Pharmaceutical combinations comprising a substituted thiophene fused cyclohexanone derivative and a cyclooxygenase (COX) inhibitor, and their use for the treatment of pain

Abstract

There is provided a pharmaceutical combination comprising a cyclooxygenase (COX) inhibitor and a compound having the Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the COX inhibitor can comprise a Non-Steroidal Anti-Inflammatory Drug (NSAID). The pharmaceutical combination can be used in the treatment of pain in a subject in need thereof, such inflammatory pain. There is also provided a kit comprising a first single dose form of a cyclooxygenase (COX) inhibitor and a second single dose form of a compound having the Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and instructions for use. (I)

Description

[0001] PHARMACEUTICAL COMBINATIONS COMPRISING A SUBSTITUTED THIOPHENE FUSED CYCLOHEXANONE DERIVATIVE AND A CYCLOOXYGENASE (COX) INHIBITOR, AND THEIR USE FOR THE TREATMENT OF PAIN

[0002] PRIORITY APPLICATION

[0003] The present application claims priority from U.S. provisional application No. 63 / 519.108, filed August 11 , 2023, which is incorporated herein by reference.

[0004] TECHNICAL FIELD

[0005] The technical field generally relates to pharmaceutical combinations and their uses in the treatment of pain. The pharmaceutical combinations comprise thiophene fused cyclohexanone derivatives and cyclooxygenase (COX) inhibitors. Particularly, the thiophene fused cyclohexanone derivatives are acid-sensing ion channels (ASICs) inhibitors.

[0006] BACKGROUND

[0007] Since the discovery of acid-sensing ion channels (ASICs) in 1997, their importance in the health of neurons and other non-neuronal cells has gained significant importance. ASICs play important roles in mediating pain sensation and their activity contributes to diseases such as stroke, inflammation, arthritis, cancer, and migraine.

[0008] ASICs are permeable to Na+ ions (and other cations), they are activated by low extracellular pH and widely expressed in the central nervous system (CNS) and the peripheral nervous system (PNS). ASICs are formed by homo- and heterotrimeric assemblies of subunits including ASICIa, ASICIb, ASIC2a, ASIC2b and ASIC3. ASICIa are expressed in the PNS and CNS, ASICI b in the PNS.

[0009] Tissue injury and inflammation cause acidosis and acidification is considered a significant contributor to associated pain. The literature indicates that ASIC inhibitors might relieve pain in a variety of clinical conditions. In addition, because their mechanism of action is distinct, ASIC antagonists may provide new treatment options for patients who do not benefit from or do not tolerate the adverse side effects of certain current pain medications.

[0010] Developing new pharmaceutical combinations comprising small molecule inhibitors that are specific for ASICs is therefore important to provide alternative therapeutic treatments against ASICs-related disorders or conditions, such as pain.

[0011] SUMMARY

[0012] The present application relates to a pharmaceutical combination comprising a cyclooxygenase (COX) inhibitor and a compound which is a thiophene fused cyclohexanone derivative of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The pharmaceutical combination can be useful for the treatment of pain.

[0013] According to one aspect, the present application relates to a pharmaceutical combination comprising:

[0014] (a) a cyclooxygenase (COX) inhibitor; and

[0015] (b) a compound having the Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

[0016] Rais -NH2, -NH-OH, -OH, -NHRbor -NHRcRd;

[0017] Rbis C1-C6alkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C1-C6alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -O C1-C3alkyl, -COOH, or cyclopropyl optionally substituted with -OH, and wherein C3-C6cycloalkyl is optionally substituted with -ON;

[0018] Rcand Rdform with the nitrogen to which they are attached a 4-membered heterocycloalkyl, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C1-C3alkyl; wherein:

[0019] R is H, C1-C6alkyl or phenyl; R1and R2are independently -CN, C6-C10aryl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, - C(O)NHR5, -C(O)R6, or -C(0)OR5, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22substituents, with the proviso that when Rais -OH, represents Ao, and R1is , then R2in residue Aois different than each R5is independently C1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R9substituents; each R6is independently C3-C6cycloalkyl, 4- to 6-membered heterocycloalkyl, or C6-C10aryl; each R7is independently -OH, -C(O)R11, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), 4- to 6- membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OR20, -SC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R8is independently halogen, C1-C6alkyl, -OC1-C6alkyl, C3-C6cycloakyl, or 5- to 10- membered heteroaryl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with C1-C4alkyl; each R22is independently C1-C6alkyl optionally substituted with phenyl; each R9is independently -OH, -C(O)R15, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OC1-C6alkyl, -SC1-C6alkyl, -NH2, -NH(C1- C4alkyl), or -N(C1-C4alkyl)2, wherein each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl, and each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R11is independently -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, or 4- to 6-membered heterocycloalkyl; each R20is independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R14substituents and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, -OC1-C4alkyl, or -SPh, wherein each C1- C4alkyl is optionally substituted with -OH; each R13is independently halogen, C1-C4alkyl, C3-C6cycloalkyl, -OH, -OC1-C6alkyl, -SC1-C6alkyl, -S(O)2C1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each -OC1-C8alkyl, -SC1- C6alkyl, -S(O)2C1-C6alkyl, -NH(C1-C4alkyl), and -N(C1-C4alkyl)2is optionally substituted with 1 to 3 R9substituents; each R14is independently halogen, -OC1-C4alkyl, or C3-C6cycloalkyl; each R15is independently -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, or 4- to 6-membered heterocycloalkyl;

[0020] R4is C1-C6alkyl, C3-C8cycloalkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R9substituents, and C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10substituents, with the proviso that: (i) when Rais -OH, -NH2, each R10is independently C1-C4alkyl, halogen, -OC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1- C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens;

[0021] R2ais C1-C6alkyl, C3-C8cycloalkyl, or C6-C10aryl, wherein C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R9substituents, and C6-C10aryl is optionally substituted with 1 to 3 R10substituents;

[0022] R1aand R2bare independently -CN, C6-C10aryl, C1-C6alkyl, C3-C8cycloalkyl, -C(O)NH2, - C(O)NHR5, or -C(0)OC1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R16substituents and each C6-C10aryl is optionally substituted with 1 to 3 R17substituents; each R16is independently -OH, -C(O)NH2, -C(O)NH(C1-C4alkyl), C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), or -OC1-C4alkyl(OC1-C4alkyl), wherein each C3- C6cycloalkyl is optionally substituted with 1 to 3 R18substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R21substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl; each R17is independently halogen, C1-C6alkyl, -OC1-C6alkyl, or 5- to 10-membered heteroaryl, wherein each 5- to 10-membered heteroaryl is optionally substituted with C1-C4alkyl; each R18is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, or -OC1-C4alkyl; each R21is independently halogen or C1-C4alkyl; R4ais C1-C6alkyl or C3-C8cycloalkyl, wherein each C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R19substituents; each R19is independently halogen, -OH, -OC1-C4alkyl, -SC1-C4alkyl, -NH2, -NH(C1-C4alkyl), or - N(C1-C4alkyl)2;

[0023] R1band R2cform together with the carbon atom to which they are attached a C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R9substituents, and wherein 4- to 14-membered heterocycloalkyl, 8- to 14- membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group is optionally substituted with oxo (=0), oxime (=N-OH), C1-C3alkoxyoxime (=N- OC1-C3alkyl), or 1 to 3 substituents independently selected from -OH and -CF3;

[0024] R2dand R4bform together with the carbon atoms to which they are attached a C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R19substituents; and

[0025] R1cand R3form together with the carbon atoms to which they are attached a C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R19substituents.

[0026] In some embodiments, the pharmaceutical combination can comprise a compound of Formula (I) which is a compound of Formula (la), of Formula (la’), of Formula (lb), of Formula (lb’), of Formula (Ic), of Formula (lc’), of Formula (Id), of Formula (Id’), of Formula (le), of Formula (le’), of Formula (If), of Formula (If’), or of Formula (Ig), as described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0027] In some embodiments, the pharmaceutical combination can comprise a compound of Formula (I) which is a compound of Table 1 of the present description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0028] In some embodiments, the pharmaceutical combination is such that the COX inhibitor can comprise a Non-Steroidal Anti-Inflammatory Drug (NSAID). In some embodiments, the pharmaceutical combination is such that the COX inhibitor is acetaminophen.

[0029] In some embodiments, the pharmaceutical combination can be a synergistic pharmaceutical combination.

[0030] Another aspect relates to a pharmaceutical combination as defined herein, for use in the treatment of pain in a subject in need thereof. Similarly, this aspect relates to the use of a pharmaceutical combination as defined herein, for the treatment of pain in a subject in need thereof. Furthermore, this aspect relates to a method for the treatment of pain, comprising administering to a subject in need thereof a pharmaceutical combination as defined herein. 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 an oral treatment.

[0031] Another aspect relates to a method for the treatment of pain, comprising administering to a subject in need thereof a cyclooxygenase (COX) inhibitor and a compound having the Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein. In some embodiments, the COX inhibitor can comprise a Non-Steroidal 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 the pharmaceutically acceptable salt, solvate, or prodrug thereof are administered orally.

[0032] Another aspect relates to a kit comprising a first single dose form of a cyclooxygenase (COX) inhibitor and a second single dose form of a compound having the Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and instructions for use. In some embodiments, the kit can comprise a COX inhibitor which is a Non-Steroidal Anti-Inflammatory Drug (NSAID). In some embodiments, the COX inhibitor can 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 an oral treatment.

[0033] BRIEF DESCRIPTION OF THE FIGURES

[0034] Figure 1 shows: (A) the dose response curve of compound 61 , naproxen, and compound 61 :naproxen combination in the carrageenan-induced inflammation model. Analysis of carrageenan-treated rats using linear regression analysis reveals that the ED50 of the combination is 1.4 mg / kg, with 95% confidence limits (CL) of 1.0 and 2.0 mg / kg as compared to compound 61 or naproxen alone, which produces an ED50 of 6.7 and 8.1 mg / kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.83 (naproxen: compound 61). Non-linear regression analysis using the variable slope sigmoidal equation model. % anti-hyperalgesia = (PWL(dose)-PWL(vehicle)) I (PWL(naive)-PWL(vehicle)) X 100. Dotted lines represent 95% CL. (B) the isobologram of compound 61 to naproxen. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 61 and naproxen ED50 values) with its 95% CL never crossing the dotted line.

[0035] Figure 2 shows: (A) the dose response curve of compound 61 , naproxen, and compound 61 :naproxen combination in the carrageenan-induced inflammation model. Analysis of carrageenan-treated rats using linear regression analysis reveals that the ED50 of the combination is 1.8 mg / kg, with 95% confidence limits (CL) of 1.4 and 2.3 mg / kg as compared to compound 61 or naproxen alone, which produces an ED50 of 6.7 and 8.1 mg / kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.83 (naproxen: compound 61). Non-linear regression analysis using the variable slope sigmoidal equation model. % anti-hyperalgesia = (PWL(dose)-PWL(vehicle)) I (PWL(naive)-PWL(vehicle)) X 100. Dotted lines represent 95% CL. (B) the isobologram of compound 61 to naproxen. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 61 and naproxen ED50 values) with its 95% CL never crossing the dotted line.

[0036] Figure 3 shows: (A) the dose response curve of compound 61 , celecoxib, and compound 61 :celecoxib combination in the carrageenan-induced inflammation model. Analysis of carrageenan-treated rats using linear regression analysis reveals that the ED50 of the combination is 2.3 mg / kg, with 95% confidence limits (CL) of 1.5 and 2.9 mg / kg as compared to compound 61 or celecoxib alone, which produces an ED50 of 6.7 and 12.9 mg / kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.52 (celecoxib: compound 61). Non-linear regression analysis using the variable slope sigmoidal equation model. % anti-hyperalgesia = (PWL(dose)-PWL(vehicle)) I (PWL(naive)-PWL(vehicle)) X 100. Dotted lines represent 95% CL. (B) the isobologram of compound 61 to celecoxib. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 61 and celecoxib ED50 values) with its 95% CL never crossing the dotted line.

[0037] Figure 4 shows: (A) the dose response curve of compound 61 , ibuprofen, and compound 61 : ibuprofen combination in the carrageenan-induced inflammation model. Analysis of carrageenan- treated rats using linear regression analysis reveals that the ED50 of the combination is 2.1 mg / kg, with 95% confidence limits (CL) of 1.1 and 4.6 mg / kg as compared to compound 61 or ibuprofen alone, which produces an ED50 of 6.7 and 12.6 mg / kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.53 (ibuprofen: compound 61). Non-linear regression analysis using the variable slope sigmoidal equation model. % anti-hyperalgesia = (PWL(dose)-PWL(vehicle)) / (PWL(naive)-PWL(vehicle)) X 100. Dotted lines represent 95% CL. (B) the isobologram of compound 61 to ibuprofen. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 61 and ibuprofen ED50 values) with its 95% CL never crossing the dotted line.

[0038] Figure 5 shows: (A) the dose response curve of compound 61 , diclofenac, and compound 61 : diclofenac combination in the carrageenan-induced inflammation model. Analysis of carrageenan-treated rats using linear regression analysis reveals that the ED50 of the combination is 1.6 mg / kg, with 95% confidence limits (CL) of 0.9 and 2.8 mg / kg as compared to compound 61 or diclofenac alone, which produces an ED50 of 6.7 and 11 .7 mg / kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.57 (diclofenac: compound 61). Non-linear regression analysis using the variable slope sigmoidal equation model. % anti-hyperalgesia = (PWL(dose)-PWL(vehicle)) I (PWL(naive)-PWL(vehicle)) X 100. Dotted lines represent 95% CL. (B) the isobologram of compound 61 to diclofenac. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 61 and diclofenac ED50 values) with its 95% CL never crossing the dotted line.

[0039] Figure 6 shows: (A) the dose response curve of compound 63, naproxen, and compound 63:naproxen combination in the carrageenan-induced inflammation model. Analysis of carrageenan-treated rats using linear regression analysis reveals that the ED50 of the combination is 0.87 mg / kg, with 95% confidence limits (CL) of 0.4 and 2.0 mg / kg as compared to compound 63 or naproxen alone, which produces an ED50 of 1.4 and 8.1 mg / kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.178 (naproxen: compound 63). Non-linear regression analysis using the variable slope sigmoidal equation model. % anti-hyperalgesia = (PWL(dose)-PWL(vehicle)) I (PWL(naive)-PWL(vehicle))X 100. Dotted lines represent 95% CL. (B) the isobologram of compound 63 to naproxen. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 63 and naproxen ED50 values) with its 95% CL never crossing the dotted line.

[0040] DETAILED DESCRIPTION

[0041] General Definitions

[0042] All technical and scientific terms used herein have the same meaning as commonly understood by one ordinary skilled in the art to which the present technology pertains. For convenience, the meaning of certain terms and phrases used herein are provided below.

[0043] To the extent the definitions of terms in the publications, patents, and patent applications incorporated herein by reference are contrary to the definitions set forth in this specification, the definitions in this specification control. The section headings used herein are for organizational purposes only, and are not to be construed as limiting the subject matter disclosed. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It should be noted that, the singular forms "a", "an", and "the" include plural forms as well, unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing "a compound" also contemplates a mixture of two or more compounds. It should also be noted that the term "or" is generally employed in its sense including "and / or" unless the content clearly dictates otherwise. Furthermore, to the extent that the terms “including”, "includes", "having", "has", "with", or variants thereof are used in either the detailed description and / or the claims, such terms are intended to be inclusive in a manner similar to the term "comprising”.

[0044] The term "about" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, "about" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term "about" meaning within an acceptable error range for the particular value should be assumed.

[0045] Thiophene fused cyclohexanone derivative ASIC inhibitors

[0046] The present application relates to pharmaceutical combinations comprising thiophene fused cyclohexanone derivatives having ASIC inhibition properties, which are compounds of general Formula (I) or pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein Raand will be defined in further detail below.

[0047] The compounds described in the present application thus encompass those represented by the chemical structure of Formula I, with reference to any of the applicable embodiments described below, and exemplary compounds, such as Compounds 4, 8, 9, 14-39, 47-54, 59, 60a, 60b, 61- 72, 75, 81-84, 89, 91 , 97, 101 , 108, 109, 119-136, 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, 278-281 , 287, 288, 290, 291 , 297, 298, 305, 306, 313, 314, 321 , 322, 330, 331 , 337-349, 352-358, 360, 362, 371 , 378, 391-393, 394a, 394b, 395a, 395b, 396, 397, 401-403, 406-408, 412-414, 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 of Table 1 , as well as their pharmaceutically acceptable salts, solvates, and prodrugs when applicable.

[0048] Compounds may be identified either by their chemical structure or their chemical name. In a case where the chemical structure and chemical name would conflict, the chemical structure will prevail.

[0049] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present description. Unless otherwise stated, all tautomeric forms of the compounds are within the scope of the present description. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the present description. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present description.

[0050] Definitions of specific functional groups and chemical terms are provided below.

[0051] The chemical structures herein are drawn according to the conventional standards known in the art. Thus, where an atom, such as a carbon atom, as drawn appears to have an unsatisfied valency, then that valency is assumed to be satisfied by a hydrogen atom even though that hydrogen atom is not necessarily explicitly drawn. Hydrogen atoms should be inferred to be part of the compound.

[0052] The number of carbon atoms in a hydrocarbyl substituent can be indicated by the prefix "Cx-Cy," where x is the minimum and y is the maximum number of carbon atoms in the substituent. When reference is made to “x to y membered” heterocyclic group (e.g., heterocycloalkyl, partially unsaturated heterocyclic group, or heteroaryl), then x and y define respectively, the minimum and maximum number of atoms in the cyclic group, including carbons as well as heteroatom(s).

[0053] The term "halogen" as used herein refers to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0054] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, more particularly oxygen, sulfur, or nitrogen. The term "alkyl" as used herein, refers to a saturated, straight- (linear) or branched-chain hydrocarbon radical. In some embodiments, the alkyl group can contain from 1 to 6 carbon atoms, although alkyl groups with more than 6 carbon atoms can be contemplated. For example, "C1- C6alkyl" contains from one to six carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, te / Y-butyl, neopentyl, n- hexyl, heptyl, octyl radicals and the like.

[0055] The term "alkenyl" as used herein, denotes a straight- or branched-chain hydrocarbon radical containing one or more double bonds. In some embodiments, the alkenyl groups can contain from 2 to 6 carbon atoms, although alkenyl groups with more than 6 carbon atoms can be contemplated. For example, "C2-C6alkenyl" contains from two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, pentenyl, 1-methyl-2-buten- 1-yl, hexenyl, and the like.

[0056] The term "alkynyl" as used herein, denotes a straight- or branched-chain hydrocarbon radical containing one or more triple bonds. In some embodiments, the alkynyl groups can contain from 2 to 6 carbon atoms, although alkynyl groups with more than 6 carbon atoms can be contemplated. For example, "C2-C6alkynyl" contains from two to six carbon atoms. Alkynyl groups include, but are not limited to, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0057] The term “cycloalkyl”, used alone or as part of a larger moiety, refers to a group comprising a saturated carbocyclic ring in a monocyclic or polycyclic ring system, including spiro (sharing one atom), fused (sharing at least one bond) or bridged (sharing two or more bonds) carbocyclic ring systems, having from three to fifteen ring members. In some embodiments, the cycloalkyl groups can contain from 3 to 8 carbon atoms. For example, "C3-C8cycloalkyl" contains from three to eight carbon atoms in the cyclic ring. Examples of cycloalkyl groups can include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.2.0]octyl, norbornyl, and the like.

[0058] The term "aryl" used herein refers to a monocyclic moiety or to a bicyclic or tricyclic fused ring system wherein the ring system is carbocyclic and fully aromatic. In some embodiments, the aryl groups can contain from 6 to 14 carbon atoms, such as 6 to 10 carbon atoms for instance. For example, a "C6-C10aryl" group contains from six to ten carbon atoms in the aromatic system. In certain embodiments, "aryl" refers to an aromatic ring system which includes, without being limited to, phenyl, naphthyl, azulenyl, anthracyl, and the like.

[0059] As used herein, the term "heterocyclic group" refers to a chemically stable, saturated, partially unsaturated, or fully aromatic monocyclic or polycyclic ring system, including spiro (sharing one atom), fused (sharing at least one bond) or bridged (sharing two or more bonds) carbocyclic ring system, including at least one heteroatom as defined above. A heterocyclic group can be a heterocycloalkyl group, a heteroaryl group, or a partially unsaturated heterocyclic group, as defined herein.

[0060] The term "heterocycloalkyl" used alone or as part of a larger moiety, refers to a saturated cyclic group containing at least one heteroatom as defined herein, which can include a single ring, or two or more rings. In some embodiments, the heterocycloalkyl groups can include 3 to 14 ring atoms although heterocycloalkyl groups with more than 14 ring atoms can be contemplated. In some embodiments, the heterocycloalkyl groups can contain 4 to 14 ring atoms, or 4 to 6 ring atoms or 3 to 6 ring atoms for instance. For example, a "3- to 14-membered heterocycloalkyl group" contains from three to fourteen atoms, by counting the total number of carbon atoms and heteroatoms, in the saturated heterocyclic moiety. In some embodiments, the heterocycloalkyl group can contain from one to four heteroatoms. Heterocycloalkyl groups can include, without limitation, oxiranyl, aziridinyl, oxetanyl, tetrahydropyranyl (oxanyl), tetrahydrofuranyl (oxolanyl), pyrrolidinyl (azolidinyl), piperidinyl, dioxanyl, morpholinyl, thietanyl, azetidinyl, diazetidinyl, oxathiolanyl, oxepanyl, azocanyl (octahydroazocinyl), thiocanyl, azonanyl (octahydroazoninyl), 1 ,3-dioxolanyl, pyrazolidinyl, imidazolidinyl, piperazinyl, 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, and the like. A heterocycloalkyl can be attached to its pendant group at any heteroatom or carbon atom that results in a chemically stable structure.

[0061] The term "heteroaryl" used alone or as part of a larger moiety, refers to a fully aromatic cyclic group containing at least one heteroatom as defined herein, which can include a single ring, or two or more fused rings. In some embodiments, the heteroaryl groups can include from 5 to 10 ring atoms although heteroaryl groups with more than 10 ring atoms can be contemplated. In some embodiments, the heteroaryl group can contain from one to four heteroatoms. Heteroaryl groups can include, without limitation, 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, furopyridinyl, indolyl, indazolyl, isoindolyl, indolizinyl, purinyl, quinolyl (quinolinyl), isoquinolyl (isoquinolinyl), acridinyl, cinnolinyl, quinazolinyl, naphthyridinyl, carbazolyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and pteridinyl. A heteroaryl group can be attached to its pendant group at any heteroatom or carbon atom that results in a chemically stable structure.

[0062] As used herein, the term "partially unsaturated heterocyclic group" refers to a carbocyclic ring system including at least one double bond between ring atoms but is not fully aromatic and comprises at least one heteroatom. The "partially unsaturated heterocyclic group" is intended to encompass ring systems, which can be mono, bi or tricyclic and having one or multiple sites of unsaturation. In some embodiments, the partially unsaturated heterocyclic group can include a multicyclic ring system where at least one ring is aromatic while at least another ring is not aromatic. For instance, the partially unsaturated heterocyclic group can include an aryl fused with a heterocycloalkyl, a heteroaryl fused with a cycloalkyl, or a heteroaryl fused with a heterocycloalkyl, where each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl can itself be monocyclic or bicyclic. In some embodiments, the partially unsaturated heterocyclic groups can contain from 7 to 14 carbon atoms, such as 7 to 10 carbon atoms or 8 to 14 carbon atoms for instance. For example, a "7- to 10-membered partially unsaturated heterocyclic group" contains from seven to ten atoms, by counting the total number of carbon atoms and heteroatoms, in the heterocyclic moiety. The partially unsaturated heterocyclic group can contain, in some embodiments, from one to four heteroatoms. The partially unsaturated heterocyclic group can be attached to its pendant group at any heteroatom or carbon atom that results in a chemically stable structure. Non-limiting examples of partially unsaturated heterocyclic group include pyrazolinyl, imidazolinyl, 1 , 2,3,6- tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 1 ,3- benzodioxolyl, chromanyl, chromenyl, indolinyl, quinolonyl, isoquinolonyl, oxazepinyl, diazepinyl, thiazepinyl, phthalazinyl, quinoxalinyl, pyrido[2,3-b]-l,4-oxazin-3(4H)-one, . When used in reference to a ring atom of a heterocyclic group, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR0(as in N- substituted pyrrolidinyl).

[0063] As used herein, the term "partially unsaturated carbocyclic group" refers to a carbocyclic ring system including at least one double bond between ring atoms but is not fully aromatic. The "partially unsaturated carbocyclic group" is intended to encompass ring systems, which comprise only carbon atoms within the ring, said ring being mono, bi or tricyclic and having one or multiple sites of unsaturation. In some embodiments, the partially unsaturated carbocyclic group can include a multicyclic ring system where at least one ring is aromatic while at least another ring is not aromatic. For instance, the partially unsaturated heterocyclic group can include an aryl fused with a cycloalkyl, where each of the aryl and cycloalkyl can itself be monocyclic or bicyclic. In some embodiments, the partially unsaturated carbocyclic groups can contain from 7 to 14 carbon atoms, such as 7 to 10 carbon atoms or 8 to 14 carbon atoms for instance. For example, a "8- to 14-membered partially unsaturated carbocyclic group" contains from eight to fourteen carbon atoms in the cyclic moiety. The partially unsaturated carbocyclic group can be attached to its pendant group at any carbon atom that results in a chemically stable structure. A non-limiting example of partially unsaturated carbocyclic group includes

[0064] As described herein, various chemical groups present in the compounds of the present description, such as any of the above-defined groups, can be optionally substituted. In general, the term "substituted" means that one or more hydrogen atoms of the designated moiety is replaced with a suitable substituent. Unless otherwise indicated, a substituted chemical group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Combinations of substituents envisioned under the present description are preferably those that result in the formation of chemically stable or chemically feasible compounds. The term "chemically stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0065] In some particular embodiments, when any chemical group is substituted, it can be substituted by independent replacement of one, two, orthree or more of the hydrogen atoms with substituents including, but not limited to halogen (i.e., -F, -Cl, -Br,-I), -OH, -CO2H, alkoxy such as methoxy, ethoxy, or propyloxy, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCH2CH2OCH3, protected alkoxy, 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 (=0), thioxo (=s), oxime (=N-OH), C1-C3alkoxyoxime (=N-OC1-C3alkyl),-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(fBu), -SMe, -SO2NH(CH2)3OH, -SO2Me, -SO2Ph, -SPh, pyrazolyl, pyrrolyl, pyridyl, piperidinyl, triazolyl, tetrazolyl, morpholinyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, benzothiazolyl, benzimidazolyl,

[0066]

[0067] The expression "pharmaceutically acceptable salt" refers to those salts of the compounds of the present description which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the present description, or separately by reacting a free base function of the compound with a suitable organic or inorganic acid (acid addition salts) or by reacting an acidic function of the compound with a suitable organic or inorganic base (base-addition salts). Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, or salts of an amino group formed 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, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, 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, valerate salts, and the like. Representative base addition alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, or magnesium salts, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, sulfonate and aryl sulfonate.

[0068] The term “solvate” refers to a physical association of one of the present compounds with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include, without limitation, hydrates, hemihydrates, ethanolates, hemiethanolates, n-propanolates, iso-propanolates, 1 -butanolates, 2- butanolate, and solvates of other physiologically acceptable solvents. The compounds as herein described also include each of their solvates and mixtures thereof.

[0069] The term " prodrug" as used herein refers to those prodrugs of the compounds of the present description which are suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use. "Prodrug", as used herein means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to afford any compound delineated by the formulae of the instant description. Various forms of prodrugs are known in the art.

[0070] The compounds of the present application may be prepared by conventional chemical synthesis, such as exemplified in the general schemes provided hereafter and in Examples 1 to 260 for instance. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. In addition, the solvents, temperatures, reaction duration, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired products of the present description. Synthetic chemistry transformations and / or protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art. The synthesized compounds can be separated from a reaction mixture and further purified by standard methods such as column chromatography, high pressure liquid chromatography, or recrystallization.

