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WO2025035205A1 - Associations pharmaceutiques comprenant un dérivé de cyclohexanone fusionné par thiophène substitué et un inhibiteur de cyclooxygénase (cox) et leur utilisation pour le traitement de la douleur - Google Patents

Associations pharmaceutiques comprenant un dérivé de cyclohexanone fusionné par thiophène substitué et un inhibiteur de cyclooxygénase (cox) et leur utilisation pour le traitement de la douleur Download PDF

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Publication number
WO2025035205A1
WO2025035205A1 PCT/CA2024/051045 CA2024051045W WO2025035205A1 WO 2025035205 A1 WO2025035205 A1 WO 2025035205A1 CA 2024051045 W CA2024051045 W CA 2024051045W WO 2025035205 A1 WO2025035205 A1 WO 2025035205A1
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WIPO (PCT)
Prior art keywords
pain
alkyl
compound
formula
pharmaceutically acceptable
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PCT/CA2024/051045
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English (en)
Inventor
Giovanni MARTINO
Claudio Sturino
Youssef Laafiret Bennani
Joseph A. Mancini
Juliette SABBATANI
Kathleen Jessie BERGER
Patricia LAPLANTE
Vincent Guerin
Lorenzo SERNISSI
Maxim EPIFANOV
Catherine ST-GEORGES
Antoine Caron
Arkadii Vaisburg
Daniel Guay
Philippe Seguela
Ariel Ruben ASE
Original Assignee
Neurasic Therapeutics Inc.
The Royal Institution For The Advancement Of Learning / Mcgill University
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Application filed by Neurasic Therapeutics Inc., The Royal Institution For The Advancement Of Learning / Mcgill University filed Critical Neurasic Therapeutics Inc.
Publication of WO2025035205A1 publication Critical patent/WO2025035205A1/fr

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  • 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.
  • COX cyclooxygenase
  • the thiophene fused cyclohexanone derivatives are acid-sensing ion channels (ASICs) inhibitors.
  • ASICs acid-sensing ion channels
  • 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.
  • ASIC inhibitors might relieve pain in a variety of clinical conditions.
  • 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.
  • 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.
  • the present application relates to a pharmaceutical combination
  • 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.
  • COX cyclooxygenase
  • the pharmaceutical combination can be useful for the treatment of pain.
  • the present application relates to a pharmaceutical combination comprising:
  • R a is -NH 2 , -NH-OH, -OH, -NHR b or -NHR c R d ;
  • R b is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C 1 -C 6 alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -O C 1 -C 3 alkyl, -COOH, or cyclopropyl optionally substituted with -OH, and wherein C 3 -C 6 cycloalkyl is optionally substituted with -ON;
  • R c and R d form 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 C 1 -C 3 alkyl; wherein:
  • R is H, C 1 -C 6 alkyl or phenyl;
  • R 1 and R 2 are independently -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 8 cycloalkyl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH 2 , - C(O)NHR 5 , -C(O)R 6 , or -C(0)OR 5 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, with the proviso that when R a is -OH, represents A o , and R 1
  • R 4 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl are optionally substituted with 1 to 3 R 9 substituents, and C 6 -C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, with the proviso that: (i) when R a is -OH, -NH 2 , each R 10 is independently C 1 -C 4 alkyl, halogen, -OC 1 -C 6 alkyl, -NH 2 , -NH(C 1 -C 4 alkyl), or -N(C 1 - C 4 alkyl)2, wherein each C 1 -C 4 alkyl is optionally substituted with 1 to 3 halogens
  • R 2a is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or C 6 -C 10 aryl, wherein C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl are optionally substituted with 1 to 3 R 9 substituents, and C 6 -C 10 aryl is optionally substituted with 1 to 3 R 10 substituents;
  • R 1a and R 2b are independently -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -C(O)NH 2 , - C(O)NHR 5 , or -C(0)OC 1 -C 6 alkyl, wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 16 substituents and each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 17 substituents; each R 16 is independently -OH, -C(O)NH 2 , -C(O)NH(C 1 -C 4 alkyl), C 3 -C6cycloalkyl, -CN, C 6 -C 10 aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC 1 -C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(
  • R 2d and R 4b form together with the carbon atoms to which they are attached a C 3 -C 8 cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C 3 -C 8 cycloalkyl is optionally substituted with 1 to 3 R 19 substituents; and
  • R 1c and R 3 form together with the carbon atoms to which they are attached a C 3 -C 8 cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C 3 -C 8 cycloalkyl is optionally substituted with 1 to 3 R 19 substituents.
  • 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.
  • 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.
  • 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.
  • 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.
  • NSAID Non-Steroidal Anti-Inflammatory Drug
  • the pharmaceutical combination can be a synergistic pharmaceutical combination.
  • 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.
  • the pain is inflammatory pain, neuropathic pain or cancer pain.
  • the pain is inflammatory pain.
  • the pain is neuropathic pain.
  • the pain is cancer pain.
  • the treatment is an oral treatment.
