herein that is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Salts may be prepared in situ during the final isolation and purification of the compounds herein, or separately by reacting the free base functional group of the compound with a suitable organic or inorganic acid (acid addition salt), or by reacting the acidic functional group of the compound with a suitable organic or inorganic base (base addition salt). Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, or salts of amino groups formed by reacting with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphosulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, and lactobionate. Examples include, but are not limited to, salts of phosphate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.Typical base-added alkali metal salts or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, or magnesium. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, sulfons, and arylsulfons, where appropriate.

[0057] The term “solvate” refers to the physical association of one of the compounds with one or more solvent molecules. This physical association includes hydrogen bonding. In certain cases, solvates can be isolated, for example, if one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. “Solvate” encompasses both the solution phase and the isolateable solvate. Exemplary solvates include, but are not limited to, hydrates, hemihydrates, ethanolates, hemiethanolates, n-propanolates, isopropanolates, 1-butanolates, 2-butanolates, and solvates of other physiologically acceptable solvents. The compounds described herein also include their solvates and mixtures thereof.

[0058] As used herein, the term “prodrug” refers to a prodrug of a compound herein that is suitable for use in contact with human and lower animal tissues that have excessive toxicity, irritation, allergic reactions, etc., and is effective for their intended use in proportion to a reasonable benefit / risk ratio. As used herein, “prodrug” means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) and provides any compound described by the formula herein. Various forms of prodrugs are well known in the art.

[0059] The compounds of this application may be prepared, for example, by conventional chemical synthesis as illustrated in the general schemes and Examples 1 to 260 provided below. Further methods for synthesizing the compounds of the formulas herein will be obvious to those skilled in the art, as will be understood. Furthermore, various synthesis steps may be carried out in alternative order or sequence to obtain the desired compounds. Moreover, the solvents, temperatures, reaction durations, etc., described herein are for illustrative purposes only, and those skilled in the art will recognize that the desired products herein can be obtained by changing the reaction conditions. Synthetic chemical transformations and / or protecting group methodologies (protection and deprotection) useful for synthesizing the compounds described herein are well known in the art. The synthesized compounds may be separated from the reaction mixture and further purified by standard methods such as column chromatography, high-pressure liquid chromatography, or recrystallization.

[0060] Thiophene-condensed cyclohexanone derivatives, such as the compound of formula (I), may be modified by adding various functional groups via any synthetic means described herein to enhance their selective biological properties. Such modifications are well known in the art and include those that increase biopenetration into a given biological system (e.g., blood, lymphatic system, central nervous system), those that increase oral availability, those that increase solubility to enable administration by injection, those that alter metabolism, and those that alter excretion rate.

[0061] Therefore, in some embodiments, the thiophene-condensed cyclohexanone derivative is of formula (I):

[0062] [ka] Compounds having, Or it may be a pharmaceutically acceptable salt, solvate, or prodrug thereof. During the ceremony, R a -NH2, -NH-OH, -OH, -NHR b , or -NHRc R d , R b is C1~C6 alkyl, C3~C6 cycloalkyl, or 3-membered to 6-membered heterocycloalkyl, wherein C1~C6 alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -OC1~C3 alkyl, -COOH, or cyclopropyl optionally substituted with -OH, wherein C3~C6 cycloalkyl is optionally substituted with -CN, R c and R d together with the nitrogen to which they are bonded form a 4-membered heterocycloalkyl, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C1~C3 alkyl,

[0063]

Chemical Formula

[0064]

Chemical Formula

[0065] [ka] This represents A0, and R 1 but

[0066] [ka] If so, R in residue A0 2 teeth,

[0067] [ka] Unlike, Each R 5 These are independently C1-C6 alkyl groups, where each C1-C6 alkyl group has 1-3 R groups. 9 Substituents are optionally replaced, Each R 6 These are independently C3-C6 cycloalkyl, 4-6 member heterocycloalkyl, or C6-C 10 It is Ariel, Each R 7 These are independently -OH and -C(O)R 11 , C3~C6 cycloalkyl, -CN, C6~C 10 Aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6 alkyl), -N(C1-C4 alkyl)(C(O)OC1-C6 alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6 alkyl), -OR 20 -SC1~C6 alkyl, -NH2, -NH(C1~C4 alkyl), or -N(C1~C4 alkyl)2, where each C3~C6 cycloalkyl has 1 to 3 R 12 Substituents are optionally substituted, and each 5- to 10-membered heteroaryl has 1 to 3 R 13Substituents are optionally substituted, and each 4- to 6-membered heterocycloalkyl group is optionally substituted with a C1- to C4 alkyl group or an oxo group. Each R 8 These are independently halogens, C1-C6 alkyls, -OC1-C6 alkyls, C3-C6 cycloalkyls, or 5-membered-to-10-membered heteroaryls, where each -OC1-C6 alkyl is optionally substituted with a -OC1-C4 alkyl, and each 5-membered-to-10-membered heteroaryl is optionally substituted with a C1-C4 alkyl. Each R 22 These are independently C1-C6 alkyl groups that are optionally substituted with phenyl. Each R 9 These are independently -OH and -C(O)R 15 , C3~C6 cycloalkyl, -CN, C6~C 10 These are aryl, halogen, -C(O)OH, 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6 alkyl), -OC1-C6 alkyl, -SC1-C6 alkyl, -NH2, -NH(C1-C4 alkyl), or -N(C1-C4 alkyl)2, where each 4- to 6-membered heterocycloalkyl is optionally substituted with a C1-C4 alkyl, and each -OC1-C6 alkyl is optionally substituted with a -OC1-C4 alkyl. Each R 11 These are independently -NH2, -NH(C1~C4 alkyl), -N(C1~C4 alkyl)2, or 4-membered to 6-membered heterocycloalkyl groups. Each R 20 These are independently C1-C6 alkyl or 5- to 10-membered heteroaryl groups, where each C1-C6 alkyl group has 1-3 R groups. 14 The substituents are optionally substituted, and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH (cyclopropyl). Each R 12 These are independently C1-C4 alkyl, -SC1-C4 alkyl, -Ph, -OC1-C4 alkyl, or -SPh, where each C1-C4 alkyl is optionally substituted with -OH. Each R 13These are independently halogen, C1-C4 alkyl, C3-C6 cycloalkyl, -OH, -OC1-C6 alkyl, -SC1-C6 alkyl, -S(O)2C1-C6 alkyl, -NH2, -NH(C1-C4 alkyl), or -N(C1-C4 alkyl)2, where each of -OC1-C6 alkyl, -SC1-C6 alkyl, -S(O)2C1-C6 alkyl, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2 contains 1-3 R 9 Substituents are optionally replaced, Each R 14 These are independently halogens, -OC1~C4 alkyls, or C3~C6 cycloalkyls. Each R 15 These are independently -NH2, -NH(C1~C4 alkyl), -N(C1~C4 alkyl)2, or 4-membered to 6-membered heterocycloalkyl groups. R 4 These are C1-C6 alkyl, C3-C8 cycloalkyl, and C6-C 10 The aryl group is a 7- to 10-membered partially unsaturated heterocyclic group, or a 5- to 10-membered heteroaryl group, where C1-C6 alkyl and C3-C8 cycloalkyl groups have 1-3 R groups. 9 Substituents are optionally substituted, C6~C 10 Aryls and 5- to 10-membered heteroaryls have 1 to 3 R 10 Substituents are optionally replaced, however (i)R a is -OH, -NH2, or

[0068] [ka] And,

[0069] [ka] If represents A2, then the R in residue A2 4 Unlike -CH3, (ii)R a is -NH2,

[0070] [ka] If this represents A3, then the R in residue A3 4 Unlike -C(CH3)3, Each R 10 These are independently C1-C4 alkyl, halogen, -OC1-C6 alkyl, -NH2, -NH(C1-C4 alkyl), or -N(C1-C4 alkyl)2, where each C1-C4 alkyl is optionally substituted with 1-3 halogens. R 2a These are C1-C6 alkyl, C3-C8 cycloalkyl, or C6-C 10 It is an aryl group, where C1-C6 alkyl and C3-C8 cycloalkyl groups have 1-3 R 9 Substituents are optionally substituted, C6~C 10 A aryl has 1 to 3 R 10 Substituting with substituents, R 1a and R 2b These are independently -CN, C6~C 10 Aryl, C1-C6 alkyl, C3-C8 cycloalkyl, -C(O)NH2, -C(O)NHR 5 , or -C(O)OC1~C6 alkyl, where each C1~C6 alkyl has 1~3 R 16 Substituents are optionally substituted, and each C6~C 10 A aryl has 1 to 3 R 17 Substituents are optionally replaced, Each R 16 These are independently -OH, -C(O)NH2, -C(O)NH(C1~C4 alkyl), C3~C6 cycloalkyl, -CN, C6~C 10 These are aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6 alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6 alkyl), or -OC1-C4 alkyl(OC1-C4 alkyl), where each C3-C6 cycloalkyl has 1-3 R 18 Substituents are optionally substituted, and each 5- to 10-membered heteroaryl has 1 to 3 R 21Substituents are optionally substituted, and each 4- to 6-membered heterocycloalkyl group is optionally substituted with C1- to C4 alkyl groups. Each R 17 These are independently halogens, C1-C6 alkyl groups, -OC1-C6 alkyl groups, or 5- to 10-membered heteroaryl groups, where each 5- to 10-membered heteroaryl group is optionally substituted with a C1-C4 alkyl group. Each R 18 These are independently C1-C4 alkyl, -SC1-C4 alkyl, -Ph, or -OC1-C4 alkyl. Each R 21 These are independently halogens or C1-C4 alkyls. R 4a The C1-C6 alkyl or C3-C8 cycloalkyl group is a C1-C6 alkyl or C3-C8 cycloalkyl group, where each C1-C6 alkyl and C3-C8 cycloalkyl group has 1-3 R groups. 19 Substituents are optionally replaced, Each R 19 These are independently halogen, -OH, -OC1~C4 alkyl, -SC1~C4 alkyl, -NH2, -NH(C1~C4 alkyl), or -N(C1~C4 alkyl)2. R 1b and R 2c These, together with the carbon atoms to which they are bonded, form C3-C8 cycloalkyl groups, 4- to 14-membered heterocycloalkyl groups, 8- to 14-membered partially unsaturated heterocyclic groups, or 8- to 14-membered partially unsaturated carbocyclic groups, where the C3-C8 cycloalkyl group has 1-3 R 9 The substituents are optionally substituted, and the 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group are optionally substituted with 1 to 3 substituents independently selected from oxo (=O), oxime (=N-OH), C1-C3 alkoxyoxime (=N-OC1-C3 alkyl), or -OH and -CF3. R 2d and R 4bThese, together with the carbon atoms to which they are bonded, form C3-C8 cycloalkyl or 4-membered-14-membered heterocycloalkyl groups, where the C3-C8 cycloalkyl group has 1-3 R atoms. 19 Substituents are optionally replaced, R 1c and R 3 These, together with the carbon atoms to which they are bonded, form C3-C8 cycloalkyl or 4-membered-14-membered heterocycloalkyl groups, where the C3-C8 cycloalkyl group has 1-3 R atoms. 19 A compound having formula (I) that is optionally substituted with substituents, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0071] In some embodiments, the compound of formula (I) is (i)R a is -OH,

[0072] [ka] This represents A0, and R 1 but

[0073] [ka] If so, R in residue A0 2 teeth,

[0074] [ka] Unlike, (ii)R a is -OH,

[0075] [ka] If represents A2, then the R in residue A2 4 Unlike -CH3 and -CH2CH3, (iii)R a is -NH2,

[0076] [ka] If represents A2, then the R in residue A2 4 Unlike -CH3, (iv)R a is -NH2,

[0077] [ka] If this represents A3, then the R in residue A3 4 This is something different from -C(CH3)3.

[0078] In some embodiments, the compound of formula (I) is (i)R a is -OH,

[0079] [ka] This represents A0, and R 1 but

[0080] [ka] If so, R in residue A0 2 teeth,

[0081] [ka] Unlike, (ii)R a is -OH,

[0082] [ka] If represents A2, then the R in residue A2 4 Unlike -CH3 and -CH2CH3, (iii)R a is -NH2,

[0083] [ka] If represents A2, then the R in residue A2 4 Unlike -CH3, (iv)R a but

[0084] [ka] And,

[0085] [ka] If represents A2, then the R in residue A2 4 Unlike -CH3, (v)R a is -NH2,

[0086] [ka] If this represents A3, then the R in residue A3 4 This is something different from -C(CH3)3.

[0087] In other embodiments, the compound of formula (I) is (i)R a is -OH,

[0088] [ka] This represents A0, and R 1 but

[0089] [ka] If so, R in residue A0 2 teeth,

[0090] [ka] Unlike, (ii)R a is -OH,

[0091] [ka] If represents A2, then the R in residue A2 4 Unlike alkyl, (iii)R a is -NH2,

[0092] [ka] If represents A2, then the R in residue A2 4 Unlike -CH3, (iv)R a is -NH2,

[0093] [ka] If this represents A3, then the R in residue A3 4 This is something different from -C(CH3)3.

[0094] In other embodiments, the compound of formula (I) is (i)R a is -OH,

[0095] [ka] This represents A0, and R 1 but

[0096] [ka] If so, R in residue A0 2 teeth,

[0097] [ka] Unlike, (ii)R a is -OH,

[0098] [ka] If represents A2, then the R in residue A2 4 Unlike alkyl, (iii)R a is -NH2,

[0099] [ka] If represents A2, then the R in residue A2 4 Unlike -CH3, (iv)R a but

[0100] [ka] And,

[0101] [ka] If represents A2, then the R in residue A2 4 Unlike -CH3, (v)R a is -NH2,

[0102] [ka] If this represents A3, then the R in residue A3 4 This is something different from -C(CH3)3.

[0103] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is such that R is H.

[0104] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is R a ga-NHR b And R b Here, represents a C1-C6 alkyl, a C3-C6 cycloalkyl, or a 3- to 6-membered heterocycloalkyl, where the C1-C6 alkyl is optionally substituted with cyclopropyl which is optionally substituted with 1-3 halogens, 1-3 -OH groups, -OC1-C3 alkyl, -COOH, or -OH groups, and the C3-C6 cycloalkyl is optionally substituted with -CN.

[0105] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is R a ga-NHR b It is such that, R b teeth,

[0106] [ka] It represents.

[0107] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is R a ga-NHR b It is such that, R b -CH3,

[0108] [ka] It represents.

[0109] In some embodiments, R a Ha-NHR b And Rb teeth

[0110] [ka] It represents.

[0111] In other embodiments, R a -NR c R d And R c and R d These, together with the nitrogen to which they are bound, form a four-membered heterocycloalkyl group, where the four-membered heterocycloalkyl group is optionally substituted with -OH and at least one of C1-C3 alkyl groups.

[0112] In other embodiments, R a teeth,

[0113] [ka] That is the case.

[0114] In other embodiments, R a teeth,

[0115] [ka] That is the case.

[0116] In other embodiments, R a It is -OH.

[0117] In other embodiments, R a It is -NH2.

[0118] In other embodiments, R a It is -NH-OH.

[0119] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be in the form of a racemic mixture or any enantiomer.

[0120] In some embodiments, the compound of formula (I) may have the structures (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (Id), (Id'), (Ie), (Ie'), (If), (If'), or (Ig):

[0121] [ka] Represented by, In the formula, R 1 , R 2 , R 3 , R 4 , R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 2d , R 4a , R 4b , R and R a This is as defined herein.

[0122] Compounds of formulas (Ia) and (Ia') In some embodiments, the compound is a compound of formula (Ia) or (Ia'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0123] [ka]

[0124] Group R, R a , R 1 , and R 2 This can be as defined for the general formula (I) above.

[0125] In some embodiments, the compound is the compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0126] [ka]

[0127] base R a , R 1 and R 2 This can be as defined for the general formula (I) above.

[0128] In some embodiments, R 1 , R 2 These are independently -CN, C6~C 10 Aryl, C1-C6 alkyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 5-membered-to-10-membered heteroaryl, -C(O)NH2, -C(O)NHR 5 , -C(O)R 6 , or -C(O)OR 5 This can represent, where each C1-C6 alkyl group has 1-3 R 7 Substituents are optionally substituted, and each C6~C 10 A aryl has 1 to 3 R 8 Substituents are optionally substituted, and each 5- to 10-membered heteroaryl has 1 to 3 R 22 Optionally substituted with substituents, R 5 , R 6 , R 7 , R 8 , and R 22 This is as defined herein.

[0129] In some embodiments, R 1 and R 2 These are independently -CN, C6~C 10 These are aryl, C1-C6 alkyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH2, where each C1-C6 alkyl has 1-3 R 7 Substituents are optionally substituted, and each C6~C 10A aryl has 1 to 3 R 8 Substituents are optionally substituted, and each 5- to 10-membered heteroaryl has 1 to 3 R 22 Optionally substituted with substituents, R 7 , R 8 , and R 22 This is as defined herein.

[0130] In further embodiments, R 1 and R 2 R can independently represent -CN, phenyl, C1-C4 alkyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 5-membered heteroaryl, or -C(O)NH2, where each C1-C4 alkyl is 1 or 2 R 7 The substituents are optionally substituted, each phenyl group is optionally substituted with one or two halogens, and each five-membered heteroaryl group is optionally substituted with one or two -CH3 groups.

[0131] According to some embodiments, R 1 and R 2 These are independently -CN, C6~C 10 R represents an aryl, C1-C6 alkyl, C3-C8 cycloalkyl, or -C(O)NH2, where each C1-C6 alkyl is defined as having 1-2 R groups as defined herein. 7 Substitutions are optionally replaced.

[0132] In some embodiments, R 1 and / or R 2 ga-C(O)NHR 5 or -C(O)OR 5 When representing each R, 5 R can be a C1-C6 alkyl group. In other embodiments, R 1 and / or R 2 -C(O)R 6 When representing each R, 6 These can be 4- to 6-membered heterocycloalkyl groups.

[0133] In some embodiments, R 1 and / or R 2 However, 1 to 3 R7 For C1-C6 alkyl groups substituted with substituents, each R 7 These are independently -OH and -C(O)R 11 , C3~C6 cycloalkyl, -CN, C6~C 10 Aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6 alkyl), -N(C1-C4 alkyl)(C(O)OC1-C6 alkyl), -NH(C(O)C1-C6 alkyl), 4- to 6-membered heterocycloalkyl, -OR 20 -SC1~C6 alkyl, -NH2, or -N(C1~C4 alkyl)2, where each C3~C6 cycloalkyl has 1 to 3 R 12 Substituents are optionally substituted, and each 5- to 10-membered heteroaryl has 1 to 3 R 13 Substituents are optionally substituted, and each 4- to 6-membered heterocycloalkyl group is optionally substituted with a C1- to C4 alkyl group or an oxo group.

[0134] Several embodiments, each R 7 These are independently -OH and -C(O)R 11 , -OR 20 , C3~C6 cycloalkyl, -CN, C6~C 10 It may represent an aryl, halogen, -C(O)OH, or a 5- to 10-membered heteroaryl, where each C3-C6 cycloalkyl has 1-3 R 12 Substituents are optionally substituted, and each 5- to 10-membered heteroaryl has 1 to 3 R 13 Substitutions are optionally replaced.

[0135] In further embodiments, R 7 These are independently -OH, -C(O)NH2, and -OR 20 The group can represent a C3-C6 cycloalkyl group, -CN, phenyl, halogen, -C(O)OH, or a 5-membered heteroaryl group, where each C3-C6 cycloalkyl group is optionally substituted with -CH3.

[0136] In another embodiment, R 7These are independently -OH, -C(O)NH2, C3~C6 cycloalkyl, -CN, C6~C 10 It can represent an aryl, halogen, or 5- to 8-membered heteroaryl, where each C3-C6 cycloalkyl is optionally substituted with 1-2 C1-C4 alkyl groups, and each 5- to 8-membered heteroaryl is optionally substituted with 1-2 R 13 Substitutions are optionally replaced.

[0137] In some embodiments, the above R 11 The substituents can independently represent -NH2, -NH(C1-C4 alkyl), or 4- to 6-membered heterocycloalkyl. In some specific embodiments, R 11 This can represent -NH2.

[0138] In some embodiments, the above R 12 The substituents can independently represent C1-C4 alkyl, -SC1-C4 alkyl, -Ph, -OC1-C4 alkyl, or -SPh, where each C1-C4 alkyl is optionally substituted with -OH. In some specific embodiments, R 12 These are C1-C4 alkyl groups.

[0139] In some embodiments, the above R 13 The substituents can independently represent a halogen, a C1-C4 alkyl, or a C3-C6 cycloalkyl. In some specific embodiments, R 13 These are independently halogens or C1-C4 alkyl groups.

[0140] In some embodiments, the above R 14 The substituents can independently represent halogens, -OC1-C4 alkyls, or C3-C6 cycloalkyls. In some specific embodiments, R 14 It is a halogen.

[0141] In some embodiments, the above R 20 The substituents may independently represent a C1-C6 alkyl or a 5- to 10-membered heteroaryl, where each C1-C6 alkyl is one to three R groups as defined herein.14 Substituents are optionally substituted, and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH (cyclopropyl). In some specific embodiments, R 20 These are C1-C6 alkyl groups, where each C1-C6 alkyl group has 1-3 R groups as defined herein. 14 It is optionally substituted with substituents. In further embodiments, R 20 is a C1-C6 alkyl group, where each C1-C6 alkyl group is optionally substituted with 1-3 halogens. In some embodiments, R 20 R is a 5- to 10-membered heteroaryl substituted with -OH or -NH (cyclopropyl). In certain embodiments, R 20 is a 5- to 10-membered heteroaryl substituted with -OH. In other embodiments, R 20 These are 5-membered or 6-membered heteroaryl compounds substituted with -OH groups.

[0142] In some embodiments, the above R 22 The substituents can independently represent C1-C4 alkyl groups.

[0143] In some embodiments, R 1 and / or R 2 However, 1 to 3 R 8 C6~C substituted with substituents 10 When representing an arrow, each R 8 R can independently represent a halogen, a C1-C6 alkyl, or a -OC1-C6 alkyl, where each -OC1-C6 alkyl is optionally substituted with a -OC1-C4 alkyl. In some specific embodiments, R 8 is a halogen. In some embodiments, R 1 and / or R 2 However, 1 to 3 R 22 When representing a 5- to 10-membered heteroaryl substituted with a substituent, each R 22 R can independently represent a C1-C6 alkyl group optionally substituted with phenyl. In some embodiments, R 22 These are C1-C2 alkyl groups substituted with phenyl.

[0144] In some embodiments, R 1 and R 2 These are independently -CN, C6~C 10 Aryl, C1-C6 alkyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 5-membered-to-10-membered heteroaryl, -C(O)NH2, -C(O)NHR 5 , -C(O)R 6 , or -C(O)OR 5 Here, each C1-C6 alkyl group has 1-3 R 7 Substituents are optionally substituted, and each C6~C 10 A aryl has 1 to 3 R 8 Substituents are optionally substituted, and each 5- to 10-membered heteroaryl has 1 to 3 R 22 Substituents are optionally replaced, Each R 5 These are independently C1-C6 alkyl groups, Each R 6 These are independently 4-membered to 6-membered heterocycloalkyl groups. Each R 7 These are independently -OH and -C(O)R 11 , C3~C6 cycloalkyl, -CN, C6~C 10 Aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6 alkyl), -N(C1-C4 alkyl)(C(O)OC1-C6 alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6 alkyl), -OR 20 -SC1~C6 alkyl, -NH2, or -N(C1~C4 alkyl)2, where each C3~C6 cycloalkyl has 1 to 3 R 12 Substituents are optionally substituted, and each 5- to 10-membered heteroaryl has 1 to 3 R 13 Substituents are optionally substituted, and each 4- to 6-membered heterocycloalkyl group is optionally substituted with a C1- to C4 alkyl group or an oxo group. Each R 8 These are independently a halogen, a C1-C6 alkyl, or a -OC1-C6 alkyl, where each -OC1-C6 alkyl is optionally substituted with a -OC1-C4 alkyl. Each R 22 These are independently C1-C6 alkyl groups that are optionally substituted with phenyl. Each R 11 These are independently -NH2, -NH(C1~C4 alkyl), or 4-membered to 6-membered heterocycloalkyl groups. Each R 20 These are independently C1-C6 alkyl or 5- to 10-membered heteroaryl groups, where each C1-C6 alkyl group has 1-3 R groups. 14 The substituents are optionally substituted, and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH (cyclopropyl). Each R 12 These are independently C1-C4 alkyl, -SC1-C4 alkyl, -Ph, -OC1-C4 alkyl, or -SPh, where each C1-C4 alkyl is optionally substituted with -OH. Each R 13 These are independently halogens, C1-C4 alkyls, or C3-C6 cycloalkyls. Each R 14 These are independently halogens, -OC1-C4 alkyl groups, or C3-C6 cycloalkyl groups.

[0145] In some embodiments, R 1 and R 2 These are independently -CN, C6~C 10 These are aryl, C1-C6 alkyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH2, where each C1-C6 alkyl has 1-3 R 7 Substituents are optionally substituted, and each C6~C 10 A aryl has 1 to 3 R 8 Substituents are optionally substituted, and each 5- to 10-membered heteroaryl has 1 to 3 R 22 Substituents are optionally replaced, Each R 7 These are independently -OH and -C(O)R 11 , C3~C6 cycloalkyl, -CN, C6~C 10Aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6 alkyl), -N(C1-C4 alkyl)(C(O)OC1-C6 alkyl), -NH(C(O)C1-C6 alkyl), 4- to 6-membered heterocycloalkyl, -OR 20 -SC1~C6 alkyl, -NH2, or -N(C1~C4 alkyl)2, where each C3~C6 cycloalkyl has 1 to 3 R 12 Substituents are optionally substituted, and each 5- to 10-membered heteroaryl has 1 to 3 R 13 Substituents are optionally substituted, and each 4- to 6-membered heterocycloalkyl group is optionally substituted with a C1- to C4 alkyl group or an oxo group. Each R 8 These are independently a halogen, a C1-C6 alkyl, or a -OC1-C6 alkyl, where each -OC1-C6 alkyl is optionally substituted with a -OC1-C4 alkyl. Each R 11 These are independently -NH2, -NH(C1~C4 alkyl), or 4-membered to 6-membered heterocycloalkyl groups. Each R 20 These are independently C1-C6 alkyl or 5- to 10-membered heteroaryl groups, where each C1-C6 alkyl group has 1-3 R groups. 14 The substituents are optionally substituted, and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH (cyclopropyl). Each R 12 These are independently C1-C4 alkyl, -SC1-C4 alkyl, -Ph, -OC1-C4 alkyl, or -SPh, where each C1-C4 alkyl is optionally substituted with -OH. Each R 13 These are independently halogens, C1-C4 alkyls, or C3-C6 cycloalkyls. Each R 14 These are independently halogens, -OC1~C4 alkyls, or C3~C6 cycloalkyls. Each R 22 These are independently C1-C4 alkyl groups.

[0146] In some embodiments, R 1 and R 2 These are independently -CN, C6~C 10 These are aryl, C1-C6 alkyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH2, where each C1-C6 alkyl has 1-3 R 7 Substituents are optionally substituted, and each C6~C 10 A aryl has 1 to 3 R 8 Substituents are optionally substituted, and each 5- to 10-membered heteroaryl has 1 to 3 R 22 Substituents are optionally replaced, Each R 7 These are independently -OH and -C(O)R 11 , -OR 20 , C3~C6 cycloalkyl, -CN, C6~C 10 These are aryl, halogen, -C(O)OH, or 5- to 10-membered heteroaryl groups, where each C3-C6 cycloalkyl group has 1-3 R groups. 12 Substituents are optionally substituted, and each 5- to 10-membered heteroaryl has 1 to 3 R 13 Substituents are optionally replaced, Each R 8 It is a halogen, Each R 11 It is -NH2, Each R 20 The C1-C6 alkyl group or the 5-membered or 6-membered heteroaryl group, where each C1-C6 alkyl group has 1-3 R groups. 14 The substituents are optionally substituted, and each 5-membered or 6-membered heteroaryl is optionally substituted with -OH or -NH (cyclopropyl), Each R 12 These are C1-C4 alkyl groups, Each R 13 These are independently halogens or C1-C4 alkyls. Each R 14 It is a halogen, Each R 22 These are independently C1-C4 alkyl groups.

[0147] In some embodiments, R 1 and R 2 R independently represents -CN, phenyl, C1-C4 alkyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 5-membered heteroaryl, or -C(O)NH2, where each C1-C4 alkyl is one or two R 7 The substituents are optionally substituted, each phenyl group is optionally substituted with one or two halogens, and each 5-membered heteroaryl group is optionally substituted with one or two -CH3 groups. Each R 7 These are independently -OH, -C(O)NH2, and -OR 20 The C3-C6 cycloalkyl group is a -CN group, a phenyl group, a halogen group, a -C(O)OH group, or a 5-membered heteroaryl group, where each C3-C6 cycloalkyl group is optionally substituted with -CH3. Each R 20 The group is a C1-C6 alkyl group or a 5-membered or 6-membered heteroaryl group, where each C1-C6 alkyl group is optionally substituted with 1-3 halogens, and each 5-membered or 6-membered heteroaryl group is optionally substituted with an -OH group.

[0148] In some embodiments, R 1 and R 2 These are independently -CN, C6~C 10 This represents an aryl, C1-C6 alkyl, C3-C8 cycloalkyl, 5-membered heteroaryl, or -C(O)NH2, where each C1-C6 alkyl has 1-2 R 7 Substituents are optionally replaced, Each R 7 These are independently -OH, -C(O)NH2, C3~C6 cycloalkyl, -CN, C6~C 10 The compounds are aryl, halogen, or 5- to 8-membered heteroaryls, where each C3-C6 cycloalkyl is optionally substituted with 1-2 C1-C4 alkyl groups, and each 5- to 8-membered heteroaryl is optionally substituted with 1-2 R 13 Substituents are optionally replaced, Each R 13 These are independently halogens or C1-C4 alkyl groups.

[0149] In some embodiments, R 1 and R 2 These may be the same or different, and can represent the following:

[0150] [ka]

[0151] In some embodiments, R 1 and R 2 These may be the same or different, and can represent the following:

[0152] [ka]

[0153] In some embodiments, R 1 and R 2 These may be the same or different, and can represent the following:

[0154] [ka]

[0155] In some embodiments, R 1 and R 2 These may be the same or different, and can represent the following:

[0156] [ka]

[0157] In some embodiments, R 1 and R 2 These may be the same or different, and can represent the following:

[0158] [ka]

[0159] In some embodiments, R 1 and R 2 These may be the same or different, and can represent the following:

[0160] [ka]

[0161] In some embodiments, R 1 and R 2 These may be the same or different, and can represent the following:

[0162] [ka]

[0163] In some embodiments, R 1 and R 2 These may be the same or different, and can represent the following:

[0164] [ka]

[0165] In some embodiments, R 1 and R 2 These may be the same or different, and can represent the following:

[0166] [ka]

[0167] In some embodiments, R 1 and R 2 These may be the same or different, and can represent the following:

[0168] [ka]

[0169] In some embodiments, R 1 and R 2 These may be the same or different, and can represent the following:

[0170] [ka]

[0171] In some embodiments, R 1 and R 2 These may be the same or different, and can represent the following:

[0172] [ka]

[0173] In some specific embodiments, R 1 and R 2 They are different. In another specific embodiment, R 1 and R 2 One of these is -CN. Other embodiments include compounds of formula (Ia) or (Ia'), or pharmaceutically acceptable salts, solvates, or prodrugs thereof, where R 1 and R 2 One of them is,

[0174] [ka] That is the case.

[0175] Compounds of formulas (Ib) and (Ib') In some embodiments, the compound is a compound of formula (Ib) or (Ib'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0176] [ka]

[0177] Group R, R a , and R 4 This can be as defined for the general formula (I) above.

[0178] In some embodiments, the compound is the compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0179] [ka]

[0180] base R a and R 4 This can be as defined for the general formula (I) above.

[0181] In some embodiments, R 4 C1-C6 alkyl, C6-C 10 The aryl group can represent a 7- to 10-membered partially unsaturated heterocyclic group, or a 5- to 10-membered heteroaryl group, where the C1-C6 alkyl group has 1-3 R 9 Substituents are optionally substituted, C6~C 10 Aryls and 5- to 10-membered heteroaryls have 1 to 3 R 10 The substituent is optionally substituted, where R 9 and R 10 This is as defined herein.