[0071] The thiophene fused cyclohexanone derivatives such as the compounds of Formula (I) may be modified by appending various functionalities via any synthetic means delineated herein to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

[0072] In some embodiments, the thiophene fused cyclohexanone derivative can thus be a compound having the Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

[0073] Rais -NH2, -NH-OH, -OH, -NHRb, or -NHRcRd;

[0074] Rbis C1-C6alkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C1-C6alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -OC1-C3alkyl, -COOH, or cyclopropyl optionally substituted with -OH, and wherein C3-C6cycloalkyl is optionally substituted with -ON;

[0075] Rcand Rdform with the nitrogen to which they are attached a 4-membered heterocycloalkyl, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C1-C3alkyl; represents one of the following residues Aoto A12 and wherein:

[0076] R is H, C1-C6alkyl or phenyl;

[0077] R1and R2are independently -ON, C6-C10aryl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, - C(O)NHR5, -C(O)R6, or -C(0)OR5, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22substituents, with the proviso that when Rais -OH, represents Ao, and R1is then R2in residue Aois different than ; each R5is independently C1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R9substituents; each R6is independently C3-C6cycloalkyl, 4- to 6-membered heterocycloalkyl, or C6-C10aryl; each R7is independently -OH, -C(O)R11, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), 4- to 6- membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OR20, -SC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R8is independently halogen, C1-C6alkyl, -OC1-C6alkyl, C3-C6cycloakyl, or 5- to 10- membered heteroaryl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with C1-C4alkyl; each R22is independently C1-C6alkyl optionally substituted with phenyl; each R9is independently -OH, -C(O)R15, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OC1-C6alkyl, -SC1-C6alkyl, -NH2, -NH(C1- C4alkyl), or -N(C1-C4alkyl)2, wherein each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl, and each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R11is independently -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, or 4- to 6-membered heterocycloalkyl; each R20is independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R14substituents and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, -OC1-C4alkyl, or -SPh, wherein each C1- C4alkyl is optionally substituted with -OH; each R13is independently halogen, C1-C4alkyl, C3-C6cycloalkyl, -OH, -OC1-C6alkyl, -SC1-C6alkyl, -S(O)2C1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each -OC1-C6alkyl, -SC1- C6alkyl, -S(O)2C1-C6alkyl, -NH(C1-C4alkyl), and -N(C1-C4alkyl)2is optionally substituted with 1 to 3 R9substituents; each R14is independently halogen, -OC1-C4alkyl, or C3-Cecycloalkyl; each R15is independently -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, or 4- to 6-membered heterocycloalkyl;

[0078] R4is C1-C6alkyl, C3-C6cycloalkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R9substituents, and C8-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10substituents, with the proviso that: (i) when Rais -OH, -NH2, represents A2, then R4in residue A2is different than -CH3; and (ii) when Rais -NH2and C A

[0079] — - represents A3, then R4in residue A3is different than -C(CH3)3; each R10is independently C1-C4alkyl, halogen, -OC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1- C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens;

[0080] R2ais C1-C6alkyl, C3-C8cycloalkyl, or C6-C10aryl, wherein C1-C8alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R9substituents, and C6-C10aryl is optionally substituted with 1 to 3 R10substituents;

[0081] R1aand R2bare independently -CN, C6-C10aryl, C1-C6alkyl, C3-C8cycloalkyl, -C(O)NH2, - C(O)NHR5, or -C(0)OC1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R16substituents and each C6-C10aryl is optionally substituted with 1 to 3 R17substituents; each R16is independently -OH, -C(O)NH2, -C(O)NH(C1-C4alkyl), C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), or -OC1-C4alkyl(OC1-C4alkyl), wherein each C3- C6cycloalkyl is optionally substituted with 1 to 3 R18substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R21substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl; each R17is independently halogen, C1-C6alkyl, -OC1-C6alkyl, or 5- to 10-membered heteroaryl, wherein each 5- to 10-membered heteroaryl is optionally substituted with C1-C4alkyl; each R18is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, or -OC1-C4alkyl; each R21is independently halogen or C1-C4alkyl;

[0082] R4ais C1-C6alkyl or C3-C8cycloalkyl, wherein each C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R19substituents; each R19is independently halogen, -OH, -OC1-C4alkyl, -SC1-C4alkyl, -NH2, -NH(C1-C4alkyl), or - N(C1-C4alkyl)2;

[0083] R1band R2cform together with the carbon atom to which they are attached a C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R9substituents, and wherein 4- to 14-membered heterocycloalkyl, 8- to 14- membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group is optionally substituted with oxo (=0), oxime (=N-OH), C1-C3alkoxyoxime (=N- OC1-C3alkyl), or 1 to 3 substituents independently selected from -OH and -CF3;

[0084] R2dand R4bform together with the carbon atoms to which they are attached a C3-C3cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R19substituents; and

[0085] R1cand R3form together with the carbon atoms to which they are attached a C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R19substituents.

[0086] In some embodiments, the compound of Formula (I) is such that: (i) when Rais -OH, represents Ao, and R1is , then R2in residue Aois different than (ii) when

[0087] Rais -OH and represents A2, then R4in residue A2is different than -CH3and -CH2CH3; (iii) when Rais -NH2, and represents A2, then R4in residue A2is different than -CH3; and (iv) when Rais -NH2and represents A3, then R4in residue A3is different than -C(CH3)3.

[0088] In some embodiments, the compound of Formula (I) is such that: (i) when Rais -OH, represents Ao, and R1is , then R2in residue Aois different than O ; (ii) when

[0089] Rais -OH and represents A2, then R4in residue A2is different than -CH3and -CH2CH3; (iii) when Rais -NH2, and represents A2, then R4in residue A2is different than -CH3;

[0090] (iv) when Rais represents A2, then R4in residue A2is different than -CH3; and (v) when Rais -NH2and represents A3, then R4in residue A3is different than -C(CH3)3.

[0091] In other embodiments, the compound of Formula (I) is such that: (i) when Rais -OH, represents Ao, and R1is then R2in residue Aois different than (ii) when

[0092] Rais -OH and < represents A2, then R4in residue A2is different than alkyl; (iii) when Rais -

[0093] NH2, and represents A2, then R4in residue A2is different than -CH3; and (iv) when Rais -

[0094] NH2and represents A3, then R4in residue A3is different than -C(CH3)3. In other embodiments, the compound of Formula (I) is such that: (i) when Rais -OH, represents Ao, and R1is then R2in residue Aois different than ; (jj) when Rais -OH and represents A2, then R4in residue A2is different than alkyl; (iii) when Rais - NH2, and represents A2, then R4in residue A2is different than -CH3; (iv) when Rais and represents A2, then R4in residue A2is different than -CH3; and (v) when

[0095] Rais -NH2and represents A3, then R4in residue A3is different than -C(CH3)3.

[0096] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is such that R is H.

[0097] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is such that Rais -NHRband Rbrepresents C1-C6alkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C1-C6alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -OC1-C3alkyl , -COOH , or cyclopropyl optionally substituted with - OH, and wherein C3-C6cycloalkyl is optionally substituted with -ON.

[0098] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is such that Rais -NHRband Rbrepresents:

[0099] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is such that Rais -NHRband Rbrepresents -CH3

[0100] In some embodiments, Rais -NHRband Rbrepresents In other embodiments, Rais -NRcRdand Rcand Rdform with the nitrogen to which they are attached a 4-membered heterocycloalkyl, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C1-C3alkyl.

[0101] In other embodiments, Rais

[0102] In other embodiments, Rais

[0103] In other embodiments, Rais -OH.

[0104] In other embodiments, Rais -NH2.

[0105] In other embodiments, Rais -NH-OH.

[0106] In some embodiments, the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be in the form of a racemate or any enantiomer thereof.

[0107] In some embodiments, the compound of Formula (I) can have the following structures (la), (la’), (lb), (lb’), (Ic), (lc’), (Id), (Id’), (le), (le’), (If), (If’), or (lg): where R1, R2, R3, R4, R1a, R1b, R1c, R2a, R2b, R2c, R2d, R4a, R4b, R and Raare as defined herein.

[0108] Compounds of Formula (la) and (la”)

[0109] In some embodiments, the compound is of Formula (la) or (la’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0110] The groups R, Ra, R1and R2can be as defined for the general Formula (I) above.

[0111] In some embodiments, the compound is of Formula (la), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0112] The groups Ra, R1and R2can be as defined for the general Formula (I) above.

[0113] In some embodiments, R1and R2can independently represent -CN, C6-C10aryl, C1-C6alkyl, C2- C6alkynyl, C3-C8cycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHR5, -C(O)R6, or - C(O)OR5, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22substituents, and R5, R6, R7, R8and R22are as defined herein.

[0114] In some embodiments, R1and R2are independently -CN, C6-C10aryl, C1-C6alkyl, C2-C6alkynyl, C3- C8cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22substituents, and R7, R8and R22are as defined herein.

[0115] In further embodiments, R1and R2can independently represent -CN, phenyl, C1-C4alkyl, C2- C4alkynyl, C3-C6cycloalkyl, 5-membered heteroaryl, or -C(O)NH2, wherein each C1-C4alkyl is optionally substituted with 1 or 2 R7substituents, each phenyl is optionally substituted with 1 or 2 halogens, and each 5-membered heteroaryl is optionally substituted with 1 or 2 -CH3.

[0116] According to some embodiments, R1and R2independently represent -CN, C6-C10aryl, C1-C6alkyl, C3-C8cycloalkyl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 2 R7substituents as defined herein.

[0117] In some embodiments, when R1and / or R2represent -C(O)NHR5or -C(O)OR5, each R5can be C1-C6alkyl. In other embodiments, when R1and / or R2represent -C(O)R6each R6can be a 4- to 6-membered heterocycloalkyl.

[0118] In some embodiments, when R1and / or R2represent C1-C6alkyl substituted with 1 to 3 R7substituents, then each R7can independently represent -OH, -C(O)R11, C3-C6cycloalkyl, -CN, C6- C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1- C4alkyl)(C(O)OC1-C6alkyl), -NH(C(O)C1-C6alkyl), 4- to 6-membered heterocycloalkyl, -OR20, -SC-1-C6alkyl, -NH2, or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13substituents and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo.

[0119] In some embodiments, R7can independently represent -OH, -C(O)R11, -OR20, C3-C6cycloalkyl, - CN, C6-C10aryl, halogen, -C(O)OH, or 5- to 10-membered heteroaryl, wherein each C3- C6cycloalkyl is optionally substituted with 1 to 3 R12substituents and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13substituents.

[0120] In further embodiments, R7can independently represent -OH, -C(O)NH2, -OR20, C3-C6cycloalkyl, -CN, phenyl, halogen, -C(O)OH, or 5-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with -CH3.

[0121] In another embodiment, R7can independently represent -OH, -C(O)NH2, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 2 C1-C4alkyl, and each 5- to 8-membered heteroaryl is optionally substituted with 1 to 2 R13substituents.

[0122] In some embodiments, the R11substituents mentioned above can independently represent -NH2, -NH(C1-C4alkyl), or 4- to 6-membered heterocycloalkyl. In some particular embodiments, R11can represent -NH2. In some embodiments, the R12substituents mentioned above can independently represent C1-C4alkyl, -SC1-C4alkyl, -Ph, -OC1-C4alkyl, or -SPh, wherein each C1-C4alkyl is optionally substituted with -OH. In some particular embodiments, R12is C1-C4alkyl.

[0123] In some embodiments, the R13substituents mentioned above can independently represent halogen, C1-C4alkyl, or C3-C6cycloalkyl. In some particular embodiments, R13is independently halogen or C1-C4alkyl.

[0124] In some embodiments, the R14substituents mentioned above can independently represent halogen, -OC1-C4alkyl, or C3-C6cycloalkyl. In some particular embodiments, R14is halogen.

[0125] In some embodiments, the R20substituents mentioned above can independently represent C1- C6alkyl or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R14substituents as defined herein, and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl). In some particular embodiments, R20is C1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R14substituents as defined herein. In further embodiments, R20is C1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 halogens. In some embodiments, R20is 5- to 10-membered heteroaryl substituted with -OH or -NH(cyclopropyl). In certain embodiments, R20is 5- to 10-membered heteroaryl substituted with - OH. In other embodiments, R20is 5- or 6-membered heteroaryl substituted with -OH.

[0126] In some embodiments, the R22substituents mentioned above can independently represent C1- C4alkyl.

[0127] In some embodiments, when R1and / or R2represent C6-C10aryl substituted with 1 to 3 R8substituents, then each R8can independently represent halogen, C1-C6alkyl, or -OC1-C6alkyl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl. In some particular embodiments, R8is a halogen. In some embodiments, when R1and / or R2represent 5- to 10- membered heteroaryl substituted with 1 to 3 R22substituents, then each R22can independently represent C1-C6alkyl optionally substituted with phenyl. In some embodiments, R22is C1-C2alkyl substituted with phenyl.

[0128] In some embodiments, R1and R2are independently -CN, C6-C10aryl, C1-C6alkyl, C2-Cealkynyl, C3- C8cycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHR5, -C(O)R6, or -C(O)OR5, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22substituents, and each R5is independently C1-C6alkyl; each R6is independently a 4- to 6-membered heterocycloalkyl; each R7is independently -OH, -C(O)R11, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OR20, -SC1-C6alkyl, -NH2, or -N(C1- C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R8is independently halogen, C1-C6alkyl, or -OC1-C6alkyl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R22is independently C1-C6alkyl optionally substituted with phenyl; each R11is independently -NH2, -NH(C1-C4alkyl), or 4- to 6-membered heterocycloalkyl; each R20is independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1- C6alkyl is optionally substituted with 1 to 3 R14substituents and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, -OC1-C4alkyl, or -SPh, wherein each C1-C4alkyl is optionally substituted with -OH; each R13is independently halogen, C1-C4alkyl, or C3-C6cycloalkyl; and each R14is independently halogen, -OC1-C4alkyl, or C3-C6cycloalkyl.

[0129] In some embodiments, R1and R2are independently -ON, C6-C10aryl, C1-C6alkyl, C2-C6alkynyl, C3- C8cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22substituents, and each R7is independently -OH, -C(O)R11, C3-C6cycloalkyl, -ON, C6-C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), - NH(C(O)C1-C6alkyl), 4- to 6-membered heterocycloalkyl, -OR20, -SC1-C6alkyl, -NH2, or -N(C1- C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R8is independently halogen, C1-C6alkyl, or -OC1-C6alkyl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R11is independently -NH2, -NH(C1-C4alkyl), or 4- to 6-membered heterocycloalkyl; each R20is independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1- Cealkyl is optionally substituted with 1 to 3 R14substituents and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, -OC1-C4alkyl, or -SPh, wherein each C1-C4alkyl is optionally substituted with -OH; each R13is independently halogen, C1-C4alkyl, or C3-C6cycloalkyl; each R14is independently halogen, -OC1-C4alkyl, or C3-C6cycloalkyl; and each R22is independently C1-C4alkyl. In some embodiments, R1and R2are independently -CN, C6-C10aryl, C1-C6alkyl, C2-C6alkynyl, C3- Cscycloalkyl, 5- to 10-membered heteroaryl, or -C(0)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22substituents, and each R7is independently -OH, -C(O)R11, -OR20, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, - C(O)OH, or 5- to 10-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12substituents and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13substituents; each R8is a halogen; each R11is -NH2; each R20is C1-C6alkyl or 5- or 6-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R14substituents and each 5- or 6-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12is C1-C4alkyl; each R13is independently halogen or C1-C4alkyl; each R14is halogen; and each R22is independently C1-C4alkyl.

[0130] In some embodiments, R1and R2independently represent -CN, phenyl, C1-C4alkyl, C2-C4alkynyl, C3-C6cycloalkyl, 5-membered heteroaryl, or -C(O)NH2, wherein each C1-C4alkyl is optionally substituted with 1 or 2 R7substituents, each phenyl is optionally substituted with 1 or 2 halogens, and each 5-membered heteroaryl is optionally substituted with 1 or 2 -CH3, and each R7is independently -OH, -C(O)NH2, -OR20, C3-C6cycloalkyl, -CN, phenyl, halogen, - C(O)OH, or 5-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with -CH3; and each R20is C1-C6alkyl or 5- or 6-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 halogen and each 5- or 6-membered heteroaryl is optionally substituted with -OH.

[0131] In some embodiments, R1and R2independently represent -CN, C6-C10aryl, C1-C6alkyl, C3- C8cycloalkyl, 5-membered heteroaryl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 2 R7substituents; each R7is independently -OH, -C(O)NH2, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 2 C1- C4alkyl, and each 5- to 8-membered heteroaryl is optionally substituted with 1 to 2 R13substituents; and each R13is independently halogen or C1-C4alkyl. In some embodiments, R1and R2, which can be identical or different, can represent:

[0132] In some embodiments, R1and R2, which can be identical or different, can represent:

[0133]

[0134] In some embodiments, R1and R2, which can be identical or different, can represent:

[0135]

[0136] 10 In some embodiments, R1and R2, which can be identical or different, can represent:

[0137]

[0138] In some embodiments, R1and R2, which can be identical or different, can represent:

[0139] In some embodiments, R1and R2, which can be identical or different, can represent:

[0140] In some embodiments, R1and R2, which can be identical or different, can represent:

[0141]

[0142] In some embodiments, R1and R2, which can be identical or different, can represent:

[0143] In some embodiments, R1and R2, which can be identical or different, can represent:

[0144] In some embodiments, R1and R2, which can be identical or different, can represent:

[0145] In some embodiments, R1and R2, which can be identical or different, can represent:

[0146] In some particular embodiments, R1and R2are different. In another particular embodiment, one of R1and R2is -CN. Other embodiments include compounds of Formula (la) or (la’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, where one of R1and R2is of Formula

[0147] In some embodiments, the compound is of Formula (lb) or (lb’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0148] (lb) (lb’)

[0149] The groups R, Ra, and R4can be as defined for the general Formula (I) above.

[0150] In some embodiments, the compound is of Formula (lb), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0151] The groups Raand R4can be as defined for the general Formula (I) above.

[0152] In some embodiments, R4can represent C1-C6alkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C1-C6alkyl is optionally substituted with 1 to 3 R9substituents, and C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10substituents, and wherein R9and R10are as defined herein.

[0153] In some embodiments, R4can represent C1-C6alkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10substituents, and wherein the R10substituents are as defined herein.

[0154] In some embodiments, R4can represent C1-C4alkyl, phenyl, 9-membered partially unsaturated heterocyclic group, or 5- to 6-membered heteroaryl, wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with 1 or 2 R10substituents, and wherein the R10substituents are as defined herein.

[0155] In some embodiments, the R10substituents can independently represent C1-C4alkyl, halogen, - O C1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens.

[0156] In other embodiments, the R10substituents can independently represent C1-C4alkyl, halogen, - OC1-C6alkyl, or -N(C1-C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens.

[0157] In further embodiments, the R10substituents can independently represent -CF3, halogen, -OCH3, or -N(CH3)2.

[0158] In some embodiments, R4is C1-C6alkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10substituents, and each R10is independently C1-C4alkyl, halogen, -OC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1- C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens.

[0159] In some embodiments, R4is C1-C6alkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10substituents, and each R10is independently C1-C4alkyl, halogen, -OC1-C6alkyl, or -N(C1-C4alkyl)2, wherein each C1- C4alkyl is optionally substituted with 1 to 3 halogens.

[0160] In some embodiments, R4is C1-C4alkyl, phenyl, 9-membered partially unsaturated heterocyclic group, or 5- to 6-membered heteroaryl, wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with 1 or 2 R10substituents, and each R10is independently -CF3, halogen, -OCH3, or -N(CH3)2.

[0161] Examples of particular R4groups can include:

[0162]

[0163] Compounds of Formula (Ic) and (Ic’) In some embodiments, the compound is of Formula (Ic) or (lc’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0164] (Ic) (lc’)

[0165] The groups R, Raand R2acan be as defined for the general Formula (I) above. In some embodiments, the compound is of Formula (Ic), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0166] The groups Raand R2acan be as defined for the general Formula (I) above. In some embodiments, R2acan represent C1-C6alkyl orC6-C10aryl, wherein C1-C6alkyl is optionally substituted with 1 to 3 R9substituents and C6-C10aryl is optionally substituted with 1 to 3 R10substituents, and R9and R10are as defined herein.

[0167] In some embodiments, R2acan represent C1-C6alkyl orC6-C10aryl, wherein C1-C6alkyl is optionally substituted with 1 to 3 halogens. In some embodiments, R2ais C1-C6alkyl, such as C1-C4alkyl or preferably ethyl.

[0168] Compounds of Formula (Id) and (Id”)

[0169] In some embodiments, the compound is of Formula (Id) or (Id’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0170] The groups R, Ra, R1a, R2b, and R4acan be as defined for the general Formula (I) above.

[0171] In some embodiments, the compound is of Formula (Id), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0172] The groups Ra, R1a, R2b, and R4acan be as defined for the general Formula (I) above.

[0173] In some embodiments, R1aand R2bcan independently represent -CN, C6-C10aryl, C1-C6alkyl, C3- C8cycloalkyl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 2 R16substituents as defined herein.

[0174] In some embodiments, R1aand R2bcan independently represent -CN or C6-C10aryl.

[0175] In some embodiments, R4acan represent C1-C6alkyl.

[0176] In some embodiments, the substituents R16can independently represent -OH, -C(O)NH2, C3- C6cycloalkyl, -CN, C6-C10aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C3- C6cycloalkyl is optionally substituted with 1 to 2 C1-C4alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 R21substituents as defined herein.

[0177] In some embodiments, each R21can represent independently halogen or C1-C4alkyl.

[0178] In some embodiments, R1aand R2bare independently -CN, C6-C10aryl, C1-C6alkyl, C3- C8cycloalkyl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 2 R16substituents; each R16is independently -OH, -C(O)NH2, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, or 5- to 8- membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 2 C1- C4alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 R21substituents; and each R21is independently halogen or C1-C4alkyl.

[0179] Compounds of Formula (le) and de”)

[0180] In some embodiments, the compound is of Formula (le) or (le’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0181] The groups R, Ra, R1 b, and R2ccan be as defined for the general Formula (I) above.

[0182] In some embodiments, the compound is of Formula (le), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0183] The groups Ra, R1 b, and R2ccan be as defined for the general Formula (I) above.

[0184] In some embodiments, R1band R2ccan form together with the carbon atom to which they are attached a C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group, wherein each 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group is optionally substituted with oxo (=0), oxime (=N-OH), C1-C3alkoxyoxime (=N-OC1-C3alkyl), or 1 to 3 substituents independently selected from -OH and -CF3.

[0185] In some embodiments, R1band R2ccan form together with the carbon atom to which they are attached a C3-C8cycloalkyl or a 8- to 10-membered partially unsaturated carbocyclic group, wherein 8- to 10-membered partially unsaturated carbocyclic group is optionally substituted with oxo (=0), oxime (=N-OH), methoxyoxime (=N-OCH3), or 1 to 2 substituents independently selected from -OH and -CF3.

[0186] In some embodiments, R1band R2ccan form together with the carbon atom to which they are attached a C4-C6cycloalkyl, or a group selected from wherein the dashed lines represent the portion of the cyclohexanone moiety of the compound of formula (le) or (le’) bearing R1band R2c

[0187] In some embodiments, R1band R2cform together with the carbon atom to which they are attached a cyclopentyl, or a group selected from wherein the dashed lines represent the portion of the cyclohexanone moiety of the compound of formula (le) or (le’) bearing R1band R2c.

[0188] In some embodiments, R1band R2ccan form together with the carbon atom to which they are attached a group selected from , wherein the dashed lines represent the portion of the cyclohexanone moiety of the compound of formula (le) or (le’) bearing R1band R2c.

[0189] In some embodiments, R1band R2ccan form together with the carbon atom to which they are attached a cyclopentyl.

[0190] Compounds of Formula (If) and (If’)

[0191] In some embodiments, the compound is of (If) or (If’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0192] The groups R, Ra, R2d, and R4bcan be as defined for the general Formula (I) above.

[0193] In some embodiments, the compound is of Formula (If), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0194] The groups Ra, R2d, and R4bcan be as defined for the general Formula (I) above.

[0195] In some embodiments, R2dand R4bcan form together with the carbon atoms to which they are attached a C3-C8cycloalkyl, wherein each C3-C8cycloalkyl is optionally substituted with 1 to 3 R19substituents as defined herein.

[0196] In some embodiments, R2dand R4bcan form together with the carbon atoms to which they are attached a C3-C8cycloalkyl.

[0197] In some embodiments, R2dand R4bcan form together with the carbon atoms to which they are attached a cyclohexyl.

[0198] Compound of Formula (Iq)

[0199] In some embodiments, the compound is of Formula (Ig), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0200] The groups Ra, R1cand R3can be as defined for the general Formula (I) above.

[0201] In some embodiments, R1cand R3can form together with the carbon atoms to which they are attached a C3-C8cycloalkyl, wherein each C3-C8cycloalkyl is optionally substituted with 1 to 3 R19substituents as defined herein.

[0202] In some embodiments, R1cand R3can form together with the carbon atoms to which they are attached a C3-C8cycloalkyl.

[0203] In some embodiments, R1cand R3can form together with the carbon atoms to which they are attached a cyclohexyl.

[0204] In some embodiments, the compound of Formula (I) as described herein can be selected from Compound 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, 129, 130, 131 , 132, 133, 134, 135, 136, 138, 139, 140, 141 , 142, 143, 144, 145,

[0205] 146, 147, 148, 149, 150, 154, 155, 163, 168, 169, 170, 173, 174, 175, 178, 179, 180, 181 , 183,

[0206] 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,

[0207] 254, 255, 257, 258, 263, 264, 271 , 272, 273, 278, 279, 280, 281 , 287, 288, 290, 291 , 297, 298,

[0208] 305, 306, 313, 314, 321 , 322, 330, 331 , 337, 338, 339, 340, 341 , 342, 343, 344, 345, 346, 347,

[0209] 348, 349, 352, 353, 354, 355, 356, 357, 358, 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, 483, 486, 488, 489, 492, 495, 496, 497, 498, 511 , 512, 513, 514, 515, 520, 523, 524, and 534 of Table 1 below, or can be any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0210] Table 1

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218] In some embodiments, the compound of Formula (I) as described herein is Compound 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, 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,

[0219] 133, 134, 135, 136, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163,

[0220] 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 189, 191, 192, 193, 194, 195, 197, 198, 199,

[0221] 200, 201, 202, 211, 212, 213, 214, 215, 216, 219, 221, 228, 229, 230, 231, 232, 237, 238, 239,

[0222] 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 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0223] In some embodiments, the compound of Formula (I) as described herein is Compound 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,

[0224] 170, 173, 174, 175, 179, 180, 181, 183, 189, 191, 192, 193, 194, 195, 198, 199, 200, 201, 202,

[0225] 211, 212, 213, 214, 215, 216, 219, 228, 230, 231, 232, 237, 238, 239, 246, 247, 248, 249, 250,

[0226] 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 291, 297, 298,

[0227] 305, 306, 313, 314, 321, 322, 331, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348,

[0228] 349, 352, 353, 354, 355, 356, 357 or 358 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0229] In some embodiments, the compound of Formula (I) as described herein is Compound 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,

[0230] 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181,

[0231] 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,

[0232] 280, 281, 287, 288, 291, 297, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342,

[0233] 343, 344, 345, 346, 347, 348, 352, 353, 354, 355, 356, 357, or 358 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0234] In some embodiments, the compound of Formula (I) as described herein is Compound 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,

[0235] 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181,

[0236] 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, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278,

[0237] 279, 280, 281, 287, 288, 291, 297, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341,

[0238] 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, 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 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0239] In some embodiments, the compound of Formula (I) as described herein is Compound 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,

[0240] 62, 63, 64, 65, 66, 67, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123,

[0241] 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147,

[0242] 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 191, 192, 194, 195,

[0243] 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,

[0244] 355, 356, 357, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403, 406, 407,

[0245] 408, 413, 414, 416, 418, 422, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 453,

[0246] 454, 462, 463, 464, 465, 466, 468, 470, 472, 474, 475, 476, 479, 480, 481, 482, 486, 489, 495,

[0247] 496, 498, 511, 512, 513, 514, 515, 520, or 524 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0248] In some embodiments, the compound of Formula (I) as described herein is Compound 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, 273, 278, 279, 280, 281,

[0249] 288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 346,

[0250] 352, 353, 354, 355, 356, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403,

[0251] 406, 407, 408, 413, 414, 416, 418, 422, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450,

[0252] 451, 453, 454, 462, 463, 464, 465, 466, 468, 470, 472, 474, 475, 476, 479, 480, 481, 482, 486,

[0253] 489, 495, 496, 498, 511, 512, 513, 514, 515, 520, or 524 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0254] In some embodiments, the compound of Formula (I) as described herein is Compound 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,

[0255] 174, 175, 179, 180, 181, 183, 191, 192, 194, 195, 201, 212, 213, 214, 215, 216, 230, 231, 232,

[0256] 238, 239, 245, 246, 248, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280,

[0257] 281, 288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345,

[0258] 346, 352, 353, 354, 355, 356, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403,

[0259] 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 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0260] In some embodiments, the compound of Formula (I) as described herein is Compound 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, 145, 146, 147, 148,

[0261] 149, 150, 163, 169, 170, 174, 179, 181 , 183, 191 , 192, 194, 195, 212, 213, 214, 215, 230, 231 ,

[0262] 232, 238, 239, 246, 248, 250, 251 , 253, 254, 255, 258, 263, 264, 272, 273, 278, 279, 280, 281 ,

[0263] 288, 291 , 298, 305, 306, 313, 314, 321 , 322, 331 , 338, 339, 340, 341 , 342, 343, 344, 345, 353,

[0264] 355, 356, 358, 391 , 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407, 408, 413, 418,

[0265] 422, 428, 429, 430, 431 , 434, 445, 446, 447, 448, 449, 450, 451 , 454, 463, 464, 465, 466, 472,

[0266] 475, 476, 479, 481 , 486, 489, 495, 498, 512, 514, 515, 520, or 524 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0267] In some embodiments, the compound of Formula (I) as described herein is Compound 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,

[0268] 191 , 192, 194, 195, 212, 213, 215, 230, 231 , 232, 238, 239, 246, 248, 250, 251 , 254, 255, 258,

[0269] 263, 272, 273, 279, 281 , 288, 291 , 306, 313, 314, 321 , 322, 331 , 338, 339, 340, 341 , 342, 343,

[0270] 344, 345, 353, 355, 356, 358, 391 , 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407,

[0271] 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 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0272] In some embodiments, the compound of Formula (I) as described herein is Compound 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,

[0273] 191 , 192, 194, 195, 212, 213, 215, 230, 231 , 232, 238, 239, 246, 248, 250, 251 , 254, 255, 258,

[0274] 263, 272, 273, 279, 281 , 288, 291 , 306, 313, 314, 321 , 322, 331 , 338, 339, 340, 341 , 342, 343,

[0275] 344, 345, 353, 355, 356, 358, 391 , 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407,

[0276] 418, 428, 430, 431 , 434, 445, 446, 447, 448, 449, 450, 454, 463, 464, 465, 466, 476, 489, 512,

[0277] 514, 515, or 524 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0278] In some embodiments, the compound of Formula (I) as described herein is Compound 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 , 306, 314, 321 , 322, 331 , 338, 339, 340, 341 , 342, 345, 353, 355,

[0279] 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 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0280] In some embodiments, the compound of Formula (I) as described herein is Compound 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 ofTable 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0281] In some embodiments, the compound of Formula (I) as 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 is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 61 , 63, 75, 143, 146, 174, 230, 250, 273, or 306 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0282] In some embodiments, the compound of Formula (I) as described herein is Compound 4 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 33 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 47 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 89 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 121 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 131 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 132 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 133 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 134 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 138 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 139 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 214 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 253 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 264 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 278 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 280 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 298 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 305 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 408 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 413 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 422 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 429 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 451 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 472 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 475 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 479 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 481 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 486 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 495 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 498 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 520 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0283] In some embodiments, the compound of Formula (I) as described herein is Compound 15 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 25 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 32 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 49 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 52 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 59 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 62 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 72 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 82 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 109 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 119 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 128 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 129 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 130 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 136 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 145 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 148 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 150 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 169 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 179 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 183 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 192 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 194 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 212 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 213 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 239 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 254 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 263 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 288 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 291 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 313 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 321 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 331 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 341 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 342 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 343 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 344 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 358 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 392 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 394a of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 394b of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 395a of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 395b of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 396 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 403 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 407 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 418 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 445 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 448 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 449 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 454 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 464 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 476 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0284] In some embodiments, the compound of Formula (I) as described herein is Compound 48 of Table

[0285] 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 50 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 54 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 60b of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 61 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 63 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 75 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 83 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 97 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 101 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 127 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 135 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 140 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 141 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 143 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 144 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 146 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 147 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 149 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 163 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 170 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 174 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 181 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 191 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 195 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 215 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 230 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 231 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 232 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 238 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 246 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 248 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 250 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 251 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 255 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 258 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 272 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 273 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 279 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 281 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 306 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 314 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 322 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 338 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 339 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 340 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 345 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 353 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 355 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 356 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 391 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 393 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 397 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 402 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 428 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 430 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 431 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 434 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 446 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 447 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 450 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 463 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 465 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 466 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 489 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 512 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 514 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 515 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 524 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0286] Pharmaceutical combinations

[0287] The present application relates to pharmaceutical combinations comprising a thiophene fused cyclohexanone derivative ASIC inhibitor, which is a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a cyclooxygenase (COX) inhibitor. In some embodiments, the pharmaceutical combinations can further include pharmaceutically acceptable carriers, diluents, or excipients, as will be detailed below.