  • COX inhibitor can comprise a Non-Steroidal Anti-Inflammatory Drug (NSAID).
  • NSAID Non-Steroidal Anti-Inflammatory Drug
  • the COX inhibitor is acetaminophen.
  • the pain is inflammatory pain, neuropathic pain or cancer pain.
  • the pain is inflammatory pain.
  • the pain is neuropathic pain.
  • the pain is cancer pain.
  • the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof are administered orally.
  • kits 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.
  • the kit can comprise a COX inhibitor which is a Non-Steroidal Anti-Inflammatory Drug (NSAID).
  • the COX inhibitor can be acetaminophen.
  • the kit is for use in the treatment of pain.
  • the pain is inflammatory pain, neuropathic pain or cancer pain.
  • the pain is inflammatory pain.
  • the pain is neuropathic pain.
  • the pain is cancer pain.
  • the treatment is an oral treatment.
  • 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).
  • % 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.
  • 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).
  • % 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.
  • 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).
  • % 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.
  • 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).
  • % 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.
  • 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).
  • % 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.
  • 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).
  • % 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.
  • 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.
  • 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 R a and will be defined in further detail below.
  • 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
  • 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.
  • 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.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-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.
  • the number of carbon atoms in a hydrocarbyl substituent can be indicated by the prefix “C x -C y ,” where x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • C x -C y the number of carbon atoms in a hydrocarbyl substituent
  • x and y define respectively, the minimum and maximum number of atoms in the cyclic group, including carbons as well as heteroatom(s).
  • halogen refers to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, more particularly oxygen, sulfur, or nitrogen.
  • alkyl 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, "C 1 - C 6 alkyl” contains from one to six carbon atoms.
  • 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.
  • alkenyl denotes a straight- or branched-chain hydrocarbon radical containing one or more double bonds.
  • the alkenyl groups can contain from 2 to 6 carbon atoms, although alkenyl groups with more than 6 carbon atoms can be contemplated.
  • C 2 -C 6 alkenyl 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.
  • alkynyl denotes a straight- or branched-chain hydrocarbon radical containing one or more triple bonds.
  • the alkynyl groups can contain from 2 to 6 carbon atoms, although alkynyl groups with more than 6 carbon atoms can be contemplated.
  • C 2 -C 6 alkynyl 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.
  • cycloalkyl 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.
  • the cycloalkyl groups can contain from 3 to 8 carbon atoms.
  • C 3 -C 8 cycloalkyl contains from three to eight carbon atoms in the cyclic ring.
  • cycloalkyl groups can include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.2.0]octyl, norbornyl, and the like.
  • aryl refers to a monocyclic moiety or to a bicyclic or tricyclic fused ring system wherein the ring system is carbocyclic and fully aromatic.
  • the aryl groups can contain from 6 to 14 carbon atoms, such as 6 to 10 carbon atoms for instance.
  • a "C 6 -C 10 aryl” group contains from six to ten carbon atoms in the aromatic system.
  • "aryl” refers to an aromatic ring system which includes, without being limited to, phenyl, naphthyl, azulenyl, anthracyl, and the like.
  • 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.
  • 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.
  • the heterocycloalkyl groups can include 3 to 14 ring atoms although heterocycloalkyl groups with more than 14 ring atoms can be contemplated.
  • the heterocycloalkyl groups can contain 4 to 14 ring atoms, or 4 to 6 ring atoms or 3 to 6 ring atoms for instance.
  • 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.
  • 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, isothiazolidiny
  • 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.
  • the heteroaryl groups can include from 5 to 10 ring atoms although heteroaryl groups with more than 10 ring atoms can be contemplated.
  • 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), acridin
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, .
  • nitrogen 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 NR 0 (as in N- substituted pyrrolidinyl).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • various chemical groups present in the compounds of the present description can be optionally substituted.
  • substituted means that one or more hydrogen atoms of the designated moiety is replaced with a suitable substituent.
  • 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.
  • chemically stable 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.
  • salts 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).
  • 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • 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.
  • 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, pamo
  • 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.
  • 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.
  • prodrug 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.
  • 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.
  • 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.
  • 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.