[0182] In some embodiments, R 4 C1-C6 alkyl, C6-C 10 The aryl group can represent a 7- to 10-membered partially unsaturated heterocyclic group, or a 5- to 10-membered heteroaryl group, where C6-C 10 Aryls and 5- to 10-membered heteroaryls have 1 to 3 R 10 The substituent is optionally substituted, where R 10 The substituents are as defined herein.

[0183] In some embodiments, R 4 R can represent a C1-C4 alkyl group, a phenyl group, a 9-membered partially unsaturated heterocyclic group, or a 5-6 membered heteroaryl group, where phenyl and 5-6 membered heteroaryl groups have 1 or 2 R 10 The substituent is optionally substituted, where R 10 The substituents are as defined herein.

[0184] In some embodiments, R 10 The substituents can independently represent C1-C4 alkyl, halogen, -OC1-C6 alkyl, -NH2, -NH(C1-C4 alkyl), or -N(C1-C4 alkyl)2, where each C1-C4 alkyl is optionally substituted with 1 to 3 halogens.

[0185] In other embodiments, R 10 The substituents can independently represent C1-C4 alkyl, halogen, -OC1-C6 alkyl, or -N(C1-C4 alkyl)2, where each C1-C4 alkyl is optionally substituted with 1-3 halogens.

[0186] In further embodiments, R 10 The substituents can independently represent -CF3, halogen, -OCH3, or -N(CH3)2.

[0187] In some embodiments, R 4 C1-C6 alkyl, C6-C 10 An aryl group is a partially unsaturated heterocyclic group with 7 to 10 members, or a heteroaryl group with 5 to 10 members, where C6 to C6 10 Aryls and 5- to 10-membered heteroaryls have 1 to 3 R 10 Substituents are optionally replaced, Each R 10 These are independently C1-C4 alkyl, halogen, -OC1-C6 alkyl, -NH2, -NH(C1-C4 alkyl), or -N(C1-C4 alkyl)2, where each C1-C4 alkyl is optionally substituted with 1 to 3 halogens.

[0188] In some embodiments, R 4 C1-C6 alkyl, C6-C 10 An aryl group is a partially unsaturated heterocyclic group with 7 to 10 members, or a heteroaryl group with 5 to 10 members, where C6 to C6 10 Aryls and 5- to 10-membered heteroaryls have 1 to 3 R 10 Substituents are optionally replaced, Each R 10 These are independently C1-C4 alkyl, halogen, -OC1-C6 alkyl, or -N(C1-C4 alkyl)2, where each C1-C4 alkyl is optionally substituted with 1-3 halogens.

[0189] In some embodiments, R 4 is a C1-C4 alkyl, phenyl, a 9-membered partially unsaturated heterocyclic group, or a 5-6 membered heteroaryl, where phenyl and 5-6 membered heteroaryls are optionally substituted with one or two R10 substituents, and each R 10 These are independently -CF3, halogen, -OCH3, or -N(CH3)2.

[0190] Specific R 4 Examples of the basis include the following:

[0191] [ka]

[0192] Compounds of formulas (Ic) and (Ic') In some embodiments, the compound is a compound of formula (Ic) or (Ic'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0193] [ka]

[0194] Group R, R a and R 2aThis can be as defined for the general formula (I) above.

[0195] In some embodiments, the compound is the compound of formula (Ic), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0196] [ka]

[0197] base R a and R 2a This can be as defined for the general formula (I) above.

[0198] In some embodiments, R 2a C1-C6 alkyl or C6-C 10 It can represent an aryl group, where C1-C6 alkyl groups have 1-3 R 9 Substituents are optionally substituted, C6~C 10 A aryl has 1 to 3 R 10 Optionally substituted with substituents, R 9 and R 10 This is as defined herein.

[0199] In some embodiments, R 2a C1-C6 alkyl or C6-C 10 It can represent an aryl group, where the C1-C6 alkyl group is optionally substituted with 1-3 halogens.

[0200] In some embodiments, R 2a This is a C1-C4 alkyl group or, more preferably, a C1-C6 alkyl group such as ethyl.

[0201] Compounds of formulas (Id) and (Id') In some embodiments, the compound is a compound of formula (Id) or (Id'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0202] [ka]

[0203] Group R, R a , R 1a , R 2b , and R 4a This can be as defined for the general formula (I) above.

[0204] In some embodiments, the compound is the compound of formula (Id), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0205] [ka]

[0206] base R a , R 1a , R 2b , and R 4a This can be as defined for the general formula (I) above.

[0207] In some embodiments, R 1a and R 2b These are independently -CN, C6~C 10 The terms may represent aryl, C1-C6 alkyl, C3-C8 cycloalkyl, or -C(O)NH2, where each C1-C6 alkyl is one- or two R as defined herein. 16 Substitutions are optionally replaced.

[0208] In some embodiments, R 1a and R 2b These are independently -CN or C6~C 10 It can represent an arrow.

[0209] In some embodiments, R 4a This can represent C1-C6 alkyl groups.

[0210] In some embodiments, substituent R 16These are independently -OH, -C(O)NH2, C3~C6 cycloalkyl, -CN, C6~C 10 The terms may represent aryls, halogens, or 5- to 8-membered heteroaryls, where each C3- to C6 cycloalkyl is optionally substituted with 1-2 C1- to C4 alkyls, and each 5- to 10-membered heteroaryl is substituted with 1-2 R as defined herein. 21 Substitutions are optionally replaced.

[0211] Several embodiments, each R 21 This can independently represent a halogen or a C1-C4 alkyl group.

[0212] In some embodiments, R 1a and R 2b These are independently -CN, C6~C 10 The elements are aryl, C1-C6 alkyl, C3-C8 cycloalkyl, or -C(O)NH2, where each C1-C6 alkyl has 1-2 R 16 Substituents are optionally replaced, Each R 16 These are independently -OH, -C(O)NH2, C3~C6 cycloalkyl, -CN, C6~C 10 These are aryl, halogen, or 5- to 8-membered heteroaryl groups, where each C3-C6 cycloalkyl group is optionally substituted with 1-2 C1-C4 alkyl groups, and each 5- to 10-membered heteroaryl group is optionally substituted with 1-2 R groups. 21 Substituents are optionally replaced, Each R 21 These are independently halogens or C1-C4 alkyl groups.

[0213] Compounds of formulas (Ie) and (Ie') In some embodiments, the compound is a compound of formula (Ie) or (Ie'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0214] [ka]

[0215] Group R, R a , R 1b , and R 2c This can be as defined for the general formula (I) above.

[0216] In some embodiments, the compound is a compound of formula (Ie), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0217] [ka]

[0218] base R a , R 1b , and R 2c This can be as defined for the general formula (I) above.

[0219] In some embodiments, R 1b and R 2c These, together with the carbon atoms to which they are bonded, can form C3-C8 cycloalkyl groups, 4- to 14-membered heterocycloalkyl groups, 8- to 14-membered partially unsaturated heterocyclic groups, or 8- to 14-membered partially unsaturated carbocyclic groups, where each of the 4- to 14-membered heterocycloalkyl groups, 8- to 14-membered partially unsaturated heterocyclic groups, or 8- to 14-membered partially unsaturated carbocyclic groups is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), oxime (=N-OH), C1-C3 alkoxyoxime (=N-OC1-C3 alkyl), or -OH and -CF3.

[0220] In some embodiments, R 1b and R 2c These, together with the carbon atoms to which they are bonded, can form a C3-C8 cycloalkyl or an 8- to 10-membered partially unsaturated carbocyclic group, where the 8- to 10-membered partially unsaturated carbocyclic group is optionally substituted with 1-2 substituents independently selected from oxo (=O), oxime (=N-OH), methoxyoxime (=N-OCH3), or -OH and -CF3.

[0221] In some embodiments, R 1b and R 2c These, together with the carbon atoms to which they are bonded, form C4-C6 cycloalkyl groups, or

[0222] [ka] A base can be formed by selecting from, where the dashed line is R 1b and R 2c This represents a portion of the cyclohexanone moiety of a compound having formula (Ie) or (Ie').

[0223] In some embodiments, R 1b and R 2c Together with the carbon atoms to which they are bonded, they form cyclopentyl, or

[0224] [ka] A group is formed by selecting from, where the dashed line is R 1b and R 2c This represents a portion of the cyclohexanone moiety of a compound having formula (Ie) or (Ie').

[0225] In some embodiments, R 1b and R 2c Together with the carbon atoms to which they are bonded,

[0226] [ka] A base can be formed by selecting from, where the dashed line is R 1b and R 2c This represents a portion of the cyclohexanone moiety of a compound having formula (Ie) or (Ie').

[0227] In some embodiments, R 1b and R 2cThese can combine with the carbon atoms to which they are bonded to form cyclopentyls.

[0228] Compounds of formulas (If) and (If') In some embodiments, the compound is a compound of formula (If) or (If'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0229] [ka]

[0230] Group R, R a , R 2d , and R 4b This can be as defined for the general formula (I) above.

[0231] In some embodiments, the compound is a compound of formula (If), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0232] [ka]

[0233] base R a , R 2d , and R 4b This can be as defined for the general formula (I) above.

[0234] In some embodiments, R 2d and R 4b These, together with the carbon atoms to which they are bonded, can form C3-C8 cycloalkyl groups, each C3-C8 cycloalkyl group having 1-3 R atoms as defined herein. 19 Substitutions are optionally replaced.

[0235] In some embodiments, R 2d and R 4b These can combine with the carbon atoms to which they are bonded to form C3-C8 cycloalkyl groups.

[0236] In some embodiments, R 2d and R 4b These can combine with the carbon atoms to which they are bonded to form cyclohexyl molecules.

[0237] Compound of formula (Ig) In some embodiments, the compound is the compound of formula (Ig), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0238] [ka]

[0239] base R a , R 1c and R 3 This can be as defined for the general formula (I) above.

[0240] In some embodiments, R 1c and R 3 These, together with the carbon atoms to which they are bonded, can form C3-C8 cycloalkyl groups, each C3-C8 cycloalkyl group having 1-3 R atoms as defined herein. 19 Substitutions are optionally replaced.

[0241] In some embodiments, R 1c and R 3 These can combine with the carbon atoms to which they are bonded to form C3-C8 cycloalkyl groups.

[0242] In some embodiments, R 1c and R 3 These can combine with the carbon atoms to which they are bonded to form cyclohexyl molecules.

[0243] In some embodiments, the compounds of formula (I) described herein are compounds 4, 8, 9, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60a, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 108, 109, 119, 120, 121, 122, 12 3, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 154, 155, 163, 168, 169 ,170,173,174,175,178,179,180,181,183,189,190,191,192,193,194,195,197,198,199,200,201,202,211,212,213,214,215,216,219,221,227, 228, 229, 230, 231, 232, 237, 238, 239, 245, 246, 247, 248, 249, 250, 251, 253, 254, 255, 257, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 2 90, 291, 297, 298, 305, 306, 313, 314, 321, 322, 330, 331, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 352, 353, 354, 355, 356, 357, 35 8, 360, 362, 371, 378, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403, 406, 407, 408, 412, 413, 414, 416, 418, 422, 427, 428, 429, 430, 431 ,433,434,445,446,447,448,449,450,451,452,453,454,462,463,464,465,466,468,469,470,471,472,473,474,475,476,478,479,480,481,482,It may be selected from 483, 486, 488, 489, 492, 495, 496, 497, 498, 511, 512, 513, 514, 515, 520, 523, 524, or 534, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0244] [Table 1-1]

[0245] [Table 1-2]

[0246] [Table 1-3]

[0247] [Table 1-4]

[0248] [Table 1-5]

[0249] [Table 1-6]

[0250] [Table 1-7]

[0251] [Table 1-8]

[0252] [Table 1-9]

[0253] Table 1-10

[0254] Table 1-11

[0255] Table 1-12

[0256] Table 1-13

[0257] Table 1-14

[0258] Table 1-15

[0259] Table 1-16

[0260] In some embodiments, the compounds of formula (I) described herein are compounds 4, 9, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60a, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 7 2, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175 ,179,180,181,183,189,191,192,193,194,195,197,198,199,200,201,202,211,212,213,214,215,216,219,221,228,229,230,231,232,237,238,239,246,247,248,249,250,251,253,254,255,258,263,264,271,272,273, 278, 279, 280, 281, 287, 288, 291, 297, 298, 305, 306, 313, 314, 321, 322, 331, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 352, 353, 354, 355, 356, 357, or 358, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0261] In some embodiments, the compounds of formula (I) described herein are compounds 4, 9, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 1 75, 179, 180, 181, 183, 189, 191, 192, 193, 194, 195, 198, 199, 200, 201, 202, 211, 212, 213, 214, 215, 216, 219, 228, 230, 231, 232, 237, 238, 239, 246, 247, 248, 249, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 2 79, 280, 281, 287, 288, 291, 297, 298, 305, 306, 313, 314, 321, 322, 331, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 352, 353, 354, 355, 356, 357, or 358, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0262] In some embodiments, the compounds of formula (I) described herein are compounds 4, 9, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 71, 7 2, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 189, 191, 192, 194, 195, 198, 199, 201, 202, 212, 213, 214, 215, 216, 228, 230, 231, 232, 237, 238, 239, 246, 248, 249, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 28 0, 281, 287, 288, 291, 297, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 352, 353, 354, 355, 356, 357, or 358, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0263] In some embodiments, the compounds of formula (I) described herein are compounds 4, 9, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 127, 128, 129 ,130,131,132,133,134,135,136,138,139,140,141,143,144,145,146,147,148,149,150,155,163,168,169,170,173,174,175,179,180,181,183,189,191,192,194,195,198,199,201,202,212,213,214,215,216,228,230,231,232,237,238,239,245,246,248,249,250,251,25 3, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 291, 297, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342 , 343, 344, 345, 346, 347, 352, 353, 354, 355, 356, 357, 358, 391, 392, 39 3, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403, 406, 407, 408, 413, 4 14, 416, 418, 422, 427, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 453, 454, 462, 463, 464, 465, 466, 468, 470, 472, 474, 475, 476, 478, 479, 480, 481, 482, 486, 489, 492, 495, 496, 498, 511, 512, 513, 514, 515, 520, or 524, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0264] In some embodiments, the compounds of formula (I) described herein are compounds 4, 15, 16, 17, 20, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61, 62, 63, 64, 65, 66, 67, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 127, 128, 129, 130, 131, 1 32, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 191, 192, 194, 195, 198, 199, 201, 202, 212, 213, 214, 215, 216, 228, 230, 231, 232, 237, 238, 239, 246, 248, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344 , 345, 346, 347, 352, 353, 354, 355, 356, 357, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403, 406, 407, 408, 413, 41 4, 416, 418, 422, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 453, 454, 462, 463, 464, 465, 466, 468, 470, 472, 474, 475, 476, 479, 480, 481, 482, 486, 489, 495, 496, 498, 511, 512, 513, 514, 515, 520, or 524, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0265] In some embodiments, the compounds of formula (I) described herein are compounds 4, 15, 16, 20, 25, 26, 29, 30, 31, 32, 33, 34, 37, 47, 48, 49, 50, 51, 52, 54, 59, 60b, 61, 62, 63, 64, 65, 72, 75, 82, 83, 84, 89, 91, 97, 101, 109, 119, 121, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136 ,138,139,140,141,143,144,145,146,147,148,149,150,155,163,168,169,170,173,174,175,179,180,181,183,191,192,194,195,201,212,213,214,215,216,230,231,232,238,239,246,248,250,251,253,254,255,258,263,264,271,272,2 73, 278, 279, 280, 281, 288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 346, 352, 353, 354, 355, 356, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403, 406, 407, 408, 413, 414, 416, 418, 422, 428 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 453, 454, 462, 463, 464, 465, 466, 468, 470, 472, 474, 475, 476, 479, 480, 481, 482, 486, 489, 495, 496, 498, 511, 512, 513, 514, 515, 520, or 524, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0266] In some embodiments, the compounds of formula (I) described herein are compounds 4, 15, 16, 20, 25, 26, 29, 30, 31, 32, 33, 34, 37, 47, 48, 49, 50, 51, 52, 54, 59, 60b, 61, 62, 63, 64, 65, 72, 75, 82, 83, 84, 89, 91, 97, 101, 109, 119, 121, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135 ,136,138,139,140,141,143,144,145,146,147,148,149,150,155,163,168,169,170,173,174,175,179,180,181,183,191,192,194,195,201,212,213,214,215,216,230,231,232,238,239,245,246,248,250,251,253,254,255,258,263,2 64, 271, 272, 273, 278, 279, 280, 281, 288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 34 5, 346, 352, 353, 354, 355, 356, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407, 408, 413, 414, 416, 418 , 422, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 453, 454, 462, 463, 464, 465, 466, 468, 472, 475, 476, 479, 480, 481, 482, 486, 489, 495, 496, 498, 511, 512, 514, 515, 520, or 524, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0267] In some embodiments, the compounds of formula (I) described herein are compounds 4, 15, 25, 32, 33, 47, 48, 49, 50, 52, 54, 59, 60b, 61, 62, 63, 72, 75, 82, 83, 89, 97, 101, 109, 119, 121, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139 of Table 1 above. ,140,141,143,144,145,146,147,148,149,150,163,169,170,174,179,181,183,191,192,194,195,212,213,214,215,230,231,232,238,239,246,248,250,251,253,254,255,258,263,264,272,273,2 78, 279, 280, 281, 288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 34 5, 353, 355, 356, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407, 408, 413, 418, 422 , 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 454, 463, 464, 465, 466, 472, 475, 476, 479, 481, 486, 489, 495, 498, 512, 514, 515, 520, or 524, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0268] In some embodiments, the compounds of formula (I) described herein are compounds 15, 25, 32, 48, 49, 50, 52, 54, 59, 60b, 61, 62, 63, 72, 75, 82, 83, 97, 101, 109, 119, 127, 128, 129, 130, 135, 136, 140, 141, 143, 144, 145, 1 46, 147, 148, 149, 150, 163, 169, 170, 174, 179, 181, 183, 191, 192, 194, 195, 212, 213, 215, 230, 231, 232, 238, 239, 246, 248, 250, 251, 254, 255, 258, 263, 272, 273, 279, 281, 288, 291, 30 6, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 353, 355, 356, 358, 391, 39 2, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407, 408, 413, 418, 422, 428, 429, 430, 431 434, 445, 446, 447, 448, 449, 450, 451, 454, 463, 464, 465, 466, 472, 475, 476, 479, 481, 486, 489, 495, 498, 512, 514, 515, 520, or 524, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0269] In some embodiments, the compounds of formula (I) described herein are compounds 15, 25, 32, 48, 49, 50, 52, 54, 59, 60b, 61, 62, 63, 72, 75, 82, 83, 97, 101, 109, 119, 127, 128, 129, 130, 135, 136, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 163, 169, 170, 174, 179, 181, 183, 191, 192, 194, 195, 212, 213, 215, 230, 231, 232, 238, 239, 246, 248, 250, 251, 254, 255, 258, 263, 272, 273, 279, 281, 288, 291, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 34 3, 344, 345, 353, 355, 356, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407, 418, 428, 430, 431, 434, 445, 446, 447, 448, 449, 450, 454, 463, 464, 465, 466, 476, 489, 512, 514, 515, or 524, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0270] In some embodiments, the compounds of formula (I) described herein are compounds 48, 50, 54, 60b, 61, 63, 72, 75, 83, 97, 101, 109, 127, 135, 140, 141, 143, 144, 145, 146, 147, 149, 163, 169, 170, 174, 179, 181, 191, 194, 195, 212, 215, 230, 231, 232, 238, 246, 248, 250, 251, 255, 258, 272, 2 73, 279, 281, 291, 306, 314, 321, 322, 331, 338, 339, 340, 341, 342, 345, 353, 355, 356, 391, 393, 395a, 395b, 397, 402, 428, 430, 431, 434, 446, 447, 448, 450, 463, 464, 465, 466, 489, 512, 514, 515, or 524, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0271] In some embodiments, the compounds of formula (I) described herein are compounds 48, 50, 54, 60b, 61, 63, 75, 83, 97, 101, 127, 135, 140, 141, 143, 144, 146, 147, 149, 163, 170, 174, 181, 191, 195, 215, 230, 231, 232, 238, 246, 248, 250, 251, 255, 258, 272, 273, 279, 281, 306, 314, 322, 338, 339, 340, 345, 353, 355, 356, 391, 393, 397, 402, 428, 430, 431, 434, 446, 447, 450, 463, 465, 466, 489, 512, 514, 515, or 524, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0272] In some embodiments, the compound of formula (I) described herein is compound 54, 61, 63, 75, 140, 143, 146, 174, 215, 230, 250, 251, 273, 306, 322, 430, 446, 463, or 512 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 61, 63, 75, 143, 146, 174, 230, 250, 273, or 306 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0273] In some embodiments, the compound of formula (I) described herein is compound 4 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 33 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 47 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 89 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 121 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 131 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 132 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 133 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 134 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 138 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 139 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, the compound of formula (I) described herein is compound 214 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 253 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 264 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 278 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 280 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 298 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 305 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 408 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 413 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 422 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 429 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, the compound of formula (I) described herein is compound 451 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 472 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 475 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 479 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 481 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 486 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 495 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 498 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 520 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0274] In some embodiments, the compound of formula (I) described herein is compound 15 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 25 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 32 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 49 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 52 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 59 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 62 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 72 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 82 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 109 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 119 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, the compound of formula (I) described herein is compound 128 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 129 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 130 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 136 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 145 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 148 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 150 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 169 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 179 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 183 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 192 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, the compound of formula (I) described herein is compound 194 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 212 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 213 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 239 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 254 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 263 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 288 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 291 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 313 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 321 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 331 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, the compound of formula (I) described herein is compound 341 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 342 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 343 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 344 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 358 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 392 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 394a in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 394b in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 395a in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 395b in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 396 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, the compound of formula (I) described herein is compound 403 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 407 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 418 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 445 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 448 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 449 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 454 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 464 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 476 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0275] In some embodiments, the compound of formula (I) described herein is compound 48 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 50 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 54 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 60b in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 61 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 63 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 75 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 83 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 97 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 101 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 127 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, the compound of formula (I) described herein is compound 135 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 140 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 141 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 143 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 144 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 146 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 147 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 149 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 163 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 170 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 174 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, the compound of formula (I) described herein is compound 181 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 191 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 195 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 215 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 230 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 231 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 232 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 238 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 246 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 248 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 250 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, the compound of formula (I) described herein is compound 251 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 255 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 258 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 272 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 273 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 279 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 281 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 306 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 314 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 322 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 338 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, the compound of formula (I) described herein is compound 339 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 340 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 345 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 353 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 355 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 356 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 391 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 393 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 397 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 402 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 428 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, the compound of formula (I) described herein is compound 430 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 431 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 434 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 446 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 447 in Table 1 above, or any thereof. It is any pharmaceutically acceptable salt, solvate, or prodrug. In some embodiments, the compound of formula (I) described herein is compound 450 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 463 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 465 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 466 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 489 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 512 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 514 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 515 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of formula (I) described herein is compound 524 in Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0276] Combinations of medications This application relates to a pharmaceutical combination comprising a thiophene-condensed cyclohexanone derivative ASIC inhibitor, which is a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a cyclooxygenase (COX) inhibitor. In some embodiments, the pharmaceutical combination may further comprise a pharmaceutically acceptable carrier, diluent, or excipient, as detailed below.

[0277] As used herein, the term "ASIC inhibitor" means a compound that can inhibit an acid-sensitive ion channel, such as an acid-sensitive ion channel 1a (ASIC1a) or an acid-sensitive ion channel 1b (ASIC1b).

[0278] As used in the drug combinations of this application, “cyclooxygenase (COX) inhibitors” refer to drugs that enable the inhibition of COX enzymes, such as COX-1 and COX-2 enzymes. In some embodiments, COX inhibitors may affect both COX-1 and COX-2 enzymes. However, in some embodiments, COX inhibitors may primarily affect either COX-2 or COX-1 enzymes. In some embodiments, COX inhibitors may include NSAIDs, which may be highly selective for COX-2 enzymes, such as coxib, or non-selective, such as ibuprofen, and may affect both COX-1 and COX-2 enzymes. In other embodiments, the COX inhibitor may be acetaminophen.

[0279] In some embodiments, the pharmaceutical combinations of the present disclosure may include NSAIDs, which may be bromfenac, celecoxib, diclofenac, etodolac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketrolac, mefenamic acid, meloxicam, nabumetone, naproxen, nepafenac, piroxicam, sulindac, tenoxicam, tiaprofenic acid, diflunisal, etoricoxib, fenoprofen, phloctafenin, lumiracoxib, oxaprozin, parecoxib, lofecoxib, tolmetine, valdecoxib, meclofenamic acid, dexketoprofen, lycopherone, lornoxicam, loxoprofen, nimeslide, tolfenamic acid, phenylbutazone, firocoxib, salsalate, choline magnesium trisalicylate, acetylsalicylic acid, any pharmaceutically acceptable salts thereof, or any combination thereof.

[0280] Due to their COX-1 inhibitory effects, certain NSAIDs can cause side effects such as bleeding and gastrointestinal irritation. Side effects tend to become more common with long-term, high-dose administration. Therefore, NSAIDs are often administered concomitantly with proton pump inhibitors (PPIs) to reduce NSAID-induced gastrointestinal (GI) adverse events. Thus, in some embodiments, the pharmacologic combinations of the present disclosure may further include proton pump inhibitors (PPIs). However, in other embodiments, pain relief can be achieved using a combination of an ASIC inhibitor of formula (I) and an NSAID, and thanks to the analgesic efficacy of the ASIC inhibitor, the dose of the NSAID can be reduced. The use of PPIs can then be avoided, or at least PPIs can be used in more limited doses, thus eliminating or at least reducing NSAID-related side effects.

[0281] In some embodiments, the pharmaceutically acceptable combinations of the present disclosure may preferably include NSAIDs selected from naproxen, celecoxib, diclofenac, ibuprofen, pharmaceutically acceptable salts thereof, or any combination thereof.

[0282] In some embodiments, the pharmaceutical combinations of this disclosure may be synergistic. In other words, therapeutically active compounds, namely COX inhibitors and compounds of formula (I) or their pharmaceutically acceptable salts, solvates, or prodrugs, may produce a therapeutic effect that exceeds the sum of their individual therapeutic effects. In some embodiments, thanks to the synergistic effect that may be observed between two therapeutically active compounds, lower doses of at least one, preferably both, of the therapeutically active components can be used. In some embodiments, this may provide a combination therapy that is far safer than the corresponding monotherapy.

[0283] In some embodiments, the synergistic pharmaceutical combination may include a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof as defined herein, and a COX inhibitor which is an NSAID.

[0284] In some embodiments, the synergistic pharmaceutical combination includes a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and bromfenac, celecoxib, diclofenac, etodolac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketrolac, mefenamic acid, meloxicam, nabumeton, naproxen, nepafenac, piroxicam, sulindac, tenoxicam, tiaprofenic acid, diflunisal, etoricoxib, pheno This may include COX inhibitors, which are NSAIDs selected from profen, phloxtaphenin, lumiracoxib, oxaprozin, parecoxib, lofecoxib, tolmetine, valdecoxib, meclofenamic acid, dexketoprofen, lycopherone, lornoxicam, loxoprofen, nimeslide, tolfenamic acid, phenylbutazone, firocoxib, salsalate, choline magnesium trisalicylate, acetylsalicylic acid, any pharmaceutically acceptable salts thereof, and any combination thereof.

[0285] In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor which is an NSAID selected from naproxen, celecoxib, diclofenac, ibuprofen, a pharmaceutically acceptable salt thereof, or any combination thereof.

[0286] In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as bromfenac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as etodolac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as flurbiprofen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as indomethacin or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as ketoprofen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as ketrolac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or precursor thereof, and a COX inhibitor such as mefenamic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as meloxicam or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor, which is nabumetone or a pharmaceutically acceptable salt thereof.In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as nepafenac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as piroxicam or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as sulindac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as tenoxicam or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as tiaprofenic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as diflunisal or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as etoricoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as fenoprofen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor which is phloxataphenine or a pharmaceutically acceptable salt thereof.In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as lumiracoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as oxaprozin or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as parecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as rofecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as tolmetine or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as valdecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as meclofenamic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as dexketoprofen or a pharmaceutically acceptable salt thereof.In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as lycopherone or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as lornoxicam or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as loxoprofen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as nimeslide or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as tolfenamic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as phenylbutazone or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as firocoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor such as sarsalate or a pharmaceutically acceptable salt thereof.In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor which is choline magnesium trisalicylate or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor which is acetylsalicylic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor which is naproxen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor which is celecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor, which is diclofenac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor, which is ibuprofen or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, a synergistic pharmaceutical combination may include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a COX inhibitor, which is acetaminophen.

[0288] In some embodiments, the pharmaceutical combinations of the present disclosure may comprise a COX inhibitor and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in a single dosage form. A single dosage form means a mixture of the therapeutic active ingredient, i.e., the COX inhibitor, and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, packaged in a single dosage form. For example, but not limited to, the dosage form may include pills, tablets, capsules, beverages, or syrups.

[0289] In other embodiments, the pharmaceutical combinations of the present disclosure may comprise a COX inhibitor and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, each in a separate dosage form.

[0290] In some embodiments, the pharmaceutical combination may contain a COX inhibitor and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in amounts ranging from about 1 mg to about 1000 mg. In other words, the pharmaceutical combination may contain about 1 mg to about 1000 mg of a COX inhibitor and about 1 mg to about 1000 mg of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0291] In some embodiments, the pharmaceutical combination may contain a COX inhibitor in an amount of about 1 mg to about 900 mg, or about 1 mg to about 800 mg, or about 1 mg to about 700 mg, or about 1 mg to about 600 mg, or about 1 mg to about 500 mg, or about 1 mg to about 400 mg, or about 1 mg to about 300 mg, or about 1 mg to about 200 mg, or about 1 mg to about 100 mg, or about 1 mg to about 50 mg, or any range value between these ranges. In some embodiments, the drug combination is approximately 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 8 The product may contain a COX inhibitor in amounts of 0 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 275 mg, 300 mg, 350 mg, 375 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, or any value between these values.

[0292] In some embodiments, the pharmaceutical combination may contain a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in an amount of about 1 mg to about 900 mg, or about 1 mg to about 800 mg, or about 1 mg to about 700 mg, or about 1 mg to about 600 mg, or about 1 mg to about 500 mg, or about 1 mg to about 400 mg, or about 1 mg to about 300 mg, or about 1 mg to about 200 mg, or about 1 mg to about 100 mg, or about 1 mg to about 50 mg, or any range value between these ranges. In some embodiments, the pharmaceutical combination comprises a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in amounts of approximately 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg It may contain mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 275 mg, 300 mg, 350 mg, 375 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, or any value between these values.

[0293] In some embodiments, the pharmaceutical combination may contain a COX inhibitor and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in a weight ratio (COX inhibitor: compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug) of 1:0.1 to 1:10. In some embodiments, the ratio of the COX inhibitor to the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be 1:0.1 to 1:9 by weight, or 1:0.1 to 1:8 by weight, or 1:0.1 to 1:7 by weight, or 1:0.1 to 1:6 by weight, or 1:0.1 to 1:5 by weight, or 1:0.1 to 1:4 by weight, or 1:0.1 to 1:3 by weight, or 1:0.1 to 1:2 by weight, or 1:0.1 to 1:1 by weight. In some embodiments, the ratio of the COX inhibitor to the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug may be 1:0.1 to 1:1 by weight, or 1:0.1 to 1:0.9 by weight, or 1:0.1 to 1:0.8 by weight, or 1:0.1 to 1:0.7 by weight, or 1:0.1 to 1:0.6 by weight, or 1:0.1 to 1:0.5 by weight, or 1:0.1 to 1:0.4 by weight, or 1:0.1 to 1:0.3 by weight, or 1:0.1 to 1:0.2 by weight. In some embodiments, the ratio of the COX inhibitor to the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be 1:0.1 to 1:1 by weight, or 1:0.2 to 1:1 by weight, or 1:0.3 to 1:1 by weight, or 1:0.4 to 1:1 by weight, or 1:0.5 to 1:1 by weight, or 1:0.6 to 1:1 by weight, or 1:0.7 to 1:1 by weight, or 1:0.8 to 1:1 by weight, or 1:0.9 to 1:1 by weight. In some embodiments, the ratio of the COX inhibitor to the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be 1:1 to 1:2 by weight, or 1:1 to 1:1.9 by weight, or 1:1 to 1:1.8 by weight, or 1:1 to 1:1.7 by weight, or 1:1 to 1:1.6 by weight, or 1:1 to 1:1.5 by weight, or 1:1 to 1:1.4 by weight, or 1:1 to 1:1.3 by weight, or 1:1 to 1:1.2 by weight, or 1:1 to 1:1 by weight.