[0288] The term “ASICs inhibitor” as used herein means a compound that can inhibit acid-sensing ion channels, such as the acid-sensing ion channel 1a (ASICIa) or the acid-sensing ion channel 1 b (ASICI b). A “cyclooxygenase (COX) inhibitor” as used in the pharmaceutical combinations of the present application, refers to a drug enabling inhibition of COX enzymes, such as COX-1 and COX-2 enzymes, for instance. In some embodiments, the COX inhibitor can affect both COX-1 and COX- 2 enzymes. However, in some embodiments, the COX inhibitor can primarily affect the COX-2 enzyme or the COX-1 enzyme. In some embodiments, the COX inhibitor can comprise an NSAID, which can be highly selective for the COX-2 enzyme, such as coxibs or can be non-selective and affect both COX-1 and COX-2 enzymes, such as ibuprofen. In other embodiments, the COX inhibitor can be acetaminophen.

[0289] In some embodiments, the pharmaceutical combinations of the present disclosure can include an NSAID which can be Bromfenac, Celecoxib, Diclofenac, Etodolac, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic acid, Meloxicam, Nabumetone, Naproxen, Nepafenac, Piroxicam, Sulindac, Tenoxicam, Tiaprofenic acid, Diflunisal, Etoricoxib, Fenoprofen, Floctafenine, Lumiracoxib, Oxaprozin, Parecoxib, Rofecoxib, Tolmetin, Valdecoxib, Meclofenamic acid, Dexketoprofen, Licofelone, Lornoxicam, Loxoprofen, Nimesulide, Tolfenamic acid, Phenylbutazone, Firocoxib, Salsalate, Choline Magnesium Trisalicylate, Acetylsalicylic acid, any pharmaceutically acceptable salt thereof, or any combination thereof.

[0290] Due to their COX-1 inhibition effect, certain NSAIDs can cause side effects such as bleeding and gastrointestinal irritation for instance. Side effects tend to be more common at high doses for a long time. Accordingly, NSAIDs are often co-administered with proton-pump inhibitors (PPIs) to reduce NSAID-induced gastrointestinal (Gl) adverse events. Hence, in some embodiments, the pharmaceutical combinations of the present disclosure can further include a proton-pump inhibitor (PPI). However, in other embodiments, one can achieve pain reduction using a combination of the ASIC inhibitor of Formula (I) and the NSAID, in which the dosage of NSAID can be reduced, thanks to the pain reduction potency of the ASIC inhibitor. Then, the use of a PPI can be avoided or at least the PPI can be used in more limited dosage, thus eliminating or at least reducing side effects associated with NSAIDs.

[0291] In some embodiments, the pharmaceutical combinations of the present disclosure can include preferably, an NSAID selected from Naproxen, Celecoxib, Diclofenac, Ibuprofen, a pharmaceutically acceptable salt thereof, or any combination thereof.

[0292] In some embodiments, the pharmaceutical combinations of the present disclosure can be synergistic. In other words, the therapeutically active compounds, namely the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can produce a therapeutic effect that is more than the sum of their individual therapeutic effects. In some embodiments, thanks to the synergy that can be observed between the two therapeutically active compounds, lower doses of at least one of the therapeutically active ingredients, preferably both, can be used. In some embodiments, this can provide combination therapies that are much safer than the corresponding monotherapies.

[0293] In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is an NSAID.

[0294] In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is an NSAID selected from Bromfenac, Celecoxib, Diclofenac, Etodolac, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic acid, Meloxicam, Nabumetone, Naproxen, Nepafenac, Piroxicam, Sulindac, Tenoxicam, Tiaprofenic acid, Diflunisal, Etoricoxib, Fenoprofen, Floctafenine, Lumiracoxib, Oxaprozin, Parecoxib, Rofecoxib, Tolmetin, Valdecoxib, Meclofenamic acid, Dexketoprofen, Licofelone, Lornoxicam, Loxoprofen, Nimesulide, Tolfenamic acid, Phenylbutazone, Firocoxib, Salsalate, Choline Magnesium Trisalicylate, Acetylsalicylic acid, any pharmaceutically acceptable salt thereof, and any combination thereof.

[0295] In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is an NSAID selected from Naproxen, Celecoxib, Diclofenac, Ibuprofen, a pharmaceutically acceptable salt thereof, or any combination thereof.

[0296] In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Bromfenac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Etodolac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Flurbiprofen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Indomethacin or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Ketoprofen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Ketorolac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Mefenamic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Meloxicam or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Nabumetone or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Nepafenac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Piroxicam or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Sulindac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Tenoxicam or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Tiaprofenic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Diflunisal or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Etoricoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Fenoprofen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Floctafenine or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Lumiracoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Oxaprozin or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Parecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Rofecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Tolmetin or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Valdecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Meclofenamic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Dexketoprofen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Licofelone or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Lornoxicam or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Loxoprofen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Nimesulide or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Tolfenamic acid or an pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Phenylbutazone or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Firocoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Salsalate or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Choline Magnesium Trisalicylate or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Acetylsalicylic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Naproxen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Celecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Diclofenac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Ibuprofen or a pharmaceutically acceptable salt thereof.

[0297] In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is acetaminophen.

[0298] In some embodiments, the pharmaceutical combination of the present disclosure can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a single dosage form. Single dosage form refers to a mixture of the therapeutically active ingredients, namely the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, that are packaged in a single dosage form. For example, and without being limiting to, a dosage form can include a pill, a tablet, a capsule, a drink or a syrup.

[0299] In other embodiments, the pharmaceutical combination of the present disclosure can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, each being in an individual dosage form.

[0300] In some embodiments, the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, each in an amount ranging from about 1 mg to about 1000 mg. In other words, the pharmaceutical combination can comprise from about 1 mg to about 1000 mg of the COX inhibitor and from about 1 mg to about 1000 mg of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0301] In some embodiments, the pharmaceutical combination can comprise the COX inhibitor in an amount of from about 1 mg to about 900 mg, or from about 1 mg to about 800 mg, or from about 1 mg to about 700 mg, or from about 1 mg to about 600 mg, or from about 1 mg to about 500 mg, or from about 1 mg to about 400 mg, or from about 1 mg to about 300 mg, or from about 1 mg to about 200 mg, or from about 1 mg to about 100 mg, or from about 1 mg to about 50 mg, or any range value in between these ranges. In some embodiments, the pharmaceutical combination can comprise the COX inhibitor in an amount of about 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg,

[0302] 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, 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 in between these values.

[0303] In some embodiments, the pharmaceutical combination can comprise the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in an amount of from about 1 mg to about 900 mg, or from about 1 mg to about 800 mg, or from about 1 mg to about 700 mg, or from about 1 mg to about 600 mg, or from about 1 mg to about 500 mg, or from about 1 mg to about 400 mg, or from about 1 mg to about 300 mg, or from about 1 mg to about 200 mg, or from about 1 mg to about 100 mg, or from about 1 mg to about 50 mg, or any range value in between these ranges. In some embodiments, the pharmaceutical combination can comprise the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in an amount of about 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,

[0304] 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, 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 in between these values.

[0305] In some embodiments, the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1:0.1 to 1:10 by weight. In some embodiments, the ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be from 1:0.1 to 1:9 by weight, or from 1:0.1 to 1:8 by weight, or from 1:0.1 to 1:7 by weight, or from 1 :0.1 to 1 :6 by weight, or from 1 :0.1 to 1 :5 by weight, or from 1:0.1 to 1 :4 by weight, or from 1:0.1 to 1:3 by weight, or from 1:0.1 to 1:2 by weight, or from 1:0.1 to 1:1 by weight. In some embodiments, the ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be from 1:0.1 to 1:1 by weight, or from 1:0.1 to 1:0.9 by weight, or from 1:0.1 to 1 :0.8 by weight, or from 1:0.1 to 1 :0.7 by weight, or from 1:0.1 to 1:0.6 by weight, or from 1:0.1 to 1:0.5 by weight, or from 1:0.1 to 1:0.4 by weight, or from 1:0.1 to 1:0.3 by weight, or from 1:0.1 to 1:0.2 by weight. In some embodiments, the ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be from 1:0.1 to 1:1 by weight, or from 1:0.2 to 1:1 by weight, or from 1:0.3 to 1:1 by weight, or from 1:0.4 to 1:1 by weight, or from 1:0.5 to 1:1 by weight, or from 1:0.6 to 1:1 by weight, or from 1:0.7 to 1:1 by weight, or from 1:0.8 to 1:1 by weight, or from 1:0.9 to 1:1 by weight. In some embodiments, the ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be from 1:1 to 1:2 by weight, or from 1:1 to 1:1.9 by weight, or from 1:1 to 1:1.8 by weight, or from 1:1 to 1:1.7 by weight, or from 1:1 to 1:1.6 by weight, or from 1:1 to 1:1.5 by weight, or from 1:1 to 1:1.4 by weight, or from 1:1 to 1:1.3 by weight, or from 1:1 to 1:1.2 by weight, or from 1:1 to 1:1.1 by weight.

[0306] In some embodiments, the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1:0.1 to 1:2 by weight. In some embodiments, the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1:0.1 to 1:1 by weight.

[0307] In some embodiments, the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from about 1 :0.2 to about 1 : 1 by weight, or from about 1 :0.18 to about 1 : 1 by weight, or from about 1:0.2 to about 1:0.83 by weight, or from about 1:0.18 to about 1:0.83 by weight.

[0308] In some embodiments, the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof in a ratio by weight of COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof that results in a synergistic pharmaceutical combination. In some embodiments, the pharmaceutical combination can be synergistic and can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1 :0.1 to 1 :10 by weight. In some embodiments, the synergistic pharmaceutical combination can have a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1 :0.1 to 1 :9 by weight, or from 1 :0.1 to 1 :8 by weight, or from 1 :0.1 to 1 :7 by weight, or from 1 :0.1 to 1 :6 by weight, or from 1 :0.1 to 1 :5 by weight, or from 1 :0.1 to 1 :4 by weight, or from 1 :0.1 to 1 :3 by weight, or from 1 :0.1 to 1 :2 by weight, or from 1 :0.1 to 1 :1 by weight. In some embodiments, the synergistic pharmaceutical combination can have a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1 :0.1 to 1 :1 by weight, or from 1 :0.1 to 1 :0.9 by weight, or from 1 :0.1 to 1 :0.8 by weight, or from 1 :0.1 to 1 :0.7 by weight, or from 1 :0.1 to 1 :0.6 by weight, or from 1 :0.1 to 1 :0.5 by weight, or from 1 :0.1 to 1 :0.4 by weight, or from 1 :0.1 to 1 :0.3 by weight, or from 1 :0.1 to 1 :0.2 by weight. In some embodiments, the synergistic pharmaceutical combination can have a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1 :0.1 to 1 : 1 by weight, or from 1 :0.2 to 1 :1 by weight, or from 1 :0.3 to 1 :1 by weight, or from 1 :0.4 to 1 :1 by weight, or from 1 :0.5 to 1 :1 by weight, or from 1 :0.6 to 1 :1 by weight, or from 1:0.7 to 1 :1 by weight , or from 1 :0.8 to 1 :1 by weight, or from 1 :0.9 to 1 :1 by weight. In some embodiments, the synergistic pharmaceutical combination can have a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1 :1 to 1 :2 by weight, or from 1 :1 to 1:1.9 by weight, or from 1 :1 to 1 :1.8 by weight, or from 1 :1 to 1 :1.7 by weight, or from 1 :1 to 1 :1.6 by weight, or from 1 :1 to 1 :1.5 by weight, or from 1 :1 to 1 :1.4 by weight, or from 1 :1 to 1 :1.3 by weight, or from 1 :1 to 1 :1.2 by weight, or from 1 :1 to 1 :1.1 by weight.

[0309] In some embodiments, the pharmaceutical combination can be synergistic and can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1 :0.1 to 1 :2 by weight. In some embodiments, the pharmaceutical combination can be synergistic and can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1:0.1 to 1:1 by weight.

[0310] In some embodiments, the pharmaceutical combination can be synergistic and can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from about 1 :0.2 to about 1 : 1 by weight, or from about 1:0.18 to about 1:1 by weight, or from about 1:0.2 to about 1:0.83 by weight, or from about 1:0.18 to about 1:0.83 by weight.

[0311] In some embodiments, the pharmaceutical combination can comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1:0.1 to 1:10 by weight. In some embodiments, the ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be from 1:0.1 to 1:9 by weight, or from 1:0.1 to 1:8 by weight, or from 1:0.1 to 1:7 by weight, or from 1:0.1 to 1:6 by weight, or from 1:0.1 to 1:5 by weight, or from 1:0.1 to 1:4 by weight, orfrom 1:0.1 to 1:3 by weight, or from 1:0.1 to 1:2 by weight, or from 1:0.1 to 1:1 by weight. In some embodiments, the ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be from 1:0.1 to 1:1 by weight, orfrom 1:0.1 to 1:0.9 by weight, or from 1:0.1 to 1:0.8 by weight, orfrom 1:0.1 to 1:0.7 by weight, orfrom 1:0.1 to 1:0.6 by weight, or from 1:0.1 to 1:0.5 by weight, orfrom 1:0.1 to 1:0.4 by weight, orfrom 1:0.1 to 1:0.3 by weight, or from 1:0.1 to 1:0.2 by weight. In some embodiments, the ratio NSAIDto compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be from 1:0.1 to 1:1 by weight, or from 1:0.2 to 1:1 by weight, orfrom 1:0.3 to 1:1 by weight, orfrom 1:0.4 to 1:1 by weight, orfrom 1:0.5 to 1:1 by weight, orfrom 1:0.6 to 1:1 by weight, orfrom 1:0.7 to 1:1 by weight, orfrom 1:0.8 to 1:1 by weight, orfrom 1:0.9 to 1:1 by weight. In some embodiments, the ratio NSAIDto compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be from 1:1 to 1:2 by weight, orfrom 1:1 to 1:1.9 by weight, orfrom 1:1 to 1:1.8 by weight, orfrom 1:1 to 1:1.7 by weight, orfrom 1:1 to 1:1.6 by weight, orfrom 1:1 to 1:1.5 by weight, orfrom 1:1 to 1:1.4 by weight, orfrom 1:1 to 1:1.3 by weight, orfrom 1:1 to 1:1.2 by weight, orfrom 1:1 to 1:1.1 by weight.

[0312] In some embodiments, the pharmaceutical combination can comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1:0.1 to 1:2 by weight. In some embodiments, the pharmaceutical combination can comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1:0.1 to 1:1 by weight.

[0313] In some embodiments, the pharmaceutical combination can comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from about 1 :0.2 to about 1 :1 by weight, or from about 1 :0.18 to about 1:1 by weight, or from about 1:0.2 to about 1:0.83 by weight, or from about 1:0.18 to about 1 :0.83 by weight.

[0314] In some embodiments, the pharmaceutical combination can comprise an NSAID as the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof are provided in a ratio by weight of NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof that results in a synergistic pharmaceutical combination. In some embodiments, the pharmaceutical combination can be synergistic and comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1 :0.1 to 1:10 by weight. In some embodiments, the synergistic pharmaceutical combination can have a ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1:0.1 to 1:9 by weight, or from 1:0.1 to 1:8 by weight, or from 1:0.1 to 1:7 by weight, or from 1:0.1 to 1:6 by weight, or from 1:0.1 to 1:5 by weight, or from 1:0.1 to 1:4 by weight, orfrom 1:0.1 to 1:3 by weight, or from 1:0.1 to 1:2 by weight, or from 1:0.1 to 1:1 by weight. In some embodiments, the synergistic pharmaceutical combination can have a ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1:0.1 to 1:1 by weight, orfrom 1:0.1 to 1:0.9 by weight, orfrom 1:0.1 to 1:0.8 by weight, orfrom 1:0.1 to 1:0.7 by weight, orfrom 1:0.1 to 1:0.6 by weight, orfrom 1:0.1 to 1:0.5 by weight, orfrom 1:0.1 to 1:0.4 by weight, or from 1:0.1 to 1:0.3 by weight, or from 1:0.1 to 1:0.2 by weight. In some embodiments, the synergistic pharmaceutical combination can have a ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1:0.1 to 1:1 by weight, orfrom 1:0.2 to 1:1 by weight, orfrom 1:0.3 to 1:1 by weight, orfrom 1:0.4 to 1:1 by weight, orfrom 1:0.5 to 1:1 by weight, orfrom 1:0.6 to 1:1 by weight, orfrom 1:0.7 to 1:1 by weight , orfrom 1:0.8 to 1:1 by weight, orfrom 1:0.9 to 1:1 by weight. In some embodiments, the synergistic pharmaceutical combination can have a ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1:1 to 1:2 by weight, or from 1:1 to 1:1.9 by weight, orfrom 1:1 to 1:1.8 by weight, orfrom 1:1 to 1:1.7 by weight, orfrom 1:1 to 1:1.6 by weight, orfrom 1:1 to 1:1.5 by weight, orfrom 1:1 to 1:1.4 by weight, orfrom 1:1 to 1:1.3 by weight, orfrom 1:1 to 1:1.2 by weight, orfrom 1:1 to 1:1.1 by weight.

[0315] In some embodiments, the pharmaceutical combination can be synergistic and comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1:0.1 to 1:2 by weight. In some embodiments, the pharmaceutical combination can be synergistic and comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1:0.1 to 1:1 by weight.

[0316] In some embodiments, the pharmaceutical combination can be synergistic and comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from about 1 :0.2 to about 1 :1 by weight, or from about 1 :0.18 to about 1 :1 by weight, or from about 1 :0.2 to about 1 :0.83 by weight, or from about 1 :0.18 to about 1 :0.83 by weight.

[0317] The above-mentioned dosages and ratios are provided as examples, and one could adapt the dosages and / or ratios of the COX inhibitor and compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, for achieving a suitable treatment such as proper pain relief.

[0318] Methods, uses, formulations, kits and administration

[0319] The pharmaceutical combinations of the present disclosure, comprising a COX inhibitor and a thiophene fused cyclohexanone derivative, i.e., a compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, can be useful for the treatment of disorders or conditions including pain. In some embodiments, the treatment can involve using, or can be potentiated by using, a pharmaceutical combination of the present disclosure which can be synergistic.

[0320] In certain embodiments, the present description thus provides a method for treating pain, comprising administering to a patient or subject identified as in need thereof, a COX inhibitor and a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as disclosed herein. In some embodiments, the method for treating pain can comprise administering to a patient or subject identified as in need thereof, an effective amount of the COX inhibitor and of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the administration results in a synergistic effect thereof.

[0321] The identification of those patients who are in need of treatment for the disorders described herein is well within the ability and knowledge of one skilled in the art. Certain of the methods for identification of patients which are at risk of developing the above disorders which can be treated by the subject method are appreciated in the medical arts, such as family history, and the presence of risk factors associated with the development of that disorder state in the subject patient. A clinician skilled in the art can readily identify such candidate patients, by the use of, for example, clinical tests, physical examination and medical / family history.

[0322] As used herein, the term “effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, one can also refer to “therapeutically effective amount” which means any amount which, as compared to a corresponding subject who has not received such amount, results in treatment, healing, prevention, or amelioration of a disorder, disorder, or side effect, or a decrease in the rate of advancement of a disorder or disorder. The term also includes within its scope amounts that are effective to enhance normal physiological function.

[0323] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disorder or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0324] The terms "patient” or “subject" as used herein generally refer to a mammal. A subject therefore refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, and the like. Preferably the subject is a human. When the subject is a human, the subject may be either a patient or a healthy human.

[0325] The expression “pharmaceutically acceptable carrier, diluent, or excipient” and equivalent expressions, refer to a non-toxic carrier, diluent, or excipient that does not destroy the pharmacological activity of the compound with which it is formulated. 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, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0326] In certain embodiments, as mentioned above, the disorders or conditions that can be treated using the pharmaceutical combination comprising the COX inhibitor and the thiophene fused cyclohexanone derivative, i.e., the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, can include pain.

[0327] In some embodiments, the pain can include acute pain or chronic pain. In some embodiments, the pain can include inflammatory pain, neuropathic pain or cancer pain. In some embodiments, the pain can include nociceptive pain, inflammatory pain, neuropathic pain, cancer pain, idiopathic pain, musculoskeletal pain, visceral pain, or abdominal pain. In some embodiments, the pain can include inflammatory pain. In another embodiment, the pain can include neuropathic pain. In yet another embodiment, the pain can include cancer pain. In some embodiments, the pain can include arthritis pain, pain associated with musculoskeletal trauma or soft tissue trauma, post-operative pain, dental pain, dysmenorrhea pain, episiotomy pain, endometriosis pain, post-partum pain, headache pain, ocular pain, bursitis pain, tendinitis pain, tenosynovitis pain, or polymyalgia rheumatica pain. In some embodiments, the pain can include arthritis pain, pain associated with musculoskeletal trauma or soft tissue trauma, post-operative pain, dental pain, dysmenorrhea pain, episiotomy pain, endometriosis pain, post-partum pain, headache pain, ocular pain, bursitis pain, or tendinitis pain.

[0328] In some embodiments, the pain can include a rheumatic disorder-related pain.

[0329] In certain embodiments, the pain can include arthritis pain. In some embodiments, the pain can include adult arthritis pain or juvenile arthritis pain. In certain embodiments, the pain can include adult arthritis pain. In some embodiments, the pain can include juvenile arthritis pain.

[0330] In some embodiments, the pain can include osteoarthritis pain, rheumatoid arthritis pain, ankylosing spondylitis pain, gout pain, psoriatic arthritis pain, or periarthritis pain. In certain embodiments, the pain can include osteoarthritis pain, rheumatoid arthritis pain, ankylosing spondylitis pain, gout pain, or periarthritis pain.

[0331] In some embodiments, the pain can include osteoarthritis pain. In certain embodiments, the pain can include osteoarthritis inflammatory pain. In some embodiments, the pain can include osteoarthritis pain of the hip, osteoarthritis pain of the knee, osteoarthritis pain of the spine, osteoarthritis pain of the shoulder, osteoarthritis pain of the hand, osteoarthritis pain of the finger, osteoarthritis pain of the thumb, osteoarthritis pain of the foot, or osteoarthritis pain of the toe.

[0332] In some embodiments, the pain can include rheumatoid arthritis pain. In certain embodiments, the pain can include adult rheumatoid arthritis pain or juvenile rheumatoid arthritis pain. In some embodiments, the pain can include adult rheumatoid arthritis pain. In certain embodiments, the pain can include juvenile rheumatoid arthritis pain. In certain embodiments, the pain can include rheumatoid arthritis inflammatory pain. In some embodiments, the pain can include rheumatoid arthritis pain of the hand, rheumatoid arthritis pain of the finger, rheumatoid arthritis pain of the thumb, rheumatoid arthritis pain of the foot, rheumatoid arthritis pain of the toe, 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.

[0333] In certain embodiments, the pain can include ankylosing spondylitis pain.

[0334] In some embodiments, the pain can include gout pain. In some embodiments, the pain can include gout pain of the foot, gout pain of the toe, gout pain of the ankle, gout pain of the knee, or gout pain of the elbow. In certain embodiments, the pain can include gouty arthritis pain. In certain embodiments, the pain can include psoriatic arthritis pain.

[0335] In certain embodiments, the pain can include bursitis pain. In some embodiments, the pain can include bursitis pain of the shoulder or bursitis pain of the hip.

[0336] In certain embodiment, the pain can include tendinitis pain. In some embodiments, the pain can include tendinitis pain of the shoulder, tendinitis pain of the elbow, tendinitis pain of the hip, tendinitis pain of the wrist, tendinitis pain of the knee, or tendinitis pain of the heel.

[0337] In some embodiments, the pain can include periarthritis pain. In certain embodiments, the pain can include periarthritis pain of the shoulder or periarthritis pain of the hip.

[0338] In some embodiments, the pain can include pain associated with musculoskeletal trauma or soft tissue trauma including pain associated with a sprain, a strain, swelling or stiffness. In certain embodiments, the pain can include pain associated with musculoskeletal trauma or soft tissue trauma including pain associated with a sprain or a strain. In certain embodiments, the pain can include pain associated with musculoskeletal trauma or soft tissue trauma of the back, shoulder, or ankle. In certain embodiments, the pain can include myofascial pain syndrome. In other embodiments, the pain can include exercise-induced pain, repetitive motion injury pain, or pain due to a bone fracture. In other embodiments, the pain can include temporomandibular joint disorder pain.

[0339] In certain embodiments, the pain can include ocular pain. In certain embodiments, the ocular pain can include post-operative pain after cataract surgery, post-operative pain after refractive surgery, ocular pain from a non-penetrating wound, foreign body sensation ocular pain, burning or stinging of the eye, uveitis pain, iritis pain, retinopathy pain or optic neuritis pain.

[0340] In some embodiments, the pain can include dental pain. In certain embodiments, the dental pain can include toothache or post-operative pain after dental surgery. In some embodiments, the dental pain can include pain after dental extraction.

[0341] In certain embodiments, the pain can include post-operative pain. In some embodiments, the pain can include post-operative pain following minor surgery, post-operative pain following general surgery, post-operative pain following orthopaedic surgery, post-operative pain following bunionectomy, post-operative pain following hernioplasty, post-operative pain following herniorrhaphy, post-operative pain following arthroplasty including pain following knee arthroplasty or pain following hip arthroplasty, post-operative pain following gynecological surgery, postoperative pain following caesarean section, post-mastectomy pain syndrome (PMPS), postoperative pain following abdominoplasty, post-operative pain following laminectomy, post-operative pain following hemorrhoid removal, or post-operative pain following thoracotomy.

[0342] In certain embodiments, the pain can include dysmenorrhea pain, episiotomy pain, endometriosis pain, or post-partum pain. In certain embodiments, the pain can include dysmenorrhea pain, episiotomy pain, endometriosis pain, or post-partum cramping pain.