  • the thiophene fused cyclohexanone derivative can thus be a compound having the Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
  • R a is -NH 2 , -NH-OH, -OH, -NHR b , or -NHR c R d ;
  • R b is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C 1 -C 6 alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -OC 1 -C 3 alkyl, -COOH, or cyclopropyl optionally substituted with -OH, and wherein C 3 -C6cycloalkyl is optionally substituted with -ON;
  • R c and R d form 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 C 1 -C 3 alkyl; represents one of the following residues A o to A12 and wherein:
  • R is H, C 1 -C 6 alkyl or phenyl
  • R 1 and R 2 are independently -ON, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 8 cycloalkyl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH 2 , - C(O)NHR 5 , -C(O)R 6 , or -C(0)OR 5 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, with the proviso that when R a is -OH, represents A o , and R 1 is then R 2 in residue A o is different than ; each R 5 is independently C 1
  • R 4 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl are optionally substituted with 1 to 3 R 9 substituents, and C 8 -C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, with the proviso that: (i) when R a is -OH, -NH 2 , represents A 2 , then R 4 in residue A 2 is different than -CH 3 ; and (ii) when R a is -NH 2 and C A
  • each R 10 is independently C 1 -C 4 alkyl, halogen, -OC 1 -C 6 alkyl, -NH 2 , -NH(C 1 -C 4 alkyl), or -N(C 1 - C 4 alkyl) 2 , wherein each C 1 -C 4 alkyl is optionally substituted with 1 to 3 halogens;
  • R 2a is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or C 6 -C 10 aryl, wherein C 1 -C 8 alkyl and C 3 -C 8 cycloalkyl are optionally substituted with 1 to 3 R 9 substituents, and C 6 -C 10 aryl is optionally substituted with 1 to 3 R 10 substituents;
  • R 1a and R 2b are independently -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -C(O)NH 2 , - C(O)NHR 5 , or -C(0)OC 1 -C 6 alkyl, wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 16 substituents and each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 17 substituents; each R 16 is independently -OH, -C(O)NH 2 , -C(O)NH(C 1 -C 4 alkyl), C 3 -C6cycloalkyl, -CN, C 6 -C 10 aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC 1 -C 6 alkyl), 4- to 6-membered heterocycloalkyl, -NH(
  • R 4a is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, wherein each C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl are optionally substituted with 1 to 3 R 19 substituents; each R 19 is independently halogen, -OH, -OC 1 -C 4 alkyl, -SC 1 -C 4 alkyl, -NH 2 , -NH(C 1 -C 4 alkyl), or - N(C 1 -C 4 alkyl) 2 ;
  • R 2d and R 4b form together with the carbon atoms to which they are attached a C 3 -C 3 cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C 3 -C 8 cycloalkyl is optionally substituted with 1 to 3 R 19 substituents; and
  • R 1c and R 3 form together with the carbon atoms to which they are attached a C 3 -C 8 cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C 3 -C 8 cycloalkyl is optionally substituted with 1 to 3 R 19 substituents.
  • the compound of Formula (I) is such that: (i) when R a is -OH, represents A o , and R 1 is , then R 2 in residue A o is different than (ii) when
  • R a is -OH and represents A 2 , then R 4 in residue A 2 is different than -CH 3 and -CH 2 CH 3 ; (iii) when R a is -NH 2 , and represents A 2 , then R 4 in residue A 2 is different than -CH 3 ; and (iv) when R a is -NH 2 and represents A 3 , then R 4 in residue A 3 is different than -C(CH 3 ) 3 .
  • the compound of Formula (I) is such that: (i) when R a is -OH, represents A o , and R 1 is , then R 2 in residue A o is different than O ; (ii) when
  • R a is -OH and represents A 2 , then R 4 in residue A 2 is different than -CH 3 and -CH 2 CH 3 ; (iii) when R a is -NH 2 , and represents A 2 , then R 4 in residue A 2 is different than -CH 3 ;
  • the compound of Formula (I) is such that: (i) when R a is -OH, represents A o , and R 1 is then R 2 in residue A o is different than (ii) when
  • R a is -OH and ⁇ represents A 2 , then R 4 in residue A 2 is different than alkyl; (iii) when R a is -
  • the compound of Formula (I) is such that: (i) when R a is -OH, represents A o , and R 1 is then R 2 in residue A o is different than ; (jj) when R a is -OH and represents A 2 , then R 4 in residue A 2 is different than alkyl; (iii) when R a is - NH 2 , and represents A 2 , then R 4 in residue A 2 is different than -CH 3 ; (iv) when R a is and represents A 2 , then R 4 in residue A 2 is different than -CH 3 ; and (v) when
  • R a is -NH 2 and represents A 3 , then R 4 in residue A 3 is different than -C(CH 3 ) 3 .
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is such that R is H.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is such that R a is -NHR b and R b represents C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C 1 -C 6 alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -OC 1 -C 3 alkyl , -COOH , or cyclopropyl optionally substituted with - OH, and wherein C 3 -C6cycloalkyl is optionally substituted with -ON.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is such that R a is -NHR b and R b represents:
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is such that R a is -NHR b and R b represents -CH 3
  • R a is -NHR b and R b represents In other embodiments, R a is -NR c R d and R c and R d form 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 C 1 -C 3 alkyl.
  • R a is
  • R a is
  • R a is -OH.
  • R a is -NH2.
  • R a is -NH-OH.
  • 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.
  • 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 R 1 , R 2 , R 3 , R 4 , R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 2d , R 4a , R 4b , R and R a are as defined herein.
  • the compound is of Formula (la) or (la’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R, R a , R 1 and R 2 can be as defined for the general Formula (I) above.
  • the compound is of Formula (la), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R a , R 1 and R 2 can be as defined for the general Formula (I) above.