[0294] In some embodiments, the pharmaceutical combination may contain a COX inhibitor and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in a weight ratio of 1:0.1 to 1:2 (COX inhibitor: compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof). In some embodiments, the pharmaceutical combination may contain a COX inhibitor and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in a weight ratio of 1:0.1 to 1:1 (COX inhibitor: compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof).

[0295] In some embodiments, the pharmaceutical combination may contain a COX inhibitor and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in a weight ratio (COX inhibitor: compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug) of about 1:0.2 to about 1:1, or about 1:0.18 to about 1:1, or about 1:0.2 to about 1:0.83, or about 1:0.18 to about 1:0.83.

[0296] In some embodiments, the pharmaceutical combination may contain a COX inhibitor and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in a weight ratio (COX inhibitor: compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug) that results in a synergistic pharmaceutical combination. In some embodiments, the pharmaceutical combination may be synergistic and may contain a COX inhibitor and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in a weight ratio (COX inhibitor: compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug) of 1:0.1 to 1:10. In some embodiments, synergistic drug combinations may have a ratio of a COX inhibitor to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the range of 1:0.1 to 1:9 by weight, or 1:0.1 to 1:8 by weight, or 1:0.1 to 1:7 by weight, or 1:0.1 to 1:6 by weight, or 1:0.1 to 1:5 by weight, or 1:0.1 to 1:4 by weight, or 1:0.1 to 1:3 by weight, or 1:0.1 to 1:2 by weight, or 1:0.1 to 1:1 by weight. In some embodiments, the synergistic drug combination may have a ratio of a COX inhibitor to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the range of 1:0.1 to 1:1 by weight, or 1:0.1 to 1:0.9 by weight, or 1:0.1 to 1:0.8 by weight, or 1:0.1 to 1:0.7 by weight, or 1:0.1 to 1:0.6 by weight, or 1:0.1 to 1:0.5 by weight, or 1:0.1 to 1:0.4 by weight, or 1:0.1 to 1:0.3 by weight, or 1:0.1 to 1:0.2 by weight. In some embodiments, synergistic drug combinations may have a ratio of a COX inhibitor to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug in the range of 1:0.1 to 1:1 by weight, or 1:0.2 to 1:1 by weight, or 1:0.3 to 1:1 by weight, or 1:0.4 to 1:1 by weight, or 1:0.5 to 1:1 by weight, or 1:0.6 to 1:1 by weight, or 1:0.7 to 1:1 by weight, or 1:0.8 to 1:1 by weight, or 1:0.9 to 1:1 by weight.In some embodiments, synergistic drug combinations may have a ratio of a COX inhibitor to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug in the range of 1:1 to 1:2 by weight, or 1:1 to 1:1.9 by weight, or 1:1 to 1:1.8 by weight, or 1:1 to 1:1.7 by weight, or 1:1 to 1:1.6 by weight, or 1:1 to 1:1.5 by weight, or 1:1 to 1:1.4 by weight, or 1:1 to 1:1.3 by weight, or 1:1 to 1:1.2 by weight, or 1:1 to 1:1.1 by weight.

[0297] In some embodiments, the pharmaceutical combination may be synergistic and may contain a COX inhibitor and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in a weight ratio of 1:0.1 to 1:2 (COX inhibitor: compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof). In some embodiments, the pharmaceutical combination may be synergistic and may contain a COX inhibitor and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in a weight ratio of 1:0.1 to 1:1 (COX inhibitor: compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof).

[0298] In some embodiments, the pharmaceutical combination may be synergistic and may contain a COX inhibitor and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in a weight ratio (COX inhibitor: compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug) of about 1:0.2 to about 1:1, or about 1:0.18 to about 1:1, or about 1:0.2 to about 1:0.83, or about 1:0.18 to about 1:0.83.

[0299] In some embodiments, the drug combination may include an NSAID as a COX inhibitor, and the ratio of the NSAID to the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug may be 1:0.1 to 1:10 by weight. In some embodiments, the ratio of the NSAID to the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug may be 1:0.1 to 1:9 by weight, or 1:0.1 to 1:8 by weight, or 1:0.1 to 1:7 by weight, or 1:0.1 to 1:6 by weight, or 1:0.1 to 1:5 by weight, or 1:0.1 to 1:4 by weight, or 1:0.1 to 1:3 by weight, or 1:0.1 to 1:2 by weight, or 1:0.1 to 1:1 by weight. In some embodiments, the ratio of an NSAID to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug may be 1:0.1 to 1:1 by weight, or 1:0.1 to 1:0.9 by weight, or 1:0.1 to 1:0.8 by weight, or 1:0.1 to 1:0.7 by weight, or 1:0.1 to 1:0.6 by weight, or 1:0.1 to 1:0.5 by weight, or 1:0.1 to 1:0.4 by weight, or 1:0.1 to 1:0.3 by weight, or 1:0.1 to 1:0.2 by weight. In some embodiments, the ratio of an NSAID to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug may be 1:0.1 to 1:1 by weight, or 1:0.2 to 1:1 by weight, or 1:0.3 to 1:1 by weight, or 1:0.4 to 1:1 by weight, or 1:0.5 to 1:1 by weight, or 1:0.6 to 1:1 by weight, or 1:0.7 to 1:1 by weight, or 1:0.8 to 1:1 by weight, or 1:0.9 to 1:1 by weight. In some embodiments, the ratio of an NSAID to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug may be 1:1 to 1:2 by weight, or 1:1 to 1:1.9 by weight, or 1:1 to 1:1.8 by weight, or 1:1 to 1:1.7 by weight, or 1:1 to 1:1.6 by weight, or 1:1 to 1:1.5 by weight, or 1:1 to 1:1.4 by weight, or 1:1 to 1:1.3 by weight, or 1:1 to 1:1.2 by weight, or 1:1 to 1:1 by weight.

[0300] In some embodiments, the pharmaceutical combination may include an NSAID as a COX inhibitor, and the ratio of the NSAID to the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug may be 1:0.1 to 1:2 by weight. In some embodiments, the pharmaceutical combination may include an NSAID as a COX inhibitor, and the ratio of the NSAID to the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug may be 1:0.1 to 1:1 by weight.

[0301] In some embodiments, the pharmaceutical combination may include an NSAID as a COX inhibitor, and the ratio of the NSAID to the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be about 1:0.2 to about 1:1 by weight, or about 1:0.18 to about 1:1, or about 1:0.2 to about 1:0.83, or about 1:0.18 to about 1:0.83.

[0302] In some embodiments, the pharmaceutical combination may include an NSAID as a COX inhibitor, and the NSAID and the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug are provided in a weight ratio (NSAID: compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug) that results in a synergistic pharmaceutical combination. In some embodiments, the pharmaceutical combination may be synergistic and may include an NSAID as a COX inhibitor, and the ratio of NSAID to the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug may be 1:0.1 to 1:10 by weight. In some embodiments, synergistic pharmaceutical combinations may have a ratio of NSAID to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug in the range of 1:0.1 to 1:9 by weight, or 1:0.1 to 1:8 by weight, or 1:0.1 to 1:7 by weight, or 1:0.1 to 1:6 by weight, or 1:0.1 to 1:5 by weight, or 1:0.1 to 1:4 by weight, or 1:0.1 to 1:3 by weight, or 1:0.1 to 1:2 by weight, or 1:0.1 to 1:1 by weight. In some embodiments, synergistic drug combinations may have a ratio of NSAID to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug in the range of 1:0.1 to 1:1 by weight, or 1:0.1 to 1:0.9 by weight, or 1:0.1 to 1:0.8 by weight, or 1:0.1 to 1:0.7 by weight, or 1:0.1 to 1:0.6 by weight, or 1:0.1 to 1:0.5 by weight, or 1:0.1 to 1:0.4 by weight, or 1:0.1 to 1:0.3 by weight, or 1:0.1 to 1:0.2 by weight. In some embodiments, synergistic drug combinations may have a ratio of NSAID to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug in the range of 1:0.1 to 1:1 by weight, or 1:0.2 to 1:1 by weight, or 1:0.3 to 1:1 by weight, or 1:0.4 to 1:1 by weight, or 1:0.5 to 1:1 by weight, or 1:0.6 to 1:1 by weight, or 1:0.7 to 1:1 by weight, or 1:0.8 to 1:1 by weight, or 1:0.9 to 1:1 by weight.In some embodiments, synergistic drug combinations may have a ratio of NSAID to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug in the range of 1:1 to 1:2 by weight, or 1:1 to 1:1.9 by weight, or 1:1 to 1:1.8 by weight, or 1:1 to 1:1.7 by weight, or 1:1 to 1:1.6 by weight, or 1:1 to 1:1.5 by weight, or 1:1 to 1:1.4 by weight, or 1:1 to 1:1.3 by weight, or 1:1 to 1:1.2 by weight, or 1:1 to 1:1.1 by weight.

[0303] In some embodiments, the pharmaceutical combination may be synergistic and may include an NSAID as a COX inhibitor, and the ratio of the NSAID to the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug may be 1:0.1 to 1:2 by weight. In some embodiments, the pharmaceutical combination may be synergistic and may include an NSAID as a COX inhibitor, and the ratio of the NSAID to the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug may be 1:0.1 to 1:1 by weight.

[0304] In some embodiments, the drug combination may be synergistic and may include an NSAID as a COX inhibitor, and the ratio of the NSAID to the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug may be about 1:0.2 to about 1:1, or about 1:0.18 to about 1:1, or about 1:0.2 to about 1:0.83, or about 1:0.18 to about 1:0.83 by weight.

[0305] The above dosages and ratios are provided as examples, and the dosages and / or ratios of COX inhibitors, as well as compounds of formula (I) or their pharmaceutically acceptable salts, solvates, or prodrugs, can be adapted to achieve appropriate treatment, such as appropriate pain relief.

[0306] Methods, uses, formulations, kits and administration The pharmaceutical combinations of this disclosure, comprising COX inhibitors and thiophene-condensed cyclohexanone derivatives, i.e., compounds of formula (I) as defined herein or pharmaceutically acceptable salts, solvates, or prodrugs thereof, may be useful in the treatment of disorders or conditions, including pain. In some embodiments, treatment may include, or may be enhanced by, the use of synergistic pharmaceutical combinations of this disclosure.

[0307] Accordingly, in certain embodiments, this specification provides a method for treating pain, comprising administering a COX inhibitor and a compound of formula (I) disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to a patient or subject identified as needing such treatment. In some embodiments, a method for treating pain may comprise administering an effective amount of a COX inhibitor and a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to a patient or subject identified as needing such treatment, the administration resulting in a synergistic effect.

[0308] Identifying patients requiring treatment for the disorders described herein is well within the capabilities and knowledge of those skilled in the art. Specific methods for identifying patients at risk of developing the disorders treatable by this method are well understood in the medical field, including family history and the presence of risk factors associated with the development of the disorder in the patient. A clinician skilled in the art can easily identify such candidate patients, for example, by using clinical trials, physical examinations, and medical / family history.

[0309] As used herein, the term “effective dose” means, for example, the amount of a drug or agent that elicits a biological or medical response in a tissue, system, animal, or human, as determined by a researcher or clinician. It can also mean “therapeutic effective dose,” which means any amount that, compared to a corresponding subject not receiving such a dose, results in the treatment, cure, prevention, or improvement of a disease, disorder, or side effect, or a reduction in the rate of progression of the disease or disorder. This term also includes amounts effective in enhancing normal physiological function.

[0310] As used herein, the terms “treatment,” “to treat,” and “to treat” mean reversing, alleviating, delaying the onset of, or inhibiting the progression of a disorder or impairment, or one or more of its symptoms, as described herein. In some embodiments, treatment may be administered after the onset of one or more symptoms. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., taking into account symptom history and / or genetic or other susceptibility factors). Treatment may also be continued after the symptoms have subsided, for example, to prevent or delay their recurrence.

[0311] As used herein, the terms “patient” or “subject” generally refer to mammals. Therefore, a subject refers to, for example, a dog, cat, horse, cow, pig, guinea pig, etc. Preferably, the subject is a human. If the subject is human, it may be either a patient or a healthy human.

[0312] The expression "pharmaceutically acceptable carrier, diluent, or excipient" and equivalent expressions refer to a non-toxic carrier, diluent, or excipient that does not impair the pharmacological activity of the compound formulated with it. Examples of pharmaceutically acceptable carriers, diluents, or excipients that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolinic tallow.

[0313] In certain embodiments, as described above, disorders or conditions that can be treated with a pharmaceutical combination comprising a COX inhibitor and a thiophene-condensed cyclohexanone derivative, i.e., a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, may include pain.

[0314] In some embodiments, pain may include acute pain or chronic pain. In some embodiments, pain may include inflammatory pain, neuropathic pain, or cancer pain. In some embodiments, pain may include nociceptive pain, inflammatory pain, neuropathic pain, cancer pain, idiopathic pain, musculoskeletal pain, visceral pain, or abdominal pain. In some embodiments, pain may include inflammatory pain. In other embodiments, pain may include neuropathic pain. In yet another embodiment, pain may include cancer pain.

[0315] In some embodiments, pain may include arthritis pain, pain associated with musculoskeletal or soft tissue trauma, postoperative pain, dental pain, dysmenorrhea pain, episiotomy pain, endometriosis pain, postpartum pain, headache, eye pain, bursitis pain, tendinitis pain, tenosynovitis pain, or polymyalgia rheumatica.

[0316] In some embodiments, pain may include rheumatic disorder-related pain.

[0317] In certain embodiments, pain may include arthritis pain. In some embodiments, pain may include adult arthritis pain or juvenile arthritis pain. In certain embodiments, pain may include adult arthritis pain. In some embodiments, pain may include juvenile arthritis pain.

[0318] In some embodiments, pain may include pain from osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout, psoriatic arthritis, or periarthritis. In certain embodiments, pain may include pain from osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout, or periarthritis.

[0319] In some embodiments, pain may include osteoarthritis pain. In certain embodiments, pain may include osteoarthritis inflammatory pain. In some embodiments, pain may include osteoarthritis pain of the hip, knee, spine, shoulder, hand, fingers, thumb, foot, or toes.

[0320] In some embodiments, pain may include rheumatoid arthritis pain. In certain embodiments, pain may include adult rheumatoid arthritis pain or juvenile rheumatoid arthritis pain. In some embodiments, pain may include adult rheumatoid arthritis pain. In certain embodiments, pain may include juvenile rheumatoid arthritis pain. In certain embodiments, pain may include rheumatoid arthritis pain. In some embodiments, pain may include rheumatoid arthritis pain of the hand, rheumatoid arthritis pain of the fingers, rheumatoid arthritis pain of the thumb, rheumatoid arthritis pain of the foot, rheumatoid arthritis pain of the toes, rheumatoid arthritis pain of the wrist, rheumatoid arthritis pain of the knee, rheumatoid arthritis pain of the ankle, rheumatoid arthritis pain of the elbow, rheumatoid arthritis pain of the hip, or rheumatoid arthritis pain of the shoulder.

[0321] In certain embodiments, pain may include ankylosing spondylitis pain.

[0322] In some embodiments, pain may include gouty pain. In some embodiments, pain may include gouty pain of the foot, gouty pain of the toes, gouty pain of the ankle, gouty pain of the knee, or gouty pain of the elbow. In certain embodiments, pain may include gouty arthritis pain.

[0323] In certain embodiments, pain may include psoriatic arthritis pain.

[0324] In certain embodiments, pain may include bursitis pain. In some embodiments, pain may include shoulder bursitis pain or hip bursitis pain.

[0325] In certain embodiments, pain may include tendinitis pain. In some embodiments, pain may include shoulder tendinitis pain, elbow tendinitis pain, hip tendinitis pain, wrist tendinitis pain, knee tendinitis pain, or heel tendinitis pain.

[0326] In some embodiments, pain may include periarthritis pain. In certain embodiments, pain may include periarthritis pain of the shoulder or periarthritis pain of the hip.

[0327] In some embodiments, pain may include pain associated with musculoskeletal or soft tissue injury, including pain associated with sprains, strains, swelling, or stiffness. In certain embodiments, pain may include pain associated with musculoskeletal or soft tissue injury, including pain associated with sprains or strains. In certain embodiments, pain may include pain associated with musculoskeletal or soft tissue injury of the back, shoulder, or ankle. In certain embodiments, pain may include myofascial pain syndrome. In other embodiments, pain may include exercise-induced pain, repetitive injury pain, or pain due to fracture. In other embodiments, pain may include temporomandibular joint disorder pain.

[0328] In certain embodiments, pain may include eye pain. In certain embodiments, eye pain may include postoperative pain after cataract surgery, postoperative pain after refractive surgery, eye pain due to non-penetrating wounds, eye pain due to foreign body sensation, burning or stinging sensation of the eye, uveitis pain, iritis pain, retinopathy pain, or optic neuritis pain.

[0329] In some embodiments, pain may include dental pain. In certain embodiments, dental pain may include toothache or postoperative pain after dental surgery. In some embodiments, dental pain may include pain after tooth extraction.

[0330] In certain embodiments, pain may include postoperative pain. In some embodiments, pain may include postoperative pain after minor surgery, postoperative pain after general surgery, postoperative pain after orthopedic surgery, postoperative pain after hallux valgus excision, postoperative pain after hernia repair, postoperative pain after hernia repair, postoperative pain after arthroplasty including pain after knee or hip arthroplasty, postoperative pain after gynecological surgery, postoperative pain after cesarean section, post-mastectomy pain syndrome (PMPS), postoperative pain after abdominal wall reconstruction, postoperative pain after laminectomy, postoperative pain after hemorrhoidectomy, or postoperative pain after thoracotomy.

[0331] In certain embodiments, pain may include dysmenorrhea pain, episiotomy pain, endometriosis pain, or postpartum pain.

[0332] In some embodiments, pain may include headache. In certain embodiments, pain may include migraine pain, tension headache pain, or cluster headache pain. In some embodiments, pain may include migraine pain, including migraine pain with aura or migraine pain without aura.

[0333] In certain embodiments, pain may include pain from a common cold, pain from influenza, sore throat, sinus pain including sinusitis pain, pain from vaccination, earache, pain from fever, body aches, muscle aches, bone aches, joint aches, back aches, neck aches, or nocturnal pain.

[0334] In some embodiments, pain may include mucositis pain or stomatitis pain. In certain embodiments, pain may include lupus-related pain, including lupus-associated inflammatory pain.

[0335] In certain embodiments, pain may include osteoarthritis neuropathic pain. In certain embodiments, pain may include rheumatoid arthritis neuropathic pain.

[0336] In certain embodiments, pain may include neuralgia. In some embodiments, the pain may include trigeminal neuralgia, postherpetic neuralgia, occipital neuralgia, postoperative neuralgia, pudendal neuralgia, diabetic neuralgia, glossopharyngeal neuralgia, intercostal neuralgia, or drug-induced neuralgia, including chemotherapy-induced or antiretroviral therapy-induced neuralgia for cancer.

[0337] In certain embodiments, pain may include nerve injury pain, peripheral nerve injury pain, nerve compression pain, nerve decompression injury pain, nerve entrapment injury pain, radiculopathy pain, brachial plexus injury pain, burning mouth syndrome pain, complex regional pain syndrome type 1, complex regional pain syndrome type 2, neuroma pain, Morton's neuroma pain, spinal cord injury pain, spinal cord compression pain, nerve root pain, sciatica, spinal cord stenosis pain, cervical spine injury pain, brain injury pain, or post-stroke pain.

[0338] In some embodiments, pain may include neuropathic pain. In certain embodiments, pain may include peripheral neuropathy pain, polyneuropathy pain, mononeuropathy pain, polymononeuropathy pain, proximal neuropathy pain, sensory neuropathy pain, small fiber sensory neuropathy pain, idiopathic neuropathy pain, or distal sensory polyneuropathy pain. In certain embodiments, pain may include diabetic neuropathy pain. In some embodiments, pain may include diabetic peripheral neuropathy pain, diabetic polyneuropathy pain, diabetic proximal neuropathy pain, or diabetic mononeuropathy pain. In certain embodiments, pain may include autoimmune disease neuropathy pain. In some embodiments, pain may include Sjögren's syndrome neuropathy pain, Guillain-Barré syndrome neuropathy pain, chronic inflammatory demyelinating polyneuropathy pain, or vasculitis neuropathy pain. In some embodiments, pain may include multiple sclerosis neuropathy pain. In certain embodiments, pain may include carpal tunnel syndrome pain. In certain embodiments, pain may include neuropathic pain associated with bacterial infection or neuropathic pain associated with viral infection. In some embodiments, pain may include Lyme disease neuropathic pain, Epstein-Barr virus neuropathic pain, hepatitis B virus neuropathic pain, hepatitis C virus neuropathic pain, leprosy neuropathic pain, diphtheria neuropathic pain, or HIV neuropathic pain, including distal symmetric polyneuropathy pain caused by human immunodeficiency virus (HIV). In certain embodiments, pain may include hereditary neuropathic pain. In some embodiments, pain may include Charcot-Marie-Tooth disease neuropathic pain or hereditary neuropathy with pressure palsy (HNPP) pain. In certain embodiments, pain may include neuropathic pain caused by malignant tumors, neuropathic pain caused by benign tumors, or paraneoplastic neuropathic pain. In some embodiments, pain may include myeloma neuropathic pain, lymphoma neuropathic pain, or amyloid neuropathic pain.In certain embodiments, pain may include hepatic disease neuropathic pain, uremic neuropathic pain, connective tissue disease neuropathic pain, hypothyroidism neuropathic pain, alcohol use neuropathic pain, or vitamin deficiency neuropathic pain. In some embodiments, pain may include vitamin B deficiency neuropathic pain, including vitamin B1, niacin, vitamin B6, or vitamin B12 deficiency neuropathic pain, or vitamin E deficiency neuropathic pain. In certain embodiments, pain may include toxic substance exposure neuropathic pain, including lead exposure neuropathic pain or mercury exposure neuropathic pain. In certain embodiments, pain may include antiretroviral therapy-induced neuropathic pain or neurotoxic drug-induced neuropathic pain. In certain embodiments, pain may include chemotherapy-induced neuropathic pain, including platinum-based antitumor drug-induced neuropathic pain or chemotherapy-induced peripheral neuropathy (CIPN) pain; radiotherapy-induced pain, including radiotherapy-induced neuropathic pain; cancer-targeted therapy-induced neuropathic pain; or immunotherapy-induced neuropathic pain. In some embodiments, the pain may include central nervous system-related pain. In certain embodiments, the pain may include post-central stroke pain, spinal cord injury-related central nervous system-related pain, brain injury-related central nervous system-related pain; or multiple sclerosis-related central nervous system-related pain.

[0339] In certain embodiments, pain may include cancer pain. In some embodiments, pain may include bone cancer pain, breakthrough pain, cancer nociceptive pain, or cancer neuropathic pain, which includes nerve damage caused by a tumor compressing a nerve.

[0340] In certain embodiments, pain may include post-amputation pain. In some embodiments, pain may include phantom pain, phantom limb pain, or residual limb pain.

[0341] In certain embodiments, pain may include Paget's disease pain. In other embodiments, pain may include pain associated with fibromyalgia. In certain embodiments, pain may include lupus-related pain, including lupus-related inflammatory pain and lupus-related neuropathic pain. In some embodiments, pain may include gastrointestinal motility disorder pain, irritable bowel syndrome pain, Crohn's disease pain, ulcer-related pain, or ulcerative colitis pain. In other embodiments, pain may include incontinence pain or interstitial cystitis pain. In certain embodiments, pain may include herpes zoster pain. In certain embodiments, pain may include anguina-induced pain. In certain embodiments, pain may include burn-induced pain, including pain caused by animal bites or stings, or first-degree, second-degree, or third-degree burns.

[0342] In some embodiments, the pharmaceutical combinations disclosed herein, comprising a therapeutically effective amount of at least one COX inhibitor and a therapeutically effective amount of at least one compound of formula (I) as defined herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof, may be administered to a patient or subject alone or in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

[0343] In some embodiments, the pharmaceutical combinations described herein involve the administration of a COX inhibitor and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in separate dosage forms. In other embodiments, the pharmaceutical combinations described herein involve the administration of a COX inhibitor and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof together in a single dosage form.

[0344] In some embodiments, if the drug combination comprises a COX inhibitor and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in separate individual dosage forms (or "single dosage form," "single dose form," or "unit dose"), each separate individual dosage form may be administered simultaneously or sequentially. When administered sequentially, the individual dosage forms may be administered in any order.

[0345] The drug combinations described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, ophthalmally, transvaginally, or via an implanted reservoir. Therefore, in this disclosure, the term “oral treatment” means treatment administered orally. In other words, “oral treatment” refers to treatment in which the drug combinations of this disclosure are administered orally for the indicated treatment. As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intra-articular, intrabursal, intrasternal, intrathecal, intrahepatic, intrafocal, and intracranial injection or infusion techniques. Other modes of administration include intradermal or transdermal administration.

[0346] In some embodiments, the drug combinations described herein are administered orally, i.e., via the oral cavity, for example, buccally.

[0347] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may include, for example, inert diluents, solubilizers, and emulsifiers commonly used in the art, such as water or other solvents, e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof. In addition to inert diluents, the oral composition may also include excipients such as wetting agents, emulsifiers, and suspending agents, sweeteners, flavoring agents, and fragrances.

[0348] Preparations for injection, such as sterile aqueous or oily suspensions for injection, can be formulated according to well-known techniques using suitable dispersants or wetting agents and suspending agents. Sterile preparations for injection may be sterile injection solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable carriers and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixatives have conventionally been used as solvents or suspension media. For this purpose, any mild fixative containing synthetic monoglycerides or diglycerides may be used. Furthermore, fatty acids such as oleic acid are used in preparations for injection.

[0349] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0350] To extend the effects of the compound being administered, it is often desirable to delay the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a low-water-soluble crystalline or amorphous substance. The absorption rate of the compound depends on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered compound forms is achieved by dissolving or suspending the compound in an oil carrier. Injectable depot forms are prepared by forming a matrix of microencapsulated compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the compound-to-polymer ratio and the properties of the specific polymer used, the rate of compound release can be controlled.

[0351] Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Depot injection formulations are also prepared by encapsulating therapeutically active compounds in liposomes or microemulsions compatible with body tissues.

[0352] Formulations for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the therapeutically active compound herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active compound.

[0353] Examples of solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone (PVP), sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0354] Similar types of solid formulations may also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. The therapeutically active compound may also be in a microencapsulated form with one or more excipients as described above. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules may be prepared using coatings and shells such as enteric coatings, controlled-release coatings, and other coatings well known in the pharmaceutical field. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, e.g., sucrose, lactose, or starch. Such dosage forms may also include additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids, e.g., magnesium stearate and microcrystalline cellulose, as is common practice. In the case of capsules, tablets, and pills, the dosage form may also include a buffer. These may optionally contain an opaque agent, and may be compositions that optionally release only the active ingredient, or preferentially the active ingredient, in a delayed manner in a specific part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0355] Dosage forms for topical or transdermal administration of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, or patches. The active ingredients are mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, any required preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also intended to be within the scope of this specification. Furthermore, this specification intends for the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compounds to the body. Such dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flow of the compounds through the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compounds in a polymer matrix or gel.

[0356] The drug combinations provided herein may also be formulated for administration by inhalation using nasal aerosols or inhalants. Such formulations may be prepared according to well-known techniques in the field of pharmaceutical formulations and may be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0357] The drug combinations provided herein can be formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the drug combinations of this disclosure may be administered without food. In other embodiments, the drug combinations of this disclosure may be administered with food.

[0358] The amount of therapeutic active compound that can be combined with a carrier substance to produce a single dosage form may vary depending on the patient being treated and the specific mode of administration. The amount of individual therapeutic active compounds that can be combined with a carrier substance to produce individual dosage forms may vary depending on the patient being treated and the specific mode of administration.

[0359] It should also be understood that specific dosages and treatment regimens for any particular patient depend on a variety of factors, including age, weight, general health, sex, diet, administration time, excretion rate, drug combinations, the judgment of the treating physician, and the severity of the specific disorder being treated.

[0360] The drug combinations described herein may be administered in any amount and via any route of administration that is effective in treating or reducing the severity of the disorders intended herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disorder or condition, the specific drug, and its mode of administration. In some embodiments, the COX inhibitor, and the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug, may be formulated in unit doses for ease of administration and dose uniformity. As used herein, the terms “unit dose” or “single dosage form” refer to a physically separated unit of the therapeutically active agent in an amount appropriate for the patient being treated. In some embodiments, each unit dosage form may contain both the required amount of the COX inhibitor and the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug. In other embodiments, separate unit doses may be prepared, the first unit dose comprising the required amount of a COX inhibitor, and the second unit dose comprising the required amount of the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug. However, it will be understood that the total daily dose of therapeutically active compounds and / or combinations thereof is to be determined by the attending physician within the bounds of sound medical judgment. A specific effective dose level for any particular patient or organism depends on a variety of factors, including the disorder being treated and its severity, the activity of the specific compound used, the specific composition used, the patient's age, weight, general health, sex, and diet, the timing of administration, route of administration, and excretion rate of the specific compound used, the duration of treatment, drugs used in combination with or concurrently with the specific compound used, and similar factors well known in the medical field.

[0361] In certain embodiments, each of the COX inhibitors and the compound of formula (I) or its pharmaceutically acceptable salts, solvates, or prodrugs may be administered once or more daily at dose levels of approximately 0.01 mg to approximately 50 mg per kg of body weight of the subject, or approximately 0.01 mg / kg to approximately 40 mg / kg, or approximately 0.01 mg / kg to approximately 30 mg / kg, or approximately 0.1 mg / kg to approximately 50 mg / kg, or approximately 0.1 mg / kg to approximately 40 mg / kg, or approximately 0.1 mg / kg to approximately 30 mg / kg, or approximately 0.1 mg / kg to approximately 20 mg / kg, or approximately 0.1 mg / kg to approximately 10 mg / kg, in order to obtain the desired therapeutic effect.

[0362] In certain embodiments, the COX inhibitor may be administered once or more daily at a dose level of about 0.1 mg to about 50 mg per kg of body weight of the subject, or about 0.1 mg / kg to about 40 mg / kg, or about 0.1 mg / kg to about 30 mg / kg, or about 0.1 mg / kg to about 20 mg / kg, or about 0.1 mg / kg to about 10 mg / kg. In some preferred embodiments, the COX inhibitor may be administered at a dose level of about 0.1 to about 20 mg / kg.

[0363] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered once or more daily at dose levels of about 0.1 mg to about 50 mg per kg of body weight of the subject, or about 0.1 mg / kg to about 40 mg / kg, or about 0.1 mg / kg to about 30 mg / kg, or about 0.1 mg / kg to about 20 mg / kg, or about 0.1 mg / kg to about 10 mg / kg. In some preferred embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered at dose levels of about 0.1 to about 30 mg / kg, or about 0.1 mg / kg to about 20 mg / kg, or about 0.1 mg / kg to about 15 mg / kg.

[0364] In certain embodiments, COX inhibitors can be administered at dose levels of approximately 0.1 to approximately 20 mg / kg, and compounds of formula (I) or their pharmaceutically acceptable salts, solvates, or prodrugs can be administered at dose levels of approximately 0.1 to approximately 30 mg / kg.

[0365] In certain embodiments, COX inhibitors can be administered at dose levels of approximately 0.1 to approximately 20 mg / kg, and compounds of formula (I) or their pharmaceutically acceptable salts, solvates, or prodrugs can be administered at dose levels of approximately 0.1 mg / kg to approximately 20 mg / kg.