[0343] In some embodiments, the pain can include headache pain. In certain embodiments, the pain can include migraine pain, tension headache pain, or cluster headache pain. In some embodiments, the pain can include migraine pain including migraine with aura pain or migraine without aura pain.

[0344] In certain embodiments, the pain can include pain due to the common cold, pain due to the flu, sore throat pain, sinus pain including sinusitis pain, pain due to immunization, earache pain, fever pain, body pain, muscle pain, bone pain, joint pain, back pain, neck pain, or nighttime pain.

[0345] In some embodiments, the pain can include mucositis pain or stomatitis pain. In certain embodiments, the pain can include pain associated with lupus including lupus-related inflammatory pain.

[0346] In certain embodiments, the pain can include osteoarthritis neuropathic pain. In certain embodiments, the pain can include rheumatoid arthritis neuropathic pain.

[0347] In certain embodiments, the pain can include neuralgia. In some embodiments, that pain can include trigeminal neuralgia, postherpetic neuralgia, occipital neuralgia, post-surgical neuralgia, pudendal neuralgia, diabetic neuralgia, glossopharyngeal neuralgia, intercostal neuralgia, or drug therapy-induced neuralgia including cancer chemotherapy-induced neuralgia or anti-retroviral therapy-induced neuralgia.

[0348] In certain embodiments, the pain can include nerve injury pain, peripheral nerve injury pain, nerve compression pain, nerve avulsion 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, radicular pain, sciatica pain, spinal stenosis pain, cervical spine injury pain, brain injury pain, or post-stroke pain.

[0349] In some embodiments, the pain can include neuropathy pain. In certain embodiments, the pain can include peripheral neuropathy pain, polyneuropathy pain, mononeuropathy pain, multiple mononeuropathy pain, proximal neuropathy pain, sensory neuropathy pain, small fiber sensory neuropathy pain, idiopathic neuropathy pain, or distal sensory polyneuropathy pain. In certain embodiments, the pain can include diabetic neuropathy pain. In some embodiments, the pain can include diabetic peripheral neuropathy pain, diabetic polyneuropathy pain, diabetic proximal neuropathy pain, or diabetic mononeuropathy pain. In certain embodiments, the pain can include autoimmune disease neuropathy pain. In some embodiments, the pain can include Sjogren's syndrome neuropathy pain, Guillain-Barre syndrome neuropathy pain, chronic inflammatory demyelinating polyneuropathy pain, or vasculitis neuropathy pain. In some embodiments, the pain can include multiple sclerosis neuropathic pain. In certain embodiments, the pain can include carpal tunnel syndrome pain. In certain embodiments, the pain can include neuropathy pain associated with a bacterial infection or neuropathy pain associated with a viral infection. In some embodiments, the pain can include Lyme disease neuropathy pain, Epstein-Barr virus neuropathy pain, hepatitis B virus neuropathy pain, hepatitis C virus neuropathy pain, leprosy neuropathy pain, diphtheria neuropathy pain, or human immunodeficiency virus (HIV) neuropathy pain including HIV distal symmetric polyneuropathy pain. In certain embodiments, the pain can include hereditary neuropathy pain. In some embodiments, the pain can include Charcot-Marie-Tooth disease neuropathy pain or hereditary neuropathy with pressure palsies (HNPP) pain. In certain embodiments, the pain can include neuropathy pain caused by a malignant tumor, neuropathy pain caused by a benign tumor, or paraneoplastic neuropathy pain. In some embodiments, the pain can include myeloma neuropathy pain, lymphoma neuropathy pain, or amyloid neuropathy pain. In certain embodiments, the pain can include liver disease neuropathy pain, uremic neuropathy pain, connective tissue disorder neuropathic pain, hypothyroidism neuropathy pain, alcohol use neuropathy pain, or vitamin deficiency neuropathy pain. In some embodiments, the pain can include vitamin B deficiency neuropathy pain including vitamin B1 , niacin, vitamin B6, or vitamin B12 deficiency neuropathy pain, or vitamin E deficiency neuropathy pain. In certain embodiments, the pain can include toxic substance exposure neuropathy pain including neuropathy pain following lead exposure or neuropathy pain following mercury exposure. In certain embodiments, the pain can include anti-retroviral therapy-induced neuropathy pain or neurotoxic drug-induced neuropathic pain. In certain embodiments, the pain can include chemotherapy-induced neuropathy pain including platinum-based antineoplastic drug-induced neuropathic pain or chemotherapy-induced peripheral neuropathy (CIPN) pain, radiation therapy- induced pain including radiation therapy-induced neuropathy pain, cancer targeted therapy- induced neuropathy pain, or immunotherapy-induced neuropathy pain. In some embodiments, that pain can include central neuropathic pain. In certain embodiments, the pain can include central post-stroke pain, spinal cord injury- related central neuropathic pain, brain injury-related central neuropathic pain, or multiple sclerosis-related central neuropathic pain.

[0350] In certain embodiments, the pain can include cancer pain. In some embodiments, the pain can include bone cancer pain, breakthrough pain, cancer nociceptive pain, cancer neuropathy pain including neuropathy caused by a tumor pressing on a nerve.

[0351] In certain embodiments, the pain can include post-amputation pain. In some embodiments, the pain can include phantom pain, phantom limb pain, or residual limb pain.

[0352] In certain embodiments, the pain can include Paget’s disease pain. In other embodiments, the pain can include pain associated with fibromyalgia. In certain embodiments, the pain can include pain associated with lupus including lupus-related inflammatory pain and lupus-related neuropathy pain. In some embodiments, the pain can include gastrointestinal motility disorder pain, irritable bowel syndrome pain, Crohn’s disease pain, ulcer-related pain, or ulcerative colitis pain. In other embodiments, the pain can include incontinence pain or interstitial cystitis pain. In certain embodiments, the pain can include herpes zoster pain. In certain embodiments, the pain can include angina-induced pain. In certain embodiments, the pain can include animal bite or sting pain, or pain caused by a burn including pain caused by a first-degree, second-degree or third-degree burn.

[0353] In some embodiments, the pharmaceutical combination disclosed herein which comprises a therapeutically effective amount of at least one COX inhibitor and a therapeutically effective amount of at least one compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, can be administered to a patient or subject, alone, or admixed with a pharmaceutically acceptable carrier, diluent, or excipient.

[0354] In some embodiments, the pharmaceutical combinations described herein are such that the COX inhibitor and the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered each in an individual dosage form. In other embodiments, the pharmaceutical combinations described herein are such that the COX inhibitor and the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered together in a single dosage form.

[0355] In some embodiments, when the pharmaceutical combinations comprise separate individual dosage forms (or “single dosage form” or “single dose form” or “unit dose”) of the COX inhibitor and of the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, each separate individual dosage form can be administered either simultaneously or sequentially. When administered sequentially, the individual dosage forms can be administered in any order.

[0356] Pharmaceutical combinations described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, ophthalmically, intravaginally, or via an implanted reservoir. Hence, in the present disclosure, the term “oral treatment” means a treatment that occurs by oral administration. In other words, an “oral treatment” refers to a treatment where the pharmaceutical combinations of the present disclosure are administered orally for the indicated treatment. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Other modes of administration also include intradermal ortransdermal administration.

[0357] In some embodiments, the pharmaceutical combinations described herein are administered orally, i.e., via the oral cavity, including buccally.

[0358] 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 compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetra hydrofurfury I alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include excipients such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0359] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3- butanediol. Among the acceptable carriers and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0360] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0361] In order to prolong the effect of a provided compound, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil carrier. Injectable depot forms are made by forming matrices of the compound microencapsulated in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled.

[0362] Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the therapeutically active compound in liposomes or microemulsions that are compatible with body tissues.

[0363] Formulations for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the therapeutically active compounds of the present description with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0364] 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 extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone (PVP), sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0365] Solid formulations of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The therapeutically active compounds can also be in micro- encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0366] Dosage forms for topical or transdermal administration of a compound of the present description include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of the present description. Additionally, the description contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0367] Pharmaceutical combinations provided herein may also be formulated for administration by nasal aerosol or inhalation using inhalants. Such formulations are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promotors to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0368] Pharmaceutical combinations provided herein may be formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutical combinations of this disclosure can be administered without food. In other embodiments, pharmaceutical combinations of this disclosure can be administered with food.

[0369] The amount of therapeutically active compounds that may be combined with carrier materials to produce a formulation in a single dosage form can vary depending upon the patient to be treated and the particular mode of administration. The amount of individual therapeutically active compound that may be combined with carrier materials to produce individual dosage forms can vary depending upon the patient to be treated and the particular mode of administration.

[0370] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disorder being treated.

[0371] The pharmaceutical combinations described herein may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorders or disorders as contemplated 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 particular agent, its mode of administration, and the like. In some embodiments, the COX inhibitor and the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be formulated in unit dose for ease of administration and uniformity of dosage. The expression "unit dose" or “single dose form” as used herein refers to a physically discrete unit of therapeutically active agent(s) in an amount appropriate for the patient to be treated. In some embodiments, each unit dose form can include both the required amount of COX inhibitor and of the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof. In other embodiments, separate unit doses can be prepared, a first unit dose including the required amount of COX inhibitor and a second unit dose including the required amount of the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof. It will be understood, however, that the total daily dosage of the therapeutically active compounds and / or combination thereof will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.

[0372] In certain embodiments, each one of the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be administered at dosage levels of from about 0.01 mg / kg to about 50 mg / kg, or from about 0.01 mg / kg to about 40 mg / kg, or from about 0.01 mg / kg to about 30 mg / kg, or from about 0.1 mg / kg to about 50 mg / kg, or from about 0.1 mg / kg to about 40 mg / kg, or from about 0.1 mg / kg to about 30 mg / kg, or from about 0.1 mg / kg to about 20 mg / kg, or from about 0.1 mg / kg to about 10 mg / kg of subject body weight, one or more times a day, to obtain the desired therapeutic effect.

[0373] In certain embodiments, the COX inhibitor can be administered at dosage levels of from about 0.1 mg / kg to about 50 mg / kg, or from about 0.1 mg / kg to about 40 mg / kg, or from about 0.1 mg / kg to about 30 mg / kg, or from about 0.1 mg / kg to about 20 mg / kg, or from about 0.1 mg / kg to about 10 mg / kg of subject body weight, one or more times a day. In some preferred embodiments, the COX inhibitor can be administered at dosage levels of from about 0.1 to about 20 mg / kg.

[0374] In certain embodiments, the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be administered at dosage levels of from about 0.1 mg / kg to about 50 mg / kg, or from about 0.1 mg / kg to about 40 mg / kg, or from about 0.1 mg / kg to about 30 mg / kg, or from about 0.1 mg / kg to about 20 mg / kg, or from about 0.1 mg / kg to about 10 mg / kg of subject body weight, one or more times a day. In some preferred embodiments, the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be administered at dosage levels of from about 0.1 to about 30 mg / kg, or from about 0.1 mg / kg to about 20 mg / kg, or from about 0.1 mg / kg to about 15 mg / kg.

[0375] In certain embodiments, the COX inhibitor can be administered at dosage levels of from about 0.1 to about 20 mg / kg and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be administered at dosage levels of from about 0.1 to about 30 mg / kg.

[0376] In certain embodiments, the COX inhibitor can be administered at dosage levels of from about 0.1 to about 20 mg / kg and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be administered at dosage levels of from about 0.1 mg / kg to about 20 mg / kg.

[0377] In certain embodiments, the COX inhibitor can be administered at dosage levels of from about 0.1 to about 20 mg / kg and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be administered at dosage levels of from about 0.1 mg / kg to about 15 mg / kg.

[0378] In some embodiments, the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered in a single dosage form. In other embodiments, the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered each in an individual dosage form. In some embodiments, the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered simultaneously or sequentially. In some embodiments, the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered simultaneously. In some embodiments, the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered sequentially. It is to be noted that when the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered sequentially, they can be administered in any order. Hence, the COX inhibitor can be administered first and then the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered. Alternatively, the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered first and the COX inhibitor in second.

[0379] Upon improvement of a subject's condition, a maintenance dose of the pharmaceutical combination of the present description may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. The subject may, however, require intermittent treatment on a longterm basis upon any recurrence of disorder symptoms.

[0380] The total daily inhibitory dose of the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof as defined herein, administered to a subject in single or in divided doses, can be in amounts, for example, from 0.01 to 50 mg / kg body weight, or more usually from 0.1 to 30 mg / kg body weight. Single dose formulations may contain such amounts or submultiples thereof to make up the daily dose. In some embodiments, treatment regimens according to the present description can comprise administration to a patient in need of such treatment of from about 1 mg to about 1000 mg per day in single or multiple doses, of the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0381] The pharmaceutical combinations described herein may be commercialized in the form of a kit. The kit can comprise at least one single dose form of the COX inhibitor (also referred to as “first single dose form of the COX inhibitor”) and at least one single dose form of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein (also referred to as “second single dose form of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof’). It should be noted that the terms “first” and “second” with reference to the single dose forms of each active ingredient, are used to differentiate the single dose forms and do not relate to any order for using / administering these dose forms. In fact, each of the first and second single dose forms can be administered in any order or even simultaneously.

[0382] The kit can thus comprise separate dose forms (dose units) of the COX inhibitor and of the compound having the Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof. Each separate dose can include the same amount of the therapeutically active ingredients or different amounts thereof. In some embodiments, the kit can be tailored for a specific patient by selecting suitable amounts of each therapeutically active ingredient. The kit generally also includes instructions for its proper use by a patient.

[0383] In some embodiments, the kit is such that the first single dose form can include the COX inhibitor in any amount as described above with respect to the pharmaceutical combinations. In some embodiments, the kit is such that the second single dose form can include the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof in any amount as described above with respect to the pharmaceutical combinations.

[0384] In some embodiments, the kit is such that the amount of the COX inhibitor in the first single dose form and the amount of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof in the second single dose form, provide a ratio of the COX inhibitor to the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as described above with respect to the pharmaceutical combinations.

[0385] In some embodiments, the kit can include a first single dose form of the COX inhibitor and a second single dose form of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, and is useful for the treatment of a patient suffering from pain, such as any of the pain disclosed in the present disclosure. In some embodiments, the use of the kit, can result in a synergistic effect of the COX inhibitor and of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in alleviating pain.

[0386] EXAMPLES

[0387] General Methods

[0388] Preparation of the thiophene fused cyclohexanone derivative compounds

[0389] Reagent grade chemicals and anhydrous solvents were purchased from commercial sources and, unless otherwise mentioned, were used without further purification. The names of the products were determined using the naming software included in ChemDraw (PerkinElmer). Where it is stated that compounds were prepared analogously to earlier examples or intermediates, reaction time, number of equivalents of reagents, temperature, work-up and purification techniques may differ slightly from the described example.

[0390] Purifications

[0391] Chromatographic separations were performed on:

[0392] - Teledyne ISCO CombiFlash flash chromatography systems, using pre-packaged SiC>2 or Cis columns.

[0393] - Teledyne ISCO ACCQPrep high pressure preparative liquid chromatography system; Column: Gemini 5 urn C18 110 A, 150 x 30 mm.

[0394] - Biotage Isolera flash chromatography systems, using pre-packaged SiO2or Ci8columns.

[0395] - Waters Mass Trigger Semi-Prep HPLC; Column: Gemini 5 urn NX-C18 110 A, 100 x 30 mm.

[0396] Chiral separations were performed on:

[0397] - Mettler Toledo Berger Minigram supercritical fluid chromatography; Column: ChiralPak IG, 20 x 250 mm or ChiralPak IG, 10 x 250 mm.

[0398] - Waters ACQUITY UPC2 supercritical fluid chromatography; Column: ChiralPak IG, 10 x 250 mm.

[0399] Analytical Methods

[0400] LC-MS were performed on:

[0401] - Waters UPLC-MS; Column: Acquity UPLC, CSH C18, 1.7 urn, 2.1 x 30 mm; Methods: from 5% to 95% of CH3CN in H2O with 0.1% (v / v) formic acid in 2 min or from 5% to 95% of CH3CN in 10 mM ammonium bicarbonate in 2 min.

[0402] - Agilent HPLC-MS; Column: Kinetex EVO C18 100 A 2.6 urn, 50 x 3 mm; Method: from 10% to 95% of CH3CN with 0.1% (v / v) formic acid in H2O with 0.1% (v / v) formic acid in 4.5 min.

[0403] - Agilent UPLC-MS; Column: Kinetex EVO C18 100 A 1.7 urn, 50 x 3 mm; Method: from 5% to 95% of CH3CN with 0.1% (v / v) formic acid in H2O with 0.1% (v / v) formic acid in 3 min.

[0404] Analytical SFC were performed on Waters ACQUITY UPC2; Column: ChiralPak IG 4.6 x 250 mm or ChiralPak IC 4.6 x 150 mm. NMR spectroscopy was carried out using a Varian NMR (AS 400) 400 MHz Spectrometer with Inova interface. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (0) are given in parts-per-million using conventional abbreviations for designation of peaks: e.g. s, singlet; d, doublet; t; triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; etc. Abbreviations 9-BBN 9-Borabicyclo[3.3.1]nonane δ Chemical shift

[0405] A Angstrom

[0406] Ac Acetyl

[0407] Bn Benzyl

[0408] Boc fert-Butoxycarbonyl bs “Broad singlet”

[0409] Bu Butyl

[0410] Calcd Calculated d Doublet

[0411] DAST Diethylaminosulfur trifluoride dd Doublet of doublets dt Doublet of triplets

[0412] DCM Dichloromethane

[0413] DDQ 2,3-Dichloro-5,6-dicyano-1 ,4-benzoquinone DIBALH Diisobutylaluminium hydride

[0414] DIPEA N,N-Diisopropylethylamine

[0415] DMAP 4-Dimethylaminopyridine

[0416] DMF N,N-Dimethylformamide

[0417] DMP Dess-Martin periodinane

[0418] DMPU N,N'-Dimethylpropyleneurea

[0419] DMSO Dimethylsulfoxyde

[0420] Dppf 1 , 1 ’-Bis(diphenylphosphino)ferrocene

[0421] EA Ethyl acetate ee Enantiomeric excess

[0422] Et Ethyl

[0423] EtOH Ethanol eq Equivalents g Gram

[0424] HATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uranium

[0425] Hz Hertz HPLC High performance liquid chromatography i-Pr Isopropyl

[0426] J Coupling constant

[0427] L Liter

[0428] LC-MS Liquid chromatography-mass spectrometry

[0429] LDA Lithium diisopropylamide

[0430] LHMDS Lithium bis(trimethylsilyl)amide

[0431] M Molar m Multiplet mCPBA meta-chloroperoxybenzoic acid

[0432] Me Methyl

[0433] MeOH Methanol mg Milligram

[0434] MHz Megahertz min Minutes mL Milliliter mm Milimeter mmol Millimole mol Mole

[0435] MS Mass spectrometry

[0436] N Normal

[0437] NBS / V-bromosuccinimide

[0438] PCC Pyridinium chlorochromate pH Potential of hydrogen

[0439] Ph Phenyl

[0440] PPh3Triphenylphosphine ppm Parts per million

[0441] PyBOP Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate q Quadruplet

[0442] RT Room temperature rt Retention time

[0443] NMR Nuclear magnetic resonance s Singulet sat Saturated

[0444] SFC Supercritical fluid chromatography sxt sextuplet t tert t Triplet tt Triplet of triplet t-Bu tert-Butyl

[0445] TMS Trimethylsilyl

[0446] TFA Trifluoroacetic acid THF Tetrahydrofuran

[0447] Ts Tosyl uL Microliter umol Micromole v / v Volume / volume

[0448] ° Degree

[0449] % Percentage

[0450] Example 1 2-Amino-7-oxo-5-(2-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (4) Scheme 1

[0451] Step 1. 2-(3-Oxo-5-(2-(trifluoromethyl)phenyl)cyclohexylidene)malononitrile (2)

[0452] A solution of malononitrile (100 mg, 1.51 mmol, recrystallized from EtOH), triethylamine (253 uL, 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 uL of triethylamine (1.82 mmol) were added and the mixture was stirred at 80 °C for 16 hours. The mixture was then allowed to cool to RT, concentrated to dryness, and the crude product 2 was used in Step 2 without purification. LC-MS: rt = 1 .94 min, MS: 304.1 (calcd), 305.1 (M+H+, found).

[0453] Step 2. 2-Amino-7-oxo-5-(2-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carbonitrile (3)

[0454] A mixture of sulfur (50.9 mg, 198 umol), diethylamine (157 uL, 1.52 mmol) and 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 allowed to cool to RT and concentrated by rotary evaporation and the residue was purified by flash column chromatography (eluent gradient from 40% to 100% of EA in hexane) to afford title compound 3 as a light-brown solid (220 mg, 43% yield over two steps). LC-MS: rt = 1.73 min, MS: 336.1 (calcd), 337.0 (M+H+, found). Step 3. 2-Amino-7-oxo-5-(2-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (4)

[0455] 30% Aqueous hydrogen peroxide solution (0.33 mL) was added to a suspension of 3 (41.1 mg, 122 umol) and potassium carbonate (33.8 mg, 244 umol) in DMSO (1.64 mL). The mixture was stirred at RT for 2 hours, then partitioned between EA and water (20 mL each). The layers were separated and the aqueous phase was extracted with another 20 mL of EA. The combined organics were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and dried in vacuo to afford title compound 4 as a light-yellow solid (36.7 mg, 85% yield).

[0456] 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.06 (s, 2H), 7.90 (d, J = 8.0 Hz, 1 H), 7.76-7.68 (m, 2H), 7.49 (t, J = 7.7 Hz, 1 H), 6.96 (bs, 2H), 3.73-3.58 (m, 1 H), 3.40-3.29 (m, 1 H), 3.07-2.90 (m, 2H), 2.36 (dd, J = 16.3, 3.8 Hz, 1 H).19F NMR: 376 MHz, DMSO-d6, δ (ppm): -57.5 (s). LC- MS: rt = 1.40 min, MS: 354.1 (calcd), 355.1 (M+H+, found).

[0457] Example 2 2-Amino-N-cyclopropyl-6-ethyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (9)

[0458] Scheme 2

[0459] Step 1 . Ethyl 2-cyano-2-(4-ethyl-3-oxocyclohexylidene)acetate (6)

[0460] A mixture of 4-ethylcyclohexane-1 , 3-dione (5, 150 mg, 910 umol) (Synlett. 2012, 1 199- 1204), triethylamine (380 uL, 2.73 mmol) and ethyl 2-cyanoacetate (145 uL, 1.36 mmol) in EtOH (784 uL) was stirred at 80 °C for 16 hours. Then, another 100 uL of ethyl 2-cyanoacetate (0.94 mmol) and 130 uL of triethylamine (0.93 mmol) were added and the resulting mixture was stirred at 80 °C for another 24 hours. The mixture was then allowed to cool to RT, concentrated to dryness, and the crude product 6 was used in Step 2 without purification. LC-MS: rt = 1.73 min, MS: 235.1 (calcd), 236.1 (M+H+, found).

[0461] Step 2. Ethyl 2-amino-6-ethyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (7)

[0462] A mixture of crude 6 (214 mg, 910 umol; assuming the quantitative yield in Step 1), sulfur (30.6 mg, 1 19 umol) and diethylamine (94.1 uL, 910 umol) in EtOH (910 uL) was stirred at 80 °C for 2 hours. The mixture was then allowed to cool to RT, concentrated to dryness, and the residue was purified by flash column chromatography (eluent gradient from 5% to 50% of EA in hexane) to afford title compound 7 as a yellow solid (135.2 mg, 52% yield over two steps). LC-MS: rt = 1.77 min, MS: 267.1 (calcd), 268.1 (M+H+, found).

[0463] Step 3. 2-Amino-6-ethyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]1thiophene-3-carboxylic acid (8)

[0464] Lithium hydroxide monohydrate (68.0 mg, 1.62 mmol) was added to 7 (86.6 mg, 324 umol) 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 allowed to cool to RT, diluted with water (20 mL) and washed with EA (20 mL). The organic phase was discarded and the aqueous phase was then acidified to pH 2-3 using 3 N HCI and extracted using EA (3 x 20 mL). The combined organics were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to afford title compound 8 as an off- white solid (60.5 mg, 78% yield). The crude product was used in Step 4 with no additional purification. (See table 6 for characterization)

[0465] Step 4. 2-Amino- / V-cyclopropyl-6-ethyl-7-oxo-4,5,6,7-tetrahydroben N,N1thiophene-3- carboxamide (9)

[0466] To a solution of 8 (60.5 mg, 253 umol) in DMF (3.16 mL) were added N,N- diisopropylethylamine (132 uL, 758 umol), cyclopropylamine (19.3 uL, 278 umol) and HATU (115 mg, 303 umol). The resulting mixture was stirred at RT for 16 hours. The mixture was then diluted with saturated aqueous NH4CI (30 mL) and extracted with EA (3 x 20 mL). The combined organics were washed with ice-cold brine (40 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was first purified by flash column chromatography (eluent gradient from 1% to 10% of MeOH in DCM) and then recrystallized from hot EA to afford title compound 9 as a white solid (16.4 mg, 23% yield).

[0467] 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.68 (d, J = 5.7 Hz, 2H), 7.34 (d, J = 3.8 Hz, 1 H), 2.86 (dt, J = 17.3, 5.2 Hz, 1 H), 2.76 (ddt, J = 19.0, 7.1 , 4.2 Hz, 2H), 2.20 (ddt, J = 9.4, 7.8, 4.7 Hz, 1 H), 2.06 (dq, J = 13.2, 5.0 Hz, 1 H), 1.82-1.67 (m, 2H), 1.50-1.33 (m, 1 H), 0.90 (t, J = 7.4 Hz, 3H), 0.66 (td, J = 7.0, 4.6 Hz, 2H), 0.57-0.47 (m, 2H). LC-MS: rt = 1.26 min, MS: 278.1 (calcd), 279.1 (M+H+, found).

[0468] Example 3 2-Amino-6-(2-chlorophenyl)-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (15)

[0469] Scheme 3

[0470]

[0471] 15: Example 3

[0472] Step 1. Ethyl 2-((di-tert-butoxycarbonyl)amino)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate (11)

[0473] 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) were added triethylamine (2.85 mL, 20.4 mmol), 4-dimethylaminopyridine (228 mg, 1.85 mmol) and di-tert-butyldicarbonate (4.44 g, 20.4 mmol). The resulting solution was stirred under reflux for 4 hours. The mixture was then allowed to cool to RT, diluted with DCM (50 mL) and washed successively with 1 N HCI, water and brine (70 mL each). The organic phase was dried over Na2SO4, filtered and concentrated and the residue was purified by flash column chromatography (eluent gradient from 10% to 60% of EA in hexane) to afford title compound 11 as a light-orange solid (3.42 g, 84% yield). LC-MS: rt = 1.78 min, MS: 439.2 (calcd), 462.2 (M+Na+, found).

[0474] Step 2. Ethyl 2-((di-tert-butoxycarbonyl)amino)-6-cyano-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (12)

[0475] To a solution of LDA (10.4 mL, 1 M in THF / hexane, 10.4 mmol) cooled to -78 °C under Ar was added 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 min, 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 min, then from -78 °C to RT for 4 hours. Subsequently, the mixture was quenched with saturated aqueous NH4CI (200 mL) and extracted with DCM (2 x 200 mL). The combined organics were dried over Na2SO4, filtered and concentrated, and the residue was purified by flash column chromatography (eluent gradient from 5% to 50% of EA in hexane) to afford title compound 12 as a light-yellow solid (1.13 g, 46% yield). LC-MS: rt = 1.73 min, MS: 464.2 (calcd), 487.2 (M+Na+, found).

[0476] Step 3. Ethyl 2-((tert-butoxycarbonyl)amino)-6-(2-chlorophenyl)-6-cyano-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (13)

[0477] To a flame-dried microwave vial charged with f-BuOK (57.5 mg, 512 umol) and anhydrous DMF (860 uL) under Ar was added 12 (200 mg, 431 umol) in anhydrous DMF (1.3 mL). The resulting mixture was stirred at 0 °C for 35 min, then bis(2-chlorophenyl)iodonium tetrafluoroborate (188 mg, 431 umol) (J. Am. Chem. Soc. 2016, 13183-13186.) in anhydrous DMF (430 uL) was added dropwise and the mixture was stirred at RT for 2.5 hours. Then, more bis(2- chlorophenyl)iodonium tetrafluoroborate (40 mg, 92 umol dissolved in 500 uL of anhydrous DMF) was added and the mixture was stirred at RT for 16 hours. The mixture was then diluted with water (2 mL) and acidified with 1 N HCI to pH 6-7. Another 10 mL of water was added and the product was extracted with EA (3 x 20 mL). The combined organics were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was taken up in heptanes and concentrated by rotary evaporation several times to get rid of residual DMF. The resulting solid was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 13 as a light-yellow solid (40 mg, 20% yield). LC-MS: rt = 2.06 min, MS: 474.1 (calcd), 475.1 (M+H+, found).