  • R 1 and R 2 can independently represent -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 2 - C 6 alkynyl, C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH 2 , -C(O)NHR 5 , -C(O)R 6 , or - C(O)OR 5 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, and R 5 , R 6 , R 7 , R 8 and R 22 are as defined herein.
  • R 1 and R 2 are independently -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 3 - C 8 cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH 2 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, and R 7 , R 8 and R 22 are as defined herein.
  • R 1 and R 2 can independently represent -CN, phenyl, C 1 -C 4 alkyl, C 2 - C 4 alkynyl, C 3 -C 6 cycloalkyl, 5-membered heteroaryl, or -C(O)NH 2 , wherein each C 1 -C 4 alkyl is optionally substituted with 1 or 2 R 7 substituents, each phenyl is optionally substituted with 1 or 2 halogens, and each 5-membered heteroaryl is optionally substituted with 1 or 2 -CH 3 .
  • R 1 and R 2 independently represent -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or -C(O)NH 2 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 2 R 7 substituents as defined herein.
  • each R 5 can be C 1 -C 6 alkyl.
  • each R 6 can be a 4- to 6-membered heterocycloalkyl.
  • each R 7 can independently represent -OH, -C(O)R 11 , C 3 -C 6 cycloalkyl, -CN, C 6 - C 10 aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC 1 -C 6 alkyl), -N(C 1 - C 4 alkyl)(C(O)OC 1 -C 6 alkyl), -NH(C(O)C 1 -C 6 alkyl), 4- to 6-membered heterocycloalkyl, -OR 20 , -SC- 1 -C 6 alkyl, -NH 2 , or -N(C 1 -C 4 alkyl) 2 , wherein each C 3 -C 6 cycloalkyl is optionally substituted with 1 to 3 R 12 substituents
  • R 7 can independently represent -OH, -C(O)R 11 , -OR 20 , C 3 -C 6 cycloalkyl, - CN, C 6 -C 10 aryl, halogen, -C(O)OH, or 5- to 10-membered heteroaryl, wherein each C 3 - C 6 cycloalkyl is optionally substituted with 1 to 3 R 12 substituents and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 13 substituents.
  • R 7 can independently represent -OH, -C(O)NH 2 , -OR 20 , C 3 -C 6 cycloalkyl, -CN, phenyl, halogen, -C(O)OH, or 5-membered heteroaryl, wherein each C 3 -C 6 cycloalkyl is optionally substituted with -CH 3 .
  • R 7 can independently represent -OH, -C(O)NH 2 , C 3 -C 6 cycloalkyl, -CN, C 6 -C 10 aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C 3 -C 6 cycloalkyl is optionally substituted with 1 to 2 C 1 -C 4 alkyl, and each 5- to 8-membered heteroaryl is optionally substituted with 1 to 2 R 13 substituents.
  • the R 11 substituents mentioned above can independently represent -NH 2 , -NH(C 1 -C 4 alkyl), or 4- to 6-membered heterocycloalkyl. In some particular embodiments, R 11 can represent -NH 2 . In some embodiments, the R 12 substituents mentioned above can independently represent C 1 -C 4 alkyl, -SC 1 -C 4 alkyl, -Ph, -OC 1 -C 4 alkyl, or -SPh, wherein each C 1 -C 4 alkyl is optionally substituted with -OH. In some particular embodiments, R 12 is C 1 -C 4 alkyl.
  • the R 13 substituents mentioned above can independently represent halogen, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl. In some particular embodiments, R 13 is independently halogen or C 1 -C 4 alkyl.
  • the R 14 substituents mentioned above can independently represent halogen, -OC 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl. In some particular embodiments, R 14 is halogen.
  • the R 20 substituents mentioned above can independently represent C 1 - C 6 alkyl or 5- to 10-membered heteroaryl, wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 14 substituents as defined herein, and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl).
  • R 20 is C 1 -C 6 alkyl, wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 14 substituents as defined herein.
  • R 20 is C 1 -C 6 alkyl, wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 halogens.
  • R 20 is 5- to 10-membered heteroaryl substituted with -OH or -NH(cyclopropyl). In certain embodiments, R 20 is 5- to 10-membered heteroaryl substituted with - OH. In other embodiments, R 20 is 5- or 6-membered heteroaryl substituted with -OH.
  • the R 22 substituents mentioned above can independently represent C 1 - C 4 alkyl.
  • each R 8 can independently represent halogen, C 1 -C 6 alkyl, or -OC 1 -C 6 alkyl, wherein each -OC 1 -C 6 alkyl is optionally substituted with -OC 1 -C 4 alkyl.
  • R 8 is a halogen.
  • each R 22 when R 1 and/or R 2 represent 5- to 10- membered heteroaryl substituted with 1 to 3 R 22 substituents, then each R 22 can independently represent C 1 -C 6 alkyl optionally substituted with phenyl. In some embodiments, R 22 is C 1 -C2alkyl substituted with phenyl.