[0366] In certain embodiments, COX inhibitors can be administered at dose levels of approximately 0.1 to approximately 20 mg / kg, and compounds of formula (I) or their pharmaceutically acceptable salts, solvates, or prodrugs can be administered at dose levels of approximately 0.1 mg / kg to approximately 15 mg / kg.

[0367] In some embodiments, the COX inhibitor, and the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug, are administered in a single dosage form. In other embodiments, the COX inhibitor, and the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug, are administered in separate dosage forms. In some embodiments, the COX inhibitor, and the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug, are administered simultaneously or sequentially. In some embodiments, the COX inhibitor, and the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug, are administered simultaneously. In some embodiments, the COX inhibitor, and the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug, are administered sequentially. Note that when the COX inhibitor and the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug are administered sequentially, they can be administered in any order. Therefore, a COX inhibitor may be administered first, followed by the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered first, followed by the COX inhibitor.

[0368] After the patient's condition has improved, a maintenance dose of the drug combination described herein may be administered as needed. Thereafter, the dose, frequency, or both of the administration may be reduced as a function of the symptoms to a level at which the improved condition is maintained, and treatment should be discontinued when the symptoms have been relieved to the desired level. However, the patient may require intermittent treatment on a long-term basis in response to any recurrence of the disorder symptoms.

[0369] The total daily inhibitory dose of a COX inhibitor, as defined herein, administered to a subject in single or divided doses, and of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, may be, for example, 0.01 to 50 mg per kg of body weight, or more commonly, 0.1 to 30 mg per kg of body weight. A single-dose formulation may contain such an amount or a fraction thereof to constitute a daily dose. In some embodiments, the treatment regimens described herein may involve administering to a patient requiring such treatment approximately 1 mg to approximately 1000 mg per day in single or multiple doses of a COX inhibitor and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0370] The drug combinations described herein may be marketed in kit form. A kit may comprise at least one single-dosage form of a COX inhibitor (also referred to as the “first single-dosage form of COX inhibitor”) and at least one single-dosage form of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof (also referred to as the “second single-dosage form of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof”). It should be noted that with respect to the single-dosage forms of each active ingredient, the terms “first” and “second” are used to distinguish the single-dosage forms and do not relate to any order in which these dosage forms are used / administered. In fact, each of the first and second single-dosage forms may be administered in any order or simultaneously.

[0371] Therefore, the kit may contain separate dosage forms (dosage units) of a COX inhibitor and a compound having formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Each separate dose may contain the same amount of the therapeutic active ingredient or different amounts of the therapeutic active ingredient. In some embodiments, the kit can be tailored to a specific patient by selecting an appropriate amount of each therapeutic active ingredient. The kit generally also includes instructions for the patient's proper use.

[0372] In some embodiments, the kit is such that the first single dosage form may contain a COX inhibitor in any amount as described above with respect to the pharmaceutical combination. In some embodiments, the kit is such that the second single dosage form may contain a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in any amount as described above with respect to the pharmaceutical combination.

[0373] In some embodiments, the kit provides a COX inhibitor-to-formula ratio of the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug in the first single dosage form and the second single dosage form, as described above with respect to the pharmaceutical combination.

[0374] In some embodiments, the kit may comprise a first monodose of a COX inhibitor and a second monodose of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which is useful for treating patients suffering from pain such as any of the pains disclosed herein. In some embodiments, the use of the kit may result in a synergistic effect between the COX inhibitor and the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug in pain relief. [Examples]

[0375] General method Preparation of thiophene-condensed cyclohexanone derivative compounds Reagent-grade chemicals and anhydrous solvents were purchased from commercial sources and used without further purification unless otherwise specified. Product names were determined using naming software included in ChemDraw (PerkinElmer). Where a compound is described as being prepared in the same manner as in previous examples or intermediates, the reaction time, reagent equivalents, temperature, workup, and purification techniques may differ slightly from those described in the examples.

[0376] purification Chromatographic separation was performed as follows: - Teledyne ISCO CombiFlash flash chromatography system, pre-packaged SiO2 or C 18 Use columns. - Teledyne ISCO ACCQPrep high-pressure preparative liquid chromatography system, column: Gemini 5um C18 110Å, 150×30mm. - Biotage Isolera flash chromatography system, pre-packaged SiO2 or C 18 Use columns. - Waters Mass Trigger half-sample HPLC, column: Gemini 5μm NX-C18 110Å, 100×30mm.

[0377] Chiral separation was performed as follows: - Mettler Toledo Berger Minigram supercritical fluid chromatography, column: ChiralPak IG, 20×250mm or ChiralPak IG, 10×250mm. - Waters ACQUITY UPC2 supercritical fluid chromatography, column: ChiralPak IG, 10 × 250 mm.

[0378] Analysis method LC-MS was performed as follows: - Waters UPLC-MS, Column: Acquity UPLC, CSH C18, 1.7 μm, 2.1 × 30 mm, Method: 5% to 95% CH3CN in H2O containing 0.1% (v / v) formic acid for 2 minutes, or 5% to 95% CH3CN in 10 mM ammonium bicarbonate for 2 minutes. - Agilent HPLC-MS, column: Kinetex EVO C18 100Å 2.6μm, 50×3mm, method: 10% to 95% CH3CN containing 0.1% (v / v) formic acid in H2O containing 0.1% (v / v) formic acid for 4.5 minutes. - Agilent UPLC-MS, column: Kinetex EVO C18 100Å 1.7μm, 50×3mm, method: 5%~95% CH3CN containing 0.1%(v / v) formic acid in H2O containing 0.1%(v / v) formic acid for 3 minutes.

[0379] Analytical SFC was performed using Waters ACQUITY UPC2. Column: ChiralPak IG 4.6×250mm or ChiralPak IC 4.6×150mm.

[0380] NMR spectroscopy was performed using a Varian NMR (AS 400) 400 MHz spectrometer with an Inova interface. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shifts (δ) are given in parts per million using conventional abbreviations for peak designation. For example, s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets, etc.

[0381] Abbreviation 9-BBN 9-Borabicyclo[3.3.1]nonane δ chemical shift Å Angstrom Acetyl Bn Benzyl Boc tert-butoxycarbonyl BS "Broad Singlet" Bu butyl Calcd Calculated value d doublet DAST Diethylaminosulfur Trifluoride dd doublet doublet dt Triplet doublet DCM Dichloromethane DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DIBALH (Diisobutylaluminum Hydrogenate) DIPEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMF (N,N-dimethylformamide) DMP Des-Martin Periodinaan DMPU N,N'-dimethylpropylene urea DMSO (Dimethyl Sulfoxide) Dppf 1,1'-bis(diphenylphosphino)ferrocene EA ethyl acetate ee Enantiomeric excess Et ethyl EtOH Ethanol eq equivalent g grams HATU Hexafluorophosphate azabenzotriazole tetramethyluronium Hz (Hertz) HPLC (High-Performance Liquid Chromatography) i-Pr Isopropyl J coupling constant L (liters) LC-MS Liquid Chromatography-Mass Spectrometry LDA Lithium Diisopropylamide LHMDS Lithium bis(trimethylsilyl)amide M moles m multiplex mCPBA (Meth-chloroperoxybenzoic acid) Me methyl MeOH methanol mg milligrams MHz (megahertz) min mL (milliliter) mm (millimeters) mmol millimol mole MS mass spectrometry N Normal NBS N-bromosuccinimide PCC (Pyridinium Chlorochromate) pH (hydrogen ion concentration) Ph Phenyl PPh3 Triphenylphosphine ppm parts per million PyBOP Benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate q quartet RT room temperature rt retention time NMR nuclear magnetic resonance s singlet sat saturation SFC Supercritical Fluid Chromatography sxt sextablet t tert t triplet tt Triplet of triplets t-Butyl TMS (trimethylsilyl) TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) Ts Tosil μL (microliter) μmol (micromol) v / v volume / volume ° degrees % percent

[0382] Example 1 2-amino-7-oxo-5-(2-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(4)

[0383] [ka]

[0384] Step 1.2-(3-oxo-5-(2-(trifluoromethyl)phenyl)cyclohexylidene)malononitrile(2) A solution of malononitrile (100 mg, 1.51 mmol, recrystallized from EtOH), triethylamine (253 μL, 1.82 mmol), and 5-(2-(trifluoromethyl)phenyl)cyclohexane-1,3-dione (1,396 mg, 1.51 mmol) in EtOH (1.30 mL) was stirred at 80°C for 2 hours. Then, another 62 mg of malononitrile (0.94 mmol) and 250 μL of triethylamine (1.82 mmol) were added, and the mixture was stirred at 80°C for 16 hours. The mixture was then cooled to room temperature, concentrated to dryness, and crude product 2 was used in step 2 without purification. LC-MS: rt=1.94 min, MS: 304.1 (calculated), 305.1 (M+H + (Actual measured value).

[0385] Step 2.2-amino-7-oxo-5-(2-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrili(3) A mixture of sulfur (50.9 mg, 198 μmol), diethylamine (157 μL, 1.52 mmol), and compound 2 (461 mg, 1.52 mmol, assuming the quantitative yield in step 1) in EtOH (2.00 mL) was stirred at 80°C for 16 hours. The mixture was then cooled to room temperature, concentrated by rotary evaporation, and the residue was purified by flash column chromatography (elution gradient, 40% to 100% EA in hexane) to obtain the title compound 3 as a light brown solid (220 mg, 43% yield in 2 steps). LC-MS: rt=1.73 min, MS: 336.1 (calculated), 337.0 (M+H + (Actual measured value).

[0386] Step 3.2-amino-7-oxo-5-(2-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(4) A 30% aqueous hydrogen peroxide solution (0.33 mL) was added to a suspension of compound 3 (41.1 mg, 122 μmol) and potassium carbonate (33.8 mg, 244 μmol) in DMSO (1.64 mL). The mixture was stirred at room temperature for 2 hours, then separated into EA and water (20 mL each). The layers were separated, and the aqueous phase was extracted with another 20 mL of EA. The combined organic matter was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and dried under vacuum to obtain the title compound 4 as a pale yellow solid (36.7 mg, yield 85%).

[0387] 1 H NMR:400MHz,DMSO-d6,δ(ppm):8.06(s,2H),7.90(d,J=8.0Hz,1H),7.76-7.68(m,2H),7.49(t,J=7.7Hz,1 H),6.96(bs,2H),3.73-3.58(m,1H),3.40-3.29(m,1H),3.07-2.90(m,2H),2.36(dd,J=16.3,3.8Hz,1H). 19 F NMR:376MHz,DMSO-d6,δ(ppm):-57.5(s). LC-MS: rt=1.40 min, MS: 354.1 (calculated value), 355.1 (M+H + (Actual measured value).

[0388] Example 2 2-amino-N-cyclopropyl-6-ethyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(9)

[0389] [ka]

[0390] Step 1. 2-Cyano-2-(4-ethyl-3-oxocyclohexylidene)ethyl acetate (6) A mixture of 4-ethylcyclohexane-1,3-dione (5, 150 mg, 910 μmol) (Synlett. 2012, 1199-1204), triethylamine (380 μL, 2.73 mmol), and 2-ethyl cyanoethyl acetate (145 μL, 1.36 mmol) in EtOH (784 μL) was stirred at 80°C for 16 hours. Then, 100 μL of 2-ethyl cyanoethyl acetate (0.94 mmol) and 130 μL of triethylamine (0.93 mmol) were added, and the resulting mixture was stirred at 80°C for a further 24 hours. The mixture was then cooled to room temperature, concentrated to dryness, and the crude product 6 was used in step 2 without purification. LC-MS: rt=1.73 min, MS: 235.1 (calculated), 236.1 (M+H + (Actual measured value).

[0391] Step 2. Ethyl 2-amino-6-ethyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (7) A mixture of crude product 6 (214 mg, 910 μmol, assuming the quantitative yield in step 1), sulfur (30.6 mg, 119 μmol), and diethylamine (94.1 μL, 910 μmol) in EtOH (910 μL) was stirred at 80°C for 2 hours. The mixture was then cooled to room temperature, concentrated to dryness, and the residue was purified by flash column chromatography (elution gradient, 5%-50% EA in hexane) to obtain the title compound 7 as a yellow solid (135.2 mg, 52% yield in 2 steps). LC-MS: rt=1.77 min, MS: 267.1 (calculated value), 268.1 (M+H + (Actual measured value).

[0392] Step 3.2-amino-6-ethyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (8) Lithium hydroxide monohydrate (68.0 mg, 1.62 mmol) was added to compound 7 (86.6 mg, 324 μmol) suspended in a mixture of MeOH (4.86 mL) and H2O (1.62 mL). The resulting mixture was stirred under reflux for 2 hours, then cooled to room temperature, diluted with water (20 mL), and washed with EA (20 mL). The organic phase was discarded, and the aqueous phase was acidified to pH 2-3 using 3N HCl and extracted using EA (3 × 20 mL). The combined organic matter was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the title compound 8 as an off-white solid (60.5 mg, yield 78%). The crude product was used in step 4 without further purification. (See Table 6 for characterization.)

[0393] Step 4.2-amino-N-cyclopropyl-6-ethyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (9) To a solution of compound 8 (60.5 mg, 253 μmol) in DMF (3.16 mL), N,N-diisopropylethylamine (132 μL, 758 μmol), cyclopropylamine (19.3 μL, 278 μmol), and HATU (115 mg, 303 μmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The mixture was then diluted with saturated NH4Cl aqueous solution (30 mL) and extracted with EA (3 × 20 mL). The combined organic matter was washed with ice-cold brine (40 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was first purified by flash column chromatography (elution gradient, 1% to 10% MeOH in DCM), and then recrystallized from hot EA to obtain the title compound 9 as a white solid (16.4 mg, yield 23%).

[0394] 1H NMR:400MHz,DMSO-d6,δ(ppm):7.68(d,J=5.7Hz,2H),7.34(d,J=3.8Hz,1H),2. 86(dt,J=17.3,5.2Hz,1H),2.76(ddt,J=19.0,7.1,4.2Hz,2H),2.20(ddt,J=9. 4,7.8,4.7Hz,1H),2.06(dq,J=13.2,5.0Hz,1H),1.82-1.67(m,2H),1.50-1.33 (m,1H),0.90(t,J=7.4Hz,3H),0.66(td,J=7.0,4.6Hz,2H),0.57-0.47(m,2H). LC-MS: rt=1.26 min, MS: 278.1 (calculated value), 279.1 (M+H + (Actual measured value).

[0395] Example 3 2-amino-6-(2-chlorophenyl)-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(15)

[0396] [ka]

[0397] Step 1. Ethyl 2-((di-tert-butoxycarbonyl)amino)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (11) To a suspension of ethyl 2-amino-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (10, 2.26 g, 9.25 mmol) in DCM (58.2 mL), triethylamine (2.85 mL, 20.4 mmol), 4-dimethylaminopyridine (228 mg, 1.85 mmol), and di-tert-butyldicarbonate (4.44 g, 20.4 mmol) were added. The resulting solution was stirred under reflux for 4 hours. The mixture was then cooled to room temperature, diluted in DCM (50 mL), and washed sequentially with 1N HCl, water, and brine (70 mL each). The organic phase was dried over Na2SO4, filtered, concentrated, and the residue was purified by flash column chromatography (elution gradient, EA in hexane at 10% to 60%) to obtain the title compound 11 as a pale orange solid (3.42 g, yield 84%). LC-MS: rt=1.78 mins, MS: 439.2 (calculated value), 462.2 (M+Na + (Actual measured value).

[0398] Step 2. Ethyl 2-((di-tert-butoxycarbonyl)amino)-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (12) A solution of LDA (10.4 mL, 10.4 mmol, 1 M in THF / hexane) cooled to -78°C under Ar was mixed with a solution of 11 (2.29 g, 5.22 mmol) in anhydrous THF (16 mL). The resulting mixture was stirred at -78°C for 15 minutes, and then a solution of TsCN (975 mg, 5.22 mmol) in anhydrous THF (16 mL) was added dropwise. The mixture was stirred at -78°C for 20 minutes, and then from -78°C to room temperature for 4 hours. The mixture was then quenched with saturated aqueous NH4Cl (200 mL) and extracted with DCM (2 × 200 mL). The combined organic matter was dried over Na2SO4, filtered, concentrated, and the residue was purified by flash column chromatography (elution gradient, EA in 5%-50% hexane) to obtain the title compound 12 as a pale yellow solid (1.13 g, yield 46%). LC-MS: rt=1.73 mins, MS: 464.2 (calculated value), 487.2 (M+Na) + (Actual measured value).

[0399] Step 3. Ethyl 2-((tert-butoxycarbonyl)amino)-6-(2-chlorophenyl)-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (13) To a flame-dried microwave vial containing t-BuOK (57.5 mg, 512 μmol) and anhydrous DMF (860 μL), 12 (200 mg, 431 μmol) in anhydrous DMF (1.3 mL) was added under Ar. The resulting mixture was stirred at 0°C for 35 minutes, then bis(2-chlorophenyl)iodonium tetrafluoroborate (188 mg, 431 μmol) (J.Am.Chem.Soc. 2016, 13183-13186.) in anhydrous DMF (430 μL) was added dropwise, and the mixture was stirred at room temperature for 2.5 hours. Next, a further amount of bis(2-chlorophenyl)iodonium tetrafluoroborate (40 mg, 92 μmol dissolved in 500 μL of anhydrous DMF) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was then diluted with water (2 mL) and acidified to pH 6-7 with 1N HCl. A further 10 mL of water was added, and the product was extracted with EA (3 × 20 mL). The combined organic matter was washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was dissolved in heptane and concentrated several times by rotational evaporation to remove residual DMF. The obtained solid was purified by flash column chromatography (elution gradient, EA in hexane with 0% to 50%) to obtain the title compound 13 as a pale yellow solid (40 mg, yield 20%). LC-MS: rt=2.06 min, MS: 474.1 (calculated), 475.1 (M+H + (Actual measured value).

[0400] Step 4.2-amino-6-(2-chlorophenyl)-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (14) TFA (2.26 mL, 29.6 mmol) was added dropwise to a solution of 13 (40.0 mg, 84.2 μmol) of DCM (4.6 mL) at 0°C. The resulting mixture was stirred at 0°C for 1 hour, then concentrated to dryness to obtain a crude intermediate as a brown solid (33 mg), which was dissolved in MeOH (10 mL). An aqueous solution of lithium hydroxide monohydrate (17.4 mg, 414 μmol) (10 mL) was added to the solution and stirred under reflux for 1 hour. The mixture was then cooled to room temperature and concentrated to dryness. The residue was washed with EA (10 mL), then acidified to pH 1-2 using 1N HCl, and extracted with EA (3 × 10 mL). The combined organic matter was dried over Na₂SO₄, filtered, and concentrated to obtain the title compound 14 as a brown solid (26.9 mg, yield 94%). The crude product was used in step 5 without further purification. (See Table 6 for details on the characteristics evaluation.)

[0401] Step 5.2-amino-6-(2-chlorophenyl)-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (15) To a suspension of 14 (19.9 mg, 57.4 μmol) in CHCl3 (398 μL), N,N-diisopropylethylamine (30.0 μL, 172 μmol), saturated NH3 solution in CHCl3 (0.3 mL) (prepared in-house), and HATU (24.0 mg, 63.1 μmol) were added. The mixture was stirred at room temperature. After stirring for 5 hours, 24 mg of HATU (63.1 μmol) and 0.5 mL of saturated NH3 solution in CHCl3 were added. The mixture was stirred for 16 hours, then 25 mg of HATU (65.7 μmol) and 0.6 mL of saturated NH3 solution in CHCl3 were added, and stirring was continued for a further 4.5 hours. The mixture was then diluted with 5 mL of water and 5 mL of CHCl3. The layers were separated, and the aqueous phase was extracted with CHCl3 (2 × 5 mL). The combined organic matter was dried over Na2SO4, filtered, concentrated, and the residue was purified by reverse-phase flash column chromatography (elution gradient, 0% to 100% CH3CN in H2O containing 0.1% (v / v) formic acid) to obtain the title compound 15 as a white solid (6.2 mg, yield 31%).

[0402] 1 H NMR:400MHz,CD3OD,δ(ppm):7.73-7.68(m,1H),7.50-7.45(m,1H),7.45-7.40(m,2H),3.29-3.11(m,3H),2.48-2.41(m,1H). LC-MS: rt=1.15 min, MS: 345.0 (calculated value), 346.0 (M+H + (Actual measured value).

[0403] Examples 4-27 Compounds 16-34 (Examples 4-22) were synthesized starting from appropriately substituted diketones by following the procedure described above for the synthesis of compound 4 (Example 1, Scheme 1). Compounds 35 and 36 (Examples 23 and 24) were synthesized in a similar manner by following the procedure described above for the synthesis of compound 8 (Scheme 2). Compounds 37-39 (Examples 25-27) were synthesized in a similar manner by following the procedure described above for the synthesis of compound 9 (Scheme 2). The characterization of compounds 16-39 (Examples 4-27) is shown in Table 2.

[0404] [Table 2-1]

[0405] [Table 2-2]

[0406] [Table 2-3]

[0407] [Table 2-4]

[0408] [Table 2-5]

[0409] Example 28 2-amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (47) and Example 29 2-amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (48)

[0410] [ka]

[0411] Step 1. 8-(cyclobutylmethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile(41) In a flame-dried round-bottom flask, under Ar, a solution of LDA (2.69 mL, 1 M in THF / hexane, 2.69 mmol) in anhydrous THF (3.60 mL) was placed. The solution was cooled to -78°C, and 1,4-dioxaspiro[4.5]decane-8-carbonitrile (40, 265 μL, 1.79 mmol) was added. The mixture was stirred at -78°C for 30 minutes, and then (bromomethyl)cyclobutane (202 μL, 1.79 mmol) was added. The reaction vessel was removed from the acetone / dry ice bath, and the solution was stirred at room temperature for 64 hours. The mixture was then divided between EA and water (15 mL each), the layers were separated, and the aqueous phase was extracted with EA (2 × 15 mL). The combined organic matter was dried over Na₂SO₄, filtered, and concentrated to obtain crude title compound 41 as an orange oil, which was used in step 2 without purification or characterization.

[0412] Step 2.1-(cyclobutylmethyl)-4-oxocyclohexane-1-carbonitrile(42) A solution of 41 (422 mg, 1.79 mmol, assuming the quantitative yield in step 1) in acetone (25.3 mL) was treated with 2N HCl (4.59 mL, 9.19 mmol), and the resulting mixture was stirred at 40°C for 64 hours. The mixture was then cooled to room temperature, concentrated by rotary evaporation to remove the acetone, and the aqueous residue was extracted with EA (3 × 30 mL). The combined organic matter was dried over Na₂SO₄, filtered, and concentrated to obtain the crude title compound 42 as a brown solid, which was used in step 3 without purification or characterization.

[0413] Step 3. Ethyl 2-amino-6-cyano-6-(cyclobutylmethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (43) A suspension of ethyl 2-cyanoethyl acetate (210 μL, 1.97 mmol), morpholine (172 μL, 1.97 mmol), sulfur (63 mg, 247 μmol), and 42 (342 mg, 1.79 mmol, assuming the quantitative yield in step 2) in EtOH (1.8 mL) was stirred at 60°C for 16 hours. The mixture was cooled to room temperature and then concentrated by rotary evaporation, and the residue was separated between EA and water (20 mL each). The organic phase was dried over Na2SO4, filtered, concentrated, and the residue was purified by flash column chromatography (elution gradient, EA in hexane at 0% to 50%) to obtain the title compound 43 as a pale yellow solid (353 mg, 62% yield in 3 steps). LC-MS: rt=1.74 min, MS: 318.1 (calculated), 319.1 (M+H + (Actual measured value).

[0414] Step 4. Ethyl 2-acetamido-6-cyano-6-(cyclobutylmethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (44) A suspension of 43 (227 mg, 713 μmol) in acetic acid (4.09 mL) was treated with acetic anhydride (80.9 μL, 856 μmol), and the resulting mixture was stirred at 70°C for 3 hours. The mixture was then cooled to room temperature and concentrated to dryness. The residue was diluted with DCM (10 mL), washed sequentially with saturated NaHCO3 aqueous solution, water, and brine (10 mL each), then dried over Na2SO4, filtered, and concentrated to obtain the title compound 44 as a yellow solid (227 mg, yield 88%). LC-MS: rt=1.79 min, MS: 360.2 (calculated), 361.1 (M+H + (Actual measured value).

[0415] Step 5. Ethyl 2-acetamido-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (45) To a suspension of 44 (227 mg, 630 μmol) in acetic acid (6.3 mL) and water (2.1 mL), cerium sulfate (1.81 g, 5.44 mmol) was added. The mixture was sonicated for 1 minute and then stirred at room temperature for 88 hours. The mixture was then diluted with water and EA (30 mL each), sonicated for 3 minutes, and transferred to a separatory funnel. The layers were separated, and the organic phase was successively washed with 1 N NaOH and brine (30 mL each), then dried over Na2SO4, filtered, and concentrated to obtain the title compound 45 as a yellow gum (175.1 mg, yield 74%), which was used in step 6 without purification. LC-MS: rt=1.71 min, MS: 374.1 (calculated), 375.2 (M+H + (Actual measured value).

[0416] Step 6. Ethyl 2-amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (46) A solution of 45 (170 mg, 454 μmol) in toluene (744 μL) was treated with pyrrolidine (559 μL, 6.81 mmol) and stirred at room temperature for 1 hour. The mixture was then concentrated by rotary evaporation, and the residue was purified by flash column chromatography (elution gradient, EA in hexane from 0% to 50%) to obtain the title compound 46 as an off-white solid (118.1 mg, yield 78%). LC-MS: rt=1.63 min, MS: 332.1 (calculated), 333.1 (M+H + (Actual measured value).

[0417] Step 7.2-amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (47) A solution of lithium hydroxide monohydrate (66.9 mg, 1.59 mmol) in water (38.4 mL) was added to a solution of 46 (100 mg, 261 μmol) in MeOH (38.4 mL). The mixture was stirred under reflux for 16 hours, then cooled to room temperature and concentrated by rotary evaporation to remove most of the MeOH. The aqueous residue was washed with EA (2 × 25 mL), then acidified to pH 1-2 with 3N HCl, and extracted with EA (3 × 25 mL). The organic matter was dried over Na₂SO₄, filtered, and concentrated to obtain the title compound 47 as an off-white solid (78.2 mg, yield 81%).

[0418] 1 H NMR:400MHz,DMSO-d6,δ(ppm):12.75(bs,1H),8.48(bs,2H),3.08-3.02 (m,2H),2.55-2.42(m,1H),2.43-2.29(m,1H),2.27-2.16(m,1H),2.13-1.96(m,3H),1.93-1.61(m,5H). LC-MS: rt=1.32 min, MS: 304.1 (calculated value), 305.1 (M+H + (Actual measured value).

[0419] Step 8.2-amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (48) HATU (73.2 mg, 189 μmol) was added to a suspension of 47 (38.3 mg, 126 μmol) in DMF (1.39 mL), saturated NH3 solution in chloroform (780 μL) (prepared in-house), ammonium chloride (135 mg, 2.52 mmol), and N,N-diisopropylethylamine (43.8 μL, 252 μmol). The resulting mixture was stirred at room temperature for 16 hours, then diluted with saturated NH4Cl aqueous solution (20 mL), and extracted with EA (3 × 10 mL). The combined organic matter was washed with ice-cold brine (2 × 15 mL), dried over Na2SO4, filtered, and concentrated. The residue was first purified by reverse-phase flash column chromatography (elution gradient, 0% to 100% CH3CN in H2O containing 0.1% (v / v) formic acid), and then by half-amount HPLC-MS (elution gradient, 25% to 100% CH3CN in 10 mM ammonium bicarbonate) to obtain the title compound 48 as a white solid (14.5 mg, 38%).

[0420] 1 H NMR(400MHz,CD3OD):δ 3.16-3.08(m,2H),2.65-2.57(m,1H),2.47(ddd,J=13.3,7.7,5.4Hz,1H),2.30(ddd ,J=13.7,6.0,5.0Hz,1H),2.20-2.10(m,3H),2.00-1.90(m,2H),1.87-1.74(m,3H). LC-MS: rt=1.15 min, MS: 303.1 (calculated value), 304.1 (M+H + (Actual measured value).

[0421] Example 30 2-amino-6-cyano-6-(cyclopentylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (49) and Example 31 2-amino-6-cyano-6-(cyclopentylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(50)

[0422] [ka]

[0423] 2-amino-6-cyano-6-(cyclopentylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (49) Compound 49 (Example 30) was synthesized in the same manner as Compound 47 (Example 28, Scheme 4), starting from 1,4-dioxaspiro[4.5]decane-8-carbonitrile (40), with (bromomethyl)cyclopentane used instead of (bromomethyl)cyclobutane in the first step.

[0424] 1 H NMR:400MHz,DMSO-d6,δ(ppm):12.75(bs,1H),8.48(bs,2H),3.13-3.00(m,2H),2.48-2.38(m ,1H),2.29(dt,J=13.5,5.2Hz,1H),2.04-1.76(m,5H),1.63-1.37(m,4H),1.25-1.05(m,2H). LC-MS: rt=1.41 min, MS: 318.1 (calculated value), 319.1 (M+H + (Actual measured value).

[0425] 2-amino-6-cyano-6-(cyclopentylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(50) HATU (73.1 mg, 188 μmol) was added to a suspension of 49 (40.0 mg, 126 μmol) in DMF (1.39 mL), saturated NH3 solution in chloroform (741 μL) (prepared in-house), ammonium chloride (134 mg, 2.51 mmol), and N,N-diisopropylethylamine (43.8 μL, 252 μmol). The resulting mixture was stirred at room temperature for 16 hours, then 40 μL of N,N-diisopropylethylamine (230 μmol), 550 μL of saturated NH3 solution in chloroform, and 65 mg of HATU (167 μmol) were added, and the mixture was stirred at 40°C for 24 hours. Subsequently, the mixture was divided between saturated NH4Cl aqueous solution and EA (20 mL each), the layers were separated, the organic phase was washed with ice-cold brine (2 × 15 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase flash column chromatography (elution gradient, 0% to 100% CH3CN in H2O containing 0.1% (v / v) formic acid) to obtain the title compound 50 as an off-white solid (14.5 mg, 36%).

[0426] 1 H NMR:400MHz,CD3OD,δ(ppm):3.25-3.05(m,2H),2.54(ddd,J=13.4,7.9,5.4Hz,1H),2.38(ddd,J=13.7, 5.9,5.0Hz,1H),2.12(dd,J=13.5,6.7Hz,1H),2.07-1.85(m,4H),1.73-1.51(m,4H),1.26-1.18(m,2H). LC-MS: rt=1.25 min, MS: 317.1 (calculated value), 318.0 (M+H + (Actual measured value).

[0427] Example 32 2-amino-6-cyano-6-(cyclohexylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (51) and Example 33 2-amino-6-cyano-6-(cyclohexylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(52)

[0428] [ka]

[0429] 2-amino-6-cyano-6-(cyclohexylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (51) Compound 51 (Example 32) was synthesized in the same manner as Compound 47 (Example 28, Scheme 4), starting from 1,4-dioxaspiro[4.5]decane-8-carbonitrile (40), with (bromomethyl)cyclohexane used instead of (bromomethyl)cyclobutane in the first step.

[0430] 1 H NMR:400MHz,DMSO-d6,δ(ppm):12.69(bs,1H),8.48(bs,2H),3.12-2.97(m,2H),2.47-2.36(m,1H),2.2 7(dt,J=13.7,5.5Hz,1H),1.84-1.54(m,6H),1.53-1.46(m,1H),1.28-1.07(m,4H),1.03-0.90(m,2H). LC-MS: rt=1.49 min, MS: 332.1 (calculated value), 333.0 (M+H + (Actual measured value).