[0478] Step 4. 2-Amino-6-(2-chlorophenyl)-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (14)

[0479] TFA (2.26 mL, 29.6 mmol) was added dropwise to a solution of 13 (40.0 mg, 84.2 umol) in DCM (4.6 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour, then concentrated to dryness to afford a crude intermediate as a brown solid (33 mg), which was dissolved in MeOH (10 mL). A solution of lithium hydroxide monohydrate (17.4 mg, 414 umol) in water (10 mL) was added to the solution, which was stirred under reflux for 1 hour. The mixture was then allowed to cool to RT and concentrated to dryness. The residue was washed with EA (10 mL), then acidified to pH 1-2 using 1 N HCI and extracted with EA (3 x 10 mL). The combined organics were dried over Na2SO4, filtered and concentrated to afford title compound 14 as a brown solid (26.9 mg, 94% yield). The crude product was used in Step 5 with no additional purification. (See table 6 for characterization)

[0480] Step 5. 2-Amino-6-(2-chlorophenyl)-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (15)

[0481] To a suspension of 14 (19.9 mg, 57.4 umol) in CHCl3(398 uL) were added N,N- diisopropylethylamine (30.0 uL, 172 umol), saturated NH3solution in CHCl3(0.3 mL) (prepared in-house) and HATU (24.0 mg, 63.1 umol). The mixture was stirred at RT. After stirring for 5 hours, another 24 mg of HATU (63.1 umol) and 0.5 mL of saturated NH3solution in CHCI3were added. The mixture was stirred for 16 hours, then another 25 mg of HATU (65.7 umol) and 0.6 mL of saturated NH3solution in CHCI3were added and stirring continued for another 4.5 hours. The mixture was then diluted with 5 mL of water and 5 mL CHCl3. The layers were separated and the aqueous phase was extracted with CHCI3(2 x 5 mL). The combined organics were dried over Na2SO4, filtered and concentrated, and the residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v / v) formic acid) to afford title compound 15 as a white solid (6.2 mg, 31% yield).

[0482] 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.73-7.68 (m, 1 H), 7.50-7.45 (m, 1 H), 7.45-7.40 (m, 2H), 3.29-3.11 (m, 3H), 2.48-2.41 (m, 1 H). LC-MS: rt = 1.15 min, MS: 345.0 (calcd), 346.0 (M+H+, found). Examples 4-27

[0483] Compounds 16-34 (examples 4-22) were synthesized starting from appropriately substituted diketones by following the procedures 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 fashion by following the procedures described above for the synthesis of compound 8 (scheme 2). Compounds 37-39 (examples 25-27) were synthesized in a similar fashion by following the procedures described above for the synthesis of compound 9 (scheme 2). Characterization of compounds 16-39 (examples 4-27) is provided in the table 2.

[0484] Table 2. Characterization of compounds 16-39 (examples 4-27).

[0485] Example 28 -Amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (47) and

[0486] Example 29 2-Amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-

[0487] 3-carboxamide (48)

[0488] Scheme 4

[0489]

[0490] Step 1. 8-(Cyclobutylmethyl)-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (41)

[0491] A flame-dried round bottom flask was charged with a solution of LDA (2.69 mL, 1 M in THF / hexane, 2.69 mmol) in anhydrous THF (3.60 mL) under Ar. The solution was cooled to -78 °C and 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40, 265 uL, 1.79 mmol) was added. The mixture was stirred at -78 °C for 30 min, then (bromomethyl)cyclobutane (202 uL, 1 .79 mmol) was added. The reaction vessel was removed from the acetone / dry ice bath and the solution was stirred at RT for 64 hours. The mixture was then partitioned between EA and water (15 mL each), the layers were separated and the aqueous phase was extracted with EA (2 x 15 mL). The combined organics were dried over Na2SO4, filtered and concentrated to afford the crude title compound 41 as an orange oil, which was used in Step 2 without purification and without characterization.

[0492] Step 2. 1-(Cyclobutylmethyl)-4-oxocyclohexane-1-carbonitrile (42)

[0493] A solution of 41 (422 mg, 1.79 mmol, assuming the quantitative yield in Step 1) in acetone (25.3 mL) was treated with 2 N HCI (4.59 mL, 9.19 mmol) and the resulting mixture was stirred at 40 °C for 64 hours. The mixture was then allowed to cool to RT, concentrated by rotary evaporation to remove acetone, and the aqueous residue was extracted with EA (3 x 30 mL). The combined organics were dried over Na2SO4, filtered and concentrated to afford the crude title compound 42 as a brown solid, which was used in Step 3 without purification and without characterization.

[0494] Step 3. Ethyl 2-amino-6-cyano-6-(Cyclobutylmethy-l)4,5,6,7-tetrahydrobenzo[b]thiophene-3-

[0495] A suspension of ethyl 2-cyanoacetate (210 uL, 1.97 mmol), morpholine (172 uL, 1.97 mmol), sulfur (63 mg, 247 umol) 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 allowed to cool to RT, then concentrated by rotary evaporation and the residue was partitioned between EA and water (20 mL each). The organic phase was dried over Na2SO4, filtered and concentrated and the residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 43 as a light-yellow solid (353 mg, 62% yield over three steps). LC-MS: rt = 1.74 min, MS: 318.1 (calcd), 319.1 (M+H+, found).

[0496] Step 4. Ethyl 2-acetamido-6-cyano-6-(Cyclobutylmethy-l)4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate (44)

[0497] A suspension of 43 (227 mg, 713 umol) in acetic acid (4.09 mL) was treated with acetic anhydride (80.9 uL, 856 umol) and the resulting mixture was stirred at 70 °C for 3 hours. The mixture was then allowed to cool to RT and concentrated to dryness. The residue was diluted with DCM (10 mL) and washed successively with saturated aqueous NaHCO3, water and brine (10 mL each), then dried over Na2SO4, filtered and concentrated to afford title compound 44 as a yellow solid (227 mg, 88% yield). LC-MS: rt = 1.79 min, MS: 360.2 (calcd), 361.1 (M+H+, found).

[0498] Step 5. Ethyl 2-acetamido-6-cyano-6-(cyclobutylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (45)

[0499] To a suspension of 44 (227 mg, 630 umol) in acetic acid (2.1 mL) and water (6.3 mL) was added ceric sulfate (1 .81 g, 5.44 mmol). The mixture was sonicated for 1 min, then stirred at RT for 88 hours. Subsequently, the mixture was diluted with water and EA (30 mL each), sonicated for 3 minutes and transferred into a separatory funnel. The layers were separated and the organic phase was washed successively with 1 N NaOH and brine (30 mL each), then dried over Na2SO4, filtered and concentrated to afford title compound 45 as a yellow gum (175.1 mg, 74% yield), which was used in Step 6 without purification. LC-MS: rt = 1.71 min, MS: 374.1 (calcd), 375.2 (M+H+, found).

[0500] Step 6. Ethyl 2-amino-6-cyano-6-(cyclo butylmethyl)-7-oxo-4, 5,6,7- tetrahydro benzo[b]thiophene-3-carboxylate (46)

[0501] A solution of 45 (170 mg, 454 umol) in toluene (744 uL) was treated with pyrrolidine (559 uL, 6.81 mmol) and stirred at RT for 1 hour. The mixture was then concentrated by rotary evaporation and the residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 46 as an off-white solid (1 18.1 mg, 78% yield). LC-MS: rt = 1.63 min, MS: 332.1 (calcd), 333.1 (M+H+, found).

[0502] Step 7. 2-Amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (47)

[0503] 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 umol) in MeOH (38.4 mL). The mixture was stirred under reflux for 16 hours, then allowed to cool to RT and concentrated by rotary evaporation to remove most of MeOH. The aqueous residue was washed with EA (2 x 25 mL), then acidified to pH 1-2 using 3 N HCI and extracted with EA (3 x 25 mL). The organics were dried over Na2SO4, filtered and concentrated to afford title compound 47 as an off-white solid (78.2 mg, 81 % yield).1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.75 (bs, 1 H), 8.48 (bs, 2H), 3.08-3.02 (m, 2H), 2.55-2.42 (m, 1 H), 2.43-2.29 (m, 1 H), 2.27-2.16 (m, 1 H), 2.13-1.96 (m, 3H), 1.93-1.61 (m, 5H). LC-MS: rt = 1.32 min, MS: 304.1 (calcd), 305.1 (M+H+, found).

[0504] Step 8. 2-Amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (48)

[0505] To a suspension of 47 (38.3 mg, 126 umol), saturated NH3solution in chloroform (780 uL) (prepared in-house), ammonium chloride (135 mg, 2.52 mmol) and N,N-diisopropylethylamine (43.8 uL, 252 umol) in DMF (1.39 mL) was added HATU (73.2 mg, 189 umol). The resulting mixture was stirred at RT for 16 hours, then diluted with saturated aqueous NH4CI (20 mL) and extracted with EA (3 x 10 mL). The combined organics were washed with ice-cold brine (2 x 15 mL), dried over Na2SO4, filtered and concentrated. The residue was first purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v / v) formic acid) and then Semi-Prep HPLC-MS (eluent gradient from 25% to 100% of CH3CN in 10 mM ammonium bicarbonate) to afford title compound 48 as a white solid (14.5 mg, 38%).

[0506] 1H NMR (400 MHz, CD3OD): δ 3.16-3.08 (m, 2H), 2.65-2.57 (m, 1 H), 2.47 (ddd, J = 13.3, 7.7, 5.4 Hz, 1 H), 2.30 (ddd, J = 13.7, 6.0, 5.0 Hz, 1 H), 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 (calcd), 304.1 (M+H+, found).

[0507] 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)

[0508] Scheme 5

[0509] 2-Amino-6-cyano-6-(Cyclobutylmethyl) -7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (49)

[0510] Compound 49 (example 30) was synthesized similarly to compound 47 (example 28, scheme 4) starting from 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40) and using in the first step (bromomethyl)cyclopentane instead of (bromomethyl)cyclobutane.

[0511] 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.75 (bs, 1 H), 8.48 (bs, 2H), 3.13-3.00 (m, 2H), 2.48-2.38 (m, 1 H), 2.29 (dt, J = 13.5, 5.2 Hz, 1 H), 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 (calcd), 319.1 (M+H+, found). 2-Amino-6-cyano-6-(cyclopentylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide

[0512] To a suspension of 49 (40.0 mg, 126 umol), saturated NH3solution in chloroform (741 uL) (prepared in-house), ammonium chloride (134 mg, 2.51 mmol) and N,N-diisopropylethylamine (43.8 uL, 252 umol) in DMF (1.39 mL) was added HATU (73.1 mg, 188 umol). The resulting mixture was stirred at RT for 16 hours, then another 40 uL of N,N-diisopropylethylamine (230 umol), 550 uL of saturated NH3solution in chloroform and 65 mg of HATU (167 umol) were added and the mixture was stirred at 40 °C for 24 hours. Subsequently, the mixture was partitioned between saturated aqueous NH4CI and EA (20 mL each), the layers were separated and the organic phase was washed with ice-cold brine (2 x 15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v / v) formic acid) to afford title compound 50 as an off-white solid (14.5 mg, 36%).

[0513] 1H NMR: 400 MHz, CD3OD, δ (ppm): 3.25-3.05 (m, 2H), 2.54 (ddd, J = 13.4, 7.9, 5.4 Hz, 1H), 2.38 (ddd, J = 13.7, 5.9, 5.0 Hz, 1 H), 2.12 (dd, J = 13.5, 6.7 Hz, 1 H), 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 (calcd), 318.0 (M+H+, found).

[0514] 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)

[0515] Scheme 6

[0516] 2-Amino-6-cyano-6-(cyclohexylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- ic acid

[0517] Compound 51 (example 32) was synthesized similarly to compound 47 (example 28, scheme 4) starting from 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40) and using in the first step (bromomethyl)cyclohexane instead of (bromomethyl)cyclobutane.

[0518] 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.69 (bs, 1 H), 8.48 (bs, 2H), 3.12-2.97 (m, 2H), 2.47-2.36 (m, 1 H), 2.27 (dt, J = 13.7, 5.5 Hz, 1 H), 1.84-1.54 (m, 6H), 1.53-1.46 (m, 1 H), 1.28-1.07 (m, 4H), 1.03-0.90 (m, 2H). LC-MS: rt = 1.49 min, MS: 332.1 (calcd), 333.0 (M+H+, found). 2-Amino-6-cyano-6-(cyclohexylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (52)

[0519] To a solution of 51 (24.0 mg, 72.2 umol) in DMF (798 uL) were added PyBOP (56.5 mg, 108 umol), N,N-diisopropylethylamine (40.0 uL, 230 umol) and ammonium chloride (38.6 mg, 722 umol). The resulting mixture was stirred at RT for 80 minutes, then diluted with saturated aqueous NH4CI (5 mL) and extracted with EA (3 x 5 mL). The combined organics were washed with ice- cold brine (2 x 10 mL), dried over Na2SO4, filtered and concentrated and the residue was purified by flash column chromatography (eluent gradient from 10% to 100% of EA in hexane) to afford title compound 52 as an orange solid (13.6 mg, 57% yield).

[0520] 1H NMR: 400 MHz, CD3OD, δ (ppm): 3.18-3.09 (m, 2H), 2.51 (ddd, J = 13.3, 7.5, 5.6 Hz, 1H), 2.36 (dt, J= 13.6, 5.5 Hz, 1 H), 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 (calcd), 332.2 (M+H+, found).

[0521] Example 34 2-Amino-6-cyano-6-(cyclopropylmethyl)-7 -oxo-4, 5,6, 7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (53) and

[0522] Example 35 2-Amino-6-cyano-6-(cyclopropylmethyl)-7 -oxo-4, 5,6, 7-tetrahydrobenzo[b]thiophene-3- carboxamide (54)

[0523] 53: Example 34 54: Example 35

[0524] 2-Amino-6-cyano-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-

[0525] ✓lic acid (53).

[0526] Compound 53 (example 34) was synthesized similarly to compound 47 (example 28, scheme 4) starting from 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40) and using in the first step (bromomethyl)cyclopropane instead of (bromomethyl)cyclobutane.

[0527] 1H NMR: 400 MHz, CD3OD, δ (ppm): 3.23-3.19 (m, 2H), 2.54-2.50 (m, 1 H), 2.42-2.39 (m, 1 H), 1.89 (dd, J = 14.27, 7.15 Hz, 1 H), 1.78 (dd, J = 14.26, 6.72 Hz, 1 H), 0.91-0.87 (m, 1 H), 0.57- 0.53 (m, 2H), 0.22-0.19 (m, 2H). LC-MS: rt = 1.18 min, MS: 290.1 (calcd), 291.0 (M+H+, found).

[0528] 2-Amino-6-cyano-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (54).

[0529] To a suspension of 53 (36.4 mg, 0.125 mmol) in CHCl3(871 uL) was added HATU (52.4 mg, 0.138 mmol) and N,N-diisopropylethylamine (65.5 uL, 0.376 mmol). The mixture was stirred 20 min at RT and to it was added saturated NH3solution in CHCI3(0.8 mL) (prepared in-house) and NH4CI (6.71 mg, 0.125 mmol). The reaction mixture was stirred for 16 hours and partitioned between EA and a saturated aqueous solution of NaHCO3. The layers were separated and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 20% to 100% of EA in hexane) to afford title compound 54 as a white solid (20.0 mg, 55% yield).

[0530] 1H NMR: 400 MHz, CD3OD, δ (ppm): 3.13 (t, J = 6.03 Hz, 2H), 2.60-2.53 (m, 1 H), 2.48- 2.42 (m, 1 H), 1.93 (dd, J = 14.28, 7.11 Hz, 1 H), 1.80 (dd, J = 14.28, 6.79 Hz, 1 H), 0.94-0.84 (m, 1 H), 0.58-0.55 (m, 2H), 0.24-0.20 (m, 2H). LC-MS: rt = 1 .02 min, MS: 289.1 (calcd), 290.1 (M+H+, found).

[0531] Example 36 2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid

[0532] Step 1 . Ethyl 2-amino-6-cyano-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate (56).

[0533] To a solution of 4-oxo-1-phenylcyclohexane-1 -carbonitrile (55) (6.00 g, 30.1 mmol) and ethyl 2-cyanoacetate (2.91 mL, 27.4 mmol) in EtOH (48.0 mL) were added 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. The mixture was allowed to cool to RT and a white precipitate appeared. This solid was collected by filtration, washed with EtOH and dried in vacuo to afford title compound 56 as a white solid (8.15 g, 91% yield). LC-MS: rt = 1.55 min, MS: 326.1 (calcd), 327.0 (M+H+, found).

[0534] Step 2. Ethyl 2-acetamido-6-cyano-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate (57).

[0535] To a solution of 56 (8.15 g, 25.0 mmol) in acetic acid (143 mL) was added acetic anhydride (2.83 mL, 30.0 mmol). The mixture was stirred at 60 °C for 1 day, then allowed to cool to RT and concentrated to dryness. The residue was partitioned between DCM and water. The layers were separated and the organic phase was washed with a saturated aqueous solution of NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 57 as a white solid (9.0 g, 98% yield). LC-MS: rt = 1 .61 min, MS: 368.1 (calcd), 369.1 (M+H+, found).

[0536] Step 3. Ethyl 2-acetamido-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate (58).

[0537] To a solution of 57 (9.00 g, 24.4 mmol) in acetic acid (66 mL) and water (66 mL) was added ceric sulfate (70.1 g, 211 mmol). The mixture was sonicated until it became homogenous, and stirred at RT for 24 hours. The suspension was partitioned between EA and water. The layers were separated and the organic phase was washed with NaOH 1 N, water and brine. The organic layer was then dried over Na2SO4, filtered and concentrated to afford title compound 58 as an off- white solid (9.10 g, 97% yield). LC-MS: rt = 1.56 min, MS: 382.1 (calcd), 383.1 (M+H+, found).

[0538] Step 4. 2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (59).

[0539] To a suspension of 58 (4.00 g, 10.44 mmol) in MeOH (1.26 L) was added 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, then allowed to cool to RT. The mixture was diluted with water and concentrated to remove most of the organic solvent, then washed with EA. The aqueous layer was acidified by slow addition of HCI 3 N and extracted with EA. This organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by trituration with a DCM / pentane mixture to afford title compound 59 as a greyish solid (2.54 g, 78% yield).

[0540] 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.43-7.31 (m, 5H), 3.27-3.23 (m, 1 H), 2.88-2.73 (m, 2H), 2.71-2.61 (m, 1 H). LC-MS: rt = 1.23 min, MS: 312.1 (calcd), 313.1 (M+H+, found).

[0541] Example 37

[0542] (R)-2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (60a)

[0543] (S)-2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (60b)

[0544] Racemic compound 59 (86.0 mg) was submitted to SFC chiral separation (isocratic 35% MeOH in CO2) to afford enantioenriched compound 60a as a light-pink solid (33.1 mg, 38% separation yield) and 60b as a white solid (35.4 mg, 41% separation yield) (the absolute configurations were assigned based on resolved crystal structure of enantiomer 60a). 60a:1H NMR: same as racemic mixture (59). LC-MS: rt = 1.23 min, MS: 312.1 (calcd),

[0545] 313.1 (M+H+, found). Analytical SFC (IG column with 5-60% MeOH in water (95-40% CO2) gradient): rt = 3.84 min, ee. = 99.9%.

[0546] 60b:1H NMR: same as racemic mixture (59). LC-MS: rt = 1.23 min, MS: 312.1 (calcd), 313.1 (M+H+, found). Analytical SFC (IG column with 5-60% MeOH in water (95-40% CO2) gradient): rt = 4.76 min, ee. = 97.6%.

[0547] Example 38 2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (61) and

[0548] Example 39 2-Amino-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3,6-dicarboxamide (62) Scheme 10

[0549] Step 1 . 2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (61).

[0550] To a solution of 59 (2.54 g, 8.13 mmol) in DMF (90.0 mL) were added HATU (4.73 g, 12.2 mmol) and N,N-diisopropylethylamine (2.83 mL, 16.4 mmol) and the mixture was stirred at RT for 20 min. Then, ammonium chloride (8.74 g, 163 mmol), NH3solution 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 RT for 16 hours and partitioned between EA and a saturated aqueous solution of NaHCO3. The layers were separated, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 20% to 100% of EA in hexane) and then by reverse-phase flash column chromatography (eluent gradient from 0% to 100% CH3CN in H2O with 0.1% (v / v) formic acid) to afford title compound 61 as a white solid (1 .20 g, 47% yield).

[0551] 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.41-7.36 (m, 5H), 3.17-3.11 (m, 1 H), 2.87-2.77 (m, 2H), 2.74-2.66 (m, 1 H). LC-MS: rt = 1.04 min, MS: 311.1 (calcd), 312.0 (M+H+, found).

[0552] Step 2. 2-Amino-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3,6-dicarboxamide (62)

[0553] 30% Aqueous hydrogen peroxide solution (170 uL) was added to a suspension of 61 (13.2 mg, 42.4 umol) and potassium carbonate (11.7 mg, 84.8 umol) in DMSO (569 uL). The mixture was stirred at RT for 3 hours, then partitioned between 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 x 3 mL). The combined organics were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 70% of CH3CN in H2O with 0.1 % (v / v) formic acid) to afford title compound 62 as a white solid (3.6 mg, 28% yield).

[0554] 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.41-7.25 (m, 5H), 3.05 (dt, J = 16.8, 4.2 Hz, 1 H), 2.78-2.59 (m, 3H). LC-MS: rt = 0.86 min, MS: 329.1 (calcd), 329.9 (M+H+, found).

[0555] Example 40 (S)-2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (63) and

[0556] Example 41 (R)-2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (64)

[0557] Scheme 11

[0558] Racemic compound 61 (96.5 mg) was submitted to SFC chiral separation (isocratic: 45% of CH3CN / EtOH 1 :1 in CO2) to yield enantioenriched compound 63 as a white solid (29.0 mg, 30% separation yield) and enantioenriched compound 64 as a white s olid (29.0 mg, 30% separation yield) (the absolute configurations were assigned based on resolved crystal structure of enantiomer 64).

[0559] 63:1H NMR: same as racemic mixture (61). LC-MS: rt = 1.04 min, MS: 311.1 (calcd), 312.0 (M+H+, found). Analytical SFC (IG column with 5-60% ACN / EtOH (95-40% CO2) gradient): rt = 4.71 min, ee. = >99.9%.

[0560] 64:1H NMR: same as racemic mixture (61). LC-MS: rt = 1.04 min, MS: 311.1 (calcd), 312.0 (M+H+, found). Analytical SCF (IG column with 5-60% ACN / EtOH (95-40% CO2) gradient): rt = 4.09 min, ee. = >99.9%.

[0561] Examples 42-49

[0562] Compounds 65-71 (examples 42-48) were synthesized by following a procedure similar to the one described above for the synthesis of compound 9 (example 2, scheme 2), starting from compound 59 (example 36, scheme 8) instead of compound 8, and using cyclobutylamine, cyclopentylamine, 3-aminoxetane, 3-aminotetrahydrofurane, 4-aminotetrahydropyrane, 2,2,2- trifluoroethylamine and 2,2-difluoroethan-1-amine respectively, instead of cyclopropylamine. Compound 72 (example 49) was obtained in the same fashion starting from compound 53 (example 34, scheme 7). Characterization of compounds 65-72 (examples 42-49) is provided in the table 3.

[0563] Table 3. Characterization of compounds 65-72 (examples 42-49). Example 50 2-Amino-6-cyano-6-isobutyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (75)

[0564] Scheme 12

[0565] Step 1. 1-lsobutyl-4-oxocyclohexane-1-carbonitrile (73).

[0566] To a solution of 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40, 221 uL, 1.50 mmol, scheme 4) in THF (3.0 mL) at -78 °C was added dropwise LDA (2.39 ml, 1 M in THF / hexane, 2.39 mmol). After 30 min, 1-bromo-2-methylpropane (164 uL, 1.50 mmol) was added dropwise and the reaction mixture was stirred at RT for 72 hours. The reaction mixture was then partitioned between hexane and water. The layers were separated and the aqueous phase was extracted with EA. The combined organic layers were combined, dried over Na2SO4, filtered and concentrated. The dry residue was dissolved in acetone (19.7 mL) and HCI 3 N (4.98 mL, 15.0 mmol) was added slowly. The mixture was stirred for 16 hours, then neutralized by slowly adding saturated NaHCO3solution and concentrated to remove the organic solvent. The remaining aqueous solution was extracted with EA and the organic layer was dried over Na2SO4, filtered and concentrated to dryness to afford title compound 73 (141 mg, 52% yield over two steps). LC-MS: rt = 1.45 min, MS: 179.1 (calcd), 180.0 (M+H+, found).

[0567] Step 2. 2-Amino-6-cyano-6-isobutyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (74).

[0568] To a solution of 73 (141 mg, 0.784 mmol) and cyanoacetamide (59.9 mg, 0.713 mmol) in EtOH (713 uL) were added morpholine (67.6 uL, 0.784 mmol) and sulfur (25.2 mg, 98.3 umol). The reaction mixture was stirred at 60 °C for 19 hours, allowed to cool to RT and concentrated to dryness. The residue was partitioned between EA and water. The layers were separated and the organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane) to afford title compound 74 as a beige solid (115 mg, 58% yield). LC-MS: rt = 1.49 min, MS: 277.1 (calcd), 277.9 (M+H+, found). Step 3. 2-Amino-6-cyano-6-isobutyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (75).

[0569] To a solution of 74 (30 mg, 0.108 mmol) in DMSO (643 uL) was added selenium dioxide (12.0 mg, 0.108 mmol). The reaction mixture was stirred at RT for 12 hours, then partitioned between brine and EA. The layers were separated and the organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 10% of MeOH in DCM) then by Semi-Prep HPLC-MS (35% to 100% MeOH in 10 mM ammonium formate pH = 3.8) to afford title compound 75 as a white solid (3.20 mg, 10% yield).

[0570] 1H NMR: 400 MHz, CD3OD, δ (ppm): 3.19-3.09 (m, 2H), 2.51 (ddd, J = 13.71 , 7.59, 5.42 Hz, 1 H), 2.36 (dt, J = 13.65, 5.45 Hz, 1 H), 1.97-1.85 (m, 2H), 1.80-1.75 (m, 1 H), 1.03 (d, J = 6.05 Hz, 6 H). LC-MS: rt = 1.11 min, MS: 291.1 (calcd), 292.1 (M+H+, found).

[0571] Example 51 2-Amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (81) and

[0572] Example 52 2-Amino-6-(cyanomethyl)- N-cyclopropyl-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (82)

[0573] Scheme 13

[0574] Step 1 . Ethyl 2-amino-6-(cyanomethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-

[0575] To a solution of 2-(4-oxo-1-phenylcyclohexyl)acetonitrile (76) (Bioorg. Med. Chem. Lett.,

[0576] 21 , p. 405, 2011) (705 mg, 3.31 mmol) and ethyl 2-cyanoacetate (351 uL, 3.01 mmol) in EtOH (3.01 mL) were added morpholine (285 uL, 3.31 mmol) and sulfur (106 mg, 0.415 mmol). The mixture was stirred at 60 °C for 16 hours, then allowed to cool to RT and a white precipitate formed. This solid was collected by filtration, washed with EtOH and dried in vacuo to afford title compound 77 as a white solid (682 mg, 67% yield). LC-MS: rt = 1.55 min, MS: 340.1 (calcd),

[0577] 341.1 (M+H+, found).

[0578] Step 2. Ethyl 2-acetamido-6-(cyanomethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate (78).

[0579] To a solution of 77 (682 mg, 2.00 mmol) in acetic acid (1 1.5 mL) was added acetic anhydride (227 uL, 2.40 mmol). The mixture was stirred at 60 °C for 24 hours, then allowed to cool to RT and concentrated to dryness. The residue was partitioned between DCM and water. The layers were separated and the organic phase was washed with a saturated aqueous solution of NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 78 as a white solid (766 mg, >99% yield). LC-MS: rt = 1.61 min, MS:

[0580] 382.1 (calcd), 383.1 (M+H+, found).

[0581] Step 3. Ethyl 2-acetamido-6-(cyanomethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (79).

[0582] To a solution of 78 (766 mg, 2.00 mmol) in acetic acid (6.73 mL) and water (6.73 mL) was added ceric sulfate (5.75 g, 17.3 mmol). The suspension was sonicated until it became homogenous, and stirred at RT for 1 day, then it was partitioned between EA and water. The layers were separated and the organic phase was washed with NaOH 1 N, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 79 as an off-white solid (794 mg, >99% yield). LC-MS: rt = 1.47 min, MS: 396.1 (calcd), 397.1 (M+H+, found).

[0583] Step 4. Ethyl 2-amino-6-(cyanomethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (80).

[0584] To a suspension of 79 (793 mg, 2.00 mmol) in toluene (3.28 mL) was added pyrrolidine (2.46 mL, 30.0 mmol). The suspension turned into a solution after a few minutes of stirring and the reaction mixture was stirred at 80 °C for 1 hour, then allowed to cool to RT and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane) to afford title compound 80 as a white solid (408 mg, 57% yield). LC-MS: rt = 1 .43 min, MS: 354.1 (calcd), 355.0 (M+H+, found).

[0585] Step 5. 2-Amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene- 3-carboxylic acid (81).

[0586] To a suspension of 80 (408 mg, 1.15 mmol) in MeOH (139 mL) was added 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, then allowed to cool to RT. The mixture was diluted with water and concentrated to remove most of the organic solvent, then washed with EA. The aqueous layer was collected, acidified by slow addition of HCI 2N and extracted with EA. This organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 10% of MeOH in DCM) to afford title compound 81 as a white solid (376 mg, >99% yield).