  • R 1 and R 2 are independently -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C2-Cealkynyl, C3- C 8 cycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH 2 , -C(O)NHR 5 , -C(O)R 6 , or -C(O)OR 5 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, and each R 5 is independently C 1 -C 6 alkyl; each R 6 is independently a 4- to 6-membered heterocycloalkyl; each R 7 is independently -OH, -C(O)R 11 , C 3 -C 6 cycloalkyl
  • R 1 and R 2 are independently -ON, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 3 - C 8 cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH 2 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, and each R 7 is independently -OH, -C(O)R 11 , C 3 -C 6 cycloalkyl, -ON, C 6 -C 10 aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC 1 -C 6 alkyl), -N(C 1 -
  • R 1 and R 2 are independently -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 3 - Cscycloalkyl, 5- to 10-membered heteroaryl, or -C(0)NH 2 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, and each R 7 is independently -OH, -C(O)R 11 , -OR 20 , C 3 -C 6 cycloalkyl, -CN, C 6 -C 10 aryl, halogen, - C(O)OH, or 5- to 10-membered heteroaryl, wherein each C 3 -C 6 cycloalkyl is optionally substituted with 1
  • R 1 and R 2 independently represent -CN, phenyl, C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 5-membered heteroaryl, or -C(O)NH 2 , wherein each C 1 -C 4 alkyl is optionally substituted with 1 or 2 R 7 substituents, each phenyl is optionally substituted with 1 or 2 halogens, and each 5-membered heteroaryl is optionally substituted with 1 or 2 -CH 3 , and each R 7 is independently -OH, -C(O)NH 2 , -OR 20 , C 3 -C 6 cycloalkyl, -CN, phenyl, halogen, - C(O)OH, or 5-membered heteroaryl, wherein each C 3 -C 6 cycloalkyl is optionally substituted with -CH 3 ; and each R 20 is C 1 -C 6 alkyl
  • R 1 and R 2 independently represent -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C3- C 8 cycloalkyl, 5-membered heteroaryl, or -C(O)NH 2 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 2 R 7 substituents; each R 7 is independently -OH, -C(O)NH 2 , C 3 -C 6 cycloalkyl, -CN, C 6 -C 10 aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C 3 -C 6 cycloalkyl is optionally substituted with 1 to 2 C 1 - C 4 alkyl, and each 5- to 8-membered heteroaryl is optionally substituted with 1 to 2 R 13 substituents; and each R 13 is independently halogen or C 1 -C 4 alkyl.
  • R 1 and R 2 which can be identical or different
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 are different. In another particular embodiment, one of R 1 and R 2 is -CN.
  • Other embodiments include compounds of Formula (la) or (la’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, where one of R 1 and R 2 is of Formula
  • the compound is of Formula (lb) or (lb’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R, R a , and R 4 can be as defined for the general Formula (I) above.
  • the compound is of Formula (lb), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R a and R 4 can be as defined for the general Formula (I) above.
  • R 4 can represent C 1 -C 6 alkyl, C 6 -C 10 aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 9 substituents, and C 6 -C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, and wherein R 9 and R 10 are as defined herein.
  • R 4 can represent C 1 -C 6 alkyl, C 6 -C 10 aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C 6 -C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, and wherein the R 10 substituents are as defined herein.
  • R 4 can represent C 1 -C 4 alkyl, 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 R 10 substituents, and wherein the R 10 substituents are as defined herein.
  • the R 10 substituents can independently represent C 1 -C 4 alkyl, halogen, - O C 1 -C 6 alkyl, -NH2, -NH(C 1 -C 4 alkyl), or -N(C 1 -C 4 alkyl)2, wherein each C 1 -C 4 alkyl is optionally substituted with 1 to 3 halogens.
  • the R 10 substituents can independently represent C 1 -C 4 alkyl, halogen, - OC 1 -C 6 alkyl, or -N(C 1 -C 4 alkyl) 2 , wherein each C 1 -C 4 alkyl is optionally substituted with 1 to 3 halogens.
  • the R 10 substituents can independently represent -CF 3 , halogen, -OCH 3 , or -N(CH 3 ) 2 .
  • R 4 is C 1 -C 6 alkyl, C 6 -C 10 aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C 6 -C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, and each R 10 is independently C 1 -C 4 alkyl, halogen, -OC 1 -C 6 alkyl, -NH 2 , -NH(C 1 -C 4 alkyl), or -N(C 1 - C 4 alkyl)2, wherein each C 1 -C 4 alkyl is optionally substituted with 1 to 3 halogens.
  • R 4 is C 1 -C 6 alkyl, C 6 -C 10 aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C 6 -C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, and each R 10 is independently C 1 -C 4 alkyl, halogen, -OC 1 -C 6 alkyl, or -N(C 1 -C 4 alkyl) 2 , wherein each C 1 - C 4 alkyl is optionally substituted with 1 to 3 halogens.
  • R 4 is C 1 -C 4 alkyl, 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 R 10 substituents, and each R 10 is independently -CF 3 , halogen, -OCH 3 , or -N(CH 3 ) 2 .
  • R 4 groups can include:
  • the compound is of Formula (Ic) or (lc’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the groups R, R a and R 2a can be as defined for the general Formula (I) above.