[0431] 2-amino-6-cyano-6-(cyclohexylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(52) To a solution of 51 (24.0 mg, 72.2 μmol) in DMF (798 μL), PyBOP (56.5 mg, 108 μmol), N,N-diisopropylethylamine (40.0 μL, 230 μmol), and ammonium chloride (38.6 mg, 722 μmol) were added. The resulting mixture was stirred at room temperature for 80 minutes, then diluted with saturated NH4Cl aqueous solution (5 mL), and extracted with EA (3 × 5 mL). The combined organic matter was washed with ice-cold brine (2 × 10 mL), dried over Na2SO4, filtered, concentrated, and the residue was purified by flash column chromatography (elution gradient, EA in hexane at 10% to 100%) to obtain the title compound 52 as an orange solid (13.6 mg, yield 57%).

[0432] 1 H NMR:400MHz,CD3OD,δ(ppm):3.18-3.09(m,2H),2.51(ddd,J=13.3,7.5,5.6Hz,1H),2.36(dt,J =13.6,5.5Hz,1H),1.98-1.80(m,3H),1.79-1.59(m,5H),1.38-1.16(m,4H),1.13-0.97(m,2H). LC-MS: rt=1.34 min, MS: 331.1 (calculated value), 332.2 (M+H + (Actual measured value).

[0433] Example 34 2-amino-6-cyano-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (53) and Example 35 2-amino-6-cyano-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(54)

[0434] [ka]

[0435] 2-amino-6-cyano-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (53). Compound 53 (Example 34) was synthesized in the same manner as Compound 47 (Example 28, Scheme 4), starting from 1,4-dioxaspiro[4.5]decane-8-carbonitrile (40), with (bromomethyl)cyclopropane used instead of (bromomethyl)cyclobutane in the first step.

[0436] 1 H NMR:400MHz,CD3OD,δ(ppm):3.23-3.19(m,2H),2.54-2.50(m,1H),2.42-2.39(m,1H),1.89(dd,J=14.27 ,7.15Hz,1H),1.78(dd,J=14.26,6.72Hz,1H),0.91-0.87(m,1H),0.57-0.53(m,2H),0.22-0.19(m,2H). LC-MS: rt=1.18 min, MS: 290.1 ​​(calculated value), 291.0 (M+H + (Actual measured value).

[0437] 2-amino-6-cyano-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (54). To a suspension of 53 (36.4 mg, 0.125 mmol) in CHCl3 (871 μL), HATU (52.4 mg, 0.138 mmol) and N,N-diisopropylethylamine (65.5 μL, 0.376 mmol) were added. The mixture was stirred at room temperature for 20 minutes, and then saturated NH3 solution in CHCl3 (0.8 mL) (prepared in-house) and NH4Cl (6.71 mg, 0.125 mmol) were added. The reaction mixture was stirred for 16 hours and separated into EA and saturated NaHCO3 aqueous solution. The layers were separated, the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, EA in hexane at 20% to 100%) to obtain the title compound 54 as a white solid (20.0 mg, yield 55%).

[0438] 1 H NMR:400MHz,CD3OD,δ(ppm):3.13(t,J=6.03Hz,2H),2.60-2.53(m,1H),2.48-2.42(m,1H),1.93(dd,J=14. 28,7.11Hz,1H),1.80(dd,J=14.28,6.79Hz,1H),0.94-0.84(m,1H),0.58-0.55(m,2H),0.24-0.20(m,2H). LC-MS: rt=1.02 min, MS: 289.1 (calculated value), 290.1 ​​(M+H + (Actual measured value).

[0439] Example 36 2-amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (59)

[0440] [ka]

[0441] Step 1. Ethyl 2-amino-6-cyano-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (56). A solution of 4-oxo-1-phenylcyclohexane-1-carbonitrile (55) (6.00 g, 30.1 mmol) and 2-ethyl cyanoethyl (2.91 mL, 27.4 mmol) in EtOH (48.0 mL) was prepared by adding morpholine (2.60 mL, 30.1 mmol) and sulfur (969 mg, 3.78 mmol). The reaction mixture was stirred at 60°C for 16 hours. Upon cooling the mixture to room temperature, a white precipitate appeared. This solid was collected by filtration, washed with EtOH, and dried under vacuum to obtain the title compound 56 as a white solid (8.15 g, yield 91%). LC-MS: rt=1.55 min, MS: 326.1 (calculated), 327.0 (M+H + (Actual measured value).

[0442] Step 2. Ethyl 2-acetamido-6-cyano-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (57). To a solution of 56 (8.15 g, 25.0 mmol) in acetic acid (143 mL), acetic anhydride (2.83 mL, 30.0 mmol) was added. The mixture was stirred at 60°C for 1 day, then cooled to room temperature and concentrated to dryness. The residue was separated between DCM and water. The layers were separated, and the organic phase was washed with saturated NaHCO3 aqueous solution, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the title compound 57 as a white solid (9.0 g, yield 98%). LC-MS: rt=1.61 min, MS: 368.1 (calculated), 369.1 (M+H + (Actual measured value).

[0443] Step 3. Ethyl 2-acetamido-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (58). To a solution of 57 (9.00 g, 24.4 mmol) in acetic acid (66 mL) and water (66 mL), cerium sulfate (70.1 g, 211 mmol) was added. The mixture was sonicated until homogeneous and stirred at room temperature for 24 hours. The suspension was divided between EA and water. The layers were separated, and the organic phase was washed with 1 N NaOH, water, and brine. The organic layer was then dried over Na2SO4, filtered, and concentrated to obtain the title compound 58 as an off-white solid (9.10 g, yield 97%). LC-MS: rt=1.56 min, MS: 382.1 (calculated), 383.1 (M+H + (Actual measured value).

[0444] Step 4.2-amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (59). A suspension of 58 (4.00 g, 10.44 mmol) in MeOH (1.26 L) was mixed with a solution of lithium hydroxide monohydrate (2.20 g, 52.4 mmol) in water (1.26 L). The reaction mixture was stirred under reflux for 2 hours and then cooled to room temperature. The mixture was diluted with water, concentrated to remove most of the organic solvent, and then washed with EA. The aqueous layer was acidified by slowly adding 3N HCl and extracted with EA. This organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by grinding with a DCM / pentane mixture to obtain the title compound 59 as a grayish solid (2.54 g, 78% yield).

[0445] 1 H NMR:400MHz,CD3OD,δ(ppm):7.43-7.31(m,5H),3.27-3.23(m,1H),2.88-2.73(m,2H),2.71-2.61(m,1H). LC-MS: rt=1.23 min, MS: 312.1 (calculated value), 313.1 (M+H + (Actual measured value).

[0446] Example 37 (R)-2-amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (60a) (S)-2-amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (60b)

[0447] [ka]

[0448] Racemic compound 59 (86.0 mg) was subjected to SFC chiral separation (isocratic, 35% MeOH in CO2) to obtain enantio-enriched compound 60a as a pale pink solid (33.1 mg, 38% separation yield) and 60b as a white solid (35.4 mg, 41% separation yield) (the absolute configuration was assigned based on the resolved crystal structure of enantiomer 60a).

[0449] 60a: 1 ¹H NMR: Same as racemic mixture (59). LC-MS: rt=1.23 min, MS: 312.1 (calculated value), 313.1 (M+H + (Measured values). Analysis SFC (IG column using a 5-60% MeOH gradient in water (95-40% CO2)): rt = 3.84 mins, ee. = 99.9%.

[0450] 60b: 1 ¹H NMR: Same as racemic mixture (59). LC-MS: rt=1.23 min, MS: 312.1 (calculated value), 313.1 (M+H + (Measured values). Analysis SFC (IG column using a 5-60% MeOH gradient in water (95-40% CO2)): rt = 4.76 mins, ee. = 97.6%.

[0451] Example 38 2-amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (61) and Example 39 2-amino-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3,6-dicarboxamide(62)

[0452] [ka]

[0453] Step 1.2-amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (61). To a solution of 59 (2.54 g, 8.13 mmol) in DMF (90.0 mL), HATU (4.73 g, 12.2 mmol) and N,N-diisopropylethylamine (2.83 mL, 16.4 mmol) were added, and the mixture was stirred at room temperature for 20 minutes. Then, ammonium chloride (8.74 g, 163 mmol), NH3 solution in THF (45.0 mL, 18.0 mmol, 0.4 M), and saturated NH3 solution in chloroform (45.0 mL) (prepared in-house) were added to the mixture. The reaction mixture was stirred at room temperature for 16 hours and separated into EA and saturated NaHCO3 aqueous solution. The layers were separated, the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, 20% to 100% EA in hexane), followed by reverse-phase flash column chromatography (elution gradient, 0% to 100% CH3CN in H2O containing 0.1% (v / v) formic acid) to obtain the title compound 61 as a white solid (1.20 g, yield 47%).

[0454] 1 H NMR:400MHz,CD3OD,δ(ppm):7.41-7.36(m,5H),3.17-3.11(m,1H),2.87-2.77(m,2H),2.74-2.66(m,1H). LC-MS: rt=1.04 min, MS: 311.1 (calculated value), 312.0 (M+H + (Actual measured value).

[0455] Step 2.2-amino-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3,6-dicarboxamide(62) A 30% aqueous hydrogen peroxide solution (170 μL) was added to a suspension of 61 (13.2 mg, 42.4 μmol) and potassium carbonate (11.7 mg, 84.8 μmol) in DMSO (569 μL). The mixture was stirred at room temperature for 3 hours, and then separated into aqueous solution (EA) and water (5 mL each). The layers were separated, the organic phase was washed with 5 mL of water, and the combined aqueous phase was extracted with EA (2 × 3 mL). The combined organic matter was washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by reverse-phase flash column chromatography (elution gradient, 0% to 70% CH₃CN in H₂O containing 0.1% (v / v) formic acid) to obtain the title compound 62 as a white solid (3.6 mg, yield 28%).

[0456] 1 H NMR:400MHz,CD3OD,δ(ppm):7.41-7.25(m,5H),3.05(dt,J=16.8,4.2Hz,1H),2.78-2.59(m,3H). LC-MS: rt=0.86 min, MS: 329.1 (calculated value), 329.9 (M+H + (Actual measured value).

[0457] Example 40 (S)-2-amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (63) and Example 41 (R)-2-amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(64)

[0458] [ka]

[0459] Racemic compound 61 (96.5 mg) was subjected to SFC chiral separation (isocratic, 45% CH3CN / EtOH in CO2, 1:1) to obtain enantio-enriched compound 63 as a white solid (29.0 mg, 30% separation yield), and enantio-enriched compound 64 as a white solid (29.0 mg, 30% separation yield) (the absolute configuration was assigned based on the resolved crystal structure of enantiomer 64).

[0460] 63: 1 ¹H NMR: Same as racemic mixture (61). LC-MS: rt=1.04 min, MS: 311.1 (calculated value), 312.0 (M+H + (Measured values). Analysis SFC (IG column using a 5-60% ACN / EtOH (95-40% CO2) gradient): rt = 4.71 min, ee => 99.9%.

[0461] 64: 1 ¹H NMR: Same as racemic mixture (61). LC-MS: rt=1.04 min, MS: 311.1 (calculated value), 312.0 (M+H + (Measured values). Analysis of SCF (IG column using a 5-60% ACN / EtOH (95-40% CO2) gradient): rt = 4.09 mins, ee => 99.9%.

[0462] Examples 42-49 Compounds 65-71 (Examples 42-48) were synthesized by starting with compound 59 (Example 36, Scheme 8) instead of compound 8, and using cyclobutylamine, cyclopentylamine, 3-aminooxetane, 3-aminotetrahydrofuran, 4-aminotetrahydropyran, 2,2,2-trifluoroethylamine, and 2,2-difluoroethane-1-amine, respectively, following the same procedure as described above for the synthesis of compound 9 (Example 2, Scheme 2). Compound 72 (Example 49) was obtained in the same manner, starting with compound 53 (Example 34, Scheme 7). The characterization of compounds 65-72 (Examples 42-49) is shown in Table 3.

[0463] [Table 3-1]

[0464] [Table 3-2]

[0465] Example 50 2-amino-6-cyano-6-isobutyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(75)

[0466] [ka]

[0467] Step 1. 1-Isobutyl-4-oxocyclohexane-1-carbonitrile (73). To a THF solution (3.0 mL) of 1,4-dioxaspiro[4.5]decane-8-carbonitrile (40, 221 μL, 1.50 mmol, scheme 4), LDA (2.39 mL, 1 M in THF / hexane, 2.39 mmol) was added dropwise at -78°C. After 30 minutes, 1-bromo-2-methylpropane (164 μL, 1.50 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was then separated between hexane and water. The layers were separated, and the aqueous phase was extracted with EA. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The dried residue was dissolved in acetone (19.7 mL), and 3N HCl (4.98 mL, 15.0 mmol) was slowly added. The mixture was stirred for 16 hours, then neutralized by slowly adding saturated NaHCO3 solution, and concentrated to remove the organic solvent. The remaining aqueous solution was extracted with EA, the organic layer was dried over Na2SO4, filtered, and concentrated to dryness to obtain the title compound 73 (141 mg, 52% yield in 2 steps). LC-MS: rt=1.45 min, MS: 179.1 (calculated value), 180.0 (M+H + (Actual measured value).

[0468] Step 2.2-amino-6-cyano-6-isobutyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (74). To a solution of 73 (141 mg, 0.784 mmol) and cyanoacetamide (59.9 mg, 0.713 mmol) in EtOH (713 μL), morpholine (67.6 μL, 0.784 mmol) and sulfur (25.2 mg, 98.3 μmol) were added. The reaction mixture was stirred at 60°C for 19 hours, cooled to room temperature, and concentrated to dryness. The residue was separated between EA and water. The layers were separated, the organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, EA in hexane from 0% to 100%) to obtain the title compound 74 as a beige solid (115 mg, yield 58%). LC-MS: rt=1.49 min, MS: 277.1 (calculated), 277.9 (M+H + (Actual measured value).

[0469] Step 3.2-amino-6-cyano-6-isobutyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (75). Selenium dioxide (12.0 mg, 0.108 mmol) was added to a solution of 74 (30 mg, 0.108 mmol) in DMSO (643 μL). The reaction mixture was stirred at room temperature for 12 hours, then separated into brine and EA. The layers were separated, the organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, 0% to 10% MeOH in DCM), followed by half-portion HPLC-MS (35% to 100% MeOH in 10 mM ammonium formate, pH=3.8) to obtain the title compound 75 as a white solid (3.20 mg, yield 10%).

[0470] 1H NMR:400MHz,CD3OD,δ(ppm):3.19-3.09(m,2H),2.51(ddd,J=13.71,7.59,5.42Hz,1H),2.3 6(dt,J=13.65,5.45Hz,1H),1.97-1.85(m,2H),1.80-1.75(m,1H),1.03(d,J=6.05Hz,6H). LC-MS: rt=1.11 min, MS: 291.1 (calculated value), 292.1 (M+H + (Actual measured value).

[0471] Example 51 2-amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (81) and Example 52 2-amino-6-(cyanomethyl)-N-cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(82)

[0472] [ka]

[0473] Step 1. Ethyl 2-amino-6-(cyanomethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (77). To a solution of 2-(4-oxo-1-phenylcyclohexyl)acetonitrile (76) (Bioorg. Med. Chem. Lett., 21, p. 405, 2011) (705 mg, 3.31 mmol) and 2-ethyl cyanoethyl acetate (351 μL, 3.01 mmol) in EtOH (3.01 mL), morpholine (285 μL, 3.31 mmol) and sulfur (106 mg, 0.415 mmol) were added. The mixture was stirred at 60°C for 16 hours, then cooled to room temperature to form a white precipitate. This solid was recovered by filtration, washed with EtOH, and dried under vacuum to obtain the title compound 77 as a white solid (682 mg, yield 67%). LC-MS: rt = 1.55 min, MS: 340.1 (calculated), 341.1 (M + H +(Actual measured value).

[0474] Step 2. Ethyl 2-acetamido-6-(cyanomethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (78). To a solution of 77 (682 mg, 2.00 mmol) in acetic acid (11.5 mL), acetic anhydride (227 μL, 2.40 mmol) was added. The mixture was stirred at 60°C for 24 hours, then cooled to room temperature and concentrated to dryness. The residue was separated between DCM and water. The layers were separated, and the organic phase was washed with saturated NaHCO3 aqueous solution, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the title compound 78 as a white solid (766 mg, yield >99%). LC-MS: rt=1.61 min, MS: 382.1 (calculated), 383.1 (M+H + (Actual measured value).

[0475] Step 3. Ethyl 2-acetamido-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (79). To a solution of 78 (766 mg, 2.00 mmol) in acetic acid (6.73 mL) and water (6.73 mL), cerium sulfate (5.75 g, 17.3 mmol) was added. The suspension was sonicated until homogenized, stirred at room temperature for 1 day, and then separated into EA and water. The layers were separated, and the organic phase was washed with 1 N NaOH, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the title compound 79 as an off-white solid (794 mg, yield >99%). LC-MS: rt = 1.47 min, MS: 396.1 (calculated), 397.1 (M + H + (Actual measured value).

[0476] Step 4. Ethyl 2-amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (80). Pyrrolidine (2.46 mL, 30.0 mmol) was added to a toluene suspension (3.28 mL) of 79 (793 mg, 2.00 mmol). The suspension dissolved after stirring for several minutes. The reaction mixture was stirred at 80°C for 1 hour, then cooled to room temperature and concentrated. The residue was purified by flash column chromatography (elution gradient, EA in hexane from 0% to 100%) to obtain the title compound 80 as a white solid (408 mg, yield 57%). LC-MS: rt=1.43 min, MS: 354.1 (calculated), 355.0 (M+H + (Actual measured value).

[0477] Step 5.2-amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (81). A suspension of 80 (408 mg, 1.15 mmol) in MeOH (139 mL) was mixed with a solution of lithium hydroxide monohydrate (242 mg, 5.76 mmol) in water (139 mL). The reaction mixture was stirred under reflux for 16 hours and then cooled to room temperature. The mixture was diluted with water, concentrated to remove most of the organic solvent, and then washed with EA. The aqueous layer was collected, acidified by slowly adding 2N HCl, and extracted with EA. This organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, 0%-10% MeOH in DCM) to obtain the title compound 81 as a white solid (376 mg, yield >99%).

[0478] 1 H NMR:400MHz,CD3OD,δ(ppm):7.34-7.27(m,5H),3.35-3.30(m,1H),3.01(d,J= 16.71Hz, 1H), 2.89 (d, J=16.71Hz, 1H), 2.77-2.74 (m, 1H), 2.49-2.45 (m, 2H). LC-MS: rt=1.16 min, MS: 326.1 (calculated value), 327.0 (M+H + (Actual measured value).

[0479] Step 6.2-amino-6-(cyanomethyl)-N-cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (82). To a suspension of 81 (154 mg, 0.472 mmol) in THF (5.90 mL), HATU (359 mg, 0.944 mmol) and N,N-diisopropylethylamine (164 μL, 0.944 mmol) were added. The mixture was stirred at room temperature for 20 minutes, and then cyclopropylamine (327 μL, 4.72 mmol) was added. The reaction mixture was stirred for a further 16 hours, and then separated into EA and saturated NH4Cl aqueous solution. The layers were separated, the organic phase was recovered, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, 20% to 100% EA in hexane), and then by reverse-phase flash column chromatography (elution gradient, 0% to 100% CH3CN in H2O containing 0.1% (v / v) formic acid) to obtain the title compound 82 as a white solid (46.5 mg, yield 27%).

[0480] 1 H NMR:400MHz,CD3OD,δ(ppm):7.35-7.27(m,5H),3.00(d,J=16.70Hz,1H),2.89(d,J=16.71Hz,1H),2.82-2. 78(m,1H),2.77-2.74(m,1H),2.69-2.64(m,2H),2.49-2.42(m,1H),0.72-0.67(m,2H),0.54-0.48(m,2H). LC-MS: rt=1.20 min, MS: 365.1 (calculated value), 366.1 (M+H + (Actual measured value).

[0481] Example 53 2-amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (83) and Example 54 2-amino-6-(2-amino-2-oxoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(84)

[0482] [ka]

[0483] Step 1.2-amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (83). A suspension of 81 (50.0 mg, 0.153 mmol) in anhydrous DMF (1.69 mL) was saturated with gaseous NH3. Then, PyBOP (120 mg, 0.230 mmol) and N,N-diisopropylethylamine (53.4 μL, 0.306 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. Subsequently, the mixture was separated into EA and saturated NH4Cl aqueous solution. The layers were separated, and the aqueous phase was extracted with EA. The combined organic matter was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, 20% to 100% EA in hexane), followed by reverse-phase flash column chromatography (elution gradient, 0% to 100% CH3CN in H2O containing 0.1% (v / v) formic acid) to obtain the title compound 83 as a white solid (47.0 mg, yield 94%).

[0484] 1 H NMR:400MHz,CD3OD,δ(ppm):7.39-7.29(m,5H),3.02-2.95(m,2H),2.90(d,J=16.72Hz,1H),2.80(ddd,J=1 3.55,4.09,2.50Hz,1H),2.67(ddd,J=17.32,11.78,4.10Hz,1H),2.49(ddd,J=13.53,11.79,4.45Hz,1H). LC-MS: rt=1.01 min, MS: 325.1 (calculated value), 326.0 (M+H + (Actual measured value).

[0485] Step 2.2-amino-6-(2-amino-2-oxoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (84). A suspension of 83 (47.0 mg, 0.144 mmol) in concentrated sulfuric acid (470 μL) was stirred at room temperature for 72 hours, then poured over crushed ice, and the resulting mixture was basicized with a 4N NaOH solution. The solution was extracted by DCM. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, 0% to 10% MeOH in DCM, followed by 100% isopropanol) to obtain the title compound 84 as a white solid (17.5 mg, 35% yield).

[0486] 1 H NMR:400MHz,CD3OD,δ(ppm):7.32-7.27(m,4H),7.23-7.19(m,1H),2.99(d,J=14.78Hz, 1H),2.92-2.87(m,1H),2.78-2.71(m,1H),2.65(d,J=14.76Hz,2H),2.60-5.50(m,1H). LC-MS: rt=0.84 min, MS: 343.1 (calculated value), 344.1 (M+H + (Actual measured value).

[0487] Example 55 2-amino-6-(2-hydroxyethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (89).

[0488] [ka]

[0489] Step 1. Ethyl 2-amino-6-(2-hydroxyethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (86). To a solution of 4-(2-hydroxyethyl)-4-phenylcyclohexane-1-one (85) (Bioorg. Med. Chem. Lett., 21, p. 405, 2011) (7.95 g, 36.4 mmol) and 2-ethyl cyanoacetate (4.26 mL, 40.1 mmol) in EtOH (36.4 mL), morpholine (3.50 mL, 40.1 mmol) and sulfur (1.29 g, 5.03 mmol) were added. The reaction mixture was stirred at 60°C for 16 hours, then cooled to room temperature to form a white precipitate. This solid was recovered by filtration, washed with EtOH, and dried under vacuum to obtain the title compound 86 as a white solid (9.40 g, yield 72%). LC-MS: rt = 1.41 min, MS: 345.1 (calculated value), 346.1 (M + H + (Actual measured value).

[0490] Step 2. Ethyl 2-acetamido-6-(2-hydroxyethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (87). To a solution of 86 (8.30 g, 24.0 mmol) in acetic acid (138 mL), acetic anhydride (2.73 mL, 28.8 mmol) was added. The mixture was stirred at 60°C for 2 hours, then cooled to room temperature and concentrated to dryness to obtain the title compound 87 as a brown oil, which was used directly in the next step. LC-MS: rt = 1.78 min, MS: 387.2 (calculated value), 388.2 (M+H + (Actual measured value).

[0491] Step 3. Ethyl 2-acetamido-6-(2-hydroxyethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (88). To a solution of 87 (24.0 mmol) in acetic acid (160 mL), water (160 mL), and dioxane (160 mL), cerium sulfate (69.0 g, 208 mmol) was added. The mixture was sonicated until homogenized, stirred at room temperature for 24 hours, and separated into EA and water. The layers were separated, and the organic phase was washed with 1 N NaOH, water, and brine. The organic layer was then dried over Na2SO4, filtered, and concentrated to obtain the title compound 88 as an orange solid (9.60 g, yield 91%). LC-MS: rt=1.56 min, MS: 401.1 (calculated), 402.1 (M+H + (Actual measured value).

[0492] Step 4. 2-amino-6-(2-hydroxyethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (89). A suspension of 88 (9.60 g, 24.1 mmol) in MeOH (1.11 L) was mixed with a solution of lithium hydroxide monohydrate (6.86 g, 163.4 mmol) in water (1.11 L). The reaction mixture was stirred at 55°C for 24 hours and then cooled to room temperature. The cooled mixture was diluted with water, concentrated to remove most of the organic solvent, and then washed with EA. The aqueous layer was collected, acidified by slowly adding 2N HCl, and extracted with EA. This organic extract was dried over Na2SO4, filtered, and concentrated to obtain the title compound 89 as an orange solid (7.0 g, yield 88%).

[0493] 1 H NMR:400MHz,CD3OD,δ(ppm):7.29-7.16(m,5H),3.53-3.38(m,2H),3.20-3.12(m,1H),2.61-2.53(dt, J=13.63,3.48Hz,1H),2.44(ddd,J=18.55,11.61,4.01Hz,1H),2.34-2.23(m,1H),2.15-2.03(m,2H). LC-MS: rt=1.04 min, MS: 331.1 (calculated value), 332.0 (M+H + (Actual measured value).

[0494] Example 56 2-amino-7-oxo-5-propyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(91)

[0495] [ka]

[0496] Compound 90 (277 mg, 1.18 mmol, synthesized similarly to Compound 3 in Scheme 1, starting with 5-propyl-1,3-cyclohexanedione instead of 5-(2-(trifluoromethyl)phenyl)cyclohexane-1,3-dione) was dissolved in 98% H2SO4 (2.5 mL), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was then slowly poured into ice-cold aqueous K2CO3, diluted with water, and extracted with EA (a portion of the product precipitated, which was recovered by filtration and combined with the remaining crude product). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, 50% to 100% EA in hexane) to obtain the title compound 91 as an off-white solid (144 mg, yield 48%).

[0497] 1 H NMR:400MHz,DMSO-d6,δ(ppm):7.97(s,2H),6.96(bs,2H),2.99-2.95(m,1H),2.6 7-2.57(m,1H),2.38-2.32(m,1H),2.19-2.07(2H,m),1.36(bs,4H),0.88(bs,3H). LC-MS: rt=2.30 min, MS: 252.1 (calculated value), 253.1 (M+H + (Actual measured value).

[0498] Example 57 2-amino-6-(2,2-difluoroethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(97)

[0499] [ka]

[0500] Step 1.2-(8-phenyl-1,4-dioxaspiro[4.5]decane-8-yl)acetaldehyde (93) To a solution of 2-(8-phenyl-1,4-dioxaspiro[4.5]decane-8-yl)acetonitrile (92) (1.0 g, 3.89 mmol) (Bioorg Med. Chem Lett. 21, p. 405, 2011) in anhydrous toluene (24.5 mL), DIBALH (3.92 mL, 25% in toluene, 5.83 mmol) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 2 hours and then carefully quenched with MeOH and saturated NH4Cl solution. The mixture was then allowed to reach room temperature, diluted with Et2O, and filtered through a Celite pad. The layers were separated and the organic phase was concentrated. The residue was dissolved in THF (15.0 mL) and 1N HCl (3.89 mL, 3.89 mmol) was added. The mixture was stirred at room temperature for 15 minutes, then quenched with saturated NaHCO3 solution and extracted with Et2O. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, 5%–100% EA in hexane) to obtain title compound 93 as a colorless oil (605 mg, yield 60%), which was used directly in the next step without characterization.

[0501] Step 2. 8-(2,2-difluoroethyl)-8-phenyl-1,4-dioxaspiro[4.5]decane(94) To a solution of 93 (200 mg, 0.77 mmol) in anhydrous DCM (9.5 mL), DAST (0.19 mL, 1.54 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour, then quenched with saturated NaHCO3 solution and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the title compound 94 as a colorless oil (213 mg, 98% yield), which was used directly in the next step without characterization.

[0502] Step 3. 4-(2,2-difluoroethyl)-4-phenylcyclohexane-1-one (95) To a solution of 94 (213 mg, 0.75 mmol) in acetone (10.5 mL), 2N HCl (1.89 mL, 3.77 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then neutralized by slowly adding a saturated NaHCO3 solution, concentrated, and the organic solvent was removed. The residue was extracted with EA, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to dryness to obtain the title compound 95 as a colorless oil (169 mg, 94% yield), which was used directly in the next step without characterization.

[0503] Step 4. 2-amino-6-(2,2-difluoroethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (96) Morpholine (0.068 mL, 0.78 mmol) and sulfur (25 mg, 0.098 mmol) were added to a solution of 95 (169 mg, 0.709 mmol) and cyanoacetamide (66 mg, 0.78 mmol) in EtOH (0.7 mL). The reaction mixture was stirred at 60 °C for 16 hours, then cooled to room temperature and concentrated to dryness. The residue was separated into water and EA. The layers were separated, the organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, EA in hexane at 50%-100%) to obtain the title compound 96 (93 mg, yield 39%). LC-MS: rt=1.39 min, MS: 336.1 (calculated), 337.1 (M+H + (Actual measured value).

[0504] Step 5. 2-amino-6-(2,2-difluoroethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (97) A mixture of 96 (40 mg, 0.119 mmol) in THF (0.4 mL) and water (0.08 mL) was added dropwise to a solution of DDQ (82 mg, 0.36 mmol) in THF (0.4 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, then the mixture was quenched with saturated NaHCO3 solution and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, EA in hexane at 50%-100%) to obtain the title compound 97 as a pale yellow solid (3 mg, yield 7%).

[0505] 1 H NMR:400MHz,CDCl3,δ(ppm):7.37-7.27(m,5H),7.04(s,2H),5.80(tt,J=56.4,4.6,1H), 5.32(s,2H),2.97-2.92(m,1H),2.83-2.78(m,1H),2.65-2.57(m,1H),2.53-2.42(m,3H). 19 F NMR:376MHz, CDCl3,δ(ppm):-110.4(ddt,J=287.8,56.1,18.0Hz,1F),-111.5(ddt,J=287.8,56.5,16.3Hz,1F). LC-MS: rt=1.25 min, MS: 350.1 (calculated value), 351.0 (M+H + (Actual measured value).

[0506] Example 58 2-amino-6-cyano-6-isopropyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(101)

[0507] [ka]

[0508] Step 1. 8-Isopropyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile(98) To a solution of 1,4-dioxaspiro[4.5]decane-8-carbonitrile (40, scheme 4) (1.0 g, 5.98 mmol) in anhydrous THF (12.0 mL), LHMDS (6.88 mL, 1 M in THF, 6.88 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 1 hour, after which 2-iodopropane (0.597 mL, 5.98 mmol) was added dropwise. The reaction mixture was then slowly allowed to reach room temperature and stirred for 16 hours. The reaction mixture was then quenched with water and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness to obtain the title compound 98 as a brown solid, which was used directly in the next step. LC-MS: rt=3.05 min, MS: 209.1 (calculated), 210.1 (M+H + (Actual measured value).

[0509] Step 2. 1-Isopropyl-4-oxocyclohexane-1-carbonitrile (99) To a solution of 98 (5.98 mmol) in acetone (80 mL), 2N HCl (23.9 mL, 47.8 mmol) was added, and the reaction mixture was stirred at room temperature for 2 days. The mixture was then neutralized by slowly adding saturated NaHCO3 solution, concentrated, and the organic solvent was removed. The residue was extracted with EA, the organic layer was dried over Na2SO4, filtered, and concentrated to dryness to obtain the title compound 99 (445 mg, 45% yield in 2 steps). LC-MS: rt=2.35 min, MS: 165.2 (calculated), 166.1 (M+H + (Actual measured value).

[0510] Step 3.2-amino-6-cyano-6-isopropyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (100) Morpholine (0.24 mL, 2.69 mmol) and sulfur (87 mg, 0.338 mmol) were added to a solution of 99 (445 mg, 2.69 mmol) and cyanoacetamide (206 mg, 2.45 mmol) in EtOH (4.9 mL). The reaction mixture was stirred at 60°C for 16 hours, resulting in the appearance of a large precipitate. This solid was recovered by filtration to obtain the title compound 100 as a white solid (477 mg, yield 74%). LC-MS: rt=2.60 min, MS: 263.1 (calculated), 264.1 (M+H) + (Actual measured value).