[0587] 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.34-7.27 (m, 5H), 3.35-3.30 (m, 1 H), 3.01 (d, J = 16.71 Hz, 1 H), 2.89 (d, J = 16.71 Hz, 1 H), 2.77-2.74 (m, 1 H), 2.49-2.45 (m, 2H). LC-MS: rt = 1.16 min, MS: 326.1 (calcd), 327.0 (M+H+, found).

[0588] Step 6. 2-Amino-6-(cyanomethyl)- / V-cyclopropyl-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (82).

[0589] To a suspension of 81 (154 mg, 0.472 mmol) in THF (5.90 mL) were added HATU (359 mg, 0.944 mmol) and N,N-diisopropylethylamine (164 uL, 0.944 mmol). The mixture was stirred at RT for 20 min and then cyclopropylamine (327 uL, 4.72 mmol) was added. The reaction mixture was stirred for an additional 16 hours, then partitioned between EA and a saturated aqueous solution of NH4CI. The layers were separated and the organic phase was collected, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 20% to 100% of EA in hexane) and then by reverse-phase flash column chromatography (eluent gradient from 0% to 100% CH3CN in H2O with 0.1% (v / v) formic acid) to afford title compound 82 as a white solid (46.5 mg, 27% yield).

[0590] 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.35-7.27 (m, 5H), 3.00 (d, J = 16.70 Hz, 1 H), 2.89 (d, J = 16.71 Hz, 1 H), 2.82-2.78 (m, 1 H), 2.77-2.74 (m, 1 H), 2.69-2.64 (m, 2H), 2.49-2.42 (m, 1 H), 0.72-0.67 (m, 2H), 0.54-0.48 (m, 2H). LC-MS: rt = 1.20 min, MS: 365.1 (calcd), 366.1 (M+H+, found).

[0591] Example 53 2-Amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (83) and

[0592] Example 54 2-Amino-6-(2-amino-2-oxoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (84)

[0593] Scheme 14

[0594] 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 uL, 0.306 mmol) were added and the reaction mixture was stirred at RT for 16 hours. Afterwards, the mixture was partitioned between EA and a saturated aqueous solution of NH4CI. The layers were separated and the aqueous phase was extracted with EA. The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 20% to 100% of EA in hexane) then by reverse-phase flash column chromatography (eluent gradient from 0% to 100% CH3CN in H2O with 0.1% (v / v) formic acid) to afford title compound 83 as a white solid (47.0 mg, 94% yield).

[0595] 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.39-7.29 (m, 5H), 3.02-2.95 (m, 2H), 2.90 (d, J = 16.72 Hz, 1 H), 2.80 (ddd, J = 13.55, 4.09, 2.50 Hz, 1 H), 2.67 (ddd, J = 17.32, 11.78, 4.10 Hz, 1 H), 2.49 (ddd, J = 13.53, 11.79, 4.45 Hz, 1 H). LC-MS: rt = 1.01 min, MS: 325.1 (calcd), 326.0 (M+H+, found).

[0596] Step 2. 2-Amino-6-(2-amino-2-oxoethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (84).

[0597] A suspension of 83 (47.0 mg, 0.144 mmol) in concentrated sulfuric acid (470 uL) was stirred at RT for 72 hours, then poured on crushed ice and the resulting mixture was basified using a 4 N NaOH solution. The solution was extracted with DCM. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 10% of MeOH in DCM, then 100% isopropanol) to afford title compound 84 as a white solid (17.5 mg, 35% yield).

[0598] 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.32-7.27 (m, 4H), 7.23-7.19 (m, 1 H), 2.99 (d, J = 14.78 Hz, 1 H), 2.92-2.87 (m, 1H), 2.78-2.71 (m, 1 H), 2.65 (d, J = 14.76 Hz, 2H), 2.60-5.50 (m, 1 H). LC-MS: rt = 0.84 min, MS: 343.1 (calcd), 344.1 (M+H+, found).

[0599] Example 55 2-Amino-6-(2-hydroxyethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (89).

[0600] Scheme 15

[0601]

[0602] Step 1. Ethyl 2-amino-6-(2-hydroxyethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-

[0603] To a solution of 4-(2-hydroxyethyl)-4-phenylcyclohexan-1-one (85) (Bioorg. Med. Chem. Lett., 21 , p. 405, 2011) (7.95 g, 36.4 mmol) and ethyl 2-cyanoacetate (4.26 mL, 40.1 mmol) in EtOH (36.4 mL) were added morpholine (3.50 mL, 40.1 mmol) and sulfur (1.29 g, 5.03 mmol). The reaction mixture was stirred at 60 °C for 16 hours, then allowed to cool to RT and a white precipitate formed. This solid was collected by filtration, washed with EtOH and dried in vacuo to afford title compound 86 as a white solid (9.40 g, 72% yield). LC-MS: rt = 1.41 min, MS: 345.1 (calcd), 346.1 (M+H+, found).

[0604] Step 2. Ethyl 2-acetamido-6-(2-hydroxyethyl)-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (87).

[0605] To a solution of 86 (8.30 g, 24.0 mmol) in acetic acid (138 mL) was added acetic anhydride (2.73 mL, 28.8 mmol). The mixture was stirred at 60 °C for 2 hours, then allowed to cool to RT and concentrated to dryness to afford title compound 87 as a brown oil which was used directly for the next step. LC-MS: rt = 1.78 min, MS: 387.2 (calcd), 388.2 (M+H+, found).

[0606] Step 3. Ethyl 2-acetamido-6-(2-hydroxyethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (88).

[0607] To a solution of 87 (24.0 mmol) in acetic acid (160 mL), water (160 mL) and dioxane (160 mL) was added ceric sulfate (69.0 g, 208 mmol). The mixture was sonicated until it became homogenous, stirred at RT for 24 hours and partitioned between EA and water. The layers were separated and the organic phase was washed with NaOH 1 N, water and brine. The organic layer was then dried over Na2SO4, filtered and concentrated to afford title compound 88 as an orange solid (9.60 g, 91% yield). LC-MS: rt = 1.56 min, MS: 401.1 (calcd), 402.1 (M+H+, found).

[0608] Step 4. 2-Amino-6-(2-hydroxyethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (89).

[0609] To a suspension of 88 (9.60 g, 24.1 mmol) in MeOH (1.11 L) was added 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, then allowed to cool to RT. The cooled mixture was diluted with water and concentrated to remove most of the organic solvent, then washed with EA. The aqueous layer was collected, acidified by slow addition of HCI 2 N and extracted with EA. This organic extract was dried over Na2SO4, filtered and concentrated to afford title compound 89 as an orange solid (7.0 g, 88% yield).

[0610] 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.29-7.16 (m, 5H), 3.53-3.38 (m, 2H), 3.20-3.12 (m, 1 H), 2.61-2.53 (dt, J = 13.63, 3.48 Hz, 1 H), 2.44 (ddd, J = 18.55, 11.61 , 4.01 Hz, 1 H), 2.34-2.23 (m, 1 H), 2.15-2.03 (m, 2H). LC-MS: rt = 1.04 min, MS: 331.1 (calcd), 332.0 (M+H+, found).

[0611] Example 56 2-Amino-7-oxo-5-propyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (91)

[0612] Scheme 16

[0613] Compound 90 (277 mg, 1.18 mmol, synthesized similarly to compound 3 in scheme 1 starting from 5-propyl-1 ,3-cyclohexanedione instead of 5-(2-(trifluoromethyl)phenyl)cyclohexane- 1 ,3-dione) was dissolved in H2SO498% (2.5 mL) and the mixture was stirred at RT for 24 hours. Then, the reaction mixture was slowly poured into ice-cold aqueous K2CO3, diluted with water and extracted with EA (Part of the product precipitated. It was collected by filtration and combined with the rest of the crude). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 50% to 100% of EA in hexane) to afford title compound 91 as an off-white solid (144 mg, 48% yield).

[0614] 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.97 (s, 2H), 6.96 (bs, 2H), 2.99-2.95 (m, 1 H), 2.67-2.57 (m, 1 H), 2.38-2.32 (m, 1 H), 2.19-2.07 (2H, m), 1.36 (bs, 4H), 0.88 (bs, 3H). LC-MS: rt = 2.30 min, MS: 252.1 (calcd), 253.1 (M+H+, found).

[0615] Example 57 2-Amino-6-(2,2-difluoroethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (97)

[0616] Scheme 17

[0617]

[0618] 97: Example 57

[0619] Step 1. 2-(8-Phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)acetaldehvde (93)

[0620] To a solution of 2-(8-phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)acetonitrile (92) (1.0 g, 3.89 mmol) (Bioorg Med. Chem Lett. 21 , p. 405, 2011) in anhydrous toluene (24.5 mL) at -78 °C was added dropwise DIBALH (3.92 mL, 25% in toluene, 5.83 mmol). The reaction mixture was stirred at -78 °C for 2 hours, before being carefully quenched with MeOH and saturated NH4CI solution. Afterwards, the mixture was allowed to reach RT and diluted with Et2O, then 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 HC1 1 N (3.89 mL 3.89 mmol) was added. The mixture was stirred at RT for 15 min, before being quenched with saturated NaHCO3solution and extracted with Et2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 5% to 100% of EA in hexane) to afford title compound 93 (605 mg, 60% yield) as a colorless oil, which was not characterized and used directly for the next step.

[0621] Step 2. 8-(2,2-Difluoroethyl)-8-phenyl-1 ,4-dioxaspiro[4.51decane (94)

[0622] To a solution of 93 (200 mg, 0.77 mmol) in anhydrous DCM (9.5 mL) at 0 °C was added DAST (0.19 mL, 1.54 mmol). The reaction mixture was stirred at RT for 1 hour, then it was quenched with saturated NaHCO3solution and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 94 (213 mg, 98% yield) as a colorless oil, which was not characterized and used directly for the next step.

[0623] Step 3. 4-(2,2-Difluoroethyl)-4-phenylcyclohexan-1-one (95) To a solution of 94 (213 mg, 0.75 mmol) in acetone (10.5 mL) was added HCI 2 N (1.89 mL, 3.77 mmol) and the reaction mixture was stirred at RT for 16 hours. Then, the mixture was neutralized by slowly adding saturated NaHCO3solution and concentrated to remove the organic solvent. The residue was extracted with EA and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to dryness to afford title compound 95 (169 mg, 94% yield) as a colorless oil, which was not characterized and used directly for the next step.

[0624] Step 4. 2-Amino-6-(2,2-difluoroethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (96)

[0625] To a solution of 95 (169 mg, 0.709 mmol) and cyanoacetamide (66 mg, 0.78 mmol) in EtOH (0.7 mL) were added morpholine (0.068 mL, 0.78 mmol) and sulfur (25 mg, 0.098 mmol). The reaction mixture was stirred at 60 °C for 16 hours, then allowed to cool to RT and concentrated to dryness. The residue was partitioned between water and EA. The layers were separated and the organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 50% to 100% of EA in hexane) to afford title compound 96 (93 mg, 39% yield). LC-MS: rt = 1.39 min, MS: 336.1 (calcd), 337.1 (M+H+, found).

[0626] Step 5. 2-Amino-6-(2,2-difluoroethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (97)

[0627] To a mixture of 96 (40 mg, 0.119 mmol) in THF (0.4 mL) and water (0.08 mL) at 0 °C was added dropwise a solution of DDQ (82 mg, 0.36 mmol) in THF (0.4 mL). The reaction mixture was stirred at 0 °C for 30 min, then the mixture was quenched with saturated NaHCO3solution and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 50% to 100% of EA in hexane) to afford title compound 97 as a pale-yellow solid (3 mg, 7% yield).

[0628] 1H NMR: 400 MHz, CDCI3, δ (ppm): 7.37-7.27 (m, 5H), 7.04 (s, 2H), 5.80 (tt, J = 56.4, 4.6, 1 H), 5.32 (s, 2H), 2.97-2.92 (m, 1 H), 2.83-2.78 (m, 1 H), 2.65-2.57 (m, 1 H), 2.53-2.42 (m, 3H).19F NMR: 376 MHz, CDCI3, δ (ppm): -110.4 (ddt, J = 287.8, 56.1 , 18.0 Hz, 1 F), -111.5 (ddt, J = 287.8, 56.5, 16.3 Hz, 1 F). LC-MS: rt = 1.25 min, MS: 350.1 (calcd), 351.0 (M+H+, found).

[0629] Example 58 2-Amino-6-cyano-6-isopropyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (101)

[0630] Scheme 18

[0631]

[0632] 100 101 : Example 58

[0633] Step 1. 8-lsopropyl-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (98)

[0634] 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) at 0 °C was added dropwise LHMDS (6.88 mL, 1 M in THF, 6.88 mmol). The reaction mixture was stirred at 0 °C for 1 hour, before adding dropwise 2- iodopropane (0.597 mL, 5.98 mmol). Then, the reaction mixture was allowed to slowly reach RT and stirred for 16 hours. Afterwards, the reaction mixture was quenched with water and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to dryness to afford title compound 98 as a brown solid, which was used directly for the next step. LC-MS: rt = 3.05 min, MS: 209.1 (calcd), 210.1 (M+H+, found).

[0635] Step 2. 1-lsopropyl-4-oxocyclohexane-1-carbonitrile (99)

[0636] To a solution of 98 (5.98 mmol) in acetone (80 mL) was added HCI 2 N (23.9 mL, 47.8 mmol) and the reaction mixture was stirred at RT for 2 days. Then, the mixture was neutralized by slowly adding saturated NaHCO3solution and concentrated to remove the organic solvent. The residue was extracted with EA and the organic layer was dried over Na2SO4, filtered and concentrated to dryness to afford title compound 99 (445 mg, 45% yield over two steps). LC-MS: rt = 2.35 min, MS: 165.2 (calcd), 166.1 (M+H+, found).

[0637] Step 3. 2-Amino-6-cyano-6-isopropyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (100)

[0638] To a solution of 99 (445 mg, 2.69 mmol) and cyanoacetamide (206 mg, 2.45 mmol) in EtOH (4.9 mL) were added morpholine (0.24 mL, 2.69 mmol) and sulfur (87 mg, 0.338 mmol). The reaction mixture was stirred at 60 °C for 16 hours and an abundant precipitate appeared. This solid was collected by filtration to afford title compound 100 (477 mg, 74% yield) as a white solid. LC-MS: rt = 2.60 min, MS: 263.1 (calcd), 264.1 (M+H+, found).

[0639] Step 4. 2-Amino-6-cyano-6-isopropyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (101)

[0640] To a solution of 100 (100 mg, 0.38 mmol) in DMSO (2.25 mL) was added selenium dioxide (42 mg, 0.38 mmol). The reaction mixture was stirred at RT for 16 hours, then it was partitioned between brine and EA and the organic layer was concentrated. The residue was purified by flash column chromatography (eluent gradient from 0.5% to 10% of MeOH in DCM), then it was purified again by Semi-Prep HPLC-MS (eluent gradient from 30% to 100% of MeOH in 10 mM ammonium bicarbonate) to afford title compound 101 as a white solid (5.0 mg, 5% yield).

[0641] 1H NMR: 400 MHz, CD3OD, δ (ppm): 3.18 (ddd, J = 17.9, 8.2, 5.1 Hz, 1 H), 3.06 (dt, J = 17.9, 5.4 Hz, 1 H), 2.50-2.39 (m, 3H), 1.12-1.08 (m, 6H). LC-MS: rt = 0.97 min, MS: 277.1 (calcd), 278.1 (M+H+, found).

[0642] Example 59

[0643] 2-Amino-6-(hydroxymethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (109)

[0644] Scheme 19

[0645] Step 1. 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-Dhenylcyclohexan-1-one (103)

[0646] To a solution of 4-(hydroxymethyl)-4-phenylcyclohexan-1-one (102) (Bioorg. Med. Chem. Lett., 21 , p. 405, 2011) (890 mg, 4.36 mmol) in anhydrous DMF (40 mL) were added tert- butyldimethylsilyl chloride (737 mg, 4.79 mmol) and imidazole (653 mg, 9.59 mmol). The resulting mixture was stirred at RT for 16 hours, then diluted with water (30 mL) and extracted with EA (70 mL). The organic phase was dried over Na2SO4, filtered and concentrated, and the residue was purified by flash column chromatography (eluent gradient from 0% to 20% of EA in hexane) to afford title compound 103 as a white solid (1.20 g, 86% yield), which was not characterized and used directly for the next step.

[0647] 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 uL, 3.77 mmol), sulfur (121 mg, 473 umol) and ethyl 2-cyanoacetate (364 uL, 3.42 mmol) in EtOH (6.01 mL) was stirred at 60 °C for 16 hours. The mixture was then allowed to cool to RT and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane) to afford title compound 104 as an off-white solid (1.49 g, 97% yield). LC-MS: rt = 2.34 min, MS: 445.2 (calcd), 446.2 (M+H+, found).

[0648] Step 3. Ethyl 2-((tert-butoxycarbonyl)amino)-6-(((ferf-butyldimethylsilyl)oxy)methyl)-6- phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (105)

[0649] To a solution of 104 (1.49 g, 3.34 mmol), DMAP (41.7 mg, 334 umol) and triethylamine (699 uL, 5.01 mmol) in DCM (66.8 mL) at 0 °C was added dropwise a solution of di-tert- butyldicarbonate (802 mg, 3.68 mmol) in DCM. The resulting mixture was stirred at RT for 16 hours, then quenched with saturated aqueous NH4CI solution. The layers were separated and the aqueous phase was extracted with DCM. The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane) to afford title compound 105 as an off-white solid (1.66 g, 91% yield). LC-MS: rt = 2.63 min, MS: 545.3 (calcd), 546.0 (M+H+, found).

[0650] Step 4. Ethyl 2-((terf-butoxycarbonyl)amino)-6-(((tert-butyldimethylsilyl)oxy)methyl)-7- oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (106)

[0651] 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 allowed to cool to RT, filtered through a pad of celite and the solid residue was washed with CHCl3. The filtrate was concentrated, and the residue was purified by flash column chromatography (eluent gradient from 0% to 30% of EA in hexane) to afford title compound 106 as a white solid (395 mg, 26% yield). LC-MS: rt = 2.52 min, MS: 559.2 (calcd), 560.2 (M+H+, found).

[0652] 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)

[0653] To a solution of 106 (380 mg, 679 umol) in EtOH (20.0 mL) was added a solution of NaOH (136 mg, 3.39 mmol) in water (20.0 mL). The resulting mixture was sonicated for 1 min and then vigorously stirred at RT for 68 hours. Subsequently, the mixture was diluted with water (15 mL) and extracted with EA (3 x 30 mL). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane, then from 0% to 30% of MeOH in DCM) to afford title compound 107 as a white solid (264 mg, 73% yield). LC-MS: rt = 1.60 min, MS: 531.2 (calcd), 532.1 (M+H+, found).

[0654] 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 umol) 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 stirring continued at RT for another 2 hours.

[0655] The mixture was then concentrated, the residue was taken up in DCM and concentrated 3 times, then purified by flash column chromatography (eluent gradient from 0% to 13% of MeOH in DCM) to afford title compound 108 as a light-yellow solid (80 mg, 52% yield). (See table 6 for characterization)

[0656] Step 7. 2-Amino-6-(hydroxymethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (109)

[0657] To a suspension of 108 (54.0 mg, 170 umol), ammonium chloride (182 mg, 3.40 mmol) and HATU (97.0 mg, 255 umol) in DMF (4.00 mL) was added dropwise N,N-diisopropylethylamine (59.3 uL, 340 umol). The mixture was stirred at RT for 16 hours, then another 97 mg of HATU (255 umol) were added and stirring continued for 1 hour. The mixture was diluted with saturated aqueous NH4CI solution and extracted with EA (3 x 20 mL). The combined organics were washed successively with brine (3 x 20 mL) and 0.05 N aqueous HCI, then concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 15% of MeOH in DCM), then it was purified again by reverse-phase flash column chromatography (eluent gradient from 10% to 100% of CH3CN in H2O with 0.1% (v / v) formic acid) to afford title compound 109 as an off-white solid (17.2 mg, 32% yield).

[0658] 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.06 (s, 2H) 7.32-7.27 (m, 4H), 7.23-7.20 (m 1 H), 6.88 (bs, 2H), 4.77 (t, J = 5.5 Hz, 1 H), 3.92 (dd, J = 10.4, 5.6 Hz, 1 H), 3.35-3.32 (m, 1 H), 2.89- 2.84 (m, 1H), 2.73-2.67 (m, 1 H), 2.50-2.48 (m, 1H, partially overlapping with the solvent signal). LC-MS: rt = 0.88 min, MS: 316.1 (calcd), 317.0 (M+H+, found).

[0659] Examples 60-67 Intermediate compound 111

[0660] 1 -Benzyl-4-oxocyclohexane-1 -carbonitrile (111)

[0661] Scheme 20

[0662] Scheme 4

[0663] Step 1. 8-Benzyl-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (110). To a solution of 40 (scheme 4) (1.0 g, 5.98 mmol) in anhydrous THF (24.0 mL) at -78 °C was added dropwise LDA (6.58 mL, 1 M in THF / hexane, 6.58 mmol). The reaction mixture was stirred at -78 °C for 45 min then benzyl bromide (0.870 mL, 7.18 mmol) was added dropwise. The reaction mixture was allowed to reach RT and stirred for 2.5 hours. Afterwards, the reaction mixture was 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 (eluent gradient from 0% to 30% of EA in hexane) to afford title compound 110 (1.22 g, 79% yield) as a white solid, which was not characterized and used directly for the next step.

[0664] Step 2. 1-Benzyl-4-oxocyclohexane-1-carbonitrile (111).

[0665] To a solution of 110 (1.21 g, 4.70 mmol) in acetone (63 mL) was added HCI 2 N (11.8 mL, 23.5 mmol) and the reaction mixture was stirred at RT for 16 hours. Then, the mixture was neutralized by slowly adding saturated NaHCO3solution and concentrated to remove the organic solvent. The residue was extracted with EA and the organic layer was dried over Na2SO4, filtered and concentrated to dryness to afford title compound 111 (1 .00 g, >99% yield). LC-MS: rt = 2.93 min, MS: 213.1 (calcd), 214.1 (M+H+, found).

[0666] Intermediate compound 115 2-(8-(Cyclopropylmethyl)-1,4-dioxaspiro[4.5]decan-8-yl)ethan-1-ol (115) Scheme 21

[0667] Step 1. 8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decane-8-carbaldehvde (113)

[0668] 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 partitioned between saturated aqueous NH4CI solution (200 mL) and diethyl ether (300 mL). The mixture was allowed to slowly reach RT and a saturated aqueous solution of Rochelle’s salt (1 L) was added. The layers were separated and the organic phase was washed with brine (2 x 200 mL), dried over Na2SO4, filtered and concentrated. The residue was dissolved in THF (400 mL) and treated with 2 N aqueous HCI (27.5 mL, 54.9 mmol). The mixture was stirred at RT for 1 hour, then quenched with saturated aqueous NaHCO3and concentrated to remove the organic solvent. The aqueous residue was extracted with diethyl ether and the organics were dried over Na2SO4, filtered and concentrated to afford title compound 113 as a colorless oil (24.6 g, >99% yield), which was not characterized and used directly for the next step.

[0669] Step 2. 8-(Cyclopropylmethyl)-8-vinyl-1 ,4-dioxaspiro[4.5]decane (114)

[0670] To a 1 M solution of LHMDS in THF (10 mL, 10.0 mmol) diluted with anhydrous THF (55.0 mL) at 60 °C was added methyltriphenylphosphonium bromide (2.23 g, 6.24 mmol) in 4 portions over 30 minutes. The reaction mixture was stirred at 60 °C for 1 hour after the last addition. Then,

[0671] 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 allowed to cool to RT, quenched with a saturated solution of NH4CI (40 mL) and extracted 2 times with EA (2 x 50 mL). The combined organics were dried over Na2SO4, filtered and concentrated and the residue was purified by flash column chromatography (eluent gradient from 0% to 30% of Et2O in hexane) to afford title compound 114 as a colorless oil (527 mg, 76% yield), which was not characterized and used directly for the next step.

[0672] Step 3. 2-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)ethan-1-ol (115)

[0673] To a solution of 114 (520 mg, 2.34 mmol) in anhydrous THF (12 mL) at 0 °C was added dropwise 9-BBN (9.35 mL, 0.5 M in THF, 4.68 mmol). The reaction mixture was stirred at RT for 2.5 hours, then it was cooled to 0 °C again and water (42 uL, 2.34 mmol), NaOH 1 N (7.0 mL, 7.0 mmol) and H2O230% (12 mL) were added. The reaction mixture was stirred at 0 °C for 10 min, then it was stirred at RT for 16 hours. Afterwards, the mixture was diluted with EA and water. The layers were separated, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 30% to 100% of EA in hexane) to afford title compound 115 as a colorless oil (479 mg, 85% yield), which was not characterized and used directly for the synthesis of relevant examples.

[0674] Intermediate compound 118

[0675] 2-(8-(Cyclopropylmethyl)-1,4-dioxaspiro[4.5]decan-8-yl)acetonitrile (118)

[0676] Scheme 22 Step 1. (8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)methanol (116)

[0677] Sodium borohydride (816 mg, 21.1 mmol) was added to a solution of 113 (scheme 21) (3.16 g, 14.1 mmol) in MeOH (86.8 mL) at 0 °C. The resulting solution was stirred at RT for 1 hour, then the reaction mixture was quenched with saturated aqueous NH4CI 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 organics were washed with 0.2 N HCI (50 mL) and brine, then dried over Na2SO4, filtered and concentrated to afford title compound 116 (2.95 g, 93% yield) as a colorless oil, which was not characterized and used directly for the next step.

[0678] Step 2. (8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)methyl 4- methylbenzenesulfonate (117)

[0679] To a solution of 116 (2.70 g, 11.9 mmol) in pyridine (51.9 mL) was added p- toluenesulfonyl chloride (7.96 g, 41.8 mmol) and the resulting mixture was stirred at RT 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) and the combined organics were washed with water (30 mL) and brine (2 x 30 mL), then dried over Na2SO4, filtered and concentrated. The residue was diluted with heptanes and concentrated to dryness, then purified by flash column chromatography (eluent gradient from 0% to 40% of EA in hexane) to afford title compound 117 (3.65 g, 80% yield) as a colorless oil. LC-MS: rt = 1.78 min. MS: 380.2 (calcd), 381.3 (M+H+, found).

[0680] Step 3. 2-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.5]decan-8-yl)acetonitrile (118)

[0681] To a solution of 117 (3.65 g, 9.59 mmol) in DMSO (57.1 mL) was added sodium cyanide (1 .41 g, 28.8 mmol) and the resulting mixture was stirred at 60 °C for 96 hours. The mixture was allowed to cool to RT and diluted with saturated aqueous NaHCO3solution (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 x 50 mL). The combined organics were washed with water (2 x 30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated to afford title compound 118 (2.5 g, 72% yield) as a yellow oil, which was not characterized and used directly for the synthesis of relevant examples.

[0682] Compounds 119-126

[0683] Compounds 119-123 (examples 60-64) were synthesized similarly to compound 81 (example 51 , scheme 13) starting from 4-methyl-4-phenylcyclohexan-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 similarly to 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. Characterization of compounds 119-126 (examples 60-67) is provided in the table 4. Table 4. Characterization of compounds 119-126 (examples 60-67).

[0684] Examples 68-77

[0685] Compounds 127-133 (examples 68-74) were synthesized similarly to 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 similarly to 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 similarly to compound 82 (example 52, scheme 13) starting from compound 108 (scheme 19) instead of compound 81. Characterization of compounds 127-

[0686] 136 (examples 68-77) is provided in the table 5.

[0687] Table 5. Characterization of compounds 127-136 (examples 68-77).

[0688] Example 78 2-Amino-6-(2-cyanoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (138) and

[0689] Example 79 2-Amino-6-(3-amino-3-oxopropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (139)

[0690] Scheme 23

[0691] To a solution of 137 (1 .0 g, 2.71 mmol, synthesized similarly to compound 80 in scheme 13 starting from 3-(4-oxo-1-phenylcyclohexyl)propanenitrile (Bioorg Med. Chem Lett. 21 , p. 405, 2011) instead of 2-(4-oxo-1-phenylcyclohexyl)acetonitrile (76)) in MeOH (330 mL) was added a solution of lithium hydroxide monohydrate (569 mg, 13.6 mmol) in water (330 mL). The reaction mixture was stirred at 80 °C for 16 hours, then allowed to cool to RT. The mixture was concentrated to remove most of the organic solvent. The aqueous layer was acidified by slowly adding HCI 1 N and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 30% of MeOH in DCM) to afford title compound 138 as a yellow solid (648 mg, 70% yield) and title compound 139. The latter was purified again by Semi-Prep HPLC-MS (eluent gradient from 15% to 100% of MeOH in 10 mM ammonium bicarbonate) to afford a white solid (142 mg, 15% yield).

[0692] 138:1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.51 (bs, 1 H), 8.28 (s, 2H), 7.36-7.32 (m, 2H), 7.27-7.24 (m, 3H), 3.15-3.09 (m, 1 H), 2.60-2.55 (m, 1 H), 2.48-2.42 (m, 1 H), 2.38-2.30 (m, 1 H), 2.26-2.18 (m, 2H), 2.12-2.07 (m, 2H). LC-MS: rt = 1.23 min, MS: 340.1 (calcd), 341 .1 (M+H+, found).