  • the compound is of Formula (Ic), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R a and R 2a can be as defined for the general Formula (I) above.
  • R 2a can represent C 1 -C 6 alkyl orC 6 -C 10 aryl, wherein C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 9 substituents and C 6 -C 10 aryl is optionally substituted with 1 to 3 R 10 substituents, and R 9 and R 10 are as defined herein.
  • R 2a can represent C 1 -C 6 alkyl orC 6 -C 10 aryl, wherein C 1 -C 6 alkyl is optionally substituted with 1 to 3 halogens. In some embodiments, R 2a is C 1 -C 6 alkyl, such as C 1 -C 4 alkyl or preferably ethyl.
  • the compound is of Formula (Id) or (Id’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R, R a , R 1a , R 2b , and R 4a can be as defined for the general Formula (I) above.
  • the compound is of Formula (Id), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R a , R 1a , R 2b , and R 4a can be as defined for the general Formula (I) above.
  • R 1a and R 2b can independently represent -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl, or -C(O)NH 2 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 2 R 16 substituents as defined herein.
  • R 1a and R 2b can independently represent -CN or C 6 -C 10 aryl.
  • R 4a can represent C 1 -C 6 alkyl.
  • the substituents R 16 can independently represent -OH, -C(O)NH 2 , C 3 - C 6 cycloalkyl, -CN, C 6 -C 10 aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C 3 - C 6 cycloalkyl is optionally substituted with 1 to 2 C 1 -C 4 alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 R 21 substituents as defined herein.
  • each R 21 can represent independently halogen or C 1 -C 4 alkyl.
  • R 1a and R 2b are independently -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl, or -C(O)NH 2 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 2 R 16 substituents; each R 16 is independently -OH, -C(O)NH 2 , C 3 -C 6 cycloalkyl, -CN, C 6 -C 10 aryl, halogen, or 5- to 8- membered heteroaryl, wherein each C 3 -C 6 cycloalkyl is optionally substituted with 1 to 2 C 1 - C 4 alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 R 21 substituents; and each R 21 is independently halogen or C 1 -C 4 alkyl.
  • the compound is of Formula (le) or (le’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R, R a , R 1 b , and R 2c can be as defined for the general Formula (I) above.
  • the compound is of Formula (le), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R a , R 1 b , and R 2c can be as defined for the general Formula (I) above.
  • R 1b and R 2c can form together with the carbon atom to which they are attached a C 4 -C 6 cycloalkyl, 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 R 1b and R 2c
  • R 1b and R 2c form 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 R 1b and R 2c .
  • R 1b and R 2c can 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 R 1b and R 2c .
  • R 1b and R 2c can form together with the carbon atom to which they are attached a cyclopentyl.
  • the compound is of (If) or (If’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R, R a , R 2d , and R 4b can be as defined for the general Formula (I) above.
  • the compound is of Formula (If), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R a , R 2d , and R 4b can be as defined for the general Formula (I) above.
  • R 2d and R 4b can form together with the carbon atoms to which they are attached a C 3 -C 8 cycloalkyl, wherein each C 3 -C 8 cycloalkyl is optionally substituted with 1 to 3 R 19 substituents as defined herein.
  • R 2d and R 4b can form together with the carbon atoms to which they are attached a C 3 -C 8 cycloalkyl.
  • R 2d and R 4b can form together with the carbon atoms to which they are attached a cyclohexyl.
  • the compound is of Formula (Ig), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R a , R 1c and R 3 can be as defined for the general Formula (I) above.
  • R 1c and R 3 can form together with the carbon atoms to which they are attached a C 3 -C 8 cycloalkyl, wherein each C 3 -C 8 cycloalkyl is optionally substituted with 1 to 3 R 19 substituents as defined herein.
  • R 1c and R 3 can form together with the carbon atoms to which they are attached a C 3 -C 8 cycloalkyl.
  • R 1c and R 3 can form together with the carbon atoms to which they are attached a cyclohexyl.
  • 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,
  • 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,
  • 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,
  • 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,
  • 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,
  • 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,
  • 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,
  • 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,
  • 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,
  • 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,
  • 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,
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compound of Formula (I) as described herein is Compound 48 of Table
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical combinations can further include pharmaceutically acceptable carriers, diluents, or excipients, as will be detailed below.
  • 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).
  • 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.
  • 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.
  • the COX inhibitor can be acetaminophen.
  • 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 Magnes,
  • the pharmaceutical combinations of the present disclosure can further include a proton-pump inhibitor (PPI).
  • PPI proton-pump inhibitor
  • 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.
  • an NSAID selected from Naproxen, Celecoxib, Diclofenac, Ibuprofen, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the pharmaceutical combinations of the present disclosure can be synergistic.
  • 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.
  • 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.
  • 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.
  • 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, Loxoprof
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a dosage form can include a pill, a tablet, a capsule, a drink or a syrup.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • the treatment can involve using, or can be potentiated by using, a pharmaceutical combination of the present disclosure which can be synergistic.