[0511] Step 4.2-amino-6-cyano-6-isopropyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (101) Selenium dioxide (42 mg, 0.38 mmol) was added to a solution of 100 (100 mg, 0.38 mmol) in DMSO (2.25 mL). The reaction mixture was stirred at room temperature for 16 hours, then separated between brine and EA, and the organic layer was concentrated. The residue was purified by flash column chromatography (elution gradient, 0.5% to 10% MeOH in DCM), and then half of it was purified again by HPLC-MS (elution gradient, 30% to 100% MeOH in 10 mM ammonium bicarbonate) to obtain the title compound 101 as a white solid (5.0 mg, yield 5%).

[0512] 1 H NMR:400MHz,CD3OD,δ(ppm):3.18(ddd,J=17.9,8.2,5.1Hz,1H),3.06(dt,J=17.9,5.4Hz,1H),2.50-2.39(m,3H),1.12-1.08(m,6H). LC-MS: rt=0.97 min, MS: 277.1 (calculated value), 278.1 (M+H + (Actual measured value).

[0513] Example 59 2-amino-6-(hydroxymethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(109)

[0514] [ka]

[0515] Step 1. 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-phenylcyclohexane-1-one(103) To a solution of 4-(hydroxymethyl)-4-phenylcyclohexane-1-one (102) (Bioorg. Med. Chem. Lett., 21, p. 405, 2011) (890 mg, 4.36 mmol) in anhydrous DMF (40 mL), tert-butyldimethylsilyl chloride (737 mg, 4.79 mmol) and imidazole (653 mg, 9.59 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours, then diluted with water (30 mL) and extracted with EA (70 mL). The organic phase was dried over Na2SO4, filtered, concentrated, and the residue was purified by flash column chromatography (elution gradient, EA in hexane with 0% to 20%) to obtain the title compound 103 as a white solid (1.20 g, yield 86%), which was used directly in the next step without characterization.

[0516] Step 2. Ethyl 2-amino-6-(((tert-butyldimethylsilyl)oxy)methyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate(104) A suspension of 103 (1.20 g, 3.77 mmol), morpholine (330 μL, 3.77 mmol), sulfur (121 mg, 473 μmol), and 2-ethyl cyanoethyl acetate (364 μL, 3.42 mmol) in EtOH (6.01 mL) was stirred at 60°C for 16 hours. The mixture was then cooled to room temperature and concentrated. The residue was purified by flash column chromatography (elution gradient, EA in hexane from 0% to 100%) to obtain the title compound 104 as an off-white solid (1.49 g, yield 97%). LC-MS: rt=2.34 min, MS: 445.2 (calculated), 446.2 (M+H + (Actual measured value).

[0517] Step 3. Ethyl 2-((tert-butoxycarbonyl)amino)-6-(((tert-butyldimethylsilyl)oxy)methyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (105) To a solution of 104 (1.49 g, 3.34 mmol), DMAP (41.7 mg, 334 μmol), and triethylamine (699 μL, 5.01 mmol) in DCM (66.8 mL), a solution of di-tert-butyl dicarbonate (802 mg, 3.68 mmol) in DCM was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 16 hours and then quenched with saturated NH4Cl aqueous solution. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic matter was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, EA in hexane from 0% to 100%) to obtain the title compound 105 as an off-white solid (1.66 g, yield 91%). LC-MS: rt=2.63 min, MS: 545.3 (calculated), 546.0 (M+H + (Actual measured value).

[0518] Step 4. Ethyl 2-((tert-butoxycarbonyl)amino)-6-(((tert-butyldimethylsilyl)oxy)methyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate(106) A suspension of pyridinium chlorochromate (4.50 g, 20.9 mmol), Celite (1.50 g), and 105 (1.50 g, 2.75 mmol) in anhydrous benzene (40.7 mL) was stirred at 80°C for 4 hours. The mixture was then cooled to room temperature, filtered through a Celite pad, and the solid residue was washed with CHCl3. The filtrate was concentrated, and the residue was purified by flash column chromatography (elution gradient, EA in hexane 0% to 30%) to obtain the title compound 106 as a white solid (395 mg, yield 26%). LC-MS: rt=2.52 min, MS: 559.2 (calculated), 560.2 (M+H + (Actual measured value).

[0519] Step 5.2-((tert-butoxycarbonyl)amino)-6-(((tert-butyldimethylsilyl)oxy)methyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid(107) A solution of 106 (380 mg, 679 μmol) in EtOH (20.0 mL) was mixed with a solution of NaOH (136 mg, 3.39 mmol) in water (20.0 mL). The resulting mixture was sonicated for 1 minute and then vigorously stirred at room temperature for 68 hours. The mixture was then diluted with water (15 mL) and extracted with EA (3 × 30 mL). The combined organic matter was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, 0% to 50% EA in hexane, then 0% to 30% MeOH in DCM) to obtain the title compound 107 as a white solid (264 mg, yield 73%). LC-MS: rt=1.60 min, MS: 531.2 (calculated), 532.1 (M+H + (Actual measured value).

[0520] Step 6.2-amino-6-(hydroxymethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (108) Trifluoroacetic acid (5.99 mL, 78.2 mmol) was added dropwise to a solution of 107 (260 mg, 489 μmol) in DCM (30.0 mL) at 0°C. The mixture was stirred at 0°C for 2 hours, then the reaction vessel was removed from the ice bath and stirred at room temperature for another 2 hours. The mixture was then concentrated, the residue was dissolved in DCM, concentrated three times, and then purified by flash column chromatography (elution gradient, 0% to 13% MeOH in DCM) to obtain the title compound 108 as a pale yellow solid (80 mg, yield 52%). (See Table 6 for characterization.)

[0521] Step 7.2-amino-6-(hydroxymethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (109) A suspension of 108 (54.0 mg, 170 μmol), ammonium chloride (182 mg, 3.40 mmol), and HATU (97.0 mg, 255 μmol) in DMF (4.00 mL) was met with dropwise addition of N,N-diisopropylethylamine (59.3 μL, 340 μmol). The mixture was stirred at room temperature for 16 hours, then an additional 97 mg of HATU (255 μmol) was added, and stirring was continued for 1 hour. The mixture was diluted with saturated NH4Cl aqueous solution and extracted with EA (3 × 20 mL). The combined organic matter was successively washed with brine (3 × 20 mL) and 0.05 N HCl aqueous solution, and then concentrated. The residue was purified by flash column chromatography (elution gradient, 0% to 15% MeOH in DCM), and then purified again by reverse-phase flash column chromatography (elution gradient, 10% to 100% CH3CN in H2O containing 0.1% (v / v) formic acid) to obtain the title compound 109 as an off-white solid (17.2 mg, yield 32%).

[0522] 1 H NMR:400MHz,DMSO-d6,δ(ppm):8.06(s,2H)7.32-7.27(m,4H),7.23-7.20(m 1H),6.88(bs,2H),4.77(t,J=5.5Hz,1H),3.92(dd,J=10.4,5.6Hz,1H),3.35-3.32 (m,1H), 2.89-2.84(m,1H), 2.73-2.67(m,1H), 2.50-2.48(m,1H, partially overlapped with solvent signal). LC-MS: rt=0.88 min, MS: 316.1 (calculated value), 317.0 (M+H + (Actual measured value).

[0523] Examples 60-67 intermediate compound 111 1-benzyl-4-oxocyclohexane-1-carbonitrile(111)

[0524] [ka]

[0525] Step 1. 8-benzyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile(110). To a solution of 40 (Scheme 4) (1.0 g, 5.98 mmol) in anhydrous THF (24.0 mL), LDA (6.58 mL, 1 M THF / hexane, 6.58 mmol) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 45 minutes, and then benzyl bromide (0.870 mL, 7.18 mmol) was added dropwise. The reaction mixture was allowed to reach room temperature and stirred for 2.5 hours. The reaction mixture was then quenched with water and extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, EA in hexane with 0% to 30%) to obtain the title compound 110 as a white solid (1.22 g, yield 79%), which was used directly in the next step without characterization.

[0526] Step 2.1-benzyl-4-oxocyclohexane-1-carbonitrile(111). To a solution of 110 (1.21 g, 4.70 mmol) in acetone (63 mL), 2N HCl (11.8 mL, 23.5 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then neutralized by slowly adding saturated NaHCO3 solution, concentrated, and the organic solvent was removed. The residue was extracted with EA, the organic layer was dried over Na2SO4, filtered, and concentrated to dryness to obtain the title compound 111 (1.00 g, yield >99%). LC-MS: rt=2.93 min, MS: 213.1 (calculated), 214.1 (M+H + (Actual measured value).

[0527] intermediate compound 115 2-(8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decane-8-yl)ethane-1-ol(115)

[0528] [ka]

[0529] Step 1. 8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decane-8-carbaldehyde(113) Diisobutylaluminum hydride (25% solution in toluene, 121 mL, 180.0 mmol) was added dropwise to a solution of 8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (112) (24.3 g, 110 mmol) (ACS Med. Chem. Lett. 2010, 350-354) in anhydrous toluene (600 mL) at -78°C, and the resulting mixture was stirred at -78°C for 2 hours. The reaction mixture was then quenched with methanol (15 mL) at -78°C and separated into saturated NH4Cl aqueous solution (200 mL) and diethyl ether (300 mL). The mixture was slowly allowed to reach room temperature, and saturated Rochelle salt aqueous solution (1 L) was added. The layers were separated, the organic phase was washed with brine (2 × 200 mL), dried over Na2SO4, filtered, and concentrated. The residue was dissolved in THF (400 mL) and treated with a 2N aqueous HCl solution (27.5 mL, 54.9 mmol). The mixture was stirred at room temperature for 1 hour, then quenched with a saturated aqueous NaHCO3 solution, concentrated, and the organic solvent was removed. The aqueous residue was extracted with diethyl ether, the organic matter was dried with Na2SO4, filtered, and concentrated to obtain the title compound 113 as a colorless oil (24.6 g, yield >99%), which was used directly in the next step without characterization.

[0530] Step 2. 8-(cyclopropylmethyl)-8-vinyl-1,4-dioxaspiro[4.5]decane(114) To a 1 M LHMDS solution in THF (10 mL, 10.0 mmol) diluted with anhydrous THF (55.0 mL), methyltriphenylphosphonium bromide (2.23 g, 6.24 mmol) was added in four portions over 30 minutes at 60°C. After the last addition, the reaction mixture was stirred at 60°C for 1 hour. Then, 113 (700 mg, 3.12 mmol) in anhydrous THF (10.0 mL) was added dropwise, and the reaction mixture was stirred at 60°C for another 30 minutes. The mixture was then cooled to room temperature, quenched with saturated NH4Cl solution (40 mL), and extracted twice with EA (2 × 50 mL). The combined organic matter was dried with Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, 0% to 30% Et2O in hexane) to obtain the title compound 114 as a colorless oil (527 mg, yield 76%), which was used directly in the next step without characterization.

[0531] Step 3.2-(8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decane-8-yl)ethane-1-ol(115) To a solution of 114 (520 mg, 2.34 mmol) in anhydrous THF (12 mL), 9-BBN (9.35 mL, 0.5 M in THF, 4.68 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 2.5 hours, then cooled again to 0°C, and water (42 μL, 2.34 mmol), 1 N NaOH (7.0 mL, 7.0 mmol), and 30% H2O2 (12 mL) were added. The reaction mixture was stirred at 0°C for 10 minutes, then stirred at room temperature for 16 hours. The mixture was then diluted with EA and water. The layers were separated, the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, EA in hexane from 30% to 100%) to obtain the title compound 115 as a colorless oil (479 mg, yield 85%), which was used directly in the synthesis of the relevant examples without characterization.

[0532] intermediate compound 118 2-(8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decane-8-yl)acetonitrile(118)

[0533] [ka]

[0534] Step 1. (8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decane-8-yl)methanol (116) Sodium borohydride (816 mg, 21.1 mmol) was added at 0°C to a solution of 113 (Scheme 21) (3.16 g, 14.1 mmol) in MeOH (86.8 mL). The resulting solution was stirred at room temperature for 1 hour, and the reaction mixture was then quenched with saturated NH4Cl aqueous solution (30 mL). The mixture was diluted with EA (30 mL), the layers were separated, and the aqueous layer was extracted with EA (30 mL). The combined organic matter was washed with 0.2 N HCl (50 mL) and brine, then dried over Na2SO4, filtered, and concentrated to obtain the title compound 116 as a colorless oil (2.95 g, yield 93%), which was used directly in the next step without characterization.

[0535] Step 2.4-Methylbenzenesulfonic acid (8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decane-8-yl)methyl(117) To a solution of 116 (2.70 g, 11.9 mmol) in pyridine (51.9 mL), p-toluenesulfonyl chloride (7.96 g, 41.8 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was then diluted with EA and water (30 mL each), and the layers were separated. The aqueous phase was extracted with EA (30 mL), the combined organic matter was washed with water (30 mL) and brine (2 × 30 mL), then dried over Na₂SO₄, filtered, and concentrated. The residue was diluted with heptane, concentrated to dryness, and then purified by flash column chromatography (elution gradient, EA in hexane with 0% to 40%) to obtain the title compound 117 as a colorless oil (3.65 g, yield 80%). LC-MS: rt = 1.78 min. MS: 380.2 (calculated), 381.3 (M + H + (Actual measured value).

[0536] Step 3.2-(8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decane-8-yl)acetonitrile(118) To a solution of 117 (3.65 g, 9.59 mmol) in DMSO (57.1 mL), sodium cyanide (1.41 g, 28.8 mmol) was added, and the resulting mixture was stirred at 60°C for 96 hours. The mixture was cooled to room temperature and diluted with saturated NaHCO3 aqueous solution (50 mL). The mixture was then diluted with EA (50 mL) and water (40 mL), the layers were separated, and the aqueous phase was extracted with EA (2 × 50 mL). The combined organic matter was washed with water (2 × 30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the title compound 118 as a yellow oil (2.5 g, yield 72%), which was not characterized and was used directly in the synthesis of the relevant examples.

[0537] Compounds 119~126 Compounds 119-123 (Examples 60-64) were synthesized in the same manner as compound 81 (Example 51, Scheme 13), starting from 4-methyl-4-phenylcyclohexane-1-one, compound 111 (Scheme 20), compound 73 (Scheme 12), compound 95 (Scheme 17), and compound 99 (Scheme 18), respectively, instead of 2-(4-oxo-1-phenylcyclohexyl)acetonitrile (76). Compounds 124-126 (Examples 65-67) were synthesized in the same manner as compound 47 (Example 28, Scheme 4), starting from compound 115 (Scheme 21), compound 116 (Scheme 22), and compound 118 (Scheme 22), respectively, instead of compound 41. The characterization of compounds 119-126 (Examples 60-67) is shown in Table 4.

[0538] [Table 4-1]

[0539] [Table 4-2]

[0540] Examples 68-77 Compounds 127-133 (Examples 68-74) were synthesized in the same manner as compound 82 (Example 52, Scheme 13), starting from compounds 119-125 (Examples 60-66, Table 4), respectively, instead of compound 81. Compounds 134-135 (Examples 75-76) were synthesized in the same manner as compound 9 (Example 2, Scheme 2), starting from compound 126 (Example 67, Table 4) and compound 89 (Example 55, Scheme 15), respectively, instead of compound 8. Compound 136 (Example 77) was synthesized in the same manner as compound 82 (Example 52, Scheme 13), starting from compound 108 (Scheme 19), instead of compound 81. The characterization of compounds 127-136 (Examples 68-77) is shown in Table 5.

[0541] [Table 5-1]

[0542] [Table 5-2]

[0543] [Table 5-3]

[0544] Example 78 2-amino-6-(2-cyanoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (138) and Example 79 2-amino-6-(3-amino-3-oxopropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (139)

[0545] [ka]

[0546] To a solution of 137 (1.0 g, 2.71 mmol, synthesized in the same manner as compound 80 of Scheme 13, starting with 3-(4-oxo-1-phenylcyclohexyl)propanenitrile instead of 2-(4-oxo-1-phenylcyclohexyl)acetonitrile (76)) in MeOH (330 mL), a solution of lithium hydroxide monohydrate (569 mg, 13.6 mmol) in water (330 mL) was added. The reaction mixture was stirred at 80 °C for 16 hours and then cooled to room temperature. The mixture was concentrated to remove most of the organic solvent. The aqueous layer was acidified by slowly adding 1 N HCl and extracted with EA. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, 0% to 30% MeOH in DCM) to obtain title compound 138 as a yellow solid (648 mg, yield 70%), and title compound 139 was obtained. The latter was purified again by half-portion HPLC-MS (elution gradient, 15% to 100% MeOH in 10 mM ammonium bicarbonate) to obtain a white solid (142 mg, yield 15%).

[0547] 138: 1 H NMR:400MHz,DMSO-d6,δ(ppm):12.51(bs,1H),8.28(s,2H),7.36-7.32(m,2H),7.27-7.24(m,3H),3.15-3. 09(m,1H),2.60-2.55(m,1H),2.48-2.42(m,1H),2.38-2.30(m,1H),2.26-2.18(m,2H),2.12-2.07(m,2H). LC-MS: rt=1.23 min, MS: 340.1 (calculated value), 341.1 (M+H + (Actual measured value).

[0548] 139: 1H NMR:400MHz,DMSO-d6,δ(ppm):8.30(bs,2H),7.33-7.26(m,4H),7.23-7.19(m,1H),7.18(s,1 H),6.62(s,1H),3.20-3.15(m,2H),2.45-2.37(m,1H),2.16-2.07(m,1H),2.00-1.91(m,4H). LC-MS: rt=0.98 min, MS: 358.1 (calculated value), 359.1 (M+H + (Actual measured value).

[0549] Example 80 2-amino-6-(2-cyanoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(140)

[0550] [ka]

[0551] To a suspension of 138 (500 mg, 1.47 mmol) and ammonium chloride (1.57 g, 29.4 mmol) in anhydrous DMF (16.2 mL), HATU (855 mg, 2.20 mmol) and N,N-diisopropylethylamine (0.512 mL, 2.94 mmol) were added. Then, saturated NH3 solution in CHCl3 (8.7 mL) (prepared in-house) and 0.4 M NH3 solution in THF (9.2 mL) were added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. Subsequently, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase flash column chromatography (elution gradient, 0% to 100% CH3CN in H2O containing 0.1% (v / v) formic acid) to obtain the title compound 140 as a white solid (419 mg, yield 84%).

[0552] 1H NMR:400MHz,DMSO-d6,δ(ppm):8.13(s,2H),7.37-7.24(m,5H),6.88(bs,2H),2.91-2. 84(m,1H),2.68-2.56(m,2H),2.46-2.42(m,1H),2.25-2.17(m,2H),2.13-2.07(m,2H). LC-MS: rt=1.10 min, MS: 339.1 (calculated value), 340.1 (M+H + (Actual measured value).

[0553] Example 81 2-amino-6-(2-cyanoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(141)

[0554] [ka]

[0555] Compound 141 (Example 81) was synthesized in the same manner as Compound 62 (Example 39, Scheme 10), starting with Compound 140 (Example 80, Scheme 24) instead of Compound 61.

[0556] 1 H NMR:400MHz,DMSO-d6,δ(ppm):8.08(s,2H),7.35-7.21(m,5H),7.17(s,1H),6.87(bs,2H),6.63(s, 1H), 2.91-2.84 (m, 1H), 2.73-2.65 (m, 1H), 2.55-2.53 (m, 1H), 2.20-2.12 (m, 1H), 2.02-1.90 (m, 4H). LC-MS: rt=0.88 min, MS: 357.1 (calculated value), 358.2 (M+H + (Actual measured value).

[0557] Example 82 (S)-2-amino-6-(3-amino-3-oxopropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (142) and Example 83 (R)-2-amino-6-(3-amino-3-oxopropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(143)

[0558] [ka]

[0559] 100.3 mg of racemic compound 141 was subjected to SFC chiral separation to obtain enantio-enriched title compound 142 as a white solid (29.9 mg, 30% separation yield) and enantio-enriched title compound 143 as a white solid (26.2 mg, 26% separation yield). The absolute configurations of compounds 142 and 143 were assigned based on their similarity to the assignment of absolute configurations of crystallized compounds within the same or similar series.

[0560] 142: 1 ¹H NMR: Same as racemic mixture (141). LC-MS: rt=0.88 min, MS: 357.1 (calculated value), 358.2 (M+H + (Measured values). Analysis SFC (IC column using a gradient of 5-60% MeOH + 10 mM AmFor (95-40% CO2)): rt = 5.80 min, ee. = 99.76%.

[0561] 143: 1 ¹H NMR: Same as racemic mixture (141). LC-MS: rt=0.88 min, MS: 357.1 (calculated value), 358.2 (M+H + (Measured values). Analysis SFC (IC column using a gradient of 5-60% MeOH + 10 mM AmFor (95-40% CO2)): rt = 6.45 min, ee. = 97.82%.

[0562] Example 84 2-amino-6-(2-cyanoethyl)-N-cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (144) and Example 85 2-amino-6-(3-amino-3-oxopropyl)-N-cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(145)

[0563] [ka]

[0564] Compound 144 (Example 84) was synthesized in the same manner as Compound 82 (Example 52, Scheme 13), starting with Compound 138 (Example 78, Scheme 23) instead of Compound 81.

[0565] 1 H NMR:400MHz,DMSO-d6,δ(ppm):7.87(s,2H),7.37-7.25(m,6H),2.74-2.52(m,4 H),2.48-2.41(m,1H),2.24-2.07(m,4H),0.64-0.57(m,2H),0.50-0.43(m,2H). LC-MS: rt=1.27 min, MS: 379.1 (calculated value), 380.2 (M+H + (Actual measured value).

[0566] A suspension of 144 (35 mg, 0.092 mmol) and K2CO3 (26 mg, 0.18 mmol) in MeOH (1.8 mL) and water (0.6 mL) was prepared by adding 30% H2O2 (0.09 mL). The reaction mixture was vigorously stirred at room temperature for 2 days. Then, another 30% H2O2 (0.19 mL) was added, and the reaction mixture was vigorously stirred at room temperature for a further 24 hours. The mixture was then concentrated to remove the organic solvent, and the residue was extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the title compound 145 as an off-white solid (17 mg, 46% yield).

[0567] 1H NMR:400MHz,DMSO-d6,δ(ppm):7.81(s,2H),7.35-7.21(m,6H),7.17(bs,1H),6.63(bs,1H),2.77-2.59 (m,3H),2.50-2.48(m,1H),2.16-2.08(m,1H),2.01-1.90(m,4H),0.64-0.58(m,2H),0.50-0.45(m,2H). LC-MS: rt=1.05 min, MS: 397.2 (calculated value), 398.3 (M+H + (Actual measured value).

[0568] Example 86 2-amino-6-methyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(146)

[0569] [ka]

[0570] Compound 119 (Table 4) (50 mg, 0.17 mmol) was dissolved in 17 mL of 0.4 M NH3 solution in THF, and HATU (126 mg, 0.33 mmol) and N,N-diisopropylethylamine (0.058 mL, 0.33 mmol) were added to the mixture. The reaction mixture was then stirred at room temperature for 16 hours. Subsequently, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EA. The organic layer was washed with water and brine, then dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, 40% to 100% EA in hexane), and then re-purified by half-portion HPLC-MS (elution gradient, 35% to 100% CH3CN in 10 mM ammonium bicarbonate) to obtain the title compound 146 as a white solid (22 mg, yield 44%).

[0571] 1H NMR:400MHz,CD3OD,δ(ppm):7.32-7.28(m,4H),7.24-7.19(m,1H),2.95-2.89(m,1H),2.68-2.58(m,2H),2.28-2.21(m,1H),1.48(s,3H). LC-MS: rt=1.13, MS: 300.1 (calculated value), 301.1 (M+H + (Actual measured value).

[0572] Example 87 2-amino-6-benzyl-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(147)

[0573] [ka]

[0574] To a suspension of 120 (Table 4) (50 mg, 0.153 mmol) and ammonium chloride (164 mg, 3.06 mmol) in anhydrous THF (2.0 mL), HATU (87 mg, 0.230 mmol) and N,N-diisopropylethylamine (0.053 mL, 0.306 mmol) were added. Then, saturated NH3 solution in CHCl3 (0.25 mL) (prepared in-house) was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. Subsequently, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase flash column chromatography (elution gradient, 0% to 100% CH3CN in H2O containing 0.1% (v / v) formic acid) to obtain the title compound 147 as a white solid (35 mg, yield 70%).

[0575] 1 H NMR:400MHz,DMSO-d6,δ(ppm):8.34(bs,2H),7.40-7.30(m,5H),7.13(bs,2H) ,3.25-3.16(m,2H),3.10-2.98(m,2H),2.23-2.16(m,1H),2.11-2.04(m,1H). LC-MS: rt=1.15 min, MS: 325.1 (calculated value), 326.1 (M+H+ (Actual measured value).

[0576] Example 88 2-amino-6-(cyclopropylmethyl)-6-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (148)

[0577] [ka]

[0578] Compound 148 (Example 88) was synthesized in the same manner as Compound 140 (Example 80, Scheme 24), starting with Compound 124 (Table 4) instead of Compound 138.

[0579] 1 H NMR:400MHz,CD3OD,δ(ppm):3.67-3.56(m,2H),3.03(t,J=6.1Hz,2H),2.28( dt,J=13.8,5.9Hz,1H),2.17-2.10(m,1H),2.05(ddd,J=13.7,8.9,6.1Hz,1H) ,1.85(ddd,J=13.7,8.9,6.2Hz,1H),1.74(dd,J=14.1,6.1Hz,1H),1.41(dd, J=14.2,7.2Hz,1H),0.74-0.64(m,1H),0.50-0.42(m,2H),0.11-0.00(m,2H). LC-MS: rt=0.92 min, MS: 308.1 (calculated value), 309.2 (M+H + (Actual measured value).

[0580] Example 89 2-amino-6-(cyclopropylmethyl)-6-(hydroxymethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (149)

[0581] [ka]

[0582] Compound 149 (Example 89) was synthesized in the same manner as Compound 140 (Example 80, Scheme 24), starting with Compound 125 (Table 4) instead of Compound 138.

[0583] 1 H NMR:400MHz,DMSO-d6,δ(ppm):7.97(s,2H),6.92(bs,2H),4.54(t,J=5.4Hz,1H),3. 71(dd,J=10.5,5.5Hz,1H),3.39(dd,J=10.5,5.3Hz,1H),3.03-2.87(m,2H),2.17-2. 10(m,1H),2.07-2.01(m,1H),1.54(dd,J=14.0,6.5Hz,1H),1.32(dd,J=14.0,7.0Hz ,1H),0.64-0.55(m,1H),0.40-0.32(m,2H),0.07-0.01(m,1H),-0.05--0.09(m,1H). LC-MS: rt=0.88 min, MS: 294.1 (calculated value), 295.0 (M+H + (Actual measured value).

[0584] Example 90 2-amino-6-(cyanomethyl)-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (150)

[0585] [ka]

[0586] Compound 150 (Example 90) was synthesized in the same manner as Compound 109 (Example 59, Scheme 19), starting with Compound 126 (Table 4) instead of Compound 108.

[0587] 1H NMR:400MHz,DMSO-d6,δ(ppm):8.06(s,2H),6.97(bs,2H),3.16-3.03(m,1H),2.99-2.81(m,3H),2. 16-2.02(m,2H),1.60-1.44(m,2H),0.66-0.57(m,1H),0.47-0.35(m,2H),0.13-0.07(m,1H),-0.01- -0.07(m,1H). LC-MS: rt=0.94 min. MS: 303.1 (calculated value), 304.0 (M+H + (Actual measured value).

[0588] Example 91 2-amino-7-oxo-4,7-dihydro-5H-spiro[benzo[b]thiophene-6,1'-cyclopentane]-3-carboxamide(155)

[0589] [ka]

[0590] Step 1. Ethyl 2-amino-4,7-dihydro-5H-spiro[benzo[b]thiophene-6,1'-cyclopentane]-3-carboxylate (152) Spiro[4.5]decane-8-one (151) (199 mg, 1.31 mmol) and 2-ethyl cyanoethyl (0.139 mL, 1.31 mmol) were dissolved in EtOH (1.3 mL), to which morpholine (0.126 mL, 1.44 mmol) and sulfur (46 mg, 0.18 mmol) were added. The reaction mixture was stirred at 60 °C for 16 hours, then cooled to room temperature and concentrated to dryness. The residue was purified by flash column chromatography to obtain the title compound 152 (270 mg, yield 74%). LC-MS: rt=1.98 min, MS: 279.1 (calculated), 280.1 (M+H + (Actual measured value).

[0591] Step 2. Ethyl 2-amino-7-oxo-4,7-dihydro-5H-spiro[benzo[b]thiophene-6,1'-cyclopentane]-3-carboxylate (153) A mixture of 152 (100 mg, 0.358 mmol) in THF (1.2 mL) and water (0.2 mL) was added dropwise to a solution of DDQ (81 mg, 0.358 mmol) in THF (1.0 mL) at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was then quenched with saturated NaHCO3 solution and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to obtain the title compound 153 (15 mg, yield 14%). LC-MS: rt=1.63 min, MS: 293.1 (calculated), 294.1 (M+H + (Actual measured value).

[0592] Step 3.2-amino-7-oxo-4,7-dihydro-5H-spiro[benzo[b]thiophene-6,1'-cyclopentane]-3-carboxylic acid (154) A solution of 153 (15 mg, 0.051 mmol) in MeOH (1.1 mL) was mixed with a solution of lithium hydroxide monohydrate (7 mg, 0.283 mmol) in water (1.1 mL). The reaction mixture was stirred under reflux for 16 hours and then cooled to room temperature. The mixture was diluted with water and concentrated to remove most of the organic solvent. The aqueous layer was acidified by slowly adding 1 N HCl and extracted with EA. The organic layer was dried over Na₂SO₄, filtered, and concentrated to obtain the title compound 154 as a white solid (6 mg, yield 44%). (See Table 6 for characterization.)

[0593] Step 4.2-amino-7-oxo-4,7-dihydro-5H-spiro[benzo[b]thiophene-6,1'-cyclopentane]-3-carboxamide (155) Compound 154 (6 mg, 0.023 mmol) was dissolved in 1.5 mL of 0.4 M NH3 solution in THF, and HATU (17 mg, 0.045 mmol) and N,N-diisopropylethylamine (0.008 mL, 0.045 mmol) were added to the mixture. The reaction mixture was then stirred at room temperature for 16 hours. Subsequently, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EA. The organic layer was washed with water and brine, then dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to obtain the title compound 155 as a white solid (3.7 mg, 62% yield).

[0594] 1 H NMR:400MHz,CD3OD,δ(ppm):2.99(t,J=6.0Hz,2H),2.06(t,J=6.0Hz,2H),2.03-1.97(m,2H),1.79-1.68(m,4H),1.62-1.56(m,2H). LC-MS: rt=1.07 min, MS: 264.1 (calculated value), 265.1 (MH + (Actual measured value).

[0595] Example 92 2-amino-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(163)

[0596] [ka]

[0597] Step 1.3-(8-phenyl-1,4-dioxaspiro[4.5]decane-8-yl)propanoic acid (157) To a solution of 3-(8-phenyl-1,4-dioxaspiro[4.5]decane-8-yl)propanenitrile (156) (2.30 g, 8.48 mmol) (Bioorg Med. Chem Lett. 21, p. 405, 2011) in ethylene glycol (40.0 mL), potassium hydroxide (3.80 g, 67.8 mmol) and water (0.030 mL, 1.70 mmol) were added. The reaction mixture was stirred at 170 °C for 16 hours, then cooled to room temperature and diluted with water and DCM. The layers were separated, and the aqueous phase was acidified by slowly adding 2N HCl and extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated to obtain the title compound 157 as a brown solid (2.03 g, yield 82%). LC-MS: rt=0.84 mins, MS: 290.2 (calculated value), 289.2 ([MH] - (Actual measured value).

[0598] Step 2. Methyl 3-(8-phenyl-1,4-dioxaspiro[4.5]decane-8-yl)propanoate (158) To a solution of 157 (1.30 g, 4.48 mmol) in anhydrous DMF (10.0 mL), potassium carbonate (1.86 g, 13.4 mmol) and iodomethane (0.418 mL, 6.72 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 16 hours, then diluted with water and extracted with Et2O. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to obtain the title compound 158 as oil (1.35 g, 99% yield). LC-MS: rt=1.53 min, MS: 304.2 (calculated), 305.2 (M+H + (Actual measured value).