[0693] 139:1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.30 (bs, 2H), 7.33-7.26 (m, 4H), 7.23-7.19 (m, 1H), 7.18 (s, 1H), 6.62 (s, 1 H), 3.20-3.15 (m, 2H), 2.45-2.37 (m, 1 H), 2.16-2.07 (m, 1 H), 2.00- 1.91 (m, 4H). LC-MS: rt = 0.98 min, MS: 358.1 (calcd), 359.1 (M+H+, found).

[0694] Example 80 2-Amino-6-(2-cyanoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (140)

[0695] Scheme 24

[0696] 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) were added HATU (855 mg, 2.20 mmol) and N,N- diisopropylethylamine (0.512 mL, 2.94 mmol). Then, saturated NH3 solution in CHCl3(8.7 mL) (prepared in-house) and NH30.4 M solution in THF (9.2 mL) were added dropwise and the reaction mixture was stirred at RT for 16 hours. Afterwards, the reaction mixture was quenched with a saturated NH4CI 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 (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v / v) formic acid) to afford title compound 140 as a white solid (419 mg, 84% yield).

[0697] 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.13 (s, 2H), 7.37-7.24 (m, 5H), 6.88 (bs, 2H), 2.91-2.84 (m, 1 H), 2.68-2.56 (m, 2H), 2.46-2.42 (m, 1 H), 2.25-2.17 (m, 2H), 2.13-2.07 (m, 2H). LC-MS: rt = 1.10 min, MS: 339.1 (calcd), 340.1 (M+H+, found).

[0698] Example 81 2-Amino-6-(2-cyanoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (141)

[0699] Compound 141 (example 81) was synthesized similarly to compound 62 (example 39, scheme 10) starting from compound 140 (example 80, scheme 24) instead of compound 61. 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.08 (s, 2H), 7.35-7.21 (m, 5H), 7.17 (s, 1 H), 6.87 (bs, 2H), 6.63 (s, 1 H), 2.91-2.84 (m, 1 H), 2.73-2.65 (m, 1 H), 2.55-2.53 (m, 1 H), 2.20-2.12 (m, 1 H), 2.02-1.90 (m, 4H). LC-MS: rt = 0.88 min, MS: 357.1 (calcd), 358.2 (M+H+, found).

[0700] 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)

[0701] Scheme 25

[0702] 100.3 mg of racemic compound 141 were submitted to SFC Chiral Separation to afford enantioenriched title compound 142 as a white solid (29.9 mg, 30% separation yield) and enantioenriched title compound 143 as a white solid (26.2 mg, 26% separation yield). Absolute configurations of compounds 142 and 143 were assigned based on analogy with the assignment of the absolute configuration of a crystallized compound within the same or similar series.

[0703] 142:1H NMR: same as racemic mixture (141). LC-MS: rt = 0.88 min, MS: 357.1 (calcd), 358.2 (M+H+, found). Analytical SFC (IC column with 5-60% MeOH + 10mM AmFor (95-40% CO2) gradient): rt = 5.80 min, ee. = 99.76%.

[0704] 143:1H NMR: same as racemic mixture (141). LC-MS: rt = 0.88 min, MS: 357.1 (calcd), 358.2 (M+H+, found). Analytical SFC (IC column with 5-60% MeOH + 10mM AmFor (95-40% CO2) gradient): rt = 6.45 min, ee. = 97.82%.

[0705] 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)

[0706] Scheme 26

[0707] Compound 144 (example 84) was synthesized similarly to compound 82 (example 52, scheme 13) starting from compound 138 (example 78, scheme 23) instead of compound 81.

[0708] 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.87 (s, 2H), 7.37-7.25 (m, 6H), 2.74-2.52 (m, 4H), 2.48-2.41 (m, 1 H), 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 (calcd), 380.2 (M+H+, found).

[0709] To 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 added H2O230% (0.09 mL). The reaction mixture was vigorously stirred at RT for 2 days. Then, more H2O230% (0.19 mL) was added and the reaction mixture was vigorously stirred at RT for another 24 hours. Afterwards, the mixture was concentrated to remove the organic solvent and the residue was extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 145 as an off-white solid (17 mg, 46% yield).1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.81 (s, 2H), 7.35-7.21 (m, 6H), 7.17 (bs, 1 H), 6.63 (bs, 1 H), 2.77-2.59 (m, 3H), 2.50-2.48 (m, 1 H), 2.16-2.08 (m, 1 H), 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 (calcd), 398.3 (M+H+, found).

[0710] Example 86

[0711] 2-Amino-6-methyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (146)

[0712] Scheme 27

[0713] Table 4

[0714] Compound 119 (table 4) (50 mg, 0.17 mmol) was dissolved in a NH30.4 M solution in THF (17 mL) and HATU (126 mg, 0.33 mmol) and N,N-diisopropylethylamine (0.058 mL, 0.33 mmol) were added to the mixture. Then, the reaction mixture was stirred at RT for 16 hours. Afterwards, the reaction mixture was quenched with a saturated NH4CI solution and extracted with EA. The organic layer was washed with water and brine, then dried over Na3SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 40% to 100% of EA in hexane), then it was purified again by Semi-Prep HPLC-MS (eluent gradient from 35% to 100% of CH3CN in 10 mM ammonium bicarbonate) to afford title compound 146 as a white solid (22 mg, 44% yield).

[0715] 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.32-7.28 (m, 4H), 7.24-7.19 (m, 1 H), 2.95-2.89 (m, 1 H), 2.68-2.58 (m, 2H), 2.28-2.21 (m, 1H), 1.48 (s, 3H). LC-MS: rt = 1.13, MS: 300.1 (calcd), 301.1 (M+H+, found).

[0716] Example 87

[0717] 2-Amino-6-benzyl-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide 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) were added HATU (87 mg, 0.230 mmol) and N,N- diisopropylethylamine (0.053 mL, 0.306 mmol). Then, saturated NH3solution in CHCI3(0.25 mL) (prepared in-house) was added dropwise and the reaction mixture was stirred at RT for 16 hours. Afterwards, the reaction mixture was quenched with a saturated NH4CI 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 (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v / v) formic acid) to afford title compound 147 as a white solid (35 mg, 70% yield).

[0718] 1H NMR: 400 MHz, 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, 1 H), 2.11-2.04 (m, 1 H). LC-MS: rt = 1.15 min, MS: 325.1 (calcd), 326.1 (M+H+, found).

[0719] Example 88 2-Amino-6-(cyclopropylmethyl)-6-(2-hydroxyethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (148)

[0720] 148: Example 88

[0721] Compound 148 (example 88) was synthesized similarly to compound 140 (example 80, scheme 24) starting from compound 124 (table 4) instead of compound 138.

[0722] 1H NMR: 400 MHz, CD3OD, δ (ppm): 3.67-3.56 (m, 2H), 3.03 (t, J = 6.1 Hz, 2H), 2.28 (dt, J = 13.8, 5.9 Hz, 1 H), 2.17-2.10 (m, 1 H), 2.05 (ddd, J = 13.7, 8.9, 6.1 Hz, 1 H), 1.85 (ddd, J = 13.7, 8.9, 6.2 Hz, 1 H), 1.74 (dd, J = 14.1 , 6.1 Hz, 1 H), 1.41 (dd, J = 14.2, 7.2 Hz, 1H), 0.74-0.64 (m, 1 H), 0.50-0.42 (m, 2H), 0.11-0.00 (m, 2H). LC-MS: rt = 0.92 min, MS: 308.1 (calcd), 309.2 (M+H+, found).

[0723] Example 89 2-Amino-6-(cyclopropylmethyl)-6-(hydroxymethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (149)

[0724] 149: Example 89

[0725] Compound 149 (example 89) was synthesized similarly to compound 140 (example 80, scheme 24) starting from compound 125 (table 4) instead of compound 138.1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.97 (s, 2H), 6.92 (bs, 2H), 4.54 (t, J = 5.4 Hz, 1 H), 3.71 (dd, J = 10.5, 5.5 Hz, 1 H), 3.39 (dd, J = 10.5, 5.3 Hz, 1 H), 3.03-2.87 (m, 2H), 2.17-

[0726] 2.10 (m, 1 H), 2.07-2.01 (m, 1 H), 1.54 (dd, J = 14.0, 6.5 Hz, 1 H), 1.32 (dd, J = 14.0, 7.0 Hz, 1 H), 0.64-0.55 (m, 1 H), 0.40-0.32 (m, 2H), 0.07-0.01 (m, 1 H), -0.05 - -0.09 (m, 1 H). LC-MS: rt = 0.88 min, MS: 294.1 (calcd), 295.0 (M+H+, found).

[0727] Example 90 2-Amino-6-(cyanomethyl)-6-(cyclopropylmethyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (150)

[0728] 150: Example 90

[0729] Compound 150 (example 90) was synthesized similarly to compound 109 (example 59, scheme 19) starting from compound 126 (table 4) instead of compound 108.

[0730] 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.06 (s, 2H), 6.97 (bs, 2H), 3.16-3.03 (m, 1 H), 2.99-2.81 (m, 3H), 2.16-2.02 (m, 2H), 1.60-1.44 (m, 2H), 0.66-0.57 (m, 1 H), 0.47-0.35 (m, 2H), 0.13-0.07 (m, 1H), -0.01 - -0.07 (m, 1 H). LC-MS: rt = 0.94 min. MS: 303.1 (calcd), 304.0 (M+H+, found).

[0731] Example 91 2-Amino-7-oxo-4,7-dihydro-5H-spiro[benzo[b]thiophene-6,1'-cyclopentane]-3- carboxamide (155)

[0732] Scheme 29

[0733] Step 1. Ethyl 2-amino-4,7-dihydro-5H-spiro[benzo[b]thiophene-6,1'-cyclopentanel-3- carboxylate (152)

[0734] To a solution of spiro[4.5]decan-8-one (151) (199 mg, 1.31 mmol) and ethyl 2- cyanoacetate (0.139 mL, 1.31 mmol) in EtOH (1.3 mL) were added morpholine (0.126 mL, 1.44 mmol) and sulfur (46 mg, 0.18 mmol). The reaction mixture was stirred at 60 °C for 16 hours, then allowed to cool to RT and concentrated to dryness. The residue was purified by flash column chromatography to afford title compound 152 (270 mg, 74% yield). LC-MS: rt = 1.98 min, MS:

[0735] 279.1 (calcd), 280.1 (M+H+, found).

[0736] Step 2. Ethyl 2-amino-7-oxo-4,7-dihydro-5H-spiro[benzo[b]thiophene-6, 1'-cyclopentane1- 3-carboxylate (153)

[0737] To a mixture of 152 (100 mg, 0.358 mmol) in THF (1.2 mL) and water (0.2 mL) at 0 °C was added dropwise a solution of DDQ (81 mg, 0.358 mmol) in THF (1.0 mL) and the reaction mixture was stirred at 0 °C for 30 min. Then, the reaction mixture was quenched with saturated NaHCO3solution and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography to afford title compound 153 (15 mg, 14% yield). LC-MS: rt = 1.63 min, MS: 293.1 (calcd), 294.1 (M+H+, found).

[0738] Step 3. 2-Amino-7-oxo-4,7-dihydro-5H-spiro[benzo[b]thiophene-6, 1 '-cyclopentanel-3- carboxylic acid (154)

[0739] To a solution of 153 (15 mg, 0.051 mmol) in MeOH (1.1 mL) was added 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, then allowed to cool to RT. The mixture was diluted with water and concentrated to remove most of the organic solvent. The aqueous layer was acidified by slowly adding HCI 1 N and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 154 as a white solid (6 mg, 44% yield). (See table 6 for characterization)

[0740] Step 4. 2-Amino-7-oxo-4,7-dihydro-5H-spiro[benzo[b]thiophene-6, 1 '-cyclopentanel-3- carboxamide (155)

[0741] Compound 154 (6 mg, 0.023 mmol) was dissolved in a NH30.4 M solution in THF (1.5 mL) and HATU (17 mg, 0.045 mmol) and N,N-diisopropylethylamine (0.008 mL, 0.045 mmol) were added to the mixture. Then, the reaction mixture was stirred at RT for 16 hours. Afterwards, the reaction mixture was quenched with a saturated NH4CI 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 afford title compound 155 as a white solid (3.7 mg, 62% yield).

[0742] 1H NMR: 400 MHz, CD3OD, δ (ppm): 2.99 (t, J = 6.0 Hz, 2H), 2.06 (t, J = 6.0 Hz, 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 (calcd),

[0743] 265.1 (M-H+, found).

[0744] Example 92 2-Amino-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (163)

[0745] Scheme 30

[0746]

[0747] Step 1. 3-(8-Phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)propanoic acid (157)

[0748] To a solution of 3-(8-phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)propanenitrile (156) (2.30 g, 8.48 mmol) (Bioorg Med. Chem Lett. 21 , p. 405, 2011) in ethylene glycol (40.0 mL) were added potassium hydroxide (3.80 g, 67.8 mmol) and water (0.030 mL, 1.70 mmol). The reaction mixture was stirred at 170 °C for 16 hours, then allowed to cool to RT and diluted with water and DCM. The layers were separated and the aqueous phase was acidified by slowly adding HCI 2 N and extracted with DCM. This organic layer was dried over MgSO4, filtered and concentrated to afford title compound 157 (2.03 g, 82% yield) as a brown solid. LC-MS: rt = 0.84 min, MS: 290.2 (calcd), 289.2 ([M-H] , found).

[0749] Step 2. Methyl 3-(8-phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)propanoate (158)

[0750] To a solution of 157 (1.30 g, 4.48 mmol) in anhydrous DMF (10.0 mL) at 0 °C were added potassium carbonate (1.86 g, 13.4 mmol) and iodomethane (0.418 mL, 6.72 mmol). The reaction mixture was stirred at RT for 16 hours, then diluted with water and extracted with Et2O. This organic layer was washed with brine and dried over MgSO4, filtered and concentrated to afford title compound 158 (1.35 g, 99% yield) as an oil. LC-MS: rt = 1.53 min, MS: 304.2 (calcd), 305.2 (M+H+, found).

[0751] Step 3. 3-(8-Phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)propan-1-ol (159)

[0752] To a solution of lithium aluminum hydride (6.25 mL, 1 M in THF, 6.25 mmol) in anhydrous THF (7.0 mL) at 0 °C was added dropwise a solution of 158 (865 mg, 2.84 mmol) in anhydrous THF (10.0 mL). The reaction mixture was stirred at 0 °C for 1 hour, before being carefully quenched with MeOH and water at 0 °C. Then, the mixture was diluted with EA and saturated Rochelle’s salt solution and stirred at RT for 30 min. 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 (eluent gradient from 0% to 70% of EA in hexane) to afford title compound 159 (760 mg, 97% yield) as a yellow oil. LC- MS: rt = 1.28 min, MS: 276.2 (calcd), 277.2 (M+H+, found).

[0753] Step 4. 4-(3-Hydroxypropyl)-4-phenylcyclohexan-1-one (160)

[0754] To a solution of 159 (368 mg, 1.33 mmol) in acetone (18.0 mL) was added HCI 2 N (3.33 mL, 6.66 mmol) and the reaction mixture was stirred at RT for 16 hours. Then, the mixture was neutralized by slowly adding saturated aqueous NaHCO3solution and concentrated to remove the organic solvent. The residue was extracted with EA and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to dryness to afford title compound 160 (289 mg, 94% yield) as a yellow oil, which was not characterized and used directly for the next step.

[0755] Step 5. 4-(3-((tert-Butyldimethylsilyl)oxy)propyl)-4-phenylcyclohexan-1-one (161)

[0756] To a solution of 160 (196 mg, 0.84 mmol) in anhydrous DMF (4.2 mL) were added tert- butyldimethylsilyl chloride (162 mg, 1.08 mmol) and imidazole (144 mg, 2.11 mmol). The reaction mixture was stirred at RT for 16 hours, then it was diluted with water and EA. The layers were separated and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 30% of EA in hexane) to afford title compound 161 (259 mg, 89% yield) as a pale-yellow oil which was not characterized and used directly for the next step.

[0757] Step 6. 2-Amino-6-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (162)

[0758] To a solution of 161 (259 mg, 0.747 mmol) and cyanoacetamide (57 mg, 0.679 mmol) in EtOH (1 .4 mL) were added morpholine (0.065 mL, 0.747 mmol) and sulfur (24 mg, 0.093 mmol). The reaction mixture was stirred at 60 °C for 16 hours, allowed to cool to RT and concentrated to dryness. The residue was purified by flash column chromatography (eluent gradient from 0% to 10% of MeOH in DCM) to afford title compound 162 (200 mg, 60% yield). LC-MS: rt = 2.07 min, MS: 444.2 (calcd), 445.3 (M+H+, found).

[0759] Step 7. 2-Amino-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (163)

[0760] To a mixture of 162 (200 mg, 0.450 mmol) in THF (1.5 mL) and water (0.25 mL) at 0 °C was added dropwise a solution of DDQ (306 mg, 1.35 mmol) in THF (1.25 mL). The reaction mixture was allowed to slowly reach RT and stirred for 16 hours. Then, the mixture was quenched with saturated NaHCO3solution 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 (eluent gradient from 2% to 10% of MeOH in DCM), then it was purified again by Semi-Prep HPLC-MS (eluent gradient from 30% to 100% of MeOH in 10 mM ammonium bicarbonate) to afford title compound 163 as a white solid (10 mg, 6% yield).

[0761] 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.34-7.28 (m, 4H), 7.23-7.19 (m, 1 H), 3.54-3.43 (m, 2H), 2.96 (ddd, J = 17.1 , 4.4, 3.1 Hz, 1 H), 2.75-2.69 (m, 1 H), 2.67-2.60 (m, 1 H), 2.41-2.33 (m, 1 H), 2.00-1 .83 (m, 2H), 1 .58-1 .44 (m, 2H). LC-MS: rt = 0.96 min, MS: 344.1 (calcd), 345.1 (M+H+, found).

[0762] Example 93 2-Amino-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (168) and

[0763] Example 94 2-Amino-N-cyclopropyl-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (169)

[0764] Scheme 31

[0765] 169: Example 94

[0766] Step 1. Ethyl 2-amino-6-(3-hydroxypropyl)-6-phenyl-4,5,6,7- To a solution of 160 (scheme 30) (289 mg, 1.24 mmol) and ethyl 2-cyanoacetate (0.149 mL, 1.37 mmol) in EtOH (10.0 mL) were added morpholine (0.120 mL, 1.37 mmol) and sulfur (44 mg, 0.172 mmol). The reaction mixture was stirred at 60 °C for 24 hours, then allowed to cool to RT and concentrated to dryness. The residue was partitioned 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 (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 164 as a white solid (336 mg, 75% yield). LC-MS: rt = 1.53 min, MS: 359.2 (calcd), 360.2 (M+H+, found).

[0767] Step 2. Ethyl 2-acetamido-6-(3-acetoxypropyl)-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (165)

[0768] To a suspension of 164 (336 mg, 0.935 mmol) in anhydrous DCM (3.0 mL) were added acetic anhydride (0.265 mL, 2.80 mmol) and acetic acid (0.054 mL, 0.935 mmol). The reaction mixture was stirred at RT for 4 days, then it was diluted with DCM and washed with saturated NaHCO3solution, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 165 as a white solid (208 mg, 50% yield). LC-MS: rt = 1.86 min, MS: 443.2 (calcd), 444.3 (M+H+, found).

[0769] Step 3. Ethyl 2-acetamido-6-(3-acetoxypropyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (166)

[0770] Intermediate 165 (208 mg, 0.469 mmol) and ceric 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 make the suspension homogeneous and the reaction mixture was vigourously stirred at RT for 16 hours. Afterwards, the mixture was diluted with water and extracted with EA. The organic layer was washed with NaOH 1 N, water and brine, then dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 45% of EA in hexane) to afford title compound 166 as a white solid (122 mg, 57% yield). LC-MS: rt = 1 .73 min, MS: 457.2 (calcd), 458.3 (M+H+, found).

[0771] Step 4. Ethyl 6-(3-acetoxypropyl)-2-amino-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (167)

[0772] To a solution of 166 (122 mg, 0.267 mmol) in toluene (0.5 mL) was added pyrrolidine (0.35 mL, 4.26 mmol) and the reaction mixture was stirred at RT for 1 hour. Afterwards, the mixture was diluted with brine and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 167 as a dark orange oil, which was used directly for the next step. LC-MS: rt = 1.64 min, MS: 415.2 (calcd), 416.3 (M+H+, found).

[0773] Step 5. 2-Amino-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (168) To a solution of 167 (0.267 mmol) in MeOH (4.0 mL) was added a solution of lithium hydroxide monohydrate (162 mg, 3.86 mmol) in water (2.0 mL). The reaction mixture was stirred at 60 °C for 3 days, then allowed to cool to RT. The mixture was concentrated to remove most of the organic solvent. The aqueous layer was acidified by slowly adding HC1 1 N and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 50% to 100% of EA in hexane) to afford title compound 168 as a yellow solid (70 mg, 76% yield over two steps).

[0774] 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.32-7.28 (m, 4H), 7.23-7.18 (m, 1 H), 3.53-3.43 (m, 2H), 3.26-3.19 (m, 1H), 2.60-2.51 (m, 2H), 2.35-2.27 (m, 1 H), 1.98-1.83 (m, 2H), 1.55-1.44 (m, 2H). LC-MS: rt = 1.09 min, MS: 345.1 (calcd), 346.0 (M+H+, found).

[0775] Step 6. 2-Amino- / V-cyclopropyl-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (169)

[0776] To a solution of 168 (54 mg, 0.156 mmol) in anhydrous DMF (1 .95 mL) were added HATU (119 mg, 0.313 mmol), N,N-diisopropylethylamine (0.082 mL, 0.469 mmol) and cyclopropylamine (0.012 mL, 0.172 mmol). Then, the reaction mixture was stirred at RT for 16 hours. Afterwards, the reaction mixture was diluted with EA and washed with saturated NaHCO3solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 30% to 100% of EA in hexane) to afford title compound 169 as an off-white solid (46 mg, 77% yield).

[0777] 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.33-7.26 (m, 4H), 7.21-7.17 (m, 1 H), 3.52-3.42 (m, 2H), 2.81 (ddd, J = 17.3, 4.4, 3.3 Hz, 1 H), 2.70-2.62 (m, 2H), 2.58 (dt, J = 13.9, 3.7 Hz, 1 H), 2.31 (ddd, J = 13.8, 11.2, 4.6 Hz, 1 H), 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 (calcd), 385.1 (M+H+, found).

[0778] Example 95 2-Amino-6-cyano-N-cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (170)

[0779] Scheme 32

[0780] Scheme 8

[0781] To a solution of 59 (example 36, scheme 8) (2.03 g, 6.50 mmol) in anhydrous DMF (72 mL) at 0 °C were added PyBOP (3.73 g, 7.15 mmol), N,N-diisopropylethylamine (2.26 mL, 13.0 mmol) and cyclopropylamine (2.25 mL, 32.5 mmol). Then, the reaction mixture was stirred at RT for 16 hours. Afterwards, the reaction mixture was quenched with saturated NH4CI solution and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 40% to 100% of EA in hexane), then it was purified again by reverse-phase flash column chromatography (eluent gradient from 10% to 100% of CH3CN in H2O with 0.1% (v / v) formic acid) to afford title compound 170 as an off-white solid (1.48 g, 65% yield).

[0782] 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.16 (s, 2H), 7.61-7.59 (m, 1 H), 7.47-7.38 (m, 5H), 3.04-2.97 (m, 1 H), 2.80-2.70 (m, 3H), 2.64-2.57 (m, 1 H), 0.68-0.60 (m, 2H), 0.54-0.48 (m, 2H). LC-MS: rt = 1.25 min, MS: 351.1 (calcd), 352.2 (M+H+, found).

[0783] Example 96 2-Amino-6-cyano-6-((1-methylcyclopropyl)methyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (174)

[0784] Intermediate compound 172 8-((1-Methylcyclopropyl)methyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (172) Scheme 33

[0785] Scheme 4

[0786] Step 1. 8-(2-Methylallyl)-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (171)

[0787] To a solution of 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40, scheme 4) (0.696 mL, 4.44 mmol) in anhydrous THF (10 mL) at -78 °C was added dropwise LDA (6.67 mL, 1 M in THF / hexane, 6.67 mmol). The reaction mixture was stirred at -78 °C for 30 min, before adding dropwise a solution of 3-bromo-2-methylpropene (0.448 mL, 4.44 mmol) in anhydrous THF (10 mL). Then, the reaction mixture was allowed to reach RT and stirred for 3 days. Afterwards, the reaction mixture was quenched with saturated NH4CI solution and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 171 (753 mg, 77% yield) as a colorless oil, which was not characterized and used directly for the next step.

[0788] Step 2. 8-((1-Methylcyclopropyl)methyl)-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (172)

[0789] To a solution of 171 (650 mg, 2.94 mmol) in anhydrous DCM (29 mL) at -10 °C were added diethylzinc (5.87 mL, 1 M in hexane, 5.87 mmol) and diiodomethane (0.946 mL, 11.7 mmol). The reaction mixture was stirred at -10 °C for 30 min, then it was allowed to reach RT and stirred for 3 days. Afterwards, the reaction mixture was quenched with saturated NH4CI solution and the layers were separated. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 172 (233 mg, 34% yield) as a colorless oil, which was not characterized and used directly for the synthesis of relevant examples.

[0790] 2-Amino-6-cyano-6-((1-methylcyclopropyl)methyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (174)

[0791] Scheme 34

[0792] To a suspension of 173 (See table 6 for characterization) (synthesized similarly to compound 47 (scheme 4) starting from compound 172 (scheme 33) instead of compound 41) (46 mg, 0.151 mmol) and ammonium chloride (162 mg, 3.02 mmol) in anhydrous DMF (2.0 mL) were added HATU (88 mg, 0.227 mmol) and N,N-diisopropylethylamine (0.053 mL, 0.302 mmol). Then, saturated NH3solution in CHCI3(0.9 mL) (prepared in-house) and NH30.4 M in THF (0.9 mL) were added dropwise and the reaction mixture was stirred at RT for 16 hours. Afterwards, the reaction mixture was quenched with a saturated NH4CI 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 (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v / v) formic acid) to afford title compound 174 as a white solid (26 mg, 57% yield).

[0793] 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.24 (s, 2H), 7.09 (bs, 2H), 3.15-3.01 (m, 2H), 2.46-2.43 (m, 1 H), 2.39-2.32 (m, 1 H), 1.88 (s, 2H), 1.12 (s, 3H), 0.46-0.38 (m, 1 H), 0.32-0.24 (m, 3H). LC-MS: rt = 1.12 min, MS: 303.1 (calcd), 304.1 (M+H+, found).

[0794] Example 97 2-Amino-N3-cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3,6- dicarboxamide (175)

[0795] 175: Example 97

[0796] Compound 175 (example 97) was synthesized similarly to compound 145 (example 85, scheme 26) starting from compound 170 (example 95, scheme 32) instead of compound 144.1H NMR: 400 MHz, CD3OD, δ (ppm): 7.35-7.33 (m, 4H), 7.32-7.28 (m, 1H), 2.92 (dt, J = 17.1 , 4.8 Hz, 1H), 2.73-2.68 (m, 3H), 2.58 (ddd, J = 17.1 , 7.9, 5.5 Hz, 1 H), 0.76-0.71 (m, 2H), 0.57-0.53 (m, 2H). LC-MS: rt = 1.02 min, MS: 369.1 (calcd), 370.2 (M+H+, found).

[0797] Example 98 2-Amino-6-(but-3-yn-1-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (179)

[0798] Intermediate compound 177

[0799] 8-(But-3-yn-1 -yl)-8-phenyl-1 ,4-dioxaspiro[4.5]decane (177)

[0800] Scheme 35

[0801] Scheme 30

[0802] Step 1. 3-(8-Phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)propanal (176)

[0803] To a solution of 3-(8-phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)propanenitrile (156, scheme 30) (1 .40 g, 5.16 mmol) (Bioorg Med. Chem Lett. 21 , p. 405, 2011) in anhydrous toluene (33 mL) at -78 °C was added dropwise DIBALH (4.16 mL, 25% in toluene, 6.19 mmol). The reaction mixture was stirred at -78 °C for 5 min, then it was quenched with saturated NH4CI solution. Afterwards, the mixture was allowed to reach RT and HCI 2 N (2.58 mL, 5.16 mmol) was added. The mixture was extracted with Et20 and this organic layer was washed with saturated NaHCO3solution and brine, dried over Na2SO4, filtered and concentrated to afford title compound 176 as a colorless oil, which was used directly for the next step without characterization.