  • 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.
  • 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.
  • 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.
  • treatment refers 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.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • 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.
  • 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.
  • the subject is a human.
  • the subject may be either a patient or a healthy human.
  • pharmaceutically acceptable carrier diluent, or excipient
  • pharmaceutically acceptable carrier refers to a non-toxic carrier, diluent, or excipient that does not destroy the pharmacological activity of the compound with which it is formulated.
  • 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.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate,
  • 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.
  • the pain can include acute pain or chronic pain.
  • the pain can include inflammatory pain, neuropathic pain or cancer pain.
  • the pain can include nociceptive pain, inflammatory pain, neuropathic pain, cancer pain, idiopathic pain, musculoskeletal pain, visceral pain, or abdominal pain.
  • the pain can include inflammatory pain.
  • the pain can include neuropathic pain.
  • the pain can include cancer pain.
  • 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.
  • 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.
  • the pain can include a rheumatic disorder-related pain.
  • 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.
  • 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.
  • the pain can include osteoarthritis pain.
  • the pain can include osteoarthritis inflammatory pain.
  • 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.
  • 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.
  • 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.
  • the pain can include ankylosing spondylitis pain.
  • 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.
  • the pain can include bursitis pain. In some embodiments, the pain can include bursitis pain of the shoulder or bursitis pain of the hip.
  • the pain can include tendinitis pain.
  • 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.
  • the pain can include periarthritis pain. In certain embodiments, the pain can include periarthritis pain of the shoulder or periarthritis pain of the hip.
  • 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.
  • the pain can include ocular pain.
  • 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, ulceris pain, retinopathy pain or optic neuritis pain.
  • the pain can include dental pain.
  • the dental pain can include toothache or post-operative pain after dental surgery.
  • the dental pain can include pain after dental extraction.
  • the pain can include post-operative pain.
  • 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.
  • PMPS post-mastectomy pain syndrome
  • 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.
  • the pain can include headache pain.
  • the pain can include migraine pain, tension headache pain, or cluster headache pain.
  • the pain can include migraine pain including migraine with aura pain or migraine without aura pain.
  • 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.
  • 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.
  • the pain can include osteoarthritis neuropathic pain. In certain embodiments, the pain can include rheumatoid arthritis neuropathic pain.
  • the pain can include neuralgia.
  • 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.
  • 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.
  • the pain can include neuropathy pain.
  • 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.
  • the pain can include diabetic neuropathy pain.
  • the pain can include diabetic peripheral neuropathy pain, diabetic polyneuropathy pain, diabetic proximal neuropathy pain, or diabetic mononeuropathy pain.
  • the pain can include autoimmune disease neuropathy pain.
  • the pain can include Sjogren's syndrome neuropathy pain, Guillain-Barre syndrome neuropathy pain, chronic inflammatory demyelinating polyneuropathy pain, or vasculitis neuropathy pain.
  • the pain can include multiple sclerosis neuropathic pain.
  • the pain can include carpal tunnel syndrome pain.
  • the pain can include neuropathy pain associated with a bacterial infection or neuropathy pain associated with a viral infection.
  • 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.
  • the pain can include hereditary neuropathy pain.
  • the pain can include Charcot-Marie-Tooth disease neuropathy pain or hereditary neuropathy with pressure palsies (HNPP) pain.
  • the pain can include neuropathy pain caused by a malignant tumor, neuropathy pain caused by a benign tumor, or paraneoplastic neuropathy pain.
  • the pain can include myeloma neuropathy pain, lymphoma neuropathy pain, or amyloid neuropathy pain.
  • 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.
  • 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.
  • the pain can include toxic substance exposure neuropathy pain including neuropathy pain following lead exposure or neuropathy pain following mercury exposure.
  • the pain can include anti-retroviral therapy-induced neuropathy pain or neurotoxic drug-induced neuropathic pain.
  • 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.
  • that pain can include central neuropathic pain.
  • 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.
  • the pain can include cancer pain.
  • 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.
  • the pain can include post-amputation pain. In some embodiments, the pain can include phantom pain, phantom limb pain, or residual limb pain.
  • 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.
  • 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.
  • 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.
  • each separate individual dosage form can be administered either simultaneously or sequentially.
  • the individual dosage forms can be administered in any order.
  • oral treatment means a treatment that occurs by oral administration.
  • an “oral treatment” refers to a treatment where the pharmaceutical combinations of the present disclosure are administered orally for the indicated treatment.
  • parenteral 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.
  • the pharmaceutical combinations described herein are administered orally, i.e., via the oral cavity, including buccally.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • 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.
  • the oral compositions can also include excipients
  • 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.
  • acceptable carriers and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • 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.
  • biodegradable polymers examples 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.
  • 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.
  • 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.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • 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
  • 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.
  • 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.
  • additional substances other than inert diluents e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose.
  • 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.
  • embedding compositions that can be used include polymeric substances and waxes.
  • 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.
  • 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.
  • compositions 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.