[0599] Step 3.3-(8-phenyl-1,4-dioxaspiro[4.5]decane-8-yl)propan-1-ol(159) To a solution of lithium aluminum hydride (6.25 mL, 1 M in THF, 6.25 mmol) in anhydrous THF (7.0 mL), a solution of 158 (865 mg, 2.84 mmol) in anhydrous THF (10.0 mL) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 1 hour, and then carefully quenched with MeOH and water at 0°C. The mixture was then diluted with EA and saturated Rochelle salt solution and stirred at room temperature for 30 minutes. The layers were separated, and the aqueous phase was extracted with EA. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, EA in hexane from 0% to 70%) to obtain the title compound 159 as a yellow oil (760 mg, yield 97%). LC-MS: rt=1.28 min, MS: 276.2 (calculated), 277.2 (M+H + (Actual measured value).

[0600] Step 4. 4-(3-hydroxypropyl)-4-phenylcyclohexane-1-one (160) To a solution of 159 (368 mg, 1.33 mmol) in acetone (18.0 mL), 2N HCl (3.33 mL, 6.66 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then neutralized by slowly adding saturated aqueous NaHCO3 solution, concentrated, and the organic solvent was removed. The residue was extracted with EA, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to dryness to obtain the title compound 160 as a yellow oil (289 mg, 94% yield), which was used directly in the next step without characterization.

[0601] Step 5.4-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-phenylcyclohexane-1-one(161) To a solution of 160 (196 mg, 0.84 mmol) in anhydrous DMF (4.2 mL), tert-butyldimethylsilyl chloride (162 mg, 1.08 mmol) and imidazole (144 mg, 2.11 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours, and then diluted with water and EA. The layers were separated, the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, EA in hexane with 0% to 30%) to obtain the title compound 161 as a pale yellow oil (259 mg, yield 89%), which was used directly in the next step without characterization.

[0602] Step 6.2-amino-6-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (162) To a solution of 161 (259 mg, 0.747 mmol) and cyanoacetamide (57 mg, 0.679 mmol) in EtOH (1.4 mL), morpholine (0.065 mL, 0.747 mmol) and sulfur (24 mg, 0.093 mmol) were added. The reaction mixture was stirred at 60°C for 16 hours, cooled to room temperature, and concentrated to dryness. The residue was purified by flash column chromatography (elution gradient, 0% to 10% MeOH in DCM) to obtain the title compound 162 (200 mg, yield 60%). LC-MS: rt=2.07 min, MS: 444.2 (calculated), 445.3 (M+H + (Actual measured value).

[0603] Step 7.2-amino-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (163) A mixture of 162 (200 mg, 0.450 mmol) in THF (1.5 mL) and water (0.25 mL) was added dropwise at 0°C to a solution of DDQ (306 mg, 1.35 mmol) in THF (1.25 mL). The reaction mixture was slowly allowed to reach room temperature and stirred for 16 hours. The mixture was then quenched with saturated NaHCO3 solution and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, 2% to 10% MeOH in DCM), and then re-purified by half-portion HPLC-MS (elution gradient, 30% to 100% MeOH in 10 mM ammonium bicarbonate) to obtain the title compound 163 as a white solid (10 mg, yield 6%).

[0604] 1 H NMR:400MHz,CD3OD,δ(ppm):7.34-7.28(m,4H),7.23-7.19(m,1H),3.54-3.43(m,2H),2.96(ddd,J=17.1,4.4 ,3.1Hz,1H),2.75-2.69(m,1H),2.67-2.60(m,1H),2.41-2.33(m,1H),2.00-1.83(m,2H),1.58-1.44(m,2H). LC-MS: rt=0.96 min, MS: 344.1 (calculated value), 345.1 (M+H + (Actual measured value).

[0605] Example 93 2-amino-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (168) and Example 94 2-amino-N-cyclopropyl-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (169)

[0606] [ka]

[0607] Step 1. Ethyl 2-amino-6-(3-hydroxypropyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (164) To a solution of 160 (Scheme 30) (289 mg, 1.24 mmol) and 2-ethyl cyanoethyl (0.149 mL, 1.37 mmol) in EtOH (10.0 mL), morpholine (0.120 mL, 1.37 mmol) and sulfur (44 mg, 0.172 mmol) were added. The reaction mixture was stirred at 60°C for 24 hours, then cooled to room temperature and concentrated to dryness. The residue was separated between EA and water. The layers were separated, and the aqueous phase was extracted with EA. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, EA in hexane with 0% to 50%) to obtain the title compound 164 as a white solid (336 mg, yield 75%). LC-MS: rt=1.53 min, MS: 359.2 (calculated), 360.2 (M+H + (Actual measured value).

[0608] Step 2. Ethyl 2-acetamido-6-(3-acetoxypropyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (165) To a suspension of 164 (336 mg, 0.935 mmol) in anhydrous DCM (3.0 mL), anhydrous acetic acid (0.265 mL, 2.80 mmol) and acetic acid (0.054 mL, 0.935 mmol) were added. The reaction mixture was stirred at room temperature for 4 days, then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, EA in 0% to 50% hexane) to obtain the title compound 165 as a white solid (208 mg, yield 50%). LC-MS: rt=1.86 min, MS: 443.2 (calculated), 444.3 (M+H + (Actual measured value).

[0609] Step 3. Ethyl 2-acetamido-6-(3-acetoxypropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (166) Intermediate 165 (208 mg, 0.469 mmol) and cerium sulfate (1.35 g, 4.05 mmol) were added to a 1:1:1 acetic acid / water / dioxane mixture (15 mL). The flask was sonicated to homogenize the suspension, and the reaction mixture was vigorously stirred at room temperature for 16 hours. The mixture was then diluted with water and extracted with EA. The organic layer was washed with 1N NaOH, water, and brine, then dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, EA in hexane with 0% to 45%) to obtain the title compound 166 as a white solid (122 mg, yield 57%). LC-MS: rt=1.73 min, MS: 457.2 (calculated), 458.3 (M+H + (Actual measured value).

[0610] Step 4. Ethyl 6-(3-acetoxypropyl)-2-amino-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (167) To a solution of 166 (122 mg, 0.267 mmol) in toluene (0.5 mL), pyrrolidine (0.35 mL, 4.26 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was then diluted with brine and extracted with EA. The organic layer was dried over Na₂SO₄, filtered, and concentrated to obtain the title compound 167 as a dark orange oil, which was used directly in the next step. LC-MS: rt=1.64 min, MS: 415.2 (calculated), 416.3 (M+H + (Actual measured value).

[0611] Step 5.2-amino-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (168) To a 4.0 mL solution of 167 (0.267 mmol) in MeOH, an aqueous solution (2.0 mL) of lithium hydroxide monohydrate (162 mg, 3.86 mmol) was added. The reaction mixture was stirred at 60°C for 3 days and then cooled to room temperature. The mixture was concentrated to remove most of the organic solvent. The aqueous layer was acidified by slowly adding 1N HCl and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, EA in hexane at 50%-100%) to obtain the title compound 168 as a yellow solid (70 mg, 76% yield in 2 steps).

[0612] 1 H NMR:400MHz,CD3OD,δ(ppm):7.32-7.28(m,4H),7.23-7.18(m,1H),3.53-3.43(m,2H),3.26 -3.19(m,1H),2.60-2.51(m,2H),2.35-2.27(m,1H),1.98-1.83(m,2H),1.55-1.44(m,2H). LC-MS: rt=1.09 min, MS: 345.1 (calculated value), 346.0 (M+H + (Actual measured value).

[0613] Step 6.2-Amino-N-cyclopropyl-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (169) To a solution of 168 (54 mg, 0.156 mmol) in anhydrous DMF (1.95 mL), HATU (119 mg, 0.313 mmol), N,N-diisopropylethylamine (0.082 mL, 0.469 mmol), and cyclopropylamine (0.012 mL, 0.172 mmol) were added. The reaction mixture was then stirred at room temperature for 16 hours. Subsequently, the reaction mixture was diluted with EA and washed with saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, EA in hexane from 30% to 100%) to obtain the title compound 169 as an off-white solid (46 mg, yield 77%).

[0614] 1 H NMR:400MHz,CD3OD,δ(ppm):7.33-7.26(m,4H),7.21-7.17(m,1H),3.52-3.42(m,2H),2.81(ddd,J=17.3,4.4,3.3Hz,1H),2.70-2.62(m,2H),2 .58(dt,J=13.9,3.7Hz,1H),2.31(ddd,J=13.8,11.2,4.6Hz,1H),1.98 -1.81(m,2H),1.56-1.41(m,2H),0.76-0.68(m,2H),0.57-0.50(m,2H). LC-MS: rt=1.13 min, MS: 384.1 (calculated value), 385.1 (M+H + (Actual measured value).

[0615] Example 95 2-amino-6-cyano-N-cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(170)

[0616] [ka]

[0617] To a 72 mL solution of anhydrous DMF containing 59 (Example 36, Scheme 8) (2.03 g, 6.50 mmol), PyBOP (3.73 g, 7.15 mmol), N,N-diisopropylethylamine (2.26 mL, 13.0 mmol), and cyclopropylamine (2.25 mL, 32.5 mmol) were added at 0°C. The reaction mixture was then stirred at room temperature for 16 hours. Subsequently, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (elution gradient, 40% to 100% EA in hexane...

Claims

1. It is a combination of medicines, (a) Cyclooxygenase (COX) inhibitors, and (b) Compounds having formula (I), 【Chemistry 1】 or comprising a pharmaceutically acceptable salt, solvate, or prodrug thereof, During the ceremony, R ａ However, -NH ２ , -NH-OH, -OH, -NHR ｂ , or -NR ｃ R ｄ And, R ｂ is C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C １ -C ６ alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -OC １ -C ３ alkyl, -COOH, or cyclopropyl optionally substituted with -OH, wherein C ３ -C ６ cycloalkyl is optionally substituted with -CN, R ｃ and R ｄ However, together with the nitrogen to which they are bonded, they form a four-membered heterocycloalkyl group, where the four-membered heterocycloalkyl group consists of -OH and C １ ~C ３ It is optionally substituted with at least one alkyl group. 【Chemistry 2】 However, the following residue A ０ ~Residue A １２ It represents one of the following: 【Transformation 3】 During the ceremony, R is H, C １ ~C ６ Alkyl or phenyl, R １ and R ２ However, independently, -CN, C ６ ~C １０ Ariel, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ８ Cycloalkyl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH ２ , -C(O)NHR ５ , -C(O)R ６ , or -C(O)OR ５ And here, each C １ ~C ６ Alkyl groups consist of 1 to 3 R groups. ７ Substituents are optionally substituted, and each C ６ ~C １０ Aaryl has 1 to 3 R ８ Substituents are optionally substituted, and each 5- to 10-membered heteroaryl has 1 to 3 R ２２ Substituents are optionally substituted, however R ａ is -OH, 【Chemistry 4】 A ０ Represents R １ but 【Transformation 5】 If this is the case, residue A ０ R inside ２ teeth, 【Transformation 6】 Unlike, Each R ５ However, independently, C １ ~C ６ It is alkyl, and here each C １ ~C ６ Alkyl groups: 1 to 3 R ９ Substituents are optionally replaced, Each R ６ However, independently, C ３ ~C ６ Cycloalkyl, 4-membered to 6-membered heterocycloalkyl, or C ６ ~C １０ It is Ariel, Each R ７ is independently -OH, -C(O)R １１ , C ３ to C ６ cycloalkyl, -CN, C ６ to C １０ aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC １ to C ６ alkyl), -N(C １ to C ４ alkyl)(C(O)OC １ to C ６ alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C １ to C ６ alkyl), -OR ２０ , -SC １ to C ６ alkyl, -NH ２ , -NH(C １ to C ４ alkyl), or -N(C １ to C ４ alkyl) ２ , wherein each C ３ to C ６ cycloalkyl is optionally substituted with 1 to 3 R １２ substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R １３ substituents, each 4- to 6-membered heterocycloalkyl is optionally substituted with C １ to C ４ alkyl or oxo, Each R ８ is independently halogen, C １ -C ６ alkyl, -OC １ -C ６ alkyl, C ３ -C ６ cycloalkyl, or 5- to 10-membered heteroaryl, wherein each -OC １ -C ６ alkyl is optionally substituted with -OC １ -C ４ alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with C １ -C ４ alkyl, Each R ２２ However, independently, C is optionally substituted with phenyl. １ ~C ６ It is alkyl, Each R ９ However, independently, -OH, -C(O)R １５ , C ３ ~C ６ Cycloalkyl, -CN, C ６ ~C １０ Aryl, halogen, -C(O)OH, 4- to 6-membered heterocycloalkyl, -NH(C(O)C １ ~C ６ Alkyl), -OC １ ~C ６ Alkyl, -SC １ ~C ６ Alkyl, -NH ２ ,-NH(C １ ~C ４ Alkyl), or -N(C) １ ~C ４ Alkyl) ２ Here, each of the 4-membered to 6-membered heterocycloalkyl groups is C １ ~C ４ Optionally substituted with alkyl, each -OC １ ~C ６ Alkyl, -OC １ ~C ４ Optionally substituted with alkyl groups, Each R １１ However, it became independent, -NH ２ ,-NH(C １ ~C ４ Alkyl), -N(C １ ~C ４ Alkyl) ２ , or a 4-membered to 6-membered heterocycloalkyl, Each R ２０ However, independently, C １ ~C ６ It is an alkyl or a 5-membered to 10-membered heteroaryl, where each C １ ~C ６ Alkyl groups: 1 to 3 R １４ The substituents are optionally substituted, and each 5-membered to 10-membered heteroaryl is optionally substituted with -OH or -NH (cyclopropyl), Each R １２ However, independently, C １ ~C ４ Alkyl, -SC １ ~C ４ Alkyl, -Ph, -OC １ ~C ４ Alkyl or -SPh, where each C １ ~C ４ The alkyl group is optionally substituted with -OH. Each R １３ However, independently, halogen, C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, -OH, -OC １ ~C ６ Alkyl, -SC １ ~C ６ Alkyl, -S(O) ２ C １ ~C ６ Alkyl, -NH ２ ,-NH(C １ ~C ４ Alkyl), or -N(C) １ ~C ４ Alkyl) ２ And here, each -OC １ ~C ６ Alkyl, -SC １ ~C ６ Alkyl, -S(O) ２ C １ ~C ６ Alkyl, -NH(C) １ ~C ４ Alkyl), and -N(C １ ~C ４ Alkyl) ２ However, 1 to 3 R ９ Substituents are optionally replaced, Each R １４ However, independently, halogen, -OC １ ~C ４ Alkyl, or C ３ ~C ６ It is a cycloalkyl, Each R １５ However, it became independent, -NH ２ ,-NH(C １ ~C ４ Alkyl), -N(C １ ~C ４ Alkyl) ２ , or a 4-membered to 6-membered heterocycloalkyl, R ４ However, C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, C ６ ~C １０ The aryl group is a 7- to 10-membered partially unsaturated heterocyclic group, or a 5- to 10-membered heteroaryl group, where C １ ~C ６ Alkyl and C ３ ~C ８ Cycloalkyl groups, 1 to 3 R ９ Substituents are optionally replaced with C ６ ~C １０ Aryl and 5- to 10-membered heteroaryl groups, with 1 to 3 R １０ Substituents are optionally replaced, however (i)R ａ -OH, -NH ２ , or 【Transformation 7】 And, 【Transformation 8】 A ２ When representing residue A, ２ R inside ４ is, -CH ３ Unlike, (ii)R ａ ga-NH ２ And, 【Chemistry 9】 A ３ When representing residue A, ３ R inside ４ is -C(CH ３ ) ３ Unlike, Each R １０ However, independently, C １ ~C ４ Alkyl, halogen, -OC １ ~C ６ Alkyl, -NH ２ ,-NH(C １ ~C ４ Alkyl), or -N(C) １ ~C ４ Alkyl) ２ And here, each C １ ~C ４ The alkyl group is optionally substituted with 1 to 3 halogens. R ２ａ However, C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, or C ６ ~C １０ It is aryl, and here, C １ ~C ６ Alkyl and C ３ ~C ８ Cycloalkyl groups, 1 to 3 R ９ Substituents are optionally replaced with C ６ ~C １０ aryl has 1 to 3 R １０ Substituting with substituents, R １ａ and R ２ｂ However, independently, -CN, C ６ ~C １０ Ariel, C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, -C(O)NH ２ , -C(O)NHR ５ , or -C(O)OC １ ~C ６ It is alkyl, and here each C １ ~C ６ Alkyl groups: 1 to 3 R １６ Substituents are optionally substituted, and each C ６ ~C １０ aryl has 1 to 3 R １７ Substituents are optionally replaced, Each R １６ However, independently, -OH, -C(O)NH ２ , -C(O)NH(C １ ~C ４ Alkyl), C ３ ~C ６ Cycloalkyl, -CN, C ６ ~C １０ Aryl, halogen, -C(O)OH, 5-membered to 10-membered heteroaryl, -NH(C(O)OC １ ~C ６ Alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C １ ~C ６ Alkyl), or -OC １ ~C ４ Alkyl (OC １ ~C ４ Alkyl) and here each C ３ ~C ６ Cycloalkyl groups, 1 to 3 R １８ The substituents are optionally substituted, and each 5-membered to 10-membered heteroaryl has 1 to 3 R ２１ Substituents are optionally chosen to replace each 4-membered to 6-membered heterocycloalkyl group, C １ ~C ４ Optionally substituted with alkyl groups, Each R １７ However, independently, halogen, C １ ~C ６ Alkyl, -OC １ ~C ６ Alkyl or 5- to 10-membered heteroaryl, where each 5- to 10-membered heteroaryl is C １ ~C ４ Optionally substituted with alkyl groups, Each R １８ However, independently, C １ ~C ４ Alkyl, -SC １ ~C ４ Alkyl, -Ph, or -OC １ ~C ４ It is alkyl, Each R ２１ However, independently, halogen or C １ ~C ４ It is alkyl, R ４ａ However, C １ ~C ６ Alkyl or C ３ ~C ８ It is a cycloalkyl, where each C １ ~C ６ Alkyl and C ３ ~C ８ Cycloalkyl groups, 1 to 3 R １９ Substituents are optionally replaced, Each R １９ However, independently, halogen, -OH, -OC １ ~C ４ Alkyl, -SC １ ~C ４ Alkyl, -NH ２ ,-NH(C １ ~C ４ Alkyl), or -N(C) １ ~C ４ Alkyl) ２ And, R １ｂ and R ２ｃ Together with the carbon atoms to which they are bonded, C ３ ~C ８ It forms a cycloalkyl, a 4- to 14-membered heterocycloalkyl, an 8- to 14-membered partially unsaturated heterocyclic group, or an 8- to 14-membered partially unsaturated carbocyclic group, where C ３ ~C ８ Cycloalkyl groups, 1 to 3 R ９ The substituents are optionally substituted with 4- to 14-membered heterocycloalkyl groups, 8- to 14-membered partially unsaturated heterocyclic groups, or 8- to 14-membered partially unsaturated carbocyclic groups, and are oxo (=O), oxime (=N-OH), or C １ ~C ３ Alkoxy oxime (= N-OC) １ ~C ３ Alkyl), or -OH and -CF ３ It is optionally substituted with 1 to 3 substituents that are independently selected from the original, R ２ｄ and R ４ｂ Together with the carbon atoms to which they are bonded, C ３ ~C ８ It forms a cycloalkyl or a 4-membered to 14-membered heterocycloalkyl, where C ３ ~C ８ Cycloalkyl groups, 1 to 3 R １９ Substituents are optionally replaced, R １ｃ and R ３ Together with the carbon atoms to which they are bonded, C ３ ~C ８ It forms a cycloalkyl or a 4-membered to 14-membered heterocycloalkyl, where C ３ ~C ８ Cycloalkyl groups, 1 to 3 R １９ A combination of pharmaceuticals in which substituents are optionally substituted.

2. The pharmaceutical combination according to claim 1, wherein R is H in the compound of formula (I) or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug.

3. The compound of formula (I) is of formula (Ia) or (Ia'): 【Chemistry 10】 Represented by, In the formula, R １ , R ２ , R, and R ａ However, as defined in claim 1 or 2, A pharmaceutical combination according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

4. The compound of formula (I) is of formula (Ia): 【Chemistry 11】 Represented by, In the formula, R １ , R ２ , and R ａ However, as defined in claim 1, The pharmaceutical combination described in claim 3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

5. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ and R ２ However, independently, -CN, C ６ ~C １０ Ariel, C １ ~C ６ Alkyl, C ２ ~C ６ Alkinyl, C ３ ~C ８ Cycloalkyl, 5-membered to 10-membered heteroaryl, -C(O)NH ２ , -C(O)NHR ５ , -C(O)R ６ , or -C(O)OR ５ And here, each C １ ~C ６ Alkyl groups: 1 to 3 R ７ Substituents are optionally substituted, and each C ６ ~C １０ aryl has 1 to 3 R ８ The substituents are optionally substituted, and each 5-membered to 10-membered heteroaryl has 1 to 3 R ２２ Optionally substituted with substituents, R ５ , R ６ , R ７ , R ８ , and R ２２ The pharmaceutical combination according to any one of claims 1 to 4, as defined in claim 1.

6. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ and R ２ However, independently, -CN, C ６ ~C １０ Ariel, C １ ~C ６ Alkyl, C ２ ~C ６ Alkinyl, C ３ ~C ８ Cycloalkyl, 5-membered to 10-membered heteroaryl, -C(O)NH ２ , -C(O)NHR ５ , -C(O)R ６ , or -C(O)OR ５ And here, each C １ ~C ６ Alkyl groups: 1 to 3 R ７ Substituents are optionally substituted, and each C ６ ~C １０ aryl has 1 to 3 R ８ The substituents are optionally substituted, and each 5-membered to 10-membered heteroaryl has 1 to 3 R ２２ Substituents are optionally replaced, Each R ５ However, independently, C １ ~C ６ It is alkyl, Each R ６ However, they are independently 4- to 6-membered heterocycloalkyl groups. Each R ７ However, independently, -OH and -C(O)R １１ , C ３ ~C ６ Cycloalkyl, -CN, C ６ ~C １０ Aryl, halogen, -C(O)OH, 5-membered to 10-membered heteroaryl, -NH(C(O)OC １ ~C ６ Alkyl), -N(C １ ~C ４ Alkyl) (C(O)OC １ ~C ６ Alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C １ ~C ６ Alkyl), -OR ２０ , -SC １ ~C ６ Alkyl, -NH ２ , or -N(C) １ ~C ４ Alkyl) ２ And here, each C ３ ~C ６ Cycloalkyl groups, 1 to 3 R １２ The substituents are optionally substituted, and each 5-membered to 10-membered heteroaryl has 1 to 3 R １３ Substituents are optionally chosen to replace each 4-membered to 6-membered heterocycloalkyl group, C １ ~C ４ Optionally substituted with alkyl or oxo, Each R ８ However, independently, halogen, C １ ~C ６ Alkyl, or -OC １ ~C ６ It is alkyl, where each -OC １ ~C ６ Alkyl, -OC １ ~C ４ Optionally substituted with alkyl groups, Each R ２２ However, independently, C is optionally substituted with phenyl. １ ~C ６ It is alkyl, Each R １１ However, it became independent, -NH ２ ,-NH(C １ ~C ４ Alkyl, or 4-membered to 6-membered heterocycloalkyl, Each R ２０ However, independently, C １ ~C ６ It is an alkyl or a 5-membered to 10-membered heteroaryl, where each C １ ~C ６ Alkyl groups: 1 to 3 R １４ The substituents are optionally substituted, and each 5-membered to 10-membered heteroaryl is optionally substituted with -OH or -NH (cyclopropyl), Each R １２ However, independently, C １ ~C ４ Alkyl, -SC １ ~C ４ Alkyl, -Ph, -OC １ ~C ４ Alkyl or -SPh, where each C １ ~C ４ The alkyl group is optionally substituted with -OH. Each R １３ However, independently, halogen, C １ ~C ４ Alkyl, or C ３ ~C ６ It is a cycloalkyl, Each R １４ However, independently, halogen, -OC １ ~C ４ Alkyl, or C ３ ~C ６ A pharmaceutical combination according to any one of claims 1 to 5, wherein the compound is cycloalkyl.

7. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ and R ２ However, independently, -CN, C ６ ~C １０ Ariel, C １ ~C ６ Alkyl, C ２ ~C ６ Alkinyl, C ３ ~C ８ Cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH ２ And here, each C １ ~C ６ Alkyl groups consist of 1 to 3 R groups. ７ Substituents are optionally substituted, and each C ６ ~C １０ Aaryl has 1 to 3 R ８ Substituents are optionally substituted, and each 5- to 10-membered heteroaryl has 1 to 3 R ２２ Optionally substituted with substituents, R ７ , R ８ , and R ２２ The pharmaceutical combination according to any one of claims 1 to 5, wherein the combination is as defined in claim 1.

8. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ and R ２ However, independently, -CN, C ６ ~C １０ Ariel, C １ ~C ６ Alkyl, C ２ ~C ６ Alkinyl, C ３ ~C ８ Cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH ２ And here, each C １ ~C ６ Alkyl groups: 1 to 3 R ７ Substituents are optionally substituted, and each C ６ ~C １０ aryl has 1 to 3 R ８ The substituents are optionally substituted, and each 5-membered to 10-membered heteroaryl has 1 to 3 R ２２ Substituents are optionally replaced, in the formula, Each R ７ However, independently, -OH and -C(O)R １１ , C ３ ~C ６ Cycloalkyl, -CN, C ６ ~C １０ Aryl, halogen, -C(O)OH, 5-membered to 10-membered heteroaryl, -NH(C(O)OC １ ~C ６ Alkyl), -N(C １ ~C ４ Alkyl) (C(O)OC １ ~C ６ Alkyl), -NH(C(O)C １ ~C ６ Alkyl), 4- to 6-membered heterocycloalkyl, -OR ２０ , -SC １ ~C ６ Alkyl, -NH ２ , or -N(C) １ ~C ４ Alkyl) ２ And here, each C ３ ~C ６ Cycloalkyl groups, 1 to 3 R １２ The substituents are optionally substituted, and each 5-membered to 10-membered heteroaryl has 1 to 3 R １３ Substituents are optionally chosen to replace each 4-membered to 6-membered heterocycloalkyl group, C １ ~C ４ Optionally substituted with alkyl or oxo, Each R ８ However, independently, halogen, C １ ~C ６ Alkyl, or -OC １ ~C ６ It is alkyl, where each -OC １ ~C ６ Alkyl, -OC １ ~C ４ Optionally substituted with alkyl groups, Each R １１ However, it became independent, -NH ２ ,-NH(C １ ~C ４ Alkyl, or 4-membered to 6-membered heterocycloalkyl, Each R ２０ However, independently, C １ ~C ６ It is an alkyl or a 5-membered to 10-membered heteroaryl, where each C １ ~C ６ Alkyl groups: 1 to 3 R １４ The substituents are optionally substituted, and each 5-membered to 10-membered heteroaryl is optionally substituted with -OH or -NH (cyclopropyl), Each R １２ However, independently, C １ ~C ４ Alkyl, -SC １ ~C ４ Alkyl, -Ph, -OC １ ~C ４ Alkyl or -SPh, where each C １ ~C ４ The alkyl group is optionally substituted with -OH. Each R １３ However, independently, halogen, C １ ~C ４ Alkyl, or C ３ ~C ６ It is a cycloalkyl, Each R １４ However, independently, halogen, -OC １ ~C ４ Alkyl, or C ３ ~C ６ It is a cycloalkyl, Each R ２２ However, independently, C １ ~C ４ - A pharmaceutical combination according to any one of claims 1 to 5, wherein the compound is alkyl.

9. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ and R ２ However, independently, -CN, C ６ ~C １０ Ariel, C １ ~C ６ Alkyl, C ２ ~C ６ Alkinyl, C ３ ~C ８ Cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH ２ And here, each C １ ~C ６ Alkyl groups: 1 to 3 R ７ Substituents are optionally substituted, and each C ６ ~C １０ aryl has 1 to 3 R ８ The substituents are optionally substituted, and each 5-membered to 10-membered heteroaryl has 1 to 3 R ２２ Substituents are optionally replaced, Each R ７ However, independently, -OH, -C(O)R １１ , -OR ２０ , C ３ ~C ６ Cycloalkyl, -CN, C ６ ~C １０ The aryl, halogen, -C(O)OH, or 5-membered to 10-membered heteroaryl, where each C ３ ~C ６ Cycloalkyl groups, 1 to 3 R １２ The substituents are optionally substituted, and each 5-membered to 10-membered heteroaryl has 1 to 3 R １３ Substituents are optionally replaced, Each R ８ However, it is a halogen, Each R １１ However, -NH ２ And, Each R ２０ However, C １ ~C ６ It is an alkyl or a 5-membered or 6-membered heteroaryl, where each C １ ~C ６ Alkyl groups: 1 to 3 R １４ The substituents are optionally substituted, and each 5-membered or 6-membered heteroaryl is optionally substituted with -OH or -NH (cyclopropyl), Each R １２ However, C １ ~C ４ It is alkyl, Each R １３ However, independently, halogen or C １ ~C ４ It is alkyl, Each R １４ However, it is a halogen, Each R ２２ However, independently, C １ ~C ４ - A pharmaceutical combination according to any one of claims 1 to 5, wherein the compound is alkyl.

10. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ and R ２ However, independently, -CN, phenyl, C １ ~C ４ Alkyl, C ２ ~C ４ Alkinyl, C ３ ~C ６ Cycloalkyl, 5-membered heteroaryl, or -C(O)NH ２ And here, each C １ ~C ４ Alkyl group has 1 or 2 R ７ The substituents are optionally substituted, each phenyl group is optionally substituted with one or two halogens, and each five-membered heteroaryl group has one or two -CH ３ Replaced by optional selection, Each R ７ However, independently, -OH, -C(O)NH ２ , -OR ２０ , C ３ ~C ６ The C1 is a cycloalkyl, -CN, phenyl, halogen, -C(O)OH, or 5-membered heteroaryl, where each C ３ ~C ６ Cycloalkyl is -CH ３ Replaced by optional selection, Each R ２０ However, C １ ~C ６ It is an alkyl or a 5-membered or 6-membered heteroaryl, where each C １ ~C ６ The pharmaceutical combination according to any one of claims 1 to 5, wherein the alkyl group is optionally substituted with 1 to 3 halogens, and each 5-membered or 6-membered heteroaryl group is optionally substituted with -OH.

11. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ and R ２ However, they became independent, 【Chemistry 12】 A combination of pharmaceuticals according to any one of claims 1 to 5, representing the above.

12. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ and R ２ However, they became independent, 【Chemistry 13】 A combination of pharmaceuticals according to any one of claims 1 to 5, representing the above.

13. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ and R ２ However, they became independent, 【Chemistry 14】 A combination of pharmaceuticals according to any one of claims 1 to 5, representing the above.

14. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ and R ２ However, they became independent, 【Chemistry 15】 A combination of pharmaceuticals according to any one of claims 1 to 5, representing the above.

15. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ and R ２ However, independently, -CN, C ６ ~C １０ Ariel, C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, 5-membered heteroaryl, or -C(O)NH ２ And here, each C １ ~C ６ Alkyl groups: 1-2 R ７ Substituents are optionally replaced, Each R ７ However, independently, -OH, -C(O)NH ２ , C ３ ~C ６ Cycloalkyl, -CN, C ６ ~C １０ The aryl, halogen, or 5- to 8-membered heteroaryl, where each C ３ ~C ６ Cycloalkyl groups have 1 to 2 carbon atoms. １ ~C ４ The alkyl group is optionally substituted, with each 5-membered to 8-membered heteroaryl group having 1 to 2 R groups. １３ Substituents are optionally replaced, Each R １３ However, independently, halogen or C １ ~C ４ A pharmaceutical combination according to any one of claims 1 to 5, wherein the compound is alkyl.

16. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ and R ２ A combination of pharmaceuticals according to any one of claims 1 to 15, wherein the two are different.

17. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ and R ２ A pharmaceutical combination according to any one of claims 1 to 16, wherein one of them is -CN.

18. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ and R ２ One of them is 【Chemistry 16】 The pharmaceutical combination according to any one of claims 1 to 17.

19. The compound of formula (I) is of formula (Ib) or (Ib'): 【Chemistry 17】 Represented by, In the formula, R ４ , R, and R ａ However, as defined in claim 1 or 2, A pharmaceutical combination according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

20. The compound of formula (I) is of formula (Ib): 【Chemistry 18】 Represented by, In the formula, R ４ and R ａ However, as defined in claim 1, The pharmaceutical combination described in claim 19, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

21. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ４ However, C １ ~C ６ Alkyl, C ６ ~C １０ The aryl group is a 7- to 10-membered partially unsaturated heterocyclic group, or a 5- to 10-membered heteroaryl group, where C １ ~C ６ Alkyl groups: 1 to 3 R ９ Substituents are optionally replaced with C ６ ~C １０ Aryl and 5- to 10-membered heteroaryl groups, with 1 to 3 R １０ Optionally substituted with substituents, R ９ and R １０ The pharmaceutical combination according to any one of claims 1, 2, 19, and 20, wherein the combination is as defined in claim 1.

22. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ４ However, C １ ~C ６ Alkyl, C ６ ~C １０ The aryl group is a 7- to 10-membered partially unsaturated heterocyclic group, or a 5- to 10-membered heteroaryl group, where C ６ ~C １０ Aryl and 5- to 10-membered heteroaryl groups, with 1 to 3 R １０ The substituent is optionally substituted, and here, Each R １０ However, independently, C １ ~C ４ Alkyl, halogen, -OC １ ~C ６ Alkyl, -NH ２ ,-NH(C １ ~C ４ Alkyl), or -N(C) １ ~C ４ Alkyl) ２ And here, each C １ ~C ４ The pharmaceutical combination according to any one of claims 1, 2, 19, and 20, wherein the alkyl group is optionally substituted with one to three halogens.

23. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ４ However, C １ ~C ６ Alkyl, C ６ ~C １０ The aryl group is a 7- to 10-membered partially unsaturated heterocyclic group, or a 5- to 10-membered heteroaryl group, where C ６ ~C １０ Aryl and 5- to 10-membered heteroaryl groups, with 1 to 3 R １０ The substituent is optionally substituted, and here, Each R １０ However, independently, C １ ~C ４ Alkyl, halogen, -OC １ ~C ６ Alkyl, or -N(C) １ ~C ４ Alkyl) ２ And here, each C １ ~C ４ The pharmaceutical combination according to any one of claims 1, 2, 19, and 20, wherein the alkyl group is optionally substituted with one to three halogens.

24. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ４ However, C １ ~C ４ Alkyl, phenyl, a 9-membered partially unsaturated heterocyclic group, or a 5- to 6-membered heteroaryl, where phenyl and the 5- to 6-membered heteroaryl are associated with 1 or 2 R １０ The substituent is optionally substituted, and here, Each R １０ However, independently, -CF ３ , halogen, -OCH ３ , or -N(CH ３ ) ２ The pharmaceutical combination according to any one of claims 1, 2, 19, and 20.

25. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ４ but, 【Chemistry 19】 A pharmaceutical combination according to any one of claims 1, 2, 19, and 20, representing the above.

26. The compound of formula (I) is of formula (Ic) or (Ic'): 【Chemistry 20】 Represented by, In the formula, R ２ａ , R, and R ａ However, as defined in claim 1 or 2, A pharmaceutical combination according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

27. The compound of formula (I) is of formula (Ic): 【Chemistry 21】 Represented by, In the formula, R ２ａ and R ａ However, as defined in claim 1, The pharmaceutical combination described in claim 26, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

28. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ２ａ However, C １ ~C ６ Alkyl or C ６ ~C １０ It is aryl, and here, C １ ~C ６ Alkyl groups consist of 1 to 3 R groups. ９ Substituents are optionally replaced with C ６ ~C １０ aryl has 1 to 3 R １０ Optionally substituted with substituents, R ９ and R １０ A pharmaceutical combination according to any one of claims 1, 2, 26, and 27, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined in claim 1.

29. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ２ａ However, C １ ~C ６ Alkyl or C ６ ~C １０ It is aryl, and here, C １ ~C ６ A pharmaceutical combination according to any one of claims 1, 2, 26, and 27, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the alkyl group is optionally substituted with one to three halogens.

30. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ２ａ C １ ~C ６ A pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is alkyl, according to any one of claims 1, 2, 26, and 27.

31. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ２ａ C １ ~C ４ A pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is alkyl, according to any one of claims 1, 2, 26, and 27.

32. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ２ａ A pharmaceutical combination according to any one of claims 1, 2, 26, and 27, wherein is ethyl.

33. The compound of formula (I) is of formula (Id) or (Id'): 【Chemistry 22】 Represented by, In the formula, R １ａ , R ２ｂ , R ４ａ , R, and R ａ However, as defined in claim 1 or 2, A pharmaceutical combination according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

34. The compound of formula (I) is of formula (Id): 【Chemistry 23】 Represented by, In the formula, R １ａ , R ２ｂ , R ４ａ , and R ａ However, as defined in claim 1, The pharmaceutical combination described in claim 33, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

35. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ａ and R ２ｂ However, independently, -CN, C ６ ~C １０ Ariel, C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, or -C(O)NH ２ And here, each C １ ~C ６ Alkyl groups consist of 1-2 R groups. １６ Substituents are optionally replaced, Each R １６ However, independently, -OH, -C(O)NH ２ , C ３ ~C ６ Cycloalkyl, -CN, C ６ ~C １０ The aryl, halogen, or 5- to 8-membered heteroaryl, where each C ３ ~C ６ Cycloalkyl groups have 1 to 2 carbon atoms. １ ~C ４ The alkyl group is optionally substituted, with each 5-membered to 10-membered heteroaryl group having 1 to 2 R groups. ２１ Substituents are optionally replaced, Each R ２１ However, independently, halogen or C １ ~C ４ A pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is alkyl, according to any one of claims 1, 2, 33, and 34.

36. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ａ and R ２ｂ However, independently, -CN or C ６ ~C １０ A pharmaceutical combination according to any one of claims 1, 2, 33, and 34, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is an aryl.

37. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ４ａ C １ ~C ６ A pharmaceutically acceptable salt, solvate, or prodrug thereof, which is alkyl, according to any one of claims 1, 2, 33, 34, 35, and 36.

38. The compound of formula (I) is of formula (Ie) or (Ie'): 【Chemistry 24】 Represented by, In the formula, R, R ａ , R １ｂ , and R ２ｃ However, as defined in claim 1 or 2, A pharmaceutical combination according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

39. The compound of formula (I) is of formula (Ie): 【Chemistry 25】 Represented by, In the formula, R ａ , R １ｂ , and R ２ｃ However, as defined in claim 1, The pharmaceutical combination described in claim 38, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

40. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ｂ and R ２ｃ Together with the carbon atoms to which they are bonded, C ３ ~C ８ The groups form cycloalkyl groups, 4- to 14-membered heterocycloalkyl groups, 8- to 14-membered partially unsaturated heterocyclic groups, or 8- to 14-membered partially unsaturated carbocyclic groups, where each of the 4- to 14-membered heterocycloalkyl groups, 8- to 14-membered partially unsaturated heterocyclic groups, or 8- to 14-membered partially unsaturated carbocyclic groups is oxo (=O), oxime (=N-OH), C １ ~C ３ Alkoxy oxime (= N-OC) １ ~C ３ Alkyl), or -OH and -CF ３ A pharmaceutically acceptable salt, solvate, or prodrug thereof according to any one of claims 1, 2, 38, and 39, which is optionally substituted with one to three substituents independently selected from the above.

41. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ｂ and R ２ｃ Together with the carbon atoms to which they are bonded, C ３ ~C ８ A cycloalkyl or 8- to 10-membered partially unsaturated carbon ring group is formed, where the 8- to 10-membered partially unsaturated carbon ring group is oxo (=O), oxime (=N-OH), or methoxyoxime (=N-OCH) ３ ), or -OH and -CF ３ A pharmaceutically acceptable salt, solvate, or prodrug thereof according to any one of claims 1, 2, 38, and 39, which is optionally substituted with one or two substituents independently selected from the above.

42. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ｂ and R ２ｃ Together with the carbon atoms to which they are bonded, C ４ ~C ６ Cycloalkyl, or 【Chemistry 26】 A group is formed by selecting from, where the dashed line is R １ｂ and R ２ｃ A pharmaceutical combination according to any one of claims 1, 2, 38, and 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, representing a portion of the cyclohexanone moiety of a compound of formula (Ie) or (Ie') having the above formula.

43. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ｂ and R ２ｃ Together with the carbon atoms to which they are bonded, they form cyclopentyl, or 【Chemistry 27】 A group is formed by selecting from, where the dashed line is R １ｂ and R ２ｃ A pharmaceutical combination according to any one of claims 1, 2, 38, and 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, representing a portion of the cyclohexanone moiety of a compound of formula (Ie) or (Ie') having the above formula.

44. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R １ｂ and R ２ｃ Together with the carbon atoms to which they are bonded, 【Chemistry 28】 A group is formed by selecting from, where the dashed line is R １ｂ and R ２ｃ A pharmaceutical combination according to any one of claims 1, 2, 38, and 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, representing a portion of the cyclohexanone moiety of a compound of formula (Ie) or (Ie') having the above formula.

45. The compound of formula (I) is of formula (If) or (If'): 【Chemistry 29】 Represented by, In the formula, R, R ａ , R ４ｂ , and R ２ｄ However, as defined in claim 1 or 2, A pharmaceutical combination according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

46. The compound of formula (I) is of formula (If): 【Transformation 30】 Represented by, In the formula, R ａ , R ４ｂ , and R ２ｄ However, as defined in claim 1, The pharmaceutical combination described in claim 45, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

47. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ２ｄ and R ４ｂ Together with the carbon atoms to which they are bonded, C ３ ~C ８ A cycloalkyl group is formed, where each C ３ ~C ８ The cycloalkyl group has 1 to 3 R groups as defined in claim 1. １９ A pharmaceutically acceptable salt, solvate, or prodrug thereof according to any one of claims 1, 2, 45, and 46, which is optionally substituted with a substituent.

48. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ２ｄ and R ４ｂ Together with the carbon atoms to which they are bonded, C ３ ~C ８ A pharmacokinetic combination according to any one of claims 1, 2, 45, and 46, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which forms a cycloalkyl group.

49. The compound of formula (I) is of formula (Ig): 【Chemistry 31】 Represented by, In the formula, R ａ , R １ｃ , and R ３ However, as defined in claim 1, A pharmaceutical combination according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

50. In the compound of formula (I), or the pharmaceutically acceptable salt, the solvate, or the prodrug thereof, R １ｃ and R ３ , together with the carbon atoms to which they are bonded, form a C ３ -C ８ cycloalkyl, wherein each C ３ -C ８ cycloalkyl is optionally substituted with 1 to 3 R １９ substituents as defined in claim 1. The pharmaceutical combination according to any one of claims 1, 2 and 49, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

51. In the compound of the formula (I), or the pharmaceutically acceptable salt, the solvate, or the prodrug thereof, R １ｃ and R ３ , together with the carbon atoms to which they are bonded, form C ３ -C ８ cycloalkyl, wherein the pharmaceutical combination according to any one of claims 1, 2 and 49, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

52. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ａ ga-NHR ｂ And R ｂ but, 【Chemistry 32】 A pharmaceutical combination according to any one of claims 1 to 51, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

53. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ａ ga-NHR ｂ And R ｂ but, 【Transformation 33】 A pharmaceutical combination according to any one of claims 1 to 52, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

54. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ａ ga-NHR ｂ And R ｂ but 【Transformation 34】 A pharmaceutical combination according to any one of claims 1 to 53, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

55. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ａ but, 【Chemistry 35】 The pharmaceutical combination according to any one of claims 1 to 51, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

56. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ａ but, 【Transformation 36】 A pharmaceutical combination according to any one of claims 1 to 51 and 55, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

57. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ａ The pharmaceutical combination according to any one of claims 1 to 51, wherein is -OH.

58. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ａ ga-NH ２ The pharmaceutical combination according to any one of claims 1 to 51.

59. In the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug, R ａ The pharmaceutical combination according to any one of claims 1 to 51, wherein is -NH-OH.

60. The pharmaceutical combination according to any one of claims 1 to 59, wherein the compound of formula (I), or the pharmaceutically acceptable salt thereof, the solvate, or the prodrug is in the form of a racemic mixture or any enantiomer thereof.

61. The aforementioned compounds are compounds 4, 8, 9, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60a, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 108, 109, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 1 29, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 154, 155, 163, 168, 169, 170, 173, 174, 175, 178, 17 9, 180, 181, 183, 189, 190, 191, 192, 193, 194, 195, 197, 198, 199, 200, 201, 202, 211, 212, 213, 214, 215, 216, 219, 221, 227, 228, 229, 230, 231, 232, 237 ,238,239,245,246,247,248,249,250,251,253,254,255,257,258,263,264,271,272,273,278,279,280,281,287,288,290,291,297,298,305,306, 313, 314, 321, 322, 330, 331, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 352, 353, 354, 355, 356, 357, 358, 360, 362, 371, 378, 391, 3 92, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403, 406, 407, 408, 412 , 413, 414, 416, 418, 422, 427, 428, 429, 430, 431, 433, 434, 445, 446, 447, 44 8, 449, 450, 451, 452, 453, 454, 462, 463, 464, 465, 466, 468, 469, 470, 471, 472, 473, 474, 475, 476, 478, 479, 480, 481, 482, 483, 486, 488, 489, 492, 495,The pharmaceutical combination according to claim 1, wherein 496, 497, 498, 511, 512, 513, 514, 515, 520, 523, 524, or 534, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

62. The aforementioned compound is one of the compounds 4, 15, 16, 17, 20, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61, 62, 63, 64, 65, 66, 67, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136 of Table 1 of this specification. 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 191, 192, 194, 195, 198, 199, 201, 202, 212, 213, 214, 215, 216, 228, 230, 231, 232, 237, 238, 239, 246, 248, 250, 251, 253, 254, 255, 258, 263, 264, 271 , 272, 273, 278, 279, 280, 281, 287, 288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 352, 353, 354, 355, 356, 357, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403, 406, 407, 408, 413, 414, 416, 418, 4 The pharmaceutical combination according to claim 1, wherein the combination is 22, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 453, 454, 462, 463, 464, 465, 466, 468, 470, 472, 474, 475, 476, 479, 480, 481, 482, 486, 489, 495, 496, 498, 511, 512, 513, 514, 515, 520, or 524, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

63. The aforementioned compounds are compounds 4, 15, 25, 32, 33, 47, 48, 49, 50, 52, 54, 59, 60b, 61, 62, 63, 72, 75, 82, 83, 89, 97, 101, 109, 119, 121, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, and 14 of Table 1 of this specification. 5, 146, 147, 148, 149, 150, 163, 169, 170, 174, 179, 181, 183, 191, 192, 194, 195, 212, 213, 214, 215, 230, 231, 232, 238, 239, 246, 248, 250, 251, 253, 254, 255, 258, 263, 264, 272, 273, 278, 279, 280, 281, 288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 353, 355, 356 , 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407, 408, 413, 418, 422, 428, 429, 43 The pharmaceutical combination according to claim 1, wherein the combination is 0, 431, 434, 445, 446, 447, 448, 449, 450, 451, 454, 463, 464, 465, 466, 472, 475, 476, 479, 481, 486, 489, 495, 498, 512, 514, 515, 520, or 524, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

64. The aforementioned compounds are compounds 48, 50, 54, 60b, 61, 63, 72, 75, 83, 97, 101, 109, 127, 135, 140, 141, 143, 144, 145, 146, 147, 149, 163, 169, 170, 174, 179, 181, 191, 194, 195, 212, 215, 230, 231, 232, 238, 246, 248, 250, 251, 255, 258, 272, 273, 279, 281, 291, The pharmaceutical combination according to claim 1, wherein the combination is 306, 314, 321, 322, 331, 338, 339, 340, 341, 342, 345, 353, 355, 356, 391, 393, 395a, 395b, 397, 402, 428, 430, 431, 434, 446, 447, 448, 450, 463, 464, 465, 466, 489, 512, 514, 515, or 524, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

65. The pharmaceutical combination according to claim 1, wherein the compound is compound 54, 61, 63, 75, 140, 143, 146, 174, 215, 230, 250, 251, 273, 306, 322, 430, 446, 463, or 512 of Table 1 of this specification, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

66. The pharmaceutical combination according to any one of claims 1 to 65, wherein the COX inhibitor comprises a nonsteroidal anti-inflammatory drug (NSAID).

67. The aforementioned NSAIDs include bromfenac, celecoxib, diclofenac, etodolac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketrolac, mefenamic acid, meloxicam, nabumetone, naproxen, nepafenac, piroxicam, sulindac, tenoxicam, tiaprofenic acid, diflunisal, etoricoxib, fenoprofen, phloxtaphenin, lumiracoxib, oxaprozin, and parenchyma. The pharmaceutical combination according to claim 66, selected from the group consisting of coxib, lofecoxib, tolmetine, valdecoxib, meclofenamic acid, dexketoprofen, lycopherone, lornoxicam, loxoprofen, nimeslide, tolfenamic acid, phenylbutazone, firocoxib, salsalate, choline magnesium trisalicylate, acetylsalicylic acid, any pharmaceutically acceptable salts thereof, and any combination thereof.

68. The pharmaceutical combination according to claim 66, wherein the NSAID is naproxen, celecoxib, diclofenac, ibuprofen, pharmaceutically acceptable salts thereof, or any combination thereof.

69. The pharmaceutical combination according to any one of claims 1 to 65, wherein the COX inhibitor is acetaminophen.

70. The pharmaceutical combination according to any one of claims 1 to 69, wherein the COX inhibitor and the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof are combined in a single dosage form.

71. The pharmaceutical combination according to any one of claims 1 to 69, wherein the COX inhibitor and the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug are each individual dosage forms.

72. A pharmaceutical combination according to any one of claims 1 to 71, comprising the COX inhibitor and the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug, each in an amount ranging from about 1 mg to about 1000 mg.

73. A pharmaceutical combination according to any one of claims 1 to 72, comprising the COX inhibitor and the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug in a weight ratio of 1:0.1 to 1:

10.

74. A pharmaceutical combination according to any one of claims 1 to 73, comprising the COX inhibitor and the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug in a weight ratio of 1:0.1 to 1:

1.

75. The pharmaceutical combination according to any one of claims 1 to 74, wherein the pharmaceutical combination is a synergistic pharmaceutical combination.

76. A pharmaceutical combination according to any one of claims 1 to 75, for use in treating pain in a person requiring it.

77. Use of the pharmaceutical combination according to any one of claims 1 to 75 for the treatment of pain in a subject requiring treatment of the pain.

78. A method for treating pain, comprising administering a combination of pharmaceuticals described in any one of claims 1 to 75 to a subject who requires it.

79. The pharmaceutical combination for use according to claim 76, the use according to claim 77, or the method according to claim 78, wherein the pain is inflammatory pain, neuropathic pain, or cancer pain.

80. The pharmaceutical combination for use according to claim 76, the use according to claim 77, or the method according to claim 78, wherein the pain is inflammatory pain.

81. The pharmaceutical combination for use according to claim 76, the use according to claim 77, or the method according to claim 78, wherein the pain is neuropathic pain.

82. The pharmaceutical combination for use according to claim 76, the use according to claim 77, or the method according to claim 78, wherein the pain is cancer pain.

83. The combination of pharmaceuticals for use according to claim 76, 79, or 80, the use according to claim 77, 79, or 80, or the method according to claim 78, 79, or 80, wherein the pain is arthritis pain, pain associated with musculoskeletal trauma or soft tissue trauma, postoperative pain, dental pain, dysmenorrhea pain, episiotomy pain, endometriosis pain, postpartum pain, headache, eye pain, bursitis pain, or tendinitis pain.

84. A pharmaceutical combination for use according to claim 83, a use according to claim 83, or a method according to claim 83, wherein the pain is arthritis pain, and the arthritis pain is osteoarthritis pain, rheumatoid arthritis pain, ankylosing spondylitis pain, gout pain, or periarthritis pain.

85. The pharmaceutical combination for use according to claim 83, the use according to claim 83, or the method according to claim 83, wherein the pain is pain related to musculoskeletal trauma or soft tissue trauma, and the pain related to musculoskeletal trauma or soft tissue trauma is pain related to a sprain or pain related to a contusion.

86. The combination of pharmaceuticals for use according to claim 83, the use according to claim 83, or the method according to claim 83, wherein the pain is postoperative pain, and the postoperative pain is postoperative pain after minor surgery, postoperative pain after general surgery, postoperative pain after orthopedic surgery, postoperative pain after hallux valgus excision, postoperative pain after hernia repair, postoperative pain after hernia repair, postoperative pain after arthroplasty including pain after knee arthroplasty or hip arthroplasty, postoperative pain after gynecological surgery, postoperative pain after cesarean section, postmastectomy pain syndrome, postoperative pain after abdominal wall repair, postoperative pain after laminectomy, postoperative pain after hemorrhoidectomy, or postoperative pain after thoracotomy.

87. The pharmaceutical combination for use according to claim 83, the use according to claim 83, or the method according to claim 83, wherein the pain is dental pain, and the dental pain is toothache or postoperative pain after dental surgery.

88. The pharmaceutical combination for use according to claim 83, the use according to claim 83, or the method according to claim 83, wherein the pain is dental pain and the dental pain is post-extraction pain.

89. The pharmaceutical combination for use according to claim 83, the use according to claim 83, or the method according to claim 83, wherein the pain is dysmenorrhea pain, episiotomy pain, endometriosis pain, or postpartum cramp pain.

90. The combination of pharmaceuticals for use according to claim 83, the use according to claim 83, or the method according to claim 83, wherein the pain is a headache, and the headache is a migraine, a tension headache, or a cluster headache.

91. The pharmaceutical combination for use according to claim 83, the use according to claim 83, or the method according to claim 83, wherein the pain is ocular pain, and the ocular pain is postoperative pain after cataract surgery, postoperative pain after refractive surgery, ocular pain from a non-penetrating wound, foreign body ocular pain, burning or stinging sensation of the eye, uveitis pain, iritis pain, retinopathy pain, or optic neuritis pain.

92. A combination of pharmaceuticals for use according to any one of claims 76 and 79-91, the use according to any one of claims 77 and 79-91, or the method according to any one of claims 78-91, wherein the treatment is an oral treatment.

93. A pharmaceutical combination for use according to any one of claims 76 and 79-92, a use according to any one of claims 77 and 79-92, or a method according to any one of claims 78-92, wherein the subject is a mammal.

94. A combination of pharmaceuticals for use according to any one of claims 76 and 79-93, a use according to any one of claims 77 and 79-93, or a method according to any one of claims 78-93, wherein the subject is a human.

95. A pain treatment method that involves administering cyclooxygenase (COX) inhibitors to those who require it. A method comprising administering a compound having formula (I) as described in any one of claims 1 to 65, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

96. The method according to claim 95, wherein the COX inhibitor comprises a nonsteroidal anti-inflammatory drug (NSAID).

97. The method according to claim 96, wherein the NSAID is selected from the group consisting of bromfenac, celecoxib, diclofenac, etodolac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketrolac, mefenamic acid, meloxicam, nabumetone, naproxen, nepafenac, piroxicam, slindac, tenoxicam, tiaprofenic acid, diflunisal, etoricoxib, fenoprofen, phloctafenin, lumiracoxib, oxaprozin, parecoxib, lofecoxib, tolmetin, valdecoxib, meclofenamic acid, dexketoprofen, lycopherone, lornoxicam, loxoprofen, nimeslide, tolfenamic acid, phenylbutazone, firocoxib, salsalate, choline magnesium trisalicylate, acetylsalicylic acid, any pharmaceutically acceptable salts thereof, and any combination thereof.

98. The method according to claim 96, wherein the NSAID is naproxen, celecoxib, diclofenac, ibuprofen, pharmaceutically acceptable salts thereof, or any combination thereof.

99. The method according to claim 95, wherein the COX inhibitor is acetaminophen.

100. The method according to any one of claims 95 to 99, wherein the pain is inflammatory pain, neuropathic pain, or cancer pain.

101. The method according to any one of claims 95 to 100, wherein the pain is inflammatory pain.

102. The method according to any one of claims 95 to 100, wherein the pain is neuropathic pain.

103. The method according to any one of claims 95 to 100, wherein the pain is cancer pain.

104. The method according to any one of claims 95 to 101, wherein the pain is arthritis pain, pain associated with musculoskeletal trauma or soft tissue trauma, postoperative pain, dental pain, dysmenorrhea pain, episiotomy pain, endometriosis pain, postpartum pain, headache, eye pain, bursitis pain, or tendinitis pain.

105. The method according to claim 104, wherein the pain is arthritis pain, and the arthritis pain is osteoarthritis pain, rheumatoid arthritis pain, ankylosing spondylitis pain, gout pain, or periarthritis pain.

106. The method according to claim 104, wherein the pain is pain related to musculoskeletal trauma or soft tissue trauma, and the pain related to musculoskeletal trauma or soft tissue trauma is pain related to a sprain or pain related to a contusion.

107. The method according to claim 104, wherein the pain is postoperative pain, and the postoperative pain is postoperative pain after minor surgery, postoperative pain after general surgery, postoperative pain after orthopedic surgery, postoperative pain after hallux valgus excision, postoperative pain after hernia repair, postoperative pain after hernia repair, postoperative pain after arthroplasty including pain after knee arthroplasty or hip arthroplasty, postoperative pain after gynecological surgery, postoperative pain after cesarean section, postmastectomy pain syndrome (PMPS), postoperative pain after abdominal wall repair, postoperative pain after laminectomy, postoperative pain after hemorrhoidectomy, or postoperative pain after thoracotomy.

108. The method according to claim 104, wherein the pain is dental pain, and the dental pain is toothache or postoperative pain after dental surgery.

109. The method according to claim 104, wherein the pain is dental pain, and the dental pain is post-extraction pain.

110. The method according to claim 104, wherein the pain is dysmenorrhea pain, episiotomy pain, endometriosis pain, or postpartum spasm pain.

111. The method according to claim 104, wherein the pain is a headache, and the headache is a migraine, a tension headache, or a cluster headache.

112. The method according to claim 104, wherein the pain is eye pain, and the eye pain is postoperative pain after cataract surgery, postoperative pain after refractive surgery, eye pain from a non-penetrating wound, foreign body pain, burning or stinging sensation in the eye, uveitis pain, iritis pain, retinopathy pain, or optic neuritis pain.

113. The method according to any one of claims 95 to 112, wherein the COX inhibitor and the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug are administered simultaneously or sequentially.

114. The method according to any one of claims 95 to 112, wherein the COX inhibitor and the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug are administered simultaneously.

115. The method according to any one of claims 95 to 114, wherein the COX inhibitor and the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug are each administered in individual dosage forms.

116. The method according to any one of claims 95 to 114, wherein the COX inhibitor and the compound of formula (I) or a pharmaceutically acceptable salt thereof, the solvate, or the prodrug are administered in a single dosage form.

117. The method according to any one of claims 95 to 116, wherein the COX inhibitor and the compound of formula (I) or a pharmaceutically acceptable salt thereof, the solvate, or the prodrug are administered orally.

118. The method according to any one of claims 95 to 117, wherein the COX inhibitor is administered in a dose of 0.1 to 20 mg / kg.

119. The method according to any one of claims 95 to 118, wherein the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug is administered in a dose of 0.1 to 30 mg / kg, preferably 0.1 to 15 mg / kg.

120. The method according to any one of claims 95 to 119, wherein the subject is a mammal.

121. The method according to any one of claims 95 to 120, wherein the subject is a human.

122. A kit comprising: a first single dosage form of a cyclooxygenase (COX) inhibitor; a second single dosage form of a compound having formula (I) as described in any one of claims 1 to 65, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and instructions for use.

123. The kit according to claim 122, wherein the COX inhibitor comprises a nonsteroidal anti-inflammatory drug (NSAID).

124. The aforementioned NSAIDs include bromfenac, celecoxib, diclofenac, etodolac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketrolac, mefenamic acid, meloxicam, nabumetone, naproxen, nepafenac, piroxicam, sulindac, tenoxicam, tiaprofenic acid, diflunisal, etoricoxib, fenoprofen, phloxtaphenin, lumiracoxib, oxaprozin, pa The kit according to claim 123, selected from the group consisting of recoxib, lofecoxib, tolmetine, valdecoxib, meclofenamic acid, dexketoprofen, lycopherone, lornoxicam, loxoprofen, nimeslide, tolfenamic acid, phenylbutazone, firocoxib, salsalate, choline magnesium trisalicylate, acetylsalicylic acid, any pharmaceutically acceptable salts thereof, and any combination thereof.

125. The kit according to claim 123, wherein the NSAID is naproxen, celecoxib, diclofenac, ibuprofen, a pharmaceutically acceptable salt thereof, or any combination thereof.

126. The kit according to claim 122, wherein the COX inhibitor is acetaminophen.

127. The kit according to any one of claims 122 to 126, wherein the first single dosage form comprises an amount of the COX inhibitor in the range of about 1 mg to about 1000 mg, and the second single dosage form comprises an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the solvate, or the prodrug in the range of about 1 mg to about 1000 mg.

128. A kit according to any one of claims 122 to 127 for use in the treatment of pain.

129. The kit for use according to claim 128, wherein the pain is inflammatory pain, neuropathic pain, or cancer pain.

130. The kit for use according to claim 128 or 129, wherein the pain is inflammatory pain.

131. The kit for use according to claim 128 or 129, wherein the pain is neuropathic pain.

132. The kit for use according to claim 128 or 129, wherein the pain is cancer pain.

133. A kit for use according to any one of claims 128 to 130, wherein the pain is arthritis pain, pain associated with musculoskeletal trauma or soft tissue trauma, postoperative pain, dental pain, dysmenorrhea pain, episiotomy pain, endometriosis pain, postpartum pain, headache, eye pain, bursitis pain, or tendinitis pain.

134. A kit for use according to any one of claims 128 to 130, wherein the pain is arthritis pain, and the arthritis pain is osteoarthritis pain, rheumatoid arthritis pain, ankylosing spondylitis pain, gout pain, or periarthritis pain.

135. A kit for use according to any one of claims 128 to 130, wherein the pain is pain associated with musculoskeletal trauma or soft tissue trauma, and the pain associated with musculoskeletal trauma or soft tissue trauma is pain associated with a sprain or pain associated with a contusion.

136. A kit for use according to any one of claims 128 to 130, wherein the pain is postoperative pain, and the postoperative pain is postoperative pain after minor surgery, postoperative pain after general surgery, postoperative pain after orthopedic surgery, postoperative pain after hallux valgus excision, postoperative pain after hernia repair, postoperative pain after hernia repair, postoperative pain after arthroplasty including pain after knee arthroplasty or hip arthroplasty, postoperative pain after gynecological surgery, postoperative pain after cesarean section, postmastectomy pain syndrome, postoperative pain after abdominal wall repair, postoperative pain after laminectomy, postoperative pain after hemorrhoidectomy, or postoperative pain after thoracotomy.

137. A kit for use according to any one of claims 128 to 130, wherein the pain is dental pain, and the dental pain is toothache or postoperative pain after dental surgery.

138. A kit for use according to any one of claims 128 to 130, wherein the pain is dental pain, and the dental pain is post-extraction pain.

139. A kit for use according to any one of claims 128 to 130, wherein the pain is dysmenorrhea pain, episiotomy pain, endometriosis pain, or postpartum cramp pain.

140. A kit for use according to any one of claims 128 to 130, wherein the pain is a headache, and the headache is a migraine, a tension headache, or a cluster headache.

141. A kit for use according to any one of claims 128 to 130, wherein the pain is ocular pain, and the ocular pain is postoperative pain after cataract surgery, postoperative pain after refractive surgery, ocular pain from a non-penetrating wound, foreign body pain, burning or stinging sensation of the eye, uveitis pain, iritis pain, retinopathy pain, or optic neuritis pain.

142. A kit for use according to any one of claims 128 to 141, wherein the treatment is an oral treatment.

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