[0804] Step 2. 8-(But-3-yn-1-yl)-8-phenyl-1 ,4-dioxaspiro[4.51decane (177)

[0805] To a solution of triphenylphosphine (3.59 g, 13.4 mmol) in anhydrous DCM (32 mL) at 0 °C was added carbon tetrabromide (2.22 g, 6.71 mmol). The reaction mixture was stirred at RT for 30 min, then it was cooled to 0 °C again and a solution of 176 (5.16 mmol) in anhydrous DCM (8 mL) was added and the reaction mixture was stirred at 0 °C for 30 min. Afterwards, the reaction mixture was diluted with hexane, filtered through a celite pad and concentrated. The residue was diluted with hexane, filtered through a celite pad and concentrated again. This residue was dissolved in anhydrous THF (23 mL) and the solution was cooled to -78 °C. Then, n-butyl lithium (4.13 mL, 2.5 M in hexane, 10.3 mmol) was added dropwise and the reaction mixture was stirred at -78 °C for 1 hour. Afterwards, the reaction mixture was quenched with saturated NH4CI 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 (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 177 as a white solid (734 mg, 53% yield over two steps), which was not characterized and used directly for the synthesis of relevant examples.

[0806] 2-Amino-6-(but-3-yn-1-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (179)

[0807] Scheme 36

[0808] A solution of 178 (See table 6 for characterization) (synthesized similarly to compound 47 (scheme 4) starting from compound 177 (scheme 35) instead of compound 41) (83 mg, 0.25 mmol) in anhydrous DMF (2.7 mL) was saturated with bubbling NH3from a balloon. Then PyBOP (191 mg, 0.37 mmol) and N,N-diisopropylethylamine (0.085 mL, 0.49 mmol) were added and the reaction mixture was stirred at RT for 16 hours. Afterwards, the reaction mixture was quenched with saturated N...

Claims

CLAIMS1 . A pharmaceutical combination comprising:(a) a cyclooxygenase (COX) inhibitor; and(b) a compound having the Formula (I)or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:Rais -NH2, -NH-OH, -OH, -NHRbor -NRcRd;Rbis C1-C6alkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C1-C6alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -OC1-C3alkyl, -COOH, or cyclopropyl optionally substituted with -OH, and wherein C3-C6cycloalkyl is optionally substituted with -ON;Rcand Rdform with the nitrogen to which they are attached a 4-membered heterocycloalkyl, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C1-C3alkyl; represents one of the following residues Aoto A12wherein:R is H, C1-C6alkyl or phenyl;R1and R2are independently -CN, C6-C10aryl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- Cscycloalkyl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, - C(O)NHR5, -C(O)R6, or -C(0)OR5, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22substituents, with the proviso that when Rais -OH,represents Ao,then R2in residue Aois different thaneach R5is independently C1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R9substituents; each R6is independently C3-C6cycloalkyl, 4- to 6-membered heterocycloalkyl, or C6-C10aryl; each R7is independently -OH, -C(O)R11, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), 4- to 6- membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OR20, -SC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R8is independently halogen, C1-C6alkyl, -OC1-C6alkyl, C3-C6cycloakyl, or 5- to 10- membered heteroaryl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with C1-C4alkyl; each R22is independently C1-C6alkyl optionally substituted with phenyl; each R9is independently -OH, -C(O)R15, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OC1-C6alkyl, -SC1-C6alkyl, -NH2, -NH(C1- C4alkyl), or -N(C1-C4alkyl)2, wherein each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl, and each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R11is independently -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, or 4- to 6-membered heterocycloalkyl; each R20is independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R14substituents and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, -OC1-C4alkyl, or -SPh, wherein each C1- C4alkyl is optionally substituted with -OH;each R13is independently halogen, C1-C4alkyl, C3-C6cycloalkyl, -OH, -OC1-C6alkyl, -SC1-C6alkyl, -S(O)2C1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each -OC1-C8alkyl, -SC1- C6alkyl, -S(O)2C1-C6alkyl, -NH(C1-C4alkyl), and -N(C1-C4alkyl)2is optionally substituted with 1 to 3 R9substituents; each R14is independently halogen, -OC1-C4alkyl, or C3-C6cycloalkyl; each R15is independently -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, or 4- to 6-membered heterocycloalkyl;R4is C1-C6alkyl, C3-C8cycloalkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R9substituents, and C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10substituents, with the proviso that: (i) when Rais -OH, -NH2, represents A2, then R4in residue A2is different than -CH3; and (ii) whenresents A3, then R4in residue A3is different than -C(CH3)3; each R10is independently C1-C4alkyl, halogen, -OC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1- C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens;R2ais C1-C6alkyl, C3-C8cycloalkyl, or C6-C10aryl, wherein C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R9substituents, and C6-C10aryl is optionally substituted with 1 to 3 R10substituents;R1aand R2bare independently -CN, C6-C10aryl, C1-C6alkyl, C3-C8cycloalkyl, -C(O)NH2, - C(O)NHR5, or -C(0)OC1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R16substituents and each C6-C10aryl is optionally substituted with 1 to 3 R17substituents; each R16is independently -OH, -C(O)NH2, -C(O)NH(C1-C4alkyl), C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), or -OC1-C4alkyl(OC1-C4alkyl), wherein each C3- C6cycloalkyl is optionally substituted with 1 to 3 R18substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R21substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl; each R17is independently halogen, C1-C6alkyl, -OC1-C6alkyl, or 5- to 10-membered heteroaryl, wherein each 5- to 10-membered heteroaryl is optionally substituted with C1-C4alkyl; each R18is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, or -OC1-C4alkyl; each R21is independently halogen or C1-C4alkyl;R4ais C1-C6alkyl or C3-C8cycloalkyl, wherein each C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R19substituents; each R19is independently halogen, -OH, -OC1-C4alkyl, -SC1-C4alkyl, -NH2, -NH(C1-C4alkyl), or - N(C1-C4alkyl)2;R1band R2cform together with the carbon atom to which they are attached a C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R9substituents, and wherein 4- to 14-membered heterocycloalkyl, 8- to 14- membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group is optionally substituted with oxo (=0), oxime (=N-OH), C1-C3alkoxyoxime (=N- OC1-C3alkyl), or 1 to 3 substituents independently selected from -OH and -CF3;R2dand R4bform together with the carbon atoms to which they are attached a C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R19substituents; andR1cand R3form together with the carbon atoms to which they are attached a C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R19substituents.

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

3. The pharmaceutical combination of claim 1 or 2, wherein the compound of Formula (I) is represented by the formula (la) or (la’):wherein R1, R2, R and Raare as defined in claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

4. The pharmaceutical combination of claim 3, wherein the compound of Formula (I) is represented by the formula (la):wherein R1, R2and Raare as defined in claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

5. The pharmaceutical combination of any one of claims 1 to 4, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R1and R2are independently -CN, C6-C10aryl, C1-C6alkyl, C2-Cealkynyl, C3-C6cycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHR5, -C(O)R6, or -C(O)OR5, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22substituents, and R5, R6, R7, R8and R22are as defined in claim 1.

6. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof:R1and R2are independently -CN, C6-C10aryl, C1-C6alkyl, C2-Cealkynyl, C3-C6cycloalkyl, 5- to 10- membered heteroaryl, -C(O)NH2, -C(O)NHR5, -C(O)R6, or -C(0)OR5, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22substituents, and wherein: each R5is independently C1-C6alkyl; each R6is independently a 4- to 6-membered heterocycloalkyl; each R7is independently -OH, -C(O)R11, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, - C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1- C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OR20, -SC1-C6alkyl, - NH2, or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R8is independently halogen, C1-C6alkyl, or -OC1-C6alkyl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R22is independently C1-C6alkyl optionally substituted with phenyl;each R11is independently -NH2, -NH(C1-C4alkyl), or 4- to 6-membered heterocycloalkyl; each R20is independently C1-C8alkyl or 5- to 10-membered heteroaryl, wherein each C1- C6alkyl is optionally substituted with 1 to 3 R14substituents and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, -OC1-C4alkyl, or -SPh, wherein each C1-C4alkyl is optionally substituted with -OH; each R13is independently halogen, C1-C4alkyl, or C3-C6cycloalkyl; and each R14is independently halogen, -OC1-C4alkyl, or C3-C6cycloalkyl.

7. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R1and R2are independently -ON, C6-C10aryl, C1-C6alkyl, C2-C6alkynyl, C3-C8cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22substituents, and R7, R8, and R22are as defined in claim 1 .

8. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof:R1and R2are independently -CN, C6-C10aryl, C1-C6alkyl, C2-C6alkynyl, C3-C8cycloalkyl, 5- to 10- membered heteroaryl, or -C(O)NH2, wherein each C1-C8alkyl is optionally substituted with 1 to 3 R7substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22substituents, and wherein: each R7is independently -OH, -C(O)R11, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, - C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1- C6alkyl), -NH(C(O)C1-C6alkyl), 4- to 6-membered heterocycloalkyl, -OR20, -SC1-C6alkyl, - NH2, or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R8is independently halogen, C1-C6alkyl, or -OC1-C6alkyl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R11is independently -NH2, -NH(C1-C4alkyl), or 4- to 6-membered heterocycloalkyl;each R20is independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1- Cealkyl is optionally substituted with 1 to 3 R14substituents and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, -OC1-C4alkyl, or -SPh, wherein each C1-C4alkyl is optionally substituted with -OH; each R13is independently halogen, C1-C4alkyl, or C3-C6cycloalkyl; each R14is independently halogen, -OC1-C4alkyl, or C3-C6cycloalkyl; and each R22is independently C1-C4alkyl.

9. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof:R1and R2are independently -ON, C6-C10aryl, C1-C6alkyl, C2-C6alkynyl, C3-C8cycloalkyl, 5- to 10- membered heteroaryl, or -C(0)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22substituents, and wherein: each R7is independently -OH, -C(O)R11, -OR20, C3-C6cycloalkyl, -ON, C6-C10aryl, halogen, -C(O)OH, or 5- to 10-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12substituents and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13substituents; each R8is a halogen; each R11is -NH2; each R20is C1-C6alkyl or 5- or 6-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R14substituents and each 5- or 6-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12is C1-C4alkyl; each R13is independently halogen or C1-C4alkyl; each R14is halogen; and each R22is independently C1-C4alkyl.

10. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof:R1and R2are independently -ON, phenyl, C1-C4alkyl, C2-C4alkynyl, C3-C6cycloalkyl, 5-membered heteroaryl, or -C(O)NH2, wherein each C1-C4alkyl is optionally substituted with 1 or 2 R7substituents, each phenyl is optionally substituted with 1 or 2 halogens, and each 5-membered heteroaryl is optionally substituted with 1 or 2 -CH3, and wherein: each R7is independently -OH, -C(O)NH2, -OR20, C3-C6cycloalkyl, -ON, phenyl, halogen, - C(O)OH, or 5-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with -CH3; and each R20is C1-C6alkyl or 5- or 6-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 halogen and each 5- or 6-membered heteroaryl is optionally substituted with -OH.11 . The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R1and R2independently represent:

12. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound ofFormula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R1and R2independently represent:

13. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R1and R2independently represent:

14. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R1and R2independently represent:

15. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof:R1and R2are independently -CN, C6-C10aryl, C1-C6alkyl, C3-C8cycloalkyl, 5-membered heteroaryl, or -C(0)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 2 R7substituents;each R7is independently -OH, -C(O)NH2, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, or 5- to 8- membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 2 C1- C4alkyl, and each 5- to 8-membered heteroaryl is optionally substituted with 1 to 2 R13substituents; and wherein each R13is independently halogen or C1-C4alkyl.

16. The pharmaceutical combination of any one of claims 1 to 15, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R1and R2are different.

17. The pharmaceutical combination of any one of claims 1 to 16, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, one of R1and R2is -CN.

18. The pharmaceutical combination of any one of claims 1 to 17, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, one of R1and19. The pharmaceutical combination of claim 1 or 2, wherein the compound of Formula (I) is represented by the formula (lb) or (lb’):wherein R4, R and Raare as defined in claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

20. The pharmaceutical combination of claim 19, wherein the compound of Formula (I) is represented by the formula (lb):wherein R4and Raare as defined in claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

21. The pharmaceutical combination of any one of claims 1 , 2, 19 and 20, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R4is C1-C6alkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10- membered heteroaryl, wherein C1-C6alkyl is optionally substituted with 1 to 3 R9substituents, and C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10substituents, and R9and R10are as defined in claim 1.

22. The pharmaceutical combination of any one of claims 1 , 2, 19 and 20, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R4is C1-C6alkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10- membered heteroaryl, wherein C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10substituents, and wherein: each R10is independently C1-C4alkyl, halogen, -OC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or - N(C1-C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens.

23. The pharmaceutical combination of any one of claims 1 , 2, 19 and 20, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R4is C1-C6alkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10- membered heteroaryl, wherein C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10substituents, and wherein: each R10is independently C1-C4alkyl, halogen, -OC1-C6alkyl, or -N(C1-C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens.

24. The pharmaceutical combination of any one of claims 1 , 2, 19 and 20, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R4is C1-C4alkyl, phenyl, 9-membered partially unsaturated heterocyclic group, or 5- to 6-membered heteroaryl, wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with 1 or 2 R10substituents, and wherein: each R10is independently -CF3, halogen, -OCH3, or -N(CH3)2.

25. The pharmaceutical combination of any one of claims 1 , 2, 19 and 20, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R4represents:

26. The pharmaceutical combination of claim 1 or 2, wherein the compound of Formula (I) is represented by the formula (Ic) or (lc’):wherein R2a, R and Raare as defined in claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

27. The pharmaceutical combination of claim 26, wherein the compound of Formula (I) is represented by the formula (Ic):wherein R2aand Raare as defined in claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

28. The pharmaceutical combination of any one of claims 1 , 2, 26 and 27, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R2ais C1-C6alkyl or C6-C10aryl, wherein C1-C6alkyl is optionally substituted with 1 to 3 R9substituents and C6-C10aryl is optionally substituted with 1 to 3 R10substituents, and R9and R10are as defined in claim 1.

29. The pharmaceutical combination of any one of claims 1 , 2, 26 and 27, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R2ais C1-C6alkyl or C6-C10aryl, wherein C1-C6alkyl is optionally substituted with 1 to 3 halogens.

30. The pharmaceutical combination of any one of claims 1 , 2, 26 and 27, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R2ais C1-C6alkyl.

31. The pharmaceutical combination of any one of claims 1 , 2, 26 and 27, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R2ais C1-C4alkyl.

32. The pharmaceutical combination of any one of claims 1 , 2, 26 and 27, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R2ais ethyl.

33. The pharmaceutical combination of claim 1 or 2, wherein the compound of Formula (I) is represented by the formula (Id) or (Id’):wherein R1a, R2b, R4a, R and Raare as defined in claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

34. The pharmaceutical combination of claim 33, wherein the compound of Formula (I) is represented by the formula (Id):wherein R1a, R2b, R4aand Raare as defined in claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

35. The pharmaceutical combination of any one of claims 1 , 2, 33 and 34, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R1aand R2bare independently -CN, C6-C10aryl, C1-C6alkyl, C3-C8cycloalkyl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 2 R16substituents, and wherein: each R16is independently -OH, -C(O)NH2, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 2 C1-C4alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 R21substituents; and each R21is independently halogen or C1-C4alkyl.

36. The pharmaceutical combination of any one of claims 1 , 2, 33 and 34, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R1aand R2bare independently -CN or C6-C10aryl.

37. The pharmaceutical combination of any one of claims 1 , 2, 33, 34, 35 and 36, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R4ais C1-C6alkyl.

38. The pharmaceutical combination of claim 1 or 2, wherein the compound of Formula (I) is represented by the formula (le) or (le’):wherein R, Ra, R1 band R2care as defined in claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

39. The pharmaceutical combination of claim 38, wherein the compound of Formula (I) is represented by the formula (le):wherein Ra, R1band R2care as defined in claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

40. The pharmaceutical combination of any one of claims 1 , 2, 38 and 39, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R1band R2cform together with the carbon atom to which they are attached a C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group, wherein each 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14- membered partially unsaturated carbocyclic group is optionally substituted with oxo (=0), oxime (=N-OH), C1-C3alkoxyoxime (=N-OC1-C3alkyl), or 1 to 3 substituents independently selected from -OH and -CF3.

41. The pharmaceutical combination of any one of claims 1 , 2, 38 and 39, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R1band R2cform together with the carbon atom to which they are attached a C3-C8cycloalkyl or a 8- to 10-membered partially unsaturated carbocyclic group, wherein 8- to 10-membered partially unsaturated carbocyclic group is optionally substituted with oxo (=0), oxime (=N-OH), methoxyoxime (=N-OCH3), or 1 to 2 substituents independently selected from -OH and -CF3.

42. The pharmaceutical combination of any one of claims 1 , 2, 38 and 39, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R1band R2cform together with the carbon atom to which they are attached a C4C6cycloalkyl, or a group selected fromwherein the dashed lines represent the portion of the cyclohexanone moiety of the compound of formula (le) or (le’) bearing R1band R2c.

43. The pharmaceutical combination of any one of claims 1 , 2, 38 and 39, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R1band R2cform together with the carbon atom to which they are attached a cyclopentyl, or a group selected fromwherein the dashed lines represent the portion of the cyclohexanone moiety of the compound of formula (le) or (le’) bearing R1band R2c.

44. The pharmaceutical combination of any one of claims 1 , 2, 38 and 39, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R1band R2cform together with the carbon atom to which they are attached a group selected from, wherein the dashed lines represent the portion of the cyclohexanone moiety of the compound of formula (le) or (le’) bearing R1band R2c.

45. The pharmaceutical combination of claim 1 or 2, wherein the compound of Formula (I) is represented by the formula (If) or (If’):wherein R, Ra, R4band R2dare as defined in claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

46. The pharmaceutical combination of claim 45, wherein the compound of Formula (I) is represented by the formula (If):wherein Ra, R4band R2dare as defined in claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

47. The pharmaceutical combination of any one of claims 1 , 2, 45 and 46, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R2dand R4bform together with the carbon atoms to which they are attached a C3-C8cycloalkyl, wherein each C3-C8cycloalkyl is optionally substituted with 1 to 3 R19substituents as defined in claim 1.

48. The pharmaceutical combination of any one of claims 1 , 2, 45 and 46, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R2dand R4bform together with the carbon atoms to which they are attached a C3-C8cycloalkyl.

49. The pharmaceutical combination of claim 1 or 2, wherein the compound of Formula (I) is represented by the formula (Ig):wherein Ra, R1cand R3are as defined in claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

50. The pharmaceutical combination of any one of claims 1 , 2 and 49, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R1cand R3form together with the carbon atoms to which they are attached a C3-C8cycloalkyl, wherein each C3-C8cycloalkyl is optionally substituted with 1 to 3 R19substituents as defined in claim 1.

51. The pharmaceutical combination of any one of claims 1 , 2 and 49, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R1cand R3form together with the carbon atoms to which they are attached a C3-C8cycloalkyl.

52. The pharmaceutical combination of any one of claims 1 to 51 , wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, Rais -NHRband Rbrepresents:

53. The pharmaceutical combination of any one of claims 1 to 52, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, Rais -NHRband Rbrepresents:

54. The pharmaceutical combination of any one of claims 1 to 53, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, Rais -NHRband Rbrepresents55. The pharmaceutical combination of any one of claims 1 to 51 , wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, Rais56. The pharmaceutical combination of any one of claims 1 to 51 and 55, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, Ra57. The pharmaceutical combination of any one of claims 1 to 51 , wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, Rais -OH.

58. The pharmaceutical combination of any one of claims 1 to 51 , wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, Rais -NH2.

59. The pharmaceutical combination of any one of claims 1 to 51 , wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, Rais -NH-OH.

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

61. The pharmaceutical combination of claim 1, wherein the compound is Compound 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, 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, 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, 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, 483, 486, 488, 489, 492, 495, 496, 497, 498, 511,512, 513, 514, 515, 520, 523, 524, or 534 of Table 1 of the description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

62. The pharmaceutical combination of claim 1, wherein the compound is Compound 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, 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, 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 of Table 1 of the description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

63. The pharmaceutical combination of claim 1, wherein the compound is Compound 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, 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, 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, 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 of Table 1 of the description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

64. The pharmaceutical combination of claim 1 , wherein the compound is Compound 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 , 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 of Table 1 of the description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

65. The pharmaceutical combination of 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 the description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

66. The pharmaceutical combination of any one of claims 1 to 65, wherein the COX inhibitor comprises a Non-Steroidal Anti-Inflammatory Drug (NSAID).

67. The pharmaceutical combination of claim 66, wherein the NSAID is selected from the group consisting of Bromfenac, Celecoxib, Diclofenac, Etodolac, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic acid, Meloxicam, Nabumetone, Naproxen, Nepafenac, Piroxicam, Sulindac, Tenoxicam, Tiaprofenic acid, Diflunisal, Etoricoxib, Fenoprofen, Floctafenine, Lumiracoxib, Oxaprozin, Parecoxib, Rofecoxib, Tolmetin, Valdecoxib, Meclofenamic acid, Dexketoprofen, Licofelone, Lornoxicam, Loxoprofen, Nimesulide, Tolfenamic acid, Phenylbutazone, Firocoxib, Salsalate, Choline Magnesium Trisalicylate, Acetylsalicylic acid, any pharmaceutically acceptable salt thereof, and any combination thereof.

68. The pharmaceutical combination of claim 66, wherein the NSAID is Naproxen, Celecoxib, Diclofenac, Ibuprofen, a pharmaceutically acceptable salt thereof, or any combination thereof.

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

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

71. The pharmaceutical combination of any one of claims 1 to 69, wherein the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof are each in an individual dosage form.

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

73. The pharmaceutical combination of any one of claims 1 to 72, comprising the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof in a ratio of 1 :0.1 to 1 : 10 by weight.

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

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

76. The pharmaceutical combination of any one of claims 1 to 75, for use in the treatment of pain in a subject in need thereof.

77. Use of a pharmaceutical combination as defined in any one of claims 1 to 75, for the treatment of pain in a subject in need thereof.

78. A method for the treatment of pain, comprising administering to a subject in need thereof the pharmaceutical combination as defined in any one of claims 1 to 75.

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

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

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

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

83. The pharmaceutical combination for use of claim 76, 79 or 80, the use of claim 77, 79 or 80, or the method of claim 78, 79 or 80, wherein the pain is arthritis pain, pain associated with musculoskeletal trauma or soft tissue trauma, post-operative pain, dental pain, dysmenorrhea pain, episiotomy pain, endometriosis pain, post-partum pain, headache pain, ocular pain, bursitis pain, or tendinitis pain.

84. The pharmaceutical combination for use of claim 83, the use of claim 83, or the method of 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 of claim 83, the use of claim 83, or the method of claim 83, 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 strain.

86. The pharmaceutical combination for use of claim 83, the use of claim 83, or the method of claim 83, wherein the pain is post-operative pain, and the post-operative pain is post-operative pain following minor surgery, post-operative pain following general surgery, post-operative pain following orthopaedic surgery, post-operative pain following bunionectomy, post-operative pain following hernioplasty, post-operative pain following herniorrhaphy, post-operative pain following arthroplasty including pain following knee arthroplasty or pain following hip arthroplasty, postoperative pain following gynecological surgery, post-operative pain following cesarean section, post-mastectomy pain syndrome (PMPS), post-operative pain following abdominoplasty, postoperative pain following laminectomy, post-operative pain following hemorrhoid removal, or postoperative pain following thoracotomy.

87. The pharmaceutical combination for use of claim 83, the use of claim 83, or the method of claim 83, wherein the pain is dental pain, and the dental pain is toothache or post-operative pain after dental surgery.

88. The pharmaceutical combination for use of claim 83, the use of claim 83, or the method of claim 83, wherein the pain is dental pain, and the dental pain is pain after dental extraction.

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

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

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

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

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

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

95. A method for the treatment of pain, comprising administering to a subject in need thereof a cyclooxygenase (COX) inhibitor and a compound having the Formula (I) as defined in any one of claims 1 to 65 or the pharmaceutically acceptable salt, solvate, or prodrug thereof.

96. The method of claim 95, wherein the COX inhibitor comprises a Non-Steroidal Anti- Inflammatory Drug (NSAID).

97. The method of claim 96, wherein the NSAID is selected from the group consisting of Bromfenac, Celecoxib, Diclofenac, Etodolac, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic acid, Meloxicam, Nabumetone, Naproxen, Nepafenac, Piroxicam, Sulindac, Tenoxicam, Tiaprofenic acid, Diflunisal, Etoricoxib, Fenoprofen, Floctafenine, Lumiracoxib, Oxaprozin, Parecoxib, Rofecoxib, Tolmetin, Valdecoxib, Meclofenamic acid, Dexketoprofen, Licofelone, Lornoxicam, Loxoprofen, Nimesulide, Tolfenamic acid, Phenylbutazone, Firocoxib, Salsalate, Choline Magnesium Trisalicylate, Acetylsalicylic acid, any pharmaceutically acceptable salt thereof, and any combination thereof.

98. The method of claim 96, wherein the NSAID is Naproxen, Celecoxib, Diclofenac, Ibuprofen, a pharmaceutically acceptable salt thereof, or any combination thereof.

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

100. The method of any one of claims 95 to 99, wherein the pain is inflammatory pain, neuropathic pain or cancer pain.101 . The method of any one of claims 95 to 100, wherein the pain is inflammatory pain.

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

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

104. The method of any one of claims 95 to 101 , wherein the pain is arthritis pain, pain associated with musculoskeletal trauma or soft tissue trauma, post-operative pain, dental pain, dysmenorrhea pain, episiotomy pain, endometriosis pain, post-partum pain, headache pain, ocular pain, bursitis pain, or tendinitis pain.

105. The method of 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 of claim 104, 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 strain.

107. The method of claim 104, wherein the pain is post-operative pain, and the post-operative pain is post-operative pain following minor surgery, post-operative pain following general surgery,post-operative pain following orthopaedic surgery, post-operative pain following bunionectomy, post-operative pain following hernioplasty, post-operative pain following herniorrhaphy, postoperative pain following arthroplasty including pain following knee arthroplasty or pain following hip arthroplasty, post-operative pain following gynecological surgery, post-operative pain following caesarean section, post-mastectomy pain syndrome (PMPS), post-operative pain following abdominoplasty, post-operative pain following laminectomy, post-operative pain following hemorrhoid removal, or post-operative pain following thoracotomy.

108. The method of claim 104, wherein the pain is dental pain, and the dental pain is toothache or post-operative pain after dental surgery.

109. The method of claim 104, wherein the pain is dental pain, and the dental pain is pain after dental extraction.

110. The method of claim 104, wherein the pain is dysmenorrhea pain, episiotomy pain, endometriosis pain, or post-partum cramping pain.

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

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

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

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

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

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

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

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

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

120. The method of any one of claims 95 to 119, wherein the subject is a mammal.121 . The method of any one of claims 95 to 120, wherein the subject is a human.

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

123. The kit of claim 122, wherein the COX inhibitor comprises a Non-Steroidal Anti- Inflammatory Drug (NSAID).

124. The kit of claim 123, wherein the NSAID is selected from the group consisting of Bromfenac, Celecoxib, Diclofenac, Etodolac, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic acid, Meloxicam, Nabumetone, Naproxen, Nepafenac, Piroxicam, Sulindac, Tenoxicam, Tiaprofenic acid, Diflunisal, Etoricoxib, Fenoprofen, Floctafenine, Lumiracoxib, Oxaprozin, Parecoxib, Rofecoxib, Tolmetin, Valdecoxib, Meclofenamic acid, Dexketoprofen, Licofelone, Lornoxicam, Loxoprofen, Nimesulide, Tolfenamic acid, Phenylbutazone, Firocoxib, Salsalate, Choline Magnesium Trisalicylate, Acetylsalicylic acid, any pharmaceutically acceptable salt thereof, and any combination thereof.

125. The kit of claim 123, wherein the NSAID is Naproxen, Celecoxib, Diclofenac, Ibuprofen, a pharmaceutically acceptable salt thereof, or any combination thereof.

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

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

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

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

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

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

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

133. The kit for use of any one of claims 128 to 130, wherein the pain is arthritis pain, pain associated with musculoskeletal trauma or soft tissue trauma, post-operative pain, dental pain, dysmenorrhea pain, episiotomy pain, endometriosis pain, post-partum pain, headache pain, ocular pain, bursitis pain, or tendinitis pain.

134. The kit for use of 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. The kit for use of 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 strain.

136. The kit for use of any one of claims 128 to 130, wherein the pain is post-operative pain, and the post-operative pain is post-operative pain following minor surgery, post-operative pain following general surgery, post-operative pain following orthopaedic surgery, post-operative pain following bunionectomy, post-operative pain following hernioplasty, post-operative pain following herniorrhaphy, post-operative pain following arthroplasty including pain following knee arthroplasty or pain following hip arthroplasty, post-operative pain following gynecological surgery, post-operative pain following cesarean section, post-mastectomy pain syndrome(PMPS), post-operative pain following abdominoplasty, post-operative pain following laminectomy, post-operative pain following hemorrhoid removal, or post-operative pain following thoracotomy.

137. The kit for use of any one of claims 128 to 130, wherein the pain is dental pain, and the dental pain is toothache or post-operative pain after dental surgery.

138. The kit for use of any one of claims 128 to 130, wherein the pain is dental pain, and the dental pain is pain after dental extraction.

139. The kit for use of any one of claims 128 to 130, wherein the pain is dysmenorrhea pain, episiotomy pain, endometriosis pain, or post-partum cramping pain.

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

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

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

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