  • compositions 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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’).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 H 2 O (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 Na 2 SO 4 , 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)
  • 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)
  • 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)
  • 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.
  • Step 1 Ethyl 2-amino-6-cyano-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate (56).
  • Racemic compound 59 (86.0 mg) was submitted to SFC chiral separation (isocratic 35% MeOH in CO 2 ) 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 1 H NMR: same as racemic mixture (59).
  • LC-MS: rt 1.23 min, MS: 312.1 (calcd),
  • Step 1 2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (61).
  • reaction mixture was stirred at RT for 16 hours and partitioned between EA and a saturated aqueous solution of NaHCO 3 . The layers were separated, and the organic phase was washed with brine, dried over Na 2 SO 4 , 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% CH 3 CN in H 2 O with 0.1% (v/v) formic acid) to afford title compound 61 as a white solid (1 .20 g, 47% yield).
  • 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 Na 2 SO4, filtered and concentrated.
  • Racemic compound 61 (96.5 mg) was submitted to SFC chiral separation (isocratic: 45% of CH 3 CN/EtOH 1 :1 in CO 2 ) 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).
  • Step 4 Ethyl 2-amino-6-(cyanomethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (80).
  • 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.
  • PyBOP 120 mg, 0.230 mmol
  • 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 NH 4 CI.
  • 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 NaHCO 3 solution and concentrated to remove the organic solvent. The residue was extracted with EA and the organic layer was washed with brine, dried over Na 2 SO 4 , 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.
  • 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.
  • Step 1 8-Benzyl-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (110).
  • 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).
  • 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.
  • 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.
  • reaction mixture was then quenched with methanol (15 mL) at -78 °C and partitioned between saturated aqueous NH 4 CI 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 Na 2 SO 4 , filtered and concentrated. The residue was dissolved in THF (400 mL) and treated with 2 N aqueous HCI (27.5 mL, 54.9 mmol).
  • 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)
  • 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)
  • reaction mixture was quenched with a saturated NH 4 CI solution and extracted with EA.
  • organic layer was dried over Na 2 SO 4 , filtered and concentrated.
  • the residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH 3 CN in H 2 O with 0.1% (v/v) formic acid) to afford title compound 147 as a white solid (35 mg, 70% yield).
  • Step 1 Ethyl 2-amino-6-(3-hydroxypropyl)-6-phenyl-4,5,6,7-
  • 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 Na 2 SO 4 , filtered and concentrated.
  • reaction mixture was quenched with saturated NH 4 CI solution and extracted with EA.
  • organic layer was dried over Na 2 SO 4 , 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.
  • reaction mixture was quenched with a saturated NH 4 CI solution and extracted with EA.
  • organic layer was dried over Na 2 SO 4 , filtered and concentrated.
  • the residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH 3 CN in H 2 O with 0.1% (v/v) formic acid) to afford title compound 174 as a white solid (26 mg, 57% yield).
  • Step 1 3-(8-Phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)propanal (176)
  • Step 1 (4-(2-Amino-3-carbamoyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b1]thiophen-6- yl)but-1-yn-1-yl)copper (182)
  • Step 6a 2-Amino-6-(2-cyanoethyl)-6-(cyclopropylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (189) and 2-Amino-6-(3-amino-3-oxopropyl)-6- (cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (190)
  • Step 6b 2-Amino-6-(2-cyanoethyl)-/V-cyclopropyl-6-(cyclopropylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (192)
  • Example 105 194 Example 106
  • Racemic compound 192 (scheme 40) (1.14 g) was submitted to SFC chiral separation (isocratic: 50% of MeOH 1 :1 in CO 2 ) to yield enantioenriched compound 193 as a orange solid (468.9 mg, 41% separation yield) and enantioenriched compound 194 as an off-white solid (424.5 mg, 37% separation yield) (the absolute configurations were assigned based on resolved crystal structure of enantiomer 194).

Abstract

L'invention concerne une association pharmaceutique comprenant un inhibiteur de cyclooxygénase (COX) et un composé de formule (I) ou un sel, solvate ou promédicament pharmaceutiquement acceptable de celui-ci. Dans certains modes de réalisation, l'inhibiteur de COX peut comprendre un médicament anti-inflammatoire non stéroïdien (AINS). L'association pharmaceutique peut être utilisée dans le traitement de la douleur chez un patient en ayant besoin, telle que pour une douleur inflammatoire. L'invention concerne également un kit comprenant une première forme à dose unique d'un inhibiteur de cyclooxygénase (COX) et une seconde forme à dose unique d'un composé ayant la formule (I) ou un sel, un solvate ou un promédicament pharmaceutiquement acceptable de celui-ci, ainsi que des instructions d'utilisation. (I)
PCT/CA2024/051045 2023-08-11 2024-08-08 Associations pharmaceutiques comprenant un dérivé de cyclohexanone fusionné par thiophène substitué et un inhibiteur de cyclooxygénase (cox) et leur utilisation pour le traitement de la douleur WO2025035205A1 (fr)